Proline and Lewis base co-catalyzed addition of α,β-unsaturated aldehydes to nitrostyrenes

Article abstract of DOI:10.1016/j.tetlet.2007.12.069

A novel proline and DABCO co-catalyzed reaction between unmodified α,β-unsaturated aldehydes and nitrostyrenes, which gives access to α-(1-aryl-2-nitro)ethyl-α,β-unsaturated aldehydes, is presented.

Full text of DOI:10.1016/j.tetlet.2007.12.069

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1137–1140
Proline and Lewis base co-catalyzed addition
of a,b-unsaturated aldehydes to nitrostyrenes
*
´
Jan Vesely, Ramon Rios, Armando Cordova
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Received 5 October 2007; revised 3 December 2007; accepted 12 December 2007
Abstract
A novel proline and DABCO co-catalyzed reaction between unmodified a,b-unsaturated aldehydes and nitrostyrenes, which gives
access to a-(1-aryl-2-nitro)ethyl-a,b-unsaturated aldehydes, is presented.
Ó 2007 Elsevier Ltd. All rights reserved.
Continuing development in synthetic organic chemistry
relies on discovering new selective reactions. The Morita–
Baylis–Hillman (MBH) reaction is an organocatalytic reac-
tion involving the coupling of the a-position of activated
alkenes with carbonyl electrophiles such as an aldehyde
or ketone via the catalytic influence of a nucleophilic spe-
cies.1,2 The concept of this reaction has been applied to
intermolecular reactions between activated alkenes and
other electrophiles including imines,3 salicylaldehydes,4
azodicarboxylate esters5 and activated allyl halides.6 More-
over, tertiary phosphine-catalyzed intermolecular MBH
reactions have been developed.7 Recently, Shi and co-
workers reported a dual catalytic system based on the
combination of enamine and Lewis base catalysis for the
Baylis–Hillman type reaction between methyl vinyl ketone
and aryl carbaldehydes.8 Miller and co-workers have also
applied this strategy for inter- and intramolecular MBH
type reactions with aldehydes as electrophiles.9 Recently,
Barbas reported an enamine and Lewis base co-catalytic
system for the reaction between enals and N-p-methoxy-
phenyl-(PMP) protected a-imino glyoxylate.10 We have
developed an enamine and Lewis base co-catalyzed aza-
MBH type reaction between a,b-unsaturated aldehydes
and Boc-protected imines (Eq. 1).11 While a variety of elec-
trophiles have been studied extensively since the first
reports of the MBH reaction, the direct organomediated
application of nitroolefins as electrophiles in the MBH
reaction has not been reported.
COOH
N
Boc
Ar
Boc
H
H
O
NH
O
N
(40 mol%)
+
H
H
Ar
DABCO
(20 mol%)
R1
R
R1
R
45-61% yield, 97->99% ee
ð1Þ
Based on the use of co-catalyst systems involving proline or
peptide derivatives and organic nucleophilic amines for
mediating asymmetric MBH8,9 and aza-MBH reac-
tions,10,11 we envisioned the possibility of developing a
reaction between a,b-unsaturated aldehydes and nitrosty-
renes (Scheme 1).12
Thus, we predicted that an iminium intermediate
derived from the reaction between the amino acid catalyst
and the enal donor could be activated by an amine to form
two different possible enamine intermediates (Scheme 1).
These in situ generated enamines could subsequently
undergo nucleophilic Michael addition to the nitrostyrene
and give the corresponding a-(2-nitroethyl)-a,b-unsatu-
rated carbonyl compounds. These types of product are
valuable synthons for the preparation of a large variety
*
Corresponding author. Tel.: +46 8 162479; fax: +46 8 154908.
E-mail addresses: acordova@organ.su.se, acordova1a@netscape.net
´
(A. Cordova).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.069

