Regio- and Stereoselective Oxysulfonylation of Allenes

Article abstract of DOI:10.1021/acs.orglett.6b01575

A highly regio- and stereoselective oxysulfonylation of allenes was developed that provided direct access to 2-sulfonyl allylic alcohols in good yields. By means of dioxygen activation, selective difunctionlization of allenes could be successfully achieved under mild metal-free conditions. Preliminary mechanistic investigation disclosed that this transformation probably goes through a radical process.

Full text of DOI:10.1021/acs.orglett.6b01575

Letter
pubs.acs.org/OrgLett
Regio- and Stereoselective Oxysulfonylation of Allenes
Zhiyuan Huang,†,§ Qingquan Lu,†,§ Yichang Liu,† Dong Liu,† Jian Zhang,† and Aiwen Lei*,†,‡
†College of Chemistry and Molecular Sciences, the Institute for Advanced Studies (IAS), Wuhan University, Wuhan, Hubei 430072,
P. R. China
‡State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Lanzhou 730000, P. R.
China
S
* Supporting Information
ABSTRACT: A highly regio- and stereoselective oxysulfonylation of allenes was developed that provided direct access to 2-
sulfonyl allylic alcohols in good yields. By means of dioxygen activation, selective difunctionlization of allenes could be
successfully achieved under mild metal-free conditions. Preliminary mechanistic investigation disclosed that this transformation
probably goes through a radical process.
llenes, which contain the interesting and special functional
sustainability and atom efficiency. On the other hand, primary
Agroups of two cumulative carbon−carbon double bonds, alcohols were generated in this transformation. Notably, it is
quite uncommon in similar dioxygen-involved reactions, in
which aldehydes or ketones were usually the dominant
products.9
have been widely used in the synthesis of complicated natural
products1 as well as pharmacologically active compounds.2
However, due to the diverse possibilities of reactive sites in
allenes, challenges still remain in controlling the reaction
selectivity.3 In 2014, two research groups, Ma4 and Kanai,5
independently used TEMPO as an oxygen source to build the
C−O bond when allenes were used as substrates. In 2015, Liu’s
group6 also reported a copper-catalyzed trifluoromethylazida-
tion and trifluoromethylthiocyanation of allenes. However,
highly regio- and stereoselective oxysulfonylation of allenes has
not yet been achieved.
Radicals exist widely in nature, and radical reactions have also
been proven to be powerful tools in modern organic synthesis.7
Although radical reactions have been fully developed and
widely utilized in various organic synthesis for a quite long time,
challenges still remain in this area. Among them, appropriate
radical initiators and good reaction selectivity might be the key
aspects. However, toxic transition metals were often used as
radical initiators or oxidants in these reactions, thus making
these transformations not environmentally friendly. On the
other hand, molecular oxygen, which could be easily photo-
synthesized by green plants, exists widely in nature. Among
those molecular oxygen involved organic transformations,
dioxygen activation has now been extensively studied for its
high reactivity and amity to the environment.8 Therefore,
introducing dioxygen activation into selective oxysulfonylation
of allenes would be quite charming and significant, which will
also broaden the scope of allene chemistry. Herein, we report a
highly regio- and stereoselective oxysulfonylation of allenes
through dioxygen activation under mild metal-free conditions.
Basically, as a green oxidizer, dioxygen bears evident advantages
over toxic metal salts and complex organic reagents for its
Our study was initiated with the reaction between phenyl-
allene (1a) and benzenesulfinic acid (2a) as the starting
materials with DCE (1,2-dichloroethane) as the solvent at
room temperature. As a result, complex product mixtures were
generated presumably due to the high reactivity of the
substrates. Based on our previous finding that base could
help eliminate byproducts,10 pyridine was added into this
reaction system. Notably, oxysulfonylation product 3aa was
predominantly formed with high selectivity. Furthermore,
single X-ray diffraction measurement of the acylated product
confirmed the accurate product structure (Scheme 1).11
Afterward, the influence of different kinds of bases to the
reaction was investigated thoroughly. As seen in Table 1, base
played a crucial role in terms of selectivity and chemical yield
(Table 1, entry 1 vs entries 2−6), among which pyridine
demonstrated the best reactivity (Table 1, entry 6). Increasing
or decreasing the amount of pyridine (Table 1, entries 7 and 8)
afforded slightly decreased yields. Screening the solvent for the
reaction conditions, DCE was found to be the best, which
might be explained partly by the solubility of the reactants in
different solvents (see Table S1). Due to the auto-oxidation and
disproportionation of benzenesulfinic acid itself,12 reactant 2a is
usually used with excess amount. Therefore, the ratio of 1a/2a
was also tested. Initially, a ratio of 1a/2a 1:5 was employed.
