Aryl Nitriles from Alkynes Using tert -Butyl Nitrite: Metal-Free Approach to C≡C Bond Cleavage

Article abstract of DOI:10.1021/acs.orglett.6b00147

Alkyne C≡C bond breaking, outside of alkyne metathesis, remains an underdeveloped area in reaction discovery. Recently, nitrogenation has been reported to allow nitrile formation from alkynes. A new protocol for the metal-free C≡C bond cleavage of terminal alkynes to produce nitriles is reported. This method provides an opportunity to synthesize a vast range of nitriles containing aryl, heteroaryl, and natural product derivatives (38 examples). In addition, the potential of ^tBuONO to act as a powerful nitrogenating agent for terminal aryl alkynes is demonstrated. (Figure Presented).

Full text of DOI:10.1021/acs.orglett.6b00147

Letter
pubs.acs.org/OrgLett
Aryl Nitriles from Alkynes Using tert-Butyl Nitrite: Metal-Free
Approach to CC Bond Cleavage
Uttam Dutta,†,‡ David W. Lupton,*,‡,§ and Debabrata Maiti*,†,‡
†Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai-400 076, India
‡IITB-Monash Research Academy, IIT Bombay, Powai, Mumbai-400076, India
§School of Chemistry, Monash University, Clayton 3800, Victoria, Australia
S
* Supporting Information
ABSTRACT: Alkyne CC bond breaking, outside of alkyne
metathesis, remains an underdeveloped area in reaction
discovery. Recently, nitrogenation has been reported to allow
nitrile formation from alkynes. A new protocol for the metal-
free CC bond cleavage of terminal alkynes to produce
nitriles is reported. This method provides an opportunity to
synthesize a vast range of nitriles containing aryl, heteroaryl, and natural product derivatives (38 examples). In addition, the
t
potential of BuONO to act as a powerful nitrogenating agent for terminal aryl alkynes is demonstrated.
Scheme 1. Transformation of Alkynes
lkyne derivatizations are widely used in organic synthesis.
ASome important transformations of alkynes include
addition1 and hydration reactions,2 while alkynes have been
employed in industrially useful processes such as the Pd-
catalyzed Wacker oxidation to produce 1,2-diketones,3 and the
Sonogashira coupling to achieve C(sp)−C(sp2) bond for-
mation.4 Academically and industrially, perhaps the most widely
used reaction is the (3 + 2) cycloaddition (click chemistry).5 In
the modern era, fragmentation of alkynes has received
increasing attention. For example carboxylic acids have been
prepared by the cleavage of a carbon−carbon triple bond,6
while alkyne metathesis is the most important reaction within
this class.7
Although reactions involving CC bond cleavage are
difficult owing to high bond energy, reaction design using
this event is possible. Recently, Jiao and co-workers reported an
unprecedented silver catalyzed synthesis of nitriles from alkynes
using TMS-N3 as the nitrogenating reagent (Scheme 1, eq 1).8
The potential utility of this new entry to nitrile9 is significant
with the nitrile group prevalent in natural products,10 drug
molecules,11 dyes,12 and in the polymer industry.13 Specifically,
more than 30 nitrile-containing drugs have been approved for
the treatment of depression, breast cancer, and Parkinson’s
disease, while 20 more are in clinical trials.14 In addition nitrile
groups can be used as a synthetic precursor to install acids,
amides, ketones, etc. or as directing groups for remote C−H
activation through weak coordination.15 Yanada reported a
related CC cleavage by exploiting TMS-N3 as the nitro-
genating agent; however, this reaction is designed to cleave
both internal and terminal alkynes (eq 2).16
plague reactions with azides, defining the first metal-free
approach to aryl nitriles from terminal alkynes.
Initial investigations were carried out with phenyl acetylene
to identify optimal conditions. Under aerobic conditions
exploiting quinoline-N-oxide as oxidant, and at temperatures
suited to the homolysis of tert-butyl nitrite, we were pleased to
form benzonitrile in 30% yield (Table 1, entry 1).
Subsequently, variation of oxidant showed that 2-picoline-N-
oxide can produce the desired cyanobenzene in improved yield
(Table 1, entry 2). Though the reaction is compatible with
nonpolar aprotic solvent (Table 1, entries 1−4), THF was
found to be the best. While yield has decreased under an
oxygen atmosphere, it was drastically improved when the
reaction was carried out under inert atmosphere (Table 1, entry
Following our recent success with α-trifluoromethylation17
and oxynitration18 of alkynes, we planned to achieve a related
terminal alkyne nitrogenation using tert-butyl nitrite (eq 3).19
Such a strategy would address safety and cost concerns that can
Received: January 16, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00147
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Organic Letters
Letter
Table 1. Optimization of Reaction Conditions
Scheme 2. Synthesis of Nitriles from Arylacetylenes
a
entry
solvent
oxidant (equiv)
condition
yield (%)
1
DCE
DCM
DCE
THF
MeOH
DMSO
THF
THF
THF
THF
THF
A (2)
B (2)
B (2)
B (2)
B (2)
B (2)
B (2)
B (2)
B (2)
B (2)
B (2)
air
air
air
air
air
air
air
air
air
O2
N2
30
35
39
45
<1
<1
25
32
45
10
2
3
4
5
6
7
8
9
10
11
b
76 (70)
a
b
Yield calculated by GC except as noted. Isolated yield.
11). This may well be due to inhibition of alkyne oxidation
under an inert atmosphere.
After obtaining the optimized conditions, we examined the
substrate scope with differentially substituted phenylacetylenes
