Dual-reagent organocatalysis with a phosphine and electron-deficient alkene: application to the Henry reaction

Article abstract of DOI:10.1016/j.tetlet.2008.08.092

Triphenylphosphine in combination with methyl acrylate was found to be able to catalyze the Henry (nitroaldol) reaction of various aldehydes and α-keto esters to give the corresponding β-nitroalkanols in good to excellent yields, and a catalytic cycle involving a zwitterionic phosphine-alkene adduct was proposed for this dual-reagent organocatalysis according to the deuterium-labeling experiments with CD₃NO₂.

Full text of DOI:10.1016/j.tetlet.2008.08.092

Tetrahedron Letters 49 (2008) 6442–6444
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Dual-reagent organocatalysis with a phosphine and electron-deficient
alkene: application to the Henry reaction
*
Xiu Wang, Fan Fang, Chen Zhao, Shi-Kai Tian
Department of Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Triphenylphosphine in combination with methyl acrylate was found to be able to catalyze the Henry
Received 26 June 2008
Revised 25 August 2008
Accepted 26 August 2008
Available online 29 August 2008
(nitroaldol) reaction of various aldehydes and
a-keto esters to give the corresponding b-nitroalkanols
in good to excellent yields, and a catalytic cycle involving a zwitterionic phosphine–alkene adduct was
proposed for this dual-reagent organocatalysis according to the deuterium-labeling experiments with
CD3NO2.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Phosphines
Electron-deficient alkenes
The Henry reaction
Aldehydes
Nitroalkanes
The Michael-type additions of phosphines to electron-deficient
alkenes readily proceed to generate zwitterions (Scheme 1),1
which are able to react with electrophiles such as electron-defi-
cient alkenes (the Rauhut–Currier reaction)1b,2 and aldehydes
(the Morita–Baylis–Hillman reaction).3,4 Such zwitterions can also
behave as organic bases to deprotonate protic nucleophiles (NuH)
and catalyze the corresponding Michael additions to electron-defi-
cient alkenes.5,6 Since the deprotonated nucleophiles (NuÀ) are
conceivably reactive toward other electrophiles such as aldehydes,
it is possible to use a phosphine in combination with electron-defi-
cient alkene to promote other nucleophile–electrophile reactions.
In continuation of our program to develop new organocatalysis,7
we decided to investigate the possibility of such a dual reagent-
catalyzed nucleophile–electrophile reaction, which was expected
to proceed faster than the corresponding Rauhut–Currier reaction,
Morita–Baylis–Hillman reaction, and Michael addition when using
an appropriate phosphine and electron-deficient alkene.
EWG
Nu
EWG
EWG
Rauhut-
Currier
Michael
addition
EWG
NuH
+
PR3
+
-
R3P
Nu
R3P
EWG
EWG
EWG
-
O
Morita-Baylis-
Hillman
Dual-reagent
organocatalysis
?
R'
H
OH
OH
Nu
EWG = Electron-
Withdrawing Group
EWG
R'
R'
Scheme 1. Some reactions involving zwitterionic phosphine–alkene adducts.
The Henry (nitroaldol) reaction was selected to develop such a
dual-reagent organocatalysis with a phosphine and electron-defi-
cient alkene. This important carbon–carbon bond-forming reaction
is able to produce b-nitroalkanols that are useful intermediates in
the synthesis of biologically relevant compounds, and have been
demonstrated to be catalyzed by a range of organic bases.8,9
Although trialkylphosphines and electron-rich triarylphosphines
were employed by Chisholm and Weeden as effective catalysts
for the Henry reaction in the presence of 5.0 equiv of nitromethane,
triphenylphosphine showed sluggish activity toward the same
reaction.10,11 However, triphenylphosphine was reported to under-
go Michael-type addition to electron-deficient alkenes smoothly in
the presence of appropriate proton sources,1a,12 so we decided to
use triphenylphosphine in combination with an electron-deficient
alkene as a surrogate organic base to catalyze the Henry reaction.
