Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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REDUCTION OF AROMATIC HALOGENIDES
The invention concerns a method for the reduction of aromatic halides.
Several methods for the reduction of aromatic halides are known.
For the reduction of aromatic halides, reducing agents such as
Cr(CI04)2/ethylene diamine
[880SCol 16/821], Sn/HBr [SSOSColl3/132], catalytic reduction with Raney
nickel
[9I CE~C 109] or Pd/hydrazine hydrate [59JOC421 ], reducing agents such as K-
selectride/CuJ
[77CC762], NaBH4/(Me3Si)3SiH [89TL2733], LiAlH4 [83JA631, 82TL1643, 59JOC917,
59JOC917, 89TH3329] or similar complex hydrides such as LiAlH4(OMe)3/CuJ
[73JA6452]
are known. The reducing agent lithium aluminum hydride has often been used
together with
anorganic halides in catalytic or stoechiometric amounts, such as CeCI3
[85CL1491], TiCl4
[73CL291], FeCl2, CoCl2, TiCl3, NiCl2 [78JOC1263], or else other reducing
agents were
generated by these additions. In reducing aromatic halides, known variants of
the use of
LiAlH4 are simultaneous photoirradiation [83CC907] or ultrasound [82TL1643].
The codes
in square brackets refer to the list of literature references.
In B. Meunier, "Reduction of aromatic halides with sodium borohydrate
catalysed by titanium
complexes. Unexpected role of air" in Journal of Organometallic Chemistry,
vol. 204(3),
345-346 [January 20, 1981, Lausanne, Switzerland]) a method for reducing
aromatic
halogenides is described in which NaBH4 which is catalyzed by Cp2TiC12 or
CpTiCl3 in the
presence of air. However only iodinated aromates are reduced by this known
process, since
for instance bromine and chlorine are not reduced.
In EP 0 370 325 A a method for the reductive dehalogenation of aromates by
treatment of the
halogenated aromates with Raney nickel and alkali formate in an aqueous
alkaline medium, at
80 - 250°C and 1 to 100 bar is described. The presence of air in the
reaction vessel is not
excluded by this state of the art.
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J. Szewcyk "An improved synthesis of galanthamine", Journal of Heterocyclic
Chemistry Vol.
25 Nr. 6, 199, p. 1809-1811 describes a process for debromination of
bromoformylnarwedine in
an amount of 3.0 grams by by boiling in THF for 12 hours under reflux. In this
way a mixture of
galanthamine and epigalanthamine is obtained with a 53% yield. The presence of
air is not
explicitly excluded in this literature document.
In spite of the number of known methods, in practice cases keep occurring
where reduction with
LiAlH4 proceeds slowly and/or with unsatisfactory yield. In spite of extending
the reaction times,
using a larger molar excess of LiAlH4, change of solvents (e.g.,
tetrahydrofuran instead of
diethylether), or increasing the reaction temperature especially larger
starting volumes often
create problems, reduced yields and side reactions. Frequently, other
additional substituents that
are present in the compound that is subjected to reduction are not compatible
with catalytic
reduction methods or hydrogen in statu nascendi. Other complex hydrides or
hydride reagents
are often not reactive enough in comparison with LiAlH4 to reduce aromatic
halogenides in
satisfactory yields.
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The invention allows to employ many reducing agents. Examples for reducing
agents that can be
used are: hydride reagents such as DiBAL-H (diisobutylaluminum hydride), DiBAL-
H/ZnCl2,
Al-isopropylate, Red-Al ~ (sodium bis-(2-methoxyethoxy)aluminum hydride
(Aldrich)), K-
selectride~ (potassium-tri-sec. butyl borohydride (Aldrich), L-selectrideC~
(lithium-tri-sec. butyl
borohydride (Aldrich)), KS-selectride~ (potassium-tri-siamyl borohydride
(Aldrich)), LS-
selectride~ (lithium-tri-siamyl borohydride (Aldrich)), Li-tri-t-butoxy-AlH,
Li-tri-t-ethoxy-A1H,
9BBN (9-boroabicyclo[3.3.1 Jnonan), Super-Hydride~ (lithium
triethylborohydride (Aldrich)),
NaBH4, Zn(BH4)2, A1H3.A1C12H or a combination of these reducing agents, LiAlH4
being
preferred.
