Bicyclic guanidine-catalyzed enantioselective phospha-Michael reaction: Synthesis of chiral β-aminophosphine oxides and β-aminophosphines

Article abstract of DOI:10.1039/b713151h

Chiral bicyclic guanidine has been found to catalyze the phospha-Michael reactions of diaryl phosphine oxide to nitroalkenes with high enantioselectivities, offering a direct methodology to prepare chiral β-aminophosphine oxides and β-aminophosphines. The

Full text of DOI:10.1039/b713151h

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Bicyclic guanidine-catalyzed enantioselective phospha-Michael
reaction: synthesis of chiral b-aminophosphine oxides and
b-aminophosphines{
Xiao Fu, Zhiyong Jiang and Choon-Hong Tan*
Received (in Cambridge, UK) 28th August 2007, Accepted 20th September 2007
First published as an Advance Article on the web 1st October 2007
DOI: 10.1039/b713151h
We found that with 10 mol% of chiral bicyclic guanidine 1, the
addition of diphenyl phosphine oxide 2a to b-nitrostyrene
proceeded smoothly in various solvents (Table 1, entries 1–3).{
Moderate enantioselectivities were obtained which improved when
ether type solvents were used (entries 4–6). Diethyl ether gave the
best results, providing the adduct 3a in 60% ee (entry 7).
Subsequently, a series of diaryl phosphine oxides 2a–f, with a
variety of substituents were tested (Table 2, entries 2–4); the
enantioselectivities obtained were similar to diphenyl phosphine
oxide 2a. Di(1-naphthyl)- and di(2-naphthyl)phosphine oxides, 2e
and 2f (entries 5 and 6) were also evaluated; enantioselectivities of
65 and 82% were obtained respectively. Most adducts except 3d
are crystalline and we were able to improve the optical purity of all
adducts to .90% ee after a single recrystallization from MeOH or
tBuOMe–CH2Cl2.
Chiral bicyclic guanidine has been found to catalyze the
phospha-Michael reactions of diaryl phosphine oxide to
nitroalkenes with high enantioselectivities, offering a direct
methodology to prepare chiral b-aminophosphine oxides and
b-aminophosphines.
Chiral compounds containing P–C bonds have found important
synthetic roles in metal-catalyzed1 and organocatalytic reactions.2
Such compounds are typically prepared using enantiopure starting
materials, chiral auxiliaries or by resolution of the racemic
phosphines.3 Successful catalytic methods include the synthesis
of chiral a-amino phosphonic acids via the hydrophosphonylation
of imines with dialkyl phosphites [(RO)2P(O)H].4 Catalysts such as
lanthanoid–potassium–BINOL complexes,5 quinine,6 thiourea,7
and chiral phosphoric acid8 were employed. It is also possible to
conduct catalytic asymmetric hydrophosphination of alkenes with
secondary phosphines (R2PH) using organonickel complexes9 or
bifunctional Cinchona alkaloid.10 Recently, hydrophosphination of
a,b-unsaturated aldehydes with secondary phosphines were
achieved with an iminium-ion strategy using chiral protected
diarylprolinols.11
The reaction between di(1-naphthyl) phosphine oxide 2f and
b-nitrostyrene can be further optimized to 91% ee by decreasing
the reaction temperature to 240 uC (Table 3, entry 1). Using the
optimized conditions, the addition of 2f to various aryl nitroalk-
enes were investigated (entries 2–9). Adducts 4a–c were obtained
using o-, m- and p-chloro substituted aryl nitroalkenes (entries 2–
4). High yields and high ees were obtained; showing that
substitution pattern on the aryl ring would not affect the
enantioselectivity. Other substrates containing bromo, nitro and
methyl substituents (entries 5–8) also gave good results. Most
substrates required only 12 h or less of reaction time, but the bulky
(E)-2-(2-nitrovinyl)naphthalene (entry 9) required .36 h for the
reaction to be complete. The optical purity of most adducts 3f and
The direct addition of P(O)–H bonds (dialkyl phosphites or
dialkyl phosphine oxides [R2P(O)H]) across activated alkenes is
one of the most convenient routes to generate P–C bonds.12
Synthetically useful examples have utilized chiral phosphite,13
P-chiral phosphine oxides14 or chiral a,b-unsaturated amides15 as
acceptors. Strong inorganic bases such as LDA, nBuLi or NaH
were generally used and these are sometimes described as phospha-
Michael reactions. A quinine-catalyzed version were recently
attempted with diphenyl phosphite and nitroalkenes.16
Table 1 Chiral bicyclic guanidine-catalyzed phospha-Michael reac-
tions of b-nitrostyrene
Phospha-Michael reactions can be effectively catalyzed by a
strong organic Brønsted base such as guanidine.17 The donors,
dialkyl phosphites or dialkyl phosphine oxides, are in equilibrium
with their s3,l3-tautomers,6b,8,18 (RO)2P(OH) and R2P(OH). In
the presence of guanidine, the equilibrium is likely to favor the
active intermediate, the s3,l3-tautomers. Chiral guanidines and
guanidinium salts are excellent enantioselective catalysts for a
variety of reactions19 including Strecker, Diels–Alder and Michael
reactions.20 Thus, we envisioned an enantioselective phospha-
Michael reaction using chiral guanidines.
