Oxidative β-C-H sulfonylation of cyclic amines

Article abstract of DOI:10.1039/c7sc04900e

A transition metal-free strategy for the dehydrogenative β-sulfonylation of tertiary cyclic amines is described. N-Iodosuccinimide facilitates regioselective oxidative sulfonylation at C-H bonds positioned β to the nitrogen atom of tertiary amines, installing enaminyl sulfone functionality in cyclic systems. Mild reaction conditions, broad functional group tolerance and a wide substrate scope are demonstrated. The nucleophilic character of the enaminyl sulfone is harnessed, demonstrating potential application for scaffold diversification.

Full text of DOI:10.1039/c7sc04900e

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Oxidative β-C–H Sulfonylation of Cyclic Amines
R. J. Griffiths,a,b W. C. Kong, a,c S. A. Richards,a G. A. Burley,b M. C. Willis,*c E. P. A. Talbot*†a
Received 00th January 20xx,
Accepted 00th January 20xx
A transition metal-free strategy for the dehydrogenative β-sulfonylation of tertiary cyclic amines is described. N-
iodosuccinimide facilitates regioselective oxidative sulfonylation at C–H bonds positioned β to the nitrogen atom of
tertiary amines, installing enaminyl sulfone functionality in cyclic systems. Mild reaction conditions, broad functional group
tolerance and a wide substrate scope are demonstrated. The nucleophilic character of the enaminyl sulfone is harnessed,
DOI: 10.1039/x0xx00000x
www.rsc.org/
demonstrating
potential
application
for
scaffold
diversification
have also been exploited.9 The varied methods available for sulfone
preparation, together with their proven worth in medicinal
chemistry, make them ideal functional groups to install using a C–H
functionalization approach.
Introduction
Aliphatic azacycles are essential motifs in drug discovery, with 59%
of unique small-molecule drugs approved by the FDA containing at
least one nitrogen heterocycle.1a Of these, the piperidine motif is
the most prevalent nitrogen ring-system, highlighting the
importance of this heterocycle in small-molecule drug discovery.1
Simple piperidines are readily available, hence methods for the
straightforward late-stage diversification of this ring-system, ideally
exploiting C–H functionalization, are valuable tools for medicinal
chemistry (Scheme 1a).2 The majority of reported methods for the
C–H functionalization of saturated nitrogen heterocycles have
primarily focused on activation of the position α to the nitrogen
atom, with methods based on direct lithiation, as well a catalytic C–
H bond cleavage being described.3 Sanford has recently reported an
elegant process for the palladium-catalyzed transannular C–H
arylation of piperidines (γ-functionalization),4a and Bull has reported
the palladium catalyzed C-3 arylation of proline derivatives (β-
functionalization);4b it should be noted that both of these systems
rely on a pre-installed directing group. Additional reports of
functionalization remote to the nitrogen atom of cyclic amines are
somewhat less well-precedented.4
a) Piperidine C-H functionalization
H
γ-C-H functionalization
limited: ref 4a
N
R
H
H
H
β-C-H functionalization
readily available
biologically relevant
scaffold
limited: ref 4b
focus of this work
N
R
H
N
R
α-C-H functionalization
many methods: ref 3
N
R
H
b) β-C-H functionalization leading to cyclic enaminyl sulfones
H
H
O
O
S
H
O
S
H
H
NIS
THF, rt
R2
R1
R1
NaO
R2
N
R
N
R
oxidative C-H sulfonylation
H
H
R1
R1
N
N
Sulfones are privileged functional groups in the pharmaceutical
and agrochemical industries,5 and serve as versatile intermediates
for organic synthesis.6 Recent methods for the preparation of
sulfones have focused on the utilization of higher valent sulfur
reagents in order to avoid oxidative transformations.7 Sulfinate salts
have been employed for the direct formation of vinyl and aryl
sulfones,8 and methods based on the trapping of sulfur dioxide
R
R
simple substrates
(no directing group)
benign reagents
mild conditions
transition metal free
broad scope
Scheme 1. a) The C–H functionalization of piperidines, and b) this work: the
preparation cyclic enaminylsulfones.
