Palladium-catalyzed regio-and enantio-selective allylic substitution reaction of monosubstituted allyl substrates with benzyl alcohols

Article abstract of DOI:10.1016/j.tetasy.2010.03.045

Regio-and enantio-selectivities in Pd-catalyzed allylic substitution reaction of monosubstituted allylic substrates with substituted benzyl alcohols were realized, affording the corresponding products in high regioselectivity (up to 93/7) and enantioselec

Full text of DOI:10.1016/j.tetasy.2010.03.045

Tetrahedron: Asymmetry 21 (2010) 1176–1178
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Tetrahedron: Asymmetry
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Palladium-catalyzed regio- and enantio-selective allylic substitution reaction
of monosubstituted allyl substrates with benzyl alcohols
a
Ping Fang a, Chang-Hua Ding a, Xue-Long Hou a,b, , Li-Xin Dai
*
a State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
b Shanghai-Hong Kong Joint Laboratory in Chemical Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Regio- and enantio-selectivities in Pd-catalyzed allylic substitution reaction of monosubstituted allylic
substrates with substituted benzyl alcohols were realized, affording the corresponding products in high
regioselectivity (up to 93/7) and enantioselectivity (up to 96%).
Received 2 March 2010
Accepted 31 March 2010
Available online 17 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
This paper is dedicated to Professor H. B.
Kagan on the occasion of his 80th birthday
1. Introduction
Cs2CO3 as a base at room temperature in toluene. Unfortunately,
only cinnamic alcohol was obtained, due to hydrolysis of acetate
Transition metal-catalyzed enantioselective allylic substitution
reaction has a long history over 30 years, and has become a very
powerful tool for construction of carbon–carbon and carbon–het-
eroatom bonds, providing important optically active materials.1
Among the various nucleophiles used in such reaction, relatively
hard oxygen nucleophiles received scarcely less attention,2 in con-
trast to widely used carbon and nitrogen nucleophiles.1 In the later
part of last century the first Pd-catalyzed enantioselective allylic
substitution of monosubstituted allylic substrate with phenols
was reported by Trost et al.3 Since then, examples of the reactions
with O-nucleophiles using other metal-catalysts such as Ir,4 Rh,5
and Ru6 appeared, and excellent selectivity was achieved. Very re-
cently, Chan documented a Pd-catalyzed asymmetric allylic substi-
tution of racemic 1,3-diphenyl-2-propenyl acetate with relatively
hard aliphatic alcohols to generate chiral ethers with excellent
enantioselectivities.7 However, Pd-catalyzed regio- and enantio-
selective allylic substitution of monosubstituted allylic substrate
with alcohols is still unknown. Our group has focused on the re-
gio-, diastereo-, and enantio-selectivities in Pd-catalyzed allylic
substitution reaction of monosubstituted allylic substrates with
different nucleophiles.8 Herein, we report a regio- and enantio-
selective allylic substitution reaction of monosubstituted allylic
substrate with substituted benzyl alcohols using Pd-catalyst with
SiocPhox as a ligand.
under basic condition. To avoid the side reaction, more bulky
tert-butyl cinnamyl carbonate 1b instead of 1a was tested, and
the desired product 3 was provided in 82% yield with branched/lin-
ear ratio of 66/34 and 58% ee for branched one. These promising re-
sults promoted us to investigate the influence of the parameters on
the reaction further (Table 1).
It can be seen that the ligand with different combination of chi-
ral elements showed its great impact on the reaction (Table 1, en-
tries 1–5). The ligands (S, Sphos, S)-L2, (S, Sphos, R)-L4, and (S, Rphos
,
R)-L5 gave much lower selectivity compared to (S, Rphos, S)-L3
(Table 1, entries 2, 4, and 5 vs entry 3). These results showed that
the ligand (S, Rphos, S)-L3 was the most effective one and demon-
strated that the chiralities in L3 were matched. With L3 as a ligand,
we investigated the solvent effects on this process (Table 1, entries
6–10). The reaction proceeded smoothly in DCM or Et2O albeit
with poor regio- and enantio-selectivity (Table 1, entries 6 and
9). The reaction became sluggish in THF or DME, providing trace
amount of product (Table 1, entries 7 and 8). No reaction occurred
in MeCN (Table 1, entry 10). However, toluene was identified as the
optimal solvent in terms of both regio and enantioselectivities
(Table 1, entry 3). To improve further the selectivity, we evaluated
the influence of temperature on the reaction (Table 1, entries
11–14). When the temperature was down to ꢀ5 °C, the regio- and
enantio-selectivities were improved greatly (Table 1, entry 11 vs en-
try 3). Both regio- and enantio-selectivities increased slightly at
ꢀ15 °C, but the yield lowered from 82% to 66% (Table 1, entry 12
vs entry 11). When the temperature dropped further to ꢀ25 °C,
the selectivity of the reaction decreased slightly, and chemical yield
lowered to 30% (Table 1, entry 13 vs entry 12). At ꢀ5 °C, ligand L6
with more bulky tBu group on oxazoline was tested, the regioselec-
tivity and enantioselectivity were improved slightly whereas with
much lower chemical yield (Table 1, entry 14 vs entry 11).
