PPh3-catalyzed synthesis of dicyano-2-methylenebut-3-enoates as efficient dienes in catalytic asymmetric inverse-electron-demand Diels-Alder reaction

Article abstract of DOI:10.1039/c1cc12834e

We present here the synthesis of dicyano-2-methylenebut-3-enoates as novel Diels-Alder dienes through an efficient PPh₃-catalyzed strategy, and an unprecedented PPh₃-catalyzed addition/all-carbon-based asymmetric inverse-electron-demand Diels-Alder sequence reaction is disclosed for the first time.

Full text of DOI:10.1039/c1cc12834e

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PPh3-catalyzed synthesis of dicyano-2-methylenebut-3-enoates as efficient
dienes in catalytic asymmetric inverse-electron-demand Diels–Alder
reactionw
Xianxing Jiang,ab Dan Fu,a Xiaomei Shi,a Shoulei Wanga and Rui Wang*ab
Received 14th May 2011, Accepted 31st May 2011
DOI: 10.1039/c1cc12834e
We present here the synthesis of dicyano-2-methylenebut-3-
enoates as novel Diels–Alder dienes through an efficient
PPh3-catalyzed strategy, and an unprecedented PPh3-catalyzed
addition/all-carbon-based asymmetric inverse-electron-demand
Diels–Alder sequence reaction is disclosed for the first time.
and a,a-dicyanoolefins. We postulated that the reaction of
alkyl propiolates with a,a-dicyanoolefins could be initiated, in
the presence of PPh3, by activating propiolates to generate the
1,3-zwitterions A,5 which undergo Michael-type reaction with
dicyanoolefins to give intermediates B. Due to the ability of
PPh3 to stabilise an adjacent carbanion, intermediates B may
coexist with intermediates C. Subsequent [1,4]-hydrogen transfer
of intermediates B or C formed the intermediates D. Finally,
the catalytic cycle was completed by [1,4]-elimination of
PPh3, and dicyano-2-methylenebut-3-enoates 3 were afforded
(Scheme 1). Our next studies were motivated by dicyano-2-
methylenebut-3-enoates as dienes in frontier-molecular-
orbital-controlled DAR with the HOMO of dienophiles via
an enamine-activated system. Recently, Jøgensen and co-workers6
reported the first catalytic asymmetric inverse-electron-
demand Diels–Alder reaction (IEDDAR)7 of aliphatic aldehydes
with a,b-unsaturated a-ketoesters through enamine activation.8
The reaction generally exhibited high stereoselectivity with the
characteristics of a concerted HOMO of dienophiles mechanism
by in situ generation of the electron-rich chiral enamine.
Afterwards, although several organocatalytic asymmetric
IEDDAR have been well described, to date, examples of
all-carbon-based catalytic asymmetric versions8a,9 are surprisingly
scarce. Undoubtedly, the novel diene-led development of
The catalytic asymmetric Diels–Alder reaction (DAR) has
been recognized as one of the most powerful and convergent
strategies for the stereoselective construction of six-membered
functionalized cyclic frameworks, often containing multiple
stereocenters. As a result of its importance and versatility in
the synthesis of diverse natural products, organic chemists are
paying increasing attention to the development of novel
asymmetric methodologies in this field. Catalytic asymmetric
variants of these [4+2] reactions have been achieved for
different diene–dienophile combinations,1 showing in several
instances outstanding synthetic utility. On the other hand,
compared with other classic reactions, it presents more
difficulties due to the governing strict principle of generation
of DAR including the suitable matching of diene with dieno-
phile in accordance with the electronic orbital theory.2 Indeed,
a long-standing limitation for the progress of asymmetric
DAR is the lack of appropriate and effective dienes. For these
reasons, we wish to address our contribution to the novel diene
development of Diels–Alder reaction through the synthesis
of dicyano-2-methylenebut-3-enoates as novel Diels–Alder
dienes via the PPh3-catalyzed addition reaction of propiolates
with a,a-dicyanoolefins.
Owing to the properties of strong nucleophilicity and ease of
ylide formation, as well as leaving group ability, tertiary
phosphanes as nucleophiles catalyzing the addition reactions3
have attracted wide attention, and elegant examples have been
reported.4 However, to the best of our knowledge, there is no
precedent for the PR3-catalyzed reactions of alkyl propiolates
a State Key Laboratory of Applied Organic Chemistry,
Institute of Biochemistry and Molecular Biology,
Key Laboratory of Preclinical Study for New Drugs of Gansu
Province, Lanzhou University, Lanzhou 730000, China.
