Chiral primary amine tagged to ionic group as reusable organocatalyst for asymmetric Michael reactions of C-nucleophiles with α,β-unsaturated ketones

Article abstract of DOI:10.1002/adsc.201200338

The first primary amine-derived organocatalyst modified with an ionic group for asymmetric Michael reactions of C-nucleophiles with α,β- unsaturated ketones was synthesized. In the presence of this catalyst and an acidic co-catalyst (AcOH), hydroxycoumarin and its sulfur-containing analogue reacted with benzylideneacetone derivatives or cyclohexenone to afford the corresponding Michael adducts in high yields (up to 97%) and with reasonable enantioselectivity (up to 80%). The catalyst could be easily recovered and efficiently reused three times, afterwards, its activity and stereodifferentiating ability gradually declined. The analysis of recovered catalyst samples by ESI-MS allowed us to detect undesirable side reactions that poisoned the catalyst, and propose an approach for its reactivation. Copyright

Full text of DOI:10.1002/adsc.201200338

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DOI: 10.1002/adsc.201200338
Chiral Primary Amine Tagged to Ionic Group as Reusable
Organocatalyst for Asymmetric Michael Reactions of
C-Nucleophiles with a,b-Unsaturated Ketones
Alexander S. Kucherenko,a Dmitry E. Siyutkin,a Albert G. Nigmatov,a
Alexander O. Chizhov,a and Sergei G. Zlotina,*
a
N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prospect, 119991 Moscow,
Russia
Fax : (+7)-499-135-5328; phone: (+7)-499-137-1353; e-mail: zlotin@ioc.ac.ru
Received: April 20, 2012; Revised: July 6, 2012; Published online: November 4, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200338.
Abstract: The first primary amine-derived organoca- easily recovered and efficiently reused three times,
talyst modified with an ionic group for asymmetric afterwards, its activity and stereodifferentiating abili-
Michael reactions of C-nucleophiles with a,b-unsatu- ty gradually declined. The analysis of recovered cata-
rated ketones was synthesized. In the presence of lyst samples by ESI-MS allowed us to detect undesir-
this catalyst and an acidic co-catalyst (AcOH), hy- able side reactions that poisoned the catalyst, and
droxycoumarin and its sulfur-containing analogue re- propose an approach for its reactivation.
acted with benzylideneacetone derivatives or cyclo-
hexenone to afford the corresponding Michael ad- Keywords: asymmetric Michael reaction; ESI-MS;
ducts in high yields (up to 97%) and with reasonable hydroxycoumarin; organocatalysis; reusable organo-
enantioselectivity (up to 80%). The catalyst could be catalysts; a,b-unsaturated ketones; warfarin
Introduction
cleophiles to a,b-unsaturated carbonyl compounds, in-
volving an iminium ion formation step, allow the
Asymmetric organocatalysis is a rapidly developing simple and efficient synthesis of a series of clinically
area of organic chemistry.[1] In the presence of low- useful medications or key intermediates for their
molecular organic catalysts, prochiral compounds can preparation.[11] Recently, Hansen, Ni, Pericꢀs, Schore,
be converted to enantiomerically enriched products Zeitler and our group independently synthesized im-
without using auxiliary chiral groups.[2] Moreover, or- mobilized forms of the most popular catalysts for
ganocatalysts are extremely attractive to pharmacolo- these reactions, a,a-diarylprolinol silyl ethers, by tag-
gy as they, unlike organometal catalysts, do not cause ging them to polymeric[12] or ionic groups.[13] Thus pre-
a contamination leading to the production of medica- pared catalysts 1 and 2 (Figure 1) could be easily re-
tions with toxic metals.[3] However, in spite of evident covered and reused in the same reaction up to 10
attractiveness, organocatalysts have not been much times[14] without a significant decrease of conversion
used in the chemical or pharmaceutical industry so or enantioselectivity values. In the presence of some
far. Modern organocatalysts based on imidazolidin-
ACHTUNGTRENNUNG
ones,[4] alkaloids,[5] amino acid derivatives,[6] other
types of chiral compounds[7] are rather expensive.
