Note: Descriptions are shown in the official language in which they were submitted.
CA 02556850 2006-08-23
r
1
TITLE: TRANSITION METAL COMPLEXES OF N-HETEROCYCLIC
CARBENES, METHOD OF PREPARATION AND USE IN TRANSITION
METAL CATALYZED ORGANIC TRANSFORMATIONS
FIELD OF THE INVENTION
The present invention relates to catalysts for chemical synthesis,
particularly catalysts of transition metal complexes of N-heterocyclic
carbenes, their methods of preparation and their use in chemical synthesis.
BACKGROUND OF THE INVENTION
The formation of C-X bonds, where X is for example C, S, N, B, O, Sn
and Si, is crucial in chemical synthesis and some of the most powerful
methodologies to create these bonds are cross-coupling reactions. Over the
last thirty years, the development of transition metal catalyzed cross-
coupling
reactions has transformed the way these bonds are created (Metal-Catalyzed
Cross-Coupling Reactions, 2 ed. (Eds.: A. de Meijere, F. Diederich), Wley
VCH, Weinheim, (2004); Handbook of Organopalladium Chemistry for
Organic Synthesis, ed. (Ed.: E. Negishi), John Wiley & Sons, New York,
(2002)] .
Within the current arsenal of transition metal catalyzed cross-coupling
protocols, palladium processes are amongst the most widely employed and
include Hiyama [Y. Hatanaka, T. Hiyama, J. Org. Chem. (1988), 53, 918],
Kumada [K. Tamao, K. Sumitani, M. Kumada, J. Am. Chem. Soc. (1972), 94,
4374], Negishi [E. Negishi, A. O. King, N. Okukado, J. Org. Chem. (1977), 42,
1821; A. O. King, N. Okukado, E. Negishi, Chem. Commun. (1977), 683],
Suzuki [N. Miyaura, K. Yamada, A. Suzuki, Tetrahedron Lett. (1979), 20,
3437] and Stille [D. Milstein, J. K. Stifle, J. Am. Chem. Soc. (1978), 700,
3636]
reactions. In spite of tremendous progress in the developments of general
methods to couple aryl and alkenyl halides, the use of alkyl halides remained
a longstanding challenge, until the advent of bulky, electron rich phosphine
ligands. In fact, central to the success of these transformations are
palladium
CA 02556850 2006-08-23
r '
2
metal centers ligated most often with tertiary phosphines or, recently N-
heterocyclic carbenes. Unfortunately, phosphines are air sensitive and some
even pyrophoric. Furthermore, because active palladium (0) complexes are
unstable and normally decompose with time, most protocols involve in situ
formation of the catalyst.
Although yearly improvements to the supporting ligands have been
made [A. Zapf, M. Beller, Chem. Commun. (2005), 431; T. E. Barder, S. D.
Walker, J. R. Martinelli, S. L. Buchwald, J. Am. Chem. Soc. (2005), 127, 4685;
C. J. O'Brien, E. A. B. Kantchev, G. A. Chass, N. Hadei, A. C. Hopkinson, M.
G. Organ, D. H. Setiadi, T. H. Tang, D. C. Fang, Tetrahedron (2005), 61,
9723; J. E. Milne, S. L. Buchwald, J. Am. Chem. Soc. (2004), 126, 13028; T.
Brenstrum, D. A. Gerristma, G. M. Adjabeng, C. S. Frampton, J. Britten, A. J.
Robertson, J. McNulty, A. Capretta, J. Org. Chem. (2004), 69, 7635; T.
Brenstrum, D. A. Gerristma, G. M. Adjabeng, C. S. Frampton, J. Britten, A. J.
Robertson, J. McNulty, A. Capretta, J. Org. Chem. (2004), 69, 7635; J. H.
Kirchhoff, C. Dai, G. C. Fu, Angew. Chem. (2002), 114, 2025; Angew. Chem.
Int. Ed. (2002), 41, 1945; M. R. Netherton, G. C. Fu, Angew. Chem. (2002),
114, 4066; Angew. Chem. Int. Ed. (2002), 41, 3910; G. A. Grasa, M. S. Viciu,
J. Huang, C. Zhang, M. L. Trudell, S. P. Nolan, Organometallics (2002), 21,
2866; M. R. Netherton, C. Dai, K. Neuschiitz, G. C. Fu, J. Am. Chem. Soc.
(2001 ), 123, 10099], advanced ligands [A. C. Frisch, M. Beller, Angevv. Chem.
(2005), 117, 680; Angew. Chem. Int. Ed. (2005), 44, 674] are still under-used
mainly due to sensitivity, difficulty-of use, limited availability and
expense.
Indeed, most synthetic chemists still rely on the reasonably versatile
Pd(PPh3)4, first synthesized by Malatesta and Angoletta in 1957 [L. Malatesta,
M. Angoletta, J. Chem. Soc. (1957), 1186].
As mentioned above, recently, an alternative to the "tried and tested"
phosphine ligands has emerged. N-Heterocyclic carbenes (NHC) have
attracted considerable interest as ligands for transition metal homogeneous
catalysis. Due to their excellent c~-donor properties and their variable
steric
bulk, NHC ligands impart excellent activity and thermal stability to the
catalysts formed. The groups of Beller [R. Jackstell, M. G. Andreu, A. C.
CA 02556850 2006-08-23
3
Frisch, K. Selvakumar, A. Zapf, H. Klein, A. Spannenberg, D. Rottger, O.
Briel, R. Karch, M. Beller, Angew. Chem. (2002), 114, 1028; Angew. Chem.
Int. Ed. (2002), 41, 986; A. C. Frisch, F. Rataboul, A. Zapf, M. Beller, J.
Organomet. Chem. (2003), 687, 403], Herrmann [G. D. Frey, J. Schutz, E.
Herdtweck, W. A. Herrmann, Organometallics (2005), 24, 4416; C. W. K.
Gstottmayr, V. P. W. Bohm, E. Herdtweck, M. Grosche, W. A. Herrmann,
Angew. Chem. (2002), 114, 1421; Angew. Chem. Int. Ed. (2002), 41, 1363;
W. A. Herrmann, C.-P. Reisinger, M. Spiegler, J. Organomet. Chem. (1998),
557, 93], Nolan [O. Navarro, N. Marion, N. M. Scott, J. Gonzalez, D. Amoroso,
A. Bell, S. P. Nolan, Tetrahedron (2005), 61, 9716; R. Singh, M. S. Viciu, N.
Kramareva, O. Navarro, S. P. Nolan, Org. Lett. (2005), 7, 1829; H. Lebel, M.
K. Janes, A. B. Charette, S. P. Nolan, J. Am. Chem. Soc. (2004), 126, 5046;
M. S. Viciu, E. D. Stevens, J. L. Petersen, S. P. Nolan, Organometallics
(2004), 23, 3752; M. S. Viciu, O. Navarro, R. F. Germaneau, R. A. Kelly III,
W.
Sommer, N. Marion, E. D. Stevens, C. Luigi, S. P. Nolan, Organometallics
(2004), 23, 1629; M. S. Viciu, R. A. Kelly, E. D. Stevens, F. Naud, M. Studer,
S. P. Nolan, Org. Lett. (2003), 5, 1479] and Sigman [D. R. Jensen, M. J.
Schultz, J. A. Mueller, M. S. Sigman, Angew. Chem. (2003), 115, 3940;
Angew. Chem. Int. Ed. (2003), 42, 3810] have made significant progress
towards the development of NHC-based palladium catalysts. However, when
compared to processes utilizing phosphine ligands, the development of NHC-
based protocols has been less successful. Indeed, palladium-NHC catalysts
lack the substrate scope and ease-of use of their phosphine cousins [Peris,
E.; Crabtree, R. H. Coord. Chem. Rev. (2004), 248, 2239-2246; Crudden, C.
M.; Allen, D. P. Coord. Chem. Rev. (2004), 248, 2247-2273; Herrmann, W. A.;
Ofele, K.; v. Preysing, D.; Schneider, K. S. J. Organomet. Chem. (2003), 687,
229-248; Herrmann, W. A. Angew. Chem., Int. Ed. (2002), 41, 1290-1309].
The high sensitivity of isolated N-heterocyclic carbenes necessitates handling
under rigorously anhydrous conditions, typically employing a glove-box.
These factors make large scale production using these catalysts unattractive
[Arentsen, K.; Caddick, S.; Cloke, F. G. N.; Herring, A. P.; Hitchcock, P. B.
Tetrahedron Lett. (2004), 45, 3511-3515; Hadei, N.; Kantchev, E. A. B.;
CA 02556850 2006-08-23
4
O'Brien, C. J.; Organ, M. G. Org. Lett. (2005), 7, 1991-1994; Arentsen, K.;
Caddick, S.; Cloke, F. G. N. Tetrahedron (2005), 61, 9710-9715; Grasa, G. A.;
Viciu, M. S.; Huang, J.; Zhang, C.; Trudell, M. L.; Nolan, S. P.
Organometallics (2002), 21, 2866-2873]. In situ preparation of active Pd-NHC
catalysts has been the dominant strategy to overcome these problems,
however such strategies have been plagued with irreproducibility and wide
yield variations [O'Brien, C. J.; Kantchev, E. A. B.; Chass, G. A.; Hadei, N.;
Hopkinson, A. C.; Organ, M. G.; Setiadi, D. H.; Tang, T.-H.; Fang, D.-C.
Tetrahedron (2005), 61, 9723-9735].
Palladium (II) complexes of N-ferrocenyl-substituted N-heterocyclic
carbenes have been reported [Bertogg, A.; Camponovo. F.; Togni, A. Eur. J.
Inorg. Chem. (2005), 347-356]. In this publication, an intermediate Pd~~
species comprising a pyridine ligand was prepared, however due to its
instability and the formation of dimeric species, this compound was converted
to a complex containing a triphenylphosphine ligand and this complex was
used in catalytic asymmetric amide cyclizations.
There is therefore a need for air-stable, easy-to-prepare-and-handle
transition metal-heterocyclic carbene complexes that are readily activated
under the reaction conditions for use in routine and industrial chemical
synthesis.
SUMMARY OF THE INVENTION
An air and moisture stable N-heterocyclic carbene-Pd(II) precatalyst
that generates a monoligated N-heterocyclic carbene-Pd(0) complex in situ
has been prepared and shown to be an effective reagent in a variety of cross-
coupling reactions. The precatalyst of the present invention comprises a
metal species bearing one N-heterocyclic carbene ligand, one or more anionic
ligands (depending on the charge of the metal) and a cooperative or throw-
away ligand.
Accordingly, the present invention is directed to transition metal
complexes of N-heterocyclic carbenes as precatalysts, their methods of
preparation and their use in chemical synthesis.