E-mail: wangrui@lzu.edu.cn; Fax: (+86)-931-8911255
b State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou 730000, China. E-mail: wangrui@lzu.edu.cn
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c1cc12834e
Scheme 1 PPh3-catalyzed synthesis of dicyano-2-methylenebut-3-
enoates as dienes in catalytic asymmetric IEDDAR.
c
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Chem. Commun., 2011, 47, 8289–8291 8289

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all-carbon-based asymmetric IEDDAR is particularly appealing.
Herein, we present an all-carbon-based asymmetric IEDDAR
of novel dicyano-2-methylenebut-3-enoates with aliphatic
aldehydes by employing a similar strategy (Scheme 1), and
disclose an unprecedented PPh3-catalyzed addition/all-
carbon-based asymmetric inverse-electron-demand Diels–
Alder sequence reaction.
Table 2 Results of survey of the organocatalytic IEDDAR of diene 3aa
To explore the possibility of the asymmetric IEDDAR,
dicyano-2-methylenebut-3-enoates were synthesized to evaluate
the efficacy of [4+2] cycloaddition (Table 1). During the
elaboration of standard conditions (see ESIw), reaction of
arylidenemalononitrile (1a) as a model substrate with 2a was
performed with a catalytic amount of PPh3 (20 mol%) in
toluene at 75 1C, and the corresponding product 3a was
obtained in 82% yield under the optimized conditions. Next,
we sought to expand the scope of the synthesis of dicyano-2-
methylenebut-3-enoates and a variety of arylidenemalono-
nitriles subjected to the reaction conditions. Gratifyingly,
arylidenemalononitrile substrates bearing various substituents,
including those with electron-rich and electron-poor aromatics,
as well as heterocycles, participated well in the reaction and
provided the dicyano-2-methylenebut-3-enoate products in
moderate to high yields (63–91% yield).
a
The reactions was performed with 3a (0.2 mmol) and 4a (0.4 mmol)
for 6 h at room temperature. b Isolated yield. c Determined by
1H NMR spectroscopy and chiral HPLC. d The ee values were
determined by HPLC, and the configuration was assigned by comparison
of HPLC data and X-ray crystal data of 5i.
isobutyraldehyde 4a was performed at room temperature in
the presence of the readily available (S)-diphenylprolinol
trimethylsilyl ether a (10 mol%) and benzoic acid (10 mol%)10
in CH3CN. The result indicated that the reaction went
smoothly, and afforded the desired product in 81% yield,
while a low enantioselectivity (30% ee) was observed (entry 1).
We found that the solvent used had a significant effect on the
yield and stereochemical outcome (entries 1–7). Gratifyingly,
subsequent screening of solvent uncovered that toluene was
the most suitable, highly enantioselective [4+2] cycloaddition
reaction was carried out with 97% ee and 94% yield (entry 6),
and an excellent diastereoselectivity (20 : 1 dr) in the adduct 5a
was demonstrated. Notably, a bulkier catalyst b showed
similar stereocontrol but with a relatively low yield of 81%
(entry 8). In order to establish a more practical method, we
further optimized the reaction process on the basis of the
aforementioned success. As indicated in Scheme 2, to our
delight, the product 5a was also obtained in 76% yield with
excellent stereoselectivity (97% ee and 20 : 1 dr) through
the PPh3-catalyzed addition/asymmetric IEDDAR sequence
reaction (for further details see ESIw).
Subsequently, we tested the efficacy of asymmetric
IEDDAR with 3a as a diene by employing an enamine-
activated strategy in Table 2, and a model reaction of 3a with
Table 1 Synthesis of dienes under the optimized conditionsa
Having established optimal reaction conditions, we explored
the scope of this PPh3-catalyzed addition/asymmetric
IEDDAR sequence in Table 3. The reaction of alkyl propiolates
with a variety of substituted arylidenemalononitriles, including
those bearing electron-withdrawing and -donating substituents
on the aryl ring, and of heterocyclic arylidenemalononitriles
with aliphatic aldehydes was examined. The results showed
that all reactions afforded the desired products with excellent
enantioselectivities (93–99% ee, entries 1–20), and in general,
a
Unless otherwise noted, the reaction was conducted with arylidene-
malononitriles 1 (2.0 mmol) and alkyl propiolates 2 (2.4 mmol) in the
presence of PPh3 (20 mol%) in toluene at 75 1C. b Isolated yield.