Normally, they are needed in significant amounts (10–
20 mol%) which are lost during product isolation,
therefore, the development of reusable versions of or-
ganocatalysts remains a challenge.[8]
Organocatalytic Michael reactions[9] along with cor-
responding aldol reactions[10] are extensively used for
enantioselective formation of carbon-carbon bonds in
Figure 1. Modified organocatalysts of asymmetric Michael
reactions between C-nucleophiles and a,b-unsaturated alde-
organic compounds. Among them, additions of C-nu- hydes (PG=polymeric group, IG=ionic group).
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Chiral Primary Amine Tagged to Ionic Group as Reusable Organocatalyst
Figure 2. Primary 1,2-diamine-derived organocatalysts modified with dendritic, fluorinated or ionic groups (DG=dendritic
group, PS=polystyrene, RF =n-C8H17).
catalysts, the reaction can be carried out as a continu-
ous flow process.[15]
We assumed that primary b-diamine derivatives 5,
bearing an ionic group remote from the catalytic site,
However, bulky a,a-diarylprolinol-type organocata- would behave better in asymmetric reactions between
lysts, being rather efficient in reactions of C-nucleo- C-nucleophiles and a,b-unsaturated ketones
philes with a,b-unsaturated aldehydes, appeared to be (Figure 2). It might be expected that the remote ionic
nearly inactive in the corresponding reactions involv- moiety, on the one hand, would reduce solubility of
ing a,b-unsaturated ketones, presumably, because of catalyst 5 in organic solvents and facilitate its recov-
special hindrances for iminium ion formation.[16] In ery and, on the other hand, would not significantly
this case, less special hindered primary amine deriva- change the energy of the transition state and deterio-
tives, especially compounds bearing a properly locat- rate the stereochemical outcome of reactions.
ed auxiliary H-donor, such as amino[17] or hydroxy
groups[18] (bifunctional catalysis[19]), exhibit better cat-
alytic performance. However, recently reported re- Results and Discussion
coverable catalysts of type 3 (Figure 2), modified with
dendritic[20] or perfluoroalkyl[21] groups, the synthesis To verify this hypothesis, we synthesized 1(R),2(R)-di-
of which is rather complicated, have not been used in aminocyclohexane 6 and 1(S),2(S)-diaminodiphenyl-
Michael additions of C-nucleophiles to a,b-unsaturat- ethane 7 derivatives modified with the 1-methylimida-
ed ketones up to now. Protonated with sulfated poly- zolium cation, the latter being linked with the nearest
À
styrene, the diamine 4 failed to catalyze asymmetric stereocenter by a spacer containing four C C and
Michael reactions.[22]
three C N bonds (Scheme 1). Starting chiral diamines
À
À
Scheme 1. Synthesis of primary amine-derived organocatalysts 6 and 7 modified with the imidazolium cation and PF6 anion.
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8 and 9 were obtained by fractional crystallization of useful for the synthesis of other chiral diamine-de-
corresponding diastereomeric (S)-(+)-tartaric salts.[23] rived supported organocatalysts. Further synthetic
Optical purity of compounds 8 and 9 was confirmed protocols included reactions of amides 11 or 12 with
by their optical rotations and by HPLC analysis of bromovaleroyl chloride and NEt3, subsequent alkyla-
the corresponding bis-tosylate derivatives (see the tion of 1-methylimidazole by the corresponding dia-
Supporting Information). The synthetic strategy was mides 13 or 14 followed by metathesis of the anion in
based on selective protection of just one of the two bromides 15 or 16 and catalytic deprotection of the
amino groups in diamines 8 and 9. Known methods resulting hexafluorophosphates 17 or 18 to respective
for mono-protection of compound 8 by the Cbz group catalysts 6 or 7. Each step of this sequence selectively
are either multi-staged[24] or require use of a large afforded intermediates or final products in high
access of the precious chiral amine 8, in both cases yields.