We recently described the iodine-mediated conversion of cyclic
amines to lactams, in what corresponds to an α-C–H
functionalization process.10 Iodine has also been used, along with
an excess of peroxide co-oxidant, for the formation of enaminyl
sulfones using simple acyclic amines and sulfinates salts as starting
a GlaxoSmithKline Medicines Research, Gunnels Wood Road, Stevenage, Hertfordshire,
SG1 2NY (UK).
b Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral
Street, Glasgow, G1 1XL (UK).
materials.11
A related, visible light mediated transformation
c Department of Chemistry, University of Oxford, CRL Mansfield Road, Oxford, OX1 3TA
(UK). E-mail: michael.willis@chem.ox.ac.uk
employing air sensitive sulfonyl chlorides and a large excess of
amine substrate ( >4 eq.) has also been reported by Zheng and
Zhang, but in both cases the product enaminyl sulfones were
obtained in only poor yields and selectivities.12 Both of these
reports focus mostly on acyclic amine substrates and propose that
an intermediary enamine attacks an electrophilic sulfonyl species.
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Equiv.
Our previous work showed evidence of proceeding via an
iminium/enamine pathway, thus we speculated that formation of
cyclic enaminyl sulfones from cyclic amines and sulfinates should be
feasible under oxidative iodine conditions, and that such a reaction
Entry
Oxidant
NIS
Reaction conditions
% 2ab
43
p-TolSO2Na
RT, 0.5 h actvc, 3h, 2:1
THFd:water, 5 eq. NaHCO3
RT, 0.5 h actv, 3h, 2:1
DMSO:water, 5 eq NaHCO3
RT, 0.5 h actv, 2h, DCM
RT, 0.5 h actv, 2h, DMSO
RT, 0.5 h actv, 2h, DMSO
RT, 0.5 h actv, 2h, DMSO
RT, 0.5 h actv, 2h, DMSO,
N2, dark
1
2
3
3
would provide
a
valuable transformation for the β-C–H
NIS
38
functionalization of piperidines (Scheme 1b). In this Article we
report the successful realization of this goal, and use the installed
functionality as a unique nucleophile for wider functionalisation.
3
4
5
6
3
3
3
3
NIS
NIS
I2
27
60
trace
-
ICl
Results and discussion
7
8
3
3
NIS
NIS
NIS
NIS
NIS
81
95
65
90
71
RT, 0.5 h actv, 2h, THFe, N2,
Important objectives at the start of our study were to define
reaction conditions that would deliver efficient and selective
reactions with good functional group tolerance. In particular, we
were keen to avoid the use of tert-butyl hydroperoxide as a
reagent, and also targeted ambient temperature reactions.
Capitalizing on our prior report of iodine-mediated α-C-H oxidation
of amines, which proceeded at room temperature, we began our
reaction optimization using iodine-based reagents. N-Benzyl
piperidine 1a was used as a model substrate and was combined
with sodium p-tolylsulfinate in our optimization studies. A robust
dark
RT, 0.5 h actv, 2h, 2-MeTHF,
N2, dark
RT, 0.5 h actv, 2h, THFe, N2,
9
3
10
11
1.5
1.5f
dark
RT, 0.5 h actv, 2h, THFe, N2,
dark
aReaction conditions: 1a (1.0 eq), oxidant (4.0 eq), solvent, 0.5 h, then p-
TolSO2Na, solvent (0.063 M), rt, 2h. b% conversion to 2a was measured by 1H
NMR analysis of the crude material against 3,4,5-trichloropyridine as an internal
screen of conditions was undertaken, surveying the parameters of standard. c“actv” refers to the pre-stirring of oxidant with 1a. dTHF contained 250
ppm BHT radical inhibitor. eTHF was inhibitor-free. p-TolSO2Li was used as the
f
solvent, concentration, temperature, type of halo-oxidant and
sulfinate salt instead. p-Tol = para-tolyl.
stoichiometry of oxidant and sulfinate salt. The optimal conditions
were identified, and THF proved to be the optimal solvent for this
transformation, and N-iodosuccinimide (NIS) the optimal oxidant
(Table 1).
In contrast to our previous work on the iodine-mediated
formation of lactams, water and base were not found to be
necessary for the formation of 2a, with anhydrous DMSO providing
Table 1. Selected optimization data for the formation of enaminyl sulfone 2a a
the best conversion to 2a (entry 4). Molecular iodine and iodine
monochloride (entries 5 and 6) were significantly inferior oxidants
than NIS. Shielding the reaction from light and oxygen was found to
be crucial to achieving more reproducible results, and led to
improved conversion to 2a (entry 7). Finally, using THF as the
solvent enabled a further increase in the formation of 2a (entry 8),
and also provided conditions that were amenable to reducing the
amount of the more expensive sulfinate salt to only 1.5 equivalents
(entry 10), with the reaction proceeding to 90% conversion. A slight
decrease in conversion to 2a (entry 11, 71%) was observed when
using the lithium sulfinate salt, suggesting an importance the less
tightly bound anion in the sodium sulfinate increases reactivity.