CA 02556850 2006-08-23
In an embodiment, the present invention relates to a compound of the
formula I:
R3 Ra
a
R1_ ~ _R2
MXb
L
5 wherein
R~ and Rz are independently or simultaneously selected from the group
consisting of C,_zoalkyl, C3_zocycloalkyl, aryl and heteroaryl, said groups
being
optionally substituted and/or one or more of the CHz groups in C~_zoalkyl
and/or C3_2ocycloalkyl is optionally replaced with a heteroatom selected from
the group consisting of O, S, and NRS;
R3 and R4 are independently or simultaneously selected from the group
consisting of H, halo, C~_zoalkyl, OC~_zoalkyl, C~zocycloalkyl,
OC~zocycloalkyl,
aryl, O-aryl, heteroaryl and O-heteroaryl, said latter 8 groups being
optionally
substituted and/or one or more of the CHz groups in C~_zoalkyl, OC~_zoalkyl,
C3_
2ocycloalkyl and/or OC3_zocycloalkyl is optionally replaced with a heteroatom
selected from the group consisting of O, S, and NRS;
or
R3 and R4 are linked to form an optionally substituted 4 to 12-membered ring
system which optionally contains one or more heteroatoms selected from the
group consisting of O, S, and NR5;
R5 is selected from the group consisting of H and C~_salkyl;
-- is a single or a double bond;
ais1,2or3;
M is a transition metal;
b is an integer representing the number of the anionic ligands X required to
fulfill the valency requirements of M;
X is an anionic ligand and when b is greater than 1, each X may be the same
or different;
CA 02556850 2006-08-23
6
L is a 5- or 6-membered optionally substituted N-containing aromatic
heterocycle coordinated to M through N, which is optionally benzofused,
and/or optionally contains one or more other heteroatoms selected from the
group consisting of O, S, and NRS, and/or one or more of the optional
substituents on the N-containing aromatic heterocycle is bonded to M in place
of one or more X;
or
L is R6-C=C-R' in which R6 and R' are independently or simultaneously
selected from the group consisting of C~_zoalkyl, OC~_zoalkyl,
C3_zocycloalkyl,
OC3_zocycloalkyl, aryl, O-aryl, heteroaryl and O-heteroaryl, said latter 8
groups
being optionally substituted;
one or more of the carbons of the alkyl and cycloalkyl groups of R6 and R' are
optionally replaced with -C(O)-, -C(O)NR5- and -C(O)O-;
aryl is an optionally substituted mono- or polycyclic aromatic radical
containing from 6 to 14 carbon atoms;
heteroaryl is a mono- or polycyclic heteroaromatic radical containing from 5
to
14 atoms, of which 1 to 5 atoms may be a heteroatom selected from the
group consisting of S, O, N and NR5; and
optionally substituted means that one or more of the hydrogens on the group
are optionally replaced with halo, OH, C~_salkyl, OC~_salkyl, fluoro-
substituted
C~_salkyl, fluoro-substituted OC~_6alkyl, aryl or aryl that is substituted
with 1-5
substituents independently or simultaneously selected from the group
consisting of fluoro, C~_4alkyl, OC,_4alkyl, fluoro-substituted C~_aalkyl and
fluoro-substituted OC~_4alkyl.
The present invention further relates to a method of preparing a
compound of formula I wherein X is halo, in particular CI or Br, the method
comprising:
combining a salt of an N-heterocyclic carbene, a ligand L and a metal
salt MXb in the presence of a base to form a reaction mixture; and
separating the compound of formula I formed in the reaction mixture;
wherein the N-heterocyclic carbene is
CA 02556850 2006-08-23
a
7
R3 Ra
a
R1_N~~ _R2
a
Ye
and R~ to R4, M, L and a are defined as above and Y is any suitable
anion. It is an embodiment of the present invention that when L is a liquid,
no
solvent is required for the preparation of compounds of formula I.
Also within the scope of the present invention is a method for
performing a metal-catalyzed cross-coupling reaction comprising: contacting
suitable cross-coupling substrates with a compound of formula I, under
conditions for the formation of cross-coupling product, to form a reaction
mixture; and, optionally separating the cross-coupling product from the
reaction mixture; wherein the compound of formula I is converted to an active
catalyst under suitable reaction conditions in the reaction mixture.
It is an embodiment of the present invention that the ligand "L" is a
"cooperative" or "throw-away" ligand which aids or improves the performance
of the precatalysts of formula I and/or the corresponding Pd(0) catalyst
formed
from the formula I compounds. For example, L may act to stabilize the
catalyst and/or enhance oxidative addition, transmetalation, reductive
elimination and/or diastereo- and/or enantioselectivity during reactions
catalyzed by these compounds.
The present invention therefore provides a NHC-Pd(II) precatalyst that
can be prepared in large scale and stored with little or no deterioration in
performance. Further, when the ligand L is a liquid in the NHC-Pd(II)
precatalyst of the present invention, the synthesis of the precatalyst can be
performed in solvent-less conditions. The NHC-Pd(II) precatalyst of the
present invention can form a monoligated NHC-Pd(0) catalytic complex in situ
and provides a clearly defined catalyst for use in subsequent coupling
reactions. Another advantage of the present invention is that the activation
of
the catalyst at a desired temperature can be easily achieved by the choice of
ligand L. Further, the performance of the catalyst can be easily altered or
tuned by the cooperative ligands. Moreover, the NHC-Pd(0) catalyst
CA 02556850 2006-08-23
generated from the NHC-Pd(II) precatalyst has been found to be an effective
reagent in a variety of cross-coupling reactions.
For purposes of summarizing the invention and the advantages
achieved over the prior art, certain objects and advantages of the invention
have been described above. Of course, it is to be understood that not
necessarily all such objects or advantages may be achieved in accordance
with any particular embodiment of the invention. Thus, for example, those
skilled in the art will recognize that the invention may be embodied or
carried
out in a manner that achieves or optimizes one advantage or group of
advantages as taught herein without necessarily achieving other objects or
advantages as may be taught or suggested herein.
Other features and advantages of the present invention will become
apparent from the following detailed description. It should be understood,
however, that the detailed description and the specific examples while
indicating preferred embodiments of the invention are given by way of
illustration only, since various changes and modifications within the spirit
and
scope of the invention will become apparent to those skilled in the art from
this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will now be described in relation to the drawings in which:
Figure 1 shows the rate studies with complexes Ih and Ij in the alkyl-alkyl
cross-couplings: (a) Suzuki reaction; (b) Negishi reaction.
Figure 2 shows a proposed activation mechanism and use of complex Ih.
Figure 3 shows the rate studies with prior art in situ catalyst Pd2(dba)~/Ila
and
complex Ih in the alkyl-alkyl Negishi reaction: (a) rate comparison with
Pd2(dba)~/Ila and complex Ih; (b) TON (turnover number) comparison
between Pd2(dba)~/Ila and complex Ih after 1 hour.
Figure 4 shows a proposed mechanism for complex Ih catalyzed Negishi
cross-coupling reactions.
DETAILED DESCRIPTION OF THE INVENTION
CA 02556850 2006-08-23
9
An array of novel Pd-N-heterocyclic carbene complexes have been
prepared and shown to have superior properties in the generation of catalysts
in transition metal cross-coupling reactions, in particular compared to
catalysts generated in situ from corresponding imidazolium salt and a
common Pd source (Pd2(dba)3) (for example as described in S.P. Nolan, U.S
patent No. 6,316,380, issued November 13, 2001 ).
Accordingly, the present invention includes a compound of the formula
R3 R4
a
R'- ~ -R2
MXb
L
I
wherein
R' and R2 are independently or simultaneously selected from the group
consisting of C~_2oalkyl, C3_2ocycloalkyl, aryl and heteroaryl, said groups
being
optionally substituted and/or one or more of the CH2 groups in C~_2oalkyl
and/or C3_2ocycloalkyl is optionally replaced with a heteroatom selected from
the group consisting of O, S, and NRS;
R3 and R4 are independently or simultaneously selected from the group
consisting of H, halo, C~_ZOalkyl, OC~_2oalkyl, C3_2ocycloalkyl,
OC3_2ocycloalkyl,
aryl, O-aryl, heteroaryl and O-heteroaryl, said latter 8 groups being
optionally
substituted and/or one or more of the CH2 groups in C,_2oalkyl, OC~_2oalkyl,
C3_
2ocycloalkyl and/or OG~2ocycloalkyl is optionally replaced with a heteroatom
selected from the group consisting of O, S, and NR5;
or
R3 and R4 are linked to form an optionally substituted 4 to 12-membered ring
system which optionally contains one or more heteroatoms selected from the
group consisting of O, S, and NR5;
R5 is selected from the group consisting of H and C~_6alkyl;
-- is a single or a double bond;
a is 1, 2 or 3;
CA 02556850 2006-08-23
M is a transition metal;
b is an integer representing the number of the anionic ligands X required to
fulfill the valency requirements of M;
X is an anionic ligand and when b is greater than 1, each X may be the same
5 or different;
L is a 5- or 6-membered optionally substituted N-containing aromatic
heterocycle coordinated to M through N, which is optionally benzofused,
and/or optionally contains one or more other heteroatoms selected from the
group consisting of O, S, and NRS, and/or one or more of the optional
10 substituents on the N-containing aromatic heterocycle is bonded to M in
place
of one or more X;
or
L is R6-C=C-R' in which R6 and R' are independently or simultaneously
selected from the group consisting of C~_2oalkyl, OC~_2oalkyl,
C3_2ocycloalkyl,
OC3_2ocycloalkyl, aryl, O-aryl, heteroaryl and O-heteroaryl, said latter 8
groups
being optionally substituted;
one or more of the carbons of the alkyl and cycloalkyl groups of R6 and R' are
optionally replaced with -C(O)-, -C(O)NR5- and -C(O)O-;
aryl is an optionally substituted mono- or polycyclic aromatic radical
containing from 6 to 14 carbon atoms;
heteroaryl is a mono- or polycyclic heteroaromatic radical containing from 5
to
14 atoms, of which 1 to 5 atoms may be a heteroatom selected from the
group consisting of S, O, N and NR5; and
optionally substituted means that one or more of the hydrogens on the group
are optionally replaced with halo, OH, C~_6alkyl, OC~_6alkyl, fluoro-
substituted
C~_6alkyl, fluoro-substituted OC~_salkyl, aryl or aryl that is substituted
with 1-5
substituents independently or simultaneously selected from the group
consisting of fluoro, C~_4alkyl, OC~_4alkyl, fluoro-substituted C~_4alkyl and
fluoro-substituted OC~~alkyl.