Entry
Solvent
t/h
Yielda (%)
eeb (%)
1
2
3
4
5c
6
7
a
CH3CN
CH2Cl2
Toluene
t-BuOMe
p-Dioxane
THF
1
4
0.5
15
27
1
91
54
82
79
60
85
64
c
12
30
40
30
40
45
60
Department of Chemistry, 3 Science Drive 3, National University of
Singapore, Singapore, 117543. E-mail: chmtanch@nus.edu.sg
{ Electronic supplementary information (ESI) available: Experimental
section. See DOI: 10.1039/b713151h
Et2O
b
13
Isolated yield. Determined by HPLC. Reaction performed at rt.
5058 | Chem. Commun., 2007, 5058–5060
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Table 2 Chiral bicyclic guanidine-catalyzed phospha-Michael reac-
tions with various diaryl phosphine oxides
Scheme 1 Phospha-Michael reaction between phosphine oxide and
Entry
2 [R]
Adduct
t/h
Yielda (%)
eeb (%)
trisubstituted nitroalkenes.
1
2
3
4c
5
6
a
2a [Ph]
3a
3b
3c
3d
3e
3f
13
14
40
40
6
64
92
85
77
92
95
60 (96)
60 (.99)
50 (91)
75d
65 (99)
82
This reaction is an attractive strategy for the synthesis of
optically active a-substituted b-aminophosphine oxides. These
chiral phosphine oxides can be investigated as catalysts for
allylation and ring opening reactions of meso-epoxides21 or as
ligands in metal-catalyzed reactions.22 However, it is the potential
to prepare novel a-substituted b-aminophosphines as P,N-
ligands23 for metal-catalyzed reactions that is particularly exciting.
These ligands will be complementary to the a-aminophosphines,
which are readily prepared from amino acids.24 The b-aminopho-
sphine oxide 7 can be obtained by the selective reduction of the
nitro group using zinc in acidic conditions (Scheme 2). The optical
activity was found to remain at .99% ee. b-Aminophosphines
oxide 7 can be further reduced to b-aminophosphines 8 using
trichlorosilane with no loss in optical activity (determined by
converting 8 back to 7 using H2O2).
2b [4-FC6H4]
2c [4-PhC6H4]
2d [2-EtC6H4]
2e [2-naphthyl]
2f [1-naphthyl]
b
8
Isolated yield. Chiral HPLC; ee in parentheses was obtained after
c
d
single recrystallization. Reaction performed at 240 uC. Adduct is
a liquid.
Table 3 Chiral bicyclic guanidine-catalyzed phospha-Michael reac-
tions of aryl nitroalkenes
Entry
Ar
Adduct
t/h
Yielda (%)
eeb (%)
1
2
3
4
5
6
7
8
9
a
Ph
3f
36
12
12
12
12
12
12
16
36
94
94
96
98
99
95
99
90
75
91 (95)
96 (.99)
90 (95)
93 (99)
93 (.99)
96 (96)
96d
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
3-NO2C6H4
2-NO2C6H4
4-MeC6H4
2-naphthyl
b
4a
4b
4cc
4d
4e
4f
Scheme 2 Synthesis of chiral b-aminophosphine oxides and b-amino-
phosphines.
4g
4h
90 (96)
92 (92)
Isolated yield. Chiral HPLC; ee in parentheses was obtained after
In summary, we have disclosed the first catalytic asymmetric
phospha-Michael reaction between diaryl phosphine oxide and
nitroalkenes. This is a direct and atom economical method to
synthesize chiral a-substituted b-phosphine oxides and b-amino-
phosphines. These novel aminophosphines are potentially useful as
organocatalysts and ligands in metal-catalyzed reactions.
We are grateful for financial supports (grant No. R-143-000-
222-112) and a scholarship (to X. F.) from National University of
Singapore. We also thank the Medicinal Chemistry Program for
their financial support.
c
single recrystallization from hexane and CH2Cl2. The absolute
configuration was determined through X-ray crystallographic
analysis of 4c. Recrystallization did not work.
d
4a–h can be further enhanced with a single crystallization.
