Green asymmetric synthesis of Warfarin and Coumachlor in pure water catalyzed by quinoline-derived 1,2-diamines

Article abstract of DOI:10.1039/c7gc03626d

Simple enantiomerically pure C₂-symmetric quinoline (isoquinoline)-derived 1,2-diamines were synthesized from the corresponding aldehydes via stereospecific diaza-Cope rearrangement with 2,2′-(1,2-diaminoethane-1,2-diyl)diphenol (HPEN). Efficient green synthesis of both enantiomers of the anticoagulant Warfarin and rodenticide Coumachlor was achieved in an aqueous medium via the asymmetric iminium-type Michael reaction in the presence of the catalysts 8e and (ent)-8e in combination with (R)- or (S)-mandelic acid, respectively. This procedure provides high enantioselectivity (up to 91% ee), which has never been attained for these bioactive compounds with the known catalysts under aqueous conditions. Nearly optically pure Warfarin (～99% ee) was prepared via a green isolation procedure, which included acidic precipitation of the crude product from a basic aqueous solution followed by single recrystallization. Furthermore, unlike the known primary amine-derived organocatalysts, the developed aqueous catalytic system does not produce parasitic byproducts and can be recovered and reused in the asymmetric reaction.

Full text of DOI:10.1039/c7gc03626d

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Page 1 of 14
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Green asymmetric synthesis of Warfarin and Coumachlor in pure
water catalyzed by quinoline-derived 1,2-diamines
Alexander S. Kucherenko, Alexey A. Kostenko, Galina M. Zhdankina, Olga Yu. Kuznetsova
and Sergei G. Zlotin*
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky
Prospect, 119991 Moscow, Russia
Abstract: Simple enantiomerically pure C2ꢀsymmetric quinoline (isoquinoline) derived 1,2ꢀ
diamines were synthesized from corresponding aldehydes via stereospecific diazaꢀCope
rearrangement with 2,2'ꢀ(1,2ꢀdiaminoethaneꢀ1,2ꢀdiyl)diphenol (HPEN). Efficient green synthesis
of both enantiomers of anticoagulant Warfarin and rodenticide Coumaclor was achieved in
aqueous medium via asymmetric iminiumꢀtype Michael reaction in the presence of catalysts 8e
and (ent)ꢀ8e in combination with (R)ꢀ or (S)ꢀmandelic acid, respectively. This procedure
provides high enantioselectivity (up to 91% ee), which have never been attained for these
bioactive compounds with the known catalysts under aqueous conditions. Nearly optically pure
warfarin (~99% ee) was prepared via a green isolation procedure which included acidic
precipitation of the crude product from basic aqueous solution followed by a single
recrystallization. Furthermore, unlike the known primaryꢀamineꢀderived organocatalysts, the
developed aqueous catalytic system does not produce parasitic byꢀproducts and can be recovered
and reused in the asymmetric reaction.
Introduction
Water is the unique abundant natural solvent, which is extremely attractive as a
renewable green medium for organic synthesis.1 It allows facile isolation of the products by
simple filtration or extraction and provides significant cost and environment safety benefits.2
Water is especially attractive for the pharmaceutical industry as a prospective substitute for the
organic solvents which can contaminate drug substances, and be difficult to remove. However,
chemical reactions in water have some peculiarities to be taken into account. A majority of the
organic compounds are poorly soluble in water and heterogeneity of reaction systems slows
down mass transfer. Furthermore, the substrate scope is limited to waterꢀtolerant reagents and
specific catalysts.3
1

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Nature successfully adapted to these peculiarities billions of years ago. Highly
enantioselective enzymatic reactions efficiently occur in living organisms in colloid reagent–
water systems affording a number of fantastically complicated natural compounds with absolute
stereoselectivity. Over the past decade, significant advances in waterꢀtolerant organic synthesis
have been associated with extensive application of chiral organocatalysts, which are considered
as manꢀmade analogs of enzymes.4 These catalysts efficiently promote a number of useful
asymmetric reactions (aldol, Michael, Mannich, cycloaddition, etc.) in the presence of water
similar to enzymatic processes.5
Among practically important catalytic reactions is asymmetric conjugate addition of 4ꢀ
hydroxycoumarin (1) to α,βꢀunsaturated ketones 2 giving adducts 3, which exhibit useful
biological activities. Warfarin (Coumadin, Marevan) 3a is one of the most efficient
anticoagulants6 and Coumachlor 3b is used as an anticoagulant rodenticide (Scheme 1). It should
be noted that Warfarin and Coumachlor are marketed as racemates, though (S)ꢀenantiomer of 3a
proved to be 2–5ꢀtimes more active than (R)ꢀenantiomer.7
Scheme 1 Synthesis of Warfarin 3a and Coumachlor 3b
Enantiomerically enriched compounds 3a,b are produced from 1 and 2a,b under catalysis
with chiral amines, in particular transꢀ1,2ꢀdiamines (commonly, C2ꢀsymmetrical)8 and their
derivatives9, αꢀamino amides,10 and some other aminocatalysts.11 These catalytic reactions
proceed with fairly good enantioselectivity in organic solvents (PhMe, THF, DCM, tBuOH, etc.)
