Practical preparation of N-(1-alkynyl)sulfonamides and their remote diastereoselective addition to aldehydes via titanation

Article abstract of DOI:10.1021/ol036396b

Aliphatic and aromatic sulfonamides were alkynylated with 1-bromo-1-alkynes in the catalytic presence of CuI to give N-(1-alkynyl) sulfonamides in good to excellent yields. The acetylene-titanium complexes generated from N-(1-alkynyl)benzosultams underwen

Full text of DOI:10.1021/ol036396b

ORGANIC
LETTERS
2004
Vol. 6, No. 5
727-729
Practical Preparation of
N-(1-Alkynyl)sulfonamides and Their
Remote Diastereoselective Addition to
Aldehydes via Titanation
,†
,‡
Shuji Hirano,† Ryoichi Tanaka,† Hirokazu Urabe,* and Fumie Sato*
Departments of Biological Information and Biomolecular Engineering,
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8501, Japan
hurabe@bio.titech.ac.jp; fsato@bio.titech.ac.jp
Received December 9, 2003
ABSTRACT
Aliphatic and aromatic sulfonamides were alkynylated with 1-bromo-1-alkynes in the catalytic presence of CuI to give N-(1-alkynyl)sulfonamides
in good to excellent yields. The acetylene−titanium complexes generated from N-(1-alkynyl)benzosultams underwent diastereoselective addition
to aldehydes.
Acetylene-group 4 metal complexes are versatile and
indispensable organometallic reagents in organic synthesis.1,2
Successful extension of the parent acetylenes to functional-
ized ones has considerably broadened the utility of these
complexes,1a-c among which we recently reported the
generation of [N-(1-alkynyl)sulfonamide]-titanium alkoxide
complexes and their regio- and (olefinic) stereoselective
coupling with acetylenes or carbonyl compounds.3 Although
their amino group should serve diastereoselective synthesis,
such an attempt was somewhat discouraged by the current
limited synthesis of the aminoacetylenes via alkynyliodonium
salts.4 Considering the recent progress in the transition metal-
catalyzed amination of organic halides,5,6 particularly the
(4) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed. 1998, 37, 489-
492. Murch, P.; Williamson, B. L.; Stang, P. J. Synthesis 1994, 1255-
1256. Witulski, B.; Go¨ssmann, M. Chem. Commun. 1999, 1879-1880. For
the latest application, see: Witulski, B.; Lumtscher, J.; Bergstra¨sser, U.
Synlett 2003, 708-710 and references therein. For a review on (1-alkynyl)-
amine derivatives, see: Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.;
Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575-7606.
(5) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem.
Res. 1998, 31, 805-818. Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852-
860. Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046-2067. Yang,
B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125-146. Prim,
D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58,
2041-2075.
(6) (a) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421-7428. During the course of our study, the following report
appeared: (b) Frederick, M. O.; Mulder, J. A.; Tracey, M. R.; Hsung, R.
P.; Huang, J.; Kurtz, K. C. M.; Shen, L.; Douglas, C. J. J. Am. Chem. Soc.
2003, 125, 2368-2369. However, this paper described that the sulfonamides
and sultams are sluggish substrates toward the alkynylation. Furthermore,
after the completion of the preparation of this manuscript, alkynylation of
a couple of sulfonamides in the presence of a stoichiometric amount of a
copper salt was reported: (c) Dunetz, J. R.; Danheiser, R. L. Org. Lett.
2003, 5, 4011-4014.
† Department of Biological Information.
‡ Department of Biomolecular Engineering.
(1) (a) Sato, F.; Urabe, H. In Titanium and Zirconium in Organic
Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp 319-
354. (b) Sato, F.; Okamoto, S. AdV. Synth. Catal. 2001, 343, 759-784. (c)
Sato, F.; Urabe, H.; Okamoto, S. Chem. ReV. 2000, 100, 2835-2886. (d)
Eisch, J. J. J. Organomet. Chem. 2001, 617-618, 148-157. (e) Kulinkovich,
O. G.; de Meijere, A. Chem. ReV. 2000, 100, 2789-2834.
(2) Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124-130.
Negishi, E. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming,
I., Eds.; Pergamon Press: Oxford, UK, 1991; Vol. 5, pp 1163-1184.
Buchwald, S. L.; Nielsen, R. B. Chem. ReV. 1988, 88, 1047-1058.
(3) Tanaka, R.; Hirano, S.; Urabe, H.; Sato, F. Org. Lett. 2003, 5, 67-
70.
10.1021/ol036396b CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/29/2004

