Exploring the reactivity of N-alkynylated sulfoximines: [2 + 2]-cycloadditions

Article abstract of DOI:10.1021/ol4026028

To assess the potential of N-alkynylated sulfoximines as new (chiral) reagents for organic synthesis, their reactivity profile in numerous synthetic processes is under investigation. When reacted with ketenes, the alkynylated-sulfoximines undergo a [2 + 2]-cycloaddition process to afford sulfoximine-functionalized cyclobutenones in excellent yields.

Full text of DOI:10.1021/ol4026028

ORGANIC
LETTERS
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Vol. XX, No. XX
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Exploring the Reactivity of N‑Alkynylated
Sulfoximines: [2 þ 2]-Cycloadditions
Ramona Pirwerdjan, Daniel L. Priebbenow, Peter Becker, Philip Lamers, and
Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1,
D-52074 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received September 9, 2013
ABSTRACT
To assess the potential of N-alkynylated sulfoximines as new (chiral) reagents for organic synthesis, their reactivity profile in numerous synthetic
processes is under investigation. When reacted with ketenes, the alkynylated-sulfoximines undergo a [2 þ 2]-cycloaddition process to afford
sulfoximine-functionalized cyclobutenones in excellent yields.
Sulfoximines have been widely applied in organic syn-
thesis, medicinal chemistry, and agrochemistry.1 The de-
velopment ofnew methods thatfacilitate the incorporation
of the sulfoximidoyl moiety into organic molecules using
mildconditions is acontinuinggoalofourresearchgroup.2
To this end, we recently reported the synthesis of a new
class of compounds, N-alkynylated sulfoximines 3,
through an oxidative copper-catalyzed coupling of term-
inal alkynes 2 with NH-sulfoximines 1 (Scheme 1).3,4
In recent years, ynamides have been successfully em-
ployed in numerous transformations including cycloaddi-
tions, nucleophilic additionreactions, cycloisomerizations,
and metal-catalyzedcross-coupling reactions.5 Tothisend,
it was envisaged that the sulfoximine ynamide analogs 3
also possessed significant potential as reagents that would
allow the incorporation of the (chiral) sulfoximidoyl moi-
ety into a broad variety of synthetic molecules.
Furthermore, cyclobutanones have been applied as use-
ful synthetic intermediates in a range of organic and
natural product syntheses often in processes that include
ring-opening and ring-expansion reactions.6 One of the
(1) For selected recent examples regarding sulfoximines, see: (a) Zhu,
Y.; Loso, M. R.; Watson, G. B.; Sparks, T. C.; Rogers, R. B.; Huang,
J. X.; Gerwick, B. C.; Babcock, J. M.; Kelley, D.; Hegde, V. B.; Nugent,
B. M.; Renga, J. M.; Denholm, I.; Gorman, K.; DeBoer, G. J.; Hasler, J.;
Meade, T.; Thomas, J. D. J. Agric. Food Chem. 2011, 59, 2950. (b) Park,
S. J.; Buschmann, H.; Bolm, C. Bioorg. Med. Chem. Lett. 2011, 21, 4888.
(c) Gais, H. J. Heteroat. Chem. 2007, 18, 472. (d) Okamura, H.; Bolm, C.
(5) (a) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.;
Zhang, Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064. (b) Evano, G.;
Coste, A.; Jouvin, K. Angew. Chem. 2010, 122, 2902. Angew. Chem., Int.
Ed. 2010, 49, 2840.
€
Chem. Lett. 2004, 33, 482. (e) Lucking, U. Angew. Chem. 2013, 125, 9570.
Angew. Chem., Int. Ed. 2013, 52, 9399.
(6) (a) Namyslo, J. C.; Kaufmann, D. E. Chem. Rev. 2003, 103, 1485.
(b) Wong, H. N. C.; Lau, K.-L.; Tam, K.-F. Top. Curr. Chem. 1986, 133,
84. (c) Bellus, D.; Ernst, B. Angew. Chem. 1988, 100, 820. Angew. Chem.,
Int. Ed. 1988, 100, 820.
(7) (a) Hyatt, J. A.; Raynolds, P. W. In Organic Reactions; Paquette,
L. A., Ed.; Wiley: New York, 1994; Vol. 45, pp 159ꢀ646. (b) Danheiser,
R. L., Ed. Science of Synthesis: Houben Weyl Methods of Molecular
Transformations; Thieme: Stuttgart, 2006; Vol. 23.
(8) For selected examples, see: (a) Hassner, A.; Dillon, J. L., Jr.
J. Org. Chem. 1983, 48, 3382. (b) Danheiser, R. L.; Sard, H. Tetrahedron
Lett. 1983, 24, 23. (c) Hasek, R. H.; Gott, G. P.; Martin, J. C. J. Org.