1138
J. Vesely et al. / Tetrahedron Letters 49 (2008) 1137–1140
-
+
N
Nu
+
O2N
Ar
COOH
COO
COOH
N
N
H
H
+
H
+
Nu
Nu
R
R
R
O2N
Ar
O
O
NO2
+
NuH
+
NuH
COOH
N
H
+
H
H
Ar
Nucleophile
R
R
+
N
-
+
N
O2N
Ar
COOH
COOH
COO
N
Nu
H
H
H
H
+
NuH
R
R
R
Scheme 1. Suggested activation pathways for the reaction between enals and nitrostyrene catalyzed by a combination of proline and an organic
nucleophile.
of valuable heterocyclic compounds.13 Herein, we present a
new intermolecular MBH-type reaction which, for the first
time, encompasses nitroolefins as the electrophilic partner
in a completely organomediated process.
In an initial catalyst, organic base and solvent screen, we
found that the combination of (S)-proline 4 and 1,4-diaza-
bicyclo[2.2.2]octane (DABCO) catalyzed the reaction
between nitrostyrene 1a (0.5 mmol) and buten-2-al 2a
(0.25 mmol) to give a-2-nitroethyl-a,b-unsaturated alde-
hyde 3a (Table 1).
The use of a nucleophilic organic amine base was essen-
tial and of the screened bases, imidazole and DABCO, only
DABCO enabled the formation of 3a. We also found that
the other chiral amines 5–7 failed to catalyze the formation
of 3a in the presence of DABCO. The combination of (S)-
proline and DABCO was effective in polar aprotic solvents
Table 1
Screening of the enantioselective reaction between 1a and 2aa
Catalyst
(20 mol%)
DABCO
O2N
Ar
O2N
Ar
NO2
O
(20 mol%)
O
O
+
+
H
H
H
Ar
Solvent, 18 h, 4 °C
1a: Ar = C6H5
2a (2 equiv)
Ph
E-3a
Z-3a
COOH
H
O
N
H2N
Ph
N
H
N
N
N
OH
O
H
H
OTMS
4
5
6
7
Entry
Catalyst
Solvent
Conv. (%)
Yieldb (%)
E/Zc
1
2
3
4
5
6
7
8
9
4
4
4
5
5
5
6
6
6
7
DMF
DMF
CHCl3
DMF
CHCl3
Toluene
DMF
THF
10
100d
0
0
0
0
0
0
0
n.d.
44d
—
—
—
—
—
—
—
>25:1
>25:1d
—
—
—
—
—
—
—
Toluene
DMF
10
a
0
—
—
Experimental conditions: A mixture of 1a (0.50 mmol), buten-2-al 2a (0.25 mmol), chiral pyrrolidine (40 mol %) and DABCO (20 mol %) in 1.0 mL of
solvent was stirred at 4 °C under the conditions displayed in Table.
b
Isolated yield of pure compound 3a.
E/Z ratio as determined by 1H NMR. n.d. = not determined.
40 mol % of catalyst was used.
c
d