The lower nucleophilicity of triphenylphosphine, compared to that
of trialkylphosphines and electron-rich triarylphosphines, was ex-
pected to reduce the consumption of electron-deficient alkenes by
slowing down the corresponding Rauhut–Currier reaction, Morita–
Baylis–Hillman reaction, and Michael addition.
* Corresponding author. Tel.: +86 551 3600871; fax: +86 551 3601592.
E-mail address: tiansk@ustc.edu.cn (S.-K. Tian).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.092

X. Wang et al. / Tetrahedron Letters 49 (2008) 6442–6444
6443
Table 2
Several inexpensive electron-deficient alkenes (10 mol %) were
The Henry reaction catalyzed by triphenylphosphine and methyl acrylatea
examined in combination with triphenylphosphine (10 mol %) in
the reaction of benzaldehyde (1a) with nitromethane (5.0 equiv)
in ethanol at room temperature (Table 1), and methyl acrylate
was found to be the best one in promoting the reaction to give
b-nitroalkanol 2aa in terms of yield and reaction time (Table 1, en-
try 5). Interestingly, no desired product was obtained at all when
using the corresponding acrylic acid (Table 1, entry 6), and the
R3
HO
R1
CH2=CHCO2Me (10 mol %),
PPh3 (10 mol %), EtOH, rt
O
NO2
R2
2
NO2
+
R1
R2
R3
1
Entry
1
R1
R2
R3
2
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16c
17d
18e
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
11
1m
1n
1o
1a
1i
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2aa
2ba
2ca
2da
2ea
2fa
2ga
2ha
2ia
2ja
2ka
2la
2ma
2na
2oa
2ab
2ib
2lb
2
1
2
24
1
1
1.5
2
1.5
1.5
2
94
98
90
65
98
96
97
99
87
99
96
90
87
97
85
92
89
91
use of either
a-substituted or b-substituted methyl acrylate just
4-O2NC6H4
4-CIC6H4
4-MeOC6H4
3-O2NC6H4
2-O2NC6H4
2-CIC6H4
2-MeOC6H4
2-Furyl
3-Pyridyl
n-C6H13
c-C6H11
Me3C
Ph
Me
Ph
2-Furyl
c-C6H11
led to sluggish reaction (Table 1, entries 7 and 8). Further investi-
gation showed that the reaction proceeded much slower in non-
protic solvents such as acetonitrile, ether, tetrahydrofuran, ethyl
acetate, dichloromethane, and toluene. Although reducing the
loading of triphenylphosphine and methyl acrylate led to extended
reaction time and lower yield, the reaction gave the desired prod-
uct in excellent yield (94%) without extension of reaction time
when the amount of nitromethane decreased from 5.0 equiv to
2.0 equiv (Table 1, entry 9).
8
H
24
9.5
2
2
2
In the presence of 10 mol % of triphenylphosphine and 10 mol %
of methyl acrylate, a wide range of aromatic, heteroaromatic, and
aliphatic aldehydes could react well with nitromethane and gave
the corresponding b-nitroalkanols in good to excellent yields
CO2Et
CO2Et
H
H
H
Me
Me
Me
11
8
(Table 2, entries 1–13).13 Activated ketones such as
a-keto esters
a
Reaction conditions:
1
(0.50 mmol), R3CH2NO2 (2.0 equiv), methyl acrylate
could also serve as excellent substrates for the catalytic Henry
reaction (Table 2, entries 14 and 15). Furthermore, the replacement
of nitromethane with nitroethane in the catalytic Henry reaction
resulted in formation of the corresponding b-nitroalkanols in
excellent yields and with up to 91:9 diastereoselectivity (Table 2,
entries 16–18).
(10 mol %), PPh3 (10 mol %), ethanol (0.050 mL), rt.
b
Isolated yield.
