Chemoselective palladium-catalyzed cyanation of alkenyl halides

Article abstract of DOI:10.1021/ol500618w

A palladium-catalyzed cyanation of alkenyl halides using acetone cyanohydrin is described. A number of structurally diverse alkenylic nitrile containing compounds was prepared in one step under optimized conditions. The reaction proved to be efficient, chemoselective, easy to perform, and tolerant of a number of functional groups.

Full text of DOI:10.1021/ol500618w

Letter
pubs.acs.org/OrgLett
Chemoselective Palladium-Catalyzed Cyanation of Alkenyl Halides
Kimberley J. Powell,† Li-Chen Han,† Pallavi Sharma,*,†,‡ and John E. Moses*,†
†School of Chemistry, University of Nottingham, University Park, Nottingham, NG7 2RD, U.K.
‡School of Life Sciences, University of Lincoln, Brayford Pool, Lincoln, LN6 7TS, U.K.
S
* Supporting Information
ABSTRACT: A palladium-catalyzed cyanation of alkenyl
halides using acetone cyanohydrin is described. A number of
structurally diverse alkenylic nitrile containing compounds was
prepared in one step under optimized conditions. The reaction
proved to be efficient, chemoselective, easy to perform, and
tolerant of a number of functional groups.
he alkenyl-nitrile1 functional group is highly versatile and
Table 1. Screening Conditions for the Palladium-Catalyzed
Cyanation of Alkenyl Bromide 1a
Twidely represented in several important dyes, herbicides,
and natural products.2 A number of important pharmaceutical
agents also comprise a crucial α,β-unsaturated nitrile group: the
anticancer agents trilostane and CC-5079; the Parkinson’s
disease drug entacapone; and the potent anti-HIV non-
nucleoside reverse transcriptase inhibitor, rilpivirine (Figure
1).3 A number of synthetic routes to alkenyl nitriles are
known,4 which include the following: amide dehydration
reactions,5 carbocyanation of alkynes,6 Wittig/Horner−Em-
mons7,8 type phosphorus, and silicon-based Peterson9,10
olefinations, although many suffer from poor yields and/or
limited stereocontrol.
Transition metal (Ni, Pd)-catalyzed alkenyl cyanation
reactions are an attractive option, although their application
has been somewhat restricted to the synthesis of substituted
cinnamonitriles.11 Hazards associated with the handling and
disposal of metal cyanide waste, coupled with the significant
ACH
a
entry
1
base
additive
addition
time
yield
Na2CO3
−
15 min
6 h
23%
23%
trace
24%
15 h
b
b
10 min
one portion 6 h
2
3
4
5
Na2CO3
Na2CO3
Na2CO3
TlOEt
−
−
17 h
1 h (18 h total) trace
Bu3SnClcat
15 min
15 min
6 h
15%
H2O
6 h
−
c
after 6 h
15 h
a
b
Isolated yield. Determined by analysis of the crude 1H NMR;
product not isolated. After reacting for 6 h, a drop of H2O was added
to form TlOH in situ. After another 15 h reaction time, there was still
no reaction and no starting material consumption.
c
problem of catalyst deactivation due to the presence of excess
dissolved cyanide ion, are also unwelcoming.12
Beller et al. pioneered the use of acetone cyanohydrin
(ACH) for the palladium-catalyzed cyanation of aryl and
heteroaryl halides.13 Using continuous slow addition of liquid
ACH via syringe pump allowed the controlled in situ release of
the cyanide ion, thereby overcoming the problem of catalyst
deactivation. We here report our development of a chemo-
selective procedure for the palladium-catalyzed cyanation of
alkenyl halides using ACH as the cyanide source.14
Our studies commenced with (E)-β-bromostyrene (1a) and
the addition of ACH over 15 min in the presence of the catalyst
mixture [Pd2(dba)3, tri(2-furyl)phosphine (TFP)] at 65 °C.
Figure 1. Representative examples of clinically important alkenyl-
nitrile containing pharmaceuticals.