The term "C~_2oalkyl" as used herein means substituted or
unsubstituted straight and/or branched chain alkyl groups containing from one
to twenty carbon atoms and includes methyl, ethyl, propyl, isopropyl, t-butyl,
CA 02556850 2006-08-23
11
pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, hexadecyl,
octadecyl, icosyl and the like.
The term "C3_ZOCycloalkyl" as used herein means saturated cyclic or
polycyclic alkyl radicals containing from three to twenty carbon atoms and
includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl,
cyclohexadecyl, cyclooctadecyl, cycloicosyl, adamantyl and the like.
The term "aryl" as used herein means a substituted or unsubstituted
monocyclic or polycyclic carbocyclic ring system containing one or two
aromatic rings and from 6 to 14 carbon atoms and includes phenyl, naphthyl,
anthraceneyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl,
indanyl, indenyl and the like.
The term "heteroaryl" as used herein means unsubstituted or
substituted mono- or polycyclic heteroaromatic radicals containing from 5 to
14 atoms, of which 1-3 atoms are a heteroatom selected from the group
consisting of S, O, N and NR'2 where R'2 is H or C~_salkyf, and includes
furanyl, thienyl, pyrrolo, pyridyl, indolo, benzofuranyl and the like.
The term "halo" as used herein means halogen and includes chloro,
fluoro, bromo, iodo and the like.
The terms "fluoro-substituted C~~alkyl", "fluoro-substituted OC~_salkyl"
and "fluoro-substituted aryl" as used herein means that, in the alkyl or aryl
portion of these groups, one or more, including all, of the hydrogen atoms are
replaced with a fluorine atom.
The term "optionally substituted" as used herein, unless otherwise
stated, means that one or more of the hydrogens on the group are optionally
replaced with halo, OH, C~_salkyl, OC~_salkyl, fluoro-substituted C~_6alkyl,
fluoro-substituted OC~_salkyl, aryl or aryl that is substituted with 1-5
substituents independently or simultaneously selected from the group
consisting of fluoro, C,_4alkyl, OC,_4alkyl, fluoro-substituted C~~alkyl and
fluoro-substituted OC~~alkyl.
The term "one or more" as used herein means that from one to the
maximum allowable substitutions that are allowed.
CA 02556850 2006-08-23
12
The present invention includes combinations of groups and
substituents that are permitted and would provide a stable chemical entity
according to standard chemical knowledge as would be known to those skilled
in the art.
The term "polycyclic" or "ring system" as used herein means a cyclic
group containing more than one ring in its structure, and includes bicyclic,
tricyclic, bridged and spiro ring systems and the like.
It is an embodiment of the invention that the compounds of formula I
include those in which R' and R2 are independently or simultaneously C~_
~oalkyl, C3_~6cycloalkyl or aryl, wherein the groups are optionally
substituted.
In an embodiment of the invention, R' and RZ are independently or
simultaneously optionally substituted C3_~ocycloalkyl or optionally
substituted
aryl. In another embodiment of the invention, R' and R2 are independently or
simultaneously optionally substituted C4_scycloalkyl or optionally substituted
phenyl. In an alternative embodiment of the invention, R' and R2 are
independently or simultaneously optionally substituted cyclopropane,
adamantyl or optionally substituted phenyl.
In an embodiment of the invention, R3 and R4 are independently or
simultaneously H, C~_~oalkyl, C3_~6cycloalkyl or aryl, wherein the latter
three
groups are optionally substituted. In a further embodiment, R3 and R4 are
independently or simultaneously H, optionally substituted C3_~ocycloalkyl or
optionally substituted phenyl. In another embodiment of the invention, R3 and
R4 are H. In a still further embodiment of the invention, R3 and R4 are linked
to form an optionally substituted 6-membered ring system, such as phenyl.
It is also another embodiment of the invention that a is 1 or 2,
specifically 1.
In an embodiment of the invention, M is selected from the group
consisting of Fe, Ru, Os, Co, Rh, Ir, Ni, Pd and Pt. In another embodiment of
the invention, M is selected from the group consisting of Fe, Ru, Rh, Ir, Pd
and Pt. In a further embodiment of the invention, M is Pd, Rh, or Pt. In a
still
further embodiment of the invention, M is Pd or Pt, suitably Pd.
CA 02556850 2006-08-23
13
In an embodiment of the inventors, L is selected from the group
consisting of pyridine, pyriazine, imidazole, quinoxaline and quinoline, ail
of
which are optionally substituted. In an embodiment of the invention, the
optional substituent is electron withdrawing in nature.
In a further embodiment of the invention, L is selected from the group
consisting of
Ra N~ R12 Rs N
R9 ~ / Rii and ~N
R1o R9 R1o
in which R8, R9, R'°, R" and R'2 are independently or simultaneously
selected
from the group consisting of H, halo, OH, C~_6alkyl, OC~_salkyl,
C3_~cylcloalkyl,
OC3_~cycloalkyl, fluoro-substituted C~_salkyl, fluoro-substituted OC~_salkyl,
aryl
and aryl that is substituted with 1-5 substituents independently or
simultaneously selected from the group consisting of fluoro, C~_4alkyl, OC~_
4alkyl, fluoro-substituted C~~alkyl and fluoro-substituted OC~_4alkyl. In a
further embodiment of the invention, R8, R9, R'°, R" and R'2 are
independently or simultaneously selected from the group consisting of H,
halo, C~~alkyl, C3_scycloalkyl and aryl. In a still further embodiment of the
invention, R8, R9, R'°, R" and R'2 are independently or simultaneously
selected from the group consisting of H, Br, CI, C~_salkyl, fluoro-substituted
C~_
salkyl, C~scycioalkyl and phenyl. In a more particular embodiment of the
invention, R8, R9, R'°, R" and R'2 are independently or simultaneously
selected from the group consisting of H, CH3, CF3, Br, CI and phenyl. It is
another embodiment of the invention that one or more R8, R9, R'°, R"
and
R'2, in particular R$ or R'2, on the N-containing aromatic heterocycle is
bonded to M in place of one or more X.
In an embodiment of the invention, L is
R$ N R12
Rs ~ R11
R1o
CA 02556850 2006-08-23
14
in which the embodiments for R8, R9, R~°, R~~ and R~2 are as defined
above.
It is an embodiment of the present invention that the ligand "L" is a
"cooperative" or "throw-away" ligand which aids or improves the performance
of the precatalysts of formula I and/or the corresponding Pd(0) catalyst
formed
from the formula I compounds. For example, L may act to stabilize the
catalyst and/or enhance oxidative addition, transmetalation, reductive
elimination and/or diastereo- and/or enantioselectivity during reactions
catalyzed by these compounds.
It is an embodiment of the invention that X is F, Br, CI, I or OC(O)CH3.
It is a more particular embodiment of the invention that X is CI or Br,
suitably
CI. It is a further embodiment of the invention that, when b is greater than
one, each of X may be the same or different. For example, when b is 2, one
X may be CI and the other may be Br, or they both may be CI or Br, suitably
CI.
It is an embodiment of the invention that the optional substituents are
selected from halo, C~_salkyl, OC~_4alkyl, aryl and aryl that is substituted
with
1-5 substituents independently or simultaneously selected from the group
consisting of fluoro, C~_4alkyl, OC~_4alkyl, fluoro-substituted C~_4alkyl and
fluoro-substituted OC~~alkyl. Further, it is an embodiment of the invention
that
the optional substituents are selected from F, methyl, ethyl, isopropyl, OCH3,
CF3, OCF3, phenyl and phenyl that is substituted with 1-3 substituents,
suitably 1-2 substituents, more suitably 1 substituent, independently or
simultaneously selected from the group consisting of fluoro, methyl, OCH3,
CF3 and OCF3.
In an embodiment of the invention, the compound of formula I is
selected from:
CA 02556850 2006-08-23
R R _
R R R
N ~ R ~ \ N N
R~ ~ ' / R R ~ ~ ' / R
Y ~ / ~ ~ ,
R MXb R MXb R MXb
L R L R L R
la 1b Ic
R
R ~ R -
n
NYN R / \ N N ~ R R
R MXb ~ ~ ' ~ ~ ~ / , ~ \ N N
R MXb ,- ~ ~ /
L R R MXb R
L
Id 1e If
R R
and NYN
MXb
L
Ig
in which R is H, methyl, ethyl, isopropyl, OCH3, CF3, OCF3 or F, and M, X, b,
5 --- and L are as defined above.
In another embodiment of the invention, the compound of formula I is
selected from:
n
/ ~ N NN \~ / j N N ~ j ~ N N
i ~ //
CI-~ CI
CI-Pd-CI N CI-Pd-CI
N , ~ I , N
I
CI ~CI
Ih I~ IJ
CA 02556850 2006-08-23
16
N N
/ \ w / / N~N \ ,- ~ N N w
CI-Pd-CI
CI-Pd-CI ~ CI-Pd-CI
and ~N
I
~CI ~CI
Ik Im In
In another embodiment of the invention, the compound of formula I is:
R3 R4
R1_ ~ _R2
X M
N
I
to
wherein R~, R2, R3, R4, M, -- and X are as defined in formula I.
In yet another embodiment of the invention, the compound of formula I
is:
iPr iPr iPr iPr
~ I n ~ I ~ I n ~ I
~N~N ~ ~N~N y
iPr iPr ~r iPr iPr
CI-M ~ I CI-M ~ I
N ~ N
~I ~I
Ip Iq
In accordance with another of its aspects, the present invention
includes a method of preparing the compounds of formula I, wherein X is CI or
Br, comprising combining a salt of an N-heterocyclic carbene, a ligand L and a
metal salt MXb in the presence of a base to form a reaction mixture; and
CA 02556850 2006-08-23
17
separating the compounds of formula I formed in the reaction mixture,
wherein the N-heterocyclic carbene is
R3 Ra
a
R'-N°~ -R2
a
Ye
and R' to R4, L, M, X, -- and b have the meanings provided above for
formula I and Y is any suitable counteranion, such as F-, CI-, Br , I- or PFs
.
For example, compounds of the invention may be prepared, by the
reaction sequence shown in Scheme 1:
Rs R4 Rs Ra
~a Ligand L a
R1-Ne~N-R2 + MXb Ry-NYN-R2
Base
Y~ MXb
L
(II) (III) (I)
Scheme 1
Accordingly, N-heterocyclic carbene salt of formula II in which R' to R4 and a
are as defined in formula I, -- is a single or double bond (as appropriate)
and
Y is any suitable counteranion, may be reacted with transition metal complex
of formula III in which M and b are as defined in formula I and X is Ci or Br,
in
the presence of a base and ligand L as defined in formula I, and optionally, a
solvent, to provide compounds of formula I. A solvent may not be required
when L is a liquid. Advantageously, the reaction may be performed without
special precautions to exclude water or oxygen. For example, the reaction
may be performed in air. Compounds of formula II, III and L are either
commercially available or may be prepared using methods known in the art.
