Highly enantioselective [4 + 2] cycloadditions of allenoates and dual activated olefins catalyzed by N-acyl aminophosphines

Article abstract of DOI:10.1039/c2ob25295c

An asymmetric organocatalytic [4 + 2] cycloaddition between α-substituted allenoates and dual activated olefins using bifunctional N-acyl aminophosphine catalysts is described. The use of 2-cyano acrylate derived olefins led to the first successful incorp

Full text of DOI:10.1039/c2ob25295c

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PAPER
Highly enantioselective [4 + 2] cycloadditions of allenoates and dual activated
olefins catalyzed by N-acyl aminophosphines†
Hua Xiao,a Zhuo Chai,b Dongdong Cao,a Hongyu Wang,a Jinghao Chenb and Gang Zhao*a,b
Received 9th February 2012, Accepted 23rd February 2012
DOI: 10.1039/c2ob25295c
An asymmetric organocatalytic [4 + 2] cycloaddition between α-substituted allenoates and dual activated
olefins using bifunctional N-acyl aminophosphine catalysts is described. The use of 2-cyano acrylate
derived olefins led to the first successful incorporation of an electrophile derived from an aliphatic
aldehyde into this reaction.
asymmetric transformation using simple amino acids-derived N-
Introduction
acyl aminophosphine catalysts.9b However, reports on the all-
Since Lu and co-workers’ pioneering studies,1 the phosphine-
catalyzed dipole cycloaddition reaction has made tremendous
carbon version of this asymmetric [4 + 2] cycloaddition leading
to chiral multifunctional cyclohexenes remains very rare,10
progress to become a powerful strategy for the construction of a
range of synthetically valuable cyclic structures from easily
accessible starting materials.2 On one hand, the incorporation of
electrophiles such as electron-deficient CvC, CvN, CvO into
this reaction enabled the synthesis of both carbo- and hetero-
cycles.3 On the other hand, based on mechanistical analysis of
the proposed zwitterionic allenoate–phosphine intermediate,
rational modifications in the allenoate or its surrogates have led
to even more interesting and useful scope extensions of this
methodology.4–6 Particularly, Kwon and co-workers initiated the
utilization of suitably substituted allenoates as four-carbon
donors in this reaction, allowing for the construction of six-mem-
bered ring structures through [4 + 2] cycloadditions with this
methodology,5 which might serve as a complementary alternative
to the Diels–Alder reaction. In contrast to this impressive pro-
gress, the development of asymmetric variants in this field some-
what lags behind as most successful works in this regard have
been restricted to asymmetric [3 + 2] cycloadditions.7,8
although its non-enantioselective version has also been reported
by Kwon & Tran in 2007.5b In view of the great importance of
the resulting chiral cyclohexenes in the total synthesis of numer-
ous natural and biologically active compounds,2g the develop-
ment of an enantioselective version of this reaction is thus highly
desirable. In addition, only the use of olefins derived from malo-
nonitriles and aryl aldehydes has been reported as successful
electrophiles in this reaction11 and thus there is still a need to test
the suitability of other dual activated olefins, especially those
capable of tolerating aliphatic aldehyde structures for this reac-
tion. As a follow-up of our ongoing program to extend the appli-
cation of these chiral N-acyl aminophosphine catalysts in
asymmetric synthesis,9 we present herein highly diastereoselec-
tive and enantioselective [4 + 2] cycloadditions between alleno-
ates and dual activated olefins catalyzed by these kind of
catalysts.
In 2005, two years after Kwon’s discovery of the non-enantio-
selective reaction,5a Fu and Wurz reported the first asymmetric
α-substituted allenoate–imine [4 + 2] cycloaddition to give chiral
multifunctional tetrahydropyridines catalyzed by a chiral mono-
dentate phosphine.5c Recently, our group also realized this
Results and discussion
Dual activated olefins were first introduced to [3 + 2] cycloaddi-
tions by Lu and co-workers to settle the issue of regioselectivi-
ty.3g In our preliminary study on the asymmetric version of the
aDepartment of Chemistry, University of Science and Technology of
China, Hefei, Anhui 230026, P. R. China. E-mail: zhaog@
mail.sioc.ac.cn; Fax: (+86) 21-64166128
bLaboratory of Modern Synthetic Chemistry, Shanghai Institute of
Organic Chemistry, 354 Fenglin Road, Shanghai 200032, P. R. China
†Electronic supplementary information (ESI) available: Experimental
details, copies of NMR and HPLC spectra for the cycloaddition pro-
ducts, X-ray crystallographic analysis of the cycloadduct 3i. CCDC
860051. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c2ob25295c
Scheme 1 Preliminary study on the asymmetric [4 + 2] cycloaddition
of α-substituted allenoate 2 and dual activated olefins.
