Chemoselective reduction of isatin-derived electron-deficient alkenes using alkylphosphanes as reduction reagents

Article abstract of DOI:10.1002/ejoc.201100017

Under mild reaction conditions, the C=C double bond inisatin-derived electron-deficient alkenes has been exclusively reduced in the presence of alkylphosphanes and water to afford the corresponding reduction products in good to excellent yields. A plausib

Full text of DOI:10.1002/ejoc.201100017

FULL PAPER
DOI: 10.1002/ejoc.201100017
Chemoselective Reduction of Isatin-Derived Electron-Deficient Alkenes Using
Alkylphosphanes as Reduction Reagents
Shu-Hua Cao,[a] Xiu-Chun Zhang,[a] Yin Wei,*[b] and Min Shi*[a,b]
Keywords: Reduction / Alkenes / Chemoselectivity / Phosphanes
Under mild reaction conditions, the C=C double bond in
isatin-derived electron-deficient alkenes has been exclu-
sively reduced in the presence of alkylphosphanes and water
to afford the corresponding reduction products in good to ex-
cellent yields. A plausible mechanism is proposed on the ba-
sis of deuterium-labeling experiments.
Introduction
Organophosphorus compounds have proven to be par-
ticularly versatile as catalysts or reagents in many types of
organic reactions, and phosphanes in particular have been
widely used as nucleophilic organocatalysts in recent dec-
ades.[1] One interesting organocatalytic reaction is the hy-
dration and hydroalkoxylation of activated olefins catalyzed
by nucleophilic phosphanes.[2] However, the use of phos-
phanes as reducing agents accompanied by a proton trans-
fer is rare. To the best of our knowledge, the Staudinger
reaction is the first report of the reduction of azides to
amines promoted by PPh3/H2O.[3] In 2006, our group re-
ported an interesting reduction of activated carbonyl
groups promoted by alkylphosphanes, which is a convenient
method for producing the corresponding α-hydroxylated
derivatives (Scheme 1).[4] Subsequently, the scope of this re-
duction process was extended to other compounds includ-
ing activated carbonyl groups such as 1-aryl-2,2,2-trifluoro-
ethanones,[5] and the reductive coupling of acyl cyanides
was also achieved (Scheme 1).[6] On the basis of our pre-
vious work, we have attempted to extend the range of sub-
strates used in the reduction reaction promoted by alkyl-
phosphanes. Thus, we investigated the reduction reactions
of activated alkenes such as isatin-derived electron-deficient
alkenes due to their easy preparation and various applica-
tions in the synthesis of natural products, drugs, and related
analogues.[7] Herein, we report an interesting, highly
chemoselective reduction reaction of isatin-derived elec-
tron-deficient alkenes promoted by alkylphosphanes.
Scheme 1. Reduction reactions promoted by alkylphosphanes.
Results and Discussion
An initial examination was carried out by treating (E)-1-
benzyl-3-(2-oxopropylidene)indolin-2-one (1a) with PBu3 in
toluene at 80 °C. We observed that the C=C double bond
was exclusively reduced to afford the corresponding re-
duction product 1-benzyl-3-(2-oxopropyl)indolin-2-one (2a)
in only 18% yield (Table 1, Entry 1). We assumed that an
additional proton source should be added to improve the
yield of the desired product. Thus, water was chosen as an
additive, which indeed increased the yield of 2a to Ͼ99%
(Table 1, Entry 2). Decreasing the amount of phosphane re-
duced the yield of the desired product (Table 1, Entries 3
and 4). Lowering the reaction temperature to room tem-
perature and increasing the amount of PBu3 to 1.2 equiv.
still produced the corresponding product 2a in good yield
(86%, Table 1, Entry 5). With PMe3 as promoter, this re-
duction reaction also proceeded smoothly to give the corre-
sponding product 2a in 86% yield (Table 1, Entry 6). We
also investigated this reaction in tetrahydrofuran (THF)
with PBu3 and PMe3 as promoters, because THF was a
good solvent in our previous studies. It turned out that we
could obtain the corresponding product 2a almost quanti-
tatively when PMe3 was used as promoter in the presence
of THF and water (Table 1, Entry 7). With PMe3 as pro-
moter, we screened other solvents (Table 1, Entries 9–11),
which demonstrated that THF was the best solvent. This
reduction reaction also proceeded smoothly by using other
[a] Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, East China University of Science and Technology,
130 Mei Long Road, Shanghai 200237, China
Fax: +86-21-64166128
E-mail: mshi@mail.sioc.ac.cn
[b] State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, China
E-mail: weiyin@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100017.