The anion Y may be any suitable anion, for example, F-, CI-, Br , I-or PF6 .
The
CA 02556850 2006-08-23
18
base may be any suitable base which is compatible with the compounds of
formula II, III and L. One of ordinary skill in the art would know the
appropriate
bases which are suitable for use in the formation of compounds of formula I.
For example, the base may be Cs2C03, K2COs, Na2C03, K3P03, CaC03 or
NaOAc. Suitably, the base is Cs2C03, K2C03 or Na2C03. Compounds of
formula II, III and L are suitably reacted in the presence of the base at a
temperature of about 40°C to about 100°C. More suitably, the
reaction
mixture is conducted at a temperature of about 60°C to about
80°C. It has
been shown that the reaction does not provide optimal yields without the
presence of a suitable base. In an embodiment of the invention, the base is
present in excess amounts, for example, at least about 1.2 times, suitably at
least about 5 times, the amount of the carbene and metal salts. This
contrasts with the method of Bertogg et al. [Bertogg, A.; Camponovo. F.;
Togni, A. Eur. J. Inorg. Chem. (2005), 347-356] which does not utilize an
extra
base, like the method of the present invention. The method described in
Bertogg also results in the formation of undesirable dimeric side products
which make up approximately 50% of the yield from the reaction. The method
of the present invention does not produce such undesirable side products and
generally provides significantly higher recovery of the desired catalyst
precursor, e.g. greater than 70 to 90 percent yield.
For compounds of formula I, wherein X is other than CI or Br, the
method of Bertogg [Bertogg, A.; Camponovo. F.; Togni, A. Eur. J. Inorg.
Chem. (2005), 347-356] or Marion et al. [Marion, N.; Ecarnot, E.C.; Navarro,
O.; Amoroso, D.; Bell, A.; Nolan, S.P. J. Org. Chem. published on the web
April 11, 2006, and references cited therein] may be utilized.
The isolation of the desired compound of the formula I is achieved
using standard purification techniques. For example, the compound of
formula I is separated from the reaction mixture by purification techniques
selected from the group consisting of filtration, recrystallization,
extraction,
chromatography and combinations thereof.
Also within the scope of the present invention is a method for
performing a metal-catalyzed cross-coupling reaction comprising: contacting
CA 02556850 2006-08-23
19
suitable cross-coupling substrates with a compound of formula I, under
conditions for the formation of cross-coupling product, to form a reaction
mixture; and, optionally separating the cross-coupling product from the
reaction mixture; wherein the compound of formula I is converted to an active
catalyst under suitable reaction conditions in the reaction mixture.
Typically,
suitable reaction conditions include the use of a suitable base, solvent and
reaction temperatures as would be well known to those skilled in the art.
The present invention further includes a use of the compounds of
formula I in metal catalyzed cross-coupling reactions. The invention also
includes a use of the compounds of formula I as a pre-catalyst in a metal
catalyzed cross-coupling reaction.
In an embodiment of the invention, the cross-coupling reaction is for
example, but not limited to, a Negishi coupling reaction, a Heck coupling
reaction, a Suzuki coupling reaction, a Hiyama coupling reaction, a
Sonogashira coupling reaction, a Stille coupling reaction, a Kumada coupling
reaction, a Buchwald-Hartwig amination reaction, an allyl substitution
reaction,
an enolate arylation reaction, a hydroformylation reaction, a carbonylation
reaction, a hydrosilylation reaction or a boronylation reaction. Reaction
conditions and suitable substrates for all of these reactions would be well
known to those skilled in the art. Representative examples are provided in
the Experimental section hereinbelow.
In certain embodiments of the invention, the NHC-Pd(II) precatalyst or
the NHC-Pd(0) catalyst is covalently tethered to a solid support, such as a
polymer bead or a resin. For example, the carbene-containing ligand of the
precatalyst or the catalyst of the present invention may be covalently
tethered
to a solid support, such as a Wang resin. Additionally, one or more of the
cross-coupling substrates may be covalently tethered to a solid support, such
as a polymer bead or a resin. Further, in certain embodiments, both
substrates may be covalently tethered to a solid support. In certain
embodiments, one or more of the substrates or the catalyst or the precatalyst
are isolated in a semi-permeable membrane, such as a dialysis bag. In
certain embodiments of the invention, the catalyst, for example, through the
CA 02556850 2006-08-23
a r
carbene-containining ligand, may be anchored or supported on a catalyst
support, including a refractory oxide, such as silica, alumina, titania, or
magnesia; or an aluminosilicate clay, or molecular sieve or zeolite, or an
organic polymeric resin or sol gel derived monolithic glass.
5 Also within the scope of the present invention is the use of the
compounds of formula I for any organic synthesis, including, for example,
library synthesis and drug discovery. For example, the compounds of formula
I may be applied in high throughput synthesis of libraries of compounds for
use in the screening of compounds for biological testing. The compounds of
10 formula I are compatible with existing high-throughput synthesis methods.
For example, the compounds of formula I may be used in applications
for solid-phase synthesis in which multi-step reactions can be performed on
resins in continuous flow or batch manner. Still further, the compounds of
formula I may be used in applications for solution phase synthesis in which
15 multi-step reactions can be performed in solution with polymer-supported
catalysts in continuous flow or batch manner.
Further, the compounds of formula I may be attached to solid supports
using methods known in the art and used in chemical transformations in this
form as described above. The compounds of formula I may also be used, for
20 example, in the synthesis of natural products, agricultural or
pharmaceutical
ingredients as single compounds regardless of scale, enantiomeric and
diastereomeric purity. The compounds of the present invention may be used
in the synthesis of materials for electronic, nanotechnology and medical
applications. The term "materials" herein is defined as small molecules,
oligomers and polymers as single substances or libraries of substances.
As used herein, the terms "comprises", "comprising", "including" and
"includes" are to be construed as being inclusive and open ended, and not
exclusive. Specifically, when used in this specification including claims, the
terms "comprises", "comprising", "including", "includes" and variations
thereof
mean the specified features, steps or components that are included. These
terms are not to be interpreted to exclude the presence of other features,
steps or components.
CA 02556850 2006-08-23
21
The following non-limiting examples are illustrative of the invention:
EXPERIMENTAL EXAMPLES:
Example 1: Synthesis of the NHC-PdClr3-chloropyridine complexes
N
R ~ R ~ ~ (IVa) R
NON \ ~ + PdCl2 / CI
R' R R ~ R K2C03 R'
CI a 80 degrees Celsius, 16 h
NHC ~ HCI
Ila R = i-Pr, R' = H; IPr~HCI Ih R = i-Pr, R' = H; 97%
Ilb R = Et, R' = H; IEt~HCI Ij R = Et, R' = H; 98%
Ilc R = Me, R' = Me; IMes~HCl Ii R = Me, R' = Me; 91
(I) General Synthesis:
In air, a vial was charged with PdCl2 (177 mg, 1.0 mmol), NHC~HCI (1.1
mmol), K2C03 (691 mg, 5.0 mmol) and a stir bar. 3-Chloropyridine (IVa, 4.0
mL) was added, the vial was capped with a Teflon~-line screw cap and heated
with vigorous stirring for 16 hours at 80 °C. After cooling to room
temperature,
the reaction mixture was diluted with CHZC12 and passed through a short pad
of silica gel covered with a pad of Celite~, eluting with CHZCIZ until the
product
was completely recovered. Most of the CH2C12 was removed (rotary
evaporator) at room temperature, and the 3-chloropyridine was then vacuum-
distilled (water aspirator vacuum) and saved for reuse. The pure complexes
were isolated after titrating with pentane, decanting of the supernatant and
drying in high vacuum.
(i) Complex Ih.
From IPr~HCI, Ila, (468 mg, 1.1 mmol), the complex Ih (677 mg, 97 %) was
obtained as a yellow solid, mp = 240 °C (with decomposition). 'H NMR
(400
MHz, CDC13): b 8.62 (d, J = 1.6 Hz, 1 H,), 8.54 (d, J = 5.6 Hz, 1 H), 7.57 (d,
J =
8.2 Hz, 1 H), 7.52 (t, J = 7.7 Hz, 2H), 7.37 (d, J = 7.7 Hz, 4H), 7.16 (s,
2H),
CA 02556850 2006-08-23
22
7.09 (dd, J = 8.0 Hz, 5.7 Hz, 1 H), 3.18 (m, 4H), 1.50 (d, J = 6.7 Hz, 12H),
1.14
(d, J = 6.8 Hz, 12H).'3C NMR (100 MHz, CDC13): 8153.5, 150.5, 149.4, 146.7,
137.4, 135.0, 132.0, 130.3, 125.1, 124.3, 124.1, 28.7, 26.3, 23.2. Anal.
Calcd.
for C32H4oC13N3Pd: C, 56.57; H, 5.93; N, 6.18. Found: C, 56.90; H, 5.99; N,
6.52.
(ii) The above reaction for the preparation of complex Ih was repeated using
other bases. The percent yield of Ih was as follows:
Na2C03- 98%
K2C03 - 97%
K3P03 - 43%
CaC03- 25%
Cs2C03- 93%
NaOAc- 60%
It should be noted that reactions performed in the absence of base did not
provide optimum amounts of desired products.
(iii) The number of equivalents of base in the above reactions was also
varied,
with the following results:
2 equiv NaOAc - 60% compound Ih
2 equiv K2C03 - 80% compound Ih
1.25 and 2.5 equiv. Na2C03- 73% compound Ih
(iv) Using the general synthesis in part (i) above, the corresponding Pt
complex (R = iPr, R' = H) was made in 60% yield using PtCl2 and K2C03 as
base.
(v) Using the corresponding saturated version of Ila, compound Ik was also
prepared:
CA 02556850 2006-08-23
23
R ~ R
N N
~ R ~ R ~
CI-Pd-CI
I
N
i
' c1
Ik R = iPr
(vi) By replacing 3-chloropyridine with 2-phenyl pyridine, NHC-PdCI-2-
phenylpyridine complex Ip was prepared:
iPr iPr
~ i n ~ i
~N N
iPr Y iP
CI-M
' i
N
i
IP
In air, a vial was charged with PdCl2 (177 mg, 1.0 mmol), NHC~HCI (468 mg,
1.1 mmol), Cs2C03 (2.3 g, 5.0 mmol) and a stir bar. 2-phenylpyridine (4.0 mL)
was added, the vial was capped with a Teflon-line screw cap and heated
with vigorous stirring for 16 h at 80°C. After cooling to room
temperature, the
reaction mixture was diluted with CH2C12 and passed through a short pad of
silica gel covered with a pad of Celite, eluting with CH2C12 until the product
was completely recovered. Most of the CH2C12 was removed (rotary
evaporator) at room temperature, and the 2-phenylpyridine was then vacuum-
distilled (water aspirator) and saved for reuse. The pale yellow complex
(480mg, 70%) was isolated after titrating with pentane, decanting of the
supernatant and drying under high vacuum.
