Lewis base promoted intramolecular acylcyanation of α-substituted activated alkenes: Construction of ketones bearing β-quaternary carbon centers

Article abstract of DOI:10.1021/ol3007716

A novel phosphine-promoted intramolecular acylcyanation of α-substituted activated alkenes has been developed, which provides a unique access to densely functionalized acyclic ketones bearing β- quaternary carbon centers with a remarkable feature that bot

Full text of DOI:10.1021/ol3007716

ORGANIC
LETTERS
2012
Vol. 14, No. 9
2354–2357
Lewis Base Promoted Intramolecular
Acylcyanation of r-Substituted Activated
Alkenes: Construction of Ketones Bearing
β-Quaternary Carbon Centers
Zhe Zhuang, Jian-Ming Chen, Feng Pan, and Wei-Wei Liao*
Department of Organic Chemistry, College of Chemistry, Jilin University, 2699 Qianjin
Street, Changchun 130012, China
wliao@jlu.edu.cn
Received March 26, 2012
ABSTRACT
A novel phosphine-promoted intramolecular acylcyanation of r-substituted activated alkenes has been developed, which provides a unique
access to densely functionalized acyclic ketones bearing β- quaternary carbon centers with a remarkable feature that both r- and β-positions of
activated alkene are functionalized.
To develop efficient strategies regarding how to con-
struct a carbonÀcarbon bond formation becomes a central
theme in synthetic organic chemistry due to its unique role
inassemblingthe diverse and complexcarbon frameworks.
Within this field, the generation of an all-carbon-substi-
tuted quaternary center is fundamentally important and
represents a great challenge.1 As one of the most straight-
forward and atom-economical CÀC bond-formation re-
actions, the transition metal-catalyzed acylcyanation reac-
tion of alkynes and alkenes has received more considerable
attention.2 In particular, a transition metal-catalyzed in-
tramolecular acylcyanation reaction of alkenes has
emerged as a powerful tool for preparing functionalized
nitriles incorporating an all-carbon-substituted quatern-
ary center, because this atom-economical transformation
allows simultaneous installation of both carbonyl and
cyano functional groups in a highly selective and efficient
manner (Scheme 1, eq 1).3 However, these intramolecular
transformations employed electron-rich alkenes as sub-
strates with limited functional group compatibility and
required harsh reaction conditions. In addition, these
processes were restricted to the cyanocarbamoylation of
alkenes which provide cyclic compounds,3 while the in-
stallations of other acyl groups have not been exploited.
With the goal of developing efficient metal-free processes
to construct the diverse carbon frameworks incorporating
quaternary carbon centers,4 we are interested in a Lewis
base catalyzed acylcyanation of electron-deficient alkenes
which may have advantages such as: (i) providing a
(1) For reviews on the construction of a quaternary carbon centers,
see: (a) Martin, S. F. Tetrahedron 1980, 36, 419. (b) Fuji, K. Chem. Rev.
1993, 93, 2037. (c) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int.
Ed. 1998, 37, 388. (d) Christoffers, J.; Mann, A. Angew. Chem., Int. Ed.
2001, 40, 4591. (e) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci.
U.S.A. 2004, 101, 5363. (f) Christoffers, J.; Baro, A. Adv. Synth. Catal.
2005, 347, 1473. (g) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (h) Bella,
M.; Gasperi, T. Synthesis 2009, 1583. (i) Hawner, C.; Alexakis, A. Chem.
Commun. 2010, 46, 7295. (j) Das, J. P.; Marek, I. Chem. Commun. 2011,
47, 4593.
