Nucleophilic addition of sulfonamides to bromoacetylenes: Facile preparation of pyrroles

Article abstract of DOI:10.1021/ol201952b

Nucleophilic addition of sulfonamides to 1-bromo-1-alkynes provided (Z)-N-(1-bromo-1-alken-2-yl)-p-toluenesulfonamides in good yield and in a highly regio- and stereoselective manner. Treatment of product (Z)-N-(1-bromo-1-octen- 2-yl)-N-allyl-p-toluenesul

Full text of DOI:10.1021/ol201952b

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4873–4875
Nucleophilic Addition of Sulfonamides
to Bromoacetylenes: Facile Preparation
of Pyrroles
Masahito Yamagishi, Ken Nishigai, Takeshi Hata, and Hirokazu Urabe*
Department of Biomolecular Engineering, Graduate School of Bioscience and
Biotechnology, Tokyo Institute of Technology, 4259-B-59 Nagatsuta-cho, Midori-ku,
Yokohama, Kanagawa 226-8501 Japan
hurabe@bio.titech.ac.jp
Received July 20, 2011
ABSTRACT
Nucleophilic addition of sulfonamides to 1-bromo-1-alkynes provided (Z)-N-(1-bromo-1-alken-2-yl)-p-toluenesulfonamides in good yield and in a
highly regio- and stereoselective manner. Treatment of product (Z)-N-(1-bromo-1-octen-2-yl)-N-allyl-p-toluenesulfonamide with a palladium
catalyst under Heck conditions afforded 1-(p-toluenesulfonyl)-2-hexyl-4-methylpyrrole in good yield. Other pyrroles with various substituents can
also be prepared in good yield by this method.
Nucleophilic addition to an electron-deficient carbonÀ
carbon multiple bond is one of the most fundamental
reactionsinorganicchemistry.1 Various potential electron-
Scheme 1. Halogen as an EWG in Nucleophilic Addition
withdrawing groups (EWGs) adjacent to olefin or acety-
lene are utilized for this process, as shown in Scheme 1. On
the other hand, the weakest possible substituents, such as
halogens, that serve as EWG should also be a subject of
interest. However, haloolefins and haloacetylenes, except
fluoro- or polyhalo-substituted compounds,2 have not
been widely investigated in this regard.3 In this study, we
readily applied to a concise preparation of pyrroles, as
shown in Scheme 2.
show that haloacetylenes undergo nucleophilic addition by
sulfonamides to give functionalized olefins, which can be
During our study on reactions of sulfonamides,4 we en-
countered their facile addition to haloacetylenes.5À7 Table 1
summarizes some fundamental data relating to the use of
various halogenated (Cl, Br, and I) 1-octynes and standard
reaction conditions regarding additive, solvent, temperature,
and reaction period are given in eq 1. Among the three
haloacetylenes 1À3 (entries 1À3), bromoacetylene 2 showed
the best results, affording (Z)-1-bromo-2-(sulfonylamino)-
1-octene (6) in good yield and in a highly regio- and stereo-
selective manner. Other isomeric products were not detected
(1) (a) Carey, F. A.; Sundberg, R. J. Advanced Organic Chemistry, 5th
ed.; Springer: New York, 2007; Part B, pp 183À200. (b) Smith, M. B.;
March, J. March’s Advanced Organic Chemistry, 6th ed.; Wiley: New
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r
10.1021/ol201952b
2011 American Chemical Society
Published on Web 08/15/2011

