Construction of highly functional quaternary carbon stereocenters via an organocatalytic tandem cyanation-allylic alkylation reaction

Article abstract of DOI:10.1021/ol202499g

The first tertiary amine-catalyzed tandem cyanation-allyic alkylation (CAA) reaction of aldehydes, appropriate cyanide sources, and Morita-Baylis-Hillman (MBH) adducts has been developed, which provides a facile access to densely functionalized products c

Full text of DOI:10.1021/ol202499g

ORGANIC
LETTERS
2011
Vol. 13, No. 23
6164–6167
Construction of Highly Functional
Quaternary Carbon Stereocenters via an
Organocatalytic Tandem
CyanationꢀAllylic Alkylation Reaction
Zhe Zhuang, Feng Pan, Jian-Guo Fu, Jian-Ming Chen, and Wei-Wei Liao*
Department of Organic Chemistry, College of Chemistry, Jilin University,
2699 Qianjin Street, Changchun 130012, China
wliao@jlu.edu.cn
Received September 14, 2011
ABSTRACT
The first tertiary amine-catalyzed tandem cyanationꢀallyic alkylation (CAA) reaction of aldehydes, appropriate cyanide sources, and
MoritaꢀBaylisꢀHillman (MBH) adducts has been developed, which provides a facile access to densely functionalized products containing
O-substituted quaternary centers.
Catalytic multistep processes, whereby one or more
catalysts promote two or more distinct chemical transfor-
mations in a single flask, have received growing attention
due to their high efficiency and economy to access valuable
molecular constructs.1 Several successful synthetic strate-
gies based on this concept have been developed to enable
the construction of diverse molecular architectures via
organocatalysis.2 As a fundamentally important chemical
transformation, to construct molecules with tetrasub-
stituted carbon stereocenters represents a stimulating
challenge in modern organic synthesis.3 Although signifi-
cant progress has been made toward this target, utilization
of novel catalytic multistep processes, especially via orga-
nocatalytic tandem pathways to access densely functiona-
lized products containing O-substituted quaternary
stereocenters, is still required.4
The addition of cyanide to carbonyl compounds is
one of the oldest known CꢀC bond-forming reactions,
and cyanohydrins have demonstrated considerable synthetic
potential as useful building blocks.5Although cyanohydrins
(3) For selected recent reviews of catalytic asymmetric reactions, see:
(a) Corey, E. J.; Guzman-Perez, A. Angew. Chem., Int. Ed. 1998, 37, 388.
(b) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5363. (c) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (d) Cozzi, P. G.;
Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969. (e)
Hawner, C.; Alexakis, A. Chem. Commun. 2010, 46, 7295. (f) Bella,
M.; Gasperi, T. Synthesis 2009, 10, 1583.
(1) For selected recent reviews on multicatalysis, see: (a) Enders, D.;
Grondal, C.; Huettl, M. R. M. Angew. Chem., Int. Ed 2007, 46, 1570. (b)
Walji, A. M.; MacMillan, D. W. C. Synlett 2007, 1477. (c) Ramachary,
D. B.; Jain, S. Org. Biomol. Chem 2011, 9, 1277. (d) Zhou, J. Chem.;
Asian J. 2010, 5, 422. (e) Ambrosini, L. M.; Lambert, T. H. ChemCatCh-
em 2010, 2, 1373.
(2) For selected recent examples: (a) Rueping, M.; Kuenkel, A.; Tato,
F.; Bats, J. W. Angew. Chem., Int. Ed. 2009, 48, 3699. (b) Reyes, E.;
Talavera, G.; Vicario, J. L.; Badia, D.; Carrillo, L. Angew. Chem., Int.
Ed. 2009, 48, 5701. (c) Brandau, S.; Maerten, E.; Jorgensen, K. A. J. Am.
Chem. Soc. 2006, 128, 14986. (d) Enders, D.; Huettl, M. R. M.; Runsink,
J.; Raabe, G.; Wendt, B. Angew. Chem., Int. Ed 2007, 46, 467. (e) Zhao,
G.-L.; Rios, R.; Vesely, J.; Eriksson, L.; Cordova, A. Angew. Chem., Int.
Ed. 2008, 47, 8468. (f) Simmons, B.; Walji, A. M.; MacMillan, D. W. C.
Angew. Chem., Int. Ed. 2009, 48, 4349. For recent reviews, see: (g)
Enders, D.; Grondal, C.; Huettl, M. R. M. Angew. Chem., Int. Ed. 2007,
46, 1570.