When the ratio decreased to 1:4, a slightly decreased yield of
59% was obtained (Table 1, entry 9), suggesting that
Received: May 31, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01575
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
react smoothly with 1a to afford the desired products in
moderate to good yields (Table 2). Generally, electron-neutral
Scheme 1. Single-Crystal X-ray Structure of the Acylated
Product
a
Table 2. Substrate Scope of the Reaction
a
Table 1. Survey of the Reaction Conditions
b
entry
base
Et3N
ratio (1a:2a)
temp (°C)
yield (%)
1
1:5
1:5
1:5
1:5
1:5
1:5
1:5
1:5
1:4
1:5
1:5
1:5
1:5
45
45
45
45
45
45
45
45
45
rt
complex
76
2
3
DBU
20
4
Et2NH
LiOH
50
5
32
6
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
pyridine
79
c
7
71
d
8
60
a
Unless otherwise specified, all reactions were carried out using 1a
e
9
59
(0.2 mmol), 2 (1.0 mmol), and pyridine (0.7 mmol) in DCE (4.0 mL)
10
11
12
13
50
20
b
at 45 °C for 1.5 h under 1 atm of air (balloon). Yield of isolated
c
60
45
45
product. 65 °C.
f
complex
g
trace
and electron-rich arylsulfinic acids demonstrated better
reactivity over electron-poor arylsulfinic acids in terms of
chemical yields (Table 2, entries 1−3 vs entries 4−6). On the
other hand, arylsulfinic acids with halogen substituents such as
F, Cl, and Br could be well tolerated in this reaction (Table 2,
entries 4−6), which allows for more diverse transformations of
these types of products. For bromo-substituted benzenesulfinic
acid, only 49% yield of the corresponding product was obtained
after the reaction, which could be further increased to 63% with
an elevated temperature (Table 2, entry 6). Additionally,
naphthalene-2-sulfinic acid also proved to be an excellent
reaction partner with 1a, generating the desired product in 79%
yield (Table 2, entry 7).
Next, various allenes were also examined under the
optimized conditions, and the results are listed in Table 3.
Typical functional groups, such as alkyl, alkoxy, fluoro, chloro,
and bromo moieties, were well tolerated under the optimized
conditions, affording the corresponding products in moderate
to good yields (Table 3, entries 1−6). Notably, when 1,1-
phenyl-substituted allene (Table 3, entry 7) was introduced
into this reaction, a diverse tetrasubstituted alkene could be
obtained in one step. In addition, besides aryl-substituted
allenes, ester group substituted allenes could also survive under
a
Unless otherwise specified, all reactions were carried out using 1a
(0.2 mmol), 2a (1.0 mmol), and base (0.7 mmol) in DCE (4.0 mL) at
45 °C for 1.5 h under 1 atm of air (balloon). Yield of isolated
product. Pyridine (0.6 mmol). Pyridine (0.8 mmol). Pyridine (0.56
mmol). Under O2. Under N2.
b
c
d
e
f
g
benzenesulfinic acid might also act as a reductant more than a
reactant during the reaction. Moreover, the concentration of
dioxygen had a great influence on the reaction. When the
reaction was carried out under dioxygen atmosphere instead of
air, it turned generated a complex product mixture (Table 1,
entry 12), while only a trace amount of product was obtained
when the reaction was under nitrogen atmosphere (Table 1,
entry 13). In addition, both an increase and a decrease of
reaction temperature resulted in poor yields (Table 1, entries
10 and 11). Therefore, the best reaction conditions were
determined to be 0.2 mmol of 1a, 1.0 mmol of 2a, and 0.7
mmol of pyridine in DCE at 45 °C for 1.5 h under air
atmosphere.