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Reduction of Isatin-Derived Electron-Deficient Alkenes
phosphanes with at least one alkyl substituent, such as Table 2. Screening of water loading in the reduction reaction.[a]
PPhMe2 or PPh2Me, to afford the corresponding product
2a in moderate to good yields (Table 1, Entries 12 and 13).
However, a sterically hindered alkylphosphane such as
PtBu3 and the aromatic phosphane PPh3 did not promote
this reaction under the same reaction conditions (Table 1,
Entries 14 and 15).
Entry
H2O [equiv.]
Yield [%][b]
Table 1. Reduction of 1a under various conditions.[a]
1
2
3
4
2.5
5.0
10.0
55.6
39
86
99
Ͼ99
[a] Reaction conditions: 1a (0.10 mmol), PMe3 (0.12 mmol), THF
(1.0 mL), H2O, r.t., 24 h. [b] Isolated yield.
lower yield (52%, Table 3, Entry 1). Varying the R2 substit-
uent from methyl to phenyl or ethyl afforded the corre-
sponding products 2c–2e in high yields (Table 3, Entries 2–
4). Irrespective of whether electron-withdrawing or -donat-
ing groups were present at the 4-, 5-, or 6-position of the
N-benzylisatins 1, the reactions proceeded smoothly to give
the corresponding products 2f–2l in good to excellent yields
when R2 was an OEt group and R3 a Bn group (Table 3,
Entries 5–11). Substrates with a substituent at the 7-posi-
tion of the N-benzylisatins (R2 = OEt and R1 = Bn) fur-
nished the corresponding products 2m and 2n in low to
moderate yields (Table 3, Entries 12 and 13). Varying the
N-substituent in substrates 1 (R2 = OEt and R1 = H) af-
forded the corresponding products 2o–2r in moderate to ex-
cellent yields (Table 3, Entries 14–17). We also used this re-
duction system in reactions with other α,β-unsaturated
compounds (Scheme 2). Unfortunately, no reduction took
place.
Entry
1[c]
2
3
4
5
6
7
8
PR3
x
Solvent
T [°C]
Yield [%][b]
PBu3
PBu3
PBu3
PBu3
PBu3
PMe3
PMe3
PBu3
PMe3
PMe3
PMe3
PPh2Me
PPhMe2
PtBu3
PPh3
1.0
1.0
0.2
0.5
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
toluene
toluene
toluene
toluene
toluene
toluene
THF
80
80
80
18
Ͼ99
18
48
86
80
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
86
Ͼ99
Ͼ84
54
99
43
THF
9
CH3CN
DCM
Et2O
THF
THF
THF
THF
10
11
12
13
14
15
39
86
[d]
–
[d]
–
[a] Reaction conditions: 1a (0.10 mmol), solvent (1.0 mL), 24 h. [b]
Isolated yield. [c] H2O was not added to the reaction mixture. [d]
The desired product was not detected.
