Separate deprotonation reactions converge mechanistically for a new cyclization of benzyl 1-Alkynyl sulfones

Article abstract of DOI:10.1021/ol202196y

A heretofore unknown LDA-induced conversion of benzyl 1-alkynyl sulfones to 1H-2-benzothiopyran-S,S-dioxides is demonstrated. A benzyl carbanion, accessible by two means, is thought to cyclize by temporary disruption of aromaticity. Key intermediates are

Full text of DOI:10.1021/ol202196y

ORGANIC
LETTERS
2011
Vol. 13, No. 19
5330–5333
Separate Deprotonation Reactions
Converge Mechanistically for a New
Cyclization of Benzyl 1-Alkynyl Sulfones
M. Selim Hossain and Adrian L. Schwan*
Department of Chemistry, University of Guelph, Guelph, Ontario, Canada
schwan@uoguelph.ca
Received August 12, 2011
ABSTRACT
A heretofore unknown LDA-induced conversion of benzyl 1-alkynyl sulfones to 1H-2-benzothiopyran-S,S-dioxides is demonstrated. A benzyl
carbanion, accessible by two means, is thought to cyclize by temporary disruption of aromaticity. Key intermediates are observed by ReactIR
analysis. Thiophene derivatives are also amenable to cyclization, forming 7H-thieno[2,3-c]thiopyran-S,S-dioxides.
Acetylenic and allenic sulfones are popular as reac-
tive and functionality rich starting materials for the
synthesis of a variety of heterocycles and carbocycles
and for the development of synthetic methods.1 Con-
jugate additions of selected nucleophiles to alkynyl and
allenyl sulfones have been used as crucial starting steps
in several methodologies2 and in the total synthesis of
natural products.3 Another example demonstrates
further the flexibility of sulfones. On selected allenyl
sulfones possessing remote functionality, deprotona-
tion of the allene brings about intramolecular anion
relocation. The new anion is then positioned to effect a
cyclization by way of conjugate attack on the unsatu-
rated sulfone.4
create R-sulfonyl carbanions.5 Such chemistries have been
used for medium rings,6 heterocycles,7 and functionalized
naphthalene derivatives.8
Recently we published a paper pertaining to 5-endo
cyclizations of transient benzyl allenyl sulfides, using sub-
stituted benzyl 1-propynyl sulfides as the starting
material.9 This prompted us to explore the base chemistry
of the 1-alkynyl sulfone analog. Hence, using KOBut as the
base, 2-iodobenzyl 1-propynyl sulfone (1a) cyclized not to
a five-membered ring but to unexpected product 2a, a 1
H-2-benzothiopyran-S,S-dioxide, in 27% yield (Scheme 1).10
Given this CÀC bond forming process and that relatively
(5) (a) Lopez Ortiz, F.; Iglesias, M. J.; Fernandez, I.; Andujar
Sanchez, C. M.; Ruiz Gomez, G. Chem. Rev. 2007, 107, 1580. (b)
Clayden, J.; Kenworthy, M. N. Synthesis 2004, 1721.
(6) Crandall, J. K.; Ayers, T. A. J. Org. Chem. 1992, 57, 2993.
(7) Padwa, A.; Filipkowski, M. A.; Kline, D. N.; Murphree, S. S.;
Yeske, P. E. J. Org. Chem. 1993, 58, 2061.
The anion stabilizing effects of the sulfone functionality
are underscored by dearomatizing conjugate additions to
(1) (a) Back, T. G. Tetrahedron 2001, 57, 5263. (b) Back, T. G.; Clary,
K. N.; Gao, D. Chem. Rev. 2010, 110, 4498.
(8) Clayden, J.; Kenworthy, M. N.; Helliwell, M. Org. Lett. 2003, 5,
831.
ꢀ
(9) Motto, J. M.; Castillo, A.; Greer, A.; Montemayer, L. K.; Sheepwash,
(2) (a) Xie, M.; Lin, G.; Zhang, J.; Li, M.; Feng, C. J. Organomet.
Chem. 2010, 695, 882. (b) Xie, M.-H.; Xie, F.-D.; Lin, G.-F.; Zhang, J.-
H. Tetrahedron Lett. 2010, 51, 1213. (c) Mukai, C.; Ukon, R.; Kuroda,
N. Tetrahedron Lett. 2003, 44, 1583. (d) Weston, M. H.; Nakajima, K.;
Back, T. G. J. Org. Chem. 2008, 73, 4630. (e) Mukai, C.; Kobayashi, M.;
Kubota, S.; Takahashi, Y.; Kitagaki, S. J. Org. Chem. 2004, 69, 2128.
(3) (a) Zhai, H.; Parvez, M.; Back, T. G. J. Org. Chem. 2007, 72, 3853.
(b) Back, T. G.; Parvez, M.; Wulff, J. E. J. Org. Chem. 2003, 68, 2223.
(4) (a) Kitagaki, S.; Teramoto, S.; Mukai, C. Org. Lett. 2007, 9, 2549.
(b) Kitagaki, S.; Teramoto, S.; Ohta, Y.; Kobayashi, H.; Takabe, M.;
Mukai, C. Tetrahedron 2010, 66, 3687.
E. E.; Schwan, A. L. Tetrahedron 2011, 67, 1002.
(10) McConachie, L. K. MSc Thesis, University of Guelph, 2000.
(11) (a) Abe, H.; Suzuki, H. Bull. Chem. Soc. Jpn. 1999, 72, 787.
(b) Cao, D.; Kolshorn, H.; Meier, H. Tetrahedron Lett. 1995, 36, 7069.
(c) Himberg, G.; Ruppmich, M.; Schmidt, U. Phosphorus, Sulfur Silicon
Relat. Elem. 1993, 74, 387. (d) Truce, W. E.; Markley, L. D. J. Org.
Chem. 1970, 35, 3275. (e) Truce, W. E.; Onken, D. W. J. Org. Chem.
1975, 40, 3200. (f) Bouillon, J.-P.; Musyanovich, R.; Portella, C.;
Shermolovich, Y. Eur. J. Org. Chem. 2001, 3625. (g) Riddell, N.; Tam,
W. J. Org. Chem. 2006, 71, 1934.
r
10.1021/ol202196y
Published on Web 09/13/2011
2011 American Chemical Society