alkynylation of amides by Hsung and co-workers6b and that
of sulfonamides quite recently reported by Danheiser’s
group,6c we report here our results on a copper-catalyzed
preparation of various N-(1-alkynyl)sulfonamides from ha-
loacetylenes and sulfonamides and their application along
the aforementioned line (eq 1).
Table 2. Preparation of N-Alkynylsulfonamides
N-Alkynylation of sulfonamides was first investigated by
taking benzosultam 17 and a 1-halo-1-octyne as the starting
materials under a variety of reaction conditions. The selected
variations summarized in Table 1 show that the reaction is
Table 1. Optimum Conditions for the Alkynylation of
Benzosultam 1
a The enantiopurity of (S)-5 (96% ee) was completely preserved in the
product (S)-14 (96% ee). b 8 (2 equiv) was used.
coupling of (silylethynyl)iodonium salt with N-benzyl-p-
toluenesulfonamide (to give 10), (ii) desilylation of 10 to
the terminal acetylene, and (iii) its alkylation.3 Thus, the
advantage of the one-step synthesis from 3 to 9 is apparent.
As the trimethylsilyl group of bromide 8 survived the reaction
conditions, N-(silylethynyl)sulfonamide 10, which is a
precursor of the versatile terminal acetylene as mentioned
above, was also readily prepared by this method (entry 2).
Sterically more demanding benzosultams 4 and 5 were
alkynylated equally well to afford the desired products
(entries 5-8). It is important to note that the enantiopurity
of optically active sultam 5 was completely retained in the
product (14, entry 7). In addition to aromatic sultams 1 and
3-5, an aliphatic counterpart 6, a useful chiral auxiliary
known as Oppolzer’s camphorsultam,9 participated in this
coupling reaction to give 16 or 17. In the latter case, the
product yield was improved by the use of excess alkylating
agent (entry 10).
The amino-substituted acetylenes obtained above should
be useful intermediates for diastereoselective synthesis, which
is demonstrated as follows (Table 3): N-(Silylethynyl)sultam
11 was first treated with a titanium(II) alkoxide reagent, Ti-
(O-i-Pr)4/2 i-PrMgCl (18),1 to generate the acetylene-
titanium complexe 19, which was then allowed to react with
benzaldehyde to give 21, after hydrolysis, with virtually
complete regio- and olefinic stereoselectivities and with high
1,5-diastereoselectivity (ds ) 96:4) in good yield (entry 1).8
entry
X
Cu+
CuI
basic salt
amine
yield (%)a
1
2
3
4
5
6
7
Br
Br
Br
Br
Br
Br
I
Cs2CO3
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
(CH2NHMe)2
(CH2NHMe)2
(CH2NHMe)2
(CH2NHMe)2
(CH2NH2)2
68
94 (68)
87
93
62
CuI
CuCN
CuSPh
CuI
CuI
CuI
(CH2NHMe)2
(CH2NHMe)2
97 (79)
77
a Yield determined by 1H NMR spectroscopy with internal standard.
Isolated yield in parentheses.
feasible under copper catalysis; and the kind of copper salts
appears not to be critical, showing little influence on the
product yield (entries 3, 4, and 6). On the other hand, Pd
catalysts were totally ineffective. The best yield was obtained
in entry 6 with alkynyl bromide rather than iodide (cf. entry
7), with K3PO4 rather than K2CO3 or Cs2CO3 (entries 1 and
2), and with N,N′-dimethylethylenediamine rather than
ethylenediamine (entry 5). Under the optimum conditions,
a virtually quantitative yield of 2 was attained.8
The generality of this reaction is shown in Table 2. Open-
chain sulfonamide 3 was smoothly alkynylated with bro-
mooctyne (7) to give 9 (entry 1). This compound was
previously prepared via a few inevitable steps, involving (i)
(7) For review, see: Liu, Z.; Takeuchi, Y. Heterocycles 2002, 56, 693-
709. Optically active benzosultams are readily prepared according to this
literature.
(9) For review, see: Oppolzer, W. Pure Appl. Chem. 1990, 62, 1241-
1250. Kim, B. H.; Curran, D. P. Tetrahedron 1993, 49, 293-318.
(8) For details, see the Supporting Information.
728
Org. Lett., Vol. 6, No. 5, 2004