yields of the target molecule were poor.[25] Mono-
We evaluated the catalytic properties of compounds
Cbz-protected 1,2-diaminodiphenylethane 12 was ap- 6 and 7 in the asymmetric reaction of 1-hydroxycou-
plied[26] as starting compound without a description of marin 19a with benzylideneacetone 20a. The product
its synthesis. We synthesized compounds 11 and 12 by of this reaction 21a is the active substance of the clini-
treatment of the corresponding trans-diamines 8 and cally useful anticoagulant warfarin, the (S)-enantio-
9 with O-benzyl-O’-phenyl carbonate 10, which had mer of which proved to be 2–5 times more active than
been earlier applied for the acylation of achiral the (R)-enantiomer.[28] Recently, several asymmetric
amines.[27] The reactions were carried out at ambient syntheses of 21a from 19a and 20a in the presence of
temperature to afford high-purity products 11 and 12 chiral organometallic[29] or organic catalysts, in partic-
(further purification was not needed) in reasonable ular imidazolidine,[30] 1,2-diamino-1,2-diarylethane,[31]
yields (61–63%). Apparently, this procedure may be b-amino alcohol,[32] prolinamide[33] and 9-amino-9-de-
Table 1. Primary amines 6 or 7-catalyzed reactions between 19a and 20a.[a]
Entry
Catalyst (mol%)
Solvent
Additive (equiv.)
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
6 (20)
7 (20)
7 (20)
7 (20)
7 (20)
7 (20)
7 (20)
7 (20)
7 (20)
7 (20)
7 (20)
7 (10)
7 (20)
7 (20)
7 (20)
THF
THF
THF
THF
THF
THF
THF
DCM
i-PrOH
neat
THF
THF
THF
THF
THF
–
–
–
45
45
100
45
45
45
45
45
45
45
70
45
45
45
45
60
73
75
97
67
74
trace
86
92
35
40
49
97
97
96
10[d]
68
54
72
64
66
–
70
69
68
79
79
78
AcOH (10)
PAA[e] (10)
H2O (10)
TFA or HCl (10)
AcOH (10)
AcOH (10)
AcOH (10)
AcOH (10)
AcOH (10)
AcOH (5)
AcOH (1)
AcOH (5)
9
10
11[f]
12
13
14
15[g]
72
80 (96[h])
[a]
The reactions were carried out using 19a (16.2 mg, 0.10 mmol), 20a (17.5 mg, 0.12 mmol), catalyst (0.02 mmol), appropri-
ate solvent (0.15 mL) and additive at room temperature.
Isolated yield of product 21a after column chromatography on silica gel.
HPLC analysis data (Chiralpak AD-H, hexane/i-PrOH=70/30, 0.7 mLminÀ1, 254 nm, tR (R)=6.2 min, tR (S)=12.5 min).
Absolute configuration was determined based on the comparison of optical rotations of products (S)-21 and (R)-21 with
reported data.
Data for (R)-21.
Polyacrylic acid (PAA) was used.
The reaction was carried out at 58C.
The reaction was carried out in a 1.0-mmol scale.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
The ee value of 21a after a single crystallization from an acetone/water mixture.
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Chiral Primary Amine Tagged to Ionic Group as Reusable Organocatalyst
Table 2. Asymmetric Michael reactions of compounds 19 with a,b-unsaturated ketones 20 in the presence of 7/AcOH cata-
lytic system.[a]
Entry
X
R1, R2
Time [h]
(21) Yield [%][b]
ee [%][c])
1
2
3
4
O (19a)
O (19a)
S (19b)
O (19a)
4-MeO-C6H4, Me (20b)
4-Cl-C6H4, Me (20c)
Ph, Me (20a)
45
45
45
45
(b) 81
(c) 70
(d) 51
(e) 91
77
77
76
50
-(CH2)3- (20d)
[a]
The reactions were carried out using 19 (0.10 mmol), 20 (0.12 mmol), 7 (10.4 mg, 0.02 mmol), THF (0.15 mL) and AcOH
(30 mL, 0.50 mmol) at room temperature.