(4) For examples of organocatalytic domino synthesis of tertiary
alcohols, see: (a) Halland, N.; Aburel, P. S.; Jorgensen, K. A. Angew.
Chem. 2004, 116, 1292. Angew. Chem., Int. Ed. 2004, 43, 1272. (b) Zhao,
ꢀ
ꢀ
G.-L.; Vesely, J.; Rios, R.; Ibrahem, I.; Sunden, H.; Cordova, A. Adv.
Synth. Catal 2008, 350, 237.
(5) For reviews, see: (a) North, M. Tetrahedron: Asymmetry 2003, 14,
147. (b) Gregory, R. J. H. Chem. Rev. 1999, 99, 3649. (c) Brunel, J.-M.;
Holmes, I. P. Angew. Chem., Int. Ed. 2004, 43, 2752. (d) North, M.;
Usanov, D. L.; Young, C. Chem. Rev. 2008, 108, 5146. (e) Wang, W. T.;
Liu, X. H.; Lin, L. L.; Feng, X. M. Eur. J. Org. Chem. 2010, 25, 4751.
r
10.1021/ol202499g
Published on Web 11/10/2011
2011 American Chemical Society

containing an acidic proton which can be employed as
nucleophilic reagents have been applied in organic
synthesis,6 to the best of our knowledge, organocatalytic
synthesis of tertiary alcohols based on cyanohydrins,
which have potential utility in organic synthesis CꢀC bond
formations, has been undeveloped.7
which contain a tertiary alcohol moiety, as well as cyanide
and allylic functional groups.
Here, we report the first CAA reaction with MBH
adducts, providing a useful protocol to prepare highly
functionalized cyanohydrins.
To assess the feasibility of an organocatalytic tandem
CAA reaction, an initial investigation was examined
with MBH carbonate 2a and preformed cyanohydrins 1a
which were prepared readily from benzaldehyde and
ethyl cyanoformate in the presence of organic Lewis base
catalysts.9,10 Gratifyingly, this reaction proceeded well
in toluene with a catalytic amount of DABCO (1,4-dia-
zabicyclo[2.2.2]octane) (Table 1, entry 1). Under these
optimized conditions, intermolecular catalytic allylic alky-
lation of MBH adducts with a spectrum of prochiral
cyanohydrins derived from aldehydes was surveyed to
explore the generality of this transformation. The results
are summarized in Table 1. For the cyanohydrins prepared
from aromatic aldehydes with electron-withdrawing or -
donating substituents, the corresponding allylic alkylation
products 3aꢀ3d, 3g were obtained in good to excellent
yields. When cyanohydrins with ortho-substituents at the
aryl group (1e and 1f) were employed, low transformations
and long reactiontimes wereobserved(72h, 17% for3e; 30
h, 42% for 3f), presumably due to a steric hindrance effect.
However, submitting this reaction in acetonitrile provided
3e and 3f in moderate to high yields (Table 1, entries 5, 6).
The allylic alkylation of MBH acetate 2c with cyano-
hydrins 1a failed to give desired product 3a. In contrast
to aromatic analogue 1a, cyanohydrin 1l possessing two
electron-withdrawing groups can smoothly react with
MBH acetate 2c to provide 3l with 95% yield (Table 1,
entries 13, 14), which reveals a dramatic dependence on the
ΔpKa between the conjugate acid of the leaving group and
the pronucleophile. The subsititution of MBH carbonate
2a with heteroaromatic substituted cyanohydrins 1h also
gave rise to desired product 3h in 71% yield. MBH adduct
2d which would allow the generation of vicinal quaternary
and tertiary carbon centers was investigated. Cyanohy-
drins 1a reacted with 2d to furnish desired product 3r in
high yield with low diastereoselectivity (dr: 1/1, Table 1,
entry 15). Furthermore, O-protected derivatives such as
O-acetyl, O-benzoyl, and O-trimethylsilyl cyanohydrins
have been investigated. O-Acetyl and O-benzoyl cyano-
hydrins readily reacted with MBH carbonate 2a to afford
desired products (Table 1, entries 10, 11), while O-TMS
cyanohydrin 1k did not provided any desired product
under standard reaction conditions (Table 1, entry 12).
As a further demonstration of the scope of this reac-
tion, catalytic allylic alkylation of MBH adducts 2 with
Figure 1. Strategy of tandem cyanationꢀallylic alkylation
reaction.
