Asymmetric organocatalytic Michael-type reaction of phosphorus ylides to nitroolefins: synthesis of γ-nitro-β-aryl-α-methylene carboxylic esters

Article abstract of DOI:10.1016/j.tetlet.2009.11.063

We report, for the first time, asymmetric organocatalytic Michael-type addition of stabilized phosphorus ylides to nitroolefins mediated by bisthiourea catalyst. Its subsequent reaction with formaldehyde provides γ-nitro-α-methylene carboxylic esters in m

Full text of DOI:10.1016/j.tetlet.2009.11.063

Tetrahedron Letters 51 (2010) 446–448
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Asymmetric organocatalytic Michael-type reaction of phosphorus ylides to
nitroolefins: synthesis of
c-nitro-b-aryl-
a
-methylene carboxylic esters
Suresh Allu a, Sermadurai Selvakumar a, Vinod K. Singh a,b,
*
a Department of Chemistry, Indian Institute of Technology, Kanpur, UP 208 016, India
b Indian Institute of Science Education and Research Bhopal, ITI (Gas Rahat) Building Govindpura, Bhopal, MP 460 023, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We report, for the first time, asymmetric organocatalytic Michael-type addition of stabilized phosphorus
ylides to nitroolefins mediated by bisthiourea catalyst. Its subsequent reaction with formaldehyde pro-
Received 14 October 2009
Revised 12 November 2009
Accepted 15 November 2009
vides
c
-nitro-
a-methylene carboxylic esters in moderate to good yields and enantioselectivities (up to
63% ee).
Ó 2009 Elsevier Ltd. All rights reserved.
Enantioselective reactions catalyzed by small organic molecules
(asymmetric organocatalysis) that mimic enzymes and utilize
hydrogen bonds for activating the electrophiles have attracted
attention from a large number of organic chemists working in
the area of asymmetric synthesis.1–4 Among them, organocatalytic
Michael reaction of various nucleophiles with nitroalkenes repre-
sents a direct and the most appealing approach to access nitroalk-
anes that are versatile intermediates in organic synthesis.5 Our
recent success with nitroolefins as Michael acceptors6 in enantio-
selective conjugate addition of carbonyl compounds prompted us
to evaluate them for other useful transformations.
As anticipated, the reaction occurred smoothly and we describe
our results in this Letter.
Furthermore, the reaction provides highly functionalized c-ni-
tro carbonyl compounds, which cannot be accessed via conven-
tional Morita–Baylis–Hillman (MBH) reaction of nitroolefins and
acrylates (Scheme 2).11
At the outset, a series of reactions were carried out between P-
ylide 2a and nitroolefin 3a in toluene with 10 mol % of chiral
Brønsted acid catalyst 1a (Fig. 1). The reaction was complete in
24 h at room temperature and the expected P-ylide was isolated
as a stable compound. This was followed by its reaction with for-
Stabilized phosphorus ylides (P-ylides), apart from the tradi-
tional Wittig reaction, have also been widely used in alkylation
reactions.7 Unlike sulfur ylides,8 thier application in asymmetric
synthesis has not been much explored. Inspired by the proven abil-
ity of stabilized phosphorous ylides to serve as good nucleophiles
for the enantioselective addition to activated electrophiles,9 we
envisioned that P-ylides could serve as nucleophilic species to at-
tack appropriately activated nitroolefins, followed by proton trans-
fer to give chiral functionalized P-ylides (Scheme 1). This could be
followed by the reaction with formaldehyde to provide the desired
malin to give c-nitro-b-aryl-a-methylenic ester 4a in 59% yield
and 10% ee (Table 1, entry 1). However, on decreasing the reaction
temperature from rt to 0 °C and À20 °C, enantioselectivity in-
creased gradually with a decrease in the rate of the reaction (Table
1, entries 2 and 3). When the catalyst loading was increased from
10 to 30 mol %, a major enhancement in chemical yield of the reac-
tion was observed, with no appreciable change in enantioselectiv-
O
O
N
NO2
Chiral catalyst
c-nitro-b-aryl-a-methylene carbonyl compounds.
OR
In recent years, chiral Brønsted acids have appeared to be effec-
O
O
R1
Michael-type
reaction
H
PPh3
tive organocatalysts for conjugate additions to nitroolefins. In par-
ticular, chiral thioureas have received much attention and have
frequently been used as catalysts for transformations related to
enantioselective activation of nitroolefins.10 We envisioned that
chiral thiourea would effectively catalyze this reaction by forming
R1
OR
*
PPh3
Proton transfer
hydrogen bonding with nitroolefins to give optically pure
b-aryl- -methylene carbonyl compound via enantioenriched phos-
phorane intermediate (Scheme 1).
c-nitro-
a
O2N
O2N
R1
O
O
HCHO
R1
*
OR
PPh3O
OR
*
PPh3
Wittig reaction
* Corresponding author. Tel.: +91 512 2597291; fax: +91 512 2597436.
