Iron-catalyzed regio- and stereoselective chlorosulfonylation of terminal alkynes with aromatic sulfonyl chlorides

Article abstract of DOI:10.1021/ol203446t

Terminal alkynes react with aromatic sulfonyl chlorides in the presence of an iron(II) catalyst and a phosphine ligand to give (E)-β- chlorovinylsulfones with 100% regio- and stereoselectivity. Various functional groups, such as chloride, bromide, iodide, nitro, ketone, and aldehyde, are tolerated under the reaction conditions. Addition of tosyl chloride to a 1,6-enyne followed by radical 5-exo-trig cyclization gave an exocyclic alkenylsulfone.

Full text of DOI:10.1021/ol203446t

ORGANIC
LETTERS
2012
Vol. 14, No. 3
954–956
Iron-Catalyzed Regio- and Stereoselective
Chlorosulfonylation of Terminal Alkynes
with Aromatic Sulfonyl Chlorides
Xiaoming Zeng, Laurean Ilies, and Eiichi Nakamura*
Department of Chemistry, School of Science, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
nakamura@chem.s.u-tokyo.ac.jp
Received December 26, 2011
ABSTRACT
Terminal alkynes react with aromatic sulfonyl chlorides in the presence of an iron(II) catalyst and a phosphine ligand to give (E)-β-
chlorovinylsulfones with 100% regio- and stereoselectivity. Various functional groups, such as chloride, bromide, iodide, nitro, ketone, and
aldehyde, are tolerated under the reaction conditions. Addition of tosyl chloride to a 1,6-enyne followed by radical 5-exo-trig cyclization gave an
exocyclic alkenylsulfone.
Regio- and stereoselective synthesis of polysubstituted
olefins has been a challenging task for synthetic chemists.1
Addition of an organic sulfonyl chloride across an acet-
ylene derivative is one attractive methodology because of
the ready availability of the starting materials and the rich
functionality in the product. Copper-catalyzed chlorosul-
fonylation of alkynes with sulfonyl chlorides has met with
various degrees of success in controlling the selectivity,2
and thermal or photochemical radical initiation has also
been used with organic sulfonyl bromides and iodides.3 We
report here a highly regio- and stereoselective synthesis of
(E)-β-chlorovinylsulfones by iron-catalyzed4 addition of
aromatic sulfonyl chlorides to terminal alkynes. The tol-
erance for chloride, bromide, iodide, nitro, ketone, and
aldehyde groups is a synthetically attractive feature of this
new reaction. The reaction can be extended to cyclization
of 1,6-enynes into a five-membered ring.
Our recent discovery of copper-catalyzed desulfitative
activation of organic sulfonyl chlorides,5 as well as our
interest in selective synthesis of olefins,6 prompted the pre-
sent study on iron catalysis, in which we have been inter-
ested for some time.7,8 After extensive experimentation, we
found that tosyl chloride (1) reacts with phenylacetylene
(2, 1.2 equiv) in the presence of Fe(acac)2 (10 mol %) and
(5) Zeng, X.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc. 2011, 133,
17638–17640.
(6) (a) Tsuji, H.; Ueda, Y.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc.
2010, 132, 11854–11855. (b) Ilies, L.; Okabe, J.; Yoshikai, N.; Nakamura,
E. Org. Lett. 2010, 12, 2838–2840. (c) Ilies, L.; Asako, S.; Nakamura, E.
J. Am. Chem. Soc. 2011, 133, 7672–7675.
(7) (a) Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010, 75, 6061–
6067 and references therein. (b) Matsumoto, A.; Ilies, L.; Nakamura, E.
J. Am. Chem. Soc. 2011, 133, 6557–6559. (c) Yoshikai, N.; Asako, S.;
Yamakawa, T.; Ilies, L.; Nakamura, E. Chem.;Asian J. 2011, 6, 3059–
3065. (d) Nakamura, Y.; Ilies, L.; Nakamura, E. Org. Lett. 2011, 13,
5998–6001.
(8) (a) Nakamura, M.; Matsuo, K.; Ito, S.; Nakamura, E. J. Am.
Chem. Soc. 2004, 126, 3686–3687. (b) Nakamura, M.; Ito, S.;
Matsuo, K.; Nakamura, E. Synlett 2005, 1794–1798. (c) Yoshikai, N.;
Mieczkowski, A.; Matsumoto, A.; Ilies, L.; Nakamura, E. J. Am. Chem.
Soc. 2011, 133, 428–429.
(1) (a) Flynn, A. B.; Ogilvie, W. W. Chem. Rev. 2007, 107, 4698–4745.
(b) Negishi, E.-i.; Huang, Z.; Wang, G.; Mohan, S.; Wang, C.; Hattori,
H. Acc. Chem. Res. 2008, 41, 1474–1485.
(2) (a) Amiel, Y. Tetrahedron Lett. 1971, 8, 661–663. (b) Amiel, Y.
J. Org. Chem. 1971, 36, 3691–3696. (c) Amiel, Y. J. Org. Chem. 1971, 36,
3697–3702. (d) Liu, X.; Duan, X.; Pan, Z.; Han, Y.; Liang, Y. Synlett
2005, 1752–1754.
(3) (a) Truce, W. E.; Wolf, G. C. J. Org. Chem. 1971, 36, 1727–1732.
(b) Amiel, Y. J. Org. Chem. 1974, 39, 3867–3870.
(4) (a) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004,
104, 6217–6254. (b) Enthaler, S.; Junge, K.; Beller, M. Angew. Chem.,
Int. Ed. 2008, 47, 3317–3321. (c) Iron Catalysis in Organic Chemistry;
Plietker, B., Ed.; Wiley-VCH: Weinheim, 2008. (d) Sherry, B. D.; F€urstner, A.
Acc. Chem. Res. 2008, 41, 1500–1511. (e) Czaplik, W. M.; Mayer, M.;
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r
10.1021/ol203446t
Published on Web 01/24/2012
2012 American Chemical Society

