Palladium-catalyzed stereospecific cross-coupling of enantioenriched allylic alcohols with boronic acids

Article abstract of DOI:10.1039/c3cc45772a

In the presence of 2.5 mol% Pd₂(dba)₃-TMEDA (1 : 4), a range of enantioenriched allylic alcohols smoothly coupled with boronic acids in a highly regioselective fashion with inversion of configuration to afford structurally diverse alkenes in good yields with perfect retention of ee.

Full text of DOI:10.1039/c3cc45772a

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Palladium-catalyzed stereospecific cross-coupling
of enantioenriched allylic alcohols with boronic
acids†
Cite this: Chem. Commun., 2014,
50, 219
Received 29th July 2013,
Accepted 30th October 2013
Hai-Bian Wu,a Xian-Tao Maa and Shi-Kai Tian*ab
DOI: 10.1039/c3cc45772a
www.rsc.org/chemcomm
In the presence of 2.5 mol% Pd2(dba)3–TMEDA (1 : 4), a range of allylic alcohols with carbon nucleophiles.11,12 Prompted by our
enantioenriched allylic alcohols smoothly coupled with boronic acids in recent exploration of substitution reactions with allylic amines,13
a highly regioselective fashion with inversion of configuration to afford we envisioned that effective retention of ee could be realized in the
structurally diverse alkenes in good yields with perfect retention of ee. cross-coupling of enantioenriched allylic alcohols with boronic acids
by screening palladium catalysts and reaction conditions. Here we
Boronic acids are widely employed in cross-coupling reactions due report, for the first time, an efficient stereospecific cross-coupling
to their ready accessibility, stability, and reactivity.1 Particularly, the reaction of enantioenriched allylic alcohols with boronic acids, which
cross-coupling of boronic acids with allylic electrophiles constitutes affords a range of optically active alkenes with excellent ee.14
a powerful approach for the formation of carbon–carbon bonds by
A number of palladium sources and ligands were examined for
introducing the allyl moiety to target compounds,2 which permit a the cross-coupling of enantioenriched allylic alcohol 1a (94% ee)
variety of chemical transformations such as oxidation, reduction, with boronic acid 2a in dioxane at 110 1C (Table 1, entries 1–10).
and addition.3 Although allylic halides4 and alcohol derivatives, Both the yield and the stereochemistry (inverted) were significantly
such as allylic esters,5 carbonates,6 and phosphates,7 have been affected by the nature of the ligand and the palladium source, and
identified as useful allylic electrophiles with varying reactivity and
selectivity in their cross-coupling reactions with boronic acids, the
use of allylic alcohols as electrophiles is more attractive with respect
Table 1 Optimization of reaction conditionsa
to atom-economy because the leaving hydroxy group has a mass of
only 17 amu,8,9 which is much smaller than common leaving
groups. Moreover, the synthetic routes for allylic alcohols, including
enantioenriched ones, are in general shorter than those for the
corresponding halides and alcohol derivatives.10
Yieldb eec
Entry [Pd]
Ligand
Solvent
(%)
(%)
Although the cross-coupling of enantioenriched allylic alcohols
with boronic acids constitutes a promising atom-economic method
for the synthesis of optically active alkenes, it has been reported to
afford racemic products.8e Clearly, the poor leaving ability and
compatibility of the hydroxy group impose formidable challenges
to the direct substitution of enantioenriched allylic alcohols with
retention of ee. To our knowledge, effective retention of ee has not
yet been disclosed for the direct substitution of enantioenriched
1
2
3
4
5
6
7
8
Pd2(dba)3
None
Dioxane
Dioxane
0
78
29
0
73
8
32
Trace
Trace
Trace
12
—
91
90
—
32
11
0
—
—
—
66
11
—
—
93
94
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(PPh3)4
Pd(OAc)2
PdCl2
TMEDA
2,20-Bipyridine Dioxane
(ꢀ)-BINOL
(ꢀ)-BINAP
dppb
TMEDA
TMEDA
TMEDA
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
MeCN
9
10
11
12
13
14
15
16
[Pd(allyl)Cl]2 TMEDA
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
10
a Department of Chemistry, University of Science and Technology of China, Hefei,
Anhui 230026, China. E-mail: tiansk@ustc.edu.cn; Fax: +86 551-6360-1592;
Tel: +86 551-6360-0871
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data, and copies of 1H NMR and 13C NMR spectra and
HPLC traces. See DOI: 10.1039/c3cc45772a
DMF
DMSO
Trace
Trace
58
t-AmOH
Dioxane–t-AmOH (1 : 1) 84
a
Reaction conditions: alcohol 1a (0.30 mmol), boronic acid 2a
(0.36 mmol), [Pd] (2.5 mol%; for entries 7–9, 5 mol%), ligand (10 mol%),
solvent (2.0 mL), 110 1C, 15 h. Isolated yield. Determined by HPLC
analysis on a chiral stationary phase.