84:16, which revealed that sultam 11 is the most suitable
one. The structure of 21 was determined by spectroscopic
means and appropriate derivatization.8 The remaining vinyl-
titanium bond in the intermediate oxatitanacycle 20, the
presence of which was confirmed by deuteriolysis (entry 1),
could be utilized in subsequent transformations. Other
aldehydes gave the adducts 22-25 in good to excellent
diastereoselectivities (entries 2-5). When the same reaction
is started with sultams having an N-octynyl group, benzo-
sultam 14 with a tert-butyl side chain is the substrate of
choice and its titanation and subsequent addition to aldehydes
afforded the coupling products 26-30, again with exclusive
regio- and olefinic stereoselectivities and good to excellent
1,5-diastereoselectivities (entries 6-10). When the reaction
was started with chiral alkynylsultam ((S)-14, 96% ee,
prepared in entry 7 of Table 2), the optically active products
were obtained without loss of the enantiopurity (entries 8
and 10).
Table 3. Remote Diastereoselective Addition of
N-Alkynylsultams to Aldehydes
aldehyde
R2
product
yield (%) 1,5-ds
0.8 21 87 (97% Da) 96:4b
sul-
In summary, N-alkynylsulfonamides are now conveniently
prepared and the titanium complexes of these functionalized
acetylenes proved to be a promising organometallic reagent.
Further application of the present transformations and the
produced amino-substituted allyl alcohols will be reported
in due course.
entry tam
equiv
1
2
3
4
5
6
7
11 Ph
11 p-ClC6H4-
11 (E)-C5H11CH)CH- 0.8 23 73
11 (E)-MeCHdCH-
11 C8H17
1
22 54
96:4
94:6
95:5
88:12
88:12
88:12
1
24 52
0.8 25 94
14 Ph
14 C8H17
8c 14d i-Pr
1
1
1
26 74
27 62
28d 88 (96% Da) 93:7
Acknowledgment. We are grateful to the Japan Society
for the Promotion of Science for financial support and R.T.
acknowledges a Grant of the 21st Century COE Program,
Ministry of Education, Culture, Sports, Science and Technol-
ogy, Japan.
9
10
14 c-C6H11
14d t-Bu
0.8 29 79
0.8 30d 93
93:7
98:2
a Result of deuteriolysis. b An isomerically pure sample of 21 could be
obtained by recrystallization from hexane-CH2Cl2. c In this case, a small
amount of a regioisomer (less than 4%) was detected and was easily
separated from 28 by silica gel chromatography. In other entries, we were
unable to identify the regioisomeric product(s). d The enantiopurity of (S)-
14 (96% ee) was retained in the product 28 (95% ee) or 30 (96% ee).
Supporting Information Available: Experimental pro-
cedures, structural determinations, and physical properties
of products. This material is available free of charge via the
Internet at http://pubs.acs.org.
The excellent level of the remote asymmetric induction (i.e.,
1,5-diastereoselectivity) is noteworthy.10 Other sultams 13,
15, and 17 having an N-(silylethynyl) group gave the
analogous adducts with benzaldehyde in the following yields
and diastereoselectivities: 73%, 97:3; 62%, 79:21; and 46%,
OL036396B
(10) Mitchell, H. J.; Nelson, A.; Warren, S. J. Chem. Soc., Perkin Trans.
1 1999, 1899-1914. Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV.
1993, 93, 1307-1370.
Org. Lett., Vol. 6, No. 5, 2004
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