With the best reaction conditions in hand, we then explored
the substrate scope. Notably, arylsulfinic acid derivatives with
different substituents at the 4-position of the phenyl ring could
B
DOI: 10.1021/acs.orglett.6b01575
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
conditions. The desired reaction was completely inhibited (eq
1). When TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) was
used as a radical-trapping agent, the same result was achieved
(eq 2). These two results indicated that this transformation is
likely to involve a radical process. Afterward, an 18O isotope
labeling experiment was carried out (eq 3). The reaction
between 1a and 2a under 18O2 afforded the 18O-labeled product
3aa′ in 86% isotopic purity. Further H218O labeling experi-
ments supported this result (see the SI for more details). These
results demonstrated that O2 took part into this reaction and
was transformed into the final product.
Table 3. Substrate Scope of the Reaction
Although the detailed mechanism remains to be elucidated, a
tentative reaction mechanism was proposed (Scheme 3).
Scheme 3. Proposed Mechanism
Initially, benzenesulfinic acid was quickly transformed into
sulfonyl anion I in the presence of pyridine. Subsequently, the
pathway was triggered by the autoxidation of I with dioxygen
via a single-electron-transfer (SET) process, affording an
oxygen-centered radical II which could resonate with sulfonyl
radical III. Thereafter, the addition of sulfonyl radical to allene
produced the reactive allyl radical IV, which could be trapped
by dioxygen under the present conditions and formed
intermediate V. Afterward, the intermediate V went through
the SET and PT process successively with I and pyridinium,
generating II/III and affording peroxide VII. Finally, VII
underwent subsequent reduction by benzenesulfinic acid and
generated 3aa.
a
Unless otherwise specified, all reactions were carried out using 1 (0.2
mmol), 2a (1.0 mmol), and pyridine (0.7 mmol) in DCE (4.0 mL) at
b
45 °C for 1.5 h under 1 atm of air (balloon). Yield of isolated
product. Reaction time: 2 h.
c
the standard conditions, in which terminal alkene products
were generated instead (Table 3, entries 8 and 9).
In order to gain insights into the reaction mechanism,
radical-trapping experiments were first conducted to elucidate
the reaction type (Scheme 2). BHT (2,6-di-tert-butyl-4-
methylphenol) was employed under the standard reaction
In conclusion, we have developed a unique approach for the
highly selective oxysulfonylation of allenes under metal-free
conditions, providing a direct access to allylic alcohols with
satisfactory yields. Different kinds of arylsulfinic acids and
allenes could be well tolerated. Preliminary mechanistic studies
disclosed that a radical process was probably involved in this
transformation. Isotopic labeling experiment demonstrated that
O2 was activated and transformed into the final product.
Ongoing research including further mechanistic details and
application of this reaction is currently underway.
Scheme 2. Radical-Trapping Experiments and 18O2 Isotope-
Labeling Experiment
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01575.
C
DOI: 10.1021/acs.orglett.6b01575
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) CCDC 1408332 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
(12) (a) Kice, J. L.; Hampton, D. C.; Fitzgerald, A. J. Org. Chem.
1965, 30, 882. (b) Wang, S.-F.; Chuang, C.-P.; Lee, J.-H.; Liu, S.-T.
Tetrahedron 1999, 55, 2273.
Experimental procedure, characterization data, and
1
copies of H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: aiwenlei@whu.edu.cn.
Author Contributions
§Z.H. and Q.L. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the 973 Program
(2012CB725302), the National Natural Science Foundation
of China (21390400, 21272180, and 21302148), the Research
Fund for the Doctor-al Program of Higher Education of China
(20120141130002), and the Ministry of Science and
Technology of China (2012YQ120060). The Program of
Introducing Talents of Discipline to Universities of China (111
Program) is also appreciated.
REFERENCES
■
(1) (a) Marshall, J. A. Chem. Rev. 2000, 100, 3163. (b) Zimmer, R.;
Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. Rev. 2000, 100, 3067.