For 2ab, syn:anti = 68:32.
For 2ib, syn:anti = 91:9.
For 2lb, syn:anti = 50:50.
c
d
e
In order to gain insights into the reaction mechanism, we car-
ried out the 1H NMR analysis of a solvent-free reaction mixture
of CD3NO2 with PhCHO (1a) in the presence of 10 mol % of triphen-
ylphosphine and 10 mol % of methyl acrylate,14 and clearly ob-
served H/D exchange at the methylene group of product 2aa and
Table 3
Deuterium-labeling experimentsa
solvent
rt, 3 h
MeNO2
+
+ PPh3
NO2
PhCHO +
1a
CO2Me
the dramatic enrichment of deuterium at the
a- and b-positions
of methyl acrylate and two of its adducts, phosphonium ion 3
and ester 4 (Table 3, entry 1).15 As indicated by the ratio of methyl
acrylate to phosphonium ion 3 and ester 4 (15:32:53), a significant
amount of methyl acrylate underwent Michael addition to nitro-
methane to give ester 4. Nevertheless, the consumption of methyl
acrylate via the Rauhut–Currier reaction and the Morita–Baylis–
Hillman reaction was not detected by 1H NMR analysis. While per-
forming this reaction in CD3OD raised the ratio of deuterium to
hydrogen in product 2aa and phosphonium ion 3, the use of CH3OH
as the solvent dramatically reduced the ratio of deuterium to
δ 6.12
g
δ 2.84
c
δ 2.47
OH
e
+
NO2
Ph3P
+
+
d
+
CO2Me
CO2Me
Ph
2aa
CO2Me
a
b
f
3
4
δ 4.62, 4.50
δ 3.87
δ 2.31
Deuteriumb (%)
δ 5.83, 6.40
Entry
MeN02
Solvent
a
b
c
d
e
f
g
1c
2
3
CD3N02
CD3NO2
CD3NO2
CH3NO2
None
87
37
>78d
95
12
6
<5
<5
55
53
38
<5
42
>95
>95f
76
CD3OD
CH3OH
CD3OD
95
75
22
80
NDe
47
NDe
24
NDe
24
4
NDe
NDe
a
Reaction conditions: 1a (0.50 mmol), MeNO2 (2.0 equiv), methyl acrylate
(10 mol %), PPh3 (10 mol %), solvent (if any, 0.050 mL), rt, 3 h.
Table 1
b
Determined by 1H NMR analysis.
Survey of electron-deficient alkenesa
c
Methyl acrylate:3:4 = 15:32:53.
d
Overlapping with a broad signal in the 1H NMR spectrum.
PPh3 (10 mol %)
alkene (10 mol %)
OH
e
Not determined.
f
No signal was detected at d 6.12 by 1H NMR analysis.
NO2
PhCHO
+ MeNO2
Ph
EtOH, rt
1a
2aa
Entry
Alkenes
Time (h)
Yieldb (%)
hydrogen in product 2aa, methyl acrylate, and ester 4 (Table 3,
entries 2 and 3). In contrast, the use of CD3OD as the solvent for
the reaction of PhCHO (1a) with CH3NO2 led to significant enrich-
ment of deuterium in product 2aa and phosphonium ion 3
(Table 3, entry 4). Furthermore, methyl acrylate was clearly
observed to undergo transesterification with solvent CD3OD (Table
3, entries 2 and 4), and it should be noted that rapid H/D exchange
of nitromethane took place in all the cases.