The method according to the invention consists in the reduction of
(hetero)aromatic halides with
a reducing agent, in particular LiAlH4, in the presence of oxygen, for
instance of air or a mixture
of oxygen and an inert gas. In contrast to commonly used reaction protocols
for reducing agents
such as LiAlH4, according to which one works under inert gases (for instance,
nitrogen, argon
or helium), oxygen which might be diluted with an inert gas is blown or sucked
through the
reaction mixture by pressure or suction. This allows to shorten the reaction
times, and to increase
the yields reproducibly.
The invention provides an efficient and industrially exploitable method for
the reduction of
(hetero)aromatic halides with a reducing agent, such as LiAlH4, in the
presence of oxygen.
According to the invention, the reduction proceeds for example according to
the following
scheme:
Scheme 1:
LiAlHg/02 -
(Het) Ar - X ---------> (Het) Ar - H
Li.AlH4 /02 .
(Het) Ar - Xn ___-_-___> (Het) Ar - Hn
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The introduction of air, in particular (synthetic) air, into a solution
containing the aromatic halide
and the reducing agent in a solvent the reduction of the aromatic halide
compounds is
significantly accelerated. In many cases it becomes possible to reduce
(hetero)aromatic halides
that are not amenable to reduction by, for example, LiAIH4 alone. Additional
advantages of the
presence of oxygen or air during reduction consist in the higher yields that
are achieved and in
diminished undesired side products, which are created during extended reaction
time (without
oxygen).
Besides the general applicability of the reduction method according to the
invention on the scale
of laboratory synthesis, the process of the invention is particularly suitable
for the reduction of
compounds of the bromonarwedine type (see scheme 2) on the kilogram scale, and
for economic
large-scale reductions.
x
All this is surprising because it was not to be expected that a reduction
would proceed without
problems under oxidant conditions, i.e., in the presence of an oxidant such as
oxygen.
Scheme 2:
CN30 11H4 fyl l~~ f H3~
,..... _ ~ - ~ ~E3
Further examples of reductions performed according to the invention are
represented in the
following scheme 3.
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Scheme 3:
Example: 1-X-naphtaline Example: n-X-thiophene
x H / \-
s x
LiAlH4/OZ / / LiAIH l0
X 4 2
~ ~
S
One of the advantages of the method according to the invention is that the
reaction time for
reducing (hetero)aromatic halides is shortened. To demonstrate this, several
aromatic and
heteroaromatic compounds that were substituted by halogen were reduced with
and without
oxygen in direct comparison, and also varying reaction batch sizes of a
reaction (bromo-
narwedineketal) was investigated with and without oxygen (Table 1).
Table 1:
Compound (batch size, S Product Reaction time in the Reaction time in the
grams) presence of oxygen absence of oxygen
(time required to (time required to
reach >99% turnover reach >99% turnover
as determined by as determined by
HPLC) HPLC)
1-fluoronaphtaline naphtaline8 hours > 16 hours
1-chloronaphtaline naphtaline4 hours > 16 hours
1-bromonaphtaline naphtaline2 hours > 16 hours
1-iodonaphtaline naphtaline1 hour > 16 hours
2-bromothiophene thiophene 2-3 hours 90 hours
3-bromothiophene thiophene 2 hours 29 hours
2-chlorothiophene thiophene 3.5 hours 120 hours
3-chlorothiophene thiophene >5 hours >95 hours
bromoformylnarwedine narwedine 2-3 hours 24 hours
propyleneglycol ketal
(50 g)
bromoformylnarwedine narwedine 3-4 hours >48 hours
propyleneglycol ketal
(200 g)
bromoformylnarwedine narwedine 3-4 hours >14 days
propyleneglycol ketal
(800 g)
bromoformylnarwedine narwedine 3-4 hours Not done
propyleneglycol ketal ( 14 kg)
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Instead of technical grade oxygen, according to the invention mixtures of
oxygen with one or
more inert gases (such as nitrogen, argon or helium) can be used.