Recently, the metal-free Lewis base catalyzed substitu-
tion of MBH adducts has emerged as a powerful tool for
preparing multifunctional compounds.8 This approach
normally relies on a tandem SN20/SN20substitution se-
quence to access allylic product. We envisioned that these
two distinct chemical transformations could be triggered
by one or more organocatalysts, therefore creating a new
CꢀC bond formation in a sequential way which may
deliver substantial increases in molecular complexity via
single-pot operations without the need for intermediate
workups or purifications, since they share similar or the
same catalysts and reaction environment. As outlined in
Figure 1, initial O-substituted cyanohydrins I from alde-
hydes would be generated by an organocatalyst in situ.
Subsequently, the deprotonation of the acidic CH group of
cyanohydrins by the oxygen-based anion generated in situ
would occur, and selective allylic alkylation would follow
to deliver valuable densely functionalized products II,
(6) For reviews, see: (a) Albright, J. D. Tetrahedron 1983, 39, 3207.
For selected examples in organic synthesis, see: (b) Moritani, Y.;
Fukushima, C.; Ukita, T.; Miyagishima, T.; Ohmizu, H.; Iwasaki, T.
J. Org. Chem. 1996, 61, 6922. (c) Katritzky, A. R.; Zhang, G.; Jiang, J.
J. Org. Chem. 1995, 60, 7589.
(7) Pd-catalyzed allylic alkylation of prochiral cyanohydrins: Tsuji,
J.; Shimizu, I.; Minami, I.; Ohashi, Y.; Sugiura, T.; Takahashi, K.
J. Org. Chem. 1985, 50, 1523.
(8) For selected examples, see: (a) Cho, C.-W.; Krische, M. J. Angew.
Chem., Int. Ed. 2004, 43, 6689. (b) Du, Y.; Han, X.; Lu, X. Tetrahedron
Lett. 2004, 45, 4967. (c) Cho, C.-W.; Kong, J.-R.; Krische, M. J. Org.
Lett. 2004, 6, 1337. (d) van Steenis, D. J. V. C.; Marcelli, T.; Lutz, M.;
Spek, A. L.; van Maarseveen, J. H.; Hiemstra, H. Adv. Synth. Catal.
2007, 349, 281. (e) Jiang, Y.-Q.; Shi, Y.-L.; Shi, M. J. Am. Chem. Soc.
2008, 130, 7202. (f) Cui, H.-L.; Feng, X.; Peng, J.; Lei, J.; Jiang, K.;
Chen, Y.-C. Angew. Chem., Int. Ed. 2009, 48, 5737. (g) Cui, H.-L.; Peng,
J.; Feng, X.; Du, W.; Jiang, K.; Chen, Y.-C. Chem.;Eur. J. 2009, 15,
1574. (h) Jiang, K.; Peng, J.; Cui, H.-L.; Chen, Y.-C. Chem. Commun.
2009, 3955. (i) Feng, X.; Yuan, Y.-Q.; Cui, H.-L.; Jiang, K.; Chen, Y.-C.
Org. Biomol. Chem. 2009, 7, 3660. (j) Cui, H.-L.; Huang, J.-R.; Lei, J.;
Wang, Z.-F.; Chen, S.; Wu, L.; Chen, Y.-C. Org. Lett. 2010, 12, 720. (k)
Huang, J.-R.; Cui, H.-L.; Lei, J.; Sun, X.-H.; Chen, Y.-C. Chem.
Commun. 2011, 4784. (l) Hong, L.; Sun, W. S.; Liu, C. X.; Zhao,
D. P.; Wang, R. Chem. Commun. 2010, 46, 2856. (m) Sun, W. S.; Hong,
L.; Liu, C. X.; Wang, R. Org. Lett. 2010, 12, 3914. (n) Jiang, L.; Lei, Q.;
Huang, X.; Cui, H. L.; Zhou, X.; Chen, Y.-C. Chem.;Eur. J. 2011, 17,
9489. (o) Yang, W.; Wei, X.; Pan, Y.; Lee, R.; Zhu, B.; Liu, H.; Yan, L.;
Huang, K. W.; Jiang, Z.; Tan, C. H. Chem.;Eur. J. 2011, 17, 8066.
(9) For examples of synthesis of racemic O-carbonylated cyanohy-
drins using nonchiral tertiary amines, see: (a) Hoffmann, H. M. R.;
Ismail, Z. M.; Hollweg, R.; Zein, A. R. Bull. Chem. Soc. Jpn. 1990, 63,
1807. (b) Poirier, D.; Berthiaume, D.; Boivin, R. P. Synlett 1999, 1423.