E-mail address: vinodks@iitk.ac.in (V.K. Singh).
Scheme 1. A novel route to chiral c-nitro carbonyl compounds.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.063

S. Allu et al. / Tetrahedron Letters 51 (2010) 446–448
447
different hydrogen bond-donating arms were screened in the
above-mentioned reaction, and the results are summarized in Ta-
ble 1. The poor enantioselectivity with catalysts having sulfon-
amide13b and sulfamide group as hydrogen bond-donating arms
clearly indicates that the presence of thiourea group is crucial to
get asymmetric induction in this reaction (Table 1, entries 7 and
8). It was also observed that the catalysts bearing both thiourea
and hydroxyl group13a on their skeleton afforded the product in
moderate yield and enantioselectivities (Table 1, entries 9 and
10). In order to see the effect of cyclohexyl backbone of bisthiourea
catalyst 1a on the enantioselectivity, catalysts with diphenyl9,12e
(1f) and binapthyl12d (1g) backbone were then studied, but the cor-
responding Michael adduct was obtained in moderate enantiose-
lectivities (Table 1, entries 11 and 12). In view of this study, the
catalyst 1a was chosen for further study.
The effect of solvent on the enantioselectivity of the reaction
was then studied (Table 2). Among the different solvents screened,
non polar solvents were found to be superior in comparison to the
polar ones. Of the different non polar solvents tested, o-xylene was
the optimum choice. Finally, we were pleased to find that cooling
the reaction mixture to À40 °C had a positive effect on the enanti-
oselectivity and the product 4a was obtained in 63% ee while a
good level of conversion was maintained (Table 2, entry 9).
Having identified the optimized condition for this reaction, we
evaluated the effect of ester substituent of P-ylides14 on yield
and enantioselectivity (Table 3). Ethyl ester 2a turned out to be
the suitable ylide for the reaction (Table 3, entry 1).
COOEt
NO2
O2N
ref. 11
O
NO2
COOEt
Ar
Ar
OEt
Ar
Not observed only product
Scheme 2. Alternate approach to
c
-nitro carbonyl compounds.
Ph
OH
O
O
H
N
S
Ph
Ph
N
N
RHN
NHR
S
H
H
O
S
Ph
1c
Ph
Ph
1a: R =
NHAr
Ar = 3,5-(CF3)2C6H3
Ph
ArHN
N
H
OH
1b: R = SO2-4-MeC6H4
1d: Ar = 3,5-(CF3)2C6H3
Ph
O
Ph
Ph
H
N
Ph
Ph
NHAr
S
S
N
H
NH HN
OH
S
ArHN
NHAr
Ph
1f: Ar = 3,5-(CF3)2C6H3
1e: Ar = 3,5-(CF3)2C6H3
S
N
H
Ylides 2b and 2c led to the addition product in low yield and
enantioselectivity (Table 3, entries 2 and 3). Reaction with bulky
tert-butyl ester 2d afforded the Michael adduct in excellent yield
and moderate enantioselectivity (Table 3, entry 4).
NHAr
NHAr
H
N
S
The scope and limitations of the Michael-type reaction cata-
lyzed by bisthiourea 1a were then examined. A wide range of nitro-
olefins including both aromatic and aliphatic nitroolefins reacted
smoothly with 2a under optimized condition to give Michael ad-
duct in moderate to good yield and enantioselectivity (Table 4).
It was observed that the electronic nature of the substituents at
the aromatic ring shows significant effect on the enantioselectivity
(Table 4, entry 2 vs 6). Heteroaromatic nitroolefin also gave the Mi-
chael adduct in moderate yield and enantioselectivity (Table 4, en-
1g: Ar = 3,5-(CF3)2C6H3
Figure 1. Chiral Brønsted acid catalysts.
Table 1
Optimization of reaction conditions for enantioselective Michael-type reactiona
1. 1, toluene
O
O2N
, THF
NO2
O
2. HCHO
rt
,
OEt
Ph
OEt
*
Ph
PPh3
2a
4a
3a
Table 2
Effect of solvent on enantioselectivitya
Entry
Catalyst
Mol%
Temp (°C)
Time (d)
Yield (%)
eeb (%)
O
1. 1a, solvent,
-20 °C, 4Å MS,
2. HCHO, THF, rt
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
10
10
10
20
30
30
30
30
30
30
30
30
rt
0
1
2
5
5
4
5
5
3
4
3
3
2
59
54
25
34
47
46
25
44
49
35
35
38
10
15
35
37
39
NO2
O2N
Ph
O
OEt
À20
À20
À20
À20
À20
À20
À20
À20
À20
À20
Ph
PPh3
OEt
*
2
4a
47c
15c
À11c
24c
39c
À37c
36c
Entry
Solvent
Time (d)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
CHCl3
THF
2
2
2
5
5
‘6
1
1
6
25
25
33
46
52
44
35
—
14
32
33
47
53
22d
08
10
11
12
Toluene
o-Xylene
Benzene
DMF
CH3CN
o-Xylene
1g
a
Reactions were carried out with 0.16 mmol of 2, and 0.24 mmol of 3 in 0.5 mL of
solvent. Then excess of HCHO was added and stirred at room temperature for 24 h.
b
e
Determined by chiral HPLC. The absolute configurations have not been assigned
—
63f
yet.
