The preparation and cycloaddition reaction of 1-sulfonyl-1-trifluoromethyl allenes

Article abstract of DOI:10.1016/j.tetlet.2017.07.050

A series of 1-sulfonyl-1-trifluoromethyl allenes were prepared for the first time from commercial available 2-bromo-3,3,3-trifluoropropene. Cycloaddition reaction of these trifluoromethylated allenes with nitrones occured readily under mild conditions, giving the corresponding trifluoromethylated isoxazolidines in high yields.

Full text of DOI:10.1016/j.tetlet.2017.07.050

Accepted Manuscript
The preparation and cycloaddition reaction of 1-sulfonyl-1-trifluoromethyl al-
lenes
Jun-Li Li, Xian-Jin Yang, Min Jiang, Jin-Tao Liu
PII:
S0040-4039(17)30905-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.050
TETL 49132
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 June 2017
11 July 2017
14 July 2017
Please cite this article as: Li, J-L., Yang, X-J., Jiang, M., Liu, J-T., The preparation and cycloaddition reaction of
1-sulfonyl-1-trifluoromethyl allenes, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.
2017.07.050
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Tetrahedron Letters
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The preparation and cycloaddition reaction of 1-sulfonyl-1-trifluoromethyl
allenes
Jun-Li Lia, Xian-Jin Yangb, Min Jianga, Jin-Tao Liua*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China
b Laboratory of Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237,
China
ARTICLE INFO
ABSTRACT
Article history:
Received
A series of 1-sulfonyl-1-trifluoromethyl allenes were prepared for the first time from
commercial available 2-bromo-3,3,3-trifluoropropene. Cycloaddition reaction of these
trifluoromethylated allenes with nitrones occured readily under mild conditions, giving the
corresponding trifluoromethylated isoxazolidines in high yields.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
trifluoromethyl
allene
isoxazolidine
cycloaddition
nitrone
In the past few decades, allene chemistry has attracted
considerable attention,1 and allenes have proven themselves to be
valuable building blocks toward complex molecular targets,
revealing their novel applications in natural product synthesis,
pharmaceutical chemistry and materials science.2 Among various
allenes, sulfonyl-containing allenes are special ones and
important in organic synthesis,3 and practical methods for their
preparation are highly desirable.4 Meanwhile, efforts have also
been made to study the chemistry of allenic sulfones. For
example, Ma’s group has studied the hydrohalogenation of 1,2-
allenic sulfones5a and the Heck-type cross-coupling reaction of
1,2-allenic sulfones with aryl halides. 5b Mukai et al. reported the
intramolecular nucleophilic addition of 1,2-allenic sulfones. 6
The introduction of fluorine atom or fluoroalkyl groups may
modulate physical and electronic properties of a molecule, which
further reflects on the reactivity and bioactivity of fluorinated
organic compounds.7 Because of their high hydrophobicities,
metabolic activities and bioavailabilities, fluorinated compounds,
especially trifluoromethylated compounds, have recently
attracted significant interest and became very important synthetic
targets in labs and industries.8 So far, most methods for the
preparation of trifluoromethylated allenes involve the
transformation of trifluoromethylated alkynes.9
allenes and studied their reaction with nitrones. The results are
reported in this paper.
According to the literature,12 allenic sulfones could be prepared
via [2,3] sigmatropic rearrangement of propargylic sulfinates,
which could be obtained by the reaction of propargylic alcohols
with sulfinyl chlorides. Therefore, we started with the reaction of
2-bromo-3,3,3-trifluoropropene (1) with ketone or aldehyde in
the presence of LDA (Lithium diisopropylamide).13 As shown in
Table 1, a series of propargylic alcohols 3 were obtained in
moderate to good yields. Subsequent esterization of alcohols 3
with methanesulfinyl chloride in the presence of pyridine
afforded the corresponding propargylic sulfinates, which
underwent thermal rearrangement in CH3CN under reflux to give
1-sulfonyl-1-trifluoromethyl allenes 4. Results in Table 1
indicated that this method was an efficient approach toward 4 and
tolerated many substituents. All acetylenic alcohols containing
methyl, ethyl, propyl, phenyl or tert-butyl group were converted
smoothly to the corresponding trifluoromethyl allenyl sulfones 4
in good yields (entries 1-7). Allenes 4h and 4i containing
cyclohexyl or cyclopentyl group were also prepared by this
method (entries 8-9). However, in the case of trisubstituted
propargylic alcohol 3j, the desired product 4j was not obtained
(entry 10).
Previously, we reported the synthesis and application of some
allenyl perfluoroalkyl sulfones,10 and found that zwitterionic
compounds can be obtained from the cycloaddition of allenyl
perfluoroalkyl sulfones.10b The iodocyclization reaction of
trifluoromethylallenic phosphonates was also achieved.11 As an
extension of our study on the chemistry of fluorine-containing
allenes, we prepared a series of 1-sulfonyl-1-trifluoromethyl
Table 1. The preparation of allenes 4