2. Results and discussion
Initially, we examined the reaction of cinnamic alcohol acetate
1a with benzyl alcohol 2a in the presence of catalyst derived from
[PdC3H5Cl]2 (2 mol %) and SiocPhox (Sphos, R)-L1 (4 mol %), using
* Corresponding author.
E-mail address: xlhou@mail.sioc.ac.cn (X.-L. Hou).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.03.045

P. Fang et al. / Tetrahedron: Asymmetry 21 (2010) 1176–1178
1177
Table 1
Optimization of the reaction parametersa
Ph
OBoc
Ph
[PdC3H5Cl]2 (2 mol%)
1b
L (4 mol%)
(eq 1)
O
Ph
Ph
O
Ph
base, solvent
Ph
OH
3b
4b
2a
R1 = H
(Sphos, R)-L1
O
N
1
R = iPr (S, Sphos, S)-
L2
R1
R1 = iPr (S, Rphos,S)-L3
1
R = iPr (S, Sphos, R)-
Fe
L4
NEt2
R1 = iPr (S, Rphos,R)-L5
P
R1 = tBu (S, Rphos,S)-
OR2
L2 L3 L6
L6
,
,
:
R2 = (S)-2-(2'-hydroxy-1,1'-bi-naphthyl)
L1 L4 L5
,
,
:
R2 = (R)-2-(2'-hydroxy-1,1'-bi-naphthyl)
Entry
T (°C)
Solvent
Base
L
Yieldb (%)
3b/4bc
eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
rt
rt
rt
rt
rt
rt
rt
rt
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
THF
DME
Et2O
MeCN
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
None
L1
L2
L3
L4
L5
L3
L3
L3
L3
L3
L3
L3
L3
L6
L3
L3
L3
82
56
80
40
80
87
66/34
29/71
70/30
65/35
56/44
50/50
—
—
50/50
—
90/10
92/8
87/13
91/9
—
58 (R)
16 (R)
85 (R)
20 (S)
63 (R)
63
—
—
60
—
Trace
Trace
71
rt
rt
nre
82
66
ꢀ5
ꢀ15
ꢀ25
ꢀ5
ꢀ5
ꢀ5
ꢀ5
96
97
94
98
30
64
nre
75
—
n-BuLi
CsF
0/100
56/44
—
30
nde
a
b
c
Molar ratio: 2a/1b/Cs2CO3/[PdC3H5Cl]2/L = 3/1/3/0.02/0.04.
Isolated yield.
Determined by 1H NMR.
d
e
Determined by HPLC.
nr = no reaction; nd = not determined.
We also investigate the influence of base on the reaction at
stituent on allyl carbonates 1. The reaction of p-MeOC6H4 substi-
tuted allylic carbonates 1d afforded product with highest
regioselectivity (Table 2, entry 3) while the incorporation of other
aryl group or other substituents on phenyl ring on the allylic carbon-
ates 1 led the slight decrease of regioselectivity (Table 2, entries 2
and 4–9 vs entries 1 and 3). Allyl carbonates 1 with 2-furyl, p-ClC6H4,
or p-BrC6H4 as substituents showed low reactivity, providing corre-
sponding branched products with moderated yield (Table 2, entries
5, 8, and 9). The substituted benzyl alcohols 2b–f, with either elec-
tron-withdrawing groups or electron-donating groups provided
the products with similar enantioselectivity but with a little bit low-
er yields (Table 2, entries 10–13). Introduction of the p-NO2 group
into benzyl alcohol retarded the reaction (Table 2, entry 14).
ꢀ5 °C. Base is necessary for the reaction, because reaction did not
take place in its absence (Table 1, entry 15). Only linear product
was obtained employing n-BuLi as base, (Table 1, entry 16). In case
of CsF as base, inferior results were provided in terms of yield and
regioselectivity (Table 1, entry 17). Several other bases such as
K2CO3, Na2CO3, ZnEt2, and NEt3 gave no product while NaH or KO-
But as base made the reaction complex (not shown in table).
