Nucleophilic additions to polarized vinylarenes

Article abstract of DOI:10.1016/j.tetlet.2016.06.033

The addition of nucleophiles to the terminal double bond carbon of a styrene incorporating an electron-withdrawing group at the ortho or para position has been studied. The conditions for this transformation have been optimized and structural modifications to the substrate have been explored. The structural changes included variation of the activating group on the aromatic ring and positioning substituents on the side chain double bond. The study revealed that nitro substitution gave the best results for addition of carbon and nitrogen nucleophiles. Cyano-substituted systems added carbon nucleophiles, but underwent polymerization or degradation with nitrogen nucleophiles. Ethoxycarbonyl-bearing substrates reacted primarily at the ester carbonyl. The reaction generally proceeded well with methyl on the α carbon of the double bond, but was slowed by methyl at the β position. The yields varied from 50% to 97% for 22 examples.

Full text of DOI:10.1016/j.tetlet.2016.06.033

Tetrahedron Letters 57 (2016) 3190–3193
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Nucleophilic additions to polarized vinylarenes
⇑
Krishna Kumar Gnanasekaran, Junghak Yoon, Richard A. Bunce
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The addition of nucleophiles to the terminal double bond carbon of a styrene incorporating an electron-
withdrawing group at the ortho or para position has been studied. The conditions for this transformation
have been optimized and structural modifications to the substrate have been explored. The structural
changes included variation of the activating group on the aromatic ring and positioning substituents on
the side chain double bond. The study revealed that nitro substitution gave the best results for addition
of carbon and nitrogen nucleophiles. Cyano-substituted systems added carbon nucleophiles, but
underwent polymerization or degradation with nitrogen nucleophiles. Ethoxycarbonyl-bearing substrates
Received 8 May 2016
Revised 7 June 2016
Accepted 8 June 2016
Available online 9 June 2016
Keywords:
Nucleophilic addition
Polarized vinylarenes
Hydroamination
Reaction optimization
Steric effects
reacted primarily at the ester carbonyl. The reaction generally proceeded well with methyl on the
a carbon
of the double bond, but was slowed by methyl at the b position. The yields varied from 50% to 97% for 22
examples.
Ó 2016 Elsevier Ltd. All rights reserved.
Carbon–carbon and carbon–nitrogen bond formations by
Michael1,2 and SNAr3,4 reactions have been important synthetic
tools for many years. The Michael reaction involves the addition
of a nucleophile to a double bond polarized by conjugation with
an electron-withdrawing group and is facilitated by stabilization
ring-fused synthetic building block ( )-ethyl 2-oxo-2,3,4,5-
tetrahydro-1H-benzo[b]azepine-3-carboxylate (2), but the overall
efficiency suffered due to the modest yield of the initial transfor-
mation (Fig. 1).6 Beyond this application, the possible addition of
amines to these systems could have potential for the preparation
of CDC25 phosphatase inhibitor analogues, such as 3, for the
treatment of cancer.7,8 The current project sought to improve this
transformation, and thus, render these targets more accessible.
Over the past few years, our efforts have focused on the
development of atom-economical,9,10 cost-efficient, and transition
of the intermediate anion
a to the polarizing group. The SNAr
typically involves displacement of an aryl-bound halide by a nucle-
ophile via an addition–elimination mechanism, which is possible
when a strong electron-withdrawing group is situated ortho or
para to the halide. This process is assisted by delocalization of
the negative charge toward the activating group on the aromatic
ring in a Meisenheimer complex. In the current reaction, we have
explored the addition of nucleophiles to several vinylarenes
(styrenes) bearing strong electron-withdrawing groups on the
aromatic ring. The effect is to polarize the double bond such that
addition of a nucleophile can take place at the side chain double
bond terminus. The resulting anion is then stabilized in a Meisen-
heimer-like complex by delocalization into the aromatic ring.
To date, only one report5 has appeared describing nucleophilic
additions to electron deficient styrene double bonds. In this
account, the addition of malonate to 2- and 4-nitrostyrene using
sodium ethoxide in alcohol (equilibrating conditions) gave
moderate yields (72% and 45%, respectively) of the single addition
products, and in the latter case, a substantial quantity (34%) of the
double addition product. We recently utilized this reaction to
prepare 1a, which was converted, using iron in acetic acid, to the
metal-free methods for the synthesis of
a wide variety of
biologically active structural motifs including benzazepines,6 dihy-
dro-quinolinones,11 tetrahydroquinolinones,12 1,3,4-oxadiazoles,13
and pyrazoloquinolinones14 among others.12 Hence, we sought to
develop an efficient route for nucleophilic addition of active
methylene compounds as well as amines to electron deficient
vinylarenes as a route to heterocycle precursors. Nucleophiles do
not normally react with styrene double bonds. However, when
electron-withdrawing groups are present at C2 or C4 of the
aromatic ring, the terminal vinyl carbon exhibits significant
electrophilic character; similar groups at C3 do not activate the
side chain
p bond. We took advantage of this phenomenon and
explored the addition of diethyl malonate anion, generated using
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), to 4-nitrostyrene in
DMF. Under these conditions, the reaction proceeded in moderate
yield, and thus, we endeavored to optimize the conditions and
expand the process.
Initial efforts evaluated various protic and aprotic solvents for
the side chain addition (Table 1) and revealed that refluxing MeCN
⇑
Corresponding author. Tel.: +1 405 744 5952; fax: +1 405 744 6007.
E-mail address: rab@okstate.edu (R.A. Bunce).
http://dx.doi.org/10.1016/j.tetlet.2016.06.033
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

