Arylation Using Sulfonamides: Phenylacetamide Synthesis through Tandem Acylation-Smiles Rearrangement

Article abstract of DOI:10.1021/acs.orglett.9b03429

A range of electron-poor and heterocyclic sulfonamides react with phenylacetyl chlorides to produce benzhydryl derivatives in a single step. The reaction proceeds via tandem amide bond formation/Dohmori-Smiles rearrangement under the simple conditions of

Full text of DOI:10.1021/acs.orglett.9b03429

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Arylation Using Sulfonamides: Phenylacetamide Synthesis through
Tandem Acylation−Smiles Rearrangement
Helen L. Barlow, Pauline T. G. Rabet, Alastair Durie, Tim Evans, and Michael F. Greaney*
School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, United Kingdom
S
* Supporting Information
ABSTRACT: A range of electron-poor and heterocyclic
sulfonamides react with phenylacetyl chlorides to produce
benzhydryl derivatives in a single step. The reaction proceeds
via tandem amide bond formation/Dohmori−Smiles rear-
rangement under the simple conditions of an aqueous base. In
the case of o-nosylamides, a further reaction takes place at the
nitro group to yield indazoles.
ryl and heteroaryl structures are fundamental to natural
products and man-made molecules and are frequently
fundamental pharmacophore in medicinal chemistry. The
Smiles rearrangement of acylsulfonamide enolates akin to 8
had precedent in seminal studies from Dohmori and coworkers
in the 1950s, representing the earliest examples of carbon
nucleophiles participating in Smiles processes.6
Our previous work indicates that electron-poor sulfonamides
are required for anionic desulfonylative Smiles processes, in
line with the literature precedent of an SNAr-type mechanism
that proceeds through a Meisenheimer intermediate (e.g., 4 in
Scheme 1).7
A
synthesized using stoichiometric organometallics and precious
transition-metal catalysts. These methods, while effective and
hugely influential, are costly and environmentally unsustain-
able, making metal-free arylation methods1 a key objective for
future strategies in synthetic chemistry. We are interested in
harnessing simple aryl sulfonamides as metal-free arylating
agents in this regard through the process set out in Scheme 1.
Scheme 1. Proposed Ketene Smiles Rearrangement
Accordingly, we began our studies using p-nosylamide 1a
and screened the reaction with excess phenylacetyl (10a) and
propionyl chloride (10b) under ketene-forming conditions in
terms of solvent and temperature (Table 1). Unfortunately, no
Table 1. Reaction Optimization
The nitrogen atom acts as a nucleophilic trap for an
electrophilic coupling partner, a benzyne in this example,
generating an incipient carbanion (3) that triggers a 1,5-
desulfonylative Smiles rearrangement.2−4 Overall, the process
repositions a cheap and readily available building block as both
an arylating and aminating agent, critical transformations in the
pharmaceutical industry, while proceeding without recourse to
metal reagents.
We have previously shown that sulfonamides can react with
sp electrophiles for the synthesis of biaryl and enaminoate
products5 and were interested in extending the chemistry to
sp2 components. Trapping a ketene, 7, for example, with a
sulfonamide 1 would generate an enolate 8 that could
rearrange via the Smiles reaction to afford phenylacetamide
derivatives 9. This process would use sulfonamides to install
aryl groups at sp3 centers, producing phenylacetamides, a
entry
R1
Ph
base
iPr2NEt (2.0)
solvent
T (°C)
product
11
1
2
3
4
5
6
7
DCM
DCM
DCM
THF
r.t.
Ph
Ph
Ph
proton sponge (1.1)
proton sponge (1.1)
iPr2NEt (2.0)
iPr2NEt (2.0)
iPr2NEt (2.0)
40
r.t.
70
11
11
11
CH3
CH3
CH3
Ph
THF
100
100
100
80
11
toluene
THF
THF
11
proton sponge (1.1)
NaOH (aq)
11
9a (87%)
b
c
8
a
Reaction conditions: 1 (1 equiv) in solvent at 0 °C, then the base
b
was added, followed by 10 (1 equiv), stirred at T °C for 16 h. 5 equiv
of 10, 1 h. Isolated yield.
c
Received: September 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03429
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Smiles reaction could be observed, with the simple acylated
product being identified as the main product in each case
(entries 1−7). A further trial with the diketene acetone adduct
at 120 °C, to generate acylketene in situ, likewise yielded only
the acylated sulfonamide. It appeared that the 1,5-desulfony-
lative Smiles reaction, in contrast with some 1,4 processes on
related enolate systems,8 requires more basic conditions to
proceed. This proved to be the case, as a survey of simple
inorganic bases identified aq NaOH as enabling the two-step
procedure (entry 8). Using aqueous THF as the solvent, p-
nosylsulfonamide reacted with phenylacetyl chloride at 80 °C
to give the Smiles product 9a in very good yield.
9a, proceeding in an excellent 89% yield. Some restrictions
were noted in terms of the substitution at the enolic position of
the acyl component, with disubstitution at this position
shutting down the Smiles process. Turning to the sulfonamide
partner, the reaction tolerated N-substitution (e.g., 9h and 9i)
without problem, but not N,N-disubstitution. Electron-poor p-
nosylamides were generally productive, and we were pleased to
