Transfer of Electrophilic NH Using Convenient Sources of Ammonia: Direct Synthesis of NH Sulfoximines from Sulfoxides

Article abstract of DOI:10.1002/anie.201602320

A new system for NH transfer is developed for the preparation of sulfoximines, which are emerging as valuable motifs for drug discovery. The protocol employs readily available sources of nitrogen without the requirement for either preactivation or for met

Full text of DOI:10.1002/anie.201602320

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International Edition: DOI: 10.1002/anie.201602320
German Edition: DOI: 10.1002/ange.201602320
Hypervalent Compounds
Transfer of Electrophilic NH Using Convenient Sources of Ammonia:
Direct Synthesis of NH Sulfoximines from Sulfoxides
Marina Zenzola+, Robert Doran+, Leonardo Degennaro, Renzo Luisi,* and James A. Bull*
Abstract: A new system for NH transfer is developed for the
preparation of sulfoximines, which are emerging as valuable
motifs for drug discovery. The protocol employs readily
available sources of nitrogen without the requirement for
either preactivation or for metal catalysts. Mixing ammonium
salts with diacetoxyiodobenzene directly converts sulfoxides
into sulfoximines. This report describes the first example of
using of ammonia sources with diacetoxyiodobenzene to
generate an electrophilic nitrogen center. Control and mecha-
nistic studies suggest a short-lived electrophilic intermediate,
which is likely to be PhINH or PhIN+.
reported a direct synthesis of unprotected (i.e. NH) aziridines
using DPH with [Rh2(esp)2] as a catalyst in trifluoroethanol.[4]
An increasingly important use of electrophilic formal
nitrene sources is in the synthesis of sulfoximines. Sulfox-
imines have been the subject of intense interest and recently
emerged as exciting motifs for drug discovery programs.[5]
Bayer first examined the sulfoximine group, which was
considered an oddity in medicinal chemistry at the time,
during the development of BAY 1000394, a pan-CDK inhib-
itor currently undergoing clinical trials for cancer in patients
with advanced solid tumors (Figure 1).[6] In comparison to
T
he transfer of nitrogen atoms is extremely valuable in the
preparation of important biologically relevant functional
groups. Electrophilic nitrogen-atom sources including nitre-
noids, metal–nitrene equivalents, or oxaziridines are there-
fore highly valuable synthetic tools.[1] These reagents com-
monly require the nitrogen atom to be activated to enhance
electrophilicity, and is usually achieved by either adding an
electron-withdrawing N-protecting group or through preacti-
vation with a leaving group. Consequently, there are very few
examples of unprotected electrophilic NH sources, which
would be more desirable as it avoids the requirement for
additional steps and improves atom economy. Activated
reagents such as O-mesitylenesulfonylhydroxylamine (MSH)
or O-(2,4-dinitrophenyl)-hydroxylamine (DPH) have been
employed but these suffer from instability and the required
additional steps for their preparation.[2,3] In an important
recent example of NH transfer, Falck, Kurti, and co-workers
Figure 1. Biologically important sulfoximine-containing compounds.
sulfones, sulfoximines have increased polarity, can present
improved solubility, and provide an additional point of
diversity and chirality to increase molecular complexity.[7]
Their expanding application in drug design is exemplified in
compound AZD6738 from AstraZeneca.[8,9] Moreover, since
their discovery in the form of MSO,[10] sulfoximines have been
developed as ligands and auxiliaries for asymmetric syn-
[13,14]
thesis[11,12] and directing groups in C H functionalization,
À
[*] M. Zenzola,[+] R. Doran,[+] Dr. J. A. Bull
Department of Chemistry, Imperial College London
South Kensington, London SW7 2AZ (UK)
E-mail: j.bull@imperial.ac.uk
as well as used in agrochemical agents such as sulfoxaflor.[15]
Sulfoximines are most often prepared by the transfer of
a protected nitrogen group to sulfoxides,[16] including the
transfer of sulfonamide,[17–19] trifluoroacetamide,[17] carba-
Homepage: http://www3.imperial.ac.uk/people/j.bull
M. Zenzola,[+] Dr. L. Degennaro, Prof. Dr. R. Luisi
Department of Pharmacy, Drug Sciences
University of Bari “A. Moro”
Via E. Orabona 4, Bari 70125 (Italy)
E-mail: renzo.luisi@uniba.it
Homepage: http://www.farmchim.uniba.it/chimica organica/
Luisi2.html
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201602320.
