Decarbethoxylative Arylation Employing Arynes: A Metal-Free Pathway to Arylfluoroamides

Article abstract of DOI:10.1021/acs.orglett.7b03072

An efficient, metal-free decarbethoxylative arylation protocol for the synthesis of α-aryl-α-fluoroamides from fluoromalonamates, under ambient reaction conditions using aryne as an electrophilic arylating agent, is reported. This decarbethoxylative arylation proceeds under mild conditions and provides a practical and effective entry to a wide range of α-aryl-α-fluoroacetamides. Interestingly, the use of the tert-butyl ester of fluoromalonamate prevented the otherwise rapid decarboxylation step, affording the arylated fluoromalonamate in moderate yield.

Full text of DOI:10.1021/acs.orglett.7b03072

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Decarbethoxylative Arylation Employing Arynes: A Metal-Free
Pathway to Arylfluoroamides
Ekta Gupta,† Ruchir Kant,‡ and Kishor Mohanan*,†,§
‡
†Medicinal & Process Chemistry Division and Molecular and Structural Biology Division, CSIR-Central Drug Research Institute,
BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, P.O. Box 173, Lucknow 226031, India
§Academy of Scientific and Innovative Research, New Delhi 110001, India
S
* Supporting Information
ABSTRACT: An efficient, metal-free decarbethoxylative
arylation protocol for the synthesis of α-aryl-α-fluoroamides
from fluoromalonamates, under ambient reaction conditions
using aryne as an electrophilic arylating agent, is reported. This
decarbethoxylative arylation proceeds under mild conditions
and provides a practical and effective entry to a wide range of α-aryl-α-fluoroacetamides. Interestingly, the use of the tert-butyl
ester of fluoromalonamate prevented the otherwise rapid decarboxylation step, affording the arylated fluoromalonamate in
moderate yield.
he strategic use of arynes as a synthetic platform for the
access of densely functionalized arenes in carbon−carbon
various electrophiles to incorporate the (fluoro)acetate moiety
into organic molecules in high yields and stereoselectivity.10,11
Although this attractive feature of malonate derivatives has been
successfully explored in a wide range of carbon−carbon bond-
forming reactions, it still remains elusive for arylation
reactions.12,13 Undoubtedly, a strategy for the decarboxylative
arylation of malonate derivatives to introduce aryl group would
be of substantial synthetic utility. Encouraged by these attractive
findings, we chose to examine the use of fluoromalonamates as a
nucleophile for the decarboxylative arylation reaction with
arynes. If successful, this strategy would offer new avenues for
the development of mild strategies for the introduction of
fluoroacetamides into arenes, an important subunit, which is
present in a wide array of pharmaceuticals and agrochemicals.14
Our efforts in this direction culminated in the development of the
first decarbethoxylative arylation reaction that employs fluo-
romalonamate as a fluoroacetamide surrogate to generate α-aryl-
α-fluoroamides in high yields.
T
and carbon−heteroatom bond-forming reactions has seen
phenomenal growth in the last decades.1,2 Indeed, the
convenient and mild generation of arynes by fluoride-induced
1,2-elimination of 2-(trimethylsilyl)aryl triflates, introduced by
Kobayashi in 1983,3 has prompted the exploration of arynes in
manifold types of reactions such as multicomponent reactions
(MCRs),4 insertion reactions,5 cycloaddition reactions,6 and
arylations (Figure 1).7 Several elegant methodologies have been
Our studies commenced with the decarboxylative arylation of
ethyl N-bromophenyl-α-fluoromalonamate 2a, a substrate easily
accessible in two steps from the corresponding aniline and
diethyl malonate using amidation/fluorination conditions. Using
this substrate and the standard conditions (CsF, CH3CN)
employed for the generation of aryne from 2-(trimethylsilyl)-
phenyl trifluoromethanesulfonate 1a, the reaction was carried
out at room temperature, and pleasingly, the arylfluoroamide
derivative 3a was obtained in 50% yield. In attempts to improve
the efficiency of the reaction, the malonamate substrate 2a was
subjected to various reaction conditions, and in all cases, fluoride
source was required to be in excess to produce compound 3a in
reasonable yields (Table 1). When the reaction was carried out at
elevated temperature using CsF, the product was obtained in
Figure 1. Reactivity of arynes.
reported wherein arynes served as a versatile structural unit for
the synthesis of diversely substituted arenes. Importantly, too,
arynes have found widespread use in natural product synthesis.8
Despite the widespread use of arynes in various carbon−carbon
bond-forming reactions, metal-free C-arylation reactions em-
ploying arynes remain sparse.9 Currently, most of the reactions of
arynes with 1,3-diactivated methylene substrates are C−C
insertion reactions, and the studies of Mhaske9a and Rodriguez9b
have shown that arylation can be achieved using malonamides
and β-ketoamides, respectively.