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Table 1 Screening of catalyst for the asymmetric [4
+
2]
Table 2 Enantioselective [4 + 2] cycloadditions of allenoate 2 with
dual activated olefins 1 catalyzed by 4ka
cycloadditiona
Entry 1, R
Product Time/h Yieldb (%) eec (%)
1
2
3
4
5
6
7
8
1a, Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
4
3
3
4
6
3
4
12
0.4
0.2
2.5
6
4
4
94
92
95
86
99
80
77
87
88
81
96
88
87
94
96
97
95
97
97
97
95
93
89
89
95
96
93
96
1b, isopropyl
1c, 2-naphthyl
1d, 4-BrC6H4
1e, 4-ClC6H4
1f, 4-FC6H4
1g, 3-BrC6H4
1h, 3-ClC6H4
1i, 2-BrC6H4
1j, 2-FC6H4
9d
10d
11
12
13
14
3j
1k, 4-MeOC6H4 3k
Entry
Catalyst
Time/h
Yieldb (%)
Drc
eed (%)
1l, 3-MeOC6H4
1m, 2-thienyl
1n, piperonyl
3l
3m
3n
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4k
24
12
12
6
24
24
24
12
16
6
1
2
2
4
79
69
54
91
Trace
35
54
85
25
82
94
94
94
94
14 : 1
15 : 1
19 : 1
14 : 1
—
14 : 1
19 : 1
19 : 1
17 : 1
15 : 1
15 : 1
15 : 1
15 : 1
19 : 1
85
88
90
92
—
83
85
52
81
73
92
90
91
96
a Reactions were carried out with 1 (0.08 mmol) and 2 (0.16 mmol) in
0.8 mL of 1,2-dichloroethane. b Yields of isolated products.
c Determined by chiral HPLC analysis. d The reaction was conducted at
room temperature.
9
10
11
12
13
14e
series of catalysts with different chiral backbones and NH func-
tionality (Table 1). Some trends in the relationship between the
reaction results and the catalyst structures could be observed: the
use of benzoyl group in the NH moiety is superior to the use of
other protecting groups such as Boc, trifluoromethylacetyl and
thiourea, which indicates the significant role of H-bonding inter-
action in this system; catalysts derived from L-isoleucine and L-t-
butylleucine showed apparent advantage over other amino acid
based catalysts, especially in terms of chemical yield (entries 4,
11–13). These findings are similar to those observed in our pre-
vious study on the [3 + 2] cycloadditions using these kinds of
catalyst.9a As a compromise between catalyst availability and
catalytic activity, catalyst 4k derived from L-isoleucine was
selected for further optimization of other reaction parameters
(entry 13). Further investigation on temperature and solvent
effect (see the ESI† for details) led to the optimum conditions
for this reaction as being 12 mol% of 4k in ClCH2CH2Cl at
−18 °C (entry 14).
Having identified the optimal reaction conditions, the scope of
the asymmetric [4 + 2] cycloaddition with regard to various dual
activated olefins was evaluated.12 As illustrated in Table 2, sub-
strates with electron-withdrawing or electron-donating substitu-
ents at the para- or meta position of the benzene ring were well
tolerated to provide a series of densely functionalized chiral
cyclohexene derivatives with three contiguous stereogenic
centers in high yields, good to excellent enantioselectivities and
diastereoselectivities. For ortho-substituted substrates, probably
due to steric reasons, the reaction needed to be run at an elevated
temperature (RT) to give satisfactory yields with a slight drop in
the enantioselectivity (Table 2, entries 9 and 10). Notably, in all
the cases examined, excellent diastereoselectivity (dr = 19 : 1)
was invariably observed, which showed an obvious advantage
a All reactions were carried out with 1a (0.08 mmol) and 2-(2-ethoxy-2-
oxoethyl)-2,3-butadienoate
2 (0.16 mmol) in the presence of 4
(0.008 mmol) in 0.8 mL of CH2Cl2. b Yields of isolated products.
1
c Determined by H NMR. d Determined by chiral HPLC analysis. e The
reaction was run with 12 mol% of 4k at −18 °C in DCE.
[4 + 2] reaction using catalyst 4c (Scheme 1), exclusive regio-
selectivity was observed with α-substituted allenoate 2, which is
also consistent with the finding of Kwon and co-workers.5b To
our delight, with phenylidenemalononitrile 1a′, the reaction
occurred smoothly to give the functionalized cyclohexene
product in excellent yield and enantioselectivity using catalyst 4c
(see Table 1 for its structure), albeit with unsatisfactory diaster-
eoselectivity. However, further optimizing efforts using different
catalysts to improve the diastereoselectivity with this substrate
did not give satisfactory results (see the ESI† for details). We
then turned our attention to the use of (E)-ethyl 2-cyano-3-phe-
nylacrylate 1a, and similarly to the observation in our previous
work on the asymmetric [3 + 2] annulation reaction with this
type of substrate,9a excellent diastereoselectivity was obtained.
Moreover, it’s assumed that the two different electron-deficient
substituents in this type of substrate may enable different selec-
tive transformations to other useful structures. Consequently,
these types of dual activated olefins were used for further
studies.
Using the reaction between (E)-ethyl 2-cyano-3- phenylacry-
late 1a and allenoate 2 as the model reaction, we first screened a
3196 | Org. Biomol. Chem., 2012, 10, 3195–3201
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The relatively bulkier R and ester groups in the product 3 prefer
to take equatorial positions, namely as in the major diastereo-
isomer product.
Conclusions
In conclusion, we have successfully achieved the asymmetric
[4 + 2] cycloaddition of α-substituted buta-2,3-dienoate and acti-
vated alkenes, providing a range of synthetically valuable cyclo-
hexene structures bearing three contiguous chiral centers with
good to excellent diastereoselectivities and enantioselectivities.
This work, together with our previous studies, demonstrates the
great potential of our N-acyl aminophosphine catalysts in asym-
metric phosphine-mediated reactions. Further studies towards a
deep understanding of the reaction mechanism as well as extend-
ing the application of these readily available and air-stable phos-
phine catalysts are underway.