(2) For alkynes as substrates, see: (a) Nozaki, K.; Sato, N.; Takaya,
H. J. Org. Chem. 1994, 59, 2679. (b) Nozaki, K.; Sato, N.; Takaya, H.
Bull. Chem. Soc. Jpn. 1996, 69, 1629. (c) Hirata, Y.; Yada, A.; Morita, E.;
Nakao, Y.; Hiyama, T.; Ohashi, M.; Ogoshi, S. J. Am. Chem. Soc. 2010,
132, 10070. For alkene as substrates, see: (d) Nishihara, Y.; Inoue, Y.;
Itazaki, M.; Takagi, K. Org. Lett. 2005, 7, 2639. (e) Nishihara, Y.; Inoue,
Y.; Izawa, S.; Miyasaka, M.; Tanemura, K.; Nakajima, K.; Takagi, K.
Tetrahedron 2006, 62, 9872. (f) Nakao, Y.; Hirata, Y.; Hiyama, T. J. Am.
Chem. Soc. 2006, 128, 7420. (g) Hirata, Y.; Inui, T.; Nakao, Y.; Hiyama,
T. J. Am. Chem. Soc. 2009, 131, 6624.
(3) For intramolecualr acylcyanation of alkenes, see: (a) Yasui, Y.;
Kamisaki, H.; Takemoto, Y. Org. Lett. 2008, 10, 3303. (b) Najara, C.;
Sansano, J. M. Angew. Chem., Int. Ed. 2009, 48, 2452. (c) Yasui, Y.;
Kamisaki, H.; Ishida, T.; Takemoto, Y. Tetrahedron 2010, 66, 1980.
(4) (a) Zhuang, Z.; Pan, F.; Fu, J.-G.; Chen, J.-M.; Liao, W.-W. Org.
Lett. 2011, 13, 6164. (b) Pan, F.; Chen, J.-M.; Zhuang, Z.; Fang, Y.-Z.;
Zhang, S. X.-A.; Liao, W.-W. Org. Biomol. Chem. 2012, 10, 2214.
r
10.1021/ol3007716
Published on Web 04/26/2012
2012 American Chemical Society

Recently, we developed a novel synthetic strategy to
furnish the highly functionalized cyanohydrins 1.4a We
envisioned that these valuable cyanohydrins 1 with a
tertiary alcohol moiety as well as cyanide and allylic
functional groups may serve as suitable scaffolds for
exploring anunique intramolecular acylcyanation reaction
with R-substituted activated alkenes as the substrate. We
hypothesized that a possible conjugate addition of Lewis
base catalyst to the activated terminal alkene moiety of
cyanohydrins 1 and followed by a tandem intramolecular
condensation with the ester group and an elimination
would afford a phosphonium salt III with cyanide ion as
a counterion. Subsequently, a SN2 substitution of inter-
mediate III could furnish densely functionalized desired
product 2 by utilizing the nucleophilicity of cyanide ion
(Scheme 2).8
To assess the feasibility of this transformation, an initial
investigation was examined with O-ethoxycarbonyl pro-
tected cyanohydrins 1aa in acetonitrile with a catalytic
amount of PPh3 (20 mol %), which were readily prepared
from the cyanation-allyic-alkylation reaction.4a Gratify-
ingly, this reaction gave rise to highly functionalized
ketone 2aa with a quaternary carbon atom incorporated,
whose structure is unambiguously supported by 1H NMR
and 13C NMR spectra, albeit rather sluggishly (Table 1,
Scheme 1. Intramolecular Acylcyanation of Alkenes Reported
and in This Work
metal-free access to highly functionalized nitriles with
diverse functional group compatibility in a single step;
(ii) from readily available starting materials; and (iii) under
neutral and mild conditions. Although Lewis base cata-
lyzed acylcyanation of carbonyl compounds and imines
have been studied extensively in recent years,5,6 an intra-
molecular acylcyanation reaction of activated alkenes
catalyzed by Lewis base has not been developed.