(c) Berthiaume, D.; Poirier, D. Tetrahedron 2000, 56, 5995. (d) Deardorff,
D. R.; Taniguchi, C. M.; Tafti, S. A.; Kim, H. Y.; Choi, S. Y.; Downey,
K. J.; Nguyen, T. V. J. Org. Chem. 2001, 66, 7191. (e) Aoki, S.; Kotani,
S.; Sugiura, M.; Nakajima, M. Tetrahedron Lett. 2010, 51, 3547. (f)
Baeza, A.; Najera, C.; Retamosa, M. G.; Sansano, J. M. Synthesis 2005,
16, 2787.
(10) See Supporting Information for details.
Org. Lett., Vol. 13, No. 23, 2011
6165

Table 1. Direct Allylic Alkylation of O-Protected Cyanohydrins
with MBH Adducts 2a
Table 2. Direct Allylic Alkylation of O-Protected Allylic Cya-
nohydrin 1 with MBH Adducts 2a
t
yield
(%)b
entry
1
R4
R5
R6
Me
3
(h)
t
yield
(%)b
entry
1
R1
R2
2
3
(h)
1
2
3
4
1m
1n
1o
1p
H
H
3m
3n
3o
3p
6
9
71
81
73
81
H
H
n-C3H7
Ph
1
1a
1b
1c
1d
1e
1f
Ph
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
COMe
COPh
TMS
2a
2a
2a
2a
2a
2a
2a
2a
2b
2a
2a
2a
2a
2c
2d
3a
3b
3c
3d
3e
3f
12
12
21
12
24
12
15
9
98
96
78
86
58
89
99
71
97
84
83
Me
H
H
15
3
2
4-ClC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
2-BrC6H4
2-naphyl
2-furyl
Ph
Me
Ph
3
4
a Reactions were performed with 1 (0.4 mmol), 2a (0.2 mmol),
(Boc)2O (0.2 mmol), and 20 mol % of DABCO in CH3CN at 30 °C.
b Isolated yield.
5c
6c
7
1g
1h
1a
1i
3g
3h
3q
3i
8
9
12
12
24
12
2
this solvent-free condition, a variety of above-mentioned
allylic substituted cyanohydrins with O-substituted qua-
ternary centers can been readily and rapidly prepared from
commercially available aldehydes and cyanoformates by
using this tandem cyanationꢀallylic alkyation reaction.10
10
11
12
13e
14f
15
Ph
1j
Ph
3j
d
1k
1l
Ph
3k
3l
ꢀ
CO2Et
CO2Et
Ph
COMe
COMe
CO2Et
92
1l
3l
2
95
88g
1a
3r
12
a Unless otherwise noted, reactions were performed with 0.3 mmol of
1a, 0.6 mmol of 2a, 0.15 mmol of (Boc)2O, and 20 mol % of DABCO in
3.0 mL of toluene at 30 °C. b Isolated yield. c The reactions was
performed in CH3CN. d No desired product was detected. e The reac-
tions was performed at 0 °C . f The reactions was performed at 18 °C .
g Mixture of diastereomers. dr: 1/1 (determined by 1H NMR).
Table 3. Tandem CyanationꢀAllylic Alkylation Reaction with
MBH Adductsa
R,β-unsaturated cyanohydrins 1 prepared from R,β-unsa-
turated aldehydes was attempted, which would provide
more synthetic useful allylic and vinyl substituted cyano-
hydrin derivatives. In contrast to the palladium-catalyzed
allylation, in which acylated R,β-unsaturated cyanohy-
drins are used to generate (π-allyl) palladium complexes
and subsequently react with nucleophiles,9d cyanohydrins
1 acted as nucleophiles and attacked activated MBH
adducts to furnish 3 (Table 2). Gratifyingly, whether upon
exposure of the β-alkyl (Table 2, entries 1, 2), or β-aryl,
R,β-substituted cyanohydrin carbonates (Table 2, entries
3, 4) and MBH carbonate 2a to modified reaction condi-
tions, efficient conversions to the corresponding allylic
products 3 were observed.
