Triarylmethyl chlorides as novel, efficient, and mild organic catalysts for the synthesis of N-sulfonyl imines under neutral conditions

Article abstract of DOI:10.1139/V08-039

A highly efficient procedure for the preparation of N-sulfonyl imines via condensation of sulfonamides with aldehydes as well as ketones in the presence of triarylmethyl chlorides as metal-free organo-catalysts at 40 °C is described. The advantages of thi

Full text of DOI:10.1139/V08-039

456
Triarylmethyl chlorides as novel, efficient, and
mild organic catalysts for the synthesis of
N-sulfonyl imines under neutral conditions
Ali Khalafi-Nezhad, Abolfath Parhami, Abdolkarim Zare, Amir Nasrolahi Shirazi,
Ahmad Reza Moosavi Zare, and Alireza Hassaninejad
Abstract: A highly efficient procedure for the preparation of N-sulfonyl imines via condensation of sulfonamides with
aldehydes as well as ketones in the presence of triarylmethyl chlorides as metal-free organo-catalysts at 40 °C is de-
scribed. The advantages of this class of catalysts over the reported ones are their efficiency and possibility of running
reactions in neutral media that makes them suitable for acid-sensitive substrates.
Key words: triarylmethyl chloride, N-sulfonyl imine, sulfonamide, aldehyde, ketone.
Résumé : On a développé une méthode très efficace pour préparer des N-sulfonylimines par le biais d’une condensa-
tion à 40 °C de sulfonamides sur des aldéhydes ou des cétones, en présence de chlorures de triarylméthyles agissant
comme catalyseurs organiques sans métaux. Les avantages de cette classe de catalyseurs par rapport d’autres qui ont
déjà été utilisés sont leur efficacité et la possibilité d’effectuer les réactions dans des milieux neutres appropriés pour
les substrats sensibles aux acides.
Mots-clés : chlorure de triarylméthyle, N-sulfonylimine, sulfonamide, aldéhyde, cétone.
[Traduit par la Rédaction] Khalafi-Nezhad et al. 461
Introduction
new method for the synthesis of N-sulfonyl imines under
neutral conditions in one-step would be desirable.
N-Sulfonyl imines are versatile intermediates in organic
synthesis (1). They are excellent substrates in aza Diels–Al-
der reactions (2–3), nucleophilic additions (3), and reduc-
tions (4), as well as in radical (5) or ene reactions (6). They
have been also used in the synthesis of aziridines (7). So far,
several synthetic methods for the preparation of N-sulfonyl
imines have been reported (8–22). Most of those methods in-
volve the condensation of sulfonamides with aldehydes or
ketones in the presence of strong Lewis or protic acids, such
as sulfamic acid (22). In many cases, strongly acidic condi-
tions are not compatible with other functionalities present in
a given substrate. Some methods need two-step procedures
or they are expensive methods and generate toxic by-
products. Moreover, several methods require prior prepara-
tion of precursors, such as oxime, sulfinylimine, or aziridine.
Many methods also need harsh reaction conditions. Because
of the limitations of the above methods, development of a
Recently, organic Lewis acids, such as NBS,
trichlorocyanuric acid, and trichloroisocyanuric acid, have
been proved to be useful to chemists in the laboratory and
industry because of the good activation of carbonyl com-
pounds, selectivity, and mild reaction conditions (23). The
use of organic catalysts instead of inorganic Lewis acids
have some advantages, including (i) the possibility to per-
form the reactions for acid sensitive substrates, (ii) perform-
ing the reactions in milder reaction conditions, and (iii) the
substrates bearing basic functional groups or electron-
donating substituents prone to capture the acidic catalysts do
not affect the reaction results. Triarylmethyl chlorides
(Ar3CCl) can be introduced as new organic catalysts that are
inexpensive and can be obtained commercially or easily pre-
pared by the known procedures (24). These type of com-
pounds has been extensively studied as bulky protective
groups for amino and primary hydroxyl functional groups in
multi-step organic synthesis (25). Furthermore, triarylmethyl
chlorides in combination with metal salts particularly SnCl2
have been employed in a few organic transformations (26);
however, the use of triarylmethyl chlorides in the absence of
a co-catalyst is really intriguing. To the best of our knowl-
edge, there is no report for the application of triarylmethyl
chlorides as catalyst in organic transformations.
Received 9 January 2008. Accepted 24 February 2008.
Published on the NRC Research Press Web site at
canjchem.nrc.ca on 11 April 2008.
A. Khalafi-Nezhad,1 A. Parhami, A.N. Shirazi, and A.R.
Moosavi Zare. Department of Chemistry, College of
Sciences, Shiraz University, Shiraz 71454, Iran.
A. Zare. Department of Chemistry, Payame Noor University
of Bushehr, Bushehr 1698, Iran.
Having the above facts in mind and also in continuation of
our previous studies on the preparation of N-sulfonyl imines
(9a, 9b) as well as catalysis in organic transformations (27),
we describe here the first procedure for the application of
triarylmethyl chlorides as catalysts in the synthesis of N-
A. Hasaninejad. Department of Chemistry, Faculty of
Sciences, Persian Gulf University, Bushehr 75169, Iran.
1Corresponding author (e-mail: ali_khalafinezhad@yahoo.com).
Can. J. Chem. 86: 456–461 (2008)
doi:10.1139/V08-039
© 2008 NRC Canada