ꢀ 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution License, which permits use, distribution and
reproduction in any medium, provided the original work is properly
cited.
Scheme 1. Synthesis of sulfoximines from sulfoxides.
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mate,[20] and amide groups[21] using transition-metal catalysis
(Scheme 1a). These sulfoximines have been deprotected to
yield the free NH derivatives, and further functionalized to
generate N-aryl, N-acyl, and N-alkyl, as well as cyclic
derivatives, offering varying properties.[22] The direct syn-
thesis of NH sulfoximines has largely involved undesirable
reaction conditions, including harsh and explosive reagents.[23]
Recently, a scalable synthesis of NH sulfoximines in contin-
uous flow was reported by Kappe and co-workers using
trimethylsilyl azide and fuming sulfuric acid to transfer an NH
group directly to a sulfoxide intermediate of AZD6738, but
racemization of the sulfur center occurred.[24] Richards and
co-workers have demonstrated the use of DPH with rhodium
catalysis for the direct preparation of NH sulfoximines under
mild reaction conditions (Scheme 1b).[25] To date there are no
direct methods for the transfer of NH to sulfoxides which use
convenient, inexpensive, and safe nitrogen sources. Improved
methods for this transfer, methods which avoid harsh
reagents, could be widely applied. Herein we report a new
process based on commercially available and inexpensive
reagents for the stereospecific preparation of NH sulfox-
imines from sulfoxides using ammonium salts, as the source of
NH, with diacetoxyiodobenzene [PhI(OAc)2], without the
requirement for a precious metal catalyst or base (Sche-
me 1c).
iodobenzene and magnesium oxide (reaction conditions i;
Scheme 2a; see the Supporting Information for details of the
optimization).
With the heterogeneous nature of the reaction in toluene,
the rate appeared controlled by the rate of dissolution of
ammonium carbamate. Therefore, more polar solvents were
investigated to reduce the reaction time. Acetonitrile and
methanol were both successful in achieving full conversion by
varying the equivalents of ammonium carbamate, without
additional base (Scheme 2). In acetonitrile the reaction gave
full conversion with 1.5 equivalents of PhI(OAc)2 at 258C
(reaction conditions ii), though different results were
obtained when running the reaction in sealed vessels com-
pared to those in open flasks; those run in an open flask gave
a slight drop in yield. The most convenient reaction conditions
with the shortest reaction time were with MeOH, and full
conversion was achieved at 258C within 30 minutes when
using 3 equivalents of PhI(OAc)2 and 4 equivalents of am-
monium carbamate (reaction conditions iii). Under these
reaction conditions the reaction was performed in an open
flask, with decarboxylation evident, and scalability was
demonstrated by performing the reaction on a 10 mmol
scale (1a, 91%). The stereochemistry of the process was
evaluated using the readily accessible enantioenriched methyl
p-tolyl sulfoxide (e.r.: 97:3). The reaction occurred stereo-
specifically with retention of configuration, thus providing the
corresponding enantioenriched sulfoximine (S)-1a (Sche-
me 2b).
The reaction scope was examined by using reaction
conditions iii (MeOH; Table 1). For certain substrates either
the MeCN or toluene reaction conditions were used depend-
ing on solubility and to provide a comparison of the different
reaction conditions. Aryl-substituted (R1) sulfoxides proved
to be generally excellent substrates for this transformation.
