Chloro/bromotrimethylsilane-Cu(NO3)2·3H2O: Safe and efficient reagent system for the decarboxylative ipso-nitration and dibromination of cinnamic acids

Article abstract of DOI:10.1016/j.tetlet.2017.06.017

Further synthetic potential of halotrimethylsilane-nitrate salt mixture is revealed. A mixture of TMSX-Cu(NO₃)₂·3H₂O system is found to be an efficient reagent system for both the decarboxylative nitration (ipso-nitration) when X?=?Cl, and dibromination of cinnamic acids, with X?=?Br, under mild conditions. The reactions are safe and simple, affording the corresponding products (E)-β-nitrostyrenes, and anti-2,3-dibromo-3-phenylpropanoic acids in high yields with high selectivity in a relatively short time. Use of hazardous and toxic nitrating systems such as acetyl nitrate and brominating agents such as molecular bromine can be avoided.

Full text of DOI:10.1016/j.tetlet.2017.06.017

Accepted Manuscript
Chloro/Bromotrimethylsilane-Cu(NO ) .3H O: Safe and Efficient Reagent Sys-
3
2
2
tem for the Decarboxylative ipso-Nitration and Dibromination of Cinnamic
Acids
Sahar Roshandel, Laxman Gurung, Thomas Mathew, G.K. Surya Prakash
PII:
S0040-4039(17)30736-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.06.017
TETL 49009
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Accepted Date:
16 May 2017
6 June 2017
Please cite this article as: Roshandel, S., Gurung, L., Mathew, T., Prakash, G.K.S., Chloro/Bromotrimethylsilane-
Cu(NO ) .3H O: Safe and Efficient Reagent System for the Decarboxylative ipso-Nitration and Dibromination of
3
2
2
Cinnamic Acids, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.06.017
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Graphical Abstract
Chloro/Bromotrimethylsilane-Nitrate Salt:
Safe and Efficient Reagent System for the
Decarboxylative ipso-Nitration and
Dibromination of Cinnamic Acids
Leave this area blank for abstract info.
Sahar Roshandel, Laxman Gurung, Thomas Mathew,* and G. K. Surya Prakash*

Tetrahedron Letters
1
Tetrahedron Letters
journal homepage: www.els evier.com
Chloro/Bromotrimethylsilane-Cu(NO ) .3H O: Safe and Efficient Reagent System for
3
2
2
the Decarboxylative ipso-Nitration and Dibromination of Cinnamic Acids
Sahar Roshandel, Laxman Gurung, Thomas Mathew,∗ and G. K. Surya Prakash∗
Loker Hydrocarbon Research Institute and Department of Chemistry, University of Southern California, Los Angeles, CA 90089-1661, USA
ARTICLE INFO
Article history:
Received
ABSTRACT: Further synthetic potential of halotrimethylsilane-nitrate salt mixture is revealed.
A mixture of TMSX-Cu(NO .3H O system is found to be an efficient reagent system for both
the decarboxylative nitration (ipso-nitration) when X = Cl, and dibromination of cinnamic acids,
3
)
2
2
Received in revised form
Accepted
with X = Br, under mild conditions. The reactions are safe and simple, affording the
corresponding products (E)-β-nitrostyrenes, and anti-2,3-dibromo-3-phenylpropanoic acids in
Available online
high yields with high selectivity in a relatively short time. Use of hazardous and toxic nitrating
systems such acetyl nitrate and brominating agents such as molecular bromine can be avoided.
Keywords:
ipso-Nitration
Cinnamic Acid
2
009 Elsevier Ltd. All rights reserved.
β
-Nitrostyrenes
Halotrimethylsilane
Copper(II) Nitrate
—
——
∗
∗
Corresponding author. e-mail: tmathew@usc.edu (Thomas Mathew)
Corresponding author. e-mail: gprakash@usc.edu (G.K. Surya Prakash)