Chem. 1964, 29, 1239. (d) Wasserman, H. H.; Piper, J. U.; Dehmlow,
E. V. J. Org. Chem. 1973, 38, 1451. (e) Kowalski, C. J.; Lal, G. S. J. Am.
Chem. Soc. 1988, 110, 3693. (f) Zificsak, C. A.; Mulder, J. A.; Hsung,
R. P.; Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575.
(2) For recent work, see: (a) Wang, J.; Frings, M.; Bolm, C. Angew.
Chem. 2013, 125, 8823. Angew. Chem., Int. Ed. 2013, 52, 8661. (b) Wang,
L.; Priebbenow, D. L.; Zou, L. H.; Bolm, C. Adv. Synth. Catal. 2013,
355, 1490.
(3) Wang, L.; Huang, H.; Priebbenow, D. L.; Pan, F.-F.; Bolm, C.
Angew. Chem. 2013, 125, 3562. Angew. Chem., Int. Ed. 2013, 52, 3478.
(4) In our recent publication (ref 3) we presented the only example of
an alkynylated sulfoximine reported in the literature. However, as
Professor Banert (TU Chemnitz) alerted us, the structure proposed in
the original publication ( Tanaka, R.; Yamabe, K. J. Chem. Soc. Chem.
Commun. 1983, 329. ) was incorrect and our report was in fact the first
describing access to N-alkynylated sulfoximines. For clarification, see:
Banert, K.; Hagedorn, M.; Wutke, J.; Ecorchard, P.; Schaarschmidt, D.;
Lang, H. Chem. Commun. 2010, 46, 4058.
r
10.1021/ol4026028
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To further explore this reaction process, a series of
alkynylated sulfoximines containing variations in both
the alkyne functionality and the sulfoximine substituents
were then reacted with the dimethyl ketene generated
in situ from isobutyryl chloride (Scheme 2). The steric pro-
perties of the alkynylated sulfoximines did not appear to
significantly affect the yield, with ortho-functionalized aryl
alkynes 4c and 4e performing well in the cycloaddition.
In addition, both electron-withdrawing and electron-
donating substituents on the aryl alkyne were tolerated.
Of note, the triethylsilyl-functionalized cyclobutenone 4g
was also formed, albeit in only moderate yield.
Scheme 1. Preparation of N-Alkynylated Sulfoximines
most common methods employed to access cyclobutanone
derivatives is the [2 þ 2]-cycloaddition of ketenes with
alkynes.7 To date, a wide range of alkynes containing aryl,
alkyl, amino-, silyoxy-, or alkoxy-substitutents have been
successfully employed in the cycloaddition process with
ketenes.8
Scheme 3. Investigation into the Range of Ketenes Applicable in
the [2 þ 2]-Cycloaddition
In 2006, Danheiser and co-workers reported the [2 þ 2]-
cycloaddition reaction of ynamides with ketenes that were
generated from the reaction of suitable acyl chlorides
with an organic base.9 To explore the potential reactivity
of N-alkynlated sulfoxmines in an analogous process,
sulfoximine 3a (R1 = Me, R2 = Ph, R3 = Ph) was reacted
with isobutyryl chloride in the presence of triethylamine
(Scheme 2). A simple workup of the reaction mixture after
refluxing for 16 h revealed that sulfoximine-functionalized
cyclobutenone 4a had formed in an exceptional yield
of 98%.
Scheme 2. Investigation into the [2 þ 2]-Cycloaddition of
N-Alkynylated Sulfoximines
Next, a range of alkyl- and aryl-substituted ketenes 5
were subjected to the cycloaddition conditions (Scheme 3).
It was found that all of them were applicable in the [2 þ 2]-
cycloaddition process with N-alkynylated sulfoximine 3a
providing the cyclobutenone derivatives in yields ranging
from 67% to 93%. When employing cyclohexane or cyclo-
propane carbonyl chlorides, spiro-cyclobutenones 4rꢀu
containing two contiguous carbocyclic rings were obtained
in high yields.
Unfortunately, in all cases using nonsymmetrical ke-
tenes, no significant diastereoinduction from the sulfox-
imine moiety was observed, and the products were isolated
as inseparable mixtures of diastereomers (typically in a
ratio of 1:1 to 2:3). As no diastereoselectivity was observed,
application of the enantiopure sulfoximine-containing
cyclobutenones was not pursued.
(9) Kohnen, A. L.; Mak, X. Y.; Lam, T. Y.; Dunetz, J. R.; Danheiser,
R. L. Tetrahedron 2006, 62, 3815.
(10) See Supporting Information for details.
B
Org. Lett., Vol. XX, No. XX, XXXX

