Chemo- and regioselective C(sp3)-H arylation of unactivated allylarenes by deprotonative cross-coupling

Article abstract of DOI:10.1002/anie.201309084

The combination of aryl bromides, allylbenzene, base and a palladium catalyst usually results in a Heck reaction. Herein we combine these same reagents, but override the Heck pathway by employing a strong base. In the presence of LiN(SiMe₃)

Full text of DOI:10.1002/anie.201309084

Angewandte
Chemie
DOI: 10.1002/anie.201309084
Synthetic Methods
3
À
Chemo- and Regioselective C(sp ) H Arylation of Unactivated
Allylarenes by Deprotonative Cross-Coupling**
Nusrah Hussain, Gustavo Frensch, Jiadi Zhang, and Patrick J. Walsh*
Abstract: The combination of aryl bromides, allylbenzene,
base and a palladium catalyst usually results in a Heck
reaction. Herein we combine these same reagents, but override
the Heck pathway by employing a strong base. In the presence
of LiN(SiMe3)2, allylbenzene derivatives undergo reversible
deprotonation. Transmetalation of the resulting allyllithium
intermediate to LPdAr(Br) and reductive elimination provide
the 1,1-diarylprop-2-enes, which are not accessible by the Heck
reaction. The regioselectivity in this deprotonative cross-
coupling process is catalyst-controlled and very high.
C
atalytic functionalization of unactivated sp3-hybridized
À
C H bonds in the absence of directing groups is highly
desirable, but remains challenging.[1,2] The level difficulty of
these functionalizations increases drastically when regio- and
chemoselectivity issues are present. In our efforts to address
Scheme 1. Overriding Heck coupling: Heck reaction (right) vs. DCCP
of allylbenzene with strong base (left).
such challenges, we recently initiated a program for the
tion and insertion of allylbenzene in the Heck coupling to
transmetalation of the metalated allyl (Scheme 1, left).[11,12]
The catalyst/ligand combination would control the regio-
selectivity of the arylation in the DCCP, thus enabling the
formation of a-arylated products that are inaccessible by the
Heck pathway. It is noteworthy that this approach is distinct
3
À
functionalization of weakly acidic sp -hybridized C H bonds
by palladium-catalyzed deprotonative cross-coupling process-
es (DCCPs). Substrates that have been successfully function-
alized using this approach include diarylmethanes,[3,4] sulf-
oxides,[5] sulfones,[6] amides,[7] and chromium-activated ben-
zylic amines (to produce enantioenriched diarylmethyl-
amines).[8] Based on these results, we hypothesized that it
might be possible to functionalize allylbenzene derivatives
and control chemo- and regioselectivity. Successful develop-
ment of such a process would require: 1) conditions for the
deprotonation of allylbenzene that are amenable to catalysis,
2) catalysts that can promote the regioselective arylation, and
3) control of base reactivity such that the more acidic product
is not deprotonated and isomerized or further functionalized.
Typically, reactions of allylbenzenes with aryl bromides in
the presence of palladium catalysts and base afford Heck-type
g-selective products, often as mixtures of regio- and geometric
isomers (Scheme 1, right).[9,10] We envisioned that a strong
base could divert the chemoselectivity from olefin coordina-
À
from known C H activation/arylations of allylbenzenes and
related substrates.[13]
3
À
Herein, we disclose the first metal-catalyzed C(sp ) H
arylation of allylbenzenes (pKa = 34 in dimethylsulfoxide
(DMSO))[14] with aryl bromides to afford 1,1-diarylprop-2-
enes. A base/catalyst combination [LiN(SiMe3)2/Pd-PCy3] is
advanced that efficiently controls the chemoselectivity and
promotes regioselective DCCP of allylbenzenes in good to
excellent yields (51–97%).
Our first challenge was to identify conditions for the
3
À
deprotonation of allylbenzeneꢀs C(sp ) H. The benzylic
À
C Hꢀs in allylbenzene have traditionally been deprotonated
with n- and sec-BuLi at À788C or with nBuMgCl.[15] These
strong bases, however, are impractical for cross-coupling
reactions because of their limited compatibility with catalysts
and coupling partners. We, therefore, focused on reversible
in situ deprotonation of allylbenzene.