2
Tetrahedron Letters
Introduction
bromotrimethylsilane (TMSBr) and much lower amount of the
nitrate salt, synthesis of the corresponding anti-2,3-dibromo-3-
phenylpropanoic acids was achieved in excellent yields, avoiding
the use of molecular bromine or other hazardous brominating
agents. Therefore, the presence of appropriate halotrimethylsilane
makes the reaction safe and efficient.
A suitable combination of nitrate salts and trimethylsilyl
halides forms an efficient reagent system, which has been
successfully used in various organic synthetic transformations
1
such as nitration of aromatics and olefins, oxidative nitration of
2
olefins to 2-nitroketones, deoximation of aldoximes/ketoximes,
3
4
In order to find the most cost effective and efficient nitrating
agent, a series of different nitrate salts was screened in the
presence of TMSCl using cinnamic acid for the ipso-nitration
(Table 1). The reaction mixture was stirred for 2 h at 100 °C and
analyzed by GC-MS. Since bismuth(III) nitrate was shown to be
an efficient ipso-nitrating agent for the ipso-nitration of
non-aqueous diazotization etc. During our studies on the ipso-
substitution of arylboronic acids, we reported that a mixture of
nitrate salt and chlorotrimethylsilane (TMSCl) is an effective and
highly selective nitrating agent for the ipso-nitration of
5
arylboronic acids. This combination was later found to be an
6
effective reagent system for the oxidation of sulfides/sulfoxides,
a
2
6
6a
arylboronic acids, we conducted the reaction initially with
bismuth(III) nitrate. While bismuth(III) and ammonium nitrates
did not lead to the desired product, small amount of the nitro
product was observed when zinc(II) nitrate or nickel(II) nitrate
was employed. However, sodium nitrate and potassium nitrate
gave 20% and 45% conversion respectively, which could not be
improved much with further attempts. Interestingly, when
silver(I) nitrate and copper(II) nitrate were employed,
quantitative conversion to the desired product was observed.
oxidative chlorination of thiols/disulfides, and α-chlorination of
acetophenones. Similarly, ipso-nitrosation of arylboronic acids
6
b
6c
was achieved using TMSCl-nitrite salt combination. Such
promising results obtained by employing metal nitrates and
trimethylsilyl halides motivated us to further explore the scope
and generality of this reagent system in achieving the preparation
of nitroolefins from α,β-unsaturated carboxylic acids. Synthesis7
of nitroolefins has been one of the most extensively studied
reactions as they are building blocks of many useful biological
and pharmaceutical compounds, and are widely used as
3 2 2
However, being less expensive, Cu(NO ) ⋅3H O was chosen as
the nitrating agent of choice for further studies of the ipso-
nitration of cinnamic acids.
8
intermediates in many reactions such as Michael reaction, Diels-
9
10
Alder reaction, Friedel-Crafts alkylation etc. Consequently, the
efficacy in synthesizing such compounds is of great importance
in organic chemistry.
Table 1. Effect of Various Nitrate Salts on the ipso-Nitration
of Cinnamic Acid
Nitroolefins can be conventionally obtained from the Henry
11,12
reaction
carboxylic acids by employing nitric acid
or could be synthesized from α,β-unsaturated
13-15
or gaseous nitrogen
2
source. Alternative methods for synthesizing
1
6
dioxide as a NO
1
7-19