K. K. Gnanasekaran et al. / Tetrahedron Letters 57 (2016) 3190–3193
3191
Table 3
CO2Et
CO2Et
Reactions of 4a–e with malonate donors 5a–b
CO2Et
CO2Et
CO2Et
R
α or Rβ
R
NO2
N
H
CO2Et
CO2Et
O
1 equiv. DBU
R'
R'
+
1a
HO
HO
2
MeCN, reflux
4-6 h
N(CH3)2
X
X
4
5
1
CH3
N
acceptor
1 equiv.
donor
1.5 equiv.
3
NO2
Acceptor
Donor
Product
Yield (%)
97
4a
5a
(R0 = H)
1a
Figure 1. Structures accessible by additions to vinylarenes.
(X = 4-NO2, R = H)
(X = 4-NO2, R, R0 = H)
4a
5b
1b
93
87
85
50
94
74
58
53
(X = 4-NO2, R = H)
(R0 = Me)
(X = 4-NO2, R = H, R0 = Me)
Table 1
Solvent optimization for addition to polarized vinylarenesa
4b
5a
(R0 = H)
1c
(X = 4-NO2, R
a
a
= Me)
= Me)
(X = 4-NO2, R
a
= Me, R0 = H)
, R0 = Me)
CO2Et
CO2Et
4b
5b
(R0 = Me)
1d
(X = 4-NO2, R
(X = 4-NO2, R
a
CO2Et
DBU
+
4c
5a
(R0 = H)
1e
solvent, reflux
(X = 4-NO2, Rb = Me, R0 = H)
CO2Et
O2N
(X = 4-NO2, Rb = Me)
O2N
4a
4d
5a
(R0 = H)
1f
5a
1a
(X = 2-NO2, R = H)
(X = 2-NO2, R, R0 = H)
Entry
Solvent/T (°C)
Time (h)
Yield (%)
4d
5b
(R0 = Me)
1g
(X = 2-NO2, R = H)
(X = 2-NO2, R = H, R0 = Me)
1
2
3
4
5
DMF/60
MeCN/82
DMSO/60
EtOH/78
THF/67
2
4
2
18
10
56
93
48
25
62
4e
5a
(R0 = H)
1h
(X = 4-CN, R = H)
(X = 4-CN, R, R0 = H)
4e
5b
(R0 = Me)
1i
(X = 4-CN, R = H)
(X = 4-CN, R = H, R0 = Me)
a
Reactions were monitored by TLC and subjected to aqueous work-up to give the
isolated yields reported.
Finally, the stoichiometry of the nucleophile was refined. While
exploratory experiments utilized 2 equiv of malonate, 1.5 equiv
also afforded good results. Further decreases, however, resulted
in significantly diminished yields. Thus, the optimized conditions
utilized 1 equiv of the vinylarene acceptor, 1.5 equiv of the
nucleophile donor, and 1 equiv of DBU.
With a standard protocol established, the scope of the reaction
using various nucleophiles and substrates was investigated
(Table 3). The optimized procedure worked well for 4-nitrostyrene
(4a) with anions derived from diethyl malonate (5a) and diethyl
methylmalonate (5b), giving excellent yields of products in
4–6 h. Substitution on the vinyl group was also examined using
provided the best results. Reactions in DMF and DMSO at 60 °C
proceeded faster, but these solvents proved more difficult to
remove from the product. Other media such as EtOH and THF at
their respective boiling points slowed the process and afforded
lower yields.
Other potential bases for the reaction were also examined.
Apart from DBU, tetramethylguanidine (TMG), 4-dimethy-
laminopyridine (DMAP), imidazole, 1,4-diazabicyclo[2.2.2]octane
(DABCO), sodium hydride (NaH) and potassium tert-butoxide
(t-BuOK) were screened. These experiments confirmed that DBU
was the base of choice for this transformation. Additionally, the
highest yields were obtained using 1.0 equiv of DBU relative to
the vinylarene (Table 2).
a
-methyl-4-nitrostyrene (4b) and b-methyl-4-nitrostyrene (4c),
and as expected, steric factors were found to be important in the
reaction. Introduction of a methyl group to the aromatic moiety
a
(viz. 4b) had little effect on the efficiency of addition, while place-
ment of a methyl b to the arene at the site of attack (viz. 4c)
allowed addition by only unhindered nucleophiles such as 5a.
Active methylene donors were also successfully added to 2-nitros-
tyrene (4d). In this series, the yield remained high for 5a, but was
lower for 5b, presumably due to a steric hindrance created by the
ortho nitro group. This steric interaction could impede approach of
the nucleophile or distort the planarity of the system, which would
decrease the electrophilicity of the side chain double bond. Finally,
modification of the substrates to include 4-cyano- and 4-ethoxy-
carbonyl-substituted aromatic rings met with only limited success.
In the case of 4-cyano-substituted acceptor 4e, malonate
nucleophiles added cleanly, but for the 4-ethoxycarbonyl-derived
substrate 4f, it was not possible to isolate acceptable yields of side
chain adducts due to competitive attack at the ester carbonyl.
The transformation was further extended to the addition of
methyl 2-oxocyclopentanecarboxylate (6). The enolate of this rela-
tively hindered b-ketoester reacted with 4a, 4b, 4d, and 4e in MeCN
(reflux, 4–6 h) to give 7a (81%), 7b (82%), 7d (80%), and 7e (51%),
Table 2
Optimization of base for addition to polarized vinylarenes
CO2Et
CO2Et
CO2Et
base
+
MeCN, reflux
4 h
CO2Et
O2N
O2N
4a
5a
1a
Yield (%)
Entry
Base
Equiv (rel to vinylarene)
1
2
3
4
5
6
7
8
9
10
TMG
DMAP
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.2
0.5
0.7
36
28
45
93
80
65
23
26
59
75
Imidazole
DBU
DABCO
NaH
t-BuOK
DBU
DBU
DBU

