Reaction of arynes with sulfoxides

Article abstract of DOI:10.1021/ol5036326

A S-O bond insertion reaction of sulfoxides with arynes is reported. This reaction represents a rare instance of semipolar single bond insertion in aryne chemistry. The study of mechanism indicates that a sulfur ylide triggered by aryne is the key intermediate, which further transfers its methylene group to carbonyl compounds to give epoxides and thioethers through a sequential process.

Full text of DOI:10.1021/ol5036326

Letter
pubs.acs.org/OrgLett
Reaction of Arynes with Sulfoxides
Hong-Ying Li,† Li-Juan Xing,† Mei-Mei Lou,† Han Wang,† Rui-Hua Liu,† and Bin Wang*,†,‡
†State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin 300071, People’s
Republic of China
‡Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin 300071, People’s Republic of China
S
* Supporting Information
ABSTRACT: A S−O bond insertion reaction of sulfoxides with arynes is
reported. This reaction represents a rare instance of semipolar single bond
insertion in aryne chemistry. The study of mechanism indicates that a
sulfur ylide triggered by aryne is the key intermediate, which further
transfers its methylene group to carbonyl compounds to give epoxides and
thioethers through a sequential process.
he highly reactive arynes are valuable species in various
carbon−carbon and carbon−heteroatom bond-forming
0.75 mmol of CsF in 0.5 mL of DMSO at 50 °C afforded
methyl(2-phenoxyphenyl)sulfane 3aa in 80% yield after 16 h
(Scheme 2). Interestingly, two molecules of benzyne and one
T
reactions.1 Among these reactions, the insertion of arynes into
σ and π bonds has been extensively studied over the past seven
decades.1g,2 Many kinds of bonds, such as C−C,3 C−N,4 C−
O,5 C−S,6 carbon−metal,7 heteroatom−heteroatom,8 heter-
oatom−metal,9 metal−metal,10 and carbon (formyl)−hydrogen
bonds,11 have been utilized in aryne insertions. These reactions
provide versatile strategies to synthesize complex ortho-
disubstituted arenes. Surprisingly, the insertion of arynes into
S−O bond is rare.12 Although the bonding nature of S−O
linkage in sulfoxides is still a matter of controversy, this bond is
generally believed to be a semipolar single bond, rather than a
double bond.13 We questioned whether ortho-oxygen sub-
stituted aryl sulfides might be created via an insertion of arynes
into the S−O bond of sulfoxides. Very recently, the Xiao and
Chen group reported elegant work on a three-component
coupling reaction of arynes, DMSO, and α-bromo carbonyl
compounds (Scheme 1)12a Herein we describe an interesting
Scheme 2. Reaction of Benzyne with DMSO
molecule of DMSO participated in assembling 3aa, accompany-
ing the demethylation of DMSO. The structure of 3aa was
confirmed unambiguously by single crystal X-ray diffraction.16
To probe mechanistic information on this novel reaction, d6-
DMSO was subjected to the current conditions (Scheme 2).
Surprisingly, a tetradeuterated analogue d4-3aa was isolated in
82% yield.15 The result indicated that one d3-methyl group of
DMSO remained intact during the reaction, and the phenoxyl
group of 3aa was labeled with a deuterium atom in its ortho-
position. We reasoned that the deuterium atom on the
phenoxyl group might be generated from another d3-methyl
group, which was removed in the conversion. This suggested to
us that a deprotonation reaction between the released methyl
group and benzyne might occur to produce a highly reactive
sulfur ylide, which could readily transfer its methylene unit to
electrophiles in the reaction mixture, leading to the
demethylation of DMSO. In further mechanistic studies and
to verify the above-mentioned idea, a sulfur ylide trapping
experiment using N-methyl isatin 4 was performed (Scheme 3).
Scheme 1. Insertion of Aryne into S−O Bond
insertion reaction of sulfoxides and arynes under very mild
conditions. The mechanism investigation disclosed that a sulfur
ylide is formed after insertion, which will make the reaction
especially attractive for generating sulfur ylide free from bases
(Scheme 1).