nitroolefins include employing tert-butyl nitrite
and transition
metal salts such as silver(I) nitrite in conjunction with TEMPO,
23
20
2
1,22
iron(III) nitrate
and cerium(IV) ammonium nitrate (CAN).
a
Entry
Nitrate Salts
Conversion (%)
The latter methods have reportedly been used to achieve a better
yield, avoiding harsh conditions, and other difficulties associated
with handling gaseous reagents. However, there are limitations
associated with the use of such methods due to the cost as well as
toxic nature of some of the reagent components. Therefore, we
searched for more economically viable and safer reagent system.
We developed the present protocol intrigued by recently reported
1
2
3
4
5
6
7
8
Bi(NO ) ⋅5H O (3equiv)
2
no reaction
3
3
b
NaNO
KNO
NH NO
Zn(NO ⋅xH
Ni(NO ⋅6H
AgNO
Cu(NO ) ⋅3H O (3.5 equiv)
3
(6 equiv)
45
20
b
3
(6 equiv)
4
3
(3 equiv)
Trace
3
3
)
2
2
O (3 equiv)
3
)
2
2
O (3 equiv)
13
2
4
nitration of cinnamic acids using anhydrous copper(II) nitrate.
We realized that anhydrous Cu(NO is not easily commercially
accessible and drying the hydrate Cu(NO .3H O is not safe and
results in decomposition to NO and CuO. The reported reaction
3
(3 equiv)
100
100
3 2
)
3
2
2
3
)
2
2
a
b
Conversion obtained by GC-MS analysis. The reactions were conducted
2
at both 50 °C and 100 °C and many side products were observed.
was shown to be affording good yields only with cinnamic acid
derivatives bearing electron donating groups in the ring. Since
the mechanism shown is ambiguous, we decided to carry out the
Optimization of the reaction conditions was carried out by
conducting reactions of cinnamic acid in dry acetonitrile at 100
3 2 2
reaction with Cu(NO ) .3H O, which is commercially available
and make the reaction more feasible and practically applicable.
When the reaction of cinnamic acid was conducted with
°
C and monitoring the progress of the reaction by GC-MS (Table
). Based on the GC-MS data, we found that benzaldehyde was
formed as a side product, which was minimized by increasing the
amount of Cu(NO ⋅3H O. After a series of trials, by using 3.5
equivalents of Cu(NO ⋅3H O, we were able to achieve
2
3 2 2
Cu(NO ) .3H O alone, the desired ipso-nitration reaction did not
occur smoothly as expected. Interestingly, in a very recent paper,
)
3 2
2
2
5
Nenajdenko et al. detailed the ipso-nitration of β-bromostyrenes
in high yield with Z-selectivity using Fe(NO .9H O in excess,
in which NO radical formed in situ is the nitrating species.
While they used Cu(NO .3H O, they could achieve the product
)
3 2
2
3
)
3
2
quantitative conversion of cinnamic acid to β-nitrostyrene
without the formation of benzaldehyde (entry 6, Table 2).
2
3
)
2
2
only in 40-55% yield. Based on the protocol for the ipso-nitration
of arylboronic acids using TMSX-metal nitrate combination
5
reported by us a decade ago, we decided to apply a similar
Table 2. Optimization of the Reaction Conditions
strategy to solve this problem. Herein, we report a simple,
economic, and highly efficient method for the decarboxylative
nitration (ipso-nitration) of cinnamic acids that affords (E)-β-
nitrostyrenes in good to excellent yields. The reaction is feasible
with cinnamic acids with both electron donating and electron
withdrawing groups in the ring. Also, by using excess amount of
a
Cu(NO
3
)
2
⋅3H
2
O
TMSCl
(equiv)
Conversion (%)
Entry
1
2a
PhCHO
(equiv)