little is known about benzyl alkynyl sulfones, particularly
under basic treatment,11,12 we sought to investigate this
reaction and learn about its mechanism.
Table 1. LDA Induced Cyclization of Benzyl 1-Propynyl Sul-
fones
Scheme 1. KOBut Induced Cyclizations of Benzyl 1-Propynyl
Sulfides and Sulfones
no.
1
R1, R2
2-I, H
2 (% yield)a
1
a
b
c
d
e
f
66b
0
2
H, H
3
4-F, H
0
4
3-CN, H
2-Cl, H
2-Me, H
2-Br, H
2-Et, H
2-CF3, H
2-OPri, H
2-Ph, H
H, Ph
0
5
0
6
13c
55
0d
51
47
80
71
7
g
h
i
8
9
The cyclization reaction was optimized by way of ex-
tensive variation of reaction conditions, including solvent,
temperature, time, base identity, and substrate concentra-
tion on both 2-iodobenzyl and benzyl 1-propynyl sulfones
(1a, 1b, respectively). Only the iodo congener 1a responded
and the formation of 2a could be optimized to 66%. The
eventual conditions proved to be 0.5 M substrate in dry
THF, with introduction of 1 equiv of LDA at À78 °C,
removing the cold bath and warming under ambient
conditionsfor 45minbeforeeventual aq. acidquenching.13
Given these conditions, other aryl substituted systems
were studied as shown in Table 1, but only those substrates
with selected ortho-substituted aryl groups provided pro-
duct. Indeed, the absence of a substituent on the benzylic
aryl group (Table 1, entry 2) prevented cyclization, while
an additional aryl group at the benzylic position (entry 12)
promoted it.
10
11
12
j
k
l
a Scale of reactions is 100À500 mg of 1. 1.0 equiv of LDA was added to
a 0.5 M solution of 1 in THF. All yields are of isolated, purified material,
unless otherwise indicated. b Yield reaches 75% when reaction is per-
formed on a 1À2 g scale. c Calculated by 1H NMR. d The cyclization
chemistry of 1h was irreproducible; product was observed on one occasion.
Table 2. LDA Induced Cyclizations of Hindered
(Het)Arylmethyl 1-Alkynyl Sulfonesa
The data seem to indicate that steric crowding around
the benzyl position plays at least a partial rolein promoting
cyclization, presumably because LDA is directed away
from benzylic deprotonation.14 With this structural con-
dition in mind, several more substrates were prepared and
subjected to cyclization conditions. Generally, the pro-
posed theory held and cyclized products were obtained in
yields of 51À91% (Table 2).
This collection of results permits some useful observa-
tions. The cyclization tolerated the change from a terminal
methyl on the alkyne to a butyl group (Table 2, entries
2À4), and those results portend that a variety of extended
chains would be suitable. Also of note is the preferential
involvement of the thiophene groupwhen itwas positioned
to compete with a benzene ring (entry 4).
a See Table 1for reactionconditions. b Scale of reactions is 100À300 mg
of 1. All yields are of isolated, purified material.
Some mechanistic information was gained through
ReactIR analysis of the reaction progress. Of particular
value was the alkynyl/cumulene section of the IR
spectrum. Figure 1 is a snapshot of that region during
the cyclization reaction of 1a, with starting material
and two proposed intermediates labeled by compound
number (see also Scheme 2).
The large absorption beginning at the bottom of the
diagram represents the starting material alkyne stretch at
2222 cmÀ1. Upon introduction of the LDA, the disappear-
ance of that absorption coincides with the immediate,
(12) The use of alkynyl benzyl sulfones removes the availability of
addition to the aromatic at a position β to the sulfone and introduces
acidic hydrogen(s) for possible deprotonation at the benzylic site.
(13) When the cyclization does not occur, undefined polymeric
material is typically obtained, regardless of substrate concentration.
(14) Ortho substituents containing heteroatoms also seem to deter
benzylic deprotonation and may be more important in this regard than
steric effects.
Org. Lett., Vol. 13, No. 19, 2011
5331