We noticed that the addition of water significantly in-
To clarify the reaction mechanism, several deuterium-
creased the yield of the desired product in this reduction labeling experiments were conducted, and the results are
reaction (Table 1, Entry 2). We thus carried out a series of summarized in Scheme 3. The first experiment was carried
reactions under the standard conditions with various out with D2O under the standard reaction conditions to
amounts of water. The results are summarized in Table 2. afford the crude product 2a in 99% yield with 56, 85, 85,
The addition of 2.5 equiv. of water to the reaction mixture and 62% D content[8] at the D1, D2, D2Ј, and D3 positions,
led to the formation of the corresponding product 2a in respectively [Scheme 3, Equation (1)]. After silica gel col-
low yield (39%, Table 2, Entry 1). Increasing the amount of umn chromatography, the D contents of the isolated prod-
water to 5 and 10 equiv. improved the yield of 2a to 86 and uct 2a were measured again, and it was found that the D
99%, respectively (Table 2, Entries 2 and 3). Continually in- contents at the D1, D2, D2Ј, and D3 positions were 49, 77,
creasing the amount of water up to 55.6 equiv. still afforded 77, and 10%, respectively. This indicates that water is the
2a in excellent yield (Table 2, Entry 4). For substrate 1a, proton source for this reduction reaction and that the
at least 10 equiv. of water was required to maximize this workup procedure leads to changes in the D content, espe-
reduction reaction. For substrates that react slowly, more cially at the D3 position. Performing the same reaction with
than 10 equiv. of water would be required for this reduction a different workup method, that is, by recrystallization in
reaction. To guarantee complete conversion of the reactant, THF/D2O, gave 2a in 90% yield with 65, 63, 63, and 36%
we chose to add 55.6 equiv. of water in the following experi- D content at the D1, D2, D2Ј, and D3 positions, respectively
ments.
[Scheme 3, Equation (2)]. The recrystallization was con-
Having identified the optimal reaction conditions, we ducted in THF/D2O, which led to a higher amount of D at
next set out to examine the scope and limitations of this C-1 than in the crude product. The recrystallization pro-
reduction reaction with PMe3 using various isatin deriva- cedure was rather long (5 d) and H/D exchange occurred
tives 1. The results are summarized in Table 3. Substrate 1b more easily at the D2, D2Ј, and D3 positions, and thus the
having a methyl group at the 5-position of the benzene ring amount of D on C-2 and C-3 is lower than in the crude
of N-benzylisatin gave the corresponding product 2b in a product.
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S.-H. Cao, X.-C. Zhang, Y. Wei, M. Shi
FULL PAPER
Table 3. Scope of the reduction reactions promoted by PMe3.[a]
Entry
R1
R2
R3
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
allyl
H
Me
Ph
Ph
5-Me (1b)
H (1c)
5-Me (1d)
H (1e)
H (1f)
52 (2b)
94 (2c)
86 (2d)
99 (2e)
99 (2f)
99 (2g)
92 (2h)
94 (2i)
74 (2j)
99 (2k)
92 (2l)
58 (2m)
16 (2n)
70 (2o)
99 (2p)
99 (2q)
53 (2r)
Et
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
4-Cl (1g)
4-Br (1h)
5-F (1i)
5-Br (1j)
5-Me (1k)
6-Br (1l)
7-Br (1m)
7-CF3 (1n)
H (1o)
Scheme 4. Control experiments.
H (1p)
H (1q)
Boc
H (1r)
[9]
The use of P(CD3)3 and water afforded product 2a in
[a] Reaction conditions: 1 (0.10 mmol), PMe3 (0.12 mmol), THF
99% isolated yield. However, no H/D exchange was ob-
served [Scheme 4, Equation (1)], which suggests that the
protons are not derived from P(CD3)3. Without PMe3, no
reaction occurred, and no H/D exchange was observed
either [Scheme 4, Equation (2)]. In the presence of D2O,
H/D exchange only took place at the D3 position of the
crude product 2a [91% D content, Scheme 4, Equation (3)],
which indicates that H/D exchange occurs easily at the D3
position and may account for why the amount of D at D3
always varies during workup. In the presence of PMe3 and
D2O, a similar result was obtained (the D content at the D3
position was 63%, see the Supporting Information);[8] the
isolated product 2a purified by silica gel column
chromatography gave similar results (see the Supporting In-
formation).
(1.0 mL), r.t., 24 h. [b] Isolated yield.
Scheme 2. Attempted reduction reactions of α,β-unsaturated com-
pounds.