t (1st/2nd, yield
entry
R1
2
R3
3
h/h) b
(%)c
1
Ph
2a Me 3a
2a Me 3f
2a Me 3g
2a Me 3h
2b Et 3m
0.5/2
1/2
92
70
91
81
67
67
61
49
2
2-BrC6H4
3d
4e
5f
6f
7f
8f
2-naphthyl
2-furyl
0.5/3
1/3
(E)-CH3CHdCH
1/2
(E)-CH3(CH2)2CHdCH 2b Et 3n
1/2
(E)-Ph(CH3)CHdCH
(E)-PhCHdCH(CH3)
2b Et 3p
2b Et 3o
1/1
1/1
We next focused our attention on the development of a
catalytic cascade version of the CAA reaction. Recently,
much effort has been focused toward achieving a facile and
environmentally friendly procedure for the synthesis of
O-substituted cyanohydrins from aldehydes.9 In particu-
lar, solvent-free synthesis makes cyanation of carbonyl
compounds more attractive due to its environmental,
safety, and economical benefits.9e,f Interestingly, simple
treatment of benzaldehyde and ethyl cyanoformate with
catalyst DABCO (20%) in the absence of solvent and
subsequent addition of MBH adducts furnished the ex-
pected products 3a in 92% yield (Table 3, entry 1). Under
a Reaction was performed with 4 (0.3 mmol), ethyl cyanoformate 5
(0.33 mmol), and 20 mol % of DABCO in neat at 30 °C during 1st step; 2
(0.6 mmol) and (BOC)2O (0.15 mmol) were added during the 2nd step.
b 1st/2nd = the 1st step time/the 2nd step time. c Isolated yield. d The
reaction was performed in CH3CN (0.1 mL). e During the 2nd step,
CH3CN (3.0 mL) was added. f Aldehyde 4 (0.40 mmol), cyanoformate 5
(0.44 mmol), and NEt3 (20%) were employed during the 1st step; 2 (0.2
mmol), (BOC)2O (0.2 mmol), and 20 mol % of DABCO were added
during the 2nd step.
Investigation of asymmetric CAA reactions of MBH
adducts were carried out by employing various chiral
6166
Org. Lett., Vol. 13, No. 23, 2011

Scheme 1. Asymmetric Allylic Alkylation Reactions of O-Pro-
tected Cyanohydrin 1 with MBH Adducts
Scheme 2. Synthetic Applications of the CAA Substitution
Adducts
tertiary amines. (DHQD)2PHAL gave the best enantios-
electivity (Scheme 1).10 When the simple MBH adduct 2a
was employed, almost racemic products were obtained
in 89% yield with 4% ee. Although the substitution of
MBH carbonate 2d with 1a afforded desired product 3q
with moderate stereoselectivity (dr: 1/1.4, ee: 75%/81%),
the low yield was obtained probably due to the lower
activity of the catalyst.
Finally, the synthetic utilities of CAA products were illu-
strated. The treatment of 3a with a K2CO3 (20%) in MeOH/
H2O solution afforded the corresponding ketone 6 in 70%
yield.9c The nitrile functionality of products can also serve as
an effective handle for further elaboration. For example, the
reaction of a Reformatsky reagent, derived from ethyl R-
bromoacetate and zinc, with 3a resulted in highly functiona-
lized 2-oxazolidinones 7 in 73% yield (Scheme 2).11
R,β-unsaturated aldehydes could be successfully applied
to give multifunctional desired products which have
potential utilities in organic synthesis. An asymmetric
version of this reaction has also been demonstrated and
displayed a moderate stereoselectivity. Furthermore, the
first organocatalytic tandem CAA reaction has been
applied on solvent-free conditions which makes it more
environmentally friendly and economical. Further stu-
dies on synthetic applications and asymmetric catalysis
are ongoing in our laboratories and will be reported in
due course.
Acknowledgment. Support of this work by NSFC (No.
21102054) and Jilin University (China) is greatly appre-
ciated. Special gratitude goes to Professor Yong Tang
(Shanghai Institute of Organic Chemistry, Chinese Acad-
emy of Sciences, Shanghai, China) for his long-term sup-
port. This work is dedicated to Prof. M. F. Semmelhack
(Department of Chemistry, Princeton University, NJ,
USA) on the occasion of his 70th birthday.
In conclusion, we have demonstrated an organocata-
lytic cyanationꢀallylic alkylation reaction with alde-
hydes, cyanoformate, and MBH adducts, which pro-
vided an efficient synthetic route for the preparation
of densely functionalized products bearing an O-sub-
stituted quaternary centers. A number of aromatic or
Supporting Information Available. General procedure
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
(11) Syed, J.; Forster, S.; Effenberger, F. Tetrahedron: Asymmetry
1998, 9, 805.
Org. Lett., Vol. 13, No. 23, 2011
6167