Wittig Ylide Mediated Decomposition of N -Sulfonylhydrazones to Sulfinates

Article abstract of DOI:10.1021/acs.orglett.7b03953

N-Sulfonylhydrazones generate sulfinates selectively when treated with a stabilized Wittig ylide in a polar aprotic solvent at elevated temperature. The transition metal and base free decomposition method is applicable to N-sulfonylhydrazones generated from a number of aromatic and heteroaromatic aldehydes and ketones. In the case of N-tosylhydrazones derived from O-allyl and O-propargyl salicylaldehydes, selective formation of sulfinate occurs over intramolecular [3 + 2]-cycloaddition reaction.

Full text of DOI:10.1021/acs.orglett.7b03953

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Wittig Ylide Mediated Decomposition of N‑Sulfonylhydrazones to
Sulfinates
Deepika Choudhary,† Vineeta Khatri,† and Ashok K. Basak*,†,‡
†Department of Chemistry, University of Rajasthan, JLN Marg, Jaipur, 302004, India
‡Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, 221005, India
S
* Supporting Information
ABSTRACT: N-Sulfonylhydrazones generate sulfinates selectively when
treated with a stabilized Wittig ylide in a polar aprotic solvent at elevated
temperature. The transition metal and base free decomposition method
is applicable to N-sulfonylhydrazones generated from a number of
aromatic and heteroaromatic aldehydes and ketones. In the case of N-
tosylhydrazones derived from O-allyl and O-propargyl salicylaldehydes,
selective formation of sulfinate occurs over intramolecular [3 + 2]-
cycloaddition reaction.
ulfinates are valuable intermediates in organic synthesis.1 In
the case of coupling reactions, sulfinates behave as both
stoichiometric amount of BF3·OEt2.5b Pan et al. reported
Cu(OTf)2 catalyzed aerobic oxidation of arylsulfonylhydrazides
to sulfonyl radicals which couple with alcohols generating
sulfinates in good yields.5c Jang and co-workers reported the
formation of sulfinates from thiophenol via aerobic oxidation
using CuI as a catalyst.5d
S
nucleophilic and electrophilic reagents depending on the
reaction conditions.2 Sulfinates are also known to exhibit
important biological activity profiles. Wu et al. reported
cytotoxic activity of a sulfinate against human leukemia cell
lines.3 Chiral sulfinates provide convenient access to the chiral
sulfur compounds including sulfoxide and sulfinamide.4 In light
of the emergence of sulfinates as important synthetic
intermediates, several methods have been reported for their
synthesis. A review of recent synthetic methods for achiral
sulfinates is summarized in Scheme 1. Wu and co-workers
reported conversion of benzylic alcohols to sulfinates using
TosMIC catalyzed by BiBr3 under mild acidic conditions.3
TosMIC was also utilized to generate sulfinates from alcohols
under Mitsunobu conditions.5a Alcohols can also be converted
to sulfinates by reaction with sodium sulfinate using a
In recent years, N-tosylhydrazones have emerged as
important electrophilic coupling component in various cross-
coupling reactions.6 The base mediated decomposition of N-
tosylhydrazone in the presence of a transition metal generates
metallocarbene complex which is responsible for effective cross-
coupling reactions). However, transition metal free trans-
formations have also gained considerable research interest after
the reports of Barluenga et al.7 N-Tosylhydrazones have been
utilized in various coupling reactions to generate new C−O,8
C−N,9 and C−S10 bonds under transition metal free
conditions. Decomposition of N-tosylhydrazones in the
presence of a base in appropriate solvents generates
dialkylidenehydrazines and oximes.11 In the presence of a
transition metal catalyst (Fe, Cu, or Rh), base mediated
decomposition of N-tosylhydrazones yields sulfones (see
Scheme 2).12 A report by Volk et al. showed that cyclic
sulfinate could be obtained via NaHCO3 mediated decom-
position of hydrazone under transition metal free conditions.13
This report describes the synthesis of sulfinates from N-
sulfonylhydrazones via a stabilized Wittig ylide mediated
decomposition in a polar aprotic solvent under neutral
conditions.
