Dual organocatalysis: Asymmetric allylic-allylic alkylation of α,α-dicyanoalkenes and Morita-Baylis-Hillman carbonates

Article abstract of DOI:10.1002/chem.200802534

The unprecedented asymmetric allylic-allylic alkylation of α,α-dicyanoalkenes and Morita-Baylis-Hillman (MBH) carbonates were developed by catalyzing by a suitable chiral tertiary amine. The resulting multifunctional alkylation products could also serve a

Full text of DOI:10.1002/chem.200802534

DOI: 10.1002/chem.200802534
Dual Organocatalysis: Asymmetric Allylic–Allylic Alkylation of
a,a-Dicyanoalkenes and Morita–Baylis–Hillman Carbonates
Hai-Lei Cui,[a] Jing Peng,[a] Xin Feng,[a] Wei Du,[a] Kun Jiang,[a] and Ying-Chun Chen*[a, b]
Asymmetric allylic alkylation (AAA) is a powerful proto-
col for accessing enantiomeric compounds that may find
wide applications for further transformations. Previous work
in this area has focused on the utilization of allylic alcohol
derivatives as the electrophilic materials catalyzed by transi-
tion-metal complexes, and an array of interesting results has
been presented over the past few decades.[1] Recently, an-
other strategy, the allylic alkylation of Morita–Baylis–Hill-
man (MBH) adducts[2] with various nucleophiles by the
metal-free catalysis of tertiary amines or phosphines,[3] has
emerged as a very versatile approach to deliver multifunc-
tional allylic-substituted compounds. High efficacy and ex-
cellent regioselectivities have been noted for a number of al-
lylic alkylation reactions of MBH adducts; however, quite
limited progress has been made in their asymmetric var-
iants.[4] Therefore, the development of effective catalytic sys-
tems and new allylic alkylation reactions for MBH adducts
is in high demand.
molecular conjugate addition;[6] thus chiral cyclohexenes
with multiple substitutions could be efficiently constructed
(Scheme 1). Furthermore, the resulting multifunctional alky-
lation products might also serve as versatile intermediates
for other synthetic transformations.
Scheme 1. Proposed allylic–allylic alkylation and successive Michael addi-
tion for accessing chiral cyclohexenes with multiple substitutions.
Recently, we and Jørgensen et al. independently estab-
lished that a,a-dicyanoalkenes can perform as useful nucleo-
philes for an array of asymmetric allylic alkylation or func-
tionalization reactions.[5] In our continuing efforts to expand
the synthetic utility of these synthons, we envisaged that an
unprecedented asymmetric allylic–allylic alkylation of a,a-
dicyanoalkenes and MBH carbonates might be developed
catalyzed by a suitable chiral tertiary amine. The counter-
parts from two reactants might further behave as Michael
donor and acceptor, respectively, to furnish a tandem intra-
The initial study with a,a-dicyanoalkene 2a and MBH
carbonate 3a catalyzed by quinidine 1a (Scheme 2,
10 mol%) was inspiring. The desired allylic–allylic alkyla-
[a] H.-L. Cui, J. Peng, X. Feng, W. Du, K. Jiang, Prof. Dr. Y.-C. Chen
Key laboratory of Drug-Targeting and Drug Delivery Systems
of the Education Ministry, Department of Medicinal Chemistry
West China School of Pharmacy
Sichuan University, Chengdu, 610041 (China)
Fax : (+86)28-8550-2609
E-mail: ycchenhuaxi@yahoo.com.cn
[b] Prof. Dr. Y.-C. Chen
Scheme 2. A variety of tertiary amine organocatalysts. (DHQD)2PHAL=
hydroquinidine 1,4-phthalazinediyl diether, (DHQD)2PYR=hydroquini-
dine-2,5-diphenyl-4,6-pyrimidinediyl diether, (DHQD)2AQN =hydroqui-
nidine (anthraquinone-1,4-diyl) diether, (DHQ)2AQN =hydroquinine
anthraquinone-1,4-diyl diether.
State Key Laboratory of Biotherapy, West China Hospital
Sichuan University, Chengdu, 610041 (China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200802534.
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COMMUNICATION
tion product 4a was isolated as a single diastereomer, al-
though the enantioselectivity was moderate (Table 1,
entry 1). The domino intramolecular Michael addition prod-
necessary (Table 1, entry 11). Gratifyingly, the reaction
could be conducted at higher temperature in 1,2-dichloro-
ethane (DCE) with little effect on the enantioselectivity
(Table 1, entry 12). Moreover, other modified cinchona alka-
loids such as 1k and 1l were tested, and even better catalyt-
ic efficacy was attained by the catalysis of (DHQD)2AQN
(1l) (Table 1, entries 13 and 14). Finally, we obtained excel-
lent results by employing two equivalents of the MBH
adduct 3a under the similar catalytic conditions (Table 1,
entry 15, 95% yield, 97% ee, in 15 h).[4d] The same results
were obtained when 10 mol% of (R)-BINOL was used
(Table 1, entry 16). On the other hand, the enantiomer 4a,
opposite to that of 1l, could be smoothly prepared in a good
ee value in the presence of (DHQ)2AQN (1m), which was
derived from dihydroquinine (Table 1, entry 17).