54
c
4 Å molecular sieves were added for this reaction (Table 2, entry 5).
a
Reactions were carried out at 0.16 mmol scale in 0.5 mL solvent,
2:3:1a = 1:1.5:0.3.
b
Isolated yield.
Determined by chiral HPLC.
ity (Table 1, entries 3–5). It was gratifying to note that an addition
of 4 Å molecular sieves showed positive effect on the enantioselec-
tivity of the reaction (Table 1, entry 6). After optimizing the reac-
tion conditions, various chiral Brønsted acid catalysts 1b–g with
c
d
Reaction was carried out at À5 °C.
e
Complex mixture.
f
Reaction was carried out at À40 °C.

448
S. Allu et al. / Tetrahedron Letters 51 (2010) 446–448
Table 3
procedure is operationally very simple and provides versatile syn-
Effect of ylides on enantioselectivitya
thetic intermediates. Further elaboration of this novel transforma-
tion, its synthetic application to determine the absolute
stereochemistry and mechanistic studies are ongoing in our
laboratory.
1a, o-Xylene,
1.
O
-40 °C, 4d,
4Å MS
2. HCHO, THF, rt
NO2
O2N
Ph
O
OR
PPh3 Ph
OR
*
Acknowledgments
4a-d
2a-d
V.K.S. thanks the Department of Science and Technology, India
for a research grant through J. C. Bose fellowship. S.A. and S.S.
thank the Council of Scientific and Industrial Research, New Delhi
for research fellowships
Entry
R
Product
Yieldb (%)
eec (%)
1
2
3
4
Et
4a
4b
4c
4d
54
56
30
72
63
36
14
41
Me
iPr
tBu
a
Reactions were carried out at 0.16 mmol scale in 0.5 mL o-xylene,
References and notes
2:3:1a = 1:1.5:0.3.
b
Isolated yield.
1. For selected examples on thiourea catalysis, see: (a) Sigman, M. S.; Jacobsen, E.
N. J. Am. Chem. Soc. 1998, 120, 4901–4902; (b) Okino, T.; Hoashi, Y.; Takemoto,
Y. J. Am. Chem. Soc. 2003, 125, 12672–12673; (c) Joly, G. D.; Jacobsen, E. N. J. Am.
Chem. Soc. 2004, 126, 4102–4103; (d) Yoon, T. P.; Jacobsen, E. N. J. Am. Chem.
Soc. 2005, 44, 466–468.
c
Determined by chiral HPLC. The absolute configurations have not been assigned
yet.
2. For a review on thiourea catalysis, see: (a) Connon, S. J. Chem. Eur. J. 2006, 12,
5418–5427; (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713–5743;
(c) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299–4306; (d) Schreiner, P. R.
Chem. Soc. Rev. 2003, 32, 289–296.
3. For examples of Brønsted acid catalyzed enantioselective reactions, see: (a)
McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003, 125, 12094–12095; (b)
Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418–
3419.
4. For a review on Brønsted acid catalysis, see: (a) Jencks, W. P. Acc. Chem. Res.
1976, 9, 425–432; (b) Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43, 2062–2064;
(c) Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L. Angew. Chem., Int. Ed. 2005, 44,
1758–1763; (d) Yamamoto, H.; Fustatsugi, K. Angew. Chem., Int. Ed. 2005, 44,
1924–1942; (e) Akiyama, T.; Itoh, J.; Fuchibe, K. Adv. Synth. Catal. 2006, 348,
999–1010; (f) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45,
1520–1543; (g) Akiyama, T. Chem. Rev. 2007, 107, 5744–5758.
Table 4
Enantioselective Michael-type addition of P-ylide with different nitroolefinsa
1. 1a, o-xylene,
-40 °C, 4Å MS,
2. HCHO, THF, rt
O
O2N
R
NO2
O
OEt
OEt
PPh3
2a
R
*
4
Entry
R
Time (d) Product Yieldb
(%)
eec (%)
1
2
3
4
5
6
7
8
9
C6H5
6
6
6
6
6
6
6
6
6
4
4a
4e
4f
4g
4h
4i
4j
4k
4l
54
63
27
26
25
35
35
35
29
52
63
63
46
39
35
24
42
41
59
11
5. For a review, see: Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002,
1877–1894.