Herein, we report an unprecedented phosphine promoted
intramolecular acylcyanation of R-substituted activated
alkenes which provides an unique access to densely functio-
nalized acyclic ketones bearing β-quaternary carbon centers
with the remarkable feature that both R- and β-positions of
activated alkene are functionalized (Scheme 2, eq 2).7
Table 1. Optimization of Phosphine Promoted Intramolecular
Acylcyanation of R-Substituted Activated Alkene 1aa
Scheme 2. Proposed Reaction Pathway
entry
cat.
solvent
temp (°C)
time (h)
yield (%)b
1
2
PPh3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
60
30
30
30
80
80
30
30
30
30
36
2
24
45
62
53
40
45
41
73
81
89
PPh2Et
PPhEt2
PBu3
3
0.5
0.5
24
24
1
4
5
DABCO
DMAP
DBU
6
7
8
PPhEt2
PPhEt2
PPhEt2
0.5
0.5
0.5
9c
10c,d
DMF
DMF
(5) For examples of Lewis base catalyzed the acylcyanation of
carbonyl compounds, see: (a) Poirier, D.; Berthiaume, D.; Boivin,
R. P. Synlett 1999, 1423. (b) Berthiaume, D.; Poirier, D. Tetrahedron
2000, 56, 5995. (c) Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123,
6195. (d) Baeza, A.; Najera, C.; Retamosa, M. G.; Sansano, J. M.
Synthesis 2005, 16, 2787. (e) Tian, S. K.; Deng, L. Tetrahedron 2006, 62,
11320. (f) Peng, D.; Zhou, H.; Liu, X.-H.; Wang, L.-W.; Chen, S.-K.;
Feng, X.-M. Synlett 2007, 2448. (g) Matsukawa, S.; Sekine, I.; Iitsuka,
A. Molecules 2009, 14, 3353.
(6) For recent examples of Lewis base catalyzed the acylcyanation of
imines, see: (a) Pan, S. C.; Zhou, J.; List, B. Synlett 2006, 3275. (b) Pan,
S. C.; List, B. Synlett 2007, 318. (c) Pan, S. C.; Zhou, J.; List, B. Angew.
Chem., Int. Ed. 2007, 46, 612. (d) Pan, S. C.; List, B. Org. Lett. 2007, 9,
1149.
(7) For reviews of nucleophilic phosphine catalysis, see: (a) Lu, X.;
Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535. (b) Methot, J. L.;
Roush, W. R. Adv. Synth. Catal. 2004, 346, 1035. (c) Ye, L.-W.; Zhou, J.;
Tang, Y. Chem. Soc. Rev. 2008, 37, 1140. (d) Cowen, B. J.; Miller, S. J.
Chem. Soc. Rev. 2009, 38, 3102. (e) Marinetti, A.; Voituriez, A. Synlett
2010, 174.
a Reactions were performed with 1aa (0.1 mmol) and 20 mol % of
catalyst in solvent (c = 0.1 M). b Isolated yield. c Reaction was carried
out in solvent (c = 0.02 M). d 4 A molecular sieve was added.
˚
entry 1). More electron-rich phosphine catalysts were
employed and afforded desired product in increased yields
(Table 1, entries 2À4). Tertiary amines, such as DMAP,
DABCO, and DBU, were also evaluated. However, all of
them gave desired product 2aa in relatively low yields, even
at elevated temperature (Table 1, entries 5À7). Solvent
optimization showed that this acylcyanation reaction
(8) Phosphine catalyzed transformations via an intramolecular SN2
substitution to release catalyst, see: Sriramurthy, V.; Barcan, G. A.;
Kwon, O. J. Am. Chem. Soc. 2007, 129, 12928.
Org. Lett., Vol. 14, No. 9, 2012
2355

proceeded well in DMF in the presence of 20 mol %
PPhEt2 or PBu3.9 Given the possibility of the intramole-
cular mechanism of this reaction involved, the reaction of
1aa was carried out at dilute concentration. Indeed, an
increased yield was observed asthe reactionwas performed
in dilute DMF (Table 1, entry 9). The yield of 2aa could be
further enhanced by employing this reaction in dilute
DMF in the presence of a molecular sieve (Table 1, entry 9).