[*] N. Hussain, G. Frensch, J. Zhang, Prof. P. J. Walsh
Department of Chemistry, University of Pennsylvania
231 S. 34th St. Philadelphia, PA 19104 (USA)
E-mail: pwalsh@sas.upenn.edu
As a surrogate for the transmetalation step in the
arylation reaction in Scheme 1, we substituted reaction of
metalated allylbenzene with benzyl chloride (Scheme 2). To
perform the benzylation, we screened six bases [LiN(SiMe3)2,
NaN(SiMe3)2, KN(SiMe3)2, LiOtBu, NaOtBu and KOtBu] at
room temperature in CPME (cyclopentyl methyl ether). As
illustrated in Scheme 2, the bases leading to benzylation
products were: KN(SiMe3)2 affording a 5:1 ratio of a:g (80%
yield), NaN(SiMe3)2 a 4:1 ratio (71% yield), and LiN(SiMe3)2
a 1:1 ratio (13% yield). The a:g ratios observed suggest that
the nature of the metal plays a significant role in the
Homepage: http://titanium.chem.upenn.edu/walsh/index.html
G. Frensch
Departamento de Quꢀmica, Universidade Federal Do Paranꢁ
CP 19081, 81531–990, Curitiba–PR (Brazil)
[**] P.J.W. acknowledges the NIH (National Institute of General Medical
Sciences GM 104349) and the NSF (CHE-1152488). G.F. acknowl-
edges the Brazilian Science Without Borders program (237849/
2012-7).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309084.
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(pKa = 32 in DMSO)[17] with aryl bromides,[3] gave a 2.6:1
ratio of a- and g-arylated products. Because PCy3 is less
expensive than Brettphos,[18] we chose PCy3 as the ligand for
optimization of the arylation reaction.
Translation of the microscale lead outlined above to
laboratory scale (0.1 mmol) using 1 equiv of allylbenzene
(1a), 3 equiv of bromobenzene (3a), 3 equiv of LiN(SiMe3)2
(2), 5 mol% of Pd(OAc)2 and 10 mol% of PCy3 in CPME at
1108C rendered the a-arylated product (4a) in 15% yield
(entry 4, Table 1). Examination of four etheral solvents [THF
(tetrahydrofuran), DME (dimethoxyethane), dioxane and
CPME] indicated that CPME was the best choice (entries 1–
4, Table 1). During the optimization we observed the
conversion of allylbenzene to trans-b-methylstyrene (major)
and cis-b-methylstyrene (minor) (Scheme 3).[19] Unfortu-
Scheme 2. Benzylation used as surrogate for the transmetalation step
in DCCP.
regioselectivity.[16] None of the MO-tBu (M = Li, Na, K) bases
generated detectable amounts of benzylation products.
Unlike bases previously used to deprotonate allylbenzene
(n- and sec-BuLi at À788C or nBu-MgCl), MN(SiMe3)2 has
a high likelihood of compatibility with catalyst, reagents, and
products in the DCCP (Scheme 1, left).
We next turned our attention to catalyst identification for
the DCCP of allylbenzene. We tested 29 sterically and
electronically diverse mono- and bidentate phosphine ligands,
three bases [LiN(SiMe3)2, NaN(SiMe3)2, KN(SiMe3)2] and
different Pd0 and PdII precursors at 1108C using microscale
high-throughput experimentation (HTE) techniques (see
Supporting Information for details). Interestingly, the results
of the HTE indicated the only base leading to the a-arylated
product (4a) was LiN(SiMe3)2 (Table 1). Note that the main
Scheme 3. Isomerization of allylbenzene to unreactive b- methyl-
styrenes.
Table 1: Optimization of palladium-catalyzed DCCP of allylbenzene.
nately, these isomers are less acidic than allylbenzene and
do not undergo deprotonation under our conditions at 1108C.
Decreasing the temperature of the reaction to 808C increased
the product yield to 30% (entry 5). Lowering of the temper-
ature to 608C decreased the product yield to 20% (entry 6).
