Organocatalytic asymmetric cyanosilylation of nitroalkenes

Article abstract of DOI:10.1002/chem.201001107

(Figure Presented) New catalyst, new reaction: The unprecedented cyanosilylation of nitroalkenes can be efficiently catalyzed by a bifunctional quinine derivative with tetraalkylammonium cyanide and thiourea moieties. The activation of the nitroalkene by hydrogen bonding to the thiourea, together with the presence of an active cyanide, provides new mode of activation that leads to products in high yields and good selec tivities (see scheme).

Full text of DOI:10.1002/chem.201001107

DOI: 10.1002/chem.201001107
Organocatalytic Asymmetric Cyanosilylation of Nitroalkenes
Pablo Bernal,[a] Rosario Fernꢀndez,*[b] and Josꢁ M. Lassaletta*[a]
Dedicated to Professor Carmen Nꢀjera on the occasion of her 60th birthday
b-Nitro nitriles are potentially useful intermediates for
the synthesis of a variety of bifunctional compounds, includ-
ing b-amino acids. An intuitive retrosynthetic analysis of
these compounds suggests a direct conjugate cyanide addi-
tion to nitroalkenes 1 as a straightforward route for such
structures. In spite of its apparent simplicity, however, the
development of this reaction is restricted by the high ten-
dency of nitroalkenes to polymerize under basic conditions.
Consequently, there is only one recent report for use of ace-
tone cyanohydrin as the cyanide source for the conjugate
addition to nitroalkenes in its racemic form[1] and a second
one for the asymmetric addition, which afforded moderate
enantioselectivities and appears to be restricted to (less
prone to polymerization) b,b-disubstituted compounds.[2]
Taking into account the relative stability of silyl nitro-
nates, we decided to focus on the use of trialkylsilyl cyanides
as reagents to obtain b-cyano silyl nitronates 2 as the pri-
mary products of the reaction, thereby avoiding the above-
mentioned polymerization. Moreover, the rich chemistry of
silyl nitronates[3] could be eventually exploited beyond the
trivial hydrolysis to b-nitronitriles 3. Surprisingly, a survey of
the literature reveals that this relatively simple reaction re-
mains hitherto unexplored, and that b-cyano silyl nitronates
have never been synthesized. We now wish to report on the
development of a practical approach for the asymmetric cy-
anosilylation of nitroalkenes (Scheme 1).
Scheme 1. Cyanosilylation of nitroalkenes.
The reaction of (E)-3-methyl-1-nitrobut-1-ene (1a) with
TMSCN (trimethylsilyl cyanide) was chosen as a model case
of study. Several types of catalysts were considered as poten-
tial candidates for the activation of the reagent and/or the
nitroalkene. Initially, cinchona alkaloids were used for the
nucleophilic activation of TMSCN.[4] Unfortunately, the re-
action proceeded with low conversions after prolonged reac-
tion times, and partial polymerization of the nitroalkene
could not be avoided. Moreover, the selectivity was low in
all cases, reaching a maximum of 67:33 enantiomeric ratio
(e.r.) for a reaction performed with 5 mol% of quinine in
nBu2O (see Supporting Information).
We next explored the behavior of bifunctional thiourea/
tertiary amine catalysts for the simultaneous activation of
the nitroalkene (by the thiourea as an hydrogen-bond donor
moiety) and the reagent (by the amino nitrogen)[5]
(Scheme 2). A higher catalytic activity and a better stereo-
chemical control were expected from these catalysts provid-
ed by more ordered catalyst–substrate–reagent complexes I.
Catalysts 4 and 5 were totally inactive, suggesting that a
more nucleophilic amine is required. On the other hand, bi-
functional catalysts 6 and 7 developed by the groups of
Soos[6] and Hiemstra,[7] respectively, afforded he expected
product 3a with higher enantiomeric ratios (75:25 and
79:21 e.r., respectively), but the catalytic activity remained
very low (conversions <20% after two days at room tem-
perature; see details in the Supporting Information).
[a] P. Bernal, Dr. J. M. Lassaletta
Instituto de Investigaciones Quꢀmicas (CSIC-US)
C/Americo Vespucio 49, 41092 Seville (Spain)
Fax : (+34)954-46-05-65
E-mail: jmlassa@iiq.csic.es
[b] Prof. R. Fernꢁndez
Departamento de Quꢀmica Orgꢁnica
Universidad de Sevilla, Apdo. de Correos 1203
41071 Seville (Spain)
Fax : (+34)954-62-49-60
E-mail: ffernan@us.es
Inspired by recent results by Maruoka et al. on the phase-
transfer-catalyzed asymmetric addition of silyl nitronates to
nitroalkenes,[8] we decided to explore the suitability of such
type of catalysts for the cyanosilylation of nitroalkenes. In
preliminary experiments, the model reaction (1a+TMSCN)
was performed in the presence of several quaternary ammo-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001107.