Recent studies have shown that malonates, their derivatives,
particularly malonic acid half thioesters (MAHTs) and their
fluorinated analogues, are versatile building blocks for the metal-
and organocatalyzed decarboxylative coupling reactions with
Received: October 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03072
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Substrate Scope for the Decarbethoxylative
Arylation: Variation of Malonamates
a
b
entry
F− source
solvent
temp (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
CsF
CH3CN
CH3CN
CH3CN
THF
25
60
25
25
25
25
25
12
12
4
50
60
81
73
<5
72
83
CsF
KF/18C-6
KF/18C-6
KF/18C-6
TBAF
12
24
4
DMF
THF
TBAF
CH3CN
1
a
General conditions: 1a (0.24 mmol), 2a (0.20 mmol), fluoride source
b
(0.50 mmol), solvent (2.0 mL). Isolated yield after silica gel column
chromatography.
60% yield. The reaction conducted using KF/18C-6 as fluoride
source provided 3a in 81% yield. The best result (83%, 1 h, entry
7) was obtained with TBAF-CH3CN conditions.
Having identified the optimal conditions for this new
decarboxylative arylation strategy, we next turned our attention
to the evaluation of the scope of this reaction for the amide
component. As shown in Scheme 1, a wide variety of functional
groups on the phenyl ring of malonamate coupling partner were
first investigated. In general, electronically varied N-arylmalona-
mate derivatives underwent this decarboxylative arylation
reaction in high yields. The reaction tolerates various
functionalities including methoxy, halo, alkyl, trifluoromethyl,
enolizable ketone, and nitro moieties at 4-position of the aryl
group (3a−j). The structure of the product was unambiguously
confirmed by X-ray analysis of compound 3a.15 Subsequently,
the electronic effects of the substituents at m- and o- positions
were examined. To our delight, both the electron-rich and
electron-withdrawing substituents were well-tolerated, and the
corresponding substrates were transformed to arylated products
in good to excellent yields (3k−o). Pleasingly, the malonamate
substrates bearing disubstituted aryl group reacted readily with
aryne to yield the corresponding arylfluoroamides in excellent
yields (3p−t). The substrates bearing a naphthyl as well as
biphenyl ring can also be successfully employed in the reaction
(3u,v). Given the interesting medicinal chemistry applications of
this class of compounds, it is important to note that heteroaryl
amides can also take part in the reaction. Malonamates bearing
heteroarenes including quinoline, pyridine, and pyrazine
performed well in the reaction to afford the fluoroamide
derivatives in good to excellent yields (3w−y). Our attempts
to further expand the generality of this reaction proved to have
little scope with aliphatic amides. Except for N-benzyl
malonamate (3z), other aliphatic amides either failed to react
or decomposed under the reaction conditions. We subsequently
examined the scope of using N,N-disubstituted malonamates in
this reaction and found tertiary amides unviable for this
transformation.
a
General conditions: 1a (0.24 mmol), 2 (0.20 mmol), TBAF (0.50
mmol), CH3CN (2.0 mL). Isolated yield after silica gel column
chromatography. Reaction time: 12 h.
b
Scheme 2. Substrate Scope for the Decarbethoxylative
Arylation: Variation of Arynes
a
We next sought to evaluate the scope of variously substituted
arynes in the decarboxylative arylation. Interestingly, electroni-
cally different symmetrical and unsymmetrical arynes also served
as effective arylating agents and exhibited high levels of
regiocontrol with respect to substitutions on arynes (Scheme
2). For instance, the reaction carried out using 1,2-naphthyne
resulted in the formation of the β-addition product as a single
regioisomer in 91% yield, presumably due to the preferred attack
a
General conditions: 1 (0.24 mmol), 2i (0.20 mmol), TBAF (0.50
mmol), CH3CN (2.0 mL). Isolated yield after silica gel column
chromatography. The ratio of regioisomers was determined by H
NMR analysis.
b
1
B
DOI: 10.1021/acs.orglett.7b03072
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
at sterically less demanding position (3ab). Similarly, 3-methoxy-
1,2-benzyne provided compound 3ac as a single regioisomer.
Moreover, a high level of regiocontrol was observed when aryne
having methyl substitution at the 3 position was used (3ad).
However, the reaction conducted using 4-methylbenzyne
resulted in the formation of an inseparable mixture of
regioisomers 3ae and 3ad in 70% yield. The reaction using 4-
methoxybenzyne also afforded the product as an inseparable
mixture of regioisomers in 72% yield. The protocol was also
compatible for disubstituted arynes such as dimethoxy, dimethyl,
and difluoroarynes, thus rendering the arylfluoroacetamides in
reasonable to good yields (3ag−ai).