3192
K. K. Gnanasekaran et al. / Tetrahedron Letters 57 (2016) 3190–3193
Table 4
Table 5
Reactions of 4a, b, d and e with cyclic b-ketoester 6
Reactions of 4a, b and d with amine donors 8–10
O
R
R
R
O
O
R
N
N
O
1 equiv. DBU
+
HN
HN
CO2Me
R
MeCN, reflux
8
9
11
MeO2C
O2N
O2N
X
4-6 h
1 equiv. DBU
X
4
6
7
+
acceptor
1 equiv.
donor
1.5 equiv.
MeCN, reflux
12-18 h
O2N
4
12
13
H
N
R
acceptor
1 equiv.
Acceptor
Product
Yield (%)
81
H2N
4a
7a
(X = 4-NO2, R = H)
(X = 4-NO2, R = H)
10
O2N
donor
1.5 equiv.
4b
7b
82a
80
(X = 4-NO2, R
a
= Me)
(X = 4-NO2, Ra = Me)
Acceptor
Donor
Product
11a
Yield (%)
95
4d
7d
(X = 2-NO2, R = H)
(X = 2-NO2, R = H)
4a
8
4e
7e
51
(4-NO2, R = H)
(4-NO2, R = H)
(X = 4-CN, R = H)
(X = 4-CN, R = H)
4a
9
12a
(4-NO2, R = H)
93
82
86
84
77
85
88
78
a
(4-NO2, R = H)
Isolated as
a mixture of diastereomers with the following relative
configurations: ( )-R,S = 39%; ( )-R,R = 43%.
4a
10
8
13a
(4-NO2, R = H)
(4-NO2, R = H)
4b
11b
(4-NO2, R = Me)
(4-NO2, R = Me)
respectively (Table 4). Notably, product 7b, derived from addition of
6 to 4b (Ra = Me), consisted of two diastereomers in a nearly 1:1
ratio. Separation by preparative TLC gave isomer A (39%), an oil,
and isomer B (43%), a white solid. A crystal of isomer B was obtained
for X-ray analysis by slow diffusion of pentane into an ether solu-
tion of the two diastereomers. Solution of the structure (Fig. 2)
showed isomer B to be racemic methyl (R,R)-2-oxo-1-[2-(4-nitro-
4b
9
12b
(4-NO2, R = Me)
(4-NO2, R = Me)
4b
10
8
13b
(4-NO2, R = Me)
(4-NO2, R = Me)
4d
11d
(2-NO2, R = H)
(2-NO2, R = H)
phenyl)propyl]cyclopentanecarboxylate
owing assignment of isomer A as ( )-(R,S)-7b.
[( )-(R,R)-7b],
all-
4d
9
12d
(2-NO2, R = H)
(2-NO2, R = H)
Further experiments explored the feasibility of hydroaminating
polarized alkenes 4a–f with morpholine (8), piperidine (9) and
benzylamine (10). Using 1.5 equiv of the amines, several of these
additions also proceeded in high yields, but longer reaction times
(12–18 h) were required relative to those involving carbon
nucleophiles. Control experiments, with and without added base,
established that DBU was also required for good conversions in
4d
10
13d
(2-NO2, R = H)
(2-NO2, R = H)
these reactions. Additions of 8–10 to nitrostyrenes 4a and 4d gave
11–13a and 11–13d, respectively, in 78–95% yields (Table 5). On
the other hand, these same robust conditions promoted rapid poly-
merization and/or degradation of the 4-cyano- and 4-ethoxycar-
bonyl substrates 4e and 4f. For the side chain substituted
acceptors, addition to
a-methyl-4-nitrostyrene (4b) gave adducts
11–13b in 77–86% yields (Table 5), while b-methyl-4-nitrostyrene
(4c) failed to react, presumably due to steric congestion at the site
of attack. In the absence of activating groups, hydroamination
processes normally require transition metal catalysis.15–23
The presumed mechanism for the reaction of 4a with 5a to give
1a is depicted in Figure 3. Deprotonation of 5a using DBU would
generate DBU-H+ and carbanion 14. In the presence of 4a, 14 would
add to the side chain double bond to generate adduct 15. Interme-
diate 15 is stabilized in much the same manner as a Meisenheimer
complex, but does not have a leaving group at the site of attack,
which would allow regeneration of the side chain double bond.
Abstraction of the proton from DBU-H+ (or excess 4a) by 15 would
then deliver the required single addition product 1a. When the cur-
rent reaction was performed using 0.2 equiv of DBU in DMF at
60 °C, a very poor yield of 1a was obtained and more of the double
addition product 17 was isolated. A likely explanation for this
observation is that intramolecular proton transfer from the active
methylene site to the benzylic anion in 15 is faster than
intermolecular proton abstraction from the dilute DBU-H+. This
would generate 16, which would then add a second molecule of
4a and protonate to form 17. Experiments to optimize the
stoichiometry of DBU indicated that a full equivalent of this
base relative to the vinylarene gave the highest conversion to the
Figure 2. X-ray structure of ( )-(R,R)-7b (CCDC 1454607). Note: The unit cell for
( )-(R,R)-7b contained one molecule of the R,R (top) and one molecule of the S,S
enantiomer (bottom).