Scheme 2 Asymmetric [4 + 2] cycloaddition of oxodiene 5 and α-sub-
stituted allenoate 2.
Experimental
General methods
1
The H NMR spectra were recorded on a DPX-300 or Varian
EM-360 (300 MHz). 13C NMR spectra were recorded on a
DPX-300 (300 MHz) or DPX-400 (400 MHz). Flash column
chromatography was performed using H silica gel. For thin-layer
chromatography (TLC), silica gel plates (HSGF 254) were used
and compounds were visualized by irradiation with UV light.
Analytical high performance liquid chromatography (HPLC)
was carried out on WATERS equipment using chiral columns.
Optical rotations were measured on a JASCO P-1010 Polari-
meter at λ = 589 nm. IR spectra were recorded on a Perkin-
Elmer 983G instrument. Mass spectra analysis was performed on
API 200 LC/MS system (Applied Biosystems Co. Ltd).
Fig. 1 A possible working mechanistic model.
over the use of olefins derived from malononitrile.13 Especially,
the very challenging substrate 1b derived from an aliphatic alde-
hyde also successfully coupled with the allenoate rapidly, and
the synthetically useful isopropyl cyclohexene product could be
obtained in 92% yield and 97% ee (Table 2, entry 2). This result
stands out as previous studies using olefins derived from ali-
phatic aldehydes and malononitrile failed to undergo this reac-
tion.5b,10 At present, we’re unable to provide a rationale for this
difference. It’s also worth mentioning that even in the corre-
sponding more studied [3 + 2] systems, successful examples
using electrophiles derived from an aliphatic aldehyde are also
very limited.8h The absolute configuration of the cycloadduct 3i
was determined by X-ray crystallographic analysis to be 1R, 2R,
3R.† The configurations of other products derived from 2-cyano
acrylates were assigned by analogy.14
General procedure for the asymmetric [4 + 2] cycloadditions
To a flame-dried test tube with a magnetic stir bar was added
α-cyanoacrylates or analogs
1 (0.08 mmol), catalyst 4
(0.0096 mmol) and 1,2-dichloroethane (0.8 mL) at room temp-
erature. The solution was allowed to stir for 10 min at −18 °C
before α-substituted 2,3-butadienoate 2 (0.16 mmol) was added
via micro-syringe in one portion, which was followed by vigor-
ously stirring at −18 °C. After the reaction was complete (indi-
cated by TLC), the mixture was directly purified by column
chromatography on silica gel (petroleum ether–ethyl acetate as
the eluent) to furnish the corresponding product.
Besides 2-cyano acrylate derived activated olefins, oxodiene 5
also worked in the reaction at RT to give compound 6 with an
excellent level of enantiocontrol, albeit with a poor diastereo-
selectivity (Scheme 2).15
In light of previous related studies,5,8a,9 a tentative mechanism
was proposed to explain the stereochemical results of the reac-
tion. As illustrated in Fig. 1, a cyclic six-membered pretransition
state I,16 which was modified from the one originally proposed
by Miller and Cowen,8a was held responsible for the enantio-
selectivity of the first addition step favoring Re-face attack on
activated olefins. The first chiral center created in this step would
induce the chirality of the second one formed in the following
step. Then after consecutive proton transfers,5 intermediate II
would be transformed to III to undergo a SN2′ reaction to close
the ring and regenerate the catalyst. The retention of the E/Z
configuration of the dual activated olefins during this reaction is
consistent with previous observations in related reactions.7a,b
(1R,3S)-Diethyl 2,2-dicyano-1,2,3,6-tetrahydro-[1,1′-biphenyl]-
3,4-dicarboxylate (3a′)5b
99% yield as a 73 : 27 mixture of cis and trans isomers; cis
isomer: Colorless, crystalline solid. m.p. = 101–103 °C; [α]D26
−97.7 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ
7.47–7.41 (m, 5H), 7.40–7.38 (m, 1H), 4.36 (d, J = 18.6 Hz,
2H), 4.27 (q, J = 7.0 Hz, 2H), 4.17 (m, 1H), 3.28 (dd, J = 11.8,
4.3 Hz, 1H), 3.13 (dd, J = 20.8, 12.0 Hz, 1H), 2.75 (d, J = 19.6
Hz, 1H), 1.35 (t, J = 7.3 Hz, 3H), 1.32 (t, J = 7.0 Hz, 3H);
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enantiomeric excess: 95%, determined by HPLC (Chiralpak
AD-H column, hexane–i-PrOH 80 : 20, flow rate 0.60 mL
min−1; tmajor = 18.4 min, tminor = 27.5 min, λ = 254 nm).
127.6, 126.9, 126.5, 125.7, 115.4, 63.0, 62.0, 61.1, 53.6, 50.2,
46.4, 29.7, 14.2, 13.9, 13.4; IR (film): 3057, 2983, 2933, 2245,
1748, 1660, 1600, 1466, 1372, 1265, 1091, 1030, 860; HRMS
(ESI): calcd for [M + Na]+(C26H27NaNO6) requires 472.1736,
found 472.1730; enantiomeric excess: 95%, determined by
HPLC (Chiralpak OD column, hexane–i-PrOH 80 : 20, flow rate
0.70 mL min−1; tmajor = 43.6 min, tminor = 20.6 min, λ =
220 nm).