Excellent optical purity (.99% ee) can be obtained for several
samples. For highly crystalline adducts (4a, 4c and 4d), a more
convenient and practical protocol was developed for their
synthesis. At 0 uC, the reactions of these substrates were completed
within 3 h. The reaction mixture was left standing in the 280 uC
freezer overnight. Adducts with excellent ee (.99%) and yield of
70–90% can be obtained by simple filtration and no further
purification was needed.
Notes and references
{ Standard bicyclic guanidine catalyzed reactions between diaryl phosphine
oxide and nitroalkenes: To a 50 ml RBF containing catalyst 1 (1.8 mg,
0.008 mmol, 10 mol%) and a stirring bar, di(1-naphthyl) phosphine oxide
2f (24.2 mg, 0.08 mmol) and anhydrous diethyl ether (25 ml), were added in
this sequence and stirred at 240 uC for 1 h. 4-Chloro-b-nitrostyrene
(73.4 mg, 0.4 mmol, 5 eq.) was added to the reaction mixture and stirred at
240 uC for 12 h. Solvent was removed from the reaction mixture and
loaded onto a short silica gel column. This was followed by flash
chromatography (gradient elution with hexane–EA mixtures; 10 : 1 to
2 : 1). Adduct 4a (36.5 mg) was obtained as a white solid in 94% yield and
96% ee.
The diastereoselectivity of this reaction were investigated
using two tri-substituted nitroalkenes, (E)-b-methyl-b-nitrostyrene
5a and (E)-b-ethyl-b-nitrostyrene 5b, which was prepared
from nitroethane and nitropropane respectively (Scheme 1).
Using di(1-naphthyl) phosphine oxide 2f as the donor, good
diastereometric ratios (dr) of 95 : 5 were observed (see ESI{
for relative stereochemistry determination). Good enantio-
selectivities of 90 and 93% ee were obtained for adducts 6a and
6b respectively.
Crystal data for 4c: CCDC 659170. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b713151h
This journal is ß The Royal Society of Chemistry 2007
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1 (a) W. Tang and X. Zhang, Chem. Rev., 2003, 103, 3029–3069; (b)
K. V. L. Cre´py and T. Imamoto, Top. Curr. Chem., 2003, 229, 1–40.
2 (a) X. Lu, C. Zhang and Z. Xu, Acc. Chem. Res., 2001, 34, 535–544; (b)
J. L. Methot and W. R. Roush, Adv. Synth. Catal., 2004, 346,
1035–1050.
3 K. M. Pietrusiewicz and M. Zablocka, Chem. Rev., 1994, 94, 1375–1411.
4 H. Gro¨ger and B. Hammer, Chem.–Eur. J., 2000, 6, 943–948.
5 H. Sasai, S. Arai, Y. Tahara and M. Shibasaki, J. Org. Chem., 1995, 60,
6656–6657.
6 (a) H. Wynberg and A. A. Smaardijk, Tetrahedron Lett., 1983, 24,
5899–5900; (b) D. Pettersen, M. Marcolini, L. Bernardi, F. Fini,
R. P. Herrera, V. Sgarzani and A. Ricci, J. Org. Chem., 2006, 71,
6269–6272.
7 G. D. Joly and E. N. Jacobsen, J. Am. Chem. Soc., 2004, 126,
4102–4103.
8 T. Akiyama, H. Morita, J. Itoh and K. Fuchibe, Org. Lett., 2005, 7,
2583–2585.
9 (a) A. D. Sadow and A. Togni, J. Am. Chem. Soc., 2005, 127,
17012–17024; (b) A. D. Sadow, I. Haller, L. Fadini and A. Togni, J. Am.
Chem. Soc., 2004, 126, 14704–14705.
10 G. Bartoli, M. Bosco, A. Carlone, M. Locatelli, A. Mazzanti, L. Sambri
and P. Melchiorre, Chem. Commun., 2007, 722–724.
11 (a) A. Carlone, G. Bartoli, M. Bosco, L. Sambri and P. Melchiorre,
Angew. Chem., Int. Ed., 2007, 46, 4504–4506; (b) I. Ibrahem, R. Rios,
J. Vesely, P. Hammar, L. Eriksson, F. Himo and A. Co´rdova, Angew.
Chem., Int. Ed., 2007, 46, 4507–4510.
12 (a) D. Enders, A. Saint-Dizier, M.-I. Lannou and A. Lenzen, Eur. J.
Org. Chem., 2006, 29–49; (b) M. Tanaka, Top. Curr. Chem., 2004, 232,
25–54.
R. Rondanin, M. Roberti and G. P. Pollini, Tetrahedron Lett., 1998, 39,
7615–7618; (c) while preparing this manuscript, we became aware,
through personal communication, that Professor Masahiro Terada and
co-workers have successfully developed a highly enantioselective
addition reaction of diphenyl phosphite to nitroalkenes catalyzed by
an axially chiral guanidine.