Phenyl, tolyl, p-chlorophenyl, and p-bromophenyl examples
were all obtained in excellent yields. The scope with respect to
R2 was also good, and included isopropyl, ethyl, ethylphenyl,
benzyl, and haloalkyl groups. A yield of 69% was observed
for the phenyl fluoromethyl sulfoximine 1c using the meth-
anol reaction conditions. The slightly lower yield resulted
from the electron-withdrawing nature of the fluoromethyl
substituent, but it was improved (78%) by using the
acetonitrile reaction conditions. Performing the reaction on
enantioenriched substrates gave the enantioenriched sulfox-
imines 1b,h with complete retention of configuration [(R)-1b,
e.r.: 98:2, (R)-1h, e.r. > 99:1]. For a secondary alkyl chloride
substrate, the d.r. of the sulfoxide (9:1) was retained in the
sulfoximine 1i. The acetophenone derivative 1j showed the
tolerance of the reaction towards aromatic ketones (64%
yield). Phenylvinylsulfoxide was a viable substrate, as was
diphenyl sulfoxide, thus leading to the corresponding sulfox-
imines 1l and 1m.
Given our previous success in the transfer of alkyl
carbamates to sulfoxides using rhodium catalysis,[20] we
considered that the use of a carbamate salt, which is
structurally comparable, might undergo a similar N transfer.
Loss of CO2 would achieve an overall NH transfer, and as
such these reagents would provide a formal nitrene equiv-
alent. Ammonium carbamate was chosen as an inexpensive
easily handled solid. This reagent has not previously been
used in the formation of electrophilic nitrogen sources,
though it was very recently used by Nicewicz and co-workers
À
as an ammonia source in arene C H amination under
photoredox catalysis.[26] We initially considered metal-cata-
lyzed processes for this transformation (using Rh and Fe
species) and found high yields of the sulfoximine resulted
when starting from methyl p-tolylsulfoxide. However, we
were delighted to find that the reaction proceeded equally
efficiently in the absence of a metal catalyst. Indeed, after
optimization complete conversion to sulfoximine 1a was
achieved when the reaction was run for 16 h at 358C in
toluene, by mixing ammonium carbamate with diacetoxy-
Upon extending the scope with to dialkyl sulfoxides, high
yields were also obtained, as demonstrated by the dibenzyl-
sulfoximine 1n, the sterically bulky tert-butylmethyl sulfox-
imine 1o, and the cyclic thiophene and thietanesulfoximines
1p and 1q, respectively (Table 1). The thietanesulfoximine 1q
was prepared on an 11 mmol scale in similarly good yield
(81%). Several unusual substituted thietane oxides were also
Scheme 2. Synthesis of sulfoximines using ammonium carbamate.
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Table 1: Substrate scope for the NH transfer from the corresponding
the vast majority of these heterocycles (see Table S4 in the
sulfoxides.[a]
Supporting Information). Only two out of the 15 heterocycles
tested, N-benzylpyrrole and N-methylindole, gave less than
85% yield with the majority yielding greater than 95%.
Importantly, heterocycles with basic nitrogen groups did not
interfere with the reaction. Excellent results in the presence
of pyridine, pyrimidine, quinolone imidazole, thiazole, ben-
zoxazole, and benzothiazole groups were achieved. Electron-
rich aromatic groups were less well tolerated. In many cases
the reaction proceeded well, but with poor recovery of the
added indole, furan, and thiophene groups. An N-benzyl-
protected pyrrole was detrimental to the reaction, yet the N-
Boc example was much better tolerated. Gratifyingly, the
reaction proved remarkably tolerant of the nine functional-
group additives tested. Alkene, alkyne, alkyl amine, phenol,
ester, aldehyde, and nitrile additives all gave greater than
96% yields with only aniline giving a more moderate yield of
65%. The recovery of the additive was also good with the
exception of benzaldehyde. These results demonstrate a high
degree of compatibility of the reaction conditions for a wide
range of pharmaceutically relevant functionality.