Scheme 1. Recent Methods for Achiral Sulfinate Synthesis
Recently, we reported the coupling of N-tosylhydrazones
with 5,5-dimethyl cyclohexane 1,3-dione under transition metal
free conditions.14 In the presence of a base, the coupling
reaction generate C−O bond in a polar aprotic solvent. In the
absence of base, the reaction follows a different pathway in
Received: December 20, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03953
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To examine the effect of the size of the alkyl group on the
reactivity, ylides having esters with varying size of alkyl groups
were tested. The results, as listed in Table 2, reveal that ylides
Scheme 2. Synthesis of Sulfone and Sulfinate from N-
Tosylhydrazone
Table 2. Screening of Ylides for Decomposition of N-
Tosylhydrazone to Sulfinate
a
entry
ylide 2
time
yield (%)
a
b
c
d
e
f
Ph3PCHCO2Et 2a
Ph3PCHCO2Me 2b
10 min
10 min
15 min
30 min
30 min
30 min
64
which two molecules of 1,3-dione undergo condensation with
N-tosylhydrazone to generate tetraketo compound exclusively
in a nonpolar solvent. Encouraged by these results, we screened
several carbon nucleophiles and observed that N-tosylhydra-
zone 1a undergoes decomposition to generate sulfinate 3a in
51% yields when heated with Wittig ylide 2a in toluene at 95
°C for 3 h (entry a, Table 1). A short solvent screening revealed
66
i
Ph3PCHCO2 Pr 2c
60
t
Ph3PCHCO2 Bu 2d
56
Ph3PCHCOCH3 2e
trace
ND
Ph3PCHCN 2f
a
All reactions were carried out using 1.0 equiv of 1a, 1.25 equiv of
ylide in DMPU (0.5 M); ND = yield not determined.
Table 1. Optimization of Reaction Conditions for
Transforming N-Tosylhydrazone to Sulfinate
incorporating esters with smaller alkyl groups provide better
results (entries a−c, Table 2). The Wittig ylide generated from
bromoacetone and bromoacetonitrile containing strong elec-
tron withdrawing groups were not effective.
The optimized condition was tested on N-tosylhydrazones
generated from several aldehydes and ketones. As presented in
Scheme 3, the reactions were successful with N-tosylhydrazones
synthesized from aryl and heteroaryl aldehyde and ketones. N-
Tosylhydrazone generated from 3,4-dimethoxybenzaldehyde
and 3,4,5-trimethoxybenzaldehyde produced the corresponding
sulfinates 3b and 3c in 68% and 70% yields, respectively. 3-
Bromobenzaldehyde derived hydrazone provided sulfinate 3d
in 60% yields. 3-Nitrobenzaldehyde derived hydrazone
generated a complex reaction mixture in DMPU. However,
sulfinate 3e could be obtained in 38% yield when the reaction
was carried out in toluene at 90 °C. Sulfinate 3f and 3g having
4-chlorophenyl and 4-cyanophenyl groups were obtained in
59% and 57% yields, respectively. 2-Fluorobenzaldehyde
derived hydrazone produced the sulfinate 3h in moderate
yields (56%). 2-Naphthaldehyde derived hydrazone furnished
sulfinate 3i in 68% yield. 4-Methoxyacetophenone derived
hydrazone gave sulfinate 3j in 66% yield while benzophenone
derived hydrazone generated the corresponding sulfinate 3k in
60% yield. Hydrazone derived from fluorenone gave sulfinate 3l
in 64% yield. Among the heterocycles, pyridine 3-carboxalde-
hyde derived hydrazone gave sulfinate 3m in 66% yield whereas
furan 2-carboxaldehyde derived hydrazone furnished the
sulfinate 3n in 68% yield. Similarly, N-Boc-5-bromoindole 3-
carboxaldehyde derived N-tosylhydrazone furnished sulfinate
3o in 54% yield. No reaction was observed with N-
tosylhydrazone derived from salicylaldehyde possibly due to
acidic nature of the phenolic hydroxyl group. However, O-allyl,
O-methyl acetate, and O-propargyl salicylaldehyde derived
substrates showed very good reactivity and generated the
corresponding sulfinates (3q−3s) selectively in good yields. N-
Tosylhydrazone derived from cyclohexane carboxaldehyde did
not react presumably due to higher pKa value of N−H proton.