(Scheme 2). Electron-rich 3-methyl, 4-methyl-, and 4-tert-butyl
phenylacetylenes gave the desired product in 65%, 68%, and
71% yields, respectively (2b, 2c, and 2d). The expected nitriles
were obtained from phenanthrene (2e and 2f, 88% and 70%)
and pyrene (2g, 95%) acetylenes. Various functional moieties
were tolerated under the standard reaction conditions and
resulted in formation of nitriles (e.g., 4-OMe, 2h, 75%; 2-Me-4-
OMe, 2i, 77%; 4-pentoxy, 2k, 78%; 4-Br, 2l, 82%). Strongly
electron-withdrawing cyano phenylacetylenes produced dini-
triles in preparatively useful yields (2m and 2n). Notably, esters
(2p, 70%; 2q, 62%; 2r, 82% and 2s, 66%), amides (2t, 69% and
2u, 78%), and ketones (2v, 78% and 2w, 81%) remained
unaffected.
a
b
6 h. Yield based on recovered starting material.
Scheme 3. Synthesis of Heterocyclic Nitriles
We have also tested the present reaction conditions with
various heterocyclic alkynes (Scheme 3). Heterocyclic nitriles
derived from quinoline and isoquinoline were formed in 67−
86% yields (3a−3d). Similarly sulfur-containing benzothio-
phene (3e and 3f) and benzofuran (3g and 3h) nitriles were
prepared in 63−81% isolated yields. Finally pyrazole-containing
alkynes were converted to the nitriles (3i and 3j).
Next, the nitrogenation of alkynes was examined in the
context of natural product derivatives. Specifically we focused
our attention on application to various natural product derived
esters. Thus, the alkynyl ester of vitamin-E was converted to
nitrile 4a in 45% yield, while the estrone derivative 4b was
prepared in 39% isolated yield (Scheme 4). Finally oleic acid
derivative 4c was prepared in 68% isolated yield.
a
b
6 h. Yield based on recovered starting material.
Despite our best efforts, different internal alkynes including
prop-1-ynylbenzene, 1,2-diphenylethyne, ethyl-3-phenylpro-
piolate, trimethyl(phenylethynyl)silane and terminal alkyl
alkynes such as oct-1-yne, ethynylcyclopentane, prop-2-
ynylbenzene failed to deliver nitriles under standard reaction
conditions.
5 was examined. We expected that a mixture of product
formation is likely due to the presence of multiple alkynes, and
the ratio will potentially clarify the roles of the electronic
substituent on the reaction. With 1,3-diethynylbenzene (5)
under standard reaction conditions, the monocyanoarene 5a
was the major product (58%) suggesting that the second
To further expand the scope of this reaction and gain
mechanistic insight, the nitrogenation of 1,3-dialkynyl benzene
B
DOI: 10.1021/acs.orglett.6b00147
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Organic Letters
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Based on these observations, a plausible mechanism has been
outlined (Scheme 7). First in situ homolysis of tert-butyl nitrite
Scheme 4. Nitriles Based on Natural Products
Scheme 7. Plausible Reaction Mechanism
a
Yield based on recovered starting material.
nitrogenation is impeeded by the first (Scheme 5). Addition of
twice the stoichiometry of nitrogenating reagent allowed
dicyanoarene 5b to form as the major product (70%) from
1,3-diethynylbenzene 5.
yields the tert-butyl oxy radical and nitroso radical. Addition of
the former to the alkyne forms a phenyl-substituted vinyl
radical I which is trapped by the nitroso radical to yield II.
Cyclization of II then provides the strained four-membered
intermediate III with elimination of formic acid leading to the
formation of benzonitrile.20 Presumably a tert-butyl cation is
formed in the conversion of III to the final product, and a
proton abstraction by the 2-picoline-N-oxide resulted iso-
butylene.
Scheme 5. Nitrile from 1,3-Diethynylbenzene, 5
Scalability of the reaction was tested successfully by
preparing 2h and 2l in 69% and 75% yields, respectively
(Scheme 8).
In order to understand the mechanism of the nitrile
formation, a number of control experiments were performed
(Scheme 6). First to probe the formation of free radical
Scheme 8. Gram-Scale Reactions
Scheme 6. Control Studies to Elucidate the Mechanism
In conclusion, we have developed the first metal-free
nitrogenation of terminal alkynes to provide arylnitrile under
mild conditions. This is the first example where tert-butyl nitrite
is used as the nitrogenating reagent for alkynes. A wide range of
functional groups are compatible with the reaction conditions.
This metal-free nitrile synthesis avoids the use of hazardous
materials, allowing potential application in industry and
academia.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00147.
intermediates, the reaction was repeated in the presence of a
number of radical quenchers (eq 6). Thus, 2,4,6-tri-tert-butyl
phenol, 2,4-di-tert-butyl phenol, and AIBN all lead to significant
retardation of the reaction suggesting that it is likely proceeding
via a radical pathway. To test whether aldehyde or ketone
intermediates are formed, various aryl aldehydes and ketones
were examined (eqs 7 and 8). In none of these cases was the
expected benzonitrile compound formed.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: dmaiti@chem.iitb.ac.in.
*E-mail: david.lupton@monash.edu.
C
DOI: 10.1021/acs.orglett.6b00147
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Organic Letters
Letter
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Authors thank IITB-Monash Research Academy. This activity is
funded by ISRO, India (B.19012/76/2015-II).
■
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