2
Tetrahedron
OH
A) -BuLi/ -Pr2NH(2.0 equiv), THF, -78 oC
O
temperature were needed for the trifluoromethylated allenic
sulfones.14 When unsymmetrical sulfonyl allene such as 4c was
used, the reaction gave complex cycloadducts as indicated by
NMR analysis.
n
i
R1
R2
F3C
F3C
Br
2
(1.1 equiv)
B)
3
1
R1 R2
1) CH3SOCl (1.4 equiv)
pyridine (1.4 equiv)
CH2Cl2, rt
SO2Me
Table 2. The reaction of allene 4 and nitrone 5
F3C
R1
.
2) CH3CN, reflux
R2
4
Entry
2, R1/R2
2a, Me/Me
2b, Et/Et
Yield (3, %)[a]
Yield (4, %) [a]
4a, 83
4b, 79
4c, 86
4d, 87
4e, 88
4f, 73
1
2
3a, 55
3b, 75
3c, 74
3d, 68
3e, 78
3f, 94
3g, 94
3h, 82
3i, 94
3j, 93
Entry[a]
4 (R1/R2)
4a, Me/Me
4a, Me/Me
4a, Me/Me
4b, Et/Et
5, R3
Yield (6, %)[b]
6a, 93
3
2c, Et/Me
2d, Me/nPr
2e, Me/ tBu
2f, Ph/Ph
1
2
3
4
5
6
7
5a, H
4
5b, Cl
5c, NO2
5a, H
6b, 93
5
6c, 88
6
6d, 93
7
2g, Ph/Me
2h, -(CH2)4-
2i, -(CH2)5-
2j, Ph/H
4g,67
4b, Et/Et
5b, Cl
5c, NO2
5a, H
6e, 90
8
4h, 80
4i, 75
4b, Et/Et
6f, 86
9
4i, -(CH2)5-
6g, 94
10
4j, -
a Reaction condition: 4 (0.15 mmol), nitrone 5 (0.21 mmol), benzene (2 mL),
room temperature, 1 h. b Isolated yield.
a Isolated yields.
Both sulfonyl and trifluoromethyl are strongly electron-
withdrawing and have activating effect on the carbon-carbon
double or triple bond with respect to conjugate additions and
cycloadditions. Therefore, allenes 4 were expected to undergo
cycloaddition reaction with nitrone. To prove this hypothesis, the
reaction of 4a with 1.4 equiv of nitrone 5a was carried out in
benzene. Gratefully, the reaction occurred smoothly at room
temperature without any catalyst and cycloaddition product 6a
was obtained in 93% isolated yield after work-up of the reaction
mixture (Scheme 1). In our previous study on the dipolar
cycloaddition of allenyl perfluoroalkyl sulfones, it was found that
homolytic cleavage of the N-O bond in the cycloadducts occured
and the subsequent rearrangement of resulting diradical
intermediate gave zwitterionic products.10b In this reaction,
isoxazolidine 6a was very stable and no further rearrangement
was observed.
In summary, we have developed an efficient method for the
synthesis of trifluoromethylated allenic sulfones. Starting from
commercial available 2-bromo-3,3,3-trifluoroproprene, a series
of 1-sulfonyl-1-trifluoromethyl allenes were prepared for the first
time in good yields. Due to the presence of strongly electron-
withdrawing sulfonyl and trifluoromethyl group, these
trifluoromethylated allenic sulfones could react easily with
nitrones under mild conditions to give the corresponding
trifluoromethylated isoxazolidine products in high yields.
Acknowledgments
We thank the National Natural Science Foundation (No.
21572257 and 21502213) and Shanghai Sailing Program (No.
15YF1414800) for financial support.
Supplementary data
O
F3C
N
Supplementary data associated with this article can be found,
at
SO2Me
MeO2S
in
http://dx.doi.org/10.1016/j.tetlet.201x.xx.xxx.
the
online
version,
benzene, rt, 1 h
O
H
.
F3C
+
N
5a
, 1.4 equiv
4a
References and notes
6a
, 93%
1. [1] (a) Krause, N.; Hashmi, A. S. K. Modern Allene Chemistry; Wiley-
VCH: Weinheim, Germany, 2004. (b) Hashmi, A. S. K. Angew. Chem.,
Int. Ed. 2000, 39, 3590-3593. (c) Marshall, J. A. Chem. Rev. 2000, 100,
3163-3185. (d) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res. 2001, 34,
535-544. (e) Bates, R.; Satcharoen, V. Chem. Soc. Rev. 2002, 31, 12-21.
(f) Sydnes, L. Chem. Rev. 2003, 103, 1133-1150. (g) Wei, L. L.; Xiong,
H.; Hsung, R. P. Acc. Chem. Res. 2003, 36, 773-782. (h) Ma, S. Acc.
Chem. Res. 2003, 36, 701-712. (i) Ma, S. Chem. Rev. 2005, 105, 2829-
2872. (j) Brasholz, M.; Reissig, H.-U.; Zimmer, R. Acc. Chem. Res.
2009, 42, 45-56. (k) Neff, R. K.; Frantz, D. E. Tetrahedron 2015, 71, 7-
18; (l) Tius, M. A. Chem. Soc. Rev. 2014, 43, 2979-3002.
Scheme 1. Reaction of 4a with nitrone 5a
Under similar conditions, the scope of the cycloaddition
addition was investigated and the results are summarized in
Table 2. All reactions took place readily at room temperature to
afford the corresponding isoxazolidine
6 in high yields.
Substituents in allenes 4 had little influence on the yields, while
nitrones 5 containing a strong electron-withdrawing substituent
(NO2) gave slightly lower yield. Generally, compared with their
non-fluorine-containing analogs, less reaction time and lower