CA 02556850 2006-08-23
24
Example 2: Catalytic Activity of the NHC-Pd catalysts Ih, Ii and Ij in alkyl-
alkyl
cross-coupling reactions
Br + /~/~M Pd-NHC catalyst Ih, Ij or Ii
(1 mol%)
and nBuZnBr (Negishi)
or tri-n-butylborane (Suzuki)
Complex Ih (Example 1, 1 mol %) was subjected to standard alkyl-alkyl
Suzuki and Negishi cross-coupling reactions. Reaction conditions are
provided in Table 1. The reactions were rapid (Suzuki 5 minutes, Negishi 30
minutes). Quantitative formation of the reaction product was observed at room
temperature (Table 1).
Example 3: Rate studies with complexes Ih and Ij in alkyl alkyl cross-
couplings shown in Example 2
The results of the rate studies with complexes Ih and Ij (see Example 1) in
the
alkyl-alkyl cross-couplings (a) Suzuki reaction, (b) Negishi reaction are
shown
in Figure 1. The yields were determined by GC/MS against a calibrated
internal standard (undecane). As seen in Figure 1, the rate of the reaction
with complex Ij was much slower than with complex Ih. While not wishing to
be limited by theory, these results are suggestive that bulky NHC ligands lead
to fast reductive elimination, which suppresses undesired side reactions or
catalyst decomposition in a manner analogous with bulky phosphines. Since
complexes Ih, Ij and Ii are air- and water tolerant and do not decompose upon
standing, heating Ih at 100 °C in DMSO-d6 for 24 hours led to no
visable
decomposition (by 'H and '3C NMR spectroscopic analysis). Thus, it is
unlikely that pyridine dissociation initiates catalyst activation considering
the
high stability of complex Ih. Rather, rapid reduction facilitated by the
organometallic reagent takes place followed by pyridine dissociation from the
generated Pd(0) species (Figure 2).
Example 4: Mechanistic Studies: Activation and use of complex Ih
CA 02556850 2006-08-23
Complex Ih (Example 1) was treated with 2 equivalents of n-heptylzinc
bromide and the reaction mixture was analyzed by GC/MS. From this
analysis, the formation of n-tetradecane and liberation of 3-chloropyridine
was
observed. DFT calculations at the B3LYP/DZVP level showed that the binding
5 enthalpy of 3-chloropyridine to NHC-ligated Pd(II) is 4.5 kcal mol-~ higher
than
to Pd(0). Also the dissociation energy of PH3 is 16.5 kcal mol-1 compared to
19.4 kcal mole for the 3-chloropyridine.
Example 5: Comparison befinreen in sifu catalyst and NHC-PdClr3-
10 chloropyridine (1h) complexes in the alkyl-alkyl Negishi reaction
A significant increase in rate was observed when catalysis with complex Ih
(Example 1) at 1 mol % was compared to the prior art (for example S.P. Nolan
et al., U.S Patent No. 6,316,380, Issued November 13, 2001) Pd2(dba)~/Ila in
situ protocol at 4 mol % (Figure 3a). Due to extremely fast rates at 1 mol %
of
15 Ih, it was not possible to reliably measure the reaction rate, therefore, a
loading of 0.1 mol % was used (Figure 3b). A comparison with the in situ
protocol is shown after 1 hour. Given that both reactions were 30 % complete
at that time, the apparent (turnover numbers) TONs suggest, assuming the
same active catalyst is generated when employing the in situ protocol, that
20 only ~ 0.1 mol % of active catalyst is actually formed, even though 4 mol %
of
the precursors are used. It should be pointed out that, in the prior art
Pd2(dba)~/Ila in situ protocol, the catalysis was weighed in a glove box,
taking
great care to avoid contact with air and water. Using the compounds of
formula I of the present invention, the catalyst (or precatalyst) could be
25 weighed in the open with no special precautions to avoid contact with air.
The
advantages in reaction time and yield when the compounds of formula I are
used in the metal-catalyzed cross-coupling reaction are clearly seen in the
graphs shown in Figure 3. Further, reliable and repeatable results could not
be obtained using the prior art catalyst owing, potentially, to the
uncertainty in
the composition of the prior art in situ generated catalyst. The methods of
the
present invention, by employing a stable catalyst precursor having a well-
CA 02556850 2006-08-23
26
defined structure, provides a significant improvement in the performance of
NHC-Pd(0) catalyst systems.
Example 6: Optimization of Suzuki conditions for boronic acids
CI B(OH)2
Pd-NHC catalyst Ih, Ij or Ii , OMe
\ + I \ (1-2 mol%) \ \
Solvent/Base
OMe Temperature (degrees Celsius)
Complexes Ih, Ij or Ii was subjected to a variety of Suzuki reaction
conditions
(Table 2). It was found that all complexes functioned as excellent catalysts
at
80 °C. In comparison to complexes Ij and Ii, it was found that complex
Ih was
advantageous as it was possible to conduct reactions in both dioxane and i-
PrOH at room temperature with a judicious choice of base (Table 2, entries,
10 and 12).
Example 7: Optimization of Suzuki conditions for potassium trifluoroborates
CI BF3K
Pd-NHC catalyst Ih / OMe
\ + I \ (2 mol%) \
Solvent/Base I \ v
OMe Temperature (degrees Celsius)
Expansion of the protocol in Example 6 to potassium trifloroboroates was
accomplished by simply changing the solvent to methanol (Table 3, entries 2,
5, 6-8).
Example 8: Suzuki cross-coupling reactions substrate scope
There are 4 different protocols for this reaction dependent on the coupling
partners. Robust functionality can be coupled at room temperature in
isopropyl alcohol (IPA) using KOt-Bu as base, while base-sensitive groups
CA 02556850 2006-08-23
27
may be coupled utilizing K2C03 at 60°C. For relatively hindered
substrates
sensitive to KOt-Bu and where K2C03 is ineffective, KOH may be used at
room temperature. Optimal to the success is ensuring that the precatalyst is
activated. When utilizing KOt Bu, a change in reaction solution color,
normally
to orange or red, is observed. When utilizing K2C03 or KOH, in the absence of
strongly colored materials the reaction is generally complete when the
solution is grey in color and contains noticeable precipitate.
The employment of a variety of reaction conditions allowed a large array of
hindered biaryls and drug-like heteroaromatics to be easily synthesized using
Suzuki cross-coupling reaction conditions (Table 4). A notable example is the
synthesis of 19 (Table 4), which when used in combination with
triethylphosphine has been demonstrated to form a highly effective
asymmetric Morita-Baylis-Hillman (MBA) protocol [McDougal, N.T.; Schaus,
S.E. J. Am. Chem. Soc. (2003) 125, 12094-12095]. Methods A, B, C and D
are described in detail below. Use of IPA/t-BuOK (Method A) allowed for
rapid cross-coupling at room temperature whereas more sensitive coupling
partners were effectively coupled utilizing mild K2C03 in dioxane (Method B)
or methanol in the case of potassium trifluoroborates (Method C).
(i) Procedure for Method A.
In air, a vial was charged with potassium tert-butoxide (154 mg, 1.30 mmol)
and complex Ih (6.8 mg, 0.01 mmol) and the vial was sealed and purged with
argon (3x). Technical grade isopropanol (1.0 mL) was added and the contents
were stirred at room temperature until a colour change from yellow to
red/brown was observed (~10 min). Under a cone of argon, the boronic acid
(1.20 mmol) was added, the vial was resealed with a septum and the
organohalide (1.00 mmol) injected via microlitre syringe. Alternatively, if
the
boronic acid was soluble in isopropanol, it was added as a solution (1.0 mL).
The solution was stirred at room temperature for the indicated period of time.
The reaction was then diluted with diethyl ether (2 mL) and transferred to a
round bottom flask. The reaction vial was rinsed with additional diethyl ether
CA 02556850 2006-08-23
28
(2 mL) and combined with the previous dilution. Each reaction was performed
in duplicate and the contents were combined, concentrated onto silica gel and
purified by flash chromatography.
(ii) Procedure for Method B.
In air, a vial was charged with complex Ih (6.8 mg, 0.01 mmol), potassium
carbonate (207 mg, 1.50 mmol), the boronic acid (0.6 mmol) and the
organohalide (0.5 mmol). The vial was sealed with a septum and purged with
argon (3x). Dioxane (2.0 mL) was added and the contents were stirred at
60°C for the specified period of time. The reaction was then diluted
with
diethyl ether (2 mL) and transferred to a round bottom flask. The reaction
vial
was rinsed with additional diethyl ether (2 mL) and combined with the
previous dilution. Each reaction was performed in duplicate and the contents
were combined, concentrated onto silica gel and purified by flash
chromatography.
(iii) Procedure for Method C.
In air, a vial was charged with complex Ih (6.8 mg, 0.01 mmol), potassium
carbonate (207 mg, 1.50 mmol), the potassium trifluoroborate (0.55 mmol)
and the organohalide (0.5 mmol). The vial was sealed with a septum and
purged with argon (3x). Technical grade methanol (2.0 mL) was added and
the contents stirred at 60°C for the specified period of time. The
reaction was
then diluted with diethyl ether (2 mL) and transferred to a round bottom
flask.
The reaction vial was rinsed with additional diethyl ether (2 mL) and combined
with the previous dilution. Each reaction was performed in duplicate and the
contents were combined, concentrated onto silica gel and purified by flash
chromatography.
(iv) Procedure for Method D.
Method B was followed however in the place of solid potassium carbonate,
solid KOH (84 mg, 1.50 mmol) was utilized. Additionally, the reaction was
carried out at room temperature instead of 60°C.
Example 9: Evaluation of Complex Ih in the Negishi reaction
CA 02556850 2006-08-23
29
A comprehensive evaluation of complex Ih in the Negishi cross-coupling
reaction was performed. The results presented in Table 5 demonstrate that
complex Ih was able to catalyze the cross-coupling of organo-chlorides,
bromides and iodides, aryl triflates and alkyl tosylates and mesylates in all
possible pairings of potential cross-coupling substrates, including all
possible
hybridization states of the atoms specifically involved in the coupling, in
high
yield at room temperature (Table 5, entries 1-3, 6-8, 12-14 and 17-19).