Scheme 2 The PPh3-catalyzed addition/asymmetric IEDDAR sequence.
c
8290 Chem. Commun., 2011, 47, 8289–8291
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Table
3
Structural variations for the PPh3-catalyzed addition/
We are grateful for the grants from the National Natural
Science Foundation of China (nos. 20932003 and 90813012)
asymmetric IEDDAR sequencea
and the National
(2009ZX09503-017).
S & T Major Project of China
Notes and references
1 For recent reviews, see: (a) P. Merino, E. Marques-Lopez, T. Tejero
and R. P. Herrera, Synthesis, 2009, 2010, 1; (b) S. Reymond and
J. Cossy, Chem. Rev., 2008, 108, 5359; (c) K. Ishihara, M. Fushimi
and M. Akakura, Acc. Chem. Res., 2007, 40, 1049; (d) E. J.
Corey, Angew. Chem., Int. Ed., 2002, 41, 1650; (e) Y. Hayashi, in
Cycloaddition Reactions in Organic Synthesis, ed. S. Kobayashi and
K. A. Jøgensen, Wiley-VCH, 2001, p. 5; (f) H. B. Kagan and
O. Riant, Chem. Rev., 1992, 92, 1007.
2 (a) J. Cossy, P.-A. Carrupt and P. Vogel, The Chemistry of Double-
Bonded Functional Groups, ed. S. Patai, John Wiley and Sons,
New York, 1989; (b) R. Sustmann, Pure Appl. Chem., 1974, 40, 569.
3 For recent reviews, see: (a) L. Ye, J. Zhou and Y. Tang, Chem. Soc.
Rev., 2008, 37, 1140; (b) V. Nair, R. Menon, A. Sreekanth,
N. Abhilash and A. Biju, Acc. Chem. Res., 2006, 39, 520;
(c) G. C. Fu, Acc. Chem. Res., 2004, 37, 542; (d) J. L. Methot and
W. R. Roush, Adv. Synth. Catal., 2004, 346, 1035; (e) D. Basavaiah,
A. J. Rao and T. Satyanarayana, Chem. Rev., 2003, 103, 811;
(f) X. Lu, C. Zhang and Z. Xu, Acc. Chem. Res., 2001, 34, 535.
4 For examples, see: (a) C. E. Aroyan and S. J. Miller, J. Am. Chem.
Soc., 2007, 129, 256; (b) V. Nair, S. C. Mathew, A. T. Biju and
E. Suresh, Angew. Chem., Int. Ed., 2007, 46, 2070; (c) L. Ye,
X. Sun, Q. Wang and Y. Tang, Angew. Chem., Int. Ed., 2007,
46, 595; (d) R. P. Wurz and G. C. Fu, J. Am. Chem. Soc., 2005,
127, 12234; (e) M. E. Krafft, K. A. Seibert, T. F. N. Haxell and
C. Hirosawa, Chem. Commun., 2005, 5772; (f) Y. Du, X. Lu and
C. Zhang, Angew. Chem., Int. Ed., 2003, 42, 1035; (g) X. Zhu,
J. Lan and O. Kwon, J. Am. Chem. Soc., 2003, 125, 4716;
(h) S. A. Frank, D. J. Mergott and W. R. Roush, J. Am. Chem.
Soc., 2002, 124, 2404; (i) L. C. Wang, A. L. Luis, K. Agapiou,
H. Jang and M. J. Krische, J. Am. Chem. Soc., 2002, 124, 2402.
5 (a) C. Li and M. Shi, Org. Lett., 2003, 5, 4273; (b) B. Liu, R. Davis,
B. Joshi and D. W. Reynolds, J. Org. Chem., 2002, 67, 4595;
(c) B. M. Trost and G. Dake, J. Am. Chem. Soc., 1997, 119, 7595;
(d) C. Zhang and X. Lu, J. Org. Chem., 1995, 60, 2906; (e) K. Nozaki,
N. Sato, K. Ikeda and H. Takaya, J. Org. Chem., 1996, 61, 4516.
6 K. Juhl and K. A. Jøgensen, Angew. Chem., Int.Ed., 2003, 42, 1498.
7 (a) D. L. Boger, in Comprehensive Organic Syntheses, ed. B. M. Trost,
Pergamon, Oxford, 1991, vol. 5; (b) M. Xie, X. Chen, Y. Zhu, B. Gao,
L. Lin, X. Liu and X. Feng, Angew. Chem., Int. Ed., 2010, 49, 3799;
(c) J. Esquivias, R. G. Arrayas and J. C. Carretero, J. Am. Chem.