We proposed that the role of the ammonium carbamate
was simply to provide a convenient source of ammonia
(Scheme 3a; see the Supporting Information). The reaction
[a] Three sets of reaction conditions (i–iii) were examined. Yield is that of
the isolated product. [b] 8 equiv H2NCO2NH4, 4 equiv of PhI(OAc)2,
24 h. Boc=tert-butoxycarbonyl.
suitable substrates.[27,28] The benzyl-substituted example 1r
was obtained from the corresponding sulfoxide in very good
yields by using reaction conditions i. Diastereomerically pure
tertiary-alcohol-containing thietane oxides led stereospecifi-
cally to the sulfoximines 1s–u. Avery good yield was obtained
for the benzothiazole-substituted sulfoximine 1v. Further-
more, protected methionine sulfoxide gave the derivative 1w
in a formal synthesis of MSO (see Figure 1).[29] A sulfoxide
bearing the electron-withdrawing trifluoromethyl group
appeared to be at the limit of reactivity for this methodology,
thus affording a 9% yield of the p-bromophenyl trifluoro-
methyl sulfoximine 1x. Oxfendazole, a benzimidazole-con-
taining anthelmintic, gave the corresponding sulfoximine 1y
in 70% under a modified set of reaction conditions, which
were required because of the low solubility of the sulfoxide.
Under these reaction conditions, the reaction was highly
selective for the formation of sulfoximines, rather than
reaction with other functionalities. To demonstrate this
selectivity, we performed a reaction robustness screen,
based on the protocol described by Glorius and co-workers,[30]
as it was designed to assess the tolerance of a reaction to
added functional groups and their stability to the reaction
conditions. We screened the range of heterocycles suggested
by Glorius and we found the reaction to be highly tolerant of
Scheme 3. Alternative ammonia sources led to successful reaction.
would be faster in methanol not only because of the increased
solubility of the ammonium carbamate, but also because
PhI(OAc)2 undergoes a fast ligand exchange reaction with the
solvent releasing acetic acid which accelerates the decom-
position of the ammonium carbamate.[31] Consistent with this
hypothesis we were pleased to observe successful reaction
through the use of a solution of ammonia in methanol.
Complete conversion was obtained using 4 equivalents of
NH3 (Scheme 3b). Interestingly, the ammonium acetate,
which is also likely to be formed in the reaction with
ammonium carbamate, also provided a suitable source of
ammonia, thus giving almost complete conversion with 8 or
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4 equivalents (Scheme 3c, reaction conditions iv). By using
these reaction conditions with ammonium acetate, also
a conveniently handled solid, additional sulfoxides were
examined and afforded the sulfoximines (S)-1a, 1p, and 1w
in good yields (Scheme 3c). Ammonium chloride was also
tested but the expected sulfoximine was not observed,
whereas the reaction with aqueous ammonia resulted in
complete recovery of the starting sulfoxide.
Initially we considered it likely that the reaction pro-
ceeded via the unprecedented iminoiodinane PhI = NH,
which may be better represented as a charge-separated
ylide with an I!N dative bond.[32] Seeking insight into the
mechanism and evidence of the iminoiodinane species, we
performed an extensive NMR investigation to monitor the
reaction in deuterated toluene, acetonitrile, and methanol
(see the Supporting Information). The reaction progressed to
completion in each case, and was clearly faster in [D4]MeOH
and [D3]MeCN than in toluene. In all cases, the only
detectable species derived from the sulfoxide under the full
reaction conditions was an iodonium salt (2) which collapsed
to the sulfoximine over time (Scheme 4).[33] Independently
detected. In another experiment, with the aim to probe the
identity of 4, 15N-labeled ammonia was employed. By using
15N-labeled ammonium acetate, the expected isotopic shift for
4 was observed (see the Supporting Information). Finally,
a radical pathway for this reaction was shown to be unlikely as
the reaction proceeded successfully in the presence of radical
inhibitors (see the Supporting Information).