In the context of the invention, the introduction of synthetic air
(nitrogen/oxygen mixture 80:20)
into the reaction mixture by external pressure, or the introduction of ambient
air by suction is
preferred. If ambient air sucked through it is preferable to dry the air to
avoid occlusion by
deposits in the introduction pipe. Moist air would consume reducing agents,
such as LiAlH4. In
particular, the danger of spontaneous combustion and explosion cannot be ruled
out with (very)
moist air.
For the reduction of bromonarwedine ketal with LiAlH4 to narwedine on the 50
gram scale, a gas
mixture of 95% N2 and 5% 02 was used, which resulted in completion of the
reaction within 3
hours. Using a mixture of 99% N2 and 1 % 02 with the same batch size gave a
complete reaction
only after 7 hours.
Also, it was found advantageous to pass the air through a gas washing bottle
to saturate the air
with the solvent used (for instance, THF) to avoid loss of solvent by
outblowing that would
otherwise require to replenish solvent constantly. Cooling the condenser unit
to -40°C using
cooling brine also significantly reduces solvent loss.
Experiments have shown that an excess of reducing agent, such as LiAlH4, is
advantageous
because for instance, LiAlH4 is decomposed by air and forms non-reactive
oxides. A sufficient
excess of the reducing agent, such as LiAlH4, should therefor be used to
guarantee the presence
of sufficient amounts of active reducing agent, such as LiAlH4, in the
reaction mixture. Trials
with 1 equivalent of LiAlH4 ( = 4 equivalents of hydride) and monohalogenated
thiophene
compounds have shown incomplete yields, while 2 equivalents gave 100% turnover
without
problems. In contrast, for naphtaline derivatives, in particular 1-bromo- and
1-iodonaphtaline, the
reaction went to completion with 1 equivalent LiAlH4 and air. On the technikum
scale, the
reaction to narwedine could be completed with 1.5 equivalents after 3 hours.
With 1.3
equivalents, complete turnover was still not reached after 6 hours because
this reduction also
requires LiAlH4 to reduce the formyl moiety (Scheme 2).
In the following examples for the method of the invention and comparative
experiments are
described.
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EXAMPLE 1
A solution of 9.7 ml of LiAIH4 (10% in THF; 24 mMol) was added dropwise to a
solution of S
g 1-bromonaphtaline (24 mMol) in 40 ml THF and at SO°C for 4 hours, air
was sucked through
a drying column filled with CaCl2 and a gas washing bottle filled with THF.
After 4 hours, thin-
layer chromatography demonstrated completeness of the reaction. The mixture
was decomposed
by addition of S ml of water and S ml of saturated aquaeous NaHC03, the
precipitate was filtered
off, washed twice with hot THF. The filtrate was evaporated and the resultant
crude product was
recrystallized from ether: 2.42 g of naphtaline as colorless cyrstals (78% of
the theoretical yield).
TLC:
petrol ether (two passages)
Comparative Example 1
A solution of 9.7 ml of LiAlH4 (10% in THF; 24 mMol) was added dropwise to a
solution of S
g 1-bromonaphtaline (24 mMol) in 40 ml THF, and the mixture was stirred at
SO°C under a gentle
argon stream. After 4 hours a thin-layer chromatogram demonstrated 2S% yield
of the reaction.
After 24 hours, SO% yield. Work-up (according to Example 1 above) and column
chromatography
(100 g silicagel 60, hexan) gave 0.95 g bromonaphtaline and 1.2 g naphtaline.