Finally, optimal reaction condition was obtained when
the reaction was conducted in dilute DMF in the presence
reaction conditions,10 O-3-methylcrotonoyol protected
cyanohydrin 1ag was employed, and unsaturated ketone
2ag was obtained in improved yield indeed (Table 2,
entry 7). O-formyl protected group of cyanohydrin 1ah
seemed to be fragile under optimal reaction conditions,
and the reaction failed to give the desired product.
Next, an intramolecular acylcyanation of a spectrum of
O- ethoxycarbonyl protected cyanohydrins with a variety
of substituents located at the R-position of the cyano-
group was surveyed to explore the generality of this
transformation. The results are summarized in Scheme 3.
The reaction proceeded well regardless of whether the
aromatic group has an electron-withdrawing (2bb) or an
˚
of 4 A MS and furnished desired product 2aa in 89% yield.
(Table 1, entry 10).
With optimal reaction conditions in hand, a variety of
different O-acyl protected cyanohydrins 1 were investi-
gated first. The results are summarized in Table 2.
Scheme 3. Phosphine Promoted Intramolecular Acylcyanation
of Various Cyanohydrinsa,b
Table 2. Phosphine-Promoted Intramolecular Acylcyanation of
Various O-acyl Protected Cyanohydrinsa
entry
R1
1
temp (°C) time (h) yield(%)b
1
2
3c
4c
5
6c
7c
8
OEt
OBn
Me
Et
1aa
1ab
1ac
1ad
1ae
30
30
60
30
30
60
60
30
0.5
2
89(2aa)
71(2ab)
80(2ac)
48(2ad)
18
6
d
Ph
À
À
(E)-PhCHdCH 1af
36
36
À
16(2af)
41(2ag)
(CH3)2CdCH
1ag
1ah
d
H
À
a
˚
Reactions were performed with 1 (0.1 mmol), 4 A molecular sieve,
and 20 mol % of PPhEt2 in DMF (c = 0.02 M). b Isolated yield.
c PBu3(20 mol %) was used. d No desired product was detected.
Besides cyanohydrin carbonate 1aa, O-benzyloxycarbo-
nyl protected cyanohydrin carbonate 1ab also furnished
the functionalized ketone 2ab in high yield (Table 2, entry 2).
Cyanohydrin esters other than carbonates were employed
and displayed the variant reactivities. O-acetyl protected
cyanohydrin 1ac, which may afford 1,4-diketone, gave the
desired product 2ac at a raised temperature in 80% yield in
the presence of 20 mol % PBu3 (Table 2, entry 3). When O-
acryl protected cyanohydrins 1ad was employed, the acyl-
cyanation reaction furnished the desired product 2ad in
48% yield (Table 2, entry 4). However, benzoyl cyanohy-
drin 1ae did not provide any desired product under the
modified reaction conditions (Table 2, entry 5), presum-
ably due to the steric hindrance effect. Further performing
this reaction with cinnamoyl analog 1af under optimal reac-
tion conditions afforded the desired unsaturated ketone
2af in low yield (Table 2, entry 6). Considering the possible
instability of R, β-unsaturated ketones under selected
a For full experimental details, see the Supporting Information.
b Isolated yield.
electron-donating (2bc) groups and whether the aromatic
group is substituted at the para- (2bb and 2bc), meta- (2bd),
or ortho- (2be and 2bf) position. β-Naphthyl and hetero-
aromatic subsititued cyanohydrins can also serve as good
substrates and provided desired products in comparably
good yields (2bg and 2bh). Cyanohydrin 1bi with an
aliphatic group located at the R-position of cyano-group
was next preparedand evaluated. Asexpected, the reaction
afforded ketone 2bi in excellent yield. Noteworthily, steri-
cally congested cyanohydrin 1bj was employed and
smoothly converted to the desired ketone 2bj with adjacent
(10) The stability of R,β-unsaturated ketone 2ca was tested. Submit-
ting 2ca to the optimal reaction conditions in 24 h, 2ca was recovered in
29% yield along with some unindentified substances.