We initiated our investigation with Kobayashi aryne
precursor 1a14 and DMSO 2a as the model substrates to
identify the optimum reaction conditions.15 After exploring
various fluorides, temperatures, and reaction times, we observed
that 0.5 mmol of the 2-(trimethylsilyl)phenyl triflate 1a and
Received: December 19, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ol5036326
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Ylide Trapping Experiment with Isatin
Scheme 5. Reaction of Benzyne with Methyl 4-Methylphenyl
Sulfoxide
Gratifyingly, the reaction did afford epoxide 5 in 19% yield in
addition to 3aa. The results indicated that a phenylmethyl-
sulfoxoniummethylide was involved in the transformation.
Generally, sulfur ylides are prepared by deprotonation of the
corresponding sulfonium salts in the presence of bases.17 To
the best of our knowledge, this novel strategy for the
preparation of sulfur ylide utilizing arynes and sulfoxides has
been very rare.12a Based on our preliminary results, a plausible
mechanism of the transformation is shown in Scheme 4. A
and demethylation under solvent-free conditions, and a 1:1
insertion reaction between 1a and 2b occurred simultaneously
to give a minor product 2-methoxyphenyl phenyl sulfane 6ab in
18% yield. In this case, besides the ylide forming/demethylation
pathway described in Scheme 4, a small amount of
benzannulated four-membered ring intermediate F also under-
went a methyl-[1,2] shift with the concomitant ring opening to
give the minor product 6ab (Scheme 5). Clearly, the
transformation leading to sulfur ylide E will be desirable in
view of synthesis application. Thus, the stoichiometry ratios of
benzyne and sulfoxide as well as various solvents were surveyed
to improve the reaction selectivity. As summarized in Table 1,
Scheme 4. Possible Mechanism
a
Table 1. Optimization of the Reaction Conditions
entry
solvent
THF
ratio (1a:2b)
3ab (%)
6ab (%)
1
2
3
4
5
6
7
8
9
1:2
1:2
1:2
1:2
1:3
2:3
1:1
3:1
5:1
trace
trace
69
0
1,4-dioxane
CH3CN
DME
0
10
8
benzannulated four-membered ring intermediate A is first
formed through a [2 + 2] cycloaddition or a stepwise pathway
involving a 1,4-zwitterionic adduct. We think that the following
reaction of instable intermediate A may take three possible
pathways, leading to the formation of sulfur ylide C. Upon
nucleophilic reaction with another equivalent of benzyne, the
intermediate A undergoes a ring-opening process to give
zwitterion B, and then an intramolecular proton transfer occurs
to afford the sulfur ylide C (path a). Recently, arynes have been
utilized as powerful enophiles in ene reactions due to their low-
lying LUMO level.18 In this case, an ene reaction may also take
place in a concerted manner, so the ene-type mechanism
involving intermediate A and benzyne has also been possible
(path b).19 In the third pathway, the ring strain of intermediate
A allows for a ready, spontaneous opening process to afford an
ortho-quinone intermediate D, which is frequently proposed in
aryne insertion reactions.4f,5a−d,20 After nucleophilic attack and
deprotonation, sulfur ylide C could be produced from
intermediate D and benzyne (path c). Finally, the resulting
sulfur ylide C reacts with N-methyl isatin 4 to yield 3aa and
epoxide 5 via a typical addition−cyclization pathway.21
71
DME
71
8
DME
72
8
DME
69
7
DME
68
7
DME
trace
trace
a
Reaction conditions: 1a (0.5 mmol) in 0.5 mL of solvent under air;
isolated yield.
the use of THF and 1,4-dioxane as solvent gave very low yields
when the 1a/2b ratio was 2:1 (Table 1, entries 1, 2). In sharp
contrast, CH3CN and DME offered good results with the ratio
1:2 of 1a and 2b (Table 1, entries 3, 4). We then screened the
ratio of 1a/2b ranging from 1:3 (0.3 equiv) to 5:1 (20 equiv)
using DME as the solvent. There was no clear improvement of
product selectivity with 1a/2b decreasing from 1:2 to 1:3
(Table 1 entries 4, 5) or increasing to 3:1 (Table 1, entries 6−
8). Using the ratio 5:1 of 1a/2b, the reaction gave a very poor
yield (Table 1, entry 9). Although the present optimized
procedure could not make the reaction give a single product
3ab, to our delight, the side product 6ab was completely
suppressed in the sulfur ylide trapping reaction with isatin
(Scheme 6S in the Supporting Information).15 The epoxide 5
was obtained in a good yield of 91%, and the result further
On the basis of the success of DMSO, we further explored
unsymmetrical sulfoxides. Methyl phenyl sulfoxide 2b was
subsequently utilized to examine the reaction (Scheme 5).