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COMMUNICATION
Disappointingly, none of the structural modifications tested
led to an improvement of the enantioselectivity. Unexpect-
edly, the nature of the counteranion proved to have a dra-
matic effect on the catalytic activity. Thus, synthetic cincho-
nidinium bromides were inactive in the model reaction,
while the corresponding chlorides or iodides showed a mod-
erate activity, affording conversions up to 50% in the best
cases (see Supporting Information for details).
The catalytic cycle initially proposed to account for the
observed results starts with a cyanide exchange of TMSCN
with the catalystꢃs counterion Xꢀ leading to the correspond-
ing quaternary ammonium cyanide (Scheme 3, mechanism I,
Step 1). Conjugate addition of this salt to the nitroalkene
yields an ammonium nitronate (Step 2A), which is then
silylACTHNURTGNEUaGN ted by the TMSX species formed in the initial step to
afford the silyl nitronate and regenerate the catalyst
(Step 3A). Alternatively, however, it came into consider-
ation a second possibility that basically differs in the order
of the above-mentioned events: after the initial TMSCN/
R4N+Xꢀ exchange (Step 1), the nitroalkene is activated by
Scheme 2. Bifunctional catalysts for the cyanosilylation of nitroalkenes.
nium salts. We were pleased to observe that TBAI (tetrabu-
tylammonium iodide; 20 mol%) successfully catalyzed the
reaction, reaching complete conversions in 32 h at room
temperature. A screening of commercially available phase-
transfer catalysts (PTCs) led to the identification of cincho-
na alkaloid derived salts 8 as the most promising candidates
for the enantioselective version of the reaction, reaching up
to 68:32 e.r. for 8d; other chiral ammonium derivatives,
such as binaphthyl-based structures, exhibited good catalytic
activity but very poor selectivity. The modular structure of
cinchona alkaloids also allowed the preparation of synthetic
derivatives with different substitution patterns at C9, C6’,
and the N-benzyl group and with different counteranions.
Scheme 3. Proposed mechanisms for tetraalkyl ammonium halides
(mechanism I) and cyanides (mechanism II) as catalysts.
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J. M. Lassaletta, R. Fernꢁndez and P. Bernal
the silylating species (TMSX, a Lewis acid; Step 2B) prior
to the attack of the cyanide (Step 3B). This second mecha-
nism is in agreement with the observed dependence of the
enantioselectivity with the reagentꢃs steric demand: using
10 mol% of catalyst 8k in nBu2O at 58C, reactions of 1a
with TMSCN and TBDMSCN afforded product 3a with
62:38 and 51:49 e.r., respectively.
fits of the bifunctional character of 11. Thus, reactions car-
ried out in toluene at ꢀ208C with a catalyst loading of 10%
yielded product 3a in 70:30 and 84:16 e.r. for 9n and 11, re-
spectively. The high catalytic activity allowed performing
the reaction at low temperatures, reaching a 92:8 e.r. in
TBME for a reaction carried out at ꢀ788C to room temper-
ature (Table 1, entry 1). Under optimized conditions, the re-
According to this proposal, the mentioned effect of the
counteranion on the catalytic activity could be explained
through a rate-limiting anion exchange (Step 1). The use of
ammonium cyanides 9 as catalysts was therefore proposed
as a strategy to solve the reactivity problem. In this way, the
exchange step is eliminated and, assuming that preactivation
of the nitroalkene takes place as previously discussed, a
single-step mechanism (Scheme 3, mechanism II) can be for-
mulated in which the attacking cyanide proceeding from the
catalyst is “regenerated” through silylation of the nitronate
by the reagent.
Table 1. Catalytic asymmetric cyanosilylation of nitroalkenes.
Product[a]
T [8C]
t [h]
Yield [%][b]
85
e.r.[c]
92:8
1
ꢀ78!ꢀ40
48
Supporting the above exposed hypothesis, the catalytic ac-
tivity of the tetraalkylammonium cyanides 9 was clearly
higher than that of the corresponding halides, leading in all
cases to complete conversions in relatively short reaction
times. Although this high catalytic activity makes it possible
to perform the reaction at lower temperatures, unfortunately
only slight improvements of the enantioselectivities were ob-
served (see Supporting Information).