Based on the results of the deuterium-labeling experi-
ment and the mechanism previously proposed in the litera-
ture,[2–4] we suggest a mechanism for this reduction reaction
(Scheme 5). Initially, Michael addition of PMe3 to com-
pound 1 forms enolate A, which abstracts a proton from
water to generate intermediate B. As a result of keto/enol
tautomerization, another intermediate C could be formed
at this stage. These intermediates could continue to ex-
change protons with water to furnish intermediate D, which
gives the complex F via transition state E.[10] The proton is
quickly transferred to the anionic moiety in complex F to
furnish the corresponding product 2 and to release the
phosphane oxide (identified by 31P NMR spectroscopy, see
the Supporting Information). Strongly basic reaction inter-
mediates such as A and several keto/enol tautomerizations
exist in the reaction process, and this might be a reason for
the H/D exchange observed at all the “acidic” positions of
Scheme 3. Deuterium-labeling experiments.
Subsequently, several control experiments were carried the final product in deuterium-labeling experiments carried
out, and the results are summarized in Scheme 4. out in D2O.
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Eur. J. Org. Chem. 2011, 2668–2672

Reduction of Isatin-Derived Electron-Deficient Alkenes
Scheme 5. Plausible mechanism for the reduction reaction.
Conclusions
Acknowledgments
We have demonstrated a novel, highly chemoselective re-
duction of the C=C double bond in isatin-derived electron-
deficient alkenes promoted by alkylphosphanes with water
under mild reaction conditions to afford the products in
good to excellent yields. Moreover, a plausible mechanism
is proposed on the basis of deuterium labeling and control
experiments as well as DFT calculations. Research is in pro-
gress to elucidate further mechanistic details of these reac-
tions and to understand their scope and limitations.
We thank the Shanghai Municipal Committee of Science and Tech-
nology (08dj1400100-2), the National Basic Research Program of
China (973-2009CB825300), the Fundamental Research Funds for
the Central Universities, and the National Natural Science Founda-
tion of China (21072206, 20872162, 20672127, 20732008,
20821002, and 20702013) for financial support.
[1] For selected reviews on phosphane-catalyzed reactions, see: a)
X. Lu, C. Zhang, Z. Xu, Acc. Chem. Res. 2001, 34, 535–544;
b) J. L. Methot, W. R. Roush, Adv. Synth. Catal. 2004, 346,
1035–1050; c) L.-W. Ye, J. Zhou, Y. Tang, Chem. Soc. Rev.
2008, 37, 1140–1152; d) D. S. Glueck, Chem. Eur. J. 2008, 14,
7108–7117; e) B. J. Cowen, S. J. Miller, Chem. Soc. Rev. 2009,
38, 3102–3116; f) A. Marinetti, A. Voituriez, Synlett 2010, 174;
g) Y. Wei, M. Shi, Acc. Chem. Res. 2010, 43, 1005–1018; for
other related reactions, see: h) X.-F. Zhu, C. E. Henry, J. Wang,
T. Dudding, O. Kwon, Org. Lett. 2005, 7, 1387–1390; i) X.-F.
Zhu, A.-P. Schaffner, R. C. Li, O. Kwon, Org. Lett. 2005, 7,
2977–2980; j) X.-F. Zhu, C. E. Henry, O. Kwon, J. Am. Chem.
Soc. 2007, 129, 6722–6723; k) X.-F. Zhu, C. E. Henry, O.
Kwon, Tetrahedron 2005, 61, 6276–6282; l) X.-F. Zhu, J. Lan,
O. Kwon, J. Am. Chem. Soc. 2003, 125, 4716–4717.
Experimental Section
General Procedure for the Reduction of Isatin-Derived Electron-
Deficient Alkenes 1: In a flame-dried Schlenk flask was placed 1
(0.10 mmol) under argon, and then anhydrous THF (1.0 mL) and
H2O (100 μL) were added slowly. PMe3 (1.0 m in THF, 0.12 mmol)
was then added quickly. The reaction mixture was stirred at room
temperature for 24 h. After that, the solvent was removed under
reduced pressure and the residue was purified by silica gel flash
column chromatography (pentane/EtOAc, 10:1) to give the corre-
sponding product 2.