Surprisingly, the major product was 2-phenoxyphenyl phenyl
sulfane 3ab, which was formed in 66% yield through insertion
B
DOI: 10.1021/ol5036326
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
supports our conclusion that a sulfur ylide is generated from
benzyne and sulfoxide.
Scheme 7. Substrate Scopes of Various Aryne Precursors
We then turned our attention to the sulfoxide substrate
scope using benzyne 1a as the reaction partner under the
conditions described in Table 1, entry 6. As shown in Scheme
6, DMSO 2a could also react smoothly to give product 3aa in a
a
Scheme 6. Substrate Scope of Various Sulfoxides
a
Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), CsF (0.75 mmol)
b
in DME (0.5 mL); isolated yields. DMSO (0.5 mL) as the solvent.
a
Reaction conditions: 1a (0.5 mmol), 2 (0.75 mmol), CsF (0.75
c
d
60 °C. 25 °C.
b
mmol) in DME (0.5 mL); isolated yield. 25 °C, 2 h.
high yield when using DME as the solvent (Scheme 6, 3aa). A
variety of substituted groups on the aromatic ring of the
sulfoxide was next investigated. Electron-donating groups such
as p-methyl, o-methoxy, and p-methoxy group were compatible,
and the reaction of 2d gave slightly better selectivity than that
of 2b. In the case of methyl 4-methoxyphenyl sulfoxide 2e, the
methyl-shift and ring-opening product 6ae was not observed.
The aromatic ring with electron-withdrawing groups such as a
halogen and cyano group also allowed the formation of 3 and 6
in low to good total yields (Scheme 6, 2f−2k). Moreover, this
novel transformation is not limited to only methyl aryl
sulfoxides. Ethyl phenyl sulfoxide 2l and benzyl phenyl
sulfoxide 2m also furnished good yields of the desired
compounds. It is noted that diphenyl sulfoxide 2o does not
react with benzyne 1a under those conditions (Scheme 6, 2o).
The insertion reaction is also applicable to a variety of
Kobayashi aryne precursors and sulfoxides. As shown in
Scheme 7, the benzyne precursor bearing two electron-
donating methoxy groups could react with DMSO 2a, methyl
phenyl sulfoxide 2b, and isopropyl phenyl sulfoxide 2n in
moderate yields and with the product 3 bias (Scheme 7, 1b).
However, the reactions using benzyne precursors with two
fluoro groups on the phenyl ring gave a mixture of the 1:1
products in low yields (Scheme 7, 1c). Noteworthy, the
reaction of 2,3-naphthalyne 1d with 2b or 2n produced
exclusively the ylide forming/dealkylation pathway product
3db, albeit in very low yields (Scheme 7, 1d). Besides the
substrates described in Schemes 6 and 7, the cyclic sulfoxides
and unsymmetrical 3-methoxybenzyne were also examined in
the reaction. However, low efficiency was observed (Schemes
7S, 8S).15
In summary, we have developed a novel and mild reaction of
sulfoxides and arynes. The reaction proceeds through a unique
insertion of arynes into the S−O bond and subsequent sulfur
ylide formation to offer thioethers and epoxides. The
generation of sulfur ylides without the use of bases is expected
to be a useful methodology for organic synthesis. Further work
on the applications and extension of the scope of the protocol,
as well as a comprehensive theoretical study on the mechanistic
details, is currently under investigation in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Procedures and full characterization of new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wangbin@nankai.edu.cn.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/ol5036326
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(12) (a) Liu, F.-L.; Chen, J.-R.; Zou, Y.-Q.; Wei, Q.; Xiao, W.-J. Org.