Received: February 26, 2014
Published: March 27, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Table 2. Optimization of the Reaction Conditions for the
Cyanation Reaction of Alkenyl Bromide 1a
Table 3. Cyanation of Alkenyl Halides
a
b
e
f
entry
Pd
L
P/Pd
T (°C)
t (h)
yield
1
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
−
TFP
3:1
3:1
3:1
3:1
3:1
3:1
3:1
4:1
6:1
3:1
3:1
4:1
6:1
−
rt
6
trace
38%
trace
38%
70%
−
c
2
TFP
100
100
65
6
f
3
TFP
3
6
4
DPPP
DPPP
PPh3
cd
,
5
100
100
100
100
100
100
100
100
100
100
2
6
6
f
f
7
PCy3
DPPP
DPPP
TFP
6
trace
49%
51%
trace
63%
73%
37%
d
8
3
cd
,
9
3
10
11
12
13
14
3
cd
,
DPPP
DPPP
DPPP
DPPP
1.5
1.5
1.5
6
cd
,
cd
,
g
−
a
b
5 mol % Pd2(dba)3, 10 mol % Pd(OAc)2 used. Reactions were
c
quenched after the indicated time period. No remaining starting
d
material detected by crude 1H NMR. Homocoupled product
observed as a minor byproduct: the ratio of homocoupled product/
e
desired product ∼0.04:1 by crude 1H NMR. Isolated yield.
f
1
Determined by analysis of the crude H NMR; product not isolated.
g
Et2O/DMA used as solvent, 15 mol % DPPP.
After 6 h of reaction time, the corresponding nitrile product 3a
was isolated in a modest 23% yield (Table 1, entry 1).
Whereas increasing the reaction time had no effect on the
overall yield, stopping the reaction after 10 min resulted in a
trace amount of desired product (Table 1, entry 1).
Interestingly, no deterioration in the yield was observed when
the ACH was added in one portion, yet syringe pump addition
of ACH over a 17 h period resulted in only trace product
1
(crude H NMR), with most of the bromostyrene starting
material remaining unreacted (Table 1, entries 2 and 3). The
use of catalytic Bu3SnCl (for in situ generation of Bu3SnCN) or
a soluble base such as TlOEt led only to a decrease in the
reaction yield (Table 1, entries 4 and 5).
Having established that the addition of ACH in one portion
was optimal for our system, we next screened a number of
catalyst mixtures by systematically changing the palladium
source and the ligand and by sampling various metal/ligand
ratios. A selection of solvent systems, temperatures, and
additives were also investigated.
The reaction temperature was found to be a very important
factor. Whereas performing the reaction at room temperature
resulted in only a trace amount of product, elevating the
temperature to 100 °C significantly increased the yield to 38%
(Table 2, entries 1 and 2). The electron-donating bidentate
ligand, 1,3-bis(diphenylphosphino)propane (DPPP), emerged
as the most efficient, leading to a dramatically improved yield of
70% at 100 °C (Table 2, entry 5). The source of the palladium
catalyst had little effect on the overall yield: changing from
Pd2(dba)3 to Pd(OAc)2 registered an almost identical yield (70
and 73%, respectively) but required a higher ligand
concentration (Table 2, entries 5 and 12). Thus, 5 mol %
Pd2(dba)3 was selected as the preferred palladium source of
choice (see Supporting Information, Table S1). A survey of
a
b
Isolated yield. Inseparable 18:1 mixture of E/Z isomers generated.
c
A reaction temperature of 100 °C gave yields of 69% and 15% from
d
1c and 1c′, respectively. Generated as an inseparable 3.5:1 mixture
with (E)-cinnamaldehyde.
reaction media (see Supporting Information, Table S2)
established that polar solvents such as dimethylformamide
(DMF) or dimethylacetamide (DMA) were essential to
maintain higher yields. The combination of Et2O/DMA (2:1)
emerged as the solvent of choice (Table S2, entry 11). The use
of additives such as zinc, TMEDA, CuI, and TBAB along with
these standardized conditions appeared to have only a
deleterious effect on yield,15 as did the substitution of
Na2CO3 for alternative bases (see Supporting Information,
Table S3).