Table 1. Screening studies of organocatalytic allylic–allylic alkylation of
a,a-dicyanoalkene 2a and MBH carbonate 3a.[a]
Entry
Cat.
T [8C]
Solvent
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1j
1j
1k
1l
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
40
40
40
40
40
40
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
DCE
DCE
DCE
DCE
DCE
84
120
72
96
13
13
11
24
24
168
120
84
84
36
15
15
19
51
82
54
42
94
94
99
–
66
33
À16
55
Having established the optimal conditions, the scope of
the novel allylic–allylic alkylation was explored with a varie-
53
75
ty of a,a-dicyanoalkenes
2 and MBH carbonates 3
À17
–
(Scheme 3). In general excellent diastereoselectivities (d.r.>
9
10
–
–
95
94
90
87
92
97
96
28
88
79
82
62
95
95
76
11[d]
12[d]
13[d]
14[d]
15[d,e]
16[e,f]
17[d,e]
1l
1l
1m
À86
[a] Unless otherwise noted, reactions were performed with 0.1 mmol of
2a, 0.1 mmol of 3a, 0.01 mmol of 1 in 1 mL solvent. [b] Yield of isolated
product. [c] Determined by chiral HPLC analysis, d.r.>99:1. [d] Adding
10 mol% of (S)-BINOL. [e] 0.2 mmol of 3a was used. [f] Adding
10 mol% of (R)-BINOL.
Scheme 3. The structures of a,a-dicyanoalkenes 2.
uct was not detected under the current catalytic conditions.
Poorer results were obtained by catalysis by the 6’-deme-
thylquinidine derivative 1b (Table 1, entry 2). The reactions
catalyzed by quinine 1c and 6’-demethylquinine 1d were
also unsatisfactory (Table 1, entries 3 and 4).[7] Nevertheless,
b-ICD 1e, prepared from quinindine,[8] exhibited much
higher catalytic activity, but the enantioselectivity was still
modest (Table 1, entry 5). On the basis of the bifunctional
characteristics of 1e, catalyst 1 f containing (S)-BINOL ((S)-
(À)-1,1’-bi-2-naphthol) and (S)-quinuclidine-3-amine struc-
tures was designed,[9] and better enantiocontrol was ob-
served (Table 1, entry 6); however, catalyst 1g, which con-
tained (S)-BINOL and (R)-quinuclidine-3-amine, afforded a
poor ee value (Table 1, entry 7). Unfortunately, the analo-
gous catalysts 1h and 1i condensed from (S)-BINOL and 9-
amino-9-deoxyepiquinidine and 9-amino-9-deoxyepiqui-
nine,[10] respectively, showed no catalytic activity in the
model reaction, probably for steric reasons (Table 1, en-
tries 8 and 9). Subsequently, it was pleasing to find that com-
mercially available modified cinchona alkaloid 1j showed
excellent enantioselectivity, but the reaction was too slug-
gish (Table 1, entry 10).[11] The presence of 10 mol% of (S)-
BINOL as a Brønsted acid co-catalyst improved the isolated
yield dramatically,[12,13] while long reaction times were still
99:1) were observed in the tested reactions. For a,a-dicya-
noalkene 2a, outstanding enantioselectivities were achieved
with MBH carbonates bearing diversely substituted aryl or
heteroaryl groups (Table 2, entries 1–11). MBH carbonates
with strong electron-withdrawing substitutions exhibited
higher reactivity, and better results were obtained at ambi-
ent temperature (Table 2, entries 5 and 6) or at 08C
(Table 2, entries 7 and 8).[14] Excellent results were achieved
with the MBH adduct from methyl vinyl ketone (Table 2,
entry 12). Nevertheless, a modest ee value was obtained for
the MBH adduct from acrylonitrile even at 08C (Table 2,
entry 13). Subsequently, the reaction scope for a,a-dicya-
noalkenes 2 was investigated. Remarkable enantioselectivi-
ties were obtained for a,a-dicyanoalkenes 2b–2d and 2 f–2i
derived from diversely structured cyclic or acyclic aryl ke-
tones (Table 2, entries 14–21). It was noteworthy that the re-
action could be conducted at much lower catalyst loadings.
The same results were obtained in the reaction of 2b and 3a
in the presence of only 2 mol% of 1l and (S)-BINOL after
30 h (Table 2, entry 15). a,a-Dicyanoalkenes derived from
aliphatic ketones also exhibited good reactivity in the allyl-
ic–allylic alkylation. Exclusive regioselectivity with excellent
stereoselectivity was obtained at the methylene position for
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Y.-C. Chen et al.
Table 2. Asymmetric allylic–allylic alkylation of a,a-dicyanoalkenes 2
and MBH carbonates 3.[a]
ucts 4b and 4i were also prepared in good ee values cata-
lyzed by 1m under similar conditions (Table 2, entries 23
and 24).