The substrate scope of the reaction was examined using the cat-
alyst derived from [PdC3H5Cl]2 and L3 in the presence of Cs2CO3 as
base in toluene (Table 2). A wide range of allyl carbonates 1 and
substituted benzyl alcohols 2 were suitable for the Pd-catalyzed re-
gio- and enantio-selective allylic substitution reaction, affording
branched products with high regioselectivity and enantioselectivity
(Table 2, entries 1–9).9 The regioselectivity was sensitive to the sub-
Primary aliphatic alcohol 2a, which could not react with the al-
lyl carbonates 1b under the reaction conditions of Table 2, afforded
[PdC3H5Cl]2 (2 mol%)
Ph
OBoc
OH
O
Ph
O
Ph
(S, Rphos, S)-L3 (4 mol%)
1b
+
+
Cs2CO3, toluene, rt
Ph
Ph
16l
yield: 89%, b/l: 51/49, ee: 65%.
ð3Þ
16b
Ph
2g

1178
P. Fang et al. / Tetrahedron: Asymmetry 21 (2010) 1176–1178
Table 2
Pd-Catalyzed regio- and enantio-selective allylic substitution reaction of monosubstituted allylic carbonates 1 with substituted benzyl alcohols 2a
[PdC3H5Cl]2 (2 mol%)
Ar2
Ar1
Ar2
OBoc
(S, Rphos,S)-L3 (4 mol%)
1
(eq 2)
O
Ar1
Ar2
O
Ar1
Cs2CO3, toluene, −5 °C
OH
3
4
2
Entry
1, Ar1
2, Ar2
Yieldb (%)
3/4c
eed (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1b, Ph
1c, p-MeC6H4
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
2a, Ph
82
87
82
93
90/10
87/13
93/7
96
90
95
93
85
88
93
92
96
92
92
92
91
—
1d, p-MeOC6H4
1e, 1-naphthyl
1f, 2-furyl
1g, m-MeOC6H4
1h, p-FC6H4
1i, p-ClC6H4
1j, p-BrC6H4
1b, Ph
1b, Ph
1b, Ph
1b, Ph
1b, Ph
88/12
71/29
81/19
82/18
83/17
88/12
87/13
76/24
93/7
62 (85e)
84
84
55 (90e)
50 (92e)
51
2a, Ph
2b, p-MeC6H4
2c, p-MeOC6H4
2d, p-FC6H4
2e, p-ClC6H4
2f, p-NO2C6H4
74
62
72
nr
83/17
—
a
b
c
Molar ratio: 2/1/Cs2CO3/[PdC3H5Cl]2/L3 = 3/1/3/0.02/0.04.
Isolated yield.
Determined by 1H NMR.
d
e
Determined by HPLC.
Yield based on the recovery of 1.
3. (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 9074; (b) Trost, B. M.;
McEachern, E. J.; Toste, F. D. J. Am. Chem. Soc. 1998, 120, 12702; (c) Trost, B. M.;
Toste, F. D. J. Am. Chem. Soc. 1999, 121, 4545; (d) Jiang, L.; Burke, S. D. Org. Lett.
2002, 4, 3411; (e) Kim, H.; Lee, C. Org. Lett. 2002, 4, 4369; (f) Trost, B. M.; Shen, H.
C.; Dong, L.; Surivet, J.-P. J. Am. Chem. Soc. 2003, 125, 9276; (g) Tietze, L. F.;
Lohmann, J. K.; Stadler, C. Synlett 2004, 1113; (h) Kirsch, S. F.; Overman, L. E.;
White, N. S. Org. Lett. 2007, 9, 5911.
4. (a) Lopez, F.; Ohmura, T.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 3426; (b)
Shu, C.; Leitner, A.; Hartwig, J. F. Angew. Chem., Int. Ed. 2004, 43, 4794; (c)
Miyabe, H.; Matsumura, A.; Moriyama, K.; Takemoto, Y. Org. Lett. 2004, 6,
4632; (d) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira, E. M. J. Am. Chem. Soc.
2004, 126, 1628; (e) Miyabe, H.; Yoshida, K.; Yamauchi, M.; Takemoto, Y. J.
Org. Chem. 2005, 70, 2148; (f) Lyothier, I.; Defieber, C.; Carreira, E. M. Angew.
Chem., Int. Ed. 2006, 45, 6204; (g) Ueno, S.; Hartwig, J. F. Angew. Chem., Int. Ed.
2008, 47, 1928.
the products in high yield by elevating reaction temperature to
room temperature, with moderate enantioselectivity and low reg-
ioselectivity (Eq. 3). For secondary and tertiary aliphatic alcohols,
there was no reaction even at room temperature.
The absolute configuration of product 3b was determined as (R)
by comparing the sign of specific rotation of 3b with that of known
compound reported in the literature.4b
3. Conclusion
In summary, we have succeeded in the Pd-catalyzed regio- and
enantio-selective allylic substitution reaction with substituted
benzyl alcohols, affording the corresponding products in high reg-
ioselectivity and enantioselectivity. The extension of the substrate
scope and the applications of the products in organic synthesis are
under way.
5. (a) Evans, P. A.; Leahy, D. J. Am. Chem. Soc. 2000, 122, 5012; (b) Evans, P. A.;
Leahy, D. J. Am. Chem. Soc. 2002, 124, 7882.