Trans isomer: Light yellow solid. m.p. = 120–122 °C; [α]D26
−24.3 (c = 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ
7.47–7.42 (m, 5H), 7.40–7.38 (m, 1H), 4.39–4.21 (m, 5H), 3.84
(dd, J = 10.9, 5.6 Hz, 1H), 3.03–2.93 (ddt, J = 20.2, 11.1, 2.1
Hz, 1H), 2.88–2.77 (dt, J = 20.2, 5.2 Hz, 1H), 1.37 (t, J = 7.0
Hz, 3H), 1.33 (t, J = 7.0 Hz, 3H); enantiomeric excess: 7%,
determined by HPLC (Chiralpak OD column, hexane–i-PrOH
80 : 20, flow rate 0.75 mL min−1; tmajor = 12.8 min, tminor
8.9 min, λ = 254 nm).
=
(1R,2R,3R)-Triethyl 4′-bromo-2-cyano-1,2,3,6-tetrahydro-
[1,1′-biphenyl]-2,3,4-tricarboxylate (3d)
Yield: 86%; Viscous, colorless oil; [α]2D6 −69.1 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 8.5 Hz, 2H), 7.28
(d, J = 8.3 Hz, 2H), 7.17 (m, 1H), 4.40 (m, 1H), 4.28–4.15 (m,
4H), 4.03 (q, J = 7.1 Hz, 2H), 3.26 (dd, J = 12.3, 4.2 Hz, 1H),
3.03 (m, 1H), 2.61 (dt, J = 19.3, 4.5 Hz, 1H), 1.31–1.23 (m,
6H), 1.01 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
168.5, 166.8, 165.6, 138.1, 135.7, 131.9, 130.1, 126.9, 122.8,
115.1, 63.2, 62.0, 61.1, 53.3, 50.1, 45.7, 29.4, 14.1, 13.9, 13.5;
IR (film): 2983, 2933, 2250, 1745, 1660, 1589, 1489, 1372,
1239, 1183, 1080, 1033, 855, 827, 765; HRMS (ESI): calcd for
(1R,2R,3R)-Triethyl 2-cyano-1,2,3,6-tetrahydro-[1,1′-biphenyl]-
2,3,4-tricarboxylate (3a)
Yield: 94%; Viscous, colorless oil; [α]2D6 −76.4 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.39–7.37 (m, 2H), 7.34–7.32
(m, 3H), 7.19 (m, 1H), 4.43 (m, 1H), 4.29–4.11 (m, 4H), 3.99
(q, J = 7.0 Hz, 2H), 3.28 (dd, J = 12.3, 5.0 Hz, 1H), 3.08 (dd, J
= 19.3, 12.8 Hz, 1H), 2.62 (d, J = 19.3 Hz, 1H), 1.31–1.24 (m,
6H), 0.93 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
168.7, 166.9, 165.7, 138.5, 136.7, 128.7, 128.6, 128.4, 126.8,
115.3, 62.9, 61.9, 61.0, 53.6, 50.1, 46.3, 29.6, 14.1, 13.9, 13.5;
IR (film): 2984, 2931, 2240, 1744, 1661, 1456, 1372, 1241,
1184, 1093, 1037, 738; HRMS (ESI): calcd for [M + Na]+
(C22H25NaNO6) requires 422.1580, found 422.1577; enantio-
meric excess: 96%, determined by HPLC (Chiralpak OD
column, hexane–i-PrOH 80 : 20, flow rate 0.75 mL min−1; tmajor
= 15.0 min, tminor = 10.4 min, λ = 220 nm).
[M
+
Na]+(C22H24NaBrNO6) requires 500.0685, found
500.0679; enantiomeric excess: 97%, determined by HPLC
(Chiralpak OD column, hexane–i-PrOH 80 : 20, flow rate
0.70 mL min−1; tmajor = 29.2.0 min, tminor = 17.7 min, λ =
220 nm).
(1R,2R,3R)-Triethyl 4′-chloro-2-cyano-1,2,3,6-tetrahydro-
[1,1′-biphenyl]-2,3,4-tricarboxylate (3e)
Yield: 99%; Viscous, colorless oil; [α]2D6 −79.3 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.33 (m, 4H), 7.19 (m, 1H), 4.42
(m, 1H), 4.28–4.15 (m, 4H), 4.04 (q, J = 7.0 Hz, 2H), 3.28 (dd,
J = 12.3, 4.1 Hz, 1H), 3.04 (dd, J = 20.5, 10.8 Hz, 1H), 2.62 (dt,
J = 19.3, 4.5 Hz, 1H), 1.32–1.24 (m, 6H), 1.01 (t, J = 7.0 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 168.5, 166.8, 165.6,
138.0, 135.2, 134.7, 129.8, 129.0, 127.0, 115.1, 63.2, 62.0, 61.1,
53.4, 50.1, 45.6, 29.6, 14.1, 13.9, 13.6; IR (film): 2983, 2929,
2245, 1743, 1660, 1494, 1466, 1372, 1239, 1184, 1094, 1026,
(1R,2R,6R)-Triethyl 1-cyano-6-isopropylcyclohex-3-ene-1,2,3-
tricarboxylate (3b)
Yield: 92%; Viscous, colorless oil; [α]2D6 −10.0 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.13 (m, 1H), 4.42–4.32 (m,
2H), 4.25–4.16 (m, 5H), 2.51 (m, 2H), 2.10 (dt, J = 10.5, 4.3
Hz, 1H), 1.84 (m, 1H), 1.40 (t, J = 7.0 Hz, 3H), 1.28–1.25 (m,
6H), 1.09 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 168.8, 167.8, 165.8, 138.9, 126.5,
115.6, 63.2, 61.9, 60.9, 51.8, 50.9, 45.3, 28.9, 22.9, 22.5, 16.5,
14.1, 14.0, 13.9; IR (film): 2979, 2240, 1745, 1662, 1468,
1372, 1233, 1180, 1110, 1069, 1035, 860, 760, 728; HRMS
(ESI): calcd for [M + Na]+ (C19H27NaNO6) requires 388.1736,
found 388.1735; enantiomeric excess: 97%, determined by
HPLC (Chiralpak OD column, hexane–i-PrOH 80 : 20, flow rate
0.65 mL min−1; tmajor = 10.5 min, tminor = 9.2 min, λ = 254 nm).