K. K. Gnanasekaran et al. / Tetrahedron Letters 57 (2016) 3190–3193
3193
CO2Et
values for the synthesis of building blocks to assemble the
backbone of several families of drug candidates.
CO2Et
DBU
4a
+
DBU-H+
CO2Et
CO2Et
Acknowledgments
5a
14
CO2Et
CO2Et
The authors are grateful to NSF (BIR-9512269), the Oklahoma
State Regents for Higher Education, the W. M. Keck Foundation,
and Conoco, Inc. for funding to establish the Oklahoma Statewide
Shared NMR Laboratory. The College of Arts and Sciences at OSU
is also acknowledged for funds to purchase a new 400 MHz NMR
for this facility. We wish to further thank the NSF (CHE-0130835)
and the University of Oklahoma for funding to establish the OU
Chemical Crystallography Laboratory. Finally, we are pleased to
acknowledge. Dr. Douglas R. Powell for his skill in acquiring the
X-ray crystal structure.
CO2Et
CO2Et
H
H
O2N
O2N
15
DBU-H+ or
excess 5a
~H+
CO2Et
CO2Et
CO2Et
DBU-H+ or
CO2Et
H
excess 5a
O2N
O2N
1a
16
Supplementary data
CO2Et
1) 4a
2) H+
Supplementary data (experimental procedures, spectral data for
the products, and details of the X-ray structure determination for
CCDC 1454607) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2016.06.033.
CO2Et
O2N
NO2
17
Figure 3. Presumed mechanism for additions to electron-deficient vinylarenes.
References and notes
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faster, the presence of higher concentrations of DBU-H+ along with
excess 4a would make more protons available from intermolecular
sources to stop the reaction at the single addition stage. Of course,
the intramolecular proton transfer and double addition would not
be an issue for reactions involving alkylated malonates such as 5b.
In conclusion, nucleophilic additions of enolates and amines to
electron deficient vinylarenes substituted in the ortho or para posi-
tions by nitro, cyano, and ethoxycarbonyl have been explored and
optimized. This reaction proceeded cleanly for nitro compounds 4a
and 4d with malonates 5a and 5b, giving better yields than earlier
reports without the need for added metal catalysts. The reaction is
operationally simple and proceeds to give high yields in refluxing
MeCN with DBU base after 4–6 h. Additions of the hindered b-
ketoester 6 were also successful. For cyano compound 4e, only
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