Pd-catalyzed diastereo- and enantioselective [3+2]-cycloaddition reaction of vinyl epoxide with nitroalkenes

Article abstract of DOI:10.1055/s-0031-1290525

A diastereoselective and enantioselective [3+2]-cycloaddition reaction of vinyl epoxide and nitroalkenes has been developed using Pd/1,1-ferrocene-P,N- ligand, providing substituted tetrahydrofurans in high yields and with high diastereo- and enantioselectivities. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290525

LETTER
▌1035
letter
Pd-Catalyzed Diastereo- and Enantioselective [3+2]-Cycloaddition Reaction of
Vinyl Epoxide with Nitroalkenes
Pd-Catalyzed Diastereo- and Enantioselective [3+2] Cycloaddition
Wen-Qiong Wu,a Chang-Hua Ding,b Xue-Long Hou*a,b
a
Shanghai–Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Road, Shanghai 200032, P. R. of China
Fax +86(21)54925100; E-Mail: xlhou@sioc.ac.cn
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling
Road, Shanghai 200032, P. R. of China
Received: 12.01.2012; Accepted after revision: 12.02.2012
(TBME) gave similar results with respect to the yields and
Abstract: A diastereoselective and enantioselective [3+2]-cycload-
the diastereoselectivity (Table 1, entries 1 and 2 vs. 3–6).
dition reaction of vinyl epoxide and nitroalkenes has been devel-
A remarkable improvement in enantioselectivity was ob-
oped using Pd/1,1′-ferrocene-P,N-ligand, providing substituted
served using acetonitrile (MeCN) and dichloromethane
(CH2Cl2) as solvent (Table 1, entries 7 and 8). However,
the yield of the product 3a was very low in these two sol-
vents, which might be attributed to the polymerization of
β-nitrostyrene as we observed the formation of precipi-
tate. Using THF–MeCN mixtures as reaction media still
afforded 3a in very low yield (Table 1, entry 9).
tetrahydrofurans in high yields and with high diastereo- and
enantioselectivities.
Key words: vinyl epoxide, nitroalkene, palladium, asymmetric ca-
talysis, [3+2] cycloaddition
The metal-catalyzed [3+2] cycloaddition reaction of vinyl
epoxides,1 aziridines,2 and cyclopropanes bearing elec-
tron-withdrawing groups,3 with activated olefins consti-
tutes a powerful approach to construct substituted
tetrahydrofurans, pyrrolidines, and cyclopentanes. The
use of isocyanates,4 carbodiimides,5 aldehydes,6 and car-
bon dioxide2e as acceptors was also documented to afford
five-membered heterocycles. However, the catalytic
asymmetric version of such cycloaddition reaction is very
limited.3d,6b,c The asymmetric [3+2] cycloaddition of vinyl
oxirane with activated olefins is unknown. Herein, we re-
port our preliminary results of palladium-catalyzed dia-
stereoselective and enantioselective [3+2] cycloaddition
of vinyl oxiranes with nitroalkenes. Substituted tetrahy-
drofurans,7 commonly occurring subunits in a broad array
of natural products and other biologically active mole-
cules,8 bearing three continuous stereocenters were af-
forded in a diastereo- and enantioselective manner.
Table 1 Solvent Optimization for Pd-Catalyzed Cycloaddition of
Vinyl Epoxide 1a with β-Nitrostyrene (2a)a
NO2
Pd2(dba)3•CHCl3 (3 mol%)
Ph
+
Ph
NO2
L1 (6 mol%), solvent, r.t.
O
O
1a
2a
3a
O
N
PPh2
i-Pr
L1
Yield (%)b drc
ee (%)d
Entry
Solvent
1
2
3
4
5
6
7
8
9
THF
70
79
81
76
65
61
7
>20:1
31
30
2
DME
>20:1
>20:1
>20:1
>20:1
>20:1
11:1
Et2O
Our initial study commenced on the reaction of 1-vinyl-1-
methyl oxirane (1a) and β-nitrostyrene (2a) in the pres-
ence of Pd2(dba)3·CHCl3 and benzylic substituted ligand
L1 in THF. Delightfully, 2,3-trans-3,4-cis-tetrahydrofu-
ran 3a was obtained as a predominant diastereomer in
70% yield, >20:1 dr, and 31% ee (Scheme 1, equation 1;
Table 1, entry 1). The relative configuration of 3a was as-
signed by an NOE experiment. The investigation of im-
pact of solvent on the reaction revealed that the reaction in
tetrahydrofuran (THF) and dimethoxyethane (DME) pro-
vided better enantioselective excess although that in di-
ethyl ether, dioxane, toluene, and methyl tert-butyl ether
dioxane
TBME
toluene
MeCN
CH2Cl2
0
20
9
77
64
68
26
33
9:1
THF–MeCN (3:2)
10:1
a Conditions: 2a (0.20 mmol), 1a (0.40 mmol), Pd2(dba)3⋅CHCl3
(0.006 mmol), L1 (0.012 mmol), solvent (1.5 mL), 24 h, 26 °C, under
Ar.