833, 765, 733; HRMS (ESI): calcd for [M
+
Na]+
(C22H24ClNaNO6) requires 456.1190, found 456.1188; enantio-
meric excess: 97%, determined by HPLC (Chiralpak OD
column, hexane–i-PrOH 80 : 20, flow rate 0.70 mL min−1; tmajor
= 22.2 min, tminor = 15.1 min, λ = 220 nm).
(1R,2R,3R)-Triethyl 2-cyano-4′-fluoro-1,2,3,6-tetrahydro-
[1,1′-biphenyl]-2,3,4-tricarboxylate (3f)
(1R,2R,6R)-Triethyl 1-cyano-6-(naphthalen-2-yl)cyclohex-3-ene-
1,2,3-tricarboxylate (3c)
Yield: 80%; Viscous, colorless oil; [α]2D6 −90.7 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.39–7.36 (m, 2H), 7.18 (m,
1H), 7.06–7.01 (m, 2H), 4.41 (m, 1H), 4.28–4.15 (m, 4H), 4.02
(q, J = 7.0 Hz, 2H), 3.29 (dd, J = 12.3, 4.3 Hz, 1H), 3.03 (m,
1H), 2.61 (dt, J = 19.4, 4.5 Hz, 1H), 1.31–1.23 (m, 6H), 1.00 (t,
J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.6, 166.9,
165.7, 164.1 (d, JC–F = 247 Hz), 138.2, 132.5 (d, JC–F = 3.7
Hz), 130.2 (d, JC–F = 8.0 Hz), 126.9, 115.8 (d, JC–F = 21.8 Hz),
115.2, 63.1, 62.0, 61.1, 53.6, 50.1, 45.5, 29.7, 14.1, 13.9, 13.6;
Yield: 95%; Viscous, colorless oil; [α]2D6 −102.2 (c = 1.1,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.83–7.82 (m, 4H),
7.53–7.48 (m, 3H), 7.22 (m, 1H), 4.48 (m, 1H), 4.29–4.16 (m,
4H), 3.93–3.84 (m, 2H), 3.45 (dd, J = 12.3, 4.2 Hz, 1H), 3.20
(m, 1H), 2.68 (dt, J = 19.3, 4.5 Hz, 1H), 1.33–1.23 (m, 6H),
0.77 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.7,
167.0, 165.8, 138.5, 134.1, 133.3, 133.2, 128.6, 128.1, 127.9,
3198 | Org. Biomol. Chem., 2012, 10, 3195–3201
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19F NMR (CDCl3, 282 MHz) δ −113.5; IR (film): 2984, 2934,
2245, 1744, 1660, 1605, 1512, 1466, 1373, 1237, 1183, 1098,
1031, 843, 766, 730; HRMS (ESI): calcd for [M + Na]+
(C22H24FNaNO6) requires 440.1485, found 440.1489; enantio-
meric excess: 97%, determined by HPLC (Chiralpak OD
column, hexane–i-PrOH 80 : 20, flow rate 0.70 mL min−1; tmajor
= 18.8 min, tminor = 14.3 min, λ = 220 nm).
52.3, 50.8, 44.1, 30.7, 14.1, 13.9, 13.5; IR (film): 2983, 2240,
1746, 1658, 1471, 1371, 1303, 1238, 1184, 1089, 1029, 856,
758; HRMS (ESI): calcd for [M + Na]+(C22H24NaBrNO6)
requires 500.0685, found 500.0681; enantiomeric excess: 89%,
determined by HPLC (Chiralpak OD column, hexane–i-PrOH
80 : 20, flow rate 0.60 mL min−1; tmajor = 20.1 min, tminor
12.4 min, λ = 220 nm).