To study the effect of the substitution on the aryl groups
attached to the S atom of the sulfonylhydrazones, we converted
a few commercially available sulfonyl chlorides to the
corresponding hydrazides15 and then treated with an aldehyde
to generate the sulfonylhydrazones (see the Supporting
a
c
entry
solvent
toluene
2a (equiv)
conditions
yield (%)
51
a
b
c
d
e
f
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.25
0.10
95 °C, 3 h
90 °C, 4 h
90 °C, 3 h
95 °C, 3 h
b
Cl2(CH2)2
CH3CN
1,4-dioxane
EtOH
45
b
48
44
b
95 °C, 10 h
NR
DMF
95 °C, 15 min
95 °C, 20 min
95 °C, 25 min
95 °C, 15 min
95 °C, 10 min
95 °C, 10 min
95 °C, 30 min
54
52
53
56
60
64
ND
g
h
i
DMSO
NMP
DMEU
DMPU
DMPU
DMPU
j
k
l
a
All reactions were carried out in 200 mg scale using 1.0 equiv of 1a in
appropriate solvent (0.5 M). Reactions were carried out in sealed
vials. Formation of sulfone was not observed under these conditions;
NR = no reaction; ND = yield not determined; NMP = N-
methylpyrrolidinone; DMEU = N,N-dimethylethylene urea; DMPU =
N,N-dimethylenepropylene urea.
b
c
that the reaction occurred in several nonprotic solvents.
Reaction in 1,2-dichloroethane generated sulfinate only in
45% yield (entry b, Table 1). In CH3CN, the reaction produced
sulfinate 3a in 48% yields. The reaction produced a similar
result in 1,4-dioxane as solvent. No reaction was observed in
EtOH even after heating for 10 h. In polar aprotic solvents, a
dramatic increase in the rate was observed (entries f−j, Table
1). In DMF, the reaction was complete within 15 min to
generate 3a in 54% yields. Similar results were observed when
the reaction was carried out in DMSO and NMP (entries g and
h, Table 1). Improved yield was observed when the reaction
was carried out in DMPU. The best yield for sulfinate 3a was
obtained when the reaction was carried out using 1.25 equiv of
ylide 2a in DMPU at 95 °C. Catalytic amount of 2a (10 mol %)
gave very low conversion (entry l, Table 1) under the reaction
conditions.
B
DOI: 10.1021/acs.orglett.7b03953
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Synthesis of Sulfinates from N-Tosylhydrazones
Scheme 4. Synthesis of Sulfinates from Various N-
Sulfonylhydrazones
a
a
All reactions were carried out in 100 mg scale using 1.0 equiv of N-
sulfonylhydrazone, 1.25 equiv of 2b in DMPU (0.5 M) at 95 °C.
Scheme 5. Mechanism for the Ylide Mediated
Decomposition of N-Sulfonylhydrazone and Controlled
Experiments
a
All reactions were carried out in 100 mg scale using 1.0 equiv of N-
tosylhydrazone, 1.25 equiv of 2b in DMPU (0.5 M) at 95 °C. NR = no
b
reaction. Reaction was carried out in toluene (0.5 M) at 90 °C.
c
Reaction was carried out at 90 °C.
Information). As shown in Scheme 4, the sulfinate formation
was effective with aryl, heteroaryl and benzyl group attached to
S atom of hydrazones. Aryl rings having electron donating
groups produced better results. Sulfinates 5b and 5c with 4-
methoxyphenyl and 3,4-dimethoxyphenyl group on the S atom
were obtained in 66% and 68% yields, respectively. Sulfinate 5d
and 5e, containing 3-(trifluoromethyl)phenyl and 4-bromo-
phenyl groups on the S atom were obtained in 63% and 60%
yields, respectively. Sulfinates 5f and 5g having mesityl and 4-
tert butylphenyl groups on S atom were also obtained in good
yields. Sulfinate 5h containing benzyl group on the S atom was
obtained in 68% yield. Sulfinates 5i and 5j having 5-
bromothiophene and 2-naphthyl group on the S atom were
obtained in 58% and 65% yields, respectively.
The possible mechanism for the ylide mediated decom-
position of sulfonylhydrazone is depicted in Scheme 5. We
believe that the reaction proceeds via proton abstraction as no
reaction occurs with 1416 (Scheme 5b). N−H proton
abstraction in 6 by ylide 2b triggers decomposition of the
sulfonylhydrazone 6 to generate ionic intermediate 9. Rapid
protonation of 9 leads to intermediate 11 which on
C
DOI: 10.1021/acs.orglett.7b03953
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
F.; Hernandez Linares, A.; Mastranzo, V. M.; Ortiz, B.; Sanchez-
Obregon, R.; Fraile, A.; Garcia Ruano, J. L. J. Org. Chem. 2011, 76,
4635. (c) Aziz, J.; Messaoudi, S.; Alami, M.; Hamze, A. Org. Biomol.