Interestingly, under the same catalytic conditions as
above, for a,a-dicyanoalkene 2e, cyclohexene derivatives
6a–6c were directly isolated in excellent enantioselectivities
with modest d.r. ratios. Apparently, the expected allylic–al-
lylic alkylation happened, followed by a domino intramolec-
ular Michael reaction, which generated the desired cyclo-
hexene products. The final protonation process gave rise to
unsatisfactory diastereoselectivity. The elimination of HCN
was observed when the mixture of 6b was treated with
KOtBu, from which the diastereomerically pure diene 7
could be separated (Scheme 5).
Entry
2
R2
E
Product Yield [%][b] ee [%][c]
1
2
3
2a Ph
COOMe 4a
COOMe 4b
COOMe 4c
COOMe 4d
COOMe 4e
COOMe 4 f
COOMe 4g
COOMe 4h
95
96
95
96
99
94
85
85
93
85
87
94
96
82
85
92
92
91
79
70
73
99
81
85
97[d]
96
96
92
95
90
84
92
93
96
93
92
76
96
96
96
97
97
97
94
95
98
2a p-Cl-Ph
2a m-Cl-Ph
2a o-Cl-Ph
2a p-F-Ph
2a m-CN-Ph
2a p-NO2-Ph
2a 3,4-Cl2-Ph
4
5[e]
6[e]
7[f]
8[f]
9
2a p-MeO-Ph COOMe 4i
10
11
12
13[f]
14
15[g]
16
17
18
19
20
21
22
23[h]
24[h]
2a m-Me-Ph
2a 2-furyl
2a Ph
2a Ph
2b Ph
2b Ph
2c Ph
2d Ph
2 f Ph
2g Ph
2h Ph
2i
2j
2a p-Cl-Ph
2a p-MeO-Ph COOMe 4i
COOMe 4j
COOMe 4k
COCH3
CN
4l
4m
COOMe 4n
COOMe 4n
COOMe 4o
COOMe 4p
COOMe 4q
COOMe 4r
COOMe 4s
COOMe 4t
COOMe 4u
COOMe 4b
Ph
Ph
À80
À80
Scheme 5. A domino process for accessing cyclohexene derivatives.
[a] Unless otherwise noted, reactions were performed with 0.1 mmol of 2,
0.2 mmol of 3, 10 mol% of 1l and 10 mol% of (S)-BINOL in 1.0 mL
DCE at 408C for 10–24 h. [b] Yield of isolated product. [c] Based on
chiral HPLC analysis, d.r.>99:1. [d] The absolute configuration of 4a
was determined by X-ray analysis, please see Supporting Information.[15]
The other products were assigned by analogy. [e] At room temperature.
[f] At 08C for 65 h. [g] With 2 mol% of 1l and (S)-BINOL at 0.5 mmol
scale, for 30 h. [h] With 1m as the catalyst.
Likewise, the allylic–allylic alkylation product 4n could
be also cyclized to give the desired cyclohexene 8 in the
presence of the stronger organic base 1,8-diazabicyclo-
AHCTUNGTREG[NNUN 5.4.0]undec-7-ene (DBU) without racemization. Neverthe-
less, the same product 8 was recovered after treating with
KOtBu (Scheme 6). On the other hand, an unexpected
cyclic product 9 was afforded when the allylic compound 4s
the unsymmetrical substrate 2j (Table 2, entry 22). Mixtures
of mono- and double-allylic alkylation products were
formed when symmetric a,a-dicyanoalkenes 2k and 2l were
applied; nevertheless, the double-allylic alkylation adducts
5a and 5b with four stereogenic centers could be isolated as
single diastereomers with remarkable ee values by employ-
ing four equivalents of the MBH carbonate 3a (Scheme 4).
Nevertheless, a,a-dicyanoalkene 2m, which was derived
from the aliphatic aldehyde, could not be successfully ap-
plied in this allylic–allylic alkylation, and the self-condensa-
tion of 2m was observed by the catalysis of basic 1l. On the
other hand, the opposite enantiomeric allylic–allylic prod-
Scheme 4. Double allylic–allylic alkylation of symmetric a,a-dicyanoal-
kenes 2k and 2l.
Scheme 6. Transformations of allylic adducts.
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Dual Organocatalysis
COMMUNICATION
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(Scheme 6).[16]
In conclusion, we have developed the first highly enantio-
selective allylic–allylic alkylation of a,a-dicyanoalkenes and
Morita–Baylis–Hillman carbonates by dual organocatalysis
of commercially available modified cinchona alkaloids and
(S)-BINOL. Excellent stereoselectivities were achieved for
a broad spectrum of substrates (d.r.> 99:1, up to 99% ee).
Several enantioenriched compounds with complex cyclic
structures were derived from the allylic products.[17] We be-
lieve that this catalytic strategy will be applicable to other
asymmetric reactions of MBH adducts and further work in
this direction is currently underway.
Acknowledgements
We are grateful for the financial support from the NSFC (20772084), the
Ministry of Education (NCET-05-0781), and the Sichuan Province Gov-
ernment (07ZQ026-027).
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Keywords: asymmetric allylic alkylation · cyclohexenes ·
dicyanoalkenes · organocatalysis · Morita–Baylis–Hillman
carbonates
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Received: December 4, 2008
Published online: January 8, 2009
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