Putting the available information into perspective, it is
clear that bifunctional catalysts 6 and 7, based on a tertiary
amine (quinuclidine)/hydrogen-bond donor (thiourea) com-
bination, afford higher levels of stereocontrol, while tetraal-
kylammonium cyanides 9 are much more active catalysts
than the free alkaloids. We therefore decided to synthesize
and essay an unprecedented type of catalysts that combine
quaternary ammonium cyanides with hzdrogen-bond donor
functionality for cooperative binding of the nitroalkene. To
this aim, catalyst 11 was synthesized from 7 by alkylation
with 2-benzyloxy-1-methyl pyridinium triflate (!10)[9] and
subsequent anion exchange with KCN (Scheme 4).
2
3
ꢀ45
20
48
98
95
87:13
80:20
ꢀ78!RT
4
5
ꢀ45
ꢀ45
96
72
91
90:10
93:7
56[d,e]
ꢀ45
ꢀ20
72
48
19[d,e]
92:8
6
88
86:14
[a] The absolute configuration of adduct 3a was assigned by comparison
of its optical rotation with literature data: see reference [11]. The abso-
lute configuration of all other adducts 3 were assigned by analogy assum-
ing a uniform reaction pathway. [b] Isolated yields. [c] Determined by
HPLC on chiral stationary phases. [d] A 3:1 trans:cis ratio was deter-
mined by 1H NMR spectroscopy in the reaction crude. [e] Yield of pure
diastereomers separated by flash chromatography.
action was extended to a variety of aliphatic substrates to
afford, in all cases, the desired adducts 3 in high yields and
good enantioselectivities (entries 2–6).[10]
In contrast with the reactions catalyzed by simple phase-
transfer catalysts, in this case the steric bulk of the reagent
had no effect either on the enantioselectivity or on the reac-
tion rate, now pointing towards an irreversible, rate-limiting,
Scheme 4. Synthesis of bifunctional catalyst 11.
ꢀ
C C bond formation through a silyl-free intermediate. A
We were pleased to observe that compound 11 efficiently
catalyzed the model reaction, affording the desired adduct
3a in near quantitative yield and improved selectivity. A
direct comparison with catalyst 9n (in which the thiourea
moiety is replaced by a methoxy group) highlights the bene-
proposed mechanism in agreement with these experimental
facts is outlined in Scheme 5. Thus, after activation of the ni-
troalkene by hydrogen bonding (Step 1), conjugate addition
of cyanide yields a hydrogen-bonded nitronate intermediate
(Step 2), which then reacts with R3SiCN to afford 2 (Step 3).
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Organocatalysis
COMMUNICATION
Experimental Section
Synthesis of catalyst 11: 2-Benzyloxy-1-methylpyridinium triflate
(203 mg, 0.22 mmol) was added to a solution of quinine thiourea deriva-
tive 7[7] (325 mg, 0.49 mmol) in dry THF/CH2Cl2 (1:3, 6 mL) under an
argon atmosphere. The mixture was stirred at room temperature for 48 h,
concentrated, and the resulting residue was purified by flash chromatog-
raphy (15:1 toluene/MeOH) to afford triflate salt 10 (203 mg; 46%) as a
1
brown solid. [a]2D3 ꢀ144.6 (c=1.0 in CHCl3); H NMR (500 MHz, CDCl3):
d=8.98 (d, J=4.4 Hz, 1H), 8.31 (s, 2H), 8.09 (s, 2H), 7.65 (d, J=4.4 Hz,
2H), 7.55–7.38 (m, 10H), 7.34 (t, J=8.2 Hz, 3H), 7.05 (s, 1H), 6.12 (s,
1H), 5.55 (ddd, J=17.1, 10.5, 6.6 Hz, 1H), 5.16 (d, J=17.2 Hz, 1H),
5.12–5.02 (m, 2H), 4.95 (d, J=11.9 Hz, 1H), 4.38 (d, J=11.9 Hz, 1H),
4.32 (d, J=12.3 Hz, 1H), 4.19–4.06 (m, 2H), 4.04 (s, 1H), 3.31–3.18 (m,
1H), 3.16–3.02 (m, 1H), 2.56 (s, 1H), 2.23–2.12 (m, 1H), 2.09 (s, 1H),
1.83–1.64 ppm (m, 2H); 13C NMR (125 MHz, CDCl3): d=179.9, 161.1,
148.9, 148.2, 146.6, 140.9, 138.9, 136.1, 131.3 (q, J=36.5 Hz), 130.8, 130.8,