[b]
[c]
Isolated yield of product 21 after column chromatography on silica gel.
HPLC analysis data (Chiralpak AD-H, hexane/i-PrOH=70/30, 0.7 mLminÀ1, 254 nm).
oxyepiquinine[34] derivatives have been developed. selectivity (entry 14). Importantly, the reaction is scal-
However, to the best of our knowledge, immobilized able under the optimal conditions and the ee value of
organocatalysts have never been applied in this reac- raw product 21a (80% ee) can be improved up to
tion.
96% ee by a single crystallization from an acetone/
First, we compared the catalytic performance of water mixture (entry 15).
compounds 6 and 7 under similar conditions (THF,
Hydroxycoumarin 19a and sulfur-containing ana-
room temperature, 45 h, 19a:20a=1:1.2, catalyst load- logue 19b reacted with benzylideneacetone deriva-
ing 20 mol%) (Table 1, entries 1 and 2). In the pres- tives 20a–c bearing donor or acceptor groups in the
ence of cyclohexane derivative 6, adduct (R)-21a was aromatic ring under the proposed conditions to afford
generated in just 10% ee, whereas the corresponding the corresponding Michael adducts 21b–d in moder-
7-catalyzed reaction afforded adduct (S)-21a with an ate to high yields and with reasonable ee values
enantiomeric enrichment of 68% ee. Therefore, we (Table 2, entries 1–3). Cyclohexenone 20d could also
further studied the reaction between compounds 19a be used as acceptor component, however, the enantio-
and 20a in the presence of catalyst 7 under various meric enrichment of product 21e was lower (entry 4).
conditions. The enantioselectivity became poorer
The catalyst 7 could be easily recovered and
when the reaction time was increased to 100 h reused. After the reaction was completed, the solvent
(entry 3). The effect of an acidic additive depended and AcOH were evaporated under vacuum (20 Torr),
on its structure. Addition of AcOH (10 equiv.) was adduct 21a was extracted with Et2O and a fresh solu-
beneficial allowing us to obtain adduct (S)-21a in tion of starting compounds and AcOH in THF was
nearly quantitative yield with an enantiomeric enrich- added to the residue (Table 3, columns 3, 4). Once or
ment of 72% ee after 45 h (entry 4). In the presence twice recovered catalyst 7 exhibited nearly the same
of the poorly soluble in THF polyacrylic acid (PAA) catalytic performance as the freshly prepared one
or water instead of AcOH, the reaction outcome was (cycles 1–3). However, after the third recovery, yield
similar to that obtained under additive-free conditions of product and to some extent enantioselectivity of
(entries 2, 5, 6). Strong acidic co-catalysts (TFA or the reaction progressively reduced (cycles 4–6). Pre-
HCl) prevented the reaction (entry 7). Carrying out sumably, the deactivation may be caused by gradual
the reaction in dichloromethane (DCM) or i-PrOH “leaching” of the catalyst during the extraction of
solution or under neat conditions resulted in a reduc- product. The assumption is in agreement with catalyst
tion of yields and ees of adduct 21a as compared with mass loss after the recovery by 10–12 wt% per cycle.
those in THF (entries 4, 8–10). The enantioselectivity However, it does not explain the reduction of the ee
improved to 79% ee when the reaction was carried values of adduct 21a, which most likely indicates the
out at 58C (entry 11) or in the presence of lower cata- formation of undesirable by-products from the cata-
lyst loading (10 mol%) (entry 12), although at the ex- lyst.
pense of product yield. The best compromise between
To identify these by-products, we studied freshly
selectivity and activity was attained in the catalytic prepared catalyst 7 and recovered samples of the cat-
system containing 20 mol% of amine 7 and 5 equiva- alyst by electrospray ionization mass spectrometry
lents of AcOH (entry 13). Further reduction of the (ESI-MS). We supposed that the ESI-MS(+) would
AcOH amount (to 1 equiv.) resulted in lower enantio- contain mainly peaks of the catalyst and of ionic com-
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Table 3. Recycling of catalyst 7 in reactions of 19a with 20a
in AcOH/THF system and in THF.