There were 4 main protocols for this reaction dependant on organohalide and
carbon hybridization present in the coupling partners. Whilst most reactions
are carried out at room temperature, sterically encumbered partners were
optimally warmed to 60-70°C to ensure efficient cross-coupling.
Furthermore,
the addition of 2 equivalents (based on organozinc) of Liar or LiCI (available
from Aldrich as 1 M anhydrous solutions in THF or DMI) is important to effect
cross-coupling in some reaction types (see Protocols below). Efficient
catalyst
formation and reaction is normally indicated by a slow color change from pale
yellow to a deep brown-colored solution when employing zinc made by the
Hou protocol in DMI (Org. Lett. 2003, 5, 423). If this change is rapid, (1-2
seconds) this is indicative of a failed reaction and is normally the result of
ineffective catalyst activation, which could be due to the steric and/or
electronic properties of the organozinc reagent. Use of organozincs formed by
Rieke zinc does not show the same color change. Additionally, the use of n-
BuLi for formation of aryl zincs should be avoided as the generated butyl
halide is a capable coupling partner for complex Ih due to its high
reactivity.
Cross-Coupling Procedures: All cross-coupling reactions were run with a final
solvent volume of 2.4 mL.
Solvent ratios
Alkyl bromides: DMI/NMP: THF, 1:2
Alkyl chlorides, iodides, tosylates and mesylates: DMI/NMP: THF, 3:1
Aryl bromides: DMI/NMP: THF, 1:2
Aryl chlorides, triflates: DMI/NMP:THF, 3:1
(sp3X-sp3ZnX): A vial was charged with Ih (3.4 mg, 1 mol%), Liar (139.0 mg,
1.6 mmol, transferred under a filter cone flowing with inert gas) and a
stirbar,
CA 02556850 2006-08-23
after which it was sealed with a septum and purged under an inert
atmosphere. THF (X mL) and DMI (X mL) or NMP (X mL) were then added
and the suspension stirred until the solids dissolved after which the
organozinc (0.8 mL, 1.0 M in DMI or NMP, 0.8 mmol) and the organohalide or
5 pseudo halide (0.5 mmol) were added. The septum was replaced with a
Teflon-lined screw cap under an inert atmosphere (e.g. under a cone of
argon, not necessarily in a glove box) and the reaction stirred for 2h. After
this
time, the mixture was diluted with ether (15 mL) and washed successively
with 1 M Na3EDTA solution (prepared from EDTA and 3 equiv of NaOH),
10 water and brine. After drying (anhydrous MgS04) the solution was filtered,
the
solvent removed in vacuo, and the residue purified by flash chromatography.
(sp3X-sp2ZnX): A vial was charged with Ih (3.4 mg, 1 mol%) and under an
inert atmosphere ZnCl2 (107 mg, 0.8 mmol, transferred under a filter cone
flowing with inert gas) and a stirbar were added. The vial was then sealed
with
15 a septum and purged under an inert atmosphere. THF (0.8 mL) was added
followed by the requisite Grignard reagent (0.8 mL, 1.0 M in THF, 0.8 mmol)
and stirring continued for 15 minutes at which time a white precipitate
formed.
Under an inert atmosphere, Liar (139.0 mg, 1.6 mmol), NMP (0.8 mL) or DMI
(0.8 mL) and the organohalide or psuedo halide (0.5 mmol) were added. The
20 septum was replaced with a TefIonC~-lined screw cap under an inert
atmosphere and the reaction stirred for 2h. After this time, the mixture was
diluted with ether (15 mL) and washed successively with 1 M Na3EDTA
solution (prepared from EDTA and 3 equiv of NaOH), water and brine. After
drying (anhydrous MgS04) the solution was filtered, the solvent removed in
25 vacuo, and the residue purified by flash chromatography.
(sp2X-sp3ZnX): A vial was charged with Ih (3.4 mg, 1 mol%), Liar (139.0 mg,
1.6 mmol, transferred under a filter cone flowing with inert gas) and a
stirbar
after which it was sealed with a septum and purged under an inert
atmosphere. THF (X mL) and DMI (X mL) or NMP (X mL) were then added
30 and the suspension stirred until the solids dissolved after which the
organozinc (0.8 mL, 1.0 M in DMI or NMP, 0.8 mmol) and the organohalide or
psuedo halide (0.5 mmol) were added. The septum was replaced with a
CA 02556850 2006-08-23
31
Teflon4-lined screw cap under an inert atmosphere and the reaction stirred
for 2h. After this time, the mixture was diluted with ether (15 mL) and washed
successively with 1 M Na3EDTA solution (prepared from EDTA and 3 equiv of
NaOH), water and brine. After drying (anhydrous MgS04), the solution was
filtered, the solvent removed in vacuo, and the residue purified by flash
chromatography.
(sp2X-sp2ZnX): In air, a vial was charged with Ih (3.4 mg, 1 mol%) and ZnCl2
(0.8 mmol, transferred under a filter cone flowing with inert gas) and a
stirbar
were added. The vial was then sealed with a septum and purged under an
inert atmosphere. THF (X mL) was then added followed by the requisite
Grignard reagent (0.8 mL, 1.0 M in THF, 0.8 mmol) and stirring continued for
minutes at which time a white precipitate formed. NMP (X mL) was then
added followed by the organohalide or pseudo halide (0.5 mmol) and the
septum was replaced with a Teflon-lined screw cap under an inert
15 atmosphere and the reaction stirred for 2h. After this time, the reaction
mixture was diluted with ether (15 mL) and washed successively with 1 M
Na3EDTA solution (prepared from EDTA and 3 equiv of NaOH), water and
brine. After drying (anhydrous MgS04) the solution was filtered, the solvent
removed in vacuo, and the residue purified by flash chromatography.
Example 10: Negishi cross-coupling reactions substrate scope
As seen in Table 6, functionalization of the reactants did not diminish the
generality of the protocols described in Example 9, with sp3(RX)-sp3(RZnX),
spa-sp2, sp2-spa and sp2-sp2 cross-coupling reactions easily accomplished
with 1 mol % complex Ih. Coupling of a range of alkyl bromides, chlorides and
tosylates was achieved at room temperature (Table 6, compounds 21-26).
Remarkably, by careful choice of reaction conditions it was possible to
selectively couple a bromide in the presence of a chloride (Table 6, compound
21). An array of functionality was tolerated including esters, nitrites,
amides
and acetals (Table 6, 21-26). Noteworthy examples are the coupling of (S)-
citronellyl bromide in high yield (Table 6, compound 27) and the stability of
the
TMS group in the reaction conditions (Table 6, compounds 25, 28 and 29).
CA 02556850 2006-08-23
32
The coupling of alkyl zinc reagents with aryl halides or aryl triflates
occurred in
high yield with no transmetalation to the aryl zinc observed (Table 6,
compounds 31-34). Aryl halides, as expected, proved to be excellent coupling
partners. Accordingly, the facile synthesis of a range of drug-like
heteroaromatics and sterically congested biaryls was accomplished in high
yield (Table 6, compounds 35-41). A significant entry is the coupling of o-
chlorotoluene and 2,4,6-triisopropylphenylzinc chloride at 60 °C (Table
6,
compound 35). N-Boc protected indole, pyridine, and multiple heteroatom
containing heterocycles were well tolerated (Table 6, compounds 31, 32, 34,
37, 39-41). Finally, the cross-coupling of a chiral zinc reagent with an acyl
chloride (Table 6, compound 33) proceeded without concomitant
decarbonylation, demonstrating the mildness of this protocol.
Example 11: Heck cross-coupling reaction
O
Br O O' \
\ ~
+ O! \ ~ \
A vial was charged with complex Ih (17.0 mg, 0.025 mmol, 5 mol%) as
defined in Example 1, Cs2C03 (326 mg, 1.0 mmol) and a stir bar. The air was
replaced with an inert gas (Ar) and dry DMA was introduced, followed by
bromobenzene (53 NL, 78.5 mg, 0.5 mmol), tert butyl acrylate (117 pL, 103
mg, 0.8 mmol) and n-undecane (GC internal standard, 50 uL). The reaction
was stirred at 120°C for 18 hours, then cooled to room temperature,
diluted
with hexane and analyzed by GC/MS after passing through a short pad of
silica gel. Quantitative conversion to (E)-tent butyl cinnamate was observed
by GC/MS. GC retention time and EI fragmentation pattern were identical to
commercially available material (Aldrich).
CA 02556850 2006-08-23
33
Example 12: Buchwald Hartwig coupling reacfion
CI
o C~
I, + C~
H I~
In air, potassium tert butoxide (127 mg, 1.10 mmol) and complex Ih (6.8 mg,
0.01 mmol, 1.0 mol%) as defined in Example 1 were weighed into a vial with a
stir bar and the vial was capped with a septum. The atmosphere was
replaced with inert gas (Ar) and 1 mL of dry DME added and stirred until all
the solids had dissolved. Chlorobenzene (102 NL, 112.56 mg, 1.0 mmol) and
morpholine (96 NL, 96 mg, 1.10 mmol) were then added in quick succession
with rapid stirring. The septum was then replaced with a Teflon~ lined cap
under inert gas (Ar) and the vial heated at 50°C for 1 hour. After this
time the
reaction mixture was cooled and partitioned between water and ether, the
organic phase was dried (anhydrous MgS04), filtered, and the solvent
removed. The resultant residue was purified by flash chromatography eluting
with 9:1 pentane:ether. N-Phenylmorpholine was obtained as a white solid
155 mg, 95% yield.
Example 13: Buchwald Hartwig coupling reactions substrate scope
H R..
Ar-X + ' ~ N-Ar
R. i N w R.. R,r
A study of the Buchwald-Hartwig coupling reaction substrate scope was
performed and the results are shown in Table 7. The general experimental
conditions were as follows:
A vial was charged with Ih (14 mg, ~2 mol%), KOt Bu (135.0 mg, 1.2 mmol
CA 02556850 2006-08-23
34
corrected for purity) and a stirbar were added after which it was sealed with
a
septum and purged with an inert atmosphere. The amine (1.1 mmol) and
organohalide (1.0 mmol) were added and stirred rapidly for 1-2 min. When
using 2,6-diisopropylaniline the reaction turns orange immediately; stirring
should continue until the solution becomes dark orange to red (note: a green
to dark green solution indicates a failure to form sufficient active
catalyst).
After this time, DME (1 mL) was added and the septum was replaced with a
Teflon~3-lined screw cap under an inert atmosphere and the reaction stirred at
RT or 50°C until complete. After this time, the mixture was diluted
with TBME
(15 mL) and washed with water. After drying (anhydrous Na2S04, the use of
MgS04 can be problematic), the solution was filtered, the solvent removed in
vacuo, and the residue purified rapidly by flash chromatography and stored
under an inert atmosphere. Pre-absorption of the crude amine product onto
silica should be avoided as this practice has been found to lead to poor
recovery.