EXAMPLE 2
To a solution of 100 ml THF and S g 1-halogenonaphtaline 1.S equivalents of
LiAIH4 in THF
(10%) were added and the mixture stirred at SO°C. Synthetic air (80%
N2, 20% 02) was
passed through the mixture at a rate of SO ml/min. under vigorous magnetic
stirring. THF was
constantly added dropwise to keep the volume constant. For analysis,
approximately 1 ml
sample was removed, decomposed with S ml of water, and extracted with 2 ml
hexane. The
hexane phase was used for analysis by gas chromatography. About O.S ml of the
organic
phase were into a gas chromatography sample vial using a syringe with a filter
inserted
between the needle and the syringe body, and the remaining volume of the
sample vial was
filled with petrol ether.
Comparative Example 2:
To a solution of 100 ml THF and S g 1-halogenonaphtaline 1.S equivalents of
LiAIH4 in THF
CA 02289992 1999-11-09
( 10%) were added and the mixture stirred at 50°C under N2. For
analysis, approximately 1 ml
sample was removed, decomposed with 5 ml of water, and extracted with 2 ml
hexane. The
hexane phase was used for analysis by gas chromatography. About 0.5 ml of the
organic phase
were pipetted into a gas chromatography sample vial using a syringe with a
filter inserted
between the needle and the syringe body, and the remaining volume of the
sample vial was filled
with petrol ether.
1-fluoro-, 1-chloro-, 1-bromo- and 1-iodonaphtaline were reduced according to
Example 2 and
Comparative Example 2. The results are summarized in Table 2:
TABLE 2:
Reduction of 1-X-naphtaline (X = F, Cl, Br, J)
X Gas 1 hour 2 4 8 l6
hours hours hours hours
Educt oductEductProductEductProductEductProductEductProduct
Pr
F N2 89 11 83 17 80 20 73 27 66 34
02 52 48 29 71 13 87 1 99 -- --
C1 N2 87 13 81 19 77 23 64 36 SO 50
02 26 64 2 98 00 100 -- -- -- --
Br N2 83 17 76 24 70 30 52 48 48 62
02 30 70 1.5 98.5 00 100 -- -- -- --
J N2 52 48 39 61 30 70 18 82 12 88
_
02 1.5 98.200 100 -- -- -- -- -- _-
Remarks to Table 2:
N2 = continuous nitrogen stream through the solution
02 = continuous stream of "synthetic air" (80% N2, 20% 02) through the
solution
Analytical Methods: -
Gas chromatography: HP 5890
Column: Silicagel Permabond OV 1 DF 0.25
Temperature Program: Starting temperature 50° C 1 min.; heating rate
10° C/min.
Retention times:
naphtaline 5.2 min.
1-fluoronaphtaline 6.65 min
1-chloronaphtaline 7.85 min.
1-bromonaphtaline 9.1 min.
1-iodonaphtaline 10.5 min.
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EXAMPLE 3
One (later, 2) equivalents of LiAlH4 solution (1 mMol in THF) was added to 1.0
g of
halogenthiophene in 10 ml anhydrous THF. The mixture was brought to the
specified reaction
temperature and vigorously magnetic stirred with a stirrer while 10-20 ml
synthetic air (N2/02
80:20) were passed through it. After the specified time, 0.5 ml of the
solution were hydrolyzed
with 10 ml 2N HCI, extracted with 2 x 5 ml diethylether, and diluted with 30
ml methanol. This
solution was then directly used for determination of content by HPLC (high-
pressure liquid
chromatography).
Comparative Example 3
One (later 2, ) equivalent of LiAlH4 solution (I Mol in THF) was added to 1.0
g of
halogenothiophene in 10 ml anhydrous THF. The mixture was brought to the
specified reaction
temperature and stirred under N2. After the specified time, 0.5 ml of the
solution were hydrolyzed
with 10 ml 2N HCI, extracted with 2 x 5 ml diethylether, and diluted with 30
ml methanol. This
solution was then directly used for determination of content by HPLC (high-
pressure liquid
chromatography).