The ESI-MS(+) of the catalyst 7, that was taken from
the reaction after 8 h from the beginning, contained
peaks of cations 22, 23 and 24 in a 4:3:1 ratio and in
the ESI-MS(+) of samples of the catalyst that had op-
erated in the reaction over one (45 h) or six (325 h)
catalytic cycles the peak of cation 24 was the major
one (Figure 3).
Along with reported literature data, these results
allowed us to monitor transformations of catalyst 7 in
the studied reaction. The main catalytic cycle can be
described by the conventional scheme,[36] which in-
cludes the condensation of the cation 22 with benzyli-
deneacetone 20a, the protonation of enimine 23 (for
example, by carbon acid 19a), followed by the reac-
tion of the iminium dication 23+H+ with hydroxy-
coumarin 19a to afford adduct 24, which may exist as
an equilibrium mixture of enamine 24a and imine 24b
isomers. The catalytic cycle was completed by the hy-
drolysis of imine 24b, followed by the elimination of
the Michael adduct 21a and release of the active
Cycle Time [h]
Reactions in THF/
AcOH system[a]
Reactions in
THF[b]
Yield [%]
ee [%]
Yield [%] ee [%]
1
2
3
4
45
45
45
45
45
100
45
97
94
93
61
42
51
–
78
78
77
76
76
73
–
73
95
90
86
75
63
87
68
60
60
59
57
53
58
5
6
7[c]
[a]
The reactions were carried out as described above (see
footnote[a] to Table 2). After extraction of product 21a
(Et2O) the residue was dried at 20–30 Torr for 30 min,
fresh portions of reagents, THF and AcOH were added
and the reaction was re-performed.
The reactions and the recovery of the catalyst were car-
ried out without AcOH additive.
The reaction was carried out in the presence of reactivat-
[b]
[c]
ed by the treatment with AcOH catalyst, which was re- cation 22 (Scheme 2).
covered from the 6th cycle.
The ESI-MS data indicated that cations 24a and/or
24b accumulated in recovered samples of catalyst 7.
The cation 24b evidently served as a source of active
pounds formed from the catalyst whereas the mole- cation 22 for each successive cycle. Along with the
cules that do not contain ionic groups would give main catalytic cycle, a side catalytic process promoted
much lower peaks.[14] In this case, the AcOH was not by secondary amine isomer 24a[37] may also take
added to the reaction mixture in order to simplify the place. Apparently, this process is responsible for re-
recovery of the catalyst and the ESI-MS(+) analysis duction of the ee value of adduct 21a in the second
of recovered samples. Recycling experiments in and subsequent cycles performed in the presence of
“pure” THF (Table 3, columns 5, 6) gave somewhat recovered catalyst samples, which did not contain
different results than that obtained in the THF/AcOH cation 22 according to ESI-MS(+) (Table 3, columns
system (Table 3, columns 3, 4). In the second cycle, 5, 6). Further reduction of both activity and selectivity
the yield of 21a became 22% higher and the ee 8% in the fifth and especially in the sixth cycles along
lower than in the first cycle. Then, both figures were with the presence of the major peak (m/z=667.3269)
gradually diminishing in each further cycle to attain in ESI-MS(+) of the 5-fold recovered catalyst indicat-
minimum magnitudes in the sixth cycle. We recorded ed that a catalytically inactive isomer, possibly, a spe-
the ESI-MS(+) of freshly prepared catalyst 7 and of cial hindered hemi-aminal 25, was generated from the
other three samples of the catalyst, one of which was imine-enamine pair 24. Intramolecular formation of
taken from the reaction stopped after 8 h from the be- stable hemi-aminals from corresponding open-chained
ginning and another two operated in the reaction compounds containing amino and hydroxy groups has
over one (45 h) and six (325 h) catalytic cycles, re- been reported.[38]
spectively (Figure 3). Basing on these mechanistic considerations, we re-
.