Example 14: Kumada Reaction
Effective coupling partners are aryl chlorides and bromides. Simple couplings
can be done at room temperature without the addition of LiCI; if this proves
unproductive, heating at 60 or 70°C normally facilitates the cross-
coupling. If
these conditions fail for challenging partners, 2 or 3 equivalents (based on
organomagnesium reagent) of anhydrous LiCI may be added and the reaction
temperature varied from RT to 70 °C.
A vial was charged with Ih (7 mg, 2 mol%) and LiCI (67.0 mg, 1.6 mmol) as
necessary followed by a stirbar under an inert atmosphere. The vial was then
sealed with a septum and purged under an inert atmosphere after which DME
(0.8 mL) was added and the suspension was stirred until Ih had dissolved.
After this time, the organohalide (0.5 mmol) and the organomagnesium (0.8
mL, 1.0 M in THF or ether, 0.8 mmol) were added (active catalyst is indicated
by the reaction solution turning orange). The septum was replaced with a
Teflon-lined screw cap under an inert atmosphere and the reaction stirred at
RT or warmed to 60 or 70°C until complete. After this time, the
mixture was
CA 02556850 2006-08-23
diluted with a suitable organic solvent (15 mL) and washed successively with
1 M Na3EDTA solution (prepared from EDTA and 3 equiv of NaOH), water
and brine. After drying (anhydrous MgS04) the solution was filtered, the
solvent removed in vacuo, and the residue purified by flash chromatography.
5 A summary of the substrate scope that was explored is presented in Table 8.
Example 15: Enolate Arylation
General procedure: In air a vial was charge with Ih or Ik (1 mol%, 6 mg),
sodium tert butoxide (1.5 mmol, 1.44 mg) the vial was then purged with Ar.
10 After which toluene (1 mL), ketone (1.1 mmol) and the aryl chloride (1.0
mmol) were added in turn and sealed with a screw cap. The vial was then
placed in an oil bath at 60°C and the mixture stirred on a stirring
plate. When
reaction reached completion, or no further conversion could be observed by
TLC, the vial was allowed to cool to room temperature. Water was added to
15 the reaction mixture; the organic layer was extracted with diethyl ether
and
dried over magnesium sulfate. The solvent was then evaporated in vacuo and
the product purified by column chromatography.
Representative Example:
o c1 o ~ I
----f
i , z4n I ,
20 so~io
Example 16: Sonogashira Reaction
(i) Primary Alkyl Bromides
Ih (0.04 Eq)
O Cul (0.08 Eq) O
Cs2C03 (1.45 Eq) ~
O '~ DMF:DME (1.5:1) O
1 eq 1.45 eq 83%
25 A powder of Ih (0.8500 g)/Cul (0.4750 g) was prepared. In air, the Ih/Cul
powder (21.2 mg) and Cs2COs (0.7 mmol, 228.0 mg) were added to a vial
CA 02556850 2006-08-23
36
equipped with a magnetic bar, and sealed with a Teflon~-lined screw cap and
fitted with a septum. The vial was purged with Argon, and DMF (1.2 mL)
followed by DME (0.8 mL) were added. The contents were allowed to stir at
room temperature for 30 min. The alkyl bromide (0.5 mmol, 67 pL), followed
by the octyne (0.73 mmol, 110 pL) were added. The vial was then placed in
an oil bath at 60°C for 18h. An aqueous workup was performed, the
organic
layer extracted with pentane and dried over MgS04. The solvent was
removed using a rotary evaporator and the product was purified using flash
chromatography with 2% ether/pentane eluent, yielding 92.6 mg of the
product.
(ii) Secondary Alkyl Bromides
Ih (0.05 Eq)
Cul (0.10 Eq)
Br + Cs2C03 (1.45 Eq)
DMF:DME (1.86:1) 8~0~0
1.45 eq CHs(CH2)~NH2 (0.2 Eq)
1 eq
A powder of Ih(0.8500 g) /Cul (0.4750 g) was prepared. In air, the Ih/Cul
powder (26.5 mg) and Cs2C03 (0.7 mmol, 228.0 mg) were added to a vial
equipped with a magnetic bar, and sealed with a Teflon~-lined screw cap and
fitted with a septum. The vial was purged with Argon and DMF (1.3 mL)
followed by DME (0.7 mL) were added. The contents were allowed to stir at
room temperature for 30 min. The octylamine (20 mol%,16.5 NL) was added
at the end of the stirring time followed by the alkyl bromide (0.5 mmol, 67
NL),
followed by the octyne (0.73 mmol, 110 NL). The vial was then placed in an
oil bath at 60°C for 18h. An aqueous workup was performed, the organic
layer extracted with pentane and dried over MgS04. The solvent was
removed using a rotary evaporator and purified using flash chromatography
with hexane eluent. 90.3 mg of the product, determined by NMR, was
CA 02556850 2006-08-23
37
isolated.
Example ~ 7: Bis Pinicol Borane
In air, a vial was charged with Ih (10.2mg, 0.015mmol, 3mol%),
bis(pinacolato)diboron (0.1397g, 0.55mmol) and KOAc (0.147g, 1.5mmol).
The vial was sealed and purged with argon. Bromobenzene (52NL, 0.5mmol)
and 3mL of DMSO were then added. The resulting mixture was then stirred
at 90°C until the reaction was complete. The product was extracted into
ether,
separated and dried over MgS04. The product was purified by column
chromatography. Results for various substrate scope and reaction conditions
are presented in Table 9.
While the present invention has been described with reference to what
are presently considered to be the preferred examples, it is to be understood
that the invention is not limited to the disclosed examples. To the contrary,
the
invention is intended to cover various modifications and equivalent
arrangements included within the spirit and scope of the appended claims.
All publications, patents and patent applications are herein
incorporated by reference in their entirety to the same extent as if each
individual publication, patent or patent application was specifically and
individually indicated to be incorporated by reference in its entirety. Where
a
term in the present application is found to be defined differently in a
document
incorporated herein by reference, the definition provided herein is to serve
as
the definition for the term.
CA 02556850 2006-08-23
38
TABLE 1: CATALYTIC ACTIVITY OF THE NHC-Pd COMPLEXES Ih, Ij AND
Ii IN ALKYL-ALKYL CROSS-COUPLING REACTIONS
enfry M yield of n-heptylbenzenea~
1 ZnBr 100 % (1h), 34 % (1j), 8.0
% (II)
2 BBu2 100 % (1h), 31 % (1j), 6.5
% (II)
3 MgBre 100% (1h)
eGC yield (internal standard-undecane) after 24 hours at room temperature;
all reactions in duplicate. bControl experiments with no catalyst showed no
conversion in all cases. ~n-Butylzinc bromide (1.3 equiv), THF-NMP = 2:1. dtri-
n-butylborane (1.2 equiv), t-BuOK (1.3 equiv), i-PrOH. en-Butyl magnesium
bromide (1.5 eq), 1-chloro-3-phenylpropane used instead of 1-bromo-3-
phenylpropane, THF:DMI = 2:1, RT, 45 min.
CA 02556850 2006-08-23
39
TABLE 2. OPTIMIZATION OF SUZUKI CONDITIONS FOR BORONIC ACIDS
entrya catalystsolvent base temp, yield (%)
~
(mol (Equiv) (C)
%)
1 Ii (2) Dioxane Cs2C03 80 74
(2)
2 Ij (2) Dioxane Cs2C03 80 95
(2)
3 Ij (2) DME Cs2C03 80 54
(2)
4 Ih (2) Dioxane K3P04 (2) 80 48
5 Ih (2) Dioxane Cs2C03 80 92
(2)
6 Ih (2) DME Cs2C03 80 77
(2)
7 Ih (2) Dioxane K2C03 (2) 80 80
8 Ih (2) Dioxane K2C03 (3) 80 95
9 Ih (2) Dioxane K2COs (3) 60 97
10 Ih (2) Dioxane K2C03 (3) rt 86
11 Ih (1) Dioxane K2C03 (3) 80 74
12 Ih (1) i-PrOH t-BuOK rt 97
aGC yield (internal standard-undecane) after 2 hours at room temperature; all
reactions in duplicate. bControl experiments with no catalyst showed no
conversion.
CA 02556850 2006-08-23
40
TABLE 3. OPTIMIZATION OF SUZUKI CONDITIONS FOR POTASSIUM
TRIFLUOROBORATES
entry solvent base temp, yield
(Equiv) (C) (/)8a
1 Dioxane K2C03 (3) 60 0
2 MeOH K2C03 (3) 60 90
3 EtOH KZCOs (3) 60 30
4 i-PrOH K2C03 (3) 60 27
MeOH K2C03 (3) rt 86
6 MeOH CsF 60 0
7 MeOH KOH 60 91
8 MeOH K3P04 60 84
aGC yield (internal standard-undecane) after 24 hours at room temperature;
all reactions in duplicate. bControl experiments with no catalyst showed no
conversion.
CA 02556850 2006-08-23
41
TABLE 4. OPTIMIZATION OF SUZUKI CONDITIONS FOR POTASSIUM
TRIFLUOROBORATES USING COMPLEX Ih AS THE CATALYST
Complex Ih
R~-X + M-R" (1-2 mol%) R,-R"
(1.2 equiv) Method A, B, C or D
rt, 60 degrees Celsius
-o
N I w O \ / / \ CFa
i
(8, 93%, 2h, Method A)e -O
(X = CI, M = B(OH)2) S \ ~ w (10, 93%, 24h Method A)e
~ (X=Br, M=B(OH)z)
(9, 88%, 2h, Method A)e N S
(X = Br, M = B(OH)p) S' ~
N-
Ii ~ -
I / {11, 98%, 6h, Method C)en
(X=Br,M=BF3K)
i i
N S
(12, 85°h, 2h, Method A)g ~
(X = CI, M = B(OH)~ (13, $5%, 2h, Method A)8 N
{X = CI, M = B(OH)2) {14, 96°~, 2h, Method B)e
(X = CI, M = B(OH)2)
O
NOZ O-
_ _ S / \ /
NC \ /
I
(15, 77%, 18h, Method B)a (16, 99%, 6h, Method B)° ''
(X = CI, M = B(OH)2)
(X = CI, M = B(OH)~
i i
/ \ ~ {1 (X ?°Br, M =~ B(OH)2)D)e
O
O H
\ / \ I
18, 60%, 6h, Method B)'
(X = Ci, M = B(OH)2) O
N-N
~ \ /
O
(19, 93%, 16h, Method B)e° (20, 92%, 6h, Method C)e
(X = Br, M = B(OH)2) (X = CI, M = BF3K)
eAll reactions were performed using ~andard laboratory technique, i.e. no
glove-box was
employed: Method A: Ih (1~mol%~ ) OBu (1.3 o~uiv.~ reagent grah a iso~ropanol
room
temperature. Method° B: Ih 2 mol ~° , dioxane, 60 ethod C: th 2
mol /o~ K2Cb3 3.0
egmv.) methanol, 60 C. Met od D: Ih~2 mol%), KOHS (3.0 aquiv.) dioxane, rt.
