Metal-Free Approach for the Synthesis of N-Aryl Sulfoximines via Aryne Intermediate

Article abstract of DOI:10.1021/acs.orglett.5b02804

A metal-free and operationally simple N-arylation of NH-sulfoximines with aryne precursors is reported. Transition metal-free reaction conditions and shorter reaction times are the highlights of the present method. The mild optimized condition was also found to be suitable with enantiopure substrates.

Full text of DOI:10.1021/acs.orglett.5b02804

Letter
pubs.acs.org/OrgLett
Metal-Free Approach for the Synthesis of N‑Aryl Sulfoximines via
Aryne Intermediate
Sravan Kumar Aithagani,†,‡ Saidulu Dara,†,‡ Gurunadham Munagala,†,‡ Hariprasad Aruri,†,‡
Mahipal Yadav,† Shweta Sharma,† Ram A. Vishwakarma,†,‡ and Parvinder Pal Singh*,†,‡
†Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-180001, India
‡Academy of Scientific and Innovative Research, Canal Road, Jammu-180001, India
S
* Supporting Information
ABSTRACT: A metal-free and operationally simple N-arylation of NH-sulfoximines with aryne precursors is reported.
Transition metal-free reaction conditions and shorter reaction times are the highlights of the present method. The mild
optimized condition was also found to be suitable with enantiopure substrates.
Scheme 1. Previous and Present Approaches for the
Synthesis of N-Aryl Sulfoximines
ulfoximines are a versatile class of compounds in organic
Schemistry because of their applicability as chiral
auxiliaries,1 as ligands in asymmetric catalysis,2 and as building
blocks in pseudopeptides.3 In the current decade, sulfoximines
have also gained significant attention in medicinal chemistry.4
Considering their importance, extensive work has been done
regarding the synthesis and functionalization of sulfoximines,
but new mild methods are still highly desired. Regarding the
functionalization of sulfoximines, N-arylated sulfoximines have
been greatly explored since the pioneering work of Bolm in
1998 via transition-metal catalysis.5 After this, several metal-
catalyzed (Pd, Cu, Ni, and Fe) approaches have been
developed using various donors such as aryl halides, aryl
triflates, nonaflates, tosylates, arylboronic acids, and diary-
liodonium salts (Scheme 1, approaches a and b).6,7
In the present decade, metal-free and mild methods
involving readily available starting materials are the choice.
In this context, arynes offer an attractive alternative and, due
to their distinct electronic properties, they are recognized as
good substrates for metal-free organic transformations.8 To
this end, we have recently developed a metal-free method for
the synthesis of variety of sulfones through an aryne
intermediate.9 Considering the electronic properties of arynes
(electrophilic) and sulfoximines (nucleophilic), we envisioned
that the arylation of NH-sulfoximines could be achieved with
arynes under metal-free conditions, which to the best of our
knowledge, has not yet been explored. Herein, we report the
first metal-free method for the synthesis of N-aryl sulfoximines
by the reaction between arynes and NH-sulfoximines at room
temperature (Scheme 1, approach c).
methylphenylsulfoximine 2a as the model substrates (Table
1).
When the reaction was performed with CsF as the fluoride
source (to generate benzyne) at room temperature in
acetonitrile, the desired product 3a was obtained in a modest
yield of 38% (Table 1, entry 1). In the next reaction, an
increase in the quantity of CsF had a minor effect on the
product yield (Table 1, entry 2). Other fluoride sources such
as KF/18-crown-6,10 TBAF,11 and TBAT12 were also tried.
Among the fluoride sources used (Table 1, entries 3−5) KF/
18-crown-6 furnished the desired product 3a in 50% yield. To
We commenced our investigation using readily available 2-
(trimethylsilyl)phenyl trifluoromethanesulfonate 1a and S,S-
Received: September 28, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02804
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
our delight, a significant increase in the yield up to 72% of 3a
was observed when THF was used as the solvent (Table 1,
entry 6). Further, the use of dioxane as the solvent did not
show any improvement (Table 1, entry 7). Using THF as the
solvent, other fluoride sources such as TBAF, CsF, and TBAT
also showed no advantage (Table 1, entries 8−10). Further, a
decrease in the amount of KF/18-crown-6 also reduced the
yield of 3a (Table 1, entry 11).