see that heterocyclic sulfonamides such as pyrimidyl (9m),
pyrimidyl (9n), and benzothiazoyl (9o) underwent a
successful reaction. The arylation of sp3 centers with these
valuable heteroarene moieties under simple metal-free
conditions is a particular strength of the approach because it
represents a challenging transformation for contemporary
transition-metal-catalyzed methods.
Screening o-nosylamide 1e in the reaction led to the
unexpected formation of 3-phenyl-1H-indazole 12a in 54%
yield (Scheme 3A). The reaction appears to be general for
phenylacetyl chlorides, with the electron-rich and electron-
poor substrates giving the indazoles 12a−f in moderate yield.
The assembly of this important heterocycle from sulfona-
mides, in a single step, has not been previously reported and
clearly involves a significant degree of bond reorganization.
With the reaction conditions in hand, we examined the
substrate scope in terms of aryl halide and the sulfonamide
component (Scheme 2). The reaction was successful for a
a
Scheme 2. Acyl Chloride Substrate Scope
a b
,
Scheme 3. 1H-Indazole Synthesis
a
Reaction conditions: 1 (1 equiv) in THF at 0 °C. Dropwise addition
of aq NaOH, followed by 10 (5 equiv), then heated to 120 °C in a
sealed vial for 1 h.
variety of phenacetyl chlorides, affording the benzhydryl
primary amides 9a−o in generally good yield. The reaction
could be demonstrated on a 1 mmol scale for the synthesis of
a
b
General conditions as Scheme 2. Isolated yields.
B
DOI: 10.1021/acs.orglett.9b03429
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
2015, 137, 964. (i) Kong, W.; Fuentes, N.; Garcia-Dominguez, A.;
Merino, E.; Nevado, C. Angew. Chem., Int. Ed. 2015, 54, 2487.
(4) Recent Smiles examples: (a) Chang, X.; Zhang, Q.; Guo, C. Org.
Lett. 2019, 21, 4915. (b) Li, J.; Liu, Z.; Wu, S.; Chen, Y. Org. Lett.
2019, 21, 2077. (c) Faderl, C.; Budde, S.; Kachkovskyi, G.; Rackl, D.;
Reiser, O. J. Org. Chem. 2018, 83, 12192. (d) Costil, R.; Lefebvre, Q.;
Clayden, J. Angew. Chem., Int. Ed. 2017, 56, 14602. (e) Wang, S.-F.;
Cao, X.-P.; Li, Y. Angew. Chem., Int. Ed. 2017, 56, 13809. (f) Costil,
R.; Dale, H. J. A.; Fey, N.; Whitcombe, G.; Matlock, J. V.; Clayden, J.
Angew. Chem., Int. Ed. 2017, 56, 12533. (g) Janssen-Mueller, D.;
Singha, S.; Lied, F.; Gottschalk, K.; Glorius, F. Angew. Chem., Int. Ed.
2017, 56, 6276. (h) Bhojgude, S. S.; Roy, T.; Gonnade, R. G.; Biju, A.
T. Org. Lett. 2016, 18, 5424.
(5) (a) Holden, C. A.; Sohel, S. M. A.; Greaney, M. F. Angew. Chem.,
Int. Ed. 2016, 55, 2450. (b) Teskey, C. J.; Sohel, S. M. A.; Bunting, D.
L.; Modha, S. G.; Greaney, M. F. Angew. Chem., Int. Ed. 2017, 56,
5263.
(6) (a) Naito, T.; Dohmori, R.; Nagase, O. Yakugaku Zasshi 1954,
74, 593. (b) Naito, T.; Dohmori, R.; Sano, M. Yakugaku Zasshi 1954,
74, 596 See ref 2b for further references on the Dohmori−Smiles
rearrangement. .
(7) For a recent discussion of concerted SNAr reactions, see:
Rohrbach, S.; Smith, A. J.; Pang, J. H.; Poole, D. L.; Tuttle, T.; Chiba,
S.; Murphy, J. A. Angew. Chem., Int. Ed. 2019, DOI: 10.1002/
anie.201902216.
(8) Wilson, M. W.; Ault-Justus, S. E.; Hodges, J. C.; Rubin, J. R.
Tetrahedron 1999, 55, 1647.
(9) Loudon, J. D.; Tennant, G. Q. Rev., Chem. Soc. 1964, 18, 389.
(10) Sundberg, R. J.; Blackburn, D. E. J. Org. Chem. 1969, 34, 2799.
(11) Yoshida, T.; Matsuura, N.; Yamamoto, K.; Doi, M.; Shimada,
K.; Morie, T.; Kato, S. Heterocycles 1996, 43, 2701.
There is, however, some limited precedent in the work from
Dohmori and Sundberg, who observed the indazole synthesis
from Smiles products via cinnoline N-oxides.6,9,10 A feasible
pathway is shown in Scheme 3B, whereby the sulfonamide
undergoes acylative Smiles rearrangement to afford 9p, which
can then undergo intramolecular N−N bond formation to
form the cinnoline N-oxide 13. From here, basic hydrolysis of
the cinnoline amide group and dehydration would form the
diazonium intermediate 14, and the intramolecular amination
of enolates analogous to 14 is a well-described method for
synthesizing indazoles.11 A final decarboxylation gives the
product 12.
To conclude, we have described a new application of
sulfonamides that captures their amphiphilic character as
electrophilic arylating and nucleophilic aminating agents. The
transformation is based on classical observations from
Dohmori and coworkers on the facility of desulfonylative
Smiles processes to mimic enolate arylation chemistry. In
contrast with conventional enolate arylations, however, the
process requires no metal catalysts and proceeds under very
simple conditions. In the case of o-nosylamides, a 3-aryl-1H-
indazole synthesis has been developed that involves substantial
changes in bond connectivity to create an important
heteroarene moiety from cheap and readily available starting
materials.
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.9b03429.
Experimental procedures and characterization data for
all new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: Michael.greaney@manchester.ac.uk.
ORCID
Michael F. Greaney: 0000-0001-9633-1135
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the EPSRC for funding.
■
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DOI: 10.1021/acs.orglett.9b03429
Org. Lett. XXXX, XXX, XXX−XXX