Given the weak acidity of allylbenzene, and the resulting low
concentration of the allyl anion, we increased the reaction
concentration from 0.1m to 0.2m. At the higher concentration,
the yield of a-arylated product (4a) increased to 40%
(entry 7). We, therefore, increased the amount of allylben-
zene to 3 equiv while using 3 equiv of LiN(SiMe3)2 and
1 equiv of bromobenzene at 0.2m. The excess allylbenzene
compensates for what appears to be an irreversible isomer-
ization of some allylbenzene to unreactive b-methylstyrenes.
Under these conditions, the a-arylated product (4a) was
obtained in 65% yield (entry 8). Further increasing the
concentration of the reaction mixture (0.3m and 0.4m) did
not have an appreciable effect on the product yield (entries 9
and 10). We, therefore, chose 0.2m as the reaction concen-
tration. When 4 equiv of allylbenzene, 4 equiv of LiN(SiMe3)2
and 1 equiv of bromobenzene were used, the product was
obtained in 74% yield (entry 11). Further optimization was
performed by changing the ratio of PCy3 with respect to the
amount of palladium (entries 12 and 13). Finally, the arylation
product (4a) was obtained in quantitative yield when employ-
ing Pd(OAc)2 (5 mol%), PCy3 (20 mol%) and a ratio of 4:4:1
of allylbenzene : LiN(SiMe3)2 : bromobenzene at 808C for
24 h (entry 13).
Entry 1a:2:3a Solvent
T
Conc.
t
Pd(OAc)2/
4a[a]
[8C] [m]
[h] PCy3 [mol%] [%]
1
2
3
4
5
6
7
8
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
1:3:3
3:3:1
3:3:1
3:3:1
4:4:1
4:4:1
4:4:1
THF
DME
dioxane 110 0.1
110 0.1
110 0.1
24 5/10
24 5/10
0
0
10
15
30
20
40
65
68
69
24 5/10
24 5/10
24 5/10
24 5/10
24 5/10
24 5/10
24 5/10
24 5/10
24 5/10
24 5/15
24 5/20
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
CPME
110 0.1
80
60
80
80
80
80
80
80
80
0.1
0.1
0.2
0.2
0.3
0.4
0.2
0.2
0.2
9
10
11
12
13
74
80
>99
1
[a] Yield determined by H NMR analysis of crude mixture with internal
standard CH2Br2; less than 4% of g-arylated product was detected by
NMR spectroscopy.
group metal is involved in both the deprotonation and the
transmetalation steps in the arylation reaction. As such, the
best base for the benzylation may not be the best for the
palladium-catalyzed reaction. Of the 29 ligands examined,
PCy3 and Brettphos afforded very high regioselectivity in the
coupling, giving exclusively the a-arylated products (see
Supporting Information). NiXantphos, the only ligand that we
found to perform well in the DCCP of diphenylmethane
With our optimized conditions (entry 13, Table 1), we
examined the substrate scope of the arylation of allylbenzene
with aryl bromides (Table 2). The DCCP showed excellent
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Table 2: Cross-coupling of allylbenzene with aryl bromides.
reactivity with aryl bromides possessing electron-donating
groups (81–97% yields, entries 2–5). A range of other
substrates exhibited good reactivity, including those with
substituents in the meta (85% yield, entry 6) and ortho
positions (83% yield, entry 7) as well as 2- and 1-bromo
naphthalene (86 and 74% yields, entries 8 and 9). Nitrogen
protected 5-bromoindole was also a good coupling partner
and furnished the a-arylated product in 86% yield
(entry 10).[20] The yields were typically lower, however, with
electron-deficient aryl bromides (52–66%, entries 11 and 12).
Ketones are well known to undergo 1,2-carbonyl addition
reactions with reactive organometallics. Additionally,
p-bromoacetophenone (pKa = 24.7 in DMSO)[21] can partic-
ipate in competitive aldol chemistry[22] and Pd-catalyzed a-
arylation of the enolate under basic condition.[2,23] Yet the a-
arylated product 4m derived from DCCP of allylbenzene was
produced in reasonable yield (65%, entry 13). Acetals are
Entry
Product
Yield
[%][a]
Entry
Product
Yield
[%][a]
1
91[b]
8
86[c]
4a
4h
À
known to undergo C O cleavage with reactive organometal-
2
88[b]
9
74[c]
lics,[24] however, the a-arylated product 4n was produced in
87% yield (entry 14).