sequently rearranged to afford sulfoximine 6 (Scheme 4),
the structure of which was subsequently confirmed by
X-ray analysis.10 The formation of amido-allenes during
the [2 þ 2]-cycloaddition process has been previously
described by several other groups.11 Steric factors appear
to have a larger influence on this reaction process than
electronic ones.12
Scheme 4. Results of the [2 þ 2]-Cycloaddition with the
Sterically Hindered Diphenyl Ketene
In summary, it was determined that N-alkynylated sulf-
oximines can be applied in [2 þ 2]-cycloaddition reactions
with ketenes affording a series of valuable sulfoximidoyl-
functionalized cyclobutenones in moderate to exceptional
yields. These results indicate that, with the sulfoximidoyl
group attached, the alkyne moiety is sufficiently electron
rich to behave as a nucleophile in the presence of a suitable
electrophile. Additional investigations into the reactivity
patterns of the N-alkynylated sulfoximines in other syn-
thetic transformations are currently underway and will be
reported in due course.
Acknowledgment. D.L.P. is grateful to the Alexander
von Humboldt Foundation for a Postdoctoral Fellowship.
This research was supported in part by the Cluster of
Excellence (Tailor-Made Fuels from Biomass) funded by
the Excellence Initiative of the German federal and state
governments. The authors thank Dr. F. Pan (RWTH
Aachen University) for a crystal structure analysis.
An interesting result was observed when alkynylated
sulfoximine 3a was reacted with the diphenylketene gen-
erated from diphenylacetyl chloride (Scheme 4). A separ-
able 1:1 mixture of the expected cycloaddition product 4v
(40% yield) and a byproduct, subsequently identified as
the tetrasubstituted allene 6 (40% yield), was obtained.
The formation of the allene derivative 6 was supposedly
due to steric interactions which forced the cycloaddition
to occur from the opposite end of the ketene resulting in
a highly strained four-membered cyclic ether which sub-
Supporting Information Available. Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org
(11) (a) Kuehne, M. E.; Sheeran, P. J. J. Org. Chem. 1968, 33, 4406.
(b) Ficini, J.; Pouliquen, J. Tetrahedron Lett. 1972, 1135. (c) Barbaro, G.;
Battaglia, A.; Giorgianni, P. J. Org. Chem. 1987, 52, 3289. (d) Schulte,
N.; Moller, M. H.; Rodewald, U.; Wurthwein, E.-U. Chem. Ber. 1994,
127, 1287.
(12) During this investigation, trace amounts of such allene bypro-
ducts were identified in some of the cycloaddition reactions performed.
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The authors declare no competing financial interest.
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