Tetrahedron Letters
3
1
2
3
4
5
6
7
1.2
1.9
2.2
2.5
3.0
3.5
3.5
1.2
1.2
1.2
1.2
1.2
1.2
0.9
0
0
0
0
0
0
0
95
96
5
4
4
3
1
0
1
anticipated. Regardless of their electronic nature, o-substitution
slightly diminishes the rate of the reaction probably due to steric
hindrance, resulting in the formation of the corresponding
96
aldehyde as
a
side product. Reaction of 4-N,N-
97
dimethylaminocinnammic acid resulted in a mixture of products
that could not be separated.
99
100
98
However, when the nitration reaction was conducted with
TMSBr, along with the nitrated product, olefinic dibromination
was also observed. Interestingly, on increasing the amount of
TMSBr, we noticed that the yield of dibromo derivative
increased. Therefore, we used TMSBr in excess amount
8
9
3.5
3.5
0.6
0
0
95
18
2
1
81
a
Conversion obtained by GC-MS.
3 2 2
compared to Cu(NO ) ⋅3H O to obtain significant enhancement
in the olefinic dibromination and maximize the yield of the
dibrominated product. The optimized conditions using four
equivalents of TMSBr and one-half equivalent of
3 2 2
Although three equivalents of Cu(NO ) ⋅3H O gave an
excellent conversion (99%), the conditions of entry 6 in Table 2
were chosen as it led to the formation of the product in almost
pure form. By simple aqueous workup followed by extraction
and evaporation of the solvent, the product could be easily
isolated in pure form without further purification. To explore the
necessity of TMSCl as the reagent partner, a few reactions were
also carried with varying amounts of TMSCl. Lower amounts of
TMSCl resulted in slight decline in the yield of the desired
product (Table 2, entry 7-8). However, when the reaction was
conducted in the absence of TMSCl, the conversion sharply
dropped to 18% (Table 2, entry 9), clearly demonstrating the
crucial role of TMSCl in improving the efficacy of the reactions
significantly.
3 2 2
Cu(NO ) ⋅3H O with respect to the cinnamic acid substrate
resulted in the formation of the corresponding anti-2,3-dibromo-
3-phenylpropanoic acid in good to excellent yields (Table 4).
Therefore, it is obvious that TMSBr can serve as an efficient
brominating agent as well in this reaction. However, it is worth
noting that the presence of Cu(NO
reaction since no reaction occurred in the absence of
Cu(NO ⋅3H O. Although bromination of cinnamic acids can be
3 2 2
) ⋅3H O is vital for this
3
)
2
2
simply carried out with molecular bromine, we believe that the
present method is much safer and less hazardous, underscoring
the importance of such protocols. Similar modification of the
conditions was carried out using TMSCl; however, the reaction
was not clean providing only some amount of the dichlorinated
product.
Table 3. ipso-Nitration of Cinnamic Acids to the
Corresponding β-Nitrostyrenes
Table 4. Bromination of Cinnamic Acids
2
a (89%)
d (60%)
2b (96%)
2e (92%)
2c (85%)
2f (97%)
3
a (92%)
d (85%)
3b (95%)
3e (95%)
3c (95%)
3f (77%)
2
3
a
2
g (96%)
2h (98%)
2k (98%)
2i (66%)
a
a
3
g (89%)
3h (96%)
3i (91%)
b
2
j (90%)
2l (mixture)
a
a
b
GC-MS conversion. 0.2 equiv TMSCl, reaction time was 1h.
Reaction time was 3 h.
Similarly, in the case of halogenated substrates also, we
were able to obtain excellent yields (2e-g). To the best of our
knowledge, among all methods of ipso-nitration of cinnamic
acids reported, the present protocol is the one that provides β-
nitrostyrenes in high yields from cinnamic acids bearing both
electron donating and electron withdrawing groups. The
proposed reagent system was found to be effective for other
similar substrates such as 3-(1-naphthyl) acrylic acid (2k) to
afford the corresponding nitroolefin in excellent yield. However,
aliphatic conjugated carboxylic acids such as acrylic acid and 1-
cyclopentene carboxylic acid did not undergo the reaction as
Plausible mechanisms for both reactions are shown in
Scheme 1. The formation of the cinnamate salt of copper was
noticed by the appearance of its typical bluish green color as
2
7
generally observed. Moreover, it is well known that TMSCl
reacts with nitrate salts and generate reactive trimethylsilyl
nitrate (TMS-O-NO ) species. In our previous studies, we have
2
shown that TMS-O-NO (formed in situ from halotrimethylsilane
2
and nitrate salt) is an efficient nitrating agent for both the ring
1
nitration of arenes (in the presence of Lewis acids) and the ipso-
5
nitration of boronic acids. In the present case also, we envisage a