However, the lithium sulfinate still proceeded well, which provides
wider applicability for sulfinates synthesized via
a lithiation
protocol. Full details of the reaction optimization can be found in
the ESI (Table S1).
With the optimized conditions in hand, the scope of the
reaction with respect to variation of sodium sulfinate salt was
explored (Table 2). Electron-rich (2b), electron-poor (2c) and halide
substituted (2d-f) aryl sulfinates provided access to enaminyl
sulfones in good to excellent conversions and yields (68-98%). This
provides an opportunity for subsequent diversification using the
pre-installed halide functional group for the development of
molecular libraries of biologically relevant molecules. Meta- and
ortho-substitution on the aryl ring was also tolerated well (2g and h,
91% and 73%, respectively), demonstrating good tolerance to steric
crowding. Larger-scale reactions, performed on 5.42 mmol and
3.75 mmol of amine, delivered products 2a (75%) and 2g (70%),
respectively, demonstrating the preparative utility of the method.
2 | J. Name., 2012, 00, 1-3
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Table 2. Variation of the sulfinate reaction component.a
Table 3. Variation of the amine reaction component.a
O O
S
O O
S
(i) NIS (4.0 equiv)
H
H
(i) NIS (4.0 equiv)
(ii) p-TolSO2Na (1.5 equiv)
R
(ii) RSO2Na (1.5 - 2.0 equiv)
R2
R2
THF, rt, 2 h
N
N
R1
3
N
N
R1
4
Me
THF, rt, 2 h
Bn
Bn
1a
2
O
S
O
O O
S
O O
S
Me
O
S
O
O
S
O
O
S
O
Bn
Bn
Bn
CF3
N
N
N
N
Tol
Ph
N
Tol
N
Tol
R
R
R
N
2a, R = Me 84% (90%)[b]
75% on a 5.42 mmol scale
2b, R = OMe 62% (68%)[c]
2c, R = NO2 63% (71%)
2g, 80% (91%)
70% on a 3.75 mmol scale
2d, R = F 55% (69%)
2e, R = Cl 63% (78%)
2f, R = Br 79% (98%)
4a, R = OMe, 79% (84%)
4b, R = NO2, 65% (79%)
4c, R = SMe, 84% (87%)
4d, 94% (96%)
ee = 99%
4e, 71% (81%)
Me
O
S
O
O O
O
S
O
Cl
O
S
O
S
O
O O
O
S
Bn
Bn
S
N
Tol
N
Tol
Bn
N
Tol
N
N
N
Cl
S
S
Cl
2j, 65% (68%)[c]
4f, 73% (84%)
4g, 90% (95%)
4h, 85% (93%)
2i, 73% (80%)
2h, 63% (73%)
O
O
O
O
O
O
O
S
O
O
S
O
O
S
S
O
Tol
MeO
Bn
S
Bn
N
Tol
Bn
S
N
N
N
N
Bn
Tol
N
X
Y
Ph
Me
2k, X = CH, Y = N 51% (55%)[c]
2l, X = N, Y = CH 24% (22%)[c]
2m, 68% (74%)[c]
2n, 47% (57%)
4i, 22%
4j, 19% (22%)[b]
4k, 51% (58%)
ee >99%
O
F
aIsolated yields shown; values in parentheses show conversion to product as
measured by 1H NMR analysis of crude product mixture using an internal
standard. b71% NMR conversion observed when TolSO2Li was used. c2.0
equivalents of RSO2Na was used.
R
Tol
O
S
O O
S
O
O
N
Tol
O
S
N
Tol
Me
N
Me
Bn
4o, 34%
4l, R = Me 51% (49%)
4m, R = OMe 27% (32%)
4n, 47% (62%)
Heterocyclic sulfinates (2i-l) also performed well, although a lower
conversion was observed for the 2-pyridyl sulfinate. Non-aryl
sulfinates failed to provide the targeted enaminyl sulfones, with the
only exceptions being the use of sodium cyclopropylsufinate and
sodium styrylsulfinate, which provided enaminyl sulfones 2m and
2n in 68% and 47% yield, respectively.