N-X-thiophene derivatives were reduced according to the methods described in
Example 3 and
Comparative Example 3. The results are summarized in Table 3.
TABLE 3
Reduction of n-X-thiophene (n = 2,3; X = Cl, Br)
X Gas Temp. Time Time Time Time Time S Remarks
1 2 3 4
(C) (figures in ~)
represent
reaction
yields
2-Br N2 SO 1 hr.: 2 hrs.:17.5 22.5 90 hrs.:
hrs.: hrs.:
23% 46% 83% 96% 100%
02 50 0.5 hrs.:1 hr.: 2 hrs.: 3.25 8.25 hrs.: lack
hrs.: of THF
46% 65% 74% ___ ___ *)
N2 30 1 hr.: 2 hrs.:4 hrs.: 19.25 45.5 hr.:
hr.:
17% 26% 33% 65% 100%
CA 02289992 1999-11-09
g _
02 30 O.S hrs.: 1 hr.:2.25 hrs.:4 hrs::8.25 1 eq. LiAlH4
hrs.:
S2% S8% S8% --- --- consumed
*)
3-Br N2 30 O.S hrs.: 2 hrs.:7.75 hrs.:29 hrs.:----
21 % 31 36% I 00%
%
02 30 O.S hrs.: 1 hr.:2 hrs.: --- ---
74% 100% 100%
2-Cl N2 30 1 hr: 2 hrs.:7.8 hrs.:29 hrs.:120 hrs.:2 eq. LiAlH4
0% 6% 2S% 48% 96% added
02 30 0.1 hrs.: I hr.:2 hrs.: 3.S --- 2 eq. LiAIH4
hrs.:
3S% S9% 94% 100% added
3-Cl N2 30 1 hr.: 3 hrs.:8.S hrs: 32 hrs.:9S hrs.:2 eq. LiAlH4
8% 9% 8% 17% 44% added
02 30 O.S hrs.: 1 hr.:2 hrs.: 4 hrs.:S.S hrs.:2 eq. LiAlH4
12% 21% 36% 42% SO% added
*) Initially, the air stream at SO°C evaporated too much THF. This
reduced the temperature to
30°C. In addition, the oxygen comsumes LiAIH4, so one equivalent LiAlH4
is not enough when
air is used. In subsequent experiments, two equivalents were employed.
Analytical methods: HPLC
Wavelength 23S nm
Injection 20 ul
volume
Mobile phase:MeOH:H20 (7S:2S)
Column: Lichrosorb RP18, 10
micrometer
Flow rate: 0.9 ml/min.
EXAMPLE 4:
Ten liters of THF (H20 < 0.1 %) and 4 kg bromoformylnarwedine-
propyleneglycoketal are filled
into a 301 double-mantle reaction vessel and 101 of LiAlH4 solution (10%) in
THF are slowly
added with mechanical stirring, whereupon massive development of gases occurs
and the mixture
reaches reflux temperature. Synthetic air (80% nitrogen, 20%oxygen) is
introduced at SO°C for
4 hours using a gas introduction tube providing a flow of 101/min.
Subsequently, 1200 ml water
and 1200 ml NaOH (1 S%) are added dropwise (massive development of gases,
reflux), S liters
of toluol are added and stirring continues for 30 min. at 60°C. The
reaction mixture is filtered
CA 02289992 1999-11-09
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through a pressure filter while hot, the precipitate is washed twice with 4 1
ToluoUTHF 1: I at
60°C, the solvent is removed from the combined organic phases using a
SO I rotavapor, the oily
residue is taken up with 1214n HCl and then warmed to 60°C for IS min.
Two extractions with
41 EtOAc follow, and the aqueous phase is added dropwise to 2.4 1 concentrated
NH40H under
vigorous mechanical stirring. The suspension is cooled to 0 - 5°C,
filtered, washed with 2 x 2000
ml water, and dried in vacuum (40 mbar, 70°C): 2104.8 g (80.5% of
theory).
