Arylation and alkenylation of activated alkyl halides using sulfonamides

Article abstract of DOI:10.1039/d0cc00220h

A variety of quaternary aryl amino acid derivatives can be synthesised using tandem S_N2/Smiles rearrangement chemistry involving aryl sulfonamides and α-chloro carbonyl compounds. The reaction harnesses a sulfur dioxide extrusion pathway to construct a C-N and C-C_aryl bond under simple conditions with no requirement for organometallics or transition metal catalysts. The reaction is also successful for alkenyl sulfonamides, producing sterically congested quaternary alkene amino acid derivatives.

Full text of DOI:10.1039/d0cc00220h

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DOI: 10.1039/D0CC00220H
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Arylation and Alkenylation of Activated Alkyl Halides using
Sulfonamides
Stuart Johnson, Ervin Kovács and Michael F. Greaney,*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A variety of quaternary aryl amino acid derivatives can be for aryl transfer. There is good precedent in the literature,
synthesised using tandem SN2 / Smiles rearrangement chemistry however, for this step with a number of nosylated amino acid
involving aryl sulfonamides and -chloro carbonyl compounds. derivatives being observed to rearrange on treatment with
The reaction harnesses a sulfur dioxide extrusion pathway to base.4 Successful reaction would produce quaternary -aryl
construct a C-N and C-Caryl bond under simple conditions with no amino acid derivatives, common motifs in drugs,
requirement for organometallics or transition metal catalysts. The agrochemicals and peptidomimetics (Scheme 1C).5
reaction is also successful for alkenyl sulfonamides, producing
A: Tandem Sulfonamide Arylations
sterically congested quaternary alkene amino acid derivatives.
O2
R1
N
R2
CO2Me
EWG
S
R2 NHR1
NHR1
SO2
NR1
-SO2
Tandem reactions of sulfonamides create powerful arylation
pathways to nitrogenous aromatic structures of the type
commonly found in pharmaceuticals. The concept is set out in
Scheme 1, and involves reacting sulfonamide 1, frequently
commercially available or easily prepared, with a suitable
electrophile to create a C-N bond. The intermediate anionic
structure 3 can then undergo a Smiles aryl transfer reaction,1
creating a C-Caryl bond with extrusion of SO2.2 Overall, the
process accesses valuable arenes under simple reaction
conditions, with no recourse to the precious metal catalysis
that is frequently required for arylation and C-N bond forming
chemistry. The intramolecular SNAr step does generally require
an electron-poor or heteroaromatic moiety for successful
reaction, but this constriction is mitigated by these functional
groups being commonly represented in biologically active
molecules.
We have previously explored sp and sp2 electrophiles in this
tandem Smiles process, and were interested in expanding this
idea to sp3 centres to create new routes to amino-arylated
products.3 Alkyl halides are readily available and versatile
electrophiles that could react via SN chemistry, setting up a
rearrangement as shown in Scheme 1B, creating a particularly
valuable quaternary arylated amine motif 8. The proposed
Smiles reaction formally requires a strained four-membered
Meisenheimer intermediate 10, distinct from our earlier work
with -electrophiles that create pentacylic re-arrangements
1
O2S
EWG
CO2Me
R2
MeO2C
R2
EWG
3
4
5
EWG
2
MeO2C
C-N and C-Caryl
bond formation
B: This Work: sp3 Aminoarylation
R2
O
R1HN
O2
S
Cl
Base
R3
R3
NHR1
+
R2
O
6
7
8
EWG
EWG
SN
2
-SO2
O
O
O2
R1
S
S
NR1
O
N
4-exo-trig Smiles
R2
R3
10
R3
EWG
R2
EWG
O
9
C: Quaternary aryl amino acid derivatives
Me
O
O
O
H
O
NHMe
N
CO2H
Me
F
O
NH
O
HO
HO
HN
Ph
HN
O
Ph
O
NH
Cl
O
Sorbinil
(aldose reductase
inhibitor)
Ketamine
(sedative)
Phenyltoin
(antiepileptic)
Fumimycin
(antibiotic)
Scheme 1: Proposed tandem Smiles aminoarylation
We began by screening reaction conditions for the tandem SN2
/ Smiles arylation of ethyl -chlorophenylacetate 7a with N-
methylnosylamide 6a. We were pleased to observe that simple
K2CO3 treatment in hot DMF led to successful conversions,
with optimal conditions being a 2:1 ratio of alkyl halide to
sulfonamide, 3 equiv of base and heating to 70 °C, forming 8a
in high yield (Scheme 2). Some simple mapping of functional
group scope established that the reaction favoured N-
substitution on the sulfonamide; primary sulfonamides gave
8b in very low yield and N,N-disubstituted sulfonamides were
unreactive. A ketone in place of the ester group led to
a. School of Chemistry, University of Manchester, Oxford Rd, Manchester M13 9PL,
UK
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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substantially diminished yields (8c), so we retained the ester is precedented in the radical regime,7 but anionic VrieewacAtrtiioclne sOnalirnee
group for scope studies. A range of aryl-substituted N- rare.8 A successful metal-free synthesisDoOfI:q10u.1a0t3e9r/nDa0rCyCa0l0k2e2n0yHl
methylnosylamides were productive (8a – 8f), along with amino acid derivatives would complement existing routes,
several weakly nucleophilic N-arylnosylamides (products 8g – which typically involve addition of sp organometallics to the
8l). Electron donating arene substituents were noticeably appropriate imine and subsequent hydrogenation to the
more effective than electron withdrawing ones (e.g. 8h and 8j alkene.9 In the event, we were pleased to observe the known
v 8l), but steric hindrance on the sulfonamide (e.g. N-mesityl alkenyl sulfonamide 13a10 undergoing successful tandem SN
/
8i) lowered yields considerably. Changing the phenyl group in alkenyl transfer reaction under the standard conditions, to give
the alkyl halide substrate was feasible, with methyl groups 14a, albeit in a low 35% yield. The N-methyl sulfonamide 13b
being tolerated (8n and 8o) and the malonate substrate was more efficient, producing the alkene 14b in 59% yield.
successfully affording the versatile diester product 8p. Finally,
the heterocyclic pyrimidine sulfonamide was productive to
yield the novel amino acid derivative 8q in 54% yield.
NR1
O
S
O
K2CO3
OEt
NHR1
OEt