4
Tetrahedron Letters
similar pathway. TMSONO
2
being an efficient precursor for
+
Acknowledgments
-
2
both a nucleophile (TMS-O ) and an electrophile (NO ),
nucleophilic addition at the Cu center leads to decarboxylation
followed by electrophilic ipso-nitration with the retention of
configuration, resulting in the selective formation of the E-isomer
of β-nitrostyrenes. Based on the amount of TMSBr required for
bromination, it is clear that olefinic dibromination occurs by the
Support by the Loker Hydrocarbon Research Instituted is
gratefully acknowledged.
Supplementary Material
1
salt via the formation of NO Br giving the anti-2,3-dibromo-3-
,2-addition of bromine generated in situ from TMSBr-nitrate
Supplementary data associated with this article can be found
in the online version.
2
phenylpropanoic acid (by comparison of the spectral data with
those of the authentic samples) in excellent yields.
References
1
2
.
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O
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O
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3
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Ph
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δ− δ+
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-
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2
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NO
δ+
2
O
TMS
NO
2
Cu OTMS
NO
2
Ph
Ph
O
+
Ph
-CO
2
(
c) Prakash GKS, Gurung L, Schmid PC, Wang F, Thomas TE,
+
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2
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9
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.
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Cu(OTMS)
2
+
2HCl
2 2
CuCl .H
2
O + (TMS) O
B. Mechanism for the dibromination of cinnamic acids
2
011;133:15212.
Cu(NO
3
)
2
+
2TMSBr
TMSBr
2
TMSO NO
+
CuBr
O
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Y-H, Wang C-C, Yao C-F. Tetrahedron. 2009;65:2436.
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2
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2
+
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2
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(TMS)
2
2
008;10 (7):1449.
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13. Das JP, Sinha P, Roy S. Org Lett. 2002;4:3055.
2
NO
2
Br
+
2NO
O
2
1
O
Br
1
4. Ramgopal S, Ramesh K, Chakradhar A, Reddy NM, Rajanna KC.
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+
Br
2
Ph
OH
Ph
OH
Br
1
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1
1
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2
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1
1
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In conclusion, we have developed a simple and efficient
protocol using TMSX-Cu(NO
ipso-nitration (X=Cl) and olefinic dibromination of cinnamic
acids (X=Br). Cu(NO ⋅3H O is commercially available at low
3 2 2
) ⋅3H O reagent system for the
2
22. Naveen T, Maity S, Sharma U, Maiti D. J Org Chem.
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cost and is nonhazardous. Although nitration occurs with
TMSBr, greater reactivity of TMSBr results in the formation of a
mixture of both ipso-nitro and dibromo products. Therefore,
TMSCl was selected for the nitration reaction. The reaction
occurs under mild conditions in a relatively short time affording
the desired products in good to excellent yields and selectivity.
2
2
2
3 2 2
While excess amount of Cu(NO ) ⋅3H O drives the reaction of
cinnamic acids towards the ipso-nitration, excess amount of
TMSBr results in the formation of anti-2,3-dibromo-3-
phenylpropanoic acids.

Tetrahedron Letters
5
Chloro/Bromotrimethylsilane-
Cu(NO ) .3H O: Safe and Efficient
Reagent System for the
3
2
2
Decarboxylative ipso-Nitration and
Dibromination of Cinnamic Acids
Sahar Roshandel, Laxman Gurung, Thomas
Mathew,∗ and G. K. Surya Prakash∗
Loker Hydrocarbon Research Institute and
Department of Chemistry, University of Southern
California, Los Angeles, CA 90089-1661, USA
Highlights
•
•
•
•
•
A safe and convenient decarboxylative
nitration method for cinnamic acids
Chlorotrimethylsilane-Cu(NO
an efficient nitrating system
Decarboxylative nitration is
stereoselective
3
)
2
.3H O is
2
Bromotrimethylsilane- Cu(NO
3
)
2
.3H O is
2
an efficient brominating system
The nitration and bromination methods
are versatile for a variety of cinnamic
acids
—
——
∗ Corresponding author. e-mail: tmathew@usc.edu (Thomas
Mathew)
∗ Corresponding author. e-mail: gprakash@usc.edu (G.K. Surya
Prakash)