6. Maya, V.; Singh, V. K. Org. Lett. 2007, 9, 1117–1119.
4-ClC6H
4-FC6H4
3-ClC6H4
3-FC6H4
4-OMeC6H4
3-MeC6H4
4-MeC6H4
3,5-MeC6H3
3,4-Methylene dioxy-
C6H3
2-Thioenyl
PhCH2CH2
7. (a) Asunskis, J.; Shechter, H. J. Org. Chem. 1968, 33, 1164–1168; (b) von
Strandtmann, M.; Cohen, M. P.; Puchalski, C.; Shavel, J., Jr. J. Org. Chem. 1968, 33,
4306–4309; (c) Connor, D. T.; von Strandtmann, M. J. Org. Chem. 1973, 38,
1047–1049.
8. For selected examples of stabilized sulfur ylides in organocatalytic reactions,
see: (a) Aggarwal, V. K.; Alonso, E.; Hynd, G.; Lydon, K. M.; Palmer, M. J.;
Porcelloni, M.; Studley, J. R. Angew. Chem., Int. Ed. 2001, 40, 1430–1433; (b)
Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew.
Chem., Int. Ed. 2001, 40, 1433–1436; (c) Kunz, R. K.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 3240–3241.
10
4m
11
12
13
6
6
4
4n
4o
4p
40
60
43
43
16
19
9. Zhang, Y.; Liu, Y.-K.; Kang, T.-R.; Hu, Z.-K.; Chen, Y.-C. J. Am. Chem. Soc. 2008,
130, 2456–2457.
Cyclohexyl
10. For selected examples see: (a) Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.;
Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119–125; (b) Huang, H.; Jacobsen, E.
N. J. Am. Chem. Soc. 2006, 128, 7170–7171; (c) Tsogoeva, S. B.; Wei, S. Chem.
Commun. 2006, 1451–1453; (d) Wang, J.; Li, H.; Zu, L.; Jiang, W.; Wang, W. Adv.
Synth. Catal. 2006, 348, 2047–2050; (e) Wang, J.; Heikkinen, L. D.; Li, H.; Zu, L.;
Jiang, W.; Xie, H.; Wang, W. Adv. Synth. Catal. 2007, 349, 1052–1056; (f)
Rabalakos, C.; Wulff, W. D. J. Am. Chem. Soc. 2008, 130, 13524–13525; (g)
Martin, N. J. A.; Cheng, X.; List, B. J. Am. Chem. Soc. 2008, 130, 13862–13863; (h)
Gao, P.; Wang, C.; Wu, Y.; Zhou, Z.; Tang, C. Eur. J. Org. Chem. 2008, 4563–4566.
11. Dadwal, M.; Mohan, R.; Panda, D.; Mobin, S. M.; Namboothri, I. N. N. Chem.
Commun. 2006, 338–340.
a
Reactions were carried out at 0.16 mmol scale in 0.5 mL o-xylene,
2:3:1a = 1:1.5:0.3.
b
Isolated yield.
c
Determined by chiral HPLC. The absolute configurations have not been assigned
yet.
try 11). With aliphatic nitroolefins, the addition products were ob-
tained in low ee (Table 4, entries 12 and 13).
12. (a) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew. Chem., Int. Ed 2005,
44, 6576–6579; (b) Herrera, R. P.; Monge, D.; Martin-Zomora, E.; Fernández, R.;
Lassaletta, J. M. Org. Lett. 2007, 9, 3303–3306; (c) Martin, N. J. A.; Ozores, L.;
List, B. J. Am. Chem. Soc. 2007, 129, 8976–8977; (d) Rampalakos, C.; Wulff, W. D.
Adv. Synth. Catal. 2008, 350, 1785–1790; (e) Sohtome, Y.; Takemura, N.; Takagi,
R.; Hashimoyo, Y.; Nagasawa, K. Tetrahedron 2008, 64, 9423–9429.
13. (a) Sibi, M. P.; Itoh, K. J. Am. Chem. Soc. 2007, 129, 8064–8065; (b) Yar, M.;
McGarrigle, E. M.; Aggarwal, V. K. Angew. Chem., Int. Ed. 2008, 47, 3784–3786.
14. Zhu, X.-F.; Schaffner, A.-P.; Li, R. C.; Kwon, O. Org. Lett. 2005, 7, 2977–2980.
In conclusion, we have developed the first asymmetric Michael-
type reaction of stabilized phosphorus ylides with nitroalkenes,
followed by its reaction with formaldehyde to provide optically ac-
tive
c-nitro-a-methylene carboxylic esters in moderate to good
yields and enantioselectivities (up to 63% ee). The reaction is cata-
lyzed by simple thiourea-based organocatalyst, which can be read-
ily synthesized from commercially available starting materials. The