(c) Wei, L.-l.; Xiong, H.; Hsung, R. P. Acc. Chem. Res. 2003, 36, 773.
(d) Ma, S. Acc. Chem. Res. 2009, 42, 1679. (e) Krause, N.; Winter, C.
Chem. Rev. 2011, 111, 1994. (f) Yu, S.; Ma, S. Chem. Commun. 2011,
47, 5384. (g) Rivera-Fuentes, P.; Diederich, F. Angew. Chem., Int. Ed.
2012, 51, 2818.
(2) (a) Ma, S. Carbopalladation of Allenes. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., de
Meijere, A., Eds.; Wiley: New York, 2002; pp 1491. (b) Ma, S.
Palladium in Organic Synthesis. In Topics in Organometallic Chemistry;
Tsuji, J., Eds.; Springer: Berlin, 2005; pp 183−210.
(3) (a) Hashmi, A. S. K. Angew. Chem., Int. Ed. 2000, 39, 3590.
(b) Alcaide, B.; Almendros, P.; Herrera, F.; Luna, A.; de Orbe, M. E.;
Torres, M. R. J. Org. Chem. 2015, 80, 4157. (c) Holemann, A.; Reißig,
̈
H.-U. Chem. - Eur. J. 2004, 10, 5493. (d) Molander, G. A.; Cormier, E.
P. J. Org. Chem. 2005, 70, 2622. (e) Alcaide, B.; Almendros, P.;
Aragoncillo, C.; Redondo, M. C. J. Org. Chem. 2007, 72, 1604. (f) Pan,
F.; Fu, C.; Ma, S. Chin. J. Org. Chem. 2004, 24, 1168.
(4) Xue, C.; Fu, C.; Ma, S. Chem. Commun. 2014, 50, 15333.
(5) Itoh, T.; Shimizu, Y.; Kanai, M. Org. Lett. 2014, 16, 2736.
(6) Zhu, N.; Wang, F.; Chen, P.; Ye, J.; Liu, G. Org. Lett. 2015, 17,
3580.
(7) (a) Xie, J.; Zhang, T.; Chen, F.; Mehrkens, N.; Rominger, F.;
Rudolph, M.; Hashmi, A. S. K. Angew. Chem., Int. Ed. 2016, 55, 2934.
(b) Xie, J.; Shi, S.; Zhang, T.; Mehrkens, N.; Rudolph, M.; Hashmi, A.
S. K. Angew. Chem., Int. Ed. 2015, 54, 6046. (c) Xie, J.; Li, J.; Wurm,
T.; Weingand, V.; Sung, H.; Rominger, F.; Rudolph, M.; Hashmi, A. S.
K. Org. Chem. Front. 2016, 3, 841.
(8) (a) Shi, Z.; Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012, 41,
3381. (b) Wu, W.; Jiang, H. Acc. Chem. Res. 2012, 45, 1736.
(c) Hashmi, A. S. K.; Blanco Jaimes, M. C.; Schuster, A. M.; Rominger,
F. J. Org. Chem. 2012, 77, 6394.
(9) For selected examples, see: (a) Cornell, C. N.; Sigman, M. S. Org.
Lett. 2006, 8, 4117. (b) Mitsudome, T.; Umetani, T.; Nosaka, N.;
Mori, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Angew. Chem., Int. Ed.
́
2006, 45, 481. (c) Bueno, A. C.; de Souza, A. O.; Gusevskaya, E. V.
Adv. Synth. Catal. 2009, 351, 2491. (d) Parreira, L. A.; Menini, L.; da
Cruz Santos, J. C.; Gusevskaya, E. V. Adv. Synth. Catal. 2010, 352,
1533.
(10) (a) Lu, Q.; Zhang, J.; Wei, F.; Qi, Y.; Wang, H.; Liu, Z.; Lei, A.
Angew. Chem., Int. Ed. 2013, 52, 7156. (b) Lu, Q.; Zhang, J.; Zhao, G.;
Qi, Y.; Wang, H.; Lei, A. J. Am. Chem. Soc. 2013, 135, 11481.
D
DOI: 10.1021/acs.orglett.6b01575
Org. Lett. XXXX, XXX, XXX−XXX