Lett. 2014, 16, 3768. (b) Cram, D. J.; Day, A. C. J. Org. Chem. 1966,
31, 1227.
(13) Oae, S.; Doi, J. Organic Sulfur Chemistry; CRC Press: 1991; Vol.
1.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the Natural Science Foundation of
China (Nos. 21172120, 21472093) and Tianjin Municipal
Science and Technology Commission (No. 14JCYBJC20600)
for the funding support.
(14) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 12,
1211.
(15) For more details, see the Supporting Information.
(16) The information for the crystal structure of 3aa (CCDC
928175) can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
(17) Corey, E. J.; Chaykovsky, M. J. Am. Chem. Soc. 1965, 87, 1353.
(18) (a) Jayanth, T. T.; Jeganmohan, M.; Cheng, M.-J.; Chu, S.-Y.;
Cheng, C.-H. J. Am. Chem. Soc. 2006, 128, 2232. (b) Candito, D. A.;
Panteleev, J.; Lautens, M. J. Am. Chem. Soc. 2011, 133, 14200.
(c) Jayanth, T. T.; Jeganmohan, M.; Cheng, M.-J.; Chu, S.-Y.; Cheng,
C.-H. J. Am. Chem. Soc. 2006, 128, 2232. (d) Karmakar, R.;
Mamidipalli, P.; Yun, S. Y.; Lee, D. Org. Lett. 2013, 15, 1938.
(19) Pirali, T.; Zhang, F.; Miller, A. H.; Head, J. L.; McAusland, D.;
Greaney, M. F. Angew. Chem., Int. Ed. 2012, 51, 1006.
(20) Yoshioka, E.; Tamenaga, H.; Miyabe, H. Tetrahedron Lett. 2014,
55, 1402.
REFERENCES
■
(1) For selected reviews of aryne chemistry, see: (a) Pellissier, H.;
Santelli, M. Tetrahedron 2003, 59, 701. (b) Wenk, H. H.; Winkler, M.;
Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502. (c) Tadross, P. M.;
Stoltz, B. M. Chem. Rev. 2012, 112, 3550. (d) Yoshida, H.; Ohshita, J.;
Kunai, A. Bull. Chem. Soc. Jpn. 2010, 83, 199. (e) Kitamura, T. Aust. J.
Chem. 2010, 63, 987. (f) Bhunia, A.; Yetra, S. R.; Biju, A. T. Chem. Soc.
Rev. 2012, 41, 3140. (g) Bhojgude, S. S.; Biju, A. T. Angew. Chem., Int.
Ed. 2012, 51, 1520. (h) Gampe, C. M.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2012, 51, 3766. (i) Wu, C.; Shi, F. Asian J. Org. Chem. 2013, 2,
116. (j) Dubrovskiy, A. V.; Markina, N. A.; Larock, R. C. Org. Biomol.
Chem. 2013, 11, 191.
(2) For the aryne insertion reviews, see: (a) Pena, D.; Per
́
ez, D.;
̃
Guitian
́
, E. Angew. Chem., Int. Ed. 2006, 45, 3579. (b) Okuma, K.
Heterocycles 2012, 85, 515. (c) Yoshida, H.; Takaki, K. Synlett 2012,
(21) Xu, H.-D.; Cai, M.-Q.; He, W.-J.; Hu, W.-H.; Shen, M.-H. RSC
Adv. 2014, 4, 7623.
23, 1725.
(3) (a) Li, R.; Wang, X.; Wei, Z.; Wu, C.; Shi, F. Org. Lett. 2013, 15,
4366. (b) Kaicharla, T.; Bhojgude, S. S.; Biju, A. T. Org. Lett. 2012, 14,
6238. (c) Huang, X.; Xue, J. J. Org. Chem. 2007, 72, 3965. (d) Liu, Y.-
L.; Liang, Y.; Pi, S.-F.; Li, J.-H. J. Org. Chem. 2009, 74, 5691. (e) Ni, C.;
Zhang, L.; Hu, J. J. Org. Chem. 2008, 73, 5699. (f) Tambar, U. K.;
Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340.