Soc., 2007, 129, 1480; (d) T. Akiyama, H. Morita and K. Fuchibe,
J. Am. Chem. Soc., 2006, 128, 13070; (e) T. Bekele, M. H. Shah,
J. Wolfer, C. J. Abraham, A. Weatherwax and T. Lectka, J. Am.
Chem. Soc., 2006, 128, 1810; (f) M. He, J. R. Struble and J. W. Bode,
J. Am. Chem. Soc., 2006, 128, 8418; (g) R. C. Clark, S. S. Pfeiffer and
D. L. Boger, J. Am. Chem. Soc., 2006, 128, 2587.
8 For examples of enamine-catalyzed asymmetric IEDDAR, see:
(a) J.-L. Li, T.-R. Kang, S.-L. Zhou, R. Li, L. Wu and
Y.-C. Chen, Angew. Chem., Int. Ed., 2010, 49, 6418; (b) B. Han,
Z.-Q. He, J.-L. Li, R. Li, K. Jiang, T.-Y. Liu and Y.-C. Chen, Angew.
Chem., Int. Ed., 2009, 48, 5474; (c) J. Wang, F. Yu, X. Zhang and
D. Ma, Org. Lett., 2008, 10, 2561; (d) H. Xie, L. Zu, H. R. Oueis,
H. Li, J. Wang and W. Wang, Org. Lett., 2008, 10, 1923;
(e) S. Samanta, J. Krause, T. Mandal and C.-G. Zhao, Org. Lett.,
2007, 9, 2745; (f) F. A. Hernandez-Juan, D. M. Cockfield and
D. J. Dixon, Tetrahedron Lett., 2007, 48, 1605.
9 For racemic examples, see: (a) M. A. Kienzler, S. Suseno and
D. Trauner, J. Am. Chem. Soc., 2008, 130, 8604; (b) M. E. Jung
and H. V. Chu, Org. Lett., 2008, 10, 3647; (c) A.-T. Dang,
D. O. Miller, L. N. Dawe and G. J. Bodwell, Org. Lett., 2008, 10, 233.
10 For reviews of (S)-diarylprolinol trimethylsilyl ether, see:
(a) L.-W. Xu, L. Li and Z.-H. Shi, Adv. Synth. Catal., 2010,
352, 243; (b) S. Bertelsen and K. A. Jøgensen, Chem. Soc. Rev.,
2009, 38, 2178; (c) P. Melchiorre, M. Marigo, A. Carlone and
G. Bartoli, Angew. Chem., Int. Ed., 2008, 47, 6138; (d) C. Palomo
and A. Mielgo, Angew. Chem., Int. Ed., 2006, 45, 7876.
a
Unless otherwise noted, the reaction sequence was conducted with
arylidenemalononitriles 1 (0.3 mmol), alkyl propiolates 2 (0.36 mmol)
and aliphatic aldehydes 3 (0.5 mmol). For experimental details, see
ESIw. b Isolated yield. c Determined by 1H NMR spectroscopy and
chiral HPLC. d The ee values were determined by HPLC, and the
configuration was assigned by comparison of HPLC data and X-ray
crystal data of 5i. e Values in parentheses are ee of minor diastereomer.
f 0.4 mmol isobutyraldehyde was used.
high to excellent diastereoselectivities could be obtained, albeit
with poor diastereoselectivities for the substrates bearing
1-napthyl (entry 3) and with substituents at the ortho position
of the aryl ring (entries 7 and 14). Notably, moderate to high
yields were obtained for a number of arylidenemalononitriles
bearing phenyl, 1-napthyl, electron-donating aryl and hetero-
cyclic groups (65–86% yield, entries 1–7, 15–16 and 19). By
contrast, electron-withdrawing aryl substituted arylidene-
malononitriles gave products with moderate yields (43–60%
yield, entries 8–14 and 20). In addition to isobutyraldehyde,
other aliphatic aldehydes, such as butyraldehyde and phenyl-
acetaldehyde were also tested. As expected, the catalytic
system also proved to be efficient for these dienophiles, again
leading to satisfactory results (up to 99% ee, 17 : 1 dr and 71%
yield), albeit with a poor diastereoselectivity when employing
butyraldehyde (entries 17 and 18). The relative and absolute
configurations of the products were determined by X-ray
crystal analysis of 5i.
In summary, we have disclosed the synthesis of dicyano-2-
methylenebut-3-enoates as novel Diels–Alder dienes via a new
PPh3-catalyzed addition reaction, and an unprecedented
PPh3-catalyzed addition/all-carbon-based asymmetric IEDDAR
sequence reaction was presented for the first time, affording the
products in high levels of enantio- and diastereoselectivity.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 8289–8291 8291