b
c
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gratifyingly, the use of Pd2(dba)3–TMEDA (1 : 4) as the catalyst system unsymmetrical p-allylpalladium intermediate from the palladium
afforded alkene 3a in 78% yield with 91% ee (Table 1, entry 2). catalyst and the allylic alcohol (see below). The reaction worked well
Moreover, the reaction proceeded with exclusive a-selectivity, and no with a variety of aryl- and alkenylboronic acids under the standard
E/Z isomerization was observed for the allyl carbon–carbon double conditions and a range of optically active alkenes were obtained in
bond. To improve the efficiency of chirality transfer, we screened a good yields with exclusive E selectivity and excellent ee (Table 2,
number of common solvents and found that replacing dioxane with entries 12–23). Nevertheless, no desired product was obtained from
a 1:1 mixture of dioxane and tertiary amyl alcohol led to complete the corresponding reaction with alkylboronic acids such as n-butyl-,
inversion of the chiral center of allylic alcohol 1a (Table 1, entry 16). cyclohexyl-, and benzylboronic acids. As demonstrated by the
In the presence of 2.5 mol% Pd2(dba)3–TMEDA (1 : 4), a range of results summarized in Table 2, the reaction tolerated a variety of
unsymmetrical enantioenriched allylic alcohols (a-substituent a functional groups such as heteroaryl, vinyl, alkoxy, chloro, fluoro,
g-substituent) smoothly coupled with boronic acid 2a in an amino, ester, and amide groups.
a-selective fashion with inversion of configuration to afford the
The regioselectivity largely depends on the structure of the
corresponding alkenes in good yields with perfect retention of ee allylic alcohol. The cross-coupling of allylic alcohol 1l (97% ee), a
and alkene geometry (Table 2, entries 1–11). The a- and g-positions regioisomer of allylic alcohol 1a, with boronic acid 2a proceeded in
of the allylic alcohols could bear various substituents such as aryl, a g-selective fashion to afford alkene ent-3a in 82% yield with
heteroaryl, alkyl, ester, and amide groups, but the reaction was not exclusive E selectivity and retention of ee (eqn (1)). The g-selectivity
applicable to a-chiral allylic alcohols with b-substituents due to probably arises from both maximizing conjugation and minimizing
poor reactivity. When the g-substituent was an alkyl group (e.g., a steric hindrance prior to the coupling of the boronic acid with the
cyclohexyl group), a considerable portion of the allylic alcohol putative p-allylpalladium intermediate (see below).
coupled with boronic acid 2a in a g-selective fashion (Table 2,
entry 9),15 which could be attributed to the generation of an
(1)
Table 2 Stereospecific cross-coupling of enantioenriched allylic alcohols
with boronic acidsa
We also examined the reaction of a symmetrical allylic alcohol
(a-substituent = g-substituent). Treatment of allylic alcohol 1m
(98% ee) with boronic acid 2b under the standard conditions led
to the formation of racemic alkene 3x (eqn (2)). The complete loss
of ee should be attributed to the generation of a symmetrical
p-allylpalladium intermediate during the reaction (see below).