2. (a) Patai, S. The Chemistry of Ketenes, Allenes and Related Compounds,
Wiley, New York, 1980. (b) Landor, S. R. The Chemistry of the Allenes,
Academic Press, London, 1982. (c) Schuster, H. F.; Coppola, G. M.
Allenes in Organic Synthesis, Wiley, New York, 1984. (d) Hassan, H. H.
A. M. Curr. Org. Synth. 2007, 4, 413-439. (e) Barbero, A.; Pulido, F. J.
Synthesis 2004, 779-785. (f) Brandsma, L.; Nedolya, N. A. Synthesis
2004, 735-745. (g) Manukyan, M. O.; Babakhanyan, A. V.; Panosyan, G.
A.; Gyul’nazaryan, A. K.; Kocharyan, S. T. Russ. J. Gen. Chem. 2007,
77, 1370-1372.
Nature 2011, 473, 470-477. (l) Hird, M. Chem. Soc. Rev. 2007, 36,
2070-2095. (m) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305-321.
8. (a) Kirsch, P. Modern Fluoroorganic Chemistry, Wiley-VCH, Weinheim,
2004. (b) Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2005, 44, 214-
231. (c) Muller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881-
1886. (d) Pacheco, M. C.; Purser, S.; Gouverneur, V. Chem. Rev. 2008,
108, 1943-1981.
9. (a) Watanabe, Y.; Yamazaki, T. Synlett 2009, 3352-3354. (b) Shimizu,
M.; Higashi, M.; Takeda, Y.; Jiang, G.; Murai, M.; Hiyama, T. Synlett
2007, 1163-1165. (c) Yamazaki, T.; Yamamoto, T.; Ichihara, R. J. Org.
Chem. 2006, 71, 6251-6253. (d) Konno, T.; Tanikawa, M.; Ishihara, T.;
Yamanaka, H. Chem. Lett. 2000, 29, 1360-1361.
3. (a) Tanaka, K.; Kaji, A. In The Chemistry of Sulphones and Sulphoxides;
Patai, S.; Rappoport, Z.; Stirling, C. J. M. Eds.; Wiley: Chichester, 1988;
Chapter 15. (b) Patai, S. The Chemistry of Ketenes, Allenes, and Related
Compounds, John Wiley & Sons: New York, 1980; Part 1. (c) Simpkins,
N. S. Sulphones in Organic Synthesis, Pergamon Press: Oxford, 1993. (d)
Fuchs, P. L.; Braish, T. F. Chem. Rev. 1986, 86, 903-917. (e) Trost, B. M.
Bull. Chem. Soc. Jpn. 1988, 61, 107-124. (f) Simpkins, N. S.
Tetrahedron 1990, 46, 6951-6984.
10. (a) Wang, X.-J.; Lin, Y.; Liu, J.-T. Chin. J. Chem. 2006, 24, 775-780. (b)
Wang, X.-J.; Liu, J.-T. Chin. J. Chem. 2007, 25, 649-652.
11. Li, P.; Liu, Z.-J.; Liu, J.-T. Tetrahedron 2010, 66, 9729-9732.
12. Braverman, S.; Mechoulam, H. Israel J. Chem. 1967, 5, 71-74.
13. (a) Yamazaki, T.; Mizutani, K.; Kitazume, T. J. Org. Chem. 1995, 60,
6046-6056. (b) Katritzky, A. R.; Qi, M.; Wells, A. P. J. Fluorine Chem.
1996, 80, 145-147. (c) Qing, F. –L.; Gao, W. –Z.; Ying, J. –W. J. Org.
Chem. 2000, 65, 2003-2006.
4. Yu, S.; Ma, S. Chem. Commun. 2011, 47, 5384-5418.
5. (a) Ma, S.; Wei, Q. J. Org. Chem. 1999, 64, 1026-1028. (b) Fu, C.; Ma,