Table 2. Substrate Scope of Various Aryne Precursors
a
Table 1. Optimization Studies
b
entry
F− source
CsF
equiv
solvent
yield (%)
1
3.0
4.0
2.0
2.0
2.5
2.5
2.5
1.5
3.0
2.0
2.0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
38
40
42
40
50
72
58
60
25
57
65
2
CsF
c
3
TBAF
d
4
TBAT
5
KF/18-crown-6
KF/18-crown-6
KF/18-crown-6
TBAF
6
7
dioxane
THF
8
9
CsF
THF
10
11
TBAT
THF
KF/18-crown-6
THF
a
Reaction conditions (unless otherwise stated): 1a (0.2 mmol, 1.0
equiv), 2a (0.2 mmol, 1.0 equiv), F− source, solvent 2 mL, under N2,
at room temperature for 4 h. Isolated yield. Tetrabutylammonium-
fluoride. Tetrabutylammonium difluorotriphenylsilicate.
b
c
d
With the optimized reaction conditions in hand, we
examined the substrate scope with various aryne precursors,
and the results are depicted in Table 2. Aryne precursors 1b
and 1c (having substitutions ortho to “yne” bond) when tried,
sulfoximine 2a attacked at the remote site exclusively (meta to
substitution) and produced corresponding N-aryl sulfoximines
3b and 3c in 63% and 65% yields, respectively. However, in
the case of aryne precursor 1d (substitution meta to “yne”
bond), nucleophile 2a reacted at two possible sites (meta and
para) and produced a mixture of inseparable regioisomers 3c/
3d in a ratio of 1:1.5 with an overall yield of 63%. Further,
naphthyl based aryne precursors 1e and 1f furnished only the
2-substituted regioisomer 3e in moderate yields, 45% and
42%, respectively. Symmetrical and highly electron-rich aryne
precursor 1g also proceeded well and afforded 3f in a yield of
58%.
Next, the reactivity of different sulfoximines was inves-
tigated, and the results are summarized in Scheme 2. An array
of sulfoximines having different electon-donating (OMe and
Me) as well as electron-withdrawing substituents (Br and Cl)
were tried. These underwent the desired transformation
smoothly and furnished the corresponding N-aryl sulfoximines
4a−d in good to high yields of 77%, 72%, 65%, and 55%,
respectively. Notably, S,S-dimethylsulfoximine was also found
to be a good substrate under optimized conditions, affording
the corresponding product 4e in a yield of 58%. Further, S,S-
tetramethylenesulfoximine also furnished the expected product
4f in a moderate yield of 45%. Unfortunately, when S,S-
diphenylsulfoximine was used under standard conditions, the
a
Reaction conditions (unless otherwise stated): 1 (0.2 mmol, 1.0
equiv), 2a (0.2 mmol, 1.0 equiv), KF/18-crown-6 (0.5 mmol, 2.5
equiv), THF 2 mL, under N2, at room temperature for 2−4 h.
b
Isolated yield.
desired product 4g was obtained in a yield of less than 5%.
Interestingly, sulfoximines having different aliphatic chain
substituents at S-center also proceeded well under the
optimized conditions and afforded the corresponding products
4h−j in moderate to good yields of 47−60%.
To determine the tolerance of the present optimized
conditions toward chiral substrates, 2-(trimethylsilyl)phenyl
trifluoromethanesulfonate 1a was treated with enantiopure
sulfoximine, (S)-(+)-S-methyl-S-phenylsulfoximine. The corre-
sponding product (S)-(+)-3a was observed in a yield of 70%
with retention of configuration (Scheme 3), suggesting that
the chiral substrates are also tolerable under present reaction
conditions.