=
(1R,2R,3R)-Triethyl 3′-bromo-2-cyano-1,2,3,6-tetrahydro-
[1,1′-biphenyl]-2,3,4-tricarboxylate (3g)
(1S,2R,3R)-Triethyl 2-cyano-2′-fluoro-1,2,3,6-tetrahydro-
[1,1′-biphenyl]-2,3,4-tricarboxylate (3j)
Yield: 77%; Viscous, colorless oil; [α]2D6 −115.9 (c = 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 2H), 7.41 (d, J
= 8.1 Hz, 1H), 7.26–7.22 (m, 1H), 7.17–7.16 (m, 1H), 4.42 (m,
1H), 4.28–4.15 (m, 4H), 4.05 (m, 2H), 3.25 (dd, J = 12.6, 4.3
Hz, 1H), 3.03 (dd, J = 19.3, 10.8 Hz, 1H), 2.61 (dt, J = 19.1, 4.5
Hz, 1H), 1.31–1.23 (m, 6H), 1.01 (t, J = 7.1 Hz, 3H); 13C NMR
(CDCl3, 100 MHz) δ 168.5, 166.8, 165.6, 138.9, 138.0, 131.9,
131.8, 130.4, 126.9, 126.7, 122.7, 115.0, 63.2, 62.1, 61.1, 53.4,
50.1, 45.8, 29.4, 14.1, 13.9, 13.6; IR (film): 2982, 2246, 1744,
1661, 1473, 1372, 1304, 1241, 1184, 1031, 858, 790; HRMS
Yield: 81%; Viscous, colorless oil; [α]2D6 −71.4 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.78–7.74 (t, J = 7.3 Hz, 1H),
7.33–7.27 (m, 1H), 7.20–7.17 (m, 2H), 7.07–7.02 (t, J = 9.1 Hz,
1H), 4.46 (m, 1H), 4.28–4.16 (m, 4H), 4.08–3.99 (m, 2H), 3.82
(dd, J = 12.3, 4.3 Hz, 1H), 3.82 (dd, J = 19.3, 10.8 Hz, 1H),
2.61 (dt, J = 19.4, 4.5 Hz, 1H), 1.32 (t, J = 7.0 Hz, 3H), 1.27 (t,
J = 7.0 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3,
100 MHz) δ 168.5, 166.4, 165.7, 161.4 (d, JC–F = 248 Hz),
138.4, 130.0 (d, JC–F = 8.8 Hz), 128.4 (d, JC–F = 2.9 Hz), 127.1,
124.8 (d, JC–F = 3.7 Hz), 124.4 (d, JC–F = 14.0 Hz), 115.8 (d,
JC–F = 23.4 Hz), 115.5, 63.1, 62.0, 61.1, 52.7, 50.4, 37.3, 30.0,
14.1, 13.9, 13.5; 19F NMR (CDCl3, 282 MHz) δ −117.8; IR
(film): 2984, 2935, 2242, 1745, 1660, 1492, 1457, 1373, 1239,
1192, 1100, 1032, 857, 763; HRMS (ESI): calcd for [M +
Na]+(C22H24FNaNO6) requires 440.1485, found 440.1484;
enantiomeric excess: 89%, determined by HPLC (Chiralpak OD
column, hexane–i-PrOH 80 : 20, flow rate 0.60 mL min−1; tmajor
= 16.9 min, tminor = 12.5 min, λ = 220 nm).
(ESI): calcd for [M
+
Na]+(C22H24NaBrNO6) requires
500.0685, found 500.0683; enantiomeric excess: 95%, deter-
mined by HPLC (Chiralpak OD column, hexane–i-PrOH 80 : 20,
flow rate 0.70 mL min−1; tmajor = 28.4 min, tminor = 15.7 min,
λ = 220 nm).
(1R,2R,3R)-Triethyl 3′-chloro-2-cyano-1,2,3,6-tetrahydro-
[1,1′-biphenyl]-2,3,4-tricarboxylate (3h)
Yield: 87%; Viscous, colorless oil; [α]2D6 −84.8 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.35–7.33 (m, 4H), 7.17 (m,
1H), 4.42 (m, 1H), 4.28–4.15 (m, 4H), 4.06–3.99 (m, 2H), 3.26
(dd, J = 12.3, 4.2 Hz, 1H), 3.05 (dd, J = 20.8, 12.8 Hz, 1H),
2.62 (dt, J = 18.9, 4.5 Hz, 1H), 1.31–1.25 (m, 6H), 1.00 (t, J =
7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.5, 166.8,
165.6, 138.7, 138.0, 134.6, 130.1, 128.9, 128.8, 127.0, 126.3,
115.0, 63.2, 62.1, 61.1, 53.4, 50.1, 45.8, 29.4, 14.1, 13.9, 13.6;
IR (film): 2982, 2928, 2856, 2266, 1746, 1660, 1596, 1572,
1473, 1441, 1372, 1238, 1184, 1089, 1028, 858, 792, 700;
HRMS (ESI): calcd for [M + Na]+(C22H24ClNaNO6) requires
456.1190, found 456.1186; enantiomeric excess: 93%, deter-
mined by HPLC (Chiralpak OD column, hexane–i-PrOH 80 : 20,
flow rate 0.70 mL min−1; tmajor = 25.1 min, tminor = 14.7 min,
λ = 220 nm).
(1R,2R,3R)-Triethyl 2-cyano-4′-methoxy-1,2,3,6-tetrahydro-
[1,1′-biphenyl]-2,3,4-tricarboxylate (3k)
Yield: 96%; Viscous, colorless oil; [α]2D6 −94.5 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.31 (d, J = 8.8 Hz, 2H), 7.18
(m, 1H), 6.87 (d, J = 8.5 Hz, 2H), 4.41 (m, 1H), 4.28–4.15 (m,
4H), 4.02 (q, J = 7.3 Hz, 2H), 3.79 (s, 3H), 3.25 (dd, J = 14.3,
4.3 Hz, 1H), 3.04 (dd, J = 17.8, 10.8 Hz, 1H), 2.59 (dt, J = 19.3,
4.5 Hz, 1H), 1.31 (t, J = 7.2 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H),
1.00 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 168.8,
167.0, 165.8, 159.8, 138.7, 129.5, 128.6, 126.8, 115.4, 114.1,
63.0, 61.9, 61.0, 55.3, 53.8, 50.1, 45.5, 29.7, 14.1, 13.9, 13.6;
IR (film): 2984, 2936, 2838, 2242, 1742, 1612, 1515, 1463,
1372, 1248, 1184, 1032, 837; HRMS (ESI): calcd for [M +
Na]+(C23H27NaNO7) requires 452.1685, found 452.1686; enan-
tiomeric excess: 95%, determined by HPLC (Chiralpak OD
column, hexane–i-PrOH 80 : 20, flow rate 0.70 mL min−1; tmajor
= 20.6 min, tminor = 15.3 min, λ = 220 nm).