1
2
3
4
5
6
7
8
9c
None
24
24
24
24
2
24
24
24
2
0
65
75
88
98
0
7
0
94
Benzoquinone
CH2@CHCONH2
CH2@CHCOMe
CH2@CHCO2Me
CH2@CHCO2H
CH2@C(Me)CO2Me
trans-PhCH@CHCO2Me
CH2@CHCO2Me
On the basis of these deuterium-labeling experiments, we pro-
pose a catalytic cycle for the dual reagent-catalyzed Henry reaction
(Scheme 2). The Michael-type addition of triphenylphosphine to
methyl acrylate generates zwitterion 5, which serves as an
a
Reaction conditions: 1a (1.0 mmol), MeNO2 (5.0 equiv), PPh3 (10 mol %), alkene
(10 mol %), ethanol (0.20 mL), rt.
b
Isolated yield.
2.0 equiv of MeNO2 and 0.10 mL of ethanol were used.
c

6444
X. Wang et al. / Tetrahedron Letters 49 (2008) 6442–6444
References and notes
Ph3P
+
-
NO2
Ph3P
CO2Me
R3
CO2Me
R3
1. For reviews, see: (a) Enders, D.; Saint-Dizier, A.; Lannou, M.-I.; Lenzen, A. Eur. J.
5
Org. Chem. 2006, 29; (b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004, 346,
1035; (c) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34, 535.
2. For recent examples, see: (a) Wang, L.-C.; Luis, A. L.; Agapiou, 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.
3. For recent reviews, see: (a) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int.
Ed. 2007, 46, 4614; (b) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811.
4. For recent examples, see: (a) Teng, W.-D.; Huang, R.; Kwong, C. K.-W.; Shi, M.;
Toy, P. H. J. Org. Chem. 2006, 71, 368; (b) Pereira, S. I.; Adrio, J.; Silva, A. M. S.;
Carretero, J. C. J. Org. Chem. 2005, 70, 10175.
5. For the phosphine-catalyzed Michael addition of active methylene compounds
to electron-deficient alkenes, see: (a) White, D. A.; Baizer, M. M. Tetrahedron
Lett. 1973, 14, 3597; (b) Yoshida, T.; Saito, S. Chem. Lett. 1982, 1587; (c)
Gimbert, C.; Lumbierres, M.; Marchi, C.; Moreno-Mañas, M.; Sebastián, R. M.;
Vallribera, A. Tetrahedron 2005, 61, 8598.
NO2
+
HO
R1
NO2
R2
-
R3
Ph3P
CO2Me
6
2
R3
+
-
O
O
R1
NO2
R2
Ph3P
CO2Me
R1
R2
7
1
Scheme 2. Proposed catalytic cycle.
organic base to deprotonate nitroalkane.1b,5a The addition of acti-
vated nitroalkane (the anion in ion pair 6) to carbonyl compound
1 followed by proton transfer releases product 2 and regenerates
zwitterion 5. The reversible formation of zwitterion 5 and the acid-
ity of phosphonium ion 3 (in ion pairs 6 and 7) can account for the
enrichment of deuterium in methyl acrylate and two of its adducts
in the deuterium-labeling experiments shown in Table 3. Most
importantly, our proposed catalytic cycle is substantially sup-
ported by the presence of much greater than 50% deuterium at
6. For the phosphine-catalyzed Michael addition of alcohols and water to
electron-deficient alkenes, see: (a) Jenner, G. Tetrahedron 2002, 58, 4311; (b)
Stewart, I. C.; Bergman, R. G.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 8696.
7. (a) Wang, X.; Tian, S.-K. Tetrhedron Lett. 2007, 48, 6010; (b) Wang, X.; Tian, S.-K.
Synlett 2007, 1416.
8. For a general review, see: (a) Luzzio, F. A. Tetrahedron 2001, 57, 915. For recent
reviews on the catalytic asymmetric Henry reaction, see: (b) Palomo, C.;
Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007, 2561; (c) Boruwa, J.; Gogoi, N.;
Saikia, P. P.; Barua, N. C. Tetrahedron: Asymmetry 2006, 17, 3315.