(9) See Supporting Information for details.
2356
Org. Lett., Vol. 14, No. 9, 2012

quaternaryand tertiarycentersin25% yield. Furthermore,
cyanohydrin carbonates with different ester moieties have
been applied in the developed process (2bk and 2bl). The
substrate 1bl with bulkily ester group gave the product 2bl
in relatively low yield.
Scheme 5. Control Experiments and Mechanistic Proposal
Scheme 4. Phosphine Promoted Intramolecular Acylcyanation
of Various Vinyl (R2) Cyanohydrinsa
followed by an insertion of VI across the CdC bond of 4a
could lead to a final product. However, this possibility
was ruled out due to the fact that treatment of ketone 4a,
ethyl cyanoformate, and PPhEt2 (20 mol %) did not
provide the desired product (Scheme 5a). Interestingly,
the treatment of substrate 1aa with tetrabutylammonium
cyanide (20 mol %) provided 2aa in 80% yield as well,
which indicated that cyanide ion can promote this process
alone (Scheme 5b).11 Based on these investigations, it is
also possible that cyanide ion generated in situ could
undertake a tandem transformation to provide the desired
product (Scheme 5, path B). Further studies of the reaction
mechanism are ongoing in our laboratories and will be
reported in due course.
In summary, we have developed a novel phosphine
promoted intramolecular acylcyanation reaction of R-sub-
stituted activated alkenes, which are prepared from readily
available starting materials. This protocol provides a facile
access to construct quaternary carbon centers under neutral
and mild conditions. The broad scope and versatility of the
process was demonstrated by the introduction of a variety of
alkyl, aryl, allylic, and heteroaryl substituents at multiple
sites in the densely functionalized ketone products.
a For full experimental details, see the Supporting Information.
b Isolated yield.
c PBu3 (20 mol %) was used.
In the course of further studies, cyanohydrin carbonates
1 with vinyl substituents located at the R-position of the
cyano group were evaluated (Scheme 4). In contrast with
phosphine promoted intramolecular acylcyanation of O-
R,β-unsaturated acyl protected cyanohydrin (1af and 1ag),
cyanohydrins 1 with vinyl substituents located at the
R-position of the cyano group add a new dimension to
the scope of these reactions. The linear vinyl substituted
cyanohydrins (1ca and 1cb) afforded unsaturated ketones
2ca and 2cb in relatively low yields (2ca and 2cb). Thus, the
branched vinyl substituted cyanohydrin carbonate 1cc was
investigated. To our delight, this process furnished the
desired unsaturated ketone 2cc in high yield with high
efficiency. Other branched vinyl substituted cyanohydrin
carbonates also provided good to excellent results under
the optimal reaction conditions (2cd and 2ce). In addition,
intramolecular acylcyanation of cyanohydrin acetate 1cf
has been investigated and gave rise to unsaturated 1,4-
diketone 2cf in 36% yield.
Acknowledgment. This work is supported by NSFC
(no. 21102054) and Open Project of State Key Laboratory
for Supramolecular Structure and Materials (sklssm201220).
Special gratitude goes to Professor Sean Xiao-An Zhang
(College of Chemistry, Jilin University, China) for his
long-term support.
To gain some preliminary mechanistic understanding of
this intramolecular transformation, control experiments
were conducted (Scheme 5). Since phosphines can undergo
1,2-addition to carbonyl compounds,7b,5g a possible alter-
native mechanism is that the attack of phosphine at the
CdO bond of O-acyl group of cyanohydrin 1aa, which
results in ketone 4a and acylphosphonium salt (VI), and
Supporting Information Available. General procedure
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org. The
authors declare no competing financial interest.
(11) Recent examples for conjugate addition of cyanide to
R,β-unsaturated carbonyl compounds, see: Tanaka, Y.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 8862; see Supporting
Information for further references..
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 9, 2012
2357