(1S,2R,3R)-Triethyl 2′-bromo-2-cyano-1,2,3,6-tetrahydro-
[1,1′-biphenyl]-2,3,4-tricarboxylate (3i)
Yield: 88%; Colorless, crystalline solid. m.p. = 88–90 °C; [α]D26
−91.8 (c = 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.93 (d,
J = 9.1 Hz, 1H), 7.58 (d, J = 9.0 Hz, 1H), 7.37 (t, J = 7.1 Hz,
1H), 7.18–7.14 (m, 2H), 4.45 (m, 1H), 4.27–4.20 (m, 4H),
4.11–4.06 (m, 1H), 4.02–3.97 (m, 2H), 2.83 (dd, J = 19.3, 12.0
Hz, 1H), 2.67 (dt, J = 19.6, 6.0 Hz, 1H), 1.32 (t, J = 7.0 Hz,
3H), 1.28 (t, J = 7.0 Hz, 3H), 1.00 (t, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 168.4, 166.0, 165.7, 138.6, 136.7,
133.5, 129.8, 128.0, 127.2, 125.0, 122.7, 115.8, 63.2, 62.0, 61.1,
(1R,2R,3R)-Triethyl 2-cyano-3′-methoxy-1,2,3,6-tetrahydro-
[1,1′-biphenyl]-2,3,4-tricarboxylate (3l)
Yield: 88%; Viscous, colorless oil; [α]2D6 −83.2 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.27 (t, J = 8.3 Hz, 1H), 7.18
(m, 1H), 6.97 (m, 2H), 6.87 (dd, J = 8.5, 1.7 Hz, 1H), 4.43 (m,
1H), 4.28–4.15 (m, 4H), 4.04 (m, 2H), 3.80 (s, 3H), 3.25 (dd, J
= 12.3, 4.3 Hz, 1H), 3.06 (dd, J = 19.4, 12.6 Hz, 1H), 2.62 (dt, J
= 19.4, 4.5 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.26 (t, J = 7.1 Hz,
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3H), 0.98 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
168.7, 166.9, 165.8, 159.8, 138.4, 129.8, 129.8, 126.8, 120.7,
115.4, 114.3, 113.9, 63.0, 62.0, 61.0, 55.3, 53.5, 50.1, 46.3,
29.6, 14.1, 13.9, 13.6; IR (film): 2983, 2933, 2245, 1745, 1660,
1602, 1491, 1463, 1372, 1233, 1184, 1094, 1035, 861, 788;
HRMS (ESI): calcd for [M + Na]+(C23H27NaNO7) requires
452.1685, found 452.1684; enantiomeric excess: 96%, deter-
mined by HPLC (Chiralpak OD column, hexane–i-PrOH 80 : 20,
flow rate 0.70 mL min−1; tmajor = 31.0 min, tminor = 16.2 min,
λ = 220 nm).
138.2, 137.1, 136.7, 129.1, 129.0, 128.7, 128.1, 127.7, 127.3,
117.7, 62.0, 61.0, 56.4, 51.8, 47.5, 29.4, 14.2, 13.7; IR (film):
3063, 2983, 2235, 1737, 1597, 1451, 1374, 1250, 1182, 1133,
1094, 1031, 970, 748; HRMS (ESI): calcd for [M + Na]+
(C26H25NaNO5) requires 454.1630, found 454.1631; enantio-
meric excess: 99%, determined by HPLC (Chiralpak OD
column, hexane–i-PrOH 80 : 20, flow rate 0.50 mL min−1; tmajor
= 24.4 min, tminor = 16.4 min, λ = 220 nm).
Trans isomer: Viscous, colorless oil; [α]2D6 −165.4 (c = 1.0,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.44–7.40 (m, 1H),
7.34–7.25 (m, 8H), 7.21–7.17 (m, 2H), 4.51 (m, 1H), 4.33–4.22
(q, J = 7.1 Hz, 2H), 4.07 (m, 1H), 3.96 (m, 1H), 3.54 (dd, J =
11.5, 4.3 Hz, 1H), 3.12 (dd, J = 18.6, 11.5 Hz, 1H), 2.65 (dt, J =
18.9, 5.1 Hz, 1H), 1.38–1.34 (t, J = 7.0 Hz, 3H), 1.00–0.96 (t, J
= 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 194.5, 168.7,
166.2, 138.4, 136.9, 136.7, 132.8, 129.5, 129.2, 128.8, 127.7,
127.1, 121.7, 61.9, 61.0, 53.6, 51.8, 48.0, 27.7, 14.2, 13.5, 13.5;
IR (film): 3062, 2982, 2928, 2240, 1722, 1677, 1596, 1449,
1373, 1259, 1187, 1104, 1030, 739; HRMS (ESI): calcd for
[M + Na]+ (C26H25NaNO5) requires 454.1630, found 454.1632;
enantiomeric excess: 90%, determined by HPLC (Chiralpak
(1S,2R,6S)-Triethyl 1-cyano-6-(thiophen-2-yl)cyclohex-3-ene-
1,2,3-tricarboxylate (3m)
Yield: 87%; Viscous, colorless oil; [α]2D6 −81.6 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.27 (m, 1H), 7.15 (m, 1H), 7.10
(m, 1H), 7.00 (m, 1H), 4.38 (m, 1H), 4.28–4.19 (m, 4H),
4.15–4.07 (m, 2H), 3.64 (dd, J = 12.0, 4.2 Hz, 1H), 3.06 (dd, J
= 19.3, 12.3 Hz, 1H), 2.62 (dt, J = 19.5, 6.1 Hz, 1H), 1.31–1.24
(m, 6H), 1.10 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz)
δ 168.5, 167.0, 165.6, 138.7, 137.9, 127.0, 126.9, 126.8, 125.5,
114.9, 63.3, 62.0, 61.1, 54.4, 49.8, 41.7, 31.2, 14.1, 13.9, 13.7;
IR (film): 2984, 2931, 2237, 1748, 1661, 1466, 1372, 1250,
1238, 1186, 1032, 855, 712; HRMS (ESI): calcd for [M +
Na]+(C20H23NaNSO6) requires 428.1144, found 428.1142; enan-
tiomeric excess: 93%, determined by HPLC (Chiralpak OD
column, hexane–i-PrOH 80 : 20, flow rate 0.70 mL min−1; tmajor
= 17.6 min, tminor = 15.1 min, λ = 220 nm).