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halides in the presence of aryl halides. Remarkably, when the
(E)-1-bromo-4-(2-bromoalkenyl)benzene (1j) was exposed to
our optimized reaction conditions, high levels of selectivity (if
not specificity)16 were observed: the corresponding alkenyl
nitrile 3j was isolated in 83% yield with no detectable formation
of benzonitrile or trans-3-(4-cyanophenyl)acrylonitrile (Table
4, entry 2). Similarly high levels of chemoselectivity were
observed when the dibromides 1k and 1l were employed; the
corresponding alkenylnitriles 3k and 3l were isolated
exclusively using our cyanation conditions (Table 4, entries 3
and 4, respectively). The level of chemoselectivity/specificity16
demonstrated is unprecedented in palladium-catalyzed cyana-
tion reactions,17 thus establishing our method as a powerful and
complementary protocol to Beller’s aryl cyanation chemistry.
The exact mechanistic details of the transformation are
currently being investigated.18,19
Table 4. Chemoselective Cyanation of Alkenyl Halides
In conclusion, we have demonstrated a straightforward access
to alkenyl nitriles via a chemoselective palladium-catalyzed
reaction of alkenyl halides and acetone cyanohydrin. The
reaction demonstrated impressive functional group tolerance
(alcohols, aldehydes and imines) and was amenable with
sterically hindered substrates. Of particular significance was the
observed chemoselective preference for the alkenyl bromide in
the presence of aryl bromides.
ASSOCIATED CONTENT
* Supporting Information
a
b
c
■
Isolated yield. No reaction. Inseparable mixture of Z/E isomers
S
generated in a ratio of 11:1 respectively.
Experimental details and procedures, compound character-
ization data, and copies of H and 13C NMR spectra for new
compounds are included. This material is available free of
charge via the Internet at http://pubs.acs.org.
1
With these encouraging results in hand we were interested in
the scope and limitations of our new protocol. Table 3 shows a
variety of different alkenyl halides tested in the palladium-
catalyzed cyanation with ACH.
The inclusion of electron-donating and -withdrawing groups
on the aromatic nucleus of the bromostyrene had minimal
effect on the reaction yield (Table 3, entries 2 and 4), although
a higher reaction temperature was required in the case of those
substrates deactivated by the electron-releasing methoxy
substituent (Table 3, entries 4 and 5). Alkenyl iodides and
chlorides were also found to be suitable substrates (Table 3,
entries 3, 5, 7, and 8).
Furthermore, the reaction conditions proved tolerant of a
number of sensitive groups including aldehyde, hydroxyl, and
imine functional groups (Table 3, entries 8−10). In contrast to
the (E)-alkenyl bromide 1a, when the (Z)-alkenyl bromide 1d
was subjected to the optimized reaction conditions, it was
found to be sluggish, with incomplete consumption of starting
alkenyl bromide even after 6 h (Table 3, entries 1 and 6). In
certain instances under the optimized reaction conditions, the
low yield could be attributed to either incomplete consumption
of the starting material or formation of undesired side products
(see Supporting Information, Table S4).
Interestingly, bromobenzene failed to react under the
standard conditions, with no trace of the aryl nitrile product
being detected even after 6 h (Table 4, entry 1). This striking
contrast in the reaction outcome for the aryl and alkenyl halides
in the palladium-catalyzed cyanation reaction was intriguing.
The fact that aryl halides required slow addition of ACH for
effective cyanation to proceed,13 while the alkenyl halides relied
upon fast addition of the cyanide ion equivalent, presented an
opportunity to exploit the reactivity difference.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: john.moses@nottingham.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We would like to thank Dr. M. McConville, and Mr. J. Moore
(School of Chemistry, University of Nottingham) for helpful
input. We also acknowledge The Leverhulme Trust for financial
support.
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