proposed mechanism. Themechanism athand has features
similar to those in the work of Mukai and co-workers that
was introduced earlier,4 including the proton transfer and
the counterattack of the anion.
On the basis of the proposed mechanism, it follows that
direct deprotonation from the benzylic site should bring
about cyclization. As such, a series of compounds posses-
sing blocking groups β to the sulfone were evaluated.
The onlyoptimizations performedonthese substrates were
dilution experiments. Working at a substrate concentra-
tion of 0.05 M, cyclization occurred as indicated in Table 3.
Figure 1. View of cumulene and alkyne region of IR spectrum
during cyclization of sulfone 1a. Key absorptions are assigned to
proposed intermediates. See text for discussion.
Table 3. Direct Induced Cyclizations of (Het)Arylmethyl 1-
Alkynyl Sulfonesa
rapid growth of another peak at 1908 cmÀ1. Over time and
with warming, the 1908 cmÀ1 peak disappears, while a
longer lived band is evident at 2199 cmÀ1
.
These bands are consistent with a mechanism that
involves immediate deprotonation of the terminal methyl
of 1a to produce allenyl anion 3a (Scheme 2). The observed
allenyl stretch of 1908 cmÀ1 is similar to that of calculated
and measured allenyl anions as reported by Lambert et
al.15 The attachment of the (primarily inductive) electron-
withdrawing sulfone might be expected to move the ab-
sorption to higher energy. Compound 3a slowly disap-
pears, and it is proposed that the longer lived 2199 cmÀ1
peak is indicative of anion 4a, which arises through
bimolecular proton exchange, promoted by the high con-
centration of substrate.16
Anion 4a then undergoes an intramolecular cyclization,
which temporarily sacrifices aromatic stabilization, a cy-
clization that may be accelerated by the warming tempera-
ture. Additional proton transfers relocate the anion
position to the benzylic position prior to quenching. Sup-
port for this latter claim is found when MeI is used to
quench the reaction; the product of monomethylation (7)
is recovered in 61% yield. The preference for thiophene
over benzene participation (Table 2, entry 4) is also con-
sistent with the aromatic disruption portion of the
a See Table 1 for reaction conditions. 1.0 equiv of LDA was added to
a 0.05 M solution of 1 in THF. b Scale of reactions is 100À300 mg of 1.
All yields are of isolated, purified material.
With phenyl groups on the triple bond, the cyclization
occurred readily (entries 1À3, 6, 7), but tert-butyl blocking
groups hindered cyclization (entries 4,5), presumably for
steric reasons. The thiophene-containing cases provided
the higher yield of product (entries 6À8), consistent with
the relative aromaticity of each ring system.
For sulfone 1a, the ReactIR data provide an amount of
certainty with regard to the initial site of proton removal.
Given the cyclizations of Table 3, it is entirely possible that
some of the entries in Table 2 arise from initial deprotona-
tion at both the benzylic position and opposite the triple
bond. Similarly, 2-thienylmethyl sulfone 1z (Table 3, entry 8)
Scheme 2. Proposed Mechanism for Cyclization of Benzyl-Hindered Sulfones 1
5332
Org. Lett., Vol. 13, No. 19, 2011