In conclusion, we have demonstrated a simple and metal-
free method for the synthesis of N-aryl sulfoximines via an
aryne intermediate. The present method enables very mild
conditions and requires shorter reaction times when
compared with previous reports.
B
DOI: 10.1021/acs.orglett.5b02804
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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a
Lett. 2003, 44, 7261−7264. (g) Harmata, M.; Pavri, N. Angew. Chem.,
Int. Ed. 1999, 38, 2419−2421. (h) Koep, S.; Gais, H.-J.; Raabe, G. J.
Am. Chem. Soc. 2003, 125, 13243−13251.
Scheme 2. Substrate Scope of Various Sulfoximines
(2) (a) Bolm, C.; Martin, M.; Simic, O.; Verrucci, M. Org. Lett.
2003, 5, 427−429. (b) Bolm, C.; Felder, M.; Muller, J. Synlett 1992,
̈
1992, 439−441. (c) Bolm, C.; Verrucci, M.; Simic, O.; Cozzi, P. G.;
Raabe, G.; Okamura, H. Chem. Commun. 2003, 2826−2827.
́
(d) Bolm, C.; Simic, O. J. Am. Chem. Soc. 2001, 123, 3830−3831.
(e) Langner, M.; Bolm, C. Angew. Chem., Int. Ed. 2004, 43, 5984−
5987. (f) Langner, M.; Remy, P.; Bolm, C. Chem. - Eur. J. 2005, 11,
6254−6265. (g) Langner, M.; Remy, P.; Bolm, C. Synlett 2005, 2005,
́
́
0781−0784. (h) Moessner, C.; Bolm, C. Angew. Chem., Int. Ed. 2005,
44, 7564−7567.
(3) (a) Senthil Kumar, P.; Bharatam, P. V. Tetrahedron 2005, 61,
5633−5639. (b) Hackenberger, C. P. R.; Raabe, G.; Bolm, C. Chem. -
Eur. J. 2004, 10, 2942−2952. (c) Bolm, C.; Muller, D.; Dalhoff, C.;
̈
Hackenberger, C. P. R.; Weinhold, E. Bioorg. Med. Chem. Lett. 2003,
13, 3207−3211. (d) Bolm, C.; Muller, D.; Hackenberger, C. P. R.
̈
Org. Lett. 2002, 4, 893−896. (e) Bolm, C.; Moll, G.; Kahmann, J. D.
Chem. - Eur. J. 2001, 7, 1118−1128. (f) Mock, W. L.; Tsay, J. T. J.
Am. Chem. Soc. 1989, 111, 4467−4472.
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2 (0.2 mmol, 1.0
equiv), KF/18-crown-6 (0.5 mmol, 2.5 equiv), THF 2 mL, under N2,
at room temperature for 2−4 h.
(4) Lucking, U. Angew. Chem., Int. Ed. 2013, 52, 9399−9408.
̈
(5) (a) Bolm, C.; Hildebrand, J. P. Tetrahedron Lett. 1998, 39,
5731.
a
Scheme 3. Reaction with Enantiopure Sulfoximine
(6) (a) Sedelmeier, J.; Bolm, C. J. Org. Chem. 2005, 70, 6904−
6906. (b) Correa, A.; Bolm, C. Adv. Synth. Catal. 2007, 349, 2673−
́
2676. (c) Cho, G. Y.; Remy, P.; Jansson, J.; Moessner, C.; Bolm, C.
Org. Lett. 2004, 6, 3293−3296.
(7) (a) Harmata, M.; Hong, X.; Ghosh, S. K. Tetrahedron Lett.
2004, 45, 5233−5236. (b) Yongpruksa, N.; Calkins, N. L.; Harmata,
́ ́
M. Chem. Commun. 2011, 47, 7665−7667. (c) Mace, Y.; Pegot, B.;
a
Guillot, R.; Bournaud, C.; Toffano, M.; Vo-Thanh, G.; Magnier, E.