Yielded 0%
after 1~h at rt. Using Ih (4 mol%) K2C 3 (6.0 equiv) and RB(OH2) ~2.4 equiv).
CA 02556850 2006-08-23
42
TABLE 5. EVALUATION OF COMPLEX Ih IN THE NEGISHI REACTION
Complex Ih
(1 mol%)
R'-X + R"-ZnBr/CI R'-R"
(1.6 equiv) Solvent
rt, 24h
Entry R~ X R ~ Yield [%
1 Ph(CH2)3CI nBu~b.9~ f ~~
88
2 Ph(CH2)3Br nBu~'9'"~ 100
3 Ph(CH2)3I nBu~~9~ 68
4 Ph(CH2)3OTs nBu~~.9~ 100
Ph(CH2)3OMs nBu~~~9~ 100
6 Ph CI nHeptyl~.9~100
7 Ph Br nHeptyl~b~9~100
8 Ph I nHeptyi~d.s~95
9 Ph OTf nHeptyl~d~9~100
Ph OMs nHeptyl~d.9~0
11 Ph OTs nHeptyl~d.9~0
12 nHeptylCI Phif.9 70
13 nHeptylBr Ph~e'9~ 100
14 nHeptylI Ph~f~9~ 100
nHeptyiOTs Ph~f.9~ 90
16 nHeptylOMs Ph~f~9~ 87
17 pTolyl CI pMeOCsH4~e~80
18 pTolyl Br pMeOC6H4~e~88
CA 02556850 2006-08-23
43
TABLE 5. EVALUATION OF COMPLEX Ih IN THE NEGISHI REACTION
(CONTINUED)
Entry R~ X R~~ Yield [%f
a~
19 pTolyl I pMeOC6H4~e~73
20 pTOlyl OTf pMeOC6H4~e~71
21 pTolyl OMs pMeOC6H4~e~0
22 pTolyl OTs pMeOC6H4~e~0
[a] GC yield against calibrated internal standard (undecane) performed in
duplicate. [b] THF:DMI, 2:1. [c] THF:DMI, 1:3. [d] THF:DMI, 1:2, [e] THF:NMP,
2:1. [f] THF:NMP, 1:2. [g] Liar or LiCI (2 equiv relative to the organozinc
reagent) was added. [h] Yield 63% after 24 hours with a catalyst loading of
0.1
mol%
CA 02556850 2006-08-23
44
TABLE 6. EVALUATION OF COMPLEX Ih IN THE NEGISHI REACTION:
SUBSTRATE SCOPE
Complex Ih
(1 mol%)
R'-X + R"-ZnBr/CI R'-R"
(1.6 equiv) THF/NMP or THF/DMI
rt to 60 degrees Celsius, 2h
sps_sps
O CI CN
I / 'N 21, 81 %, X=Br, rt
O 22, 80%, X=Br, rt O
v~ w
O VO
23, 86%, X=Br, rt
v v v v v '~Et
I
24, 87%, X=Br, rt I y
TMS
C CN
'CN
25, 74%, X=CI, rt 26, 70%, X=OTs, rt
sPs_sP2
O~
~ TMs I
27, 87%, X=Br, rt 28, 89%, X-CI, rt
I w I w I w
TMS
'F
29, 92%, X=CI, rt 30, 91 %, X=OTs, rt
CA 02556850 2006-08-23
TABLE 6. EVALUATION OF COMPLEX Ih IN THE NEGISHI REACTION:
SUBSTRATE SCOPE (CONTINUED)
sP2_sPs
NC ~ O I ~ 10
> N OEt
O
31, 81 %, X=OTf, rt 32, 98%, X=CI, rt
F Et0
I I .. ,. I \
O
O
tBu-O O
33, 87%, X=CI, rt
34, 83%, X=Br, rt
CA 02556850 2006-08-23
46
TABLE 6. EVALUATION OF COMPLEX Ih IN THE NEGISHI REACTION:
SUBSTRATE SCOPE (CONTINUED)
sp2-sp2
v
.p , ~ ° r I ,
35, 90 /°, X=CI, 60 degrees Celsius
I
o I i i
I
38, 96%, X=Br, rt
36, 89%, X=CI, 60 degrees Celsius
Ph
N=N
37, 96%, X=CI, rt
F
w i ~
SN~ I \ I \ p ~ \N"CN
'N~ ~ ~ ~ p I i
39, 90%, X=Br, rt 40, 98%, X=OTf, rt 41, 90%, X=CI, rt
CA 02556850 2006-08-23
47
TABLE 7. EVALUATION OF COMPLEX Ih IN THE BUCHWALD-HARTWIG
REACTION: SUBSTRATE SCOPE
Ar-X + R~- NH {R~) R(R~ ) N - Ar
X= CI, Br, I, OTf 1.2 Equiv
CF3 0 ~O
N NJ
~N N /
o~ G
60% rt 24hrs 87%, rt, 24hrs
92%, rt, 24hrs CI ' ' Cl, Sodmm tert-butixide
Cl
H
N
H
N NJ ~ N ~ ~ /
/
83%, rt, 24hrs 90%, rt, 24hrs 78%, rt: 24 hrs
Cl Cl, Sodium-tent-butoxide CI, Sodmm-tert-butoxide
I
O \
/\N ~ ~ \ \
O~ ~ / N~N N- -/
87%, rt, 24hrs H ~ ~
CI 88%, 50°C, 24hrs
Cl, Sodium tort-butoxide 96%, SO°C, 48hrs
Cl, Sodium tert-butoxide
~N~ o
i ~N
N
N.H ~ ~N NJ
,- ~,N
~ ~ \ N\N \ /
i
45%, rt, 24hrs 70%, 80°C, 24
CI 37%, SO°C, 24hrs hrs, Cl, Cs2C03
CI, Sodium tent-butoxide
CA 02556850 2006-08-23
48
TABLE 8. EVALUATION OF COMPLEX Ih IN THE KUMADA REACTION:
SUBSTRATE SCOPE
Ih
2 mol%
RtX + Rz-Mg7C Rt__Rz
Solvent, 50 °C
THF:DMI, 2:1
Me0-
I /
62 %, Br
THF:DME, 1:1
\ N - S
S~ \ / I ~ \ /
90 %, CI, 2.6 LiCI 81 %, CI, 3.2 LiCI°
THF
Me0 / / I
-\~ \-\
I ~ F3C
86 %, Br
>99 %. CI
/ I / / \
-\ I
\ /
S
92 %, Br
80 %, Br
I / . ~ / N I \
N-
.N I \
70 %, Brb /
90 %, CI
\ \ ~ \ OH
\ N
/
91 %, Br / /
S02Ph
67 %, Br
\ \ OH \
\-~ / /
I 65 %, CI, 70 °C
/
87 %, Br, 70 °C
aModifi~ations from the conditions above are outline immediately below the
product. Reaction conducted using IK (2 mol %). Melded 90% when the reaction
was performed with I K.
CA 02556850 2006-08-23
49
TABLE 8. EVALUATION OF COMPLEX Ih IN THE KUMADA REACTION:
SUBSTRATE SCOPE (CONTINUED)
Ih
2 mol~o
Rt_X + Rz.M9X --~ Ri___Rz
Solvent, RT
THF;DMI, 2:1 THF S
I / - \ / I / / . ~ I / S \ / I ~ \ /
I / 70 %. CI CF3
18 %, CI 90 %. CI ' I \
S 64 96, Br \ \ \ /
I/-\ / Meo / I/ /. ~ I/
60 %. Br N~ \ ' \ I I / 8. 90 %, CI
S ~
Me0 / ~N~
93 ~, Br I \
I 60 96, Br \ \ /
l \ .~ I / i . _ i N
I S N ~ ,
I \ ~~- \ / ~ I / 85 %. Br. 3.2 LiClb
O~O ~N ~ I / / \
83 96, Br 62 ~, CI
90 %, CI / \
Me0 \ / \
N-N - I \ I / \
Me0 \ / ' \ / Me0 N ' I ~ >99 ~, Br I \ \ / \
65 °~, CI
63 %, CI , SOpPh
OMe N 78 %, Br
i
N S
I 86 ~, c1 / I /
I as
I ~ \ ' \ 85 %, CI
s4 %, c1 ~ / I / ~ I
ss %, c1 ~N \ \
~0~0 77 %, er I
THF:DME,1:1 / , , S
Me0 _ S CI N
N~ \ - \ I Me0 S / \ I 85 %, CI
/ \ / S~ ~ S 81 %, Br CI
N I / \ / OMe \
70 %. C1° 18, 74 °Yo, Br ' \ I S ~ I /
Me0 87 %, Br
\ \
\ N Me0 67 %, CI I / S S /
/ 90 %, Br 87 %, Br
91 %, Br / S Ph
. \
N 87 %, CI
N I ~N ~ I
I / ' N N / I
a.~_ \ I I
97 %, CI - S \ CN I/
62 %, c1
79 %, CI 83 %. Br 79 9b, Br
aModifications from the conditions above are outline immediately below the
product.
bReaction conducted using IK (2 mol %). 'Yielded 90% when the reaction was
performed with IK.
CA 02556850 2006-08-23
TABLE 9: BIS-PINICOL BORANE REACTION RESULTS
O.B_BO + (X r_Br) ---, Ar_BO
O O O
EntryProduct CatalystSolvent Time Yield ['~fa~
mol
1 ~ 2 DMSO 20 52
O
I i
2 ~ 3 DMSO 17 60
O
I i
3 3 DMF 17 64
~
O
i
4 ~ 2 DMSO 15 min 36
O
I i
5 3 DMSO 20 58
~
O
'O
i
NC~
CA 02556850 2006-08-23
51
TABLE 9 (Continued)
Entry Product CatalystSolvent Time Yield [%fa~
mol
6 3 DMSO 20 58
~
O
i
a
~N
7 ~ 3 DMSO 19 65
O
B'O
i
02N
8 \ ~ 3 DMSO 42 57
O
w B.O
i
aYield is reported on material that has been purified by flash chromatography
on silica gel.