Table 1. Fundamental Data for Nucleophilic Addition
Scheme 2. Two-step Preparation of Pyrroles
haloacetylene
X
product
entry
4 (equiv)
yield (%)a recovered 4 (%)b
1
2
3
4
5
Cl
Br
I
1
2
3
2
2
3
5 54, 65c
3
6 74, quant.d
76
3
7 (7), (6)e
6 71
6 (54)f
Br
Br
2
1.5
in the crude reaction mixture. The use of excess sulfonamide
(2À3 equiv to bromoacetylene) is preferable to afford good
yields (entries 2 and 4 vs 5). However, in a typical run (entry 2),
the unreacted sulfonamide was completely recovered and
may be recycled; therefore, the yield of product 6 was cal-
culated to be quantitative based on consumed sulfon-
amide 4. Although a precise mechanism of this reaction is
not presently clear, it can be formally categorized as
nucleophilic addition of sulfonamides to an electron-
deficient acetylenic bond.
a Isolated yield based on haloacetylene. Values in parentheses were
determined by 1H NMR using an internal standard. b Isolated yield based
on 4. c Reaction was continued until 1 was completely consumed (6 h).
d Yield based on consumed 4. e Reaction was continued until 3 was
completely consumed (6 h). f Reaction period was extended to 4 h.
nucleophile could be particularly useful for many types
of cyclizations. Considering this fact, we investigated the
application of these products in a concise preparation of
pyrroles according to Scheme 2.8,9 In fact, upon treating
product 6 (Table 1) with a palladium catalyst under Heck
conditions,10 the desired cyclization took place providing
pyrrole 8 directly in good yield, as shown in eq 2.11,12 While
various vinyl bromides participate in the Heck reaction,
(8) For reviews on pyrrole synthesis, see: (a) Katritzky, A. R., Rees,
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While the aforementionedreaction isoperationally quite
simple, the products, 1-bromo-2-(sulfonylamino)-1-alkenes
with defined stereochemistry, are otherwise tedious to
prepare but are versatile synthetic intermediates. For in-
stance, thecisalignmentofvinylbromideandtheincoming
(5) For reviews on nucleophilic addition to haloacetylenes, see:
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completing this work, similar nucleophilic addition to haloacetylenes
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Chem. 2011, 76, 2448–2458.
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€
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following: Jeffery, T. Tetrahedron 1996, 52, 10113–10130. However, in
this reaction, 3 mol % of the Pd catalyst was sufficient (84% yield of 8),
but 10 mol % of the catalyst was routinely used to insure the complete
reaction in the runs of Table 2. Likewise, when 3 mol % of Pd was used in
eq 3, the overall yield of 8 from 2 was 55%.
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4874
Org. Lett., Vol. 13, No. 18, 2011

p-toluenesulfonamides 4 to give corresponding Z-bromo-
olefins 9À15 (entries 2À8). The mild reaction conditions
allow the presence of various functional groups, including
unprotected hydroxy groups (entries 3À8). In addition
to p-toluenesulfonamides, benzene- and methanesulfona-
mides showed the same results affording 16 and 17 (entries
9 and 10). Sulfonamides having a higher 2-alkenyl group
than allyl (entries 11À13) or a 2-alkynyl group (entry 14)
also participated in the addition to give bromoolefins
18À21. Considering the successful preparation of various
Z-bromoolefins, we proceededtothe next Heckreactionof
these intermediates. We found that the desired pyrroles
were obtained uniformly in good yields as previously seen
for 8 (eq 2). Furthermore, the conditions were compatible
with various functionalities including a terminal olefin and
hydroxy groups (pyrroles 22À28, entries 2À8). Likewise,
both aromatic and aliphatic sulfonamides 16 and 17
afforded pyrroles 29 and 30, respectively (entries 9 and
10). We emphasize that by appropriately choosing N-
alkenyl group on the sulfonamide, various 2,4-disubsti-
tuted pyrroles, such as 31À34, could be obtained by this
method (entries 11À14).
Table 2. Two-step Synthesis of Pyrroles According to eqs 1 and 2
To determine the individual results for each step
of the sequence including nucleophilic addition and
subsequent Heck cyclization, we listed the results of
each process in Table 2. However, pyrroles could
be more conveniently prepared by one-pot synthesis,
as shown in eq 3, in which the overall yield of 8
(58%)12 is comparable to that of the corresponding
two-step sequence shown in entry 1 of Table 2 (71 Â
84 = 60%).
a Bromoacetylene (1 equiv), sulfonamide (3 equiv), K3PO4 (1.5
equiv); DMF, 120 °C, 2 h. b Isolated yields based on bromoacetylene.
c Pd(OAc)2 (10 mol %), Bu4NBr (1.5 equiv), KOAc (2.5 equiv); DMF,
120 °C, 3 h. d Isolated yields. e Sulfonamide (2 equiv) was used. f Reaction
period was 4 h. g Reaction period was 8 h; K3PO4 was used in place of
KOAc. h Combined yield of an 87:13 mixture of tetra- and trisubstituted
olefinic isomers.
In conclusion, we report the facile nucleophilic addition
of sulfonamides to bromoacetylenes to exclusively give
(Z)-1-bromo-2-(sulfonylamino)-1-alkenes. These bromoole-
fins are useful synthetic intermediates that were demon-
strated by their application in a concise preparation of
pyrroles facilitated by Heck cyclization.
this transformation illustrates its successful application to
β-bromoenamine derivatives.13
Acknowledgment. This work was supported by a
Grant-in-Aid for Challenging Exploratory Research
(22655014) from JSPS, Japan.
Table 2 summarizes other results of eqs 1 and 2. Various
bromoacetylenes underwent nucleophilic addition of N-allyl-
Supporting Information Available. Experimental pro-
cedures and spectroscopic properties for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) To the best of our knowledge, aliphatic bromides of this type
have not been employed in the Heck reaction.
Org. Lett., Vol. 13, No. 18, 2011
4875