(4) (a) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew.
Chem., Int. Ed. 2002, 41, 3247. (b) Liu, Z.; Larock, R. C. J. Am. Chem.
Soc. 2005, 127, 13112. (c) Dong, Y.; Liu, B.; Chen, P.; Liu, Q.; Wang,
M. Angew. Chem., Int. Ed. 2014, 53, 3442. (d) Rao, B.; Zeng, X. Org.
Lett. 2013, 16, 314. (e) Fang, Y.; Rogness, D. C.; Larock, R. C.; Shi, F.
J. Org. Chem. 2012, 77, 6262. (f) Li, R.; Tang, H.; Fu, H.; Ren, H.;
Wang, X.; Wu, C.; Wu, C.; Shi, F. J. Org. Chem. 2014, 79, 1344.
(g) Xie, C.; Zhang, Y.; Huang, Z.; Xu, P. J. Org. Chem. 2007, 72, 5431.
(5) (a) Yoshioka, E.; Miyabe, H. Tetrahedron 2012, 68, 179.
(b) Yoshioka, E.; Tanaka, H.; Kohtani, S.; Miyabe, H. Org. Lett. 2013,
15, 3938. (c) Yoshioka, E.; Kohtani, S.; Miyabe, H. Org. Lett. 2010, 12,
1956. (d) Yoshida, H.; Watanabe, M.; Fukushima, H.; Ohshita, J.;
Kunai, A. Org. Lett. 2004, 6, 4049. (e) Łac
̧ zkowski, K. Z.; García, D.;
Pena, D.; Cobas, A. n.; Perez, D.; Guitian, E. Org. Lett. 2011, 13, 960.
́
́
̃
(f) Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2010, 12, 3117.
(g) Yoshioka, E.; Kohtani, S.; Miyabe, H. Angew. Chem., Int. Ed. 2011,
50, 6638. (h) Yoshida, H.; Ito, Y.; Ohshita, J. Chem. Commun. 2011,
47, 8512. (i) Zhang, T.; Huang, X.; Wu, L. Eur. J. Org. Chem. 2012,
3507. (j) Zhou, C.; Wang, J.; Jin, J.; Lu, P.; Wang, Y. Eur. J. Org. Chem.
2014, 2014, 1832. (k) Kivrak, A.; Larock, R. C. J. Org. Chem. 2010, 75,
7381.
(6) Biswas, K.; Greaney, M. F. Org. Lett. 2011, 13, 4946.
(7) (a) Yoshida, H.; Morishita, T.; Nakata, H.; Ohshita, J. Org. Lett.
2008, 11, 373. (b) Liu, Z.; Larock, R. C. Angew. Chem., Int. Ed. 2007,
46, 2535. (c) Lu, C.; Dubrovskiy, A. V.; Larock, R. C. J. Org. Chem.
2012, 77, 8648. (d) Liu, Z.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc.
2005, 127, 15716. (e) Zeng, Y.; Zhang, L.; Zhao, Y.; Ni, C.; Zhao, J.;
Hu, J. J. Am. Chem. Soc. 2013, 135, 2955.
(8) (a) Chakrabarty, S.; Chatterjee, I.; Tebben, L.; Studer, A. Angew.
Chem., Int. Ed. 2013, 2968. (b) Yoshida, H.; Ikadai, J.; Shudo, M.;
Ohshita, J.; Kunai, A. J. Am. Chem. Soc. 2003, 125, 6638. (c) Alajarin,
M.; Lopez-Leonardo, C.; Raja, R.; Orenes, R.-A. Org. Lett. 2011, 13,
5668. (d) Yoshida, H.; Ikadai, J.; Shudo, M.; Ohshita, J.; Kunai, A.
Organometallics 2004, 24, 156.
(9) Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48,
572.
(10) Yoshida, H.; Tanino, K.; Ohshita, J.; Kunai, A. Angew. Chem., Int.
Ed. 2004, 43, 5052.
(11) Biju, A. T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 9761.
D
DOI: 10.1021/ol5036326
Org. Lett. XXXX, XXX, XXX−XXX