b Isolated yields.
c Determined by 1H NMR.
d Determined by chiral HPLC.
SYNLETT 204012, 237, 1035–1038
Advanced online publication: 29.03.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290525; Art ID: ST-2012-W0028-L
© Georg Thieme Verlag Stuttgart · New York

1036
W.-Q. Wu et al.
LETTER
With THF as solvent, other chiral ligands were screened (Table 2, entry 5). Since ligand L5a gave the best results
(Table 2). Ligand (S)-L29 without methyl substituents at in terms of yield and enantioselectivity though with a
the benzylic position provided the product 3a with oppo- slightly lower diastereomeric ratio, we synthesized a vari-
site absolute configurations in 18% ee, 74% yield, and ety of P,N-ferrocencyl ligands L5b–j bearing a different
>20:1 dr (entry 2, Table 2). PHOX (L3) afforded the prod- substituent on the oxazoline ring and aryl group on the P
uct 3a in 58% ee with 30:1 dr and opposite absolute con- atom.11 Of the ligands L5 with a different substituent on
figuration, but the yield was 29% (Table 2, entry 3). The the oxazoline ring, L5b containing the sterically bulky
use of FcPHOX (L4) resulted in low yield although the tert-butyl group led to the highest enantioselectivity of
diastereoselectivity was excellent (Table 2, entry 4). Bi- 63% (Table 2, entry 6 vs. entries 5, 7, and 8). Then, li-
phosphine ligand such as BINAP was not suitable to the gands L5 with a tert-butyl group on the oxazoline ring and
reaction since no reaction occurred (not shown in Table a different aryl group on the P atom were examined (Table
2). However, ligand L5a,10 with a ferrocene backbone, af- 2, entries 9–12). The incorporation of an electron-defi-
forded the product 3a in 72% yield, 12:1 dr, and 44% ee cient aryl group is not beneficial for the reaction (Table 2,
entries 10 and 11). The use of ligand L5g with the 3,5-
Table 2 Ligand Optimization for Pd-Catalyzed Cycloaddition of
di(trifluoromethyl)phenyl group resulted in the reaction
being very sluggish (Table 2, entry 11). Further ligand op-
timization uncovered that ligand L5h with two methyl
groups at the 3,5-position of the phenyl ring afforded the
Vinyl Epoxide 1a with β-Nitrostyrene (2a)a
NO2
Pd2(dba)3⋅CHCl3 (3 mol%)
Ph
Ph
+
NO2
highest enantioselectivity of 71% (Table 2, entry 12).
ligand (6 mol%), THF, r.t.
O
O
1a
2a
3a
Table 3 Substrate Scope for Pd-Catalyzed Cyclization of Vinyl Ep-
oxide 1a with Nitroalkenesa,12
O
O
O
t-Bu
NO2
t-Bu
N
PPh2
N
N
Pd2(dba)3•CHCl3 (3 mol%)
Fe
PPh2
R
+
R
t-Bu
PPh2
NO2
L5h (6 mol%), THF, r.t.