(from melperone)
aIsolated yields shown; values in parentheses show conversion to product as
measured by 1H NMR analysis of crude product mixture using an internal
standard. b3.0 equivalents of p-TolSO2Na was used and DMSO as the reaction
solvent. Tol = para-tolyl.
The scope of amine component was evaluated next (Table 3).
Variation of the electronics of the N-benzyl substituent was
tolerated (4a,b), with no benzylic functionalization observed in
either reaction. Sulfone 4c, featuring an arylmethylsulfide
substituent, was obtained in 87% conversion, highlighting the
tolerance of the reaction to oxidation-sensitive functional groups.
Increasing the steric crowding around the nitrogen center was not
detrimental to the reaction, and product 4d was isolated in 94%
yield.
Sulfones 4e and 4f were obtained with high selectivities and
yields, confirming the preference for endocyclic over exocyclic
oxidation, and tolerance of a nitrile functional group. The reaction
was also tolerant and selective for different N-alkyl substituents on
the amine, with ethyl- and cyclohexyl examples performing well
(4g-h). Disappointingly, variation of the ring size of the cyclic amine
(4i-j) was not tolerated well, with the five- and seven-membered
amines providing only moderate yields of the desired enaminyl
sulfones. The presence of a methyl-substituent on the framework of
the piperidine ring steered sulfonylation to the less- hindered
position, and provided sulfone 4k with high regioselectivity. N-Aryl
amines performed moderately well, affording sulfones 4l and 4m in
49% and 32% conversion, respectively. The formation of sulfone 4n
established that oxidative sulfonylation can be achieved for non-
cyclic amines, and contrasts with our earlier iodine-mediated
oxidative formation of amides, which was restricted to cyclic
systems. The final example in Table 3 highlights the utility of the
developed reaction for the late-stage C–H functionalization of
medicinally relevant compounds; enaminyl sulfone 4o is derived
from oxidative sulfonylation of melperone, a marketed atypical
antipsychotic. The formation of 4o demonstrates how the
developed reaction could be applied for the diversification of
compound collections used in drug discovery.
As a preliminary investigation into the mechanism of the
developed reaction we performed several control reactions (Table
4). The inclusion of BHT as an additive did not lead to appreciable
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inhibition of the reaction (entry 2). Catechol, however, resulted in a under acidic silane conditions,16 affording saturated system 5 in an
substantial drop in conversion, while sulfone 2a was not observed excellent 91% yield. Alternatively, hydrogenation over Pd/C using
when TEMPO was added to the reaction (entries
respectively). Lack of inhibition by BHT despite inhibition occurring flow
3
and 4, Zn/HCl in COware delivered sulfone 6 in comparable yield. Use of a
hydrogenator enabled straightforward small-scale
with the radical scavenger TEMPO has some precedent in related hydrogenation at high pressure; the use of 25 bar pressure enabled
iodine/sulfinate reaction systems,8e thus a radical pathway could global hydrogenation to prepare piperidine 7 in which the N-benzyl
not be completely excluded at this stage.
group has been cleaved in 76% yield.
Table 4. Control experiments highlighting a putative radical pathway.
O
O
O
O
S
CF3
S
BnHN
Tol
Ar
N
N
N
H
Bn
16, 52%
5, 91%
Ar = p-BrC6H4
O
S
O
Ph
O
S
O
ArN2BF4
TFA
Et3SiH
TFA
% 2aa
90
N
Me
Entry
Variation from above
None
Bn
N
Me
Cu(OTf)2
15, 22%
O
S
O
Bn
1
2
3
H2
Pd/C
Ph2IOTf
then NaBH4
6, 90%
BHT (1.1 equiv) added
Catechol (1.1 equiv)
added
70
R
29
NCS
then KOH
H2, Pd/C
(25 bar)
N
Bn
or
4
TEMPO (1.1 equiv)
added
0
O
S
O
8
NCS
H
O
O
then BH3 then BH3
S
O
N
Tol
[a]As measured by 1H NMR analysis of crude product mixture using an internal
standard.
N
Me
Bn
Cl
O
O
X
H
7, 76%
14, 73%
S
N
Me
However, a radical clock experiment with 3p provided a mixture
of 4pα and 4pβ, with no opening of the cyclopropyl ring observed
(Scheme 2).