J. Vesely et al. / Tetrahedron Letters 49 (2008) 1137–1140
1139
Table 2
Direct organocatalytic asymmetric reactions between nitrostyrenes 1 and a,b-unsaturated aldehydes 2a
4
(40 mol%)
DABCO
O2N
O2N
Ar
O
(20 mol%)
O
O
NO2
+
+
H
Ar
H
H
DMF 4 °C, 16 h
Ar
R1
Z-3
R
R
1 (2 equiv)
Ar
2
E-3
Entry
R
Product
Yieldb (%)
E/Zc
1
2
3
4
5
6
a
Ph
Ph
Ph
Ph
2-BrC6H4
3-ClC6H4
Me
Et
3a
3b
3c
3d
3e
3f
47
57
53
62
41
55
>25:1
>25:1
>25:1
>25:1
>25:1
>25:1
n-Bu
Et
Et
Experimental conditions: A mixture of 1 (0.50 mmol), enal 2 (0.25 mmol), (S)-proline (40 mol %) and DABCO (20 mol %) in 1.0 mL of DMF was
stirred at 4 °C.
b
Isolated yield of pure compounds E/Z-3.
E/Z ratio determined by 1H NMR analysis.
c
such as DMF (entries 1 and 2). For example, (S)-proline
and DABCO co-catalyzed the formation of a-(1-aryl-2-
nitro)ethyl-enal 3a in 44% yield in DMF (entry 2). The
E/Z ratio was excellent (>25:1) as determined by 1H
NMR analysis of the crude reaction mixture and the E-iso-
mer was formed predominantly. Full conversion of the
donor enal 2a was achieved under these reaction conditions
but a small amount of competing self-MBH type reaction
of 2a occurred.14 Encouraged by these promising results,
we decided to investigate the catalytic asymmetric reaction
between various nitrostyrenes 1 and different a,b-unsatu-
rated aldehydes 2 with (S)-proline as the organocatalyst
and DABCO as the organic amine nucleophile (Table 2).15
The catalytic aza-MBH type reactions proceeded with
excellent E/Z selectivity (>25:1) and the corresponding
a,b-unsaturated aldehydes 3a–f were obtained in moderate
to good yields (41–62%). For example, the combination of
(S)-proline and DABCO catalyzed the reaction between
nitrostyrene 1a and heptenal 2d with high E/Z-selectivity
and nitro-substituted enal 3d was isolated in 62% yield
(entry 4). Moreover, the reaction tolerated a,b-unsaturated
aldehyde donors with a terminal olefin functionality (entry
3). It should be pointed out that in all cases the enal prod-
ucts 3 were obtained with very low ees (<10%). For exam-
ple, 3a had an ee of <5%.
On the basis of previous proline and DABCO co-cata-
lyzed reactions between enals and imines10,11 we propose
that the reaction proceeds as outlined in Scheme 1. We
are still studying the role of DABCO. It could either work
as a base enabling the formation of a conjugated enamine
and/or act as a nucleophile to generate an enamine inter-
mediate, which includes DABCO, according to Scheme 1.
In summary, we have reported a simple catalytic reac-
tion between unmodified enals and nitrostyrenes. This is
the first example of nitroolefins as electrophiles in MBH-
type reactions. The combined proline and DABCO cata-
lyzed transformations furnish the corresponding MBH
Michael type adducts with an a-alkylidene group in good
yields with excellent E-selectivity. Further elaboration of
this transformation, mechanistic studies, and application
of nitroolefins as electrophiles in MBH-type reactions are
ongoing in our laboratory.
Acknowledgements
We gratefully acknowledge the Swedish National
Research Council, Wenner–Gren Foundation and Carl–
Trygger Foundation for financial support.
References and notes
1. (a) Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, 1972;
Chem. Abstr. 1972, 77, 3417q.; (b) Morita, K. Japan Patent 6803364,
1968; Chem. Abstr. 1968, 69, 58828s; (c) Morita, K.; Suzuki, Z.;
Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815.
2. For excellent reviews see: (a) Masson, G.; Housserman, C.; Zhu, J.
Angew. Chem., Int. Ed. 2007, 46, 4614; (b) Basavaiah, D.; Rao, A. J.;
Satyanarayana, T. Chem. Rev. 2003, 103, 811; (c) Langer, P. Angew.
Chem., Int. Ed. 2000, 39, 3049; (d) Basavaiah, D.; Rao, P. D.;
Hayama, R. S. Tetrahedron 1996, 52, 8001.
3. For selected examples see: (a) Aggarwal, V. K.; Castro, A. M. M.;
Mereu, A.; Adams, H. Tetrahedron Lett. 2002, 43, 1577; (b) Shi, M.;
Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41, 4507; (c) Balan, D.;
Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521; (d) Kawahara, S.;
Nakano, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S. Org. Lett.
2003, 5, 3103; (e) Shi, M.; Chen, L.-H.; Li, C.-Q. J. Am. Chem. Soc.
2005, 127, 3790; (f) Matsui, K.; Takizawa, S.; Sasai, H. J. Am. Chem.
Soc. 2005, 127, 3680; (g) Matsui, K.; Tanaka, K.; Horii, A.;
Takizawa, S.; Sasai, H. Tetrahedron: Asymmetry 2006, 17, 578; (h)
Liu, Y.-H.; Chen, L.-H.; Shi, M. Adv. Synth. Catal. 2006, 348, 973; (i)
Matsui, K.; Takizawa, S.; Sasai, H. Synlett 2006, 761; (j) Buskens, P.;
Klankermayer, J.; Leitner, W. J. Am. Chem. Soc. 2005, 127, 3790; (k)
Gausepohl, R.; Buskens, P.; Kleinen, A.; Bruckmann, J.; Lehmann,
C. W.; Klankermayer, J.; Leitner, W. Angew. Chem., Int. Ed. 2006, 45,
3689; (l) Raheem, I. T.; Jacobsen, E. N. Adv. Synth. Catal. 2005, 347,
1701; (m) Balan, D.; Adolfsson, H. J. Org. Chem. 2001, 66, 6498; (n)