18 (a) G. O. Doak and L. D. Freedman, Chem. Rev., 1961, 61, 31–44; (b)
I. Schlemminger, Y. Saida, H. Gro¨ger, W. Maison, N. Durot, H. Sasai,
M. Shibasaki and J. Martens, J. Org. Chem., 2000, 65, 4818–4825.
19 (a) R. Chinchilla, C. Na´jera and P. Sa´nchez-Agullo´, Tetrahedron:
Asymmetry, 1994, 5, 1393–1402; (b) M. S. Iyer, K. M. Gigstad,
N. D. Namdev and M. Lipton, J. Am. Chem. Soc., 1996, 118,
4910–4911; (c) D. Ma and K. Cheng, Tetrahedron: Asymmetry, 1999,
10, 713–719; (d) T. Isobe, K. Fukuda, Y. Araki and T. Ishikawa, Chem.
Commun., 2001, 243–244; (e) T. Ishikawa, Y. Araki, T. Kumamoto,
H. Seki, K. Fukuda and T. Isobe, Chem. Commun., 2001, 245–246; (f)
T. Ishikawa and T. Isobe, Chem.–Eur. J., 2002, 8, 553–557; (g) D. Ma,
Q. Pan and F. Han, Tetrahedron Lett., 2002, 43, 9401–9403; (h)
J. C. McManus, T. Genski, J. S. Carey and R. J. K. Taylor, Synlett,
2003, 369–371; (i) Y. Sohtome, Y. Hashimoto and K. Nagasawa, Adv.
Synth. Catal., 2005, 347, 1643–1648; (j) M. Terada, H. Ube and
Y. Yaguchi, J. Am. Chem. Soc., 2006, 128, 1454–1455; (k)
M. Terada, M. Nakano and H. Ube, J. Am. Chem. Soc., 2006, 128,
16044–16045.
20 (a) E. J. Corey and M. J. Grogan, Org. Lett., 1999, 1, 157–160; (b)
W. Ye, D. Leow, S. L. M. Goh, C.-T. Tan, C.-H. Chian and C.-H. Tan,
Tetrahedron Lett., 2006, 47, 1007–1010; (c) J. Shen, T. T. Nguyen,
Y.-P. Goh, W. Ye, X. Fu, J. Xu and C.-H. Tan, J. Am. Chem. Soc.,
2006, 128, 13692–13693.
21 (a) C. Ogawa, M. Sugiura and S. Kobayashi, Angew. Chem., Int. Ed.,
2004, 43, 6491–6493; (b) M. Nakajima, S. Kotani, T. Ishizuka and
S. Hashimoto, Tetrahedron Lett., 2005, 46, 157–159; (c) E. Tokuoka,
S. Kotani, H. Matsunaga, T. Ishizuka, S. Hashimoto and M. Nakajima,
Tetrahedron: Asymmetry, 2005, 16, 2391–2392.
13 (a) L. Tedeschi and D. Enders, Org. Lett., 2001, 3, 3515–3517; (b)
D. Enders, L. Tedeschi and J. W. Bats, Angew. Chem., Int. Ed., 2000, 39,
4605–4607.
14 R. K. Haynes, W. W.-L. Lam and L.-L. Yeung, Tetrahedron Lett.,
1996, 37, 4729–4732.
15 (a) G. Castelot-Deliencourt, X. Pannecoucke and J.-C. Quirion,
Tetrahedron Lett., 2001, 42, 1025–1028; (b) G. Castelot-Deliencourt,
E. Roger, X. Pannecoucke and J.-C. Quirion, Eur. J. Org. Chem., 2001,
3031–3038.
16 J. Wang, L. D. Heikkinen, H. Li, L. Zu, W. Jiang, H. Xie and W. Wang,
Adv. Synth. Catal., 2007, 349, 1052–1056.
22 Y. Hamashima, M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2000,
122, 7412–7413.
23 P. J. Guiry and C. P. Saunders, Adv. Synth. Catal., 2004, 346, 497–537.
24 (a) T. Hayashi, M. Fukushima, M. Konishi and M. Kumada,
Tetrahedron Lett., 1980, 21, 79–82; (b) T. Hayashi, M. Konishi,
M. Fukushima, K. Kanehira, T. Hioki and M. Kumada, J. Org. Chem.,
1983, 48, 2195–2202.
17 (a) Z. Jiang, Y. Zhang, W. Ye and C.-H. Tan, Tetrahedron Lett., 2007,
48, 51–54; (b) D. Simoni, F. P. Invidiata, M. Manferdini, I. Lampronti,
5060 | Chem. Commun., 2007, 5058–5060
This journal is ß The Royal Society of Chemistry 2007