9. For selected examples, see: (a) Li, H.; Wang, B.; Deng, L. J. Am. Chem. Soc. 2006,
128, 732; (b) Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J. H.;
Hiemstra, H. Synlett 2005, 2817; (c) Sarkar, A.; Ilankumaram, P.; Kisanga, P.;
Verkade, J. G. Adv. Synth. Catal. 2004, 346, 1093; (d) Zhou, C.; Zhou, Y.; Wang, Z.
Chin. Chem. Lett. 2003, 14, 355; (e) Simoni, D.; Rondanin, R.; Morini, M.;
Baruchello, R.; Invidiata, F. P. Tetrahedron Lett. 2000, 41, 1607; (f) Kisanga, P. B.;
Verkade, J. G. J. Org. Chem. 1999, 64, 4298.
10. Weeden, J. A.; Chisholm, J. D. Tetrahedron Lett. 2006, 47, 9313.
11. Triphenylphosphine (10 mol %) was not able to catalyze the reaction of
benzaldehyde with nitromethane in ethanol at room temperature in 24 h
(Table 1, entry 1).
12. (a) Ohmori, H.; Takanami, T.; Shimada, H.; Masui, M. Chem. Pharm. Bull. 1987,
35, 2558; (b) Patzke, B.; Sustmann, R. J. Organomet. Chem. 1994, 480, 65; (c)
Cristau, H.-J.; Vors, J.-P.; Christol, H. Synthesis 1979, 538; (d) Galkin, V. I.;
Bakhtiyarova, Y. V.; Polezhaeva, N. A.; Shaikhutdinov, R. A.; Klochkov, V. V.;
Cherkasov, R. A. Russ. J. Gen. Chem. 1998, 68, 1052.
the
a-positions of phosphonium ion 3 and methyl acrylate in the
reaction of PhCHO (1a) with CD3NO2 (Table 3, entries 1–3). In addi-
tion, the basic intermediates generated in the catalytic cycle should
be responsible for the H/D exchange of nitroalkane, product 2, and
alcoholic solvent (Table 3), and the transesterification of methyl
acrylate with CD3OD (Table 3, entries 2 and 4).
In summary, we have developed an efficient catalytic Henry
reaction with a phosphine and electron-deficient alkene. In the
presence of 10 mol % of triphenylphosphine and 10 mol % of
methyl acrylate, a wide variety of aldehydes and
a-keto esters
could react with nitroalkanes and gave the corresponding b-nitro-
alkanols in good to excellent yields. According to the deuterium-
labeling experiments with CD3NO2, a catalytic cycle involving a
zwitterionic phosphine–alkene adduct was proposed for this
dual-reagent organocatalysis.
13. General procedure: A mixture of carbonyl compound 1 (0.50 mmol), nitroalkane
(1.0 mmol), triphenylphosphine (13.1 mg, 0.050 mmol, 10 mol %), and methyl
acrylate (4.4 mg, 4.6 lL, 0.050 mmol, 10 mol %) in ethanol (0.050 mL) was
allowed to stand in a vial at room temperature for the time as indicated in
Table 2. The resulting mixture was concentrated, and the residue was purified
by silica gel column chromatography to give b-nitroalkanol 2. All the products
are known and characterized by 1H and 13C NMR analysis.
14. A small portion (about 5 lL) of the reaction mixture was dissolved in CDCl3 and
was subjected to 1H NMR (CDCl3, 400 M) analysis.
Acknowledgments
15. The methyl groups in methyl acrylate, phosphonium ion 3, and ester 4 were
chosen as the corresponding references to determine the percentage of
deuterium. The signal for the methyl group of phosphonium ion 3 overlaps
with that of CH3OH in the 1H NMR spectrum (Table 3, entry 3). When CD3OD
was used as the solvent, the percentage of deuterium in methyl acrylate could
not be determined as a result of transesterification (Table 3, entries 2 and 4).
We are grateful for the financial support from the National
Natural Science Foundation of China (20732006 and 20672105),
the Chinese Academy of Sciences, and the University of Science
and Technology of China.