(p-Tol)3P (10 mol %) in toluene at 110 °C for 8 h to give
(E)-(2-chlorostyryl)-4-tolylsulfone (3) in56% yield ona 1 g
scale and 66% yield on a 0.5 mmol scale, together with
the recovery of 1 in 8% yield. Notably, 3 was obtained
with 100% selectivity, and we could not observe any other
stereo- or regioisomers by GC, GCꢀMS, or NMR. The
stereochemistry of 3 was determined by comparison with
the literature data2c and stereospecific reduction9 to the
corresponding (Z)-styrylsulfone. The stereochemistry of
the product determined at 2%, 4%, and 70% conversion
was uniformly 100% E, indicating that the selectivity is
kinetically determined.
With the optimized conditions in hand, we investigated
the scope of the aromatic sulfonyl chloride in the reac-
tion with phenylacetylene (Table 2). The reaction of an
electron-deficient aromatic sulfonyl chloride (entry 2)
was higher yielding than that of an electron-rich reagent
(entry 1), suggesting more facile generation of a sulfonyl
radical.2 Substitution at the ortho position did not affect
the reaction (entries 7 and 8). Aromatic sulfonyl chlorides
possessing sensitive functional groups, such as chloride
(entries 3 and 6), bromide (entry8), iodide (entry 4), ketone
(entry 5), and nitro (entry 6), gave the desired (E)-β-
chlorovinylsulfones ingoodyield withcompleteselectivity.
Alkylsulfonyl chlorides did not give the desired product
under the same reaction conditions.
The scope of the terminal alkyne is shown in Table 3.
The reaction of phenylacetylene gave the desired product
in 56%ꢀ66% yield on a scale of 100 mg to 1 g (eq 1 and
entry 1). Both electron-deficient (entries 2, 3, and 5) and
electron-rich (entry 4) alkynes reacted smoothly, and the
reaction tolerates even an aldehyde group (entry 5). An
alkyne possessing a thienyl group (entry 6) or an alkyl
group (1-hexyne, entry 7) reacted well. In all of the cases,
the product was obtained as a single isomer. An internal
alkyne, such as diphenylacetylene, was unreactive, and
only a trace amount of compounds produced by desulfi-
tative addition5 could be observed.
In the absence of the iron catalyst, the reaction did
not proceed at all, and 1 was completely recovered
(Table 1, entry 1). Fe(acac)3 gave similar results, but
FeCl2, FeCl3, and Fe(OTf)2 performed poorly (entries
4ꢀ8). CuCl2 resulted in complete recovery of the start-
ing material (entry 2). A palladium catalyst was ineffi-
cient under these conditions (entry 3). The phosphine
ligand improved the yield (entries 10 and 11), but its
presence was not mandatory (entry 4). A small excess of
phenylacetylene (2) improved the yield (cf. entry 12),
presumably because of the formation of a small amount
of uncharacterized polymeric compounds. The reac-
tion proceeded much more slowly at lower temperature
(entry 13).
Table 2. Iron-Catalyzed Chlorosulfonylation of Phenylacety-
lene with Various Aromatic Sulfonyl Chloridesa
Table 1. Investigation of the Reaction Conditions for the
Chlorosulfonylation of Phenylacetylene (2) with Tosyl Chloride
(1)a
entry
catalyst
ligand
3 (%)b
1 (%)b
1
none
none
0
98
93
80
21
25
22
34
34
41
8
2
CuCl
none
0
3
PdCl2(PPh3)2
Fe(acac)2
Fe(OTf)2
FeCl2
none
0
4
none
46
6
5
none
6
none
12
37
13
28
63
72 (66)
40
44
7
Fe(acac)3
FeCl3
none
8
none
9
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
Fe(acac)2
dtbpyc
Ph3P
10
11
12d
13e
(p-Tol)3P
(p-Tol)3P
(p-Tol)3P
8
39
65
a Reaction conditions: tosyl chloride (1, 0.50 mmol), phenylacetylene
(2, 1.2 equiv), catalyst (10 mol %), ligand (10 mol %) in toluene
(0.50 mL) at 110 °C for 8 h, unless mentioned otherwise. See the
Supporting Information for details. b NMR yield. Isolated yield in
a Reaction conditions: aromatic sulfonyl chloride (0.50 mmol),
phenylacetylene (2, 1.2 equiv), Fe(acac)2 (10 mol %), (p-Tol)3P
(10 mol %) in toluene (0.50 mL) at 110 °C for 8 h. See the Supporting
Information for details. b Isolated yield.
c
parentheses. 4,40-Di-tert-butyl-2,20-dipyridyl. d Reaction performed
with 1.0 equiv of 2. e Reaction performed at 90 °C for 12 h.
Considering that the reaction involves a radical species,
we examinedthe applicationofthis iron-catalyzedreaction
(9) Yamamoto, I.; Sakai, T.; Yamamoto, S.; Ohta, K.; Matsuzaki, K.
Synthesis 1985, 676–677.
Org. Lett., Vol. 14, No. 3, 2012
955