Scheme 4. Mechanistic Experiments
Scheme 5. Proposed Mechanistic Pathway
Moreover, the reaction was possible with various alkyl esters of
malonamate, and the corresponding product was obtained in
reasonably good yields (Scheme 3, eq 1). Interestingly, the
Scheme 3. Substrate Scope for the Arylation of tert-Butyl
Malonamates: Variation of Amides
aryl anion by the amide moiety. Protonation of intermediate B by
residual water generates the arylated malonamate C. Finally, the
hydrolysis of the ester moiety by hydroxide ion followed by
decarboxylation produces the arylfluoroacetamides 3. This
spontaneous decarbalkoxylation may be attributed to the
increased electrophilicity of the α-carbon center rendered by
fluorine as well as the newly installed aryl group. The exclusive
formation of arylated malonamate in the case of malonamate tert-
butyl esters and failed attempts using N,N-disubstituted
malonamates further supports the proposed mechanism.
We next explored the synthetic utility of arylfluoroacetamides.
The arylfluoroamide derivatives can be readily converted to the
corresponding esters using alcoholysis conditions. Moreover,
alkylation of 3a using benzyl bromide under basic conditions
provided the corresponding N-benzylated fluoroamide 8 in 63%
yield (Scheme 6).
anticipated decarbalkoxylative arylation reaction did not take
place when the tert-butyl malonamate 4d was used; instead, the
reaction generated arylated product exclusively (Scheme 3, eq 2).
This reaction, though in moderate yields, offers an efficient
strategy for the formation of fluorine-containing quaternary C-
center, and hence, a brief evaluation on the scope was carried out
(Scheme 3). Pleasingly, the reactions conducted using the tert-
butyl ester of various malonamates furnished the arylated
products in moderate yields (5a−d).
Scheme 6. Synthetic Transformations
After the scope and limitations of the methodology were
established, a few mechanistic experiments were performed to
probe the reaction mechanism. The arylation reaction carried out
in the presence of 4 Å molecular sieves afforded exclusively
arylated product 6, suggesting that the decarboxylation step most
likely involves hydrolysis of the ester moiety by the residual water
present in the media (Scheme 4, eq 1). This was further
confirmed by carrying out a reaction using malonamate naphthyl
ester 4e where we could isolate the byproduct, naphthyl alcohol,
in 60% yield along with 62% of the decarboxylative arylation
product 3a (Scheme 4, eq 2). These results show that the
reaction involves the hydrolysis of the ester moiety followed by
decarboxylation.
On the basis of the aforementioned experiments and literature
reports, a plausible mechanism is proposed (Scheme 5). The
reaction is likely initiated by the fluoride-induced generation of
aryne and the enolate of compound 2. The enolate subsequently
undergoes nucleophilic addition to aryne to generate tetrasub-
stituted malonamate B after the intramolecular protonation of
In summary, a practical, metal-free, and efficient decarbethox-
ylative arylation of fluoromalonamates yielding synthetically
valuable arylfluoroacetamides has been developed. The general-
ity of this reaction has been illustrated by employing a wide range
of fluoromalonamates including aryl, heteroaryl, and aliphatic
amides, and substituted arynes. Unlike the other reports on α-
arylation of fluoroacetic acid derivatives, this new process works
under mild and operationally simple conditions. We have further
demonstrated that the use of bulky tert-butyl ester of
malonamates can prevent the decarbalkoxylation step to
exclusively furnish the arylated products. Subsequently, it was
demonstrated that these arylfluoroamides could be readily
converted to their corresponding fluoroesters.
C
DOI: 10.1021/acs.orglett.7b03072
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
́ ́
Biju, A. T. J. Org. Chem. 2014, 79, 4757. (c) Perez, D.; Pena, D.; Guitian,
̃
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03072.
■
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Detailed experimental procedures, complete character-
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: kishor.mohanan@cdri.res.in.
ORCID
Kishor Mohanan: 0000-0001-5602-7112
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support by the Science and Engineering Research
Board, DST, Government of India (Grant No. SB/FT/CS-046/
2014), is gratefully acknowledged. E.G. is grateful to CSIR-New
Delhi for the award of Junior Research Fellowship. We thank Dr.
Tejender S. Thakur, MSB division, CSIR-CDRI, for supervising
the X-ray data collection and structure determination. We thank
the SAIF division for analytical support. CDRI Communication
No. 9572.
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DOI: 10.1021/acs.orglett.7b03072
Org. Lett. XXXX, XXX, XXX−XXX