1140
J. Vesely et al. / Tetrahedron Letters 49 (2008) 1137–1140
Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem. 2003, 68,
692; (o) Shi, Y.-L.; Shi, M. Tetrahedron 2006, 62, 461; (p) Shi, Y.-L.;
Xu, Y.-M.; Shi, M. Adv. Synth. Catal. 2004, 346, 1220.
12. For an excellent review concerning organocatalytic additions of
unmodified aldehydes to nitroolefins see: Sulzer-Mosse, S.; Alexakis,
A. Chem. Commun. 2007, 3123.
4. (a) Kaye, P. T.; Musa, M. A.; Nocada, X. W.; Robinson, R. S. Org.
Biomol. Chem. 2003, 1, 1133; (b) Kaye, P. T. S. Afr. J. Sci. 2004, 100,
545; (c) Kaye, P. T.; Musa, M. A. Synthesis 2002, 2701; (d) Lesch, B.;
Bra¨se, S. Angew. Chem., Int. Ed. 2004, 43, 115; (e) Lesch, B.; Tora¨ng,
J.; Vanderheiden, S.; Bra¨se, S. Adv. Synth. Catal. 2005, 347, 555; (f)
Zhao, G.-L.; Shi, Y.-L.; Dhi, M. Org. Lett. 2005, 7, 4527; (g) Zhao,
G.-L.; Huang, J.-W.; Shi, M. Org. Lett. 2003, 5, 4737.
13. For a three-step synthesis of similar compounds starting from Baylis
Hillman products and their application as starting materials in
heterocycle synthesis see: (a) Sing, V.; Kanojiya, S.; Batra, S.
Tetrahedron 2006, 62, 10100; (b) Lee, K. Y.; Seo, J.; Kim, J. N.
Tetrahedron Lett. 2006, 47, 3913.
14. Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Liao, J.-H. Org. Lett. 2006, 8,
2217.
5. Kamimura, A.; Gunjigake, Y.; Mitsudera, H.; Yoloyama, S. Tetra-
hedron Lett. 1998, 39, 7323.
15. Typical experimental procedure for the organocatalytic Baylis-Hillman
reactions: To a stirred mixture of (S)-proline (0.10 mmol, 40 mol %),
6. (a) Basavaiah, D.; Sharada, D. S.; Kumaragurubaran, N.; Reddy, R.
M. J. Org. Chem. 2002, 67, 7135; (b) Basavaiah, D.; Kumaraguru-
baran, N.; Sharada, D. S. Tetrahedron Lett. 2001, 42, 85.
nitrostyrene 1 (0.50 mmol, 2.0 equiv) and DABCO (0.05 mmol,
20 mol %) in DMF 1.0 mL at 4 °C was added a,b-unsaturated
aldehyde 2 (0.25 mmol, 1.0 equiv). The reaction was stirred vigor-
ously for the time and the temperature described in Table 2. Next, the
crude product was purified by silica gel chromatography (pentane–
EtOAc-mixtures) to give the corresponding enals 3. Compound 3a E-
isomer: Colorless oil. 1H NMR (400 MHz, CDCl3): d = 9.38 (d,
J = 1.6 Hz, 1H), 7.30–7.26 (m, 5H), 6.80 (q, J = 7.2 Hz, 1H), 5.32
(dd, J = 8.8 Hz, 12.8 Hz, 1H), 5.04 (dd, J = 6.4 Hz, 12.8 Hz, 1H),
4.76–4.71 (m, 1H), 2.12 (d, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): 194.7, 154.8, 137.7, 129.1, 127.9, 127.8, 76.6, 41.3,
15.3. HRMS (ESI): calcd for [M+Na]+(C12H13NO3) requires m/z
242.0788, found 242.0781. The enantiomeric excess was determined
by HPLC with an OD-H column (n-hexane–i-PrOH = 90:10, k =
230 nm), 1.0 mL/min; tR = faster enantiomer 20.2 min, slower enan-
tiomer 41.6 min.
7. (a) Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, K.; Jang, H.-Y.;
Krische, M. J. J. Am. Chem. Soc. 2002, 124, 2402; (b) Frank, S. A.;
Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc. 2002, 124, 2404; (c)
Krafft, M. E.; Haxell, T. F. N. J. Am. Chem. Soc. 2005, 127, 10168.
8. (a) Shi, M.; Jiang, J.-K.; Li, C.-Q. Tetrahedron Lett. 2002, 43, 127.
9. (a) Imbriglio, J. E.; Vasbinder, M. M.; Miller, S. J. Org. Lett. 2003, 5,
3741; (b) Aroyan, C. E.; Vasbinder, M. M.; Miller, S. J. Org. Lett.
2005, 7, 3849; (c) Vasbinder, M. M.; Imbriglio, J. E.; Miller, S. J.
Tetrahedron 2006, 62, 11450; (d) Chen, S.-H.; Hong, B.-C.; Su, C.-F.;
Sarshar, S. Tetrahedron Lett. 2005, 46, 8899.
10. Utsumi, N.; Zhang, H.; Tanaka, F.; Barbas, C. F., III. Angew. Chem.,
Int. Ed. 2007, 46, 1878.
´
11. Vesely, J.; Dziedzic, P.; Cordova, A. Tetrahedron Lett. 2007, 48, 6900.