eec (%)
3 or Yieldb
ent-3 (%)
3 or
ent-3
(2)
Entry 1 (ent-1), R1, R2
2, R3
1
1
1a, Ph, Me
1b, Ph, Et
1c, Ph, CHMe2
1d, 4-MeOC6H4, Me 2a, Ph
1e, 4-ClC6H4, Me 2a, Ph
1f, 2-MeOC6H4, Me 2a, Ph
1g, 3-pyridinyl, Me 2a, Ph
2a, Ph
2a, Ph
2a, Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
ent-3j 63
ent-3k 72
3l
3m
3n
83
73
60
77
76
76
87
81
70
99 99
97 97
91 91
94 94
96 96
96 96
93 92
95 95
97 97
96 96
97 97
99 99
99 99
99 99
99 99
99 99
99 99
99 99
99 99
99 99
99 98
99 99
94 94
2
3d
4
Based on our experimental results and previous studies,8 we
propose a catalytic cycle depicted in Scheme 1 for the stereo-
specific cross-coupling of enantioenriched allylic alcohols with
boronic acids. The hydroxy group of allylic alcohol 1 is activated
by boronic acid 2 and the allylic carbon–oxygen bond is cleaved
by palladium(0) (PdLn) with inversion of configuration to give
p-allylpalladium 5, which undergoes transmetallation followed
by reductive elimination to give alkene 3 and concurrently
5
6
7
8e
9 f
10
11
12
13
14
15
16
1h, 2-furyl, Me
2a, Ph
1i, cyclohexyl, Me 2a, Ph
ent-1j, CO2Me, Me 2a, Ph
ent-1k, CONEt2, Me 2a, Ph
1a, Ph, Me
1a, Ph, Me
1a, Ph, Me
1a, Ph, Me
1a, Ph, Me
2b, 4-MeC6H4
2c, 4-PhC6H4
2d, 4-FC6H4
2e, 4-MeO2CC6H4 3o
2f, 3-H2NC6H4
2g, 3-AcNHC6H4
2h, 3-MeO2CC6H4 3r
2i, 2-FC6H4
2j, 2-naphthyl
2k, 1-naphthyl
81
70
64
75
66
61
61
63
61
85
80
71
3p
3q
17g 1a, Ph, Me
18
1a, Ph, Me
19h 1a, Ph, Me
3s
3t
3u
20
21
22
23
1a, Ph, Me
1a, Ph, Me
1a, Ph, Me
2l, 9-phenanthrenyl 3v
1d, 4-MeOC6H4, Me 2m, (E)-PhCHQCH 3w
a
Reaction conditions: alcohol 1 or ent-1 (0.50 mmol), boronic acid 2
(0.60 mmol), Pd2(dba)3 (2.5 mol%), TMEDA (10 mol%), dioxane–
b
c
t-AmOH (1 : 1, 3.5 mL), 110 1C, 15 h. Isolated yield. Determined by
d
HPLC analysis on a chiral stationary phase. The reaction was run for
48 h. 97 : 3 a/g. 88 : 12 a/g. 98 : 2 a/g. The reaction was run for 36 h.
e
f
g
h
Scheme 1 Proposed catalytic cycle.
220 | Chem. Commun., 2014, 50, 219--221
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hols with boronic acids. In the presence of 2.5 mol% Pd2(dba)3–
TMEDA (1 : 4), a range of enantioenriched allylic alcohols
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fashion with inversion of configuration to afford structurally
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alkene geometry. The reaction tolerated a variety of functional
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alcohols with carbon nucleophiles.
We are grateful for the financial support from the National
Natural Science Foundation of China (21232007 and 21172206),
the National Basic Research Program of China (973 Program
2010CB833300), and the Program for Changjiang Scholars and
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Chem. Commun., 2014, 50, 219--221 | 221