Khalafi-Nezhad et al.
457
Scheme 1. The condensation of sulfonamides with carbonyl
compounds.
Table 1. The effect of various solvents on the reac-
tion of benzenesulfonamide with benzaldehyde in
the presence of DMTrCl at 40 °C.
Entry
Solvent
Time (min)
Yield (%)a
1
2
3
4
5
6
EtOH
EtOAc
DMF
CH2Cl2
MeCN
Solvent-free
60
100
45
80
30
50
48
65
51
54
90
46
sulfonyl imines via the reaction of sulfonamides with aro-
matic and aliphatic aldehydes as well as ketones under mild
and neutral reaction conditions (Scheme 1).
aIsolated yield.
Results and discussions
Table 2. The influence of different catalysts on the
condensation of benzenesulfonamide with
benzaldehyde in MeCN at 40 °C.
To optimize the reaction conditions, first we examined the
reaction of benzenesulfonamide (2 mmol) with
benzaldehyde (2 mmol) as a model in the presence of
DMTrCl [Ph(p-MeOC6H4)2CCl, 0.25 mmol] in MeCN
(10 mL) at room temperature. In these conditions, the corre-
sponding N-sulfonyl imine 1a was obtained in 64% yield af-
ter 30 min. Increasing the reaction time had no effect on the
efficiency of the reaction; however, enhancing the tempera-
ture to 40 °C improved the yield to 90%. In another study,
the influence of different solvents on the model reaction was
investigated. The results are summarized in Table 1. As it
can be seen from Table 1, higher yield and shorter reaction
time were obtained when MeCN was used. So, MeCN was
used as the solvent of choice in all reactions. The reaction of
benzenesulfonamide with benzaldehyde was also examined
in the absence of solvent in which the product was obtained
in 46% within 50 min (Table 1, entry 6). These results indi-
cated the preference of the solvent-phase procedure in com-
parison with solvent-free conditions. We suggest that it is
Entry
Catalyst
Time (min)
Yield (%)a
1
2
3
4
TrCl
TrOH
MMTrCl
DMTrCl
30
30
30
30
82
12
85
90
aIsolated yield.
and 12). Moreover, the presence of a halogen on the
aromatic ring of aldehydes slightly decreased the yields and
increased the reaction times (Table 3, entries 4, 5, 13, and
14). When the reaction was examined for 4-
(dimethylamino)benzaldehyde (Table 3, entry 7), the corre-
sponding bis(indolyl)alkane was obtained in good yield, in-
dicating that the amine function cannot affect the efficiency
of the reaction via irreversible complexation with catalyst. o-
Substituted aromatic aldehydes (Table 3, entry 15) and
aliphatic aldehydes (Table 3, entries 18 and 19) needed lon-
ger reaction times and afforded lower yields of the products
in comparison with the others. The reaction of
terphtalaldehyde (2 mmol) with p-toluenesulfonamide
(4 mmol) afforded the corresponding bis-N-sulfonyl imine
(Table 3, entry 20) in 51% yield as well as N-(4-
formylbenzylidene)toluenesulfonamide in 25% yield, which
shows the generality and applicability of this method for the
synthesis of bis-N-sulfonyl imine analogous. Moreover, the
reaction of terphtalaldehyde (2 mmol) and p-
due
to
the
greater
stability
of
intermediate
triphenylcarbonium ions in solvent media.
To select the best triarylmethyl chloride as catalyst, the
model reaction was performed using TrCl (Ph3CCl),
MMTrCl (Ph2(p-MeOC6H4)Cl), and DMTrCl (Ph(p-
MeOC6H4)2Cl) (Table 2). As it is shown in Table 2, there is
not a great difference between the catalysts; however; the
best yield was obtained using DMTrCl. As expected, the
methoxy groups in the catalyst can increase the extent of
ionization of triarylcarbenium chloride, thus increasing the
amount of Lewis acid in the reaction medium.
To investigate the generality and versatility of the catalyst,
the optimized reaction conditions, as described above, were
extended to various structurally diverse carbonyl compounds
(aldehydes and ketones) and sulfonamides. The results are
displayed in Table 3. As Table 3 indicates, the reactions pro-
ceeded efficiently, and the desired products were obtained in
good to high yields in short reaction times.
toluenesulfonamide
(2
mmol)
provided
N-(