Tetrahedron 2011, 67, 7575−7580. (d) Kim, J.; Ok, J.; Kim, S.; Choi,
W.; Lee, P. H. Org. Lett. 2014, 16, 4602−4605. (e) Vaddula, B.;
Leazer, J.; Varma, R. S. Adv. Synth. Catal. 2012, 354, 986−990.
(8) Bhunia, A.; Yetra, S. R.; Biju, A. T. Chem. Soc. Rev. 2012, 41,
3140−3152.
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), 2a (0.2 mmol, 1.0
equiv), KF/18-crown-6 (0.5 mmol, 2.5 equiv), THF 2 mL, under N2,
at room temperature for 2−4 h.
ASSOCIATED CONTENT
■
(9) Aithagani, S. K.; Yempalla, K. R.; Munagala, G.; Vishwakarma,
R. A.; Singh, P. P. RSC Adv. 2014, 4, 50208−50211.
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02804.
(10) (a) Mohanan, K.; Coquerel, Y.; Rodriguez, J. Org. Lett. 2012,
14, 4686−4689. (b) Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai,
A. Chem. Commun. 2005, 3292−3294. (c) Bhojgude, S. S.; Kaicharla,
T.; Biju, A. T. Org. Lett. 2013, 15, 5452−5455. (d) Yoshida, H.;
Fukushima, H.; Ohshita, J.; Kunai, A. J. Am. Chem. Soc. 2006, 128,
11040−11041. (e) Yoshida, H.; Ohshita, J.; Kunai, A. Bull. Chem.
Soc. Jpn. 2010, 83, 199−219.
General procedures regarding the synthesis of sulfox-
1
imines and N-aryl sulfoximines along with H and 13C
spectra of all synthesized compounds (PDF)
(11) (a) Pandya, V. G.; Mhaske, S. B. Org. Lett. 2014, 16, 3836−
3839. (b) Fang, Y.; Wu, C.; Larock, R. C.; Shi, F. J. Org. Chem. 2011,
76, 8840−8851. (c) Wang, C.-D.; Liu, R.-S. Org. Biomol. Chem. 2012,
10, 8948−8952.
(12) (a) Rogness, D. C.; Markina, N. A.; Waldo, J. P.; Larock, R. C.
J. Org. Chem. 2012, 77, 2743−2755. (b) Bunescu, A.; Wang, Q.; Zhu,
J. Org. Lett. 2014, 16, 1756−1759. (c) Allan, K. M.; Gilmore, C. D.;
Stoltz, B. M. Angew. Chem., Int. Ed. 2011, 50, 4488−4491.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ppsingh@iiim.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Authors acknowledge the financial support of CSIR with
research grant # HCP 0001 and BSC 0108. S.K.A., S.D., G.M.,
H.A., M.Y., and S.S. thank CSIR/UGC for their Fellowship.
The authors also thank the Instrumentation Division of CSIR-
IIIM for support. IIIM Communication No. IIIM/1861/2015.
REFERENCES
■
(1) (a) Johnson, C. R. Acc. Chem. Res. 1973, 6, 341−347. (b) Craig,
D.; Grellepois, F.; White, A. J. P. J. Org. Chem. 2005, 70, 6827−6832.
(c) Moessner, C.; Bolm, C. Org. Lett. 2005, 7, 2667−2669. (d) Gais,
H.-J.; Babu, G.S.; Gunter, M.; Das, P. Eur. J. Org. Chem. 2004, 2004,
̈
1464−1473. (e) Harmata, M.; Hong, X. J. Am. Chem. Soc. 2003, 125,
5754−5756. (f) Harmata, M.; Hong, X.; Barnes, C. L. Tetrahedron
C
DOI: 10.1021/acs.orglett.5b02804
Org. Lett. XXXX, XXX, XXX−XXX