Chem. 2014, 12, 9743. (d) Lujan-Montelongo, J. A.; Estevez, A. O.;
Fleming, F. F. Eur. J. Org. Chem. 2015, 2015, 1602.
(3) Li, H. J.; Wang, R.; Gao, J.; Wang, Y. Y.; Luo, D. H.; Wu, Y. C.
Adv. Synth. Catal. 2015, 357, 1393.
(4) For leading references, see (a) Zhang, Y.; Chitale, S.; Goyal, N.;
Li, G.; Han, Z. S.; Shen, S.; Ma, S.; Grinberg, N.; Lee, H.; Lu, B. Z.;
nucleophilic displacement by the sulfonyl group 12 generates
sulfinate 13. In DMPU, which is known to stabilize ion-pairs
and increase the nucleophilicity of anions, the decomposition of
1s leads to sulfinate 3s exclusively whereas in toluene the
decomposition yields 12% of pyrazole 15 generated via
intramolecular [3 + 2]-cycloaddition17 reaction along with the
sulfinate 3s. This suggests that the sulfinate formation occurs
via rapid protonation of intermediate 9. In the cross over
experiment between N-sulfonylhydrazones 1f and 4f, cross over
products were observed suggesting that the reaction is likely
intermolecular in nature. Although ylide 2b could be recovered
partly after the reaction, the catalytic amount of the ylide is not
sufficient for effective transformation under the present reaction
conditions. Reaction of the N-sulfonylhydrazone 1a in the
presence of a phosphazene base, tert-butylimino-tri-
(pyrrolidino)phosphorane and sulfur ylide, methyl 2-(diphen-
yl-λ4-sulfanylidene)acetate did not yield sulfinate. Transition of
the phosphorus ylide 2b to its salt and vice versa is believed to
be responsible for the effective conversion of N-sulfonylhy-
drazones to sulfinates.
In summary, a convenient method for the decomposition of
N-sulfonylhydrazones to the corresponding sulfinates is
developed under neutral reaction conditions. The transition
metal and base free decomposition method is compatible with
other functional groups and generates sulfinates in good yields.
The O-allyl and O-propargyl salicylaldehyde derived N-
tosylhydrazones selectively generated the sulfinates and did
not produce [3 + 2]-cycloadducts, which are obtained
exclusively in the presence of a base. A more detailed
investigation on this method is going on in our laboratory.
Senanayake, C. H. J. Org. Chem. 2012, 77, 690. (b) Fernan
́
dez, I.;
Khiar, N. Chem. Rev. 2003, 103, 3651.
(5) (a) Kadari, L.; Radha Krishna, P.; Prapurna, Y. L. Adv. Synth.
Catal. 2016, 358, 3863. (b) Huang, M.; Hu, L.; Shen, H.; Liu, Q.;
Hussain, M. I.; Pan, J.; Xiong, Y. Green Chem. 2016, 18, 1874. (c) Du,
B. N.; Li, Z.; Qian, P.; Han, J. L.; Pan, Y. Chem. - Asian J. 2016, 11,
478. (d) Shyam, P. K.; Kim, Y. K.; Lee, C.; Jang, H.-Y. Adv. Synth.
Catal. 2016, 358, 56.
́
(6) For recent reviews, see (a) Barluenga, J.; Valdes, C. Angew. Chem.,
Int. Ed. 2011, 50, 7486. (b) Shao, Z.; Zhang, H. Chem. Soc. Rev. 2012,
41, 560. (c) Xiao, Q.; Zhang, Y.; Wang, J. B. Acc. Chem. Res. 2013, 46,
236. (d) Jadhav, A. P.; Ray, D.; Rao, V. U. B.; Singh, R. P. Eur. J. Org.
Chem. 2016, 2016, 2369.
(7) Barluenga, J.; Tomas
Chem. 2009, 1, 494.
(8) For a selected example, see Barluenga, J.; Tomas
Aznar, F.; Valdes, C. Angew. Chem., Int. Ed. 2010, 49, 4993.
(9) (a) Hamze, A.; Treguier, B.; Brion, J.-D.; Alami, M. Org. Biomol.
́ ́
-Gamasa, M.; Aznar, F.; Valdes, C. Nat.
́
-Gamasa, M.;
́
́
Chem. 2011, 9, 6200. (b) Aziz, J.; Brion, J. D.; Hamze, A.; Alami, M.
Adv. Synth. Catal. 2013, 355, 2417. (c) Roche, M.; Frison, G.; Brion, J.