Grignard reagents,11 which assumes involvement of low-
valent iron species.
Table 3. Iron-Catalyzed Chlorosulfonylation of Various Terminal
Alkynes with Tosyl Chloridea
Additional support for the radical mechanism comes
from the reaction of naphthalenesulfonyl chloride (6) with
phenylacetylene to give a mixture of the chlorosulfonyla-
tion product 7 and a cyclic sulfone 8 (Scheme 1). Appar-
ently, competitive inter- and intramolecular reactions
took place. The intermolecular reaction giving 100% E
chlorosulfonylation product 7 suggests that the iron(III)
chloride species acts as a bulky chlorine donor. The intra-
molecular reaction necessarily takes the opposite stereo-
chemical course to give 8.
Scheme 1. Competitive Pathways for the Reaction of
Naphthalenesulfonyl Chloride with Phenylacetylene
a Reaction conditions: tosyl chloride (1, 0.50 mmol), terminal alkyne
(1.2 equiv), Fe(acac)2 (10 mol %), (p-Tol)3P (10 mol %) in toluene
(0.50 mL) at 110 °C for 8 h. See the Supporting Information for details.
b Isolated yield. c Reaction performed with 1 g of 1.
to the cyclization of the 1,6-enyne 4, a compound known to
undergo radical cyclization.10 Our standard reaction con-
ditions smoothly induced the expected addition/cycliza-
tion sequence to give the functionalized exocyclic alkenyl
sulfone 5 in good yield. The stereochemistry of this com-
pound was determined to be as shown in eq 2 by NOE
experiments (Supporting Information).
In summary, an iron catalyst was effective in the radical
addition of an aromatic sulfonyl chloride to a terminal
alkyne, producing (E)-β-chlorovinylsulfones with 100%
stereoselectivity. The reaction adds to the repertoire of
catalysis utilizing environmentally benign reagents that are
increasingly attracting the attention of chemists.12
Acknowledgment. We thank MEXT for financial sup-
port of the research (KAKENHI Specially Promoted
Research 22000008 to E.N., 23750100 to L.I.) and the
Global COE Program for Chemistry Innovation; X.Z.
thanks the Japan Society for the Promotion of Science for
Young Scientists for a Research Fellowship (No. P10033).
Given the observed cyclization and the suggested radical
mechanism of the copper-catalyzed chlorosulfonylation
reaction,2 we consider that the present reaction involves
an initial electron transfer from the iron catalyst to the
aromatic sulfonyl chloride, followed by a radical addition
of the resulting sulfonyl radical to the alkyne, and trapping
of the vinyl radical by iron(III) chloride. This stands
in contrast to the recently reported iron-catalyzed
desulfitative cross-coupling of sulfonyl chlorides with
Supporting Information Available. Experimental pro-
cedures and physical properties of the compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(11) Volla, C. M. R.; Vogel, P. Angew. Chem., Int. Ed. 2008, 47, 1305–
1307.
(12) (a) Bolm, C. Nat. Chem. 2009, 1, 420. (b) Nakamura, E.; Sato, K.
Nat. Mater. 2011, 10, 158–161.
(10) (a) Stork, G.; Mook, R., Jr. J. Am. Chem. Soc. 1987, 109, 2829–
2831. (b) Miura, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn.
1993, 66, 2348–2355. (c) Miura, K.; Saito, H.; Fujisawa, N.; Wang, D.;
Nishikori, H.; Hosomi, A. Org. Lett. 2001, 3, 4055–4057. (d) Taniguchi,
T.; Fujii, T.; Idota, A.; Ishibashi, H. Org. Lett. 2009, 11, 3298–3301.
The authors declare no competing financial interest.
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Org. Lett., Vol. 14, No. 3, 2012