The ESI-MS(+) spectra of the starting catalyst 7 activated the 5-fold recovered catalyst sample by
contained mainly a peak of the corresponding cation treating it with a solution of AcOH in THF (1/5). It
22 (m/z=377.2335). However, the relative abundance was found that the ESI-MS(+) of the obtained mate-
of other peaks presented in the spectra of the recov- rial differed considerably from that of the catalyst
ered samples along with (or instead of) the peak of before acidic treatment. Unlike the latter, it contained
cation 22 depended on the operation period of the the major peak of active cation 22 (m/z=377.2335),
catalyst. These peaks were assigned to corresponding which presumably is derived from regeneration by the
cations 23 (m/z=505.2948) and 24 (m/z=667.3269) in action of acid imine 24b, along with a low peak (~
accordance with their m/z values. Notably, Lai and 6%) of isomeric cations 24, 25 (m/z=667.3269). The
Xu with co-authors[35] recorded similar intermediates, rate and enantioselectivity of the reaction between
which were reversibly generated in the reaction mix- compounds 19a and 20a in THF solution containing
ture composed of compounds 19a, 20a and (R,R)-1,2- the reactivated catalyst (Table 3, cycle 7) were consid-
diamino-1,2-diphenylethane/LiClO4/AcOH catalytic erably higher than that in the two preceding cycles,
system under homogeneous conditions, by ESI-MS. being somewhat poorer, though, than the correspond-
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Chiral Primary Amine Tagged to Ionic Group as Reusable Organocatalyst
Figure 3. ESI-MS(+) monitoring of the composition of catalyst 7 in the Michael reaction between 19a and 20a.
ing characteristics of the reaction catalyzed by freshly ylimidazolium cation. In the presence of this catalyst
prepared or just once recovered catalyst 7. The ob- and an acidic co-catalyst (AcOH), hydroxycoumarin
tained results explain a favourable impact of acidic and its S-analogue reacted with benzylideneacetone
co-catalyst (AcOH) on the studied reaction.
derivatives or cyclohexenone to afford the corre-
sponding Michael adducts in good yields (up to 97%)
and with reasonable enantioselectivity (up to 80%).
The catalyst could be easily separated from products
and efficiently reused three times, then, in subsequent
Conclusions
In summary, we have synthesized for the first time runs, its activity and enantioselectivity of reactions
a simple recoverable organocatalyst for asymmetric became lower. The analysis of recovered catalyst sam-
Michael reactions between C-nucleophiles and a,b- ples by ESI-MS allowed us to detect plausible origins
unsaturated ketones containing the trans-1(S),2(S)-di- of the deactivation and the obtained information may
aminodiphenylethane unit modified with the 1-meth- be useful for developing robust immobilized organo-
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Scheme 2. Transformations of catalyst 7 in the asymmetric Michael reaction between 19a and 20a according to ESI-MS(+).
catalysts for asymmetric Michael reactions, involving Acknowledgements
an iminium ion formation step.
Financial support by the President of the Russian Federation
(grant for young Ph.D. No. 3551.2012.3), by the Russian
Academy of Sciences (Basic Research Program No. 1 of the
Department of Chemistry and Material Sciences) and by the
Russian Foundation of Basic Research (project 12-03-00420)
Experimental Section
are gratefully acknowledged.
Typical Procedure for the Michael Reaction
The reactions were carried out using 19a (0.10 mmol), 20a
(0.12 mmol), catalyst 7 (10.4 mg, 0.02 mmol) and AcOH References
(30 mL, if necessary) in THF (0.15 mL) at room temperature.
After the reaction was completed, the solvent and AcOH
were evaporated, the product and remaining starting com-
pounds were extracted with Et2O (5ꢂ10 mL). The ether so-
lution was evaporated under reduced pressure (20 torr) and
the residue was purified by column chromatography
(hexane/ethylacetate from 3/1 to 2/1) to afford compounds
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