6. (a) Kondo, T.; Ono, H.; Satake, N.; Mitsudo, T.; Watanabe, Y. Organometallics
1995, 14, 1945; (b) Mbaye, M. D.; Renaud, J.; Demerseman, B.; Bruneau, C. Chem.
Commun. 2004, 1870; (c) Onitsuka, K.; Okuda, H.; Sasai, H. Angew. Chem., Int. Ed.
2008, 47, 1454.
7. Lam, F.; Yeung, T.; Kwong, F.; Zhou, Z.; Wong, K.; Albert, S. C.; Chan Angew.
Chem., Int. Ed. 2008, 47, 1280.
Acknowledgments
8. (a) Dai, L.-X.; Tu, T.; You, S.-L.; Deng, W.-P.; Hou, X.-L. Acc. Chem. Res. 2003, 36,
659; (b) Yan, X. X.; Liang, C. G.; Zhang, Y.; Hong, W.; Cao, B. X.; Dai, L.-X.; Hou, X.-
L. Angew. Chem., Int. Ed. 2005, 44, 6544; (c) Zheng, W. H.; Zheng, B. H.; Zhang, Y.;
Hou, X.-L. J. Am. Chem. Soc. 2007, 129, 7718; (d) Zhang, K.; Peng, Q.; Hou, X.-L.;
Wu, Y. D. Angew. Chem., Int. Ed. 2008, 47, 1741; (e) Liu, W.; Chen, D.; Zhu, X.-Z.;
Wan, X.-L.; Hou, X.-L. J. Am. Chem. Soc. 2009, 131, 8734.
Financially supported by the Major Basic Research Develop-
ment Program (2006CB806100), National Natural Science Founda-
tion of China (20872161, 20821002, 20932008), Chinese Academy
of Sciences, and Science and Technology Commission of Shanghai
Municipality (10ZR1436800).
9. Typical experimental procedure: To
a
flame-dried Schlenk tube were added
S)-L3 (6.7 mg, 0.010 mmol),
[Pd(C3H5)Cl]2 (1.8 mg, 0.005 mmol), (S, Rphos
,
toluene (1.0 mL) with stirring for 30 min, and then allyl substrates 1b
(58.5 mg, 0.25 mmol), Cs2CO3 (244.0 mg, 0.75 mmol), benzyl alcohols 2a
(81.2 mg, 0.75 mmol), and toluene (2.0 mL) were added subsequently. The
resulting mixture was stirred at ꢀ5 °C for 40 h (TLC control). The reaction
mixture was filtrated with silica gel and washed with CH2Cl2. The solvent was
removed in vacuo. The regioselectivity was determined by 1H NMR of the crude
residue. The crude residue was purified by flash column chromatography using
mixtures of ethyl acetate/petroleum ether as the eluent affording the product 3
(45.9 mg, 82% yield).
References
1. For reviews, see: (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395; (b)
Pfaltz, A.; Lautens, M.. In Comprehensive Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: New York, 1999; Vol. 2, p 833; (c) Trost,
B. M.; Crawley, M. L. Chem. Rev. 2003, 103, 2921; (d) Lu, Z.; Ma, S. Angew. Chem.,
Int. Ed. 2008, 47, 258.
2. For racemic version of metal catalyzed allylic substitution reaction with oxygen
nucleophiles: (a) Stork, G.; Poirier, J. M. J. Am. Chem. Soc. 1983, 105, 1073; (b)
Stanton, S. A.; Felman, S. W.; Parkhurst, C. S.; Godleski, S. A. J. Am. Chem. Soc. 1983,
105, 1964; (c) Keinan, E.; Sahai, M.; Roth, Z. J. Org. Chem. 1985, 50, 3558; (d) Haight,
A. R.; Stoner, E. J.; Peterson, M. J.; Grover, V. K. J. Org. Chem. 2003, 68, 8092; (e)
Yatsumonji, Y.; Ishida, Y.; Tsubouchi, A.; Takeda, T. Org. Lett. 2007, 9, 4603.
Compound 3: ½a 2D0
ꢁ
¼ þ15:0 (c 0.99, CHCl3); 1H NMR (300 MHz, CDCl3): d (major
isomer): 7.41–7.23 (m, 10H), 6.06–5.94 (m, 1H), 5.34–5.22 (m, 2H), 4.85 (d,
J = 6.3 Hz, 1H), 4.54 (s, 2H); d (minor isomer): 6.64 (d, J = 15.9 Hz, 1H), 6.38–6.28
(m, 1H). HPLC: Chiralcel OJ–H, hexane/iPrOH = 98/2, flow rate = 0.7 mL/min,
k = 214 nm, tR = 19.0 min (minor), 23.9 min (major).