may be prone to deprotonation at both positions. The fates
of the triple bond of starting sulfones 1s and 1z were
separately followed by ReactIR analysis. Upon addition of
LDA, the IR absorptions of the triple bonds of these
substrates display a similar profile for eventual disappear-
ance, one that is noticeably slower than in the reaction of 1a.
Furthermore, no allenyl anion was observed in the spectra
(see Supporting Information). Based on these comparisons,
proton removal from the site R to the sulfone appears to be
the predominating occurrence for thiophene 1z.
The mechanism proposed above suggests that anions of
the type 6a are the most stable of the various options and are
the species that eventually get quenched. Previous reports
on cyclic sulfonyl anions including the parent benzothio-
pyran S,S-dioxide of 6a note their stability in relation to
acyclic analogs.17 Since conjugation can occur through a
sulfonyl group,18 conjugated anion 6a is anticipated to
possess some aromatic stabilization (Figure 2).17a,18a
as coumarin isosteres for the inhibition of gyrase B21 and
are known to provide protection against cardiac
arrhythmia.22 Furthermore, this ring system can act as a
source of carbocycles after extrusion of SO2.23 The 7H-
thieno[2,3-c]thiopyran-S,S-dioxide fused heterocyclic sys-
tem (2p,xÀz) is not known. The ring skeleton is known for
the sulfane oxidation state, and its formation requires
functional groups capable of promoting condensation
based ring closures.24 The chemistry presented herein
offers a general and high-yielding means of forming the
7H-thieno[2,3-c]thiopyran heterocyclic skeleton, in its sul-
fone state, without the need for additional functionality.
To summarize, a new intramolecular cyclization afford-
ing 1H-2-benzothiopyran-S,S-dioxides and 7H-thieno[2,3-c]
thiopyran-S,S-dioxides is outlined. In the cyclization, an R-
sulfonyl benzyl anion temporarily disrupts aromaticity to
effect a conjugate addition on a triple bond on the opposite
side of the sulfone. The benzyl anion can be formed through
direct deprotonation; alternatively there are a variety of
instances when the cyclization is initiated through deproto-
nation γ to the sulfone on the triple bond side of the
molecule. The stable anion after cyclization (e.g., 6a) and
the functionalized aromatic provide opportunity for adap-
tation of the cyclized products. Future work will also include
the assessment of other functional groups including eno-
lates, which are expected to hold the counterion static on the
oxygen and selected phosphorus groups.18b
Figure 2. Carbanions at the 2-position of 1H-2-benzothiopyran-
S,S-dioxides (e.g., 6a) possess some aromatic stabilization.
Acknowledgment. The authors thank NSERC of Ca-
nada for funding this research and for an RTI grant for the
ReactIR instrument. The authors also thank past Univ. of
Guelph co-workers Dr. Matthias Bierenstiel, Dr. Zhongyi
Wang, Mr. Petar Duspara, and Ms. Laura Montemayor
(nee McConachie) for valuable preliminary studies.
It follows that the transition state for cyclization also
benefits from an amount of conjugation through the sul-
fone. If that is the case the cyclization may be a 6-electron
electrocyclic ring closure. Moreover, since R-sulfonyl carba-
nions often hold the lithium counterion on one or both
sulfonyl oxygens,19,20 the cyclization which delivers R-sulfo-
nyl anion 5a from R-sulfonyl anion 4a can proceed with
minimal repositioning of the lithium counterion.
Supporting Information Available. Experimental pro-
cedures, characterization data, and copies of NMR’s of
sulfones; selected ReactIR data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Compounds with the 1H-2-benzothiopyran-S,S-dioxide
(or isothiochromene 2,2-dioxide) core have been evaluated
(20) The anionic species may also be dimeric in solution, especially
under high concentration.
(21) Peixoto, C.; Laurin, P.; Klich, M.; Dupuis-Hamelin, C.;
Mauvais, P.; Lassaigne, P.; Bonnefoy, A.; Musicki, B. Tetrahedron Lett.
2000, 41, 1741.
(22) Kleemann, H.-W.; Below, P. WO 066620A1, 2003.
(23) (a) Hall, C. R.; Smith, D. J. H. Tetrahedron Lett. 1974, 3633. (b)
Finlay, J. D.; Hall, C. R.; Smith, D. J. H. Tetrahedron Lett. 1977, 1149.
(24) (a) Saito, T.; Shizuta, T.; Kikuchi, H.; Nakagawa, J.; Hirotsu,
K.; Ohmura, H.; Motoki, S. Synthesis 1994, 727. (b) Mandal, S. S.;
Chakraborty, J.; De, A. J. Chem. Soc., Perkin Trans. 1 1999, 2639.
(15) Lambert, C.; Schleyer, P. v. R.; Wuerthwein, E. U. J. Org. Chem.
1993, 58, 6377.
(16) Monitoring the disappearance of the 1908 cmÀ1 peak by
ReactIR at À45 °C reveals the fate of 3a is not first-order decay.
(17) (a) Pagani, G.; Bradamante, P. S.; Maiorana, S.; Mangia, A. J.
Chem. Soc. B 1971, 74. (b) Pagani, G.; Bradamante, P. S.; Mangia, A. J.
Chem. Soc. B 1971, 545.
(18) (a) Bordwell, F. G.; Fried, H. E. J. Org. Chem. 1991, 56, 4218. (b)
Fraenkel, G.; Kolp, C. J.; Chow, A. J. Am. Chem. Soc. 1992, 114, 4307.
(19) Gais, H.-J. In Organosulfur Chemistry in Asymmetric Synthesis;
Toru, T., Bolm, C., Eds.; Wiley-VCH: Weinheim, 2008; Chapter 12.
Org. Lett., Vol. 13, No. 19, 2011
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