O
O
L2
L3
L4
1a
2
3
L5a: Ar = Ph, R = i-Pr
L5b: Ar = Ph, R = t-Bu
L5c: Ar = Ph, R = Ph
L5d: Ar = Ph, R = Bn
L5e: Ar = 4-MeOC6H4, R = t-Bu
L5f: Ar = 4-F3CC6H4, R = t-Bu
L5g: Ar = 3,5-(F3C)2C6H3, R = t-Bu
L5h: Ar = 3,5-Me2C6H3, R = t-Bu
Yield (%)b drc
ee (%)d
Entry
R
O
1
2
a Ph
69
47
67
99
85
13:1
71
69
71
71
72
51
4
Fe
N
R
b 4-MeOC6H4
c 4-ClC6H4
d 4-FC6H4
>10:1
9:1
PAr2
3
Yield (%)b
drc
20:1
ee (%)d
Entry
L
4
10:1
>10:1
>20:1
7:2
5
e 3-MeOC6H4
f 2-MeOC6H4
g 2-BrC6H4
h 2-F3CC6H4
i 2-furanyl
j n-Pr
1
2
L1
70
74
29
38
72
76
77
84
84
72
–
31
–18
–58
38
44
63
41
24
62
52
–
53e
74
74
77
75
6
L2
>20:1
>30:1
>50:1
12:1
15:1
14:1
17:1
15:1
20:1
–
3
L3
7
4
L4
8
7:3
44
71
64
5
L5a
L5b
L5c
L5d
L5e
L5f
L5g
L5h
9
10:1
4:1
6
10
a Conditions: 2 (0.20 mmol), 1a (0.40 mmol), Pd2(dba)3⋅CHCl3 (0.006
mmol), L5h (0.012 mmol), THF (1.5 mL), 24 h, 26 °C, under Ar.
b Isolated yields.
7
8
c Determined by 1H NMR.
9
d Determined by chiral HPLC.
10
11
12
e Reaction time of 4 d; 29% of 2f recovered.
The substrate scope was investigated under the optimized
conditions, and the results are shown in Table 3. Evalua-
tion of a range of aryl-substituted nitroalkenes 2 showed
that the incorporation of both electron-withdrawing and
electron-donating substituents in para-position had little
influence on diastereo- and enantioselectivities (Table 3,
entries 2–4), although the yield was a little bit lower for
69
13:1
71
a Conditions: 2a (0.20 mmol), 1a (0.40 mmol), Pd2(dba)3⋅CHCl3
(0.006 mmol), ligand (0.012 mmol), THF (1.5 mL), 24 h, 26 °C, under
Ar.
b Isolated yield.
c Determined by 1H NMR.
d Determined by chiral HPLC.
Synlett 2012, 23, 1035–1038
© Georg Thieme Verlag Stuttgart · New York

LETTER
Pd-Catalyzed Diastereo- and Enantioselective [3+2] Cycloaddition
1037
nitroalkene 2b with a methoxy group at the para-position
of phenyl (Table 3, entry 2). The electron-donating sub-
stituent at the meta-position was also well tolerated, main-
taining high yield and selectivity (Table 3, entry 5). The
cycloaddition worked not so well for aryl nitroalkenes
bearing ortho-positioned electron-withdrawing substitu-
ents on the phenyl ring (Table 3, entries 7 and 8), afford-
ing the products in lower diastereo- and
enantioselectivities while the selectivities still kept good
when o-methoxyphenyl-substituted nitroalkene was the
reagent (Table 3, entry 6). The reaction of furanyl deriva-
tive also afforded the corresponding 3i in 77% yield, 10:1
dr, and 71% ee (Table 3, entry 9). Notably, the cycloaddi-
tion is also applicable to alkyl-substituted nitroalkene, af-
fording a 75% yield of the desired product, albeit with a
slightly lower diastereo- and enantioselectivity (Table 3,
entry 10).
Figure 1 ORTEP drawing of compound 5
consumed (Scheme 1, equations 2 and 3). The 1H NMR of
the crude products displayed that polymerization might
occur.
NO2
NO2
O
1b
+
Pd2(dba)3•CHCl3 (3 mol%)
L1 (6 mol%), THF, r.t.
+
(1)
Ph
Ph
O
3k
39%
O
4k
27%
Ph
Ph
NO2
The product 3a was easily converted into compound 5
through reduction and amide formation in 70% yield
(Scheme 1, equation 4). X-ray diffraction analysis of com-
pound 5 showed that its absolute configuration is
2R,3S,4R and its relative stereochemistry is 2,3-trans and
3,4-cis (Figure 1).13 Accordingly, the product 3a has the
2R,3S,4R configuration.
2a
O
Pd2(dba)3•CHCl3 (3 mol%)
1c
polymerization (2)
+
L1 (6 mol%), THF, r.t.
Ph
Ph
NO2
O
2a
In conclusion, a palladium-catalyzed diastereo- and enan-
tioselective [3+2]-cycloaddition reaction of 2-vinyl-2-
methyl oxirane and nitroalkenes was developed, affording
2,3-trans-3,4-cis-trisubstituted tetrahydrofurans in good
yields with good diastereo- and enantioselectivities. 1,1′-
P,N-ferrocene ligands are the choice in the reaction. A re-
versal of enantioselectivity was also observed in this reac-
tion when ligand (S)-L2 with H as the substituent in the
benzylic position and ligand (S)-L1 with methyl were
used, respectively. Further investigations on the substrate
scope as well as the applications of the protocol are in
progress.