4b
4i
We next turned our attention to the allylbenzene scope
(Table 3). Electron-donating 4-allylanisole exhibited good
reactivity (66–88% yields, entries 1–4). Meta-substituted 3-
allyltoluene furnished the desired coupling products in 80–
91% yield (entries 5 and 6). Protected 5-bromoindole under-
went the a-arylation with 3-allyltoluene in 82% yield
(entry 7). Ortho-substituted 2-allyltoluene gave the desired
product in 60% yield despite the additional steric hindrance
at the a-center (entry 8). Electron-deficient 4-fluoro allyl-
benzene gave 64 and 66% yield with bromobenzene and
protected 5-bromoindole (entries 9 and 10, respectively).
Allyl derivatives 2- or 3-allylpyridine did not give the a-
arylated products, but only underwent isomerization to the
more stable vinyl pyridine derivatives. 2-Allylthiophene, on
the other hand, underwent DCCP with 4-bromo tert-butyl-
benzene to afford the a-arylated product 4u in 51% yield
(entry 11). These systems are significantly more acidic than
allylbenzenes and will require different catalysts to afford
synthetically useful yields. It is noteworthy that excellent
regioselectivity is observed in the substrates in Table 3, even
when the steric and electronic parameters of the allylbenzene
starting materials are varied.[10,12]
3
97[b]
10
86[c,d]
4c
4d
4e
4j
4k
4l
4
5
81[b]
11
12
66[c,d]
86[c]
52[b]
When the DCCP with TBS protected bromoindole (3j)
was scaled to 1 mmol with a ratio of 4:5:1 of 1a:2:3j in the
presence of 5 mol% Pd(OAc)2 and 20 mol% PCy3, the
product 4j was isolated in 77% yield (Scheme 4).
6
85[c,d]
13
65[c,d]
In summary, we have developed the first direct a-arylation
of unactivated allylbenzenes with aryl bromides by using
4 f
4m
7
83[c,e]
14
87[c,d]
4g
4n
[a] Less than 4% of the g products were detected by NMR spectroscopy
and no Heck product was observed under our conditions. [b] 24 h.
[c] 36 h. [d] 6 equiv of base used. [e] Concentration is 0.3m.
Scheme 4. Scaled up DCCP of allylbenzene with TBS-protected bro-
moindole. TBS=tert-butyl dimethylsilyl.
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Table 3: Cross-coupling of allylbenzenes with aryl bromides.
deprotonative cross-coupling processes. The significance of
this work is it demonstrates that very weakly acidic hydro-
carbon frameworks can be functionalized under DCCP
conditions.
Entry Product
Yield
[%][a]
Entry Product
Yield
[%][a]
The palladium-catalyzed arylation proceeded efficiently
in the presence of PCy3 and produces a-arylated 1,1-diaryl-
prop-2-enes with very high regioselectivity (> 95:5). It is
noteworthy that our approach overrides the ubiquitous Heck
reaction pathway by controlling the chemoselectivity. This is
accomplished by use of a strong base, LiN(SiMe3)2, that
reversibly deprotonates the allylbenzene. The lithiated allyl
then undergoes transmetalation with the catalyst in a process
that is faster than coordination and insertion of allylbenzene
in the Heck pathway. The regiochemistry of the arylation is
controlled by the ligand/palladium combination and is key to
the success of this process. The fact that the a-arylated
diarylallyl does not undergo base promoted isomerization to
the more conjugated 1,1-diaryl-1-propene suggests that an
enantioselective DCCP of allylbenzenes is possible and has
inspired us to investigate this possibility.
1
88
7
82
4c
4s
2
81
8
60[b]
4o
4g
Received: October 17, 2013
Revised: January 8, 2014
Published online: February 26, 2014
3
72
9
64
À
Keywords: C H functionalization · chemoselectivity ·
deprotonative cross-coupling · palladium catalysis ·
regioselectivity
.
4p
4l
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