129.7, 129.7, 129.5, 129.5, 129.4, 129.4, 129.3, 129.3, 129.21, 125.09, 124.69
(q, J=241.9 Hz), 119.53, 118.63, 113.68, 71.77, 67.14, 61.02, 50.75, 37.69,
37.16, 29.76, 26.60 ppm; HRMS (FAB): m/z: calcd for C42H39F6N4OS+:
761.2749 [M+ꢀTfO]; found 761.2759. This material was dissolved in
MeOH (5 mL) and KCN (44 mg, 0.67 mmol) was added. The mixture
was stirred until total dissolution, concentrated and extracted with meth-
ylene chloride to afford 11 (167 mg, 99%). [a]2D3 ꢀ366.6 (c=1.0 in
CHCl3); 1H NMR (500 MHz, CDCl3): d=8.81 (d, J=4.4 Hz, 1H), 8.07
(d, J=9.2 Hz, 1H), 7.54 (s, 1H), 7.46 (dd, J=14.7, 7.3 Hz, 2H), 7.33
(ddd, J=21.3, 14.3, 5.8 Hz, 14H), 6.58 (d, J=9.1 Hz, 1H), 5.75–5.64 (m,
1H), 5.08 (s, 1H), 4.91 (d, J=17.1 Hz, 1H), 4.86 (d, J=10.3 Hz, 1H),
4.45–4.28 (m, 2H), 4.02 (s, 2H), 3.33–3.10 (m, 2H), 3.01–2.89 (m, 1H),
2.64–2.43 (m, 2H), 2.26–2.15 (m, 1H), 1.82–1.63 (m, 2H), 1.63–1.49 (m,
1H), 1.47–1.36 (m, 1H), 1.26 ppm (s, 1H); 13C NMR (101 MHz, CDCl3):
d=180.6, 163.3, 149.2, 146.0, 142.1, 139.7, 138.0, 136.4, 132.2 (q, J=
34.9 Hz), 131.3, 129.6, 129.3, 129.3, 128.9, 128.9, 128.5, 128.5, 128.4, 127.9,
127.9, 123.5 (q, J=273.5 Hz), 120.9, 116.5, 114.3, 106.1, 71.3, 67.7, 61.0,
57.1, 40.2, 37.1, 28.0, 27.9 ppm; HRMS (FAB): m/z: calcd for
C42H39F6N4OS+: 761.2749 [M+ꢀCN]; found: 761.2730.
Scheme 5. Proposed mode of action and catalytic cycle for bifunctional
thiourea/ammonium catalysts.
As for simple tetraalkyl ammonium salts, the bifunctional
catalyst incorporates the “active” nucleophile (cyanide),
while TMSCN behaves as a silylating agent for the nitronate
intermediate and, simultaneously, as a reservoir of cyanide
for the regeneration of the catalyst.
Taking into account the experimental work[7] and calcula-
tions[12] performed for cinchona-based catalysts with similar
topologies in related systems, a model based on a gauche-
open geometry with the coordinated nitroalkene oriented to
the less hindered region is tentatively proposed to explain
the observed absolute configuration (Figure 1).
Cyanosilylation of nitroalkenes
General procedure: TMSCN (0.3 mmol) was added to a solution of nitro-
alkene 1 (0.1 mmol) and catalyst 11 (0.01 mmol) in tert-butyl methyl
ether (1.5 mL) and the mixture was stirred at the desired temperature
until TLC monitoring indicated consumption of the starting material. Sa-
turated NaHCO3 solution was added and the mixture was extracted with
Et2O, dried, concentrated and purified by flash chromatography (9:1 cy-
clohexane/ethyl acetate) to afford pure products 3 (see Supporting Infor-
mation for characterization).
Acknowledgements
We thank BayerCropScience, the Spanish Ministerio de Ciencia e Inno-
vaciꢄn (grants CTQ2007-00290 and CTQ2007-60244), and the Junta de
Andalucꢀa (grants 2008/FQM-3833 and 2009/FQM-4537) for financial
support.
Figure 1. Stereochemical model.
In summary, the unprecedented cyanosilylation of nitroal-
kenes has been accomplished by using a novel thiourea/tet-
ralkylammonium bifunctional catalyst that binds substrate
and reagent through a new mode of activation. Although
the applied catalyst 11 already afforded remarkable levels of
enantioselectiviy, fine tuning of this scaffold to improve ac-
tivity and selectivity, as well as its behavior in other related
reactions are now under investigation.
Keywords: asymmetric catalysis · bifunctional catalysis ·
conjugate addition
synthetic methods
· nitroalkenes · organocatalysis ·
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Received: January 5, 2010
Published online: June 8, 2010
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