Pd2(dba)3•CHCl3 (3 mol%)
1d
polymerization
O
+
(3)
(4)
Ph
L1 (6 mol%), THF, r.t.
NO2
NO2
2a
1) Zn, HCl, EtOH, r.t.
HN
Ph
O
3a
Br
Br
COCl
2)
Ph
O
CH2Cl2, 0 °C to r.t.
70% (2 steps)
5
Scheme 1
Acknowledgment
Financial supported by the Major Basic Research Development
Program (2011CB808700), National Natural Science Foundation of
China (21002113, 20821002, 21032007), the External Cooperation
Program of Chinese Academy of Sciences (GJHZ200816), the
Technology Commission of Shanghai Municipality and the Crou-
cher Foundation of Hong Kong. W.Q.W. gratefully acknowledges
the Croucher Foundation of Hong Kong for a studentship.
The reaction of different vinyl oxiranes was also investi-
gated. 1-Vinyl-oxirane (1b) was subjected to the reaction
with β-nitrostyrene (2a) in the presence of
Pd2(dba)3⋅CHCl3 and ligand L1 (Scheme 1, eq. 1). Two
isomers of 2,3-trans-3,4-cis-tetrahydrofuran 3k and 2,3-
cis-3,4-trans-tetrahydrofuran 4k were obtained in 39%
and 27% yield, respectively. Their relative stereochemis-
try was determined by NOE experiments. The enantiose-
lectivity of products 3k and 4k was not determined due to
their inseparability on HPLC. Further optimization of the
reaction conditions could not improve the diastereoselec-
tivity. In the case of vinyl oxiranes 1c and 1d, no cycliza-
tion product was observed although both reactants were
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmornifIatngonimSorfniturItagponiSutpor
References and Notes
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1035–1038

1038
W.-Q. Wu et al.
LETTER
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(12) Typical Procedure for the Cycloaddition Reaction of
Vinyl Epoxide 1a with Nitroalkenes 2: A Schlenk tube
with a magnetic stir bar was charged with Pd2dba3⋅CHCl3
(6.2 mg, 0.006 mmol), ligand L5h (6.6 mg, 0.012 mmol),
and THF (1.5 mL) under an argon atmosphere. The resulting
solution was allowed to stir for 30 min before nitroalkene 2a
(30 mg, 0.20 mmol) followed by vinyl epoxide 1a (40 μL,
0.40 mmol) were added. The reaction mixture was allowed
to stir for about 24 h at r.t. (26 °C) until the reaction was
complete (monitored by TLC). The reaction mixture was
diluted with CH2Cl2 (2 mL) before being passed through a
short plug of silica gel to remove the palladium black. After
the filtrate was concentrated, the crude product was analyzed
by 1H NMR spectroscopy to determine the diastereomeric
ratio, and then the residue was purified by flash chroma-
tography on silica gel (eluent: EtOAc–PE) to afford 32 mg
of the product 3a as a light yellow liquid.
Analytical Data for 3a: 1H NMR (300 MHz, CDCl3): δ =
1.39 (s, 3 H), 3.95 (d, J = 8.7 Hz, 1 H), 4.23 (d, J = 8.7 Hz,
1 H), 4.64 (d, J = 6.0 Hz, 1 H), 5.24–5.31 (m, 2 H), 5.62 (d,
J = 6.0 Hz, 1 H), 5.88 (dd, J = 11.1, 17.7 Hz, 1 H), 7.33–7.39
(m, 5 H). 13C NMR (75 MHz, CDCl3): δ = 23.43, 50.78,
77.64, 83.39, 100.65, 118.02, 125.31, 128.41, 128.84,
135.65, 138.82. IR (KBr): 2978, 2880, 1552, 1068 cm–1.
MS (EI): m/z (%) = 233 (8.88) [M+], 171 (100). HRMS (EI):
m/z calcd for C13H15NO3: 233.1052; found: 233.1042. HPLC
(Chiralcel OJ-H 0.46 cm × 25 cm, n-hexane–i-PrOH
(65:35); flow rate: 0.7 mL/min, UV: λ = 230 nm), tR = 10.0
min (minor), 12.6 min (major).
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(13) The crystallographic data are deposited at the Cambridge
Crystallographic Data Centre under deposition number
CCDC 865918.
Synlett 2012, 23, 1035–1038
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