Bn
9, X = F, 75%; 10, X = Cl, 85%
R
O
O
S
O
O
MgBr
X
S
X
8 or NCS
Tol
N
then
R-MgBr
Bn
S
O
N
R
Me
N
Tol
Bn
Bn
2a
O
>20:1 dr
12
11a: X = F, R = vinyl, 74%
11b: X = F, R = p-tolyl, 81%
11c: X = Cl, R = vinyl, 84%
11d: X = Cl, R = p-tolyl, 63%
Mg
MeOH
F
OTf
Cl
Cl
N
F
N
p-Tol
Bn
8
Scheme 2. Radical-clock experiment with 3p, indicating that the reaction does not
proceed via a radical-based mechanism. aIsolated yields shown; values in parentheses
show conversion to product as measured by 1H NMR analysis of crude product mixture
using an internal standard. Tol = para-tolyl.
13, 69%
Scheme 3. Cyclic enaminyl sulfones as templates for synthesis. Tol = para-tolyl.
Incorporation of fluorine and chlorine atoms onto heterocyclic
scaffolds is important for both modulating physiochemical
properties,17 and for the introduction of synthetic handles for
subsequent chemical transformations.18 Fluoropyridinium 8 proved
to be the optimal reagent to yield β-fluorinated amine 9 (75%), and
N-chlorosuccinimide enabled effective chlorination to provide β-
chlorinated piperidine 10 (85%). These reductive halogenation
reactions could be modified by replacing the borane reductant with
This result suggests that in fact the oxidative C–H sulfonylation
reaction does not proceed via a radical-mediated pathway. The
light and air-sensitivity of the reaction is indicative of formation of a
sulfonyl iodide in situ, which are known to be unstable in the
presence of light and oxygen.13 This accounts for the poorer results
observed for aliphatic and hetereoaromatic sulfinate salts, as
hetereoaromatic and alkyl sulfonyl halides have been known to be
unstable.14 The inhibition of the reaction by known radical
inhibitors is therefore proposed to arise as a result of reaction these
additives accelerating the decomposition of the sulfonyl iodide. At
this stage, the reaction is proposed to follow oxidation to an
enamine, followed by nucleophilic attack of the sulfonyl iodide,
though further studies are required.
a Grignard reagent, enabling the formation of a C–C bond in the
-
position of the piperidines. Vinyl and p-tolyl Grignard reagents were
used in both fluorination and chlorination procedures, providing
trifunctionalized piperidines 11a-d in high yields (63 – 81%). Only a
single diastereomer was observed to form under these reaction
conditions, suggesting an ordered transition state controlling the
approach of the nucleophile to the iminium intermediate (12).
Desulfonylation of 11b could be achieved using magnesium in
methanol,19 to afford stereodefined β-fluoropiperidine 13 with
good selectivity. Combining initial chlorination with a hydroxide
trap led to ring-opening of the piperidine and formation of
formamide 14. Arylation β to the amine was achieved using an
aryliodonium salt in the presence of a copper catalyst,20 producing
amine 15 in 22% yield. The formation of a congested quaternary
Despite the combination of synthetically useful functional
groups present in enaminyl sulfones, their use in synthesis has not
been well explored.15 One reason for this is presumably the lack of
convenient methods for their preparation. Accordingly, we set out
to explore the utility of the cyclic enaminyl sulfone products
obtained in this study as templates for further diversification
(Scheme 3). Selective reduction of the enamine could be achieved
4 | J. Name., 2012, 00, 1-3
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M. Couderchet, J. Schmalfuß and P. Böger, Pestic. Sci., 1998,
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center likely contributes to this low yield. Finally, reaction of 2a
with a diazonium salt induced ring-opening and loss of a methylene
unit, producing hydrazone 16 in 52% yield via a Japp-Klingemann
reaction.21
6
7
Conclusions
In conclusion, we have developed a straightforward process for
the β-C–H functionalization of piperidines. The reactions combine
piperidines and sodium sulfinates, under the action of NIS, to
provide enaminyl sulfone products. The process is achieved under
mild conditions, and shows good functional group tolerance. We
also establish that the resultant cyclic enaminyl sulfones are
versatile templates for further elaboration. We envisage that this
approach will expedite the generation of diverse compound
libraries for use in drug discovery.
8
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2004, 6, 2105–2108; (b) S. Cacchi, G. Fabrizi, A. Goggiamani,
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Financial support for this work was provided by GSK via the
GSK/University of Strathclyde Centre for Doctoral Training in
Synthetic and Medicinal Chemistry. We also thank Sean Lynn and
Richard Upton (both GSK) for their assistance with NMR analysis.
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A new and efficient process to access β-functionnalisation of cyclic amines via a mild oxidative β-sulfonylation