AS-H column, hexane–i-PrOH 80 : 20, flow rate 0.50 mL min−1
tmajor = 23.7 min, tminor = 18.2 min, λ = 254 nm).
;
Acknowledgements
The financial support from National Basic Research Program of
China (973 Program, 2010CB833200), the National Natural
Science Foundation of China (No. 21032006), Science and Tech-
nology Commission of Shanghai Municipality (11XD1406400),
and Excellent Young Scholars Foundation of National Natural
Science Foundation of China (20525208) is gratefully
acknowledged.
(1R,2R,6R)-Triethyl 6-(benzo[d][1,3]dioxol-5-yl)-1-
cyanocyclohex-3-ene-1,2,3-tricarboxylate (3n)
Yield: 94%; Viscous, colorless oil; [α]2D6 −89.3 (c = 1.0, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.17 (m, 1H), 6.92 (m, 1H), 6.81
(m, 2H), 5.95 (s, 2H), 4.40 (m, 1H), 4.26–4.15 (m, 4H), 4.06
(m, 2H), 3.21 (dd, J = 12.3, 4.0 Hz, 1H), 3.00 (dd, J = 20.9,
12.3 Hz, 1H), 2.59 (dt, J = 19.3, 4.5 Hz, 1H), 1.31–1.23 (m,
6H), 1.06 (t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
168.7, 167.0, 165.7, 148.0, 147.8, 138.5, 130.3, 126.8, 122.2,
115.3, 108.5, 108.4, 101.3, 63.1, 62.0, 61.0, 53.7, 50.1, 45.9,
29.8, 14.1, 13.9, 13.7; IR (film): 2983, 2938, 2906, 2247, 1747,
1660, 1505, 1492, 1370, 1301, 1253, 1184, 1038, 934, 813;
HRMS (ESI): calcd for [M + Na]+(C23H25NaNO8) requires
466.1478, found 466.1477; enantiomeric excess: 96%, deter-
mined by HPLC (Chiralpak OD column, hexane–i-PrOH 80 : 20,
flow rate 0.65 mL min−1; tmajor = 29.1 min, tminor = 20.8 min,
λ = 220 nm).
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10 As this manuscript is ready for submission, a paper describing asym-
metric [4 + 2] cycloaddition between α-substituted allenoate and arylide-
nemalononitrile appeared: F. Zhong, X. Han, Y. Wang and Y. Lu, Chem.
Sci., 2012, DOI: 10.1039/c2sc00963c.
11 In ref. 10, olefins derived from malononitrile and isatin were also used
successfully in this reaction.
12 Other allenoates bearing H or Ph instead of an ester group at the β′ atom
were also examined but poor conversions (<10%) were obtained, which
might be ascribed to the weaker anion-stabilizing ability of these substitu-
ents. See ref. 5 for similar phenomena.
13 See Table S1 in the ESI† and ref. 10 for comparison.
14 See the ESI† for details.
15 (Z)-Ethyl 2-nitro-3-phenylacrylate and dimethyl 2-benzylidenemalonate
were also studied but gave no reaction in this system. Oxodiene 5 worked
as a 1,4-amphiphilic reagent in Cinchona alkaloids catalyzed [4 + 2]
annulation of non-substituted allenoate: X. Wang, T. Fang and X. Tong,
Angew. Chem., Int. Ed., 2011, 50, 5361. The configurations of products 6
were determined by NOESY spectra. See the ESI† for details.
16 We thank one of our reviewers for proposing an alternative half-chair con-
formation (see below). In this model, the s-butyl group and the acyl
group on the nitrogen atom take axial positions to minimize the
possible enhanced gauche interaction between these two substituents due
to the more planar nature of the sp3 hybridized nitrogen atom in our pro-
posed chair-like pretransition state.
8 (a) B. J. Cowen and S. J. Miller, J. Am. Chem. Soc., 2007, 129, 10988;
(b) Y.-Q. Fang and E. N. Jacobsen, J. Am. Chem. Soc., 2008, 130, 5660;
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Org. Biomol. Chem., 2012, 10, 3195–3201 | 3201