S. Org. Lett. 2005, 7, 1605-1607.
6. (a) Mukai, C.; Yamashita, H.; Hanaoka, M. Org. Lett. 2001, 3, 3385-
3387. (b) Mukai, C.; Ukon, R.; Kuroda, N. Tetrahedron Lett. 2003, 44,
1583-1586. (c) Mukai, C.; Kobayashi, M.; Kubota, S.; Takahashi, Y.;
Kitagaki, S. J. Org. Chem. 2004, 69, 2128-2136. (d) Mukai, C.; Ohta,
M.; Yamishita, H.; Kitagaki, S. J. Org. Chem. 2004, 69, 6867-6873. (e)
Murai, C.; Kuroda, N.; Ukon, R.; Itoh, R. J. Org. Chem. 2005, 70, 6282-
6290.
14. (a) Padwa, A.; Carter, S. P.; Chiacchio, U.; D. N. Kline, Tetrahedron Lett.
1986, 27, 2683-2686. (b) Padwa, A.; Kline, D. N.; Koehler, K. F.;
Matzinger, M.; Venkatramanan, M. K. J. Org. Chem. 1987, 52, 3909-
3917. (c) Parpani, P.; Zecchi, G. J. Org. Chem. 1987, 52, 1417-1421. (d)
Blechert, S. Liebigs Ann Chem. 1985, 673-682. (e) Padwa, A.; Kline, D.
N.; Perumattam, J. Tetrahedron Lett. 1987, 28, 913-916. (f) Padwa, A.;
Kline, D. N.; Norman, B. H. Tetrahedron Lett. 1988, 29, 265-268. (g)
Padwa, A.; Matzinger, M.; Tomioka, Y.; Venkatramanan, M. K. J. Org.
Chem. 1988, 53, 955-963. (h) Padwa, A.; Carter, S. P.; Chiacchio, U.;
Kline, D. N.; Perumattam, J. J. Chem. Soc., Perkin Trans. 1. 1988, 2639-
2646. (i) Padwa, A.; Chiacchio, U.; Kline, D. N.; Perumattam, J. J. Org.
Chem. 1988, 53, 2238-2245. (j) Padwa, A.; Kline, D. N.; Norman, B. H.
J. Org. Chem. 1989, 54, 810-817. (k) Padwa, A.; Tomioka, Y.;
Venkatramanan, M. K. Tetrahedron Lett. 1987, 28, 755-758.
7. (a) Ojima, I. In Fluorine in Medicinal Chemistry and Chemical Biology;
Wiley-Blackwell: Chichester, U.K., 2009. (b) Umemoto, T. Chem. Rev.
1996, 96, 1757-1777. (c) Prakash, G. K. S.; Yudin, A. K. Chem. Rev.
1997, 97, 757-786. (d) Schlosser, M. Angew. Chem., Int. Ed. 2006, 45,
5432-5446. (e) Besset, T.; Schneider, C.; Cahard, D. Angew. Chem., Int.
Ed. 2012, 51, 5048-5050. (f) Studer, A. Angew. Chem., Int. Ed. 2012, 51,
8950-8958. (g) Wang, X.; Zhang, Y.; Wang, J. Scientia Sinica Chimica
2012, 42, 1417-1427. (h) Tomashenko, O. A.; Grushin, V. V. Chem. Rev.
2011, 111, 4475-4521. (i) Purser, S.; Moore, P. R.; Swallow, S.;
Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320-330. (j) Smart, B. E.
Chem. Rev. 1996, 96, 1555-1556. (k) Furuya, T.; Kamlet, A. S.; Ritter, T.

4
Tetrahedron
Research highlights:
A series of 1-sulfonyl-1-trifluoromethyl allenes
were prepared for the first time.
Cycloaddition reaction of trifluoromethylated
allenes with nitrones was investigated.
Trifluoromethylated isoxazolidines were obtained
under mild conditions.

Graphical abstract