DMF
70 C, 16 h
Cl
O
O2N
O2N
O
6
7c
11
O
S
O
Cl
K2CO3
1R2RN R3
R1
OEt
R3
OEt
N
R2
+
EWG
DMF (0.1 M)
70 °C, 16 h
EWG
O
Me
O
3 = Ph
7a
R
6
8
3 = Me
7b
R
N
N
N
OEt
OEt
OEt
O
O
O
O2N
H2N
MeHN
O2N
O2N
MeHN
OEt
Me
OEt
OEt
OEt
11a, 56%
11b, 69%
11c, 75%

O
O
O
O2
N
O2N
O2
N
O
8c, 36%
8b, 15%
8a, 92%
OMe
Cl
OEt
N
N
N
MeHN
OEt
OEt
MeHN
MeHN
NH
OEt
OEt
OEt
OEt
O
O
O2N
O2N
O
O
O2N
O2
N
O
O
O
NO2
O2
N
OMe
O2N
CF3
11d, 51%
11e, 50%
11f, 36%
8d, 42%
8e, 49%
8f, 56%
8g, 86%
Me
MeO
Cl
NH
NH
NH
NH
HN
N
NaBH4
OEt
OEt
OEt
OEt
OEt
O
O
O
NiCl2.6H2O
O
O2N
O2N
O2
N
O2
N
O
O
H2N
O2N
8h, 92%
8i, 23%
8j, 95%
8k, 76%
12a 70%
11a
,
O
Scheme 3: Substituted imine scope using ethyl chloroacetate
MeHN
Me
NH
NH
Me
O
EtO
OEt
NH
OEt
OEt
O
OEt
O2
N
O
O2
N
O2N
O
O
S
O
Cl
O2
N
R1HN
R1
+
K2CO3
8l, 25%
8m, 74%
8n, 57%
8o, 51%
OEt
N
OEt
H
DMF (0.1 M)
70 °C, 16 h
O
O2N
O
O
O2N
7a
14
13
MeHN
OEt
OEt
NH
N
OEt
O
O2
N
N
O
8p, 53%a
8q, 54%
H2N
MeHN
a
OEt
OEt
Scheme 2: Scope of tandem SN2/Smiles rearrangement. Reaction carried out at room
temp.
O
O
O2N
O2N
Reaction of the unsubstituted ethyl chloroacetate 7c with N-
aryl substituted sulfonamides unexpectedly gave rise to imine
products (Scheme 3). It appears that the initial secondary aryl
Smiles product is undergoing oxidation under the basic
conditions with adventitious air in the reaction.6 The
transformation was general for N-arylnosylamides, affording
the Schiff base aryl glyoxalate derivatives 11a – f. The aryl
glycine derivative 12a could be accessed through a Ni-
catalyzed borohydride reduction of the imine 11a.
Having established an effective aminoarylation protocol, we
wondered if we could achieve an aminoalkenylation using
similar sulfonamide SN2 / Smiles rearrangement chemistry
(Scheme 4). Alkenyl transfer through desulfonylative processes
14a, 35%
14b, 59%
Scheme 4: Vinylogous Smiles rearrangement for alkenylation
In conclusion, we have developed a new tandem process for
the rapid construction of quaternary amino acid derivatives.
The protocol takes commercially available sulfonamides and
alkyl halides, and effects C-N and C-Caryl bond formation under
simple, metal-free conditions. The reaction could be extended
to imine synthesis, using ethyl chloroacetate, and a novel
vinylogous Smiles process to access alkenylated quaternary
amino acids.
2 | J. Name., 2012, 00, 1-3
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Conflicts of interest
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DOI: 10.1039/D0CC00220H
There are no conflicts to declare.
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