DC: CHCl3/MeOH (9:1 )
HPLC: content >95%
EXAMPLE 5
According to the protocol given in Example 4, bromoformylnarwedine-
propyleneglycolketal was
reduced in batches of varying sizes either in the presence ("with 02" in the
table) or the absence
("without 02") of oxygen. The batch sizes, reaction times and yields are
documented in Table
4.
TABLE 4
Batch SizeReaction Time Yield Reaction Time Yield
(g educt) without 02 (narwedine)(with 02) (narwedine)
g 24 hours 800 2 hours 800
50 g 48 hours 720 2-3 hours 82%
200 g 6 days 56% . 3-4 hours 92%
800 g >14 days 30% 3-4 hours 78%
4 kg --- --- 3-4 hours 800
14 kg --- --- 3-4 hours 760
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The reaction scheme for the process of Examples 4 and 5 ("with 02") is
represented below:
CH C AlH4 CH30 ~ LiAlH4/tl~ CH3(
3 i f
w
r. ~ . HC1 ~
CH30
S
rac. narwedine
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References:
[550SCo113/132] Koelsch, C.F. Org. Synth. Coll. Vol_ III,
132 (1954), Sn/HBr
(59JOC421] Mosby, W.L.J.Org. Chem. 24, 421 (1959),
Pd/NzH4.H20
[59JOC917] Benington, F; Morin, R.D.; Clarck Jr.,
L.C.J.Org., Chem. 24, 917 (1959), LiAlH4
[59JOC917] Szewcyk, J_, Lewin, A.H_; Carrol, F.I.J.
Heterocycl., Chem. 25, 1809 (1988), LiAlH4
am
Bromformylnarwedin 53sI
[73CL291] Mukaiyama, T.; Hayashi, M.; Narasaka,
K.Chem_Lett, 291, (1973) LiAlH4/TiCl4
[73JA6452] Masumane, S.; Rossey, P.A.; Bates, G.S. J.
Am. Chem.Soc. 95, 6452,1973, LiAlH(OMe)3/CuI
[74CC762] Yoshida, T., Negishi, E.J. Chem. Soc_ Chem.
Commun.,762 (1994), K-Selectrid/CuI
[78JOC1263] Ashby, E.C., Lin. J_J.J.Org.Chem_43, 1263
( 1978 ) , LiAlH4/FeCl2 , CoCl2 , TiCl3 ,
NiCl2
[82TL1643] Han, B.H., Boudjouk, P.; Terahedron Lett.
23, 1643 (1982), LiAlH4
(82TL1643] Han, B.H.; Boudjouk, P Tetrahedron Lett.
23,
1643 (1982), LiAlH4/Ultraschall
[83CC907] Beckw~th, L.J. Goh. S.H_ J, Chem.Soc_Chem.
Commun. 907 (1983), LiAlH4/liv
[83JA631] Falck, J.R_ Manna, S.j. Am.Chem.Soc_ 105,
631 (1983), LiAlH4
[880SCo116/82I] Wade, R.S. Castro, C_E. Org.Synth_Coll.Vol.
VI, 821 (1988) , Cr(C104)2/HzN(CHZ)2NH2
(89TL2733] Lesage, M. Chatgilialoglu,. C_ Griller, D.
Tetrahedron Lett: 30, 2733 (1989),
(Me3Si)3SiH
[89TH3329] Vlahov, R. Krikorian, D. Spassov, G_ Chino
va, M;, LiAlH4 an Brom,
Vlahov, I. Parushev, S. Snatzke, G. Ernst
L.
Kieslich, K.,
Abraham, W.-R. Sheldrick, W.S. Tetrahedron
45, 3329 (1989), Galanthaminon 960
[85CL1491] Imamoto, T_- Takeyama, T. Kusumoto, T.
Chem.Lett. 1491, (1985), LiAlH4/CeCl3
f,
CA 02289992 1999-11-09
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[91CEX109] Nishiyama, T. Kameopka, H_ Chem_Express 6
(2) 109,
112 (1991), Raney-Ni/H3
r