D.; Provot, O.; Hamze, A.; Alami, M. J. Org. Chem. 2013, 78, 8485.
(d) Roche, M.; Bignon, J.; Brion, J. D.; Hamze, A.; Alami, M. J. Org.
Chem. 2014, 79, 7583.
(10) For selected examples, see (a) Feng, X.-W.; Wang, J.; Zhang, J.;
Yang, J.; Wang, N.; Yu, X.-Q. Org. Lett. 2010, 12, 4408. (b) Ding, Q.;
Cao, B.; Yuan, J.; Liu, X.; Peng, Y. Org. Biomol. Chem. 2011, 9, 748.
(c) Lin, Y.; Luo, P.; Zheng, Q.; Liu, Y.; Sang, X.; Ding, Q. RSC Adv.
2014, 4, 16855. (d) Mao, S.; Gao, Y.-R.; Zhu, X. Q.; Guo, D.-D.;
Wang, Y.-Q. Org. Lett. 2015, 17, 1692. (e) Li, L.-L.; Gao, L.-X.; Han,
F.-S. RSC Adv. 2015, 5, 29996. (f) Tsai, A. S.; Curto, J. M.; Rocke, B.
N.; Dechert-Schmitt, A. M. R.; Ingle, G. K.; Mascitti, V. Org. Lett.
2016, 18, 508.
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.7b03953.
Typical experimental procedure, characterization data
and copies of 1H NMR and 13C NMR spectra for all new
compounds (PDF)
(11) Sha, Q.; Wei, Y. Tetrahedron 2013, 69, 3829.
(12) (a) Zhao, J. L.; Guo, S.-H.; Qiu, J.; Gou, X.-F.; Hua, C.-W.;
Chen, B. Tetrahedron Lett. 2016, 57, 2375. (b) Barluenga, J.; Tomas
́
-
Gamasa, M.; Aznar, F.; Valdes, C. Eur. J. Org. Chem. 2011, 2011, 1520.
́
(c) Feng, X. W.; Wang, J.; Zhang, J.; Yang, J.; Wang, N.; Yu, X. Q. Org.
Lett. 2010, 12, 4408. (d) Zhang, J. L.; Chan, P. W. H.; Che, C. M.
Tetrahedron Lett. 2003, 44, 8733.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: akb31377@gmail.com
ORCID
(13) Bertha, F.; Keg
G.; Simig, G.; Volk, B. J. Org. Chem. 2017, 82, 1895.
́ ́ ́ ́
l, T.; Fetter, J.; Molnar, B.; Dancso, A.; Nemeth,
(14) Choudhary, D.; Agrawal, C.; Khatri, V.; Thakuria, R.; Basak, A.
K. Tetrahedron Lett. 2017, 58, 1132.
(15) Allwood, D. M.; Blakemore, D. C.; Brown, A. D.; Ley, S. V. J.
Org. Chem. 2014, 79, 328.
Ashok K. Basak: 0000-0002-1142-1324
Notes
The authors declare no competing financial interest.
(16) Kong, Y.; Zhang, W.; Tang, M.; Wang, H. Tetrahedron 2013, 69,
7487.
ACKNOWLEDGMENTS
■
(17) (a) Zheng, Y.; Zhang, X.; Yao, R.; Wen, Y. C.; Huang, J.; Xu, X.
J. Org. Chem. 2016, 81, 11072. (b) Divya, K. V. L.; Meena, A.; Suja, T.
D. Synthesis 2016, 48, 4207.
Research grants from SERB (Grant YSS/2014/000957) and
UGC (F.4-5/2006(BSR)), New Delhi, is gratefully acknowl-
edged. We thank MRC, MNIT Jaipur for recording the NMR
spectra. We also thank USIC, University of Rajasthan, Jaipur,
for the high-resolution mass spectrometry (HRMS) data.
REFERENCES
■
(1) For reviews on the synthesis and applications of sulfinates, see
(a) Fernandez, I.; Khiar, N. Chem. Rev. 2003, 103, 3651. (b) Robak, M.
T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600.
(2) (a) Tapia-Pineda, A.; Perez-Arrieta, C.; Silva-Cuevas, C.; Paleo,
E.; Lujan-Montelongo, J. A. J. Chem. Educ. 2016, 93, 1470. (b) Yuste,
D
DOI: 10.1021/acs.orglett.7b03953
Org. Lett. XXXX, XXX, XXX−XXX