As a result of these studies, we propose that the
ammonium carbamate or acetate provides a sufficient con-
centration of ammonia to react with PhI(OAc)2 to form either
3 or 4, which are short lived and sufficiently electrophilic to
react directly with the sulfoxide and afford the sulfoximine. It
is worth mentioning, that in all the MS experiments large
amounts of iodosylbenzene (PhI = O) were also detected. It
was assumed that 4 could derive from 3 by iodosylbenzene-
promoted oxidation. In Scheme 4, two possible pathways are
proposed and involve the intermediates 3 and 4. With the
involvement of 3, the formation of the sulfoximine may occur
by either direct attack of the sulfoxide at the nitrogen atom,
with displacement of iodobenzene,[33,36] or attack at the iodine
center, and a subsequent reductive elimination sequence
leading to the sulfoximine.[37] In the case of the 4, a direct
nucleophilic attack of the sulfur atom at the electrophilic
nitrogen atom would lead directly to 2, according to NMR
and MS data. In both pathways, the nucleophilicity of the
sulfoxide is therefore important, thus explaining the reduced
reactivity with very electron-poor sulfoxides.
In summary, we have developed an extremely facile
method for the preparation of NH sulfoximines using readily
available reagents, without the requirement for precious
metal catalysts, with ammonium salts as the nitrogen source.
Ammonium carbamate or ammonium acetate both provide
convenient sources of ammonia, which are less expensive than
pre-prepared solutions of ammonia in methanol, and easily
handled as solid reagents. The reaction works efficiently for
a wide substrate scope and tolerates a large number of
heterocycles and other functionalities. We expect this proto-
col will be of use to medicinal chemists for the preparation of
this valuable functional group and to be readily scalable. A
reactive iminoiodinane (or iodonitrene) is generated in situ,
thus removing the requirement for stoichiometric activated
amine source. This reaction constitutes the first example of
electrophilic NH transfer mediated by hypervalent iodine.
Scheme 4. Proposed reaction mechanism involving a reactive imino-
iodinane or iodonitrene.
mixing the isolated sulfoximine with PhI(OAc)2 generated the
À
same 2, containing an I N single bond, which we have
characterized by NMR spectroscopy and mass spectrometry
(see the Supporting Information). We proposed that while the
reaction was still progressing the sulfoximine product reacted
very rapidly with excess PhI(OAc)2 to give 2 (Scheme 4).
Using a longer reaction time or working up the reaction either
directly by evaporation (from the reaction in MeOH) or
through a simple aqueous base extraction caused a complete
breakdown of this species to give only the desired sulfox-
imine.
Acknowledgements
For financial support we acknowledge the EPSRC [CAF to
J.A.B. (EP/J001538/1); and Impact Acceleration Account
Throughout these NMR studies there was no evidence of
any reactive intermediate.[34] Therefore, to further probe the
mechanism, we performed mass spectrometry analysis under
flow conditions.[35] On mixing PhI(OAc)2 and ammonium
carbamate, signals consistent with the iminoiodinane 3 (PhI =
NH; Scheme 4) were observed, thus providing the first
evidence for this species, as well as the unprecedented
iodonitrene 4 (PhI = N+; see the Supporting Information),
and support for their involvement as reaction intermediates.
However, after addition of the sulfoxide, again only 2 was
(EP/K503733/1)], The Royal Society for a University
Research Fellowship (to J.A.B.), Imperial College London;
Regione Puglia: “Reti di Laboratori pubblici di ricerca”
Project code 20, and Project Laboratorio Sistema code
PONa300369 financed by MIUR, and the University of Bari.
Keywords: hypervalent compounds · nitrogen ·
reactive intermediates · sulfur · synthetic methods
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Received: March 7, 2016
Published online: April 29, 2016
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