containing acidic additives. However, in aqueous medium the optical purity of generated (S)ꢀ3a
was significantly lower (29% ee in the presence of bisꢀprolinamide 410 and 68–75% ee in the
presence of transꢀ(1S,2S)ꢀdiphenylethanediamine (DPEDA) 5/AcOH (or BzOH) catalytic
system).8b The ee value of 3a could be improved by subsequent recrystallization of the crude
product from hexane; however, at the expense of a reduced yield (Scheme 2).
2

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Scheme 2 Research strategy
Herein, we report a new efficient approach for stereocontrolled asymmetric reactions
between 1 and 2 in the aqueous medium using C2ꢀsymmetrical primary amineꢀderived
organocatalysts bearing sterically hindered quinoline fragments at the αꢀpositions with respect to
the amino groups (Scheme 2). We expected these bulky fragments would protect more
efficiently asymmetric transition state from undesirable concurrent nonꢀselective hydrogen
bonding with water.12 Furthermore, formation of properly located hydrogen bond between the
sp2ꢀhybridized quinoline nitrogen atom and the iminium cation proton could make the transition
state more rigid and improve the enantioselectivity.8a Finally, enhanced hydrophilicity of the
quinolineꢀderived diamines via their protonation with acidic coꢀcatalysts (in particular, chiral)
might reduce their leaching to the organic phase during workup and improve the efficiency of the
recycling of the catalytic system.
Results and discussion
Enantiomerically pure C2ꢀsymmetric bis(quinoline)ethylenediamines have not been reported so
far. We synthesized these diamines by a stereospecific diazaꢀCope rearrangement using chiral
2,2'ꢀ(1,2ꢀdiaminoethaneꢀ1,2ꢀdiyl)diphenol (HPEN) as an efficient stereoinductor. This highly
diastereoselective reaction13 affords excellent results for aromatic aldehydes and, as we recently
reported, can be used for stereospecific synthesis of optically pure diphenylethylenediamine
(DPEDA) pyridine analogs.14
Isomeric quinoline aldehydes 6a, c, d, e and isoquinoline 6b readily underwent
rearrangement with ((R,R)ꢀ or (S,S)ꢀHPEN) affording Schiff bases 7aꢀe with excellent
enantiomeric purity (>99% ee, HPLC data) (Scheme 3). Subsequent acidic hydrolysis
(HCl/THF) of diimines 7bꢀe followed by a oneꢀpot neutralization of generated hydrochlorides
3

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with aqueous sodium hydroxide gave enantiomerically pure (>99% ee) transꢀ1,2ꢀdiamines 8b-e
in 85ꢀ90% yields.
Scheme 3 Synthesis of diimines 7a-e and C2ꢀsymmetric diamines 8bꢀe.
The products isolated from the reaction mixture by simple filtration did not require
further chromatographic purification. The reactions are readily scalable and allow a facile
synthesis of chiral diamines 8bꢀe (as free bases) in gramꢀscale amounts over a single batch (Fig.
1). The hydrochloride 8a.4HCl produced by acidic hydrolysis of diimine 7a, appeared to be
rather unstable and underwent fast oligomerization on treatment with NaOH or even under a
baseꢀfree condition (NMRꢀtube, DMSOꢀd6, ambient temperature, ~6 h).
4

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Fig. 1 C2ꢀSymmetric transꢀ1,2ꢀdiamines 8a 4HCl and 8b-h.