[2] I. C. Stewart, R. G. Bergman, D. F. Toste, J. Am. Chem. Soc.
2003, 125, 8696–8697.
Compound 2a: White solid (28 mg, 99% yield); m.p. 119–121 °C.
[3] a) H. Staudinger, J. Meyer, Helv. Chim. Acta 1919, 2, 635–646;
for some selected references on the application of the Staud-
inger reaction, see: b) E. C. Lee, B. L. Hodous, E. Bergin, C.
Shih, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 11586–11587; c)
Y. Liang, L. Jiao, S. Zhang, J. Xu, J. Org. Chem. 2005, 70, 334–
337; d) J. Li, H.-N. Chen, H. Chang, J. Wang, C.-W. T. Chang,
Org. Lett. 2005, 7, 3061–3064; e) P. T. Nyffeler, C.-H. Liang,
K. M. Koeller, C.-H. Wong, J. Am. Chem. Soc. 2002, 124,
10773–10778.
[4] W. Zhang, M. Shi, Chem. Commun. 2006, 1218–1220.
[5] M. Shi, X.-G. Liu, Y.-W. Guo, W. Zhang, Tetrahedron 2007,
63, 12731–12734.
[6] W. Zhang, M. Shi, Tetrahedron 2006, 62, 8715–8719.
[7] F. Zhou, Y.-L. Liu, J. Zhou, Adv. Synth. Catal. 2010, 352,
1381–1407.
IR (CH Cl ): ν = 2922, 2852, 1691, 1612, 1486, 1463, 1416, 1365,
˜
2
2
1343, 1309, 1194, 1180, 1169, 1080, 748, 733, 696 cm–1. H NMR
(400 MHz, CDCl3, TMS): δ = 2.23 (s, 3 H, CH3), 2.92 (dd, J =
8.4, 18.4 Hz, 1 H, CH2), 3.32 (dd, J = 3.2, 18.4 Hz, 1 H, CH2),
3.95 (dd, J = 3.2, 8.4 Hz, 1 H, CH), 4.91 (d, J = 15.2 Hz, 1 H,
CH2), 4.96 (d, J = 15.2 Hz, 1 H, CH2), 6.71 (d, J = 8.0 Hz, 1 H,
Ar), 6.95–6.99 (m, 1 H, Ar), 7.13–7.19 (m, 2 H, Ar), 7.21–7.35 (m,
5 H, Ar) ppm. 13C NMR (100 MHz, CDCl3, TMS): δ = 29.9, 41.0,
43.8, 44.4, 109.0, 122.5, 124.1, 127.2, 127.5, 128.0, 128.8, 135.8,
143.3, 177.5, 205.2 ppm. MS (EI): m/z (%) = 279 (18.8) [M]+, 236
(47.4), 158 (25.0), 91 (100.0), 77 (9.1), 65 (16.3), 43 (12.3). HRMS
(EI): calcd. for C18H17NO2: 279.1259; found 279.1258.
1
Supporting Information (see footnote on the first page of this arti-
cle): 1H and 13C NMR spectroscopic and analytic data for com-
pounds 1 and 2 and deuterium-labeling experiments.
[8] These are average values based on two deuterium-labeling ex-
periments. For details, see the Supporting Information.
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S.-H. Cao, X.-C. Zhang, Y. Wei, M. Shi
FULL PAPER
[9] Prepared according to the procedure by: R. T. Li, S. T. Nguyen,
R. H. Grubbs, J. W. Ziller, J. Am. Chem. Soc. 1994, 116, 10032–
10040. CD3MgI was prepared from CD3I (D content Ͼ90%)
with magnesium.
[10] This step was investigated theoretically, and the transition state
F was located at the HF/3-21G* level of theory. Attempts to
locate other transition states involving simultaneous proton
transfer were unsuccessful at the HF/3-21G* and B3LYP/6-
31G(d) levels of theory. For details, see the Supporting Infor-
mation.
Received: January 7, 2011
Published Online: March 29, 2011
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Eur. J. Org. Chem. 2011, 2668–2672