At first, we examined catalytic performance of these prepared quinolineꢀderived diamines
8b-e (10 mol.%) and, for a comparison, of the known transꢀ1,2ꢀdiamines (R,R)ꢀ8f15, (S,S)ꢀ8g,14
and (S,S)ꢀ8h13c bearing the pyridine and naphthalene structural fragments, respectively, in the
asymmetric Michael reaction between 4ꢀhydroxycoumarin 1 and α,βꢀunsaturated ketone 2a (1.2
equiv.). The catalytic reactions were carried out in pure water at ambient temperature (Table 1,
entries 1ꢀ7). The highest yield (75%) of product (S)ꢀ3a and promising enantioselectivity of the
catalytic reaction (86% ee) were achieved in the presence of compound (S,S)ꢀ8e bearing the 1,2ꢀ
diaminoethane spacer bound to the Cꢀ8 quinoline atoms (Entry 4). Isomeric quinolineꢀderived
diamines 8b-d and their pyridineꢀ or naphthalineꢀbased analogs 8f-h were found to be inferior
activators and stereoinductors in the aqueous medium (Entries 1ꢀ3 and 5ꢀ7). The (S,S)ꢀ8eꢀ
catalyzed reaction in organic solvents (THF, DCM or iꢀPrOH) afforded (S)ꢀ3a in a somewhat
better yield (Entry 4, data in parenthesis). However, in this case the enantioselectivity was led to
noticeably lower than in aqueous medium.
Next, to optimize the reaction conditions, we studied the (S,S)ꢀ8e (10 mol.%) catalyzed
reaction between compounds 1 and 2a in the presence of acidic additives, in particular acetic,
tartaric (TA) or mandelic (MA) acids (20 mol.% of each). Acetic acid and both enantiomers of
TA negatively affected productivity and enantioselectivity of the asymmetric Michael reaction in
aqueous medium (Table 1, entries 8ꢀ10). However, the (S)ꢀMA additive noticeably improved the
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(S)ꢀ3a yield (Entries 11 vs. 4). Moreover, in the presence of (R)ꢀMA, Michael adduct (S)ꢀ3a was
generated with enantioselectivity 91% ee, which had not been attained for this substrate in
aqueous medium so far (Entry 12). Enantiomeric catalytic system (R,R)ꢀ8e/(S)ꢀMA afforded
antipode (R)ꢀ3a with enantioselectivity 92% ee (Entry 13). The twice reduced (S,S)-8e and (R)ꢀ
MA loadings (5 mol.% and 10 mol.%, respectively) noticeably deteriorated productivity and
stereoinduction of the catalytic reaction (Entry 14). Both reducing or enhancing the (S,S)-8e (10
mol.%)/(R)ꢀMA molar ratio (to 1:1 or 1:3) also exerted a negative effect on the reaction outcome
(Entries 15 and 16). The proposed aqueous catalytic system (S,S)ꢀ8e/(R)ꢀMA appeared to be
useful for asymmetric synthesis of Coumachlor 3b. The (S)ꢀenantiomer of 3b was obtained here
with enantioselectivity of 85% ee. However, to attain a 65% product yield, this reaction should
o
be performed at 50 C to improve the heterogeneous reaction rate (Entry 17). The antipode (R)ꢀ
3b was also readily attainable in the presence of (R,R)ꢀ8e/(S)ꢀMA with similar yield and ee
values (Entry 18). The methodology could be extended to other linear or cyclic α,βꢀunsaturated
ketones. pꢀMethoxybenzylideneacetone 2c and cyclohexenone 2d reacted with 1 in the presence
of (S,S)ꢀ8e/(R)ꢀMA to give corresponding Michael adducts 3c and 3e in the aqueous medium,
though with noticeably lower yield or enantioselectivity (Entries 19 and 20). The absolute (S)ꢀ
configuration of target drug 3a was confirmed basing on comparison of optical rotation
20
determined for prepared samples with enantiomeric purity 91% ee [αD ꢀ9.46 (c 1, MeCN)] or
20
98.6% ee [αD ꢀ10.45 (c 1, MeCN)] with reported data8b for the >99% ee sample [αD20 ꢀ10.7 (c
1, MeCN)]. Similar (S)ꢀconfiguration was assigned to compounds 3b-d by analogy. The
developed procedure is scalable. A 17ꢀfold increase in the substrate and catalyst amounts has no
negative effect on stereoinduction, though a slightly reduced productivity of the catalytic
reaction was recorded (Entry 12, data in parentheses).
Table 1 Asymmetric catalytic syntheses of Warfarin and Coumachlor in pure watera
OH
OH R1
O
8 (10 mol.%),
(Additive, 20 mol.%)
*
O
R2
+
R1
R2
H2O, r.t., 24 h
O
O
O
O
1 (1 equiv.)
3a-d
2a-d (1.2 equiv.)
Entry
2 (R1, R2)
2a (Ph, Me)
2a (Ph, Me)
Additiveb Yield of 3, %c
ee of 3, %d
44 (S)
Cat
1
2
(S,S)-8b
(S,S)-8c
ꢀ
ꢀ
3a, 50
3a, 65
51 (S)
6

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3
4
(S,S)-8d
(S,S)-8e
2a (Ph, Me)
ꢀ
ꢀ
3a, 68
48 (S)
3a, 75 (76e,
86 (80e, 78f, 72g)
2a (Ph, Me)
82f, 90g)
(S)
5
6
(R,R)-8f
(S,S)-8g
(S,S)-8h
(S,S)-8e
(S,S)-8e
(S,S)-8e
(S,S)-8e
(S,S)-8e
(R,R)ꢀ8e
(S,S)-8e
(S,S)-8e
(S,S)-8e
(S,S)-8e
(R,R)ꢀ8e
2a (Ph, Me)
2a (Ph, Me)
ꢀ
3a, 48
3a, 52
43 (S)
39 (S)
74 (S)
64 (S)
49 (S)
56 (S)
84 (S)
91 (90h) (S)
92 (R)
86 (S)
79 (S)
86 (S)
85 (S)
84 (R)
80 (S)
51 (S)
ꢀ
7
2a (Ph, Me)
ꢀ
3a, 42
8
2a (Ph, Me)
AcOH
(S,S)ꢀTA
(R,R)ꢀTA
(S)ꢀMA
(R)ꢀMA
(S)ꢀMA
(R)ꢀMA
(R)ꢀMA
(R)ꢀMA
(R)ꢀMA
(S)ꢀMA
(R)ꢀMA
(R)ꢀMA
3a, 68
9
2a (Ph, Me)
3a, 42
10
11
12
13
14i
15j
16k
17l
18l
19m
20n
2a (Ph, Me)
3a, 45
2a (Ph, Me)
3a, 85
2a (Ph, Me)
3a, 86 (80h)
entꢀ3a, 82
3a, 64
2a (Ph, Me)
2a (Ph, Me)
2a (Ph, Me)
3a, 74
2a (Ph, Me)
3a, 72
2b (4ꢀClC6H4, Me)
2b (4ꢀClC6H4, Me)
3b, 65
entꢀ3b, 67
3c, 45
(S,S)-8e 2c (4ꢀMeOC6H4, Me)
(S,S)-8e 2d (ꢀ(CH2)3ꢀ)
3d, 80
aUnless otherwise specified, the reactions were carried out with catalyst 8 (0.06 mmol), 4ꢀ
hydroxycoumarin 1 (97.2 mg, 0.60 mmol), 2a (105.1 mg, 0.72 mmol), additive (0.12 mmol), and water
(2.0 mL) at r.t. bTA – tartaric acid, MA – mandelic acid. сIsolated yield. dHPLC data were obtained on the
f
chiral phase CHIRALPAC ADꢀH. eData for the corresponding reaction in THF. Data for the
g
h
corresponding reaction in DCM. Data for the corresponding reaction in iꢀPrOH. The reaction was
carried out with (S,S)-8e (314 mg, 1.0 mmol), 1 (1.62 g, 10.0 mmol), 2a (1.75 g, 12.0 mmol), (R)ꢀMA
i
(304 mg, 2.0 mmol), and water (30.0 mL). The reaction was carried out with catalyst (S,S)-8e (9.42 mg,
0.03 mmol), 4ꢀhydroxycoumarin 1 (97.2 mg, 0.60 mmol), 2a (105.1 mg, 0.72 mmol), (R)ꢀMA (9.12 mg,
0.06 mmol), and water (2.0 mL) at r.t. jThe reaction was carried out with (S,S)-8e (10 mol.%) and (R)ꢀMA
k
l
(10 mol.%). The reaction was carried out with (S,S)-8e (10 mol.%) and (R)ꢀMA (30 mol.%). The
o
m
reaction was carried with 2b (130 mg, 0.72 mmol) at 50 C for 24 h. The reaction was carried with 2c
(126.7 mg, 0.72 mmol) at 50 oC for 48 h. nThe reaction was carried with 2d (70.0 mg, 0.72 mmol) at r.t.
for 24 h.
The 8eꢀcatalyzed reactions between substrates 1 and 2, which are poorly soluble in water
at ambient temperature, proceeded under heterogeneous conditions. A finely powdered
dispersion of 1, 2a, (S,S)-8e, and (R)ꢀMA in water was generated in 10 min after the reaction
start (Fig. 2a). However, over 6 h a significant agglomeration of the dispersed solid particles was
observed (Fig. 2b). The ripening was completed in 24 h to afford a readily separable twoꢀphase
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solid/liquid system (Fig. 2c). Resulting medication 3a could be isolated from this system in two
ways. The first one included extraction of solid organic phase with EtOAc followed by
purification of 3a by conventional flash chromatography on silica gel to afford Warfarin in 80%
yield with 91% ee. The second more convenient way comprised a simple decantation of the
aqueous phase bearing (S,S)-8e and (R)ꢀMA followed by a dissolution of remained organic
product in 1M aqueous NaOH as Warfarin sodium salt (actually, Warfarin is marketed by some
pharmaceutical companies as sodium salt). Solid impurities were filtered off the basic solution
and the product was reꢀprecipitated by aqueous HCl, dried in vacuo and reꢀcrystallized from nꢀ
hexaneꢀEtOAc (3/1) to produce pure Warfarin in 70% yield with 98.6% ee which is commonly
acceptable to chiral pharmaceuticals (for details see Supporting Information). The latter
procedure is much greener. It eliminates undesirable column chromatography and significantly
reduces process mass intensity (PMI 108 vs. 280 g/g). Obviously, the efficiency of the process
could further improved by recycling of water and organic mother solution. Both workups
allowed recovery of the (S,S)-8e / (R)ꢀMA clear aqueous solution after the catalytic reaction
(Fig. 2d).
(a)
(b)
(c)
(d)
Fig. 2 Evolution of the heterogeneous catalytic system in the (S,S)-8e/(R)ꢀMAꢀcatalyzed
asymmetric reaction between compounds 1 and 2a in pure water. (a) 10 min after the reaction
start; (b) 6 h after the reaction start; (c) 24 h after the reaction start (the reaction is completed);
(d) after isolation of product.
This aqueous solution could be used again for enantioselective catalysis of the
asymmetric Michael reaction between compounds 1 and 2a. After addition of fresh substrates,
adduct (S)ꢀ3a was generated over the same period (24 h) with similar enantioselectivity in
slightly reduced yield (Table 2, entries 1 and 2). It should be noted that the system (S,S)-8e/(R)ꢀ
MA exhibited much lower catalytic activity in THF after the first regeneration (Entries 1 and 2,
data in parenthesis), which testifies the favorable impact of water on the catalytic reaction.
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However, the aqueous catalytic system also deactivated over the 3rd and the 4th cycles (Entries 3
and 4).
Table 2 Recycling of catalytic system (S,S)-8e/(R)ꢀMA in the reaction between 1 and 2a
Cycles
1a
T, h
24
Isolated yield of 3a, %
ee, %
90 (84b)
89 (82b)
90
80 (82b)
75 (46b)
60
2c
24
3c
30
4c
48
32
87
5d
24
70
87
aThe reaction was carried out with (S,S)-8e (314 mg, 1.0 mmol), 1 (1.62 g, 10.0 mmol), 2a (1.75 g, 12.0
b
mmol), (R)ꢀMA (304 mg, 2.0 mmol), and water (30.0 mL) at r.t. Data for the corresponding reaction in
THF are given in parenthesis. сFresh portions of 1 (1.62 g, 10.0 mmol) and 2a (1.75 g, 12.0 mmol) were
added to the aqueous catalytic system recovered from the previous cycle and the reaction was reꢀ
d
performed. Fresh portions of 1 (235 mg, 1.45 mmol) and 2a (253 mg, 1.74 mmol) were added to a
1
solution of the catalytic system (S,S)-8e/(R)ꢀMA (90 mg, ~1:3 molar ratio according to H NMR)
recovered from the 4th cycle and the reaction was reꢀperformed in water (4.0 mL).
1
To identify a reason for this deactivation, we compared H NMR spectra of a freshly
prepared catalyst (Fig. 3, upper spectra) and the recovered catalyst sample that operated over 4
cycles (Fig. 3, lower spectra). Both spectra were clear and contained only signals of compounds
(S,S)-8e and (R)ꢀMA. However, the molar ratio (S,S)-8e/(R)ꢀMA changed from 1:2 in the fresh
catalyst sample to 1:3 in the trice recovered sample. This difference may be attributed to
different solubility of 8e and MA in EtOAc used for extraction of product during workup.
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2H (H3)
Fig. 3. Fragment of 1H NMRꢀspectra of fresh (upper) and four times recovered (lower) aqueous
catalytic system (S,S)-8e/(R)ꢀMA (300 MHz, DMSOꢀd6).
The ESIꢀHRMS spectra of aqueous solutions produced in the 1st and the 4th cycles
contained only the peaks of protonated product [3a + H]+ (m/z 309.1210) and catalyst [8e + H]+
(m/z 315.1592) (Fig. 4, line 1). However, the ESIꢀHRMS spectrum of the reaction mixture
generated in a similar Michael reaction performed in THF (Figure 4, line 2) was different. It
contained the peaks of iminium cation Im (m/z 444.2299) and protonated isomeric intermediates
AꢀB (m/z 605.2545), which were recorded neither in aqueous solution nor in the corresponding
organic (EtOAc) extract.
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N
N
N
N
N
N
H3N
NH
H3N
N
H3N
N H
Ph
HO
O
Ph
Ph
O
O
O
O
Im
A
B
Fig. 4 ESIꢀHRMS spectra of the aqueous solution after the 4th cycle (line 1) and of the reaction
mixture generated in the corresponding Michael reaction performed in THF after the 2nd cycle
(line 2).
Similar iminium and hemiaminal species are considered as parasitic byꢀproducts
responsible for deactivation of primary amineꢀderived supported organocatalysts in iminium type
asymmetric Michael reactions.16 Their absence under aqueous conditions may be attributed to
fast hydrolytic cleavage restoring active catalyst 8e. Most likely, in this case gradual deactivation
of catalyst 8e is caused by its leaching into the organic solution (EtOAc) during workup. Indeed,
only 15% of the initial catalyst amount (618 mg) was left in the reaction flask after evaporation
of the aqueous solution obtained in the 4th cycle. Importantly, the reaction rate and product yield
were significantly improved in the 5th cycle, where reagent loadings were corrected (reduced) in
accordance with the real catalyst content (Table 2, entry 5). According to our knowledge, this is
the first example of sustainable iminium catalysis with a primary amine organocatalyst in an
aqueous environment.
Conclusions
Novel enantiomerically pure C2ꢀsymmetric quinoline (isoquinoline) derived 1,2ꢀdiamines were
synthesized via stereospecific diazaꢀCope rearrangement. Catalysts 8e and (ent)ꢀ8e in
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combination with (R)ꢀ or (S)ꢀmandelic acid, respectively, enabled efficient green synthesis of
both enantiomers of anticoagulant Warfarin and rodenticide Coumaclor in aqueous medium via
iminiumꢀtype Michael reaction with enantioselectivity up to 91% ee, which had never been
attained with known catalysts under aqueous conditions. Nearly optically pure warfarin (~99%
ee) was prepared via a green isolation procedure which included acidic precipitation of the crude
product from basic aqueous solution followed by a single recrystallization. Furthermore, unlike
known primary amineꢀderived organocatalysts, the developed aqueous catalytic system appeared
to be stable and could be recovered and reused. Studies focused on the use of the developed
catalysts and their derivatives in other green catalytic transformations are currently under way in
our laboratory.
Conflicts of interest
There are no conflicts to declare.
Acknowledgment
This research was financially supported by the Russian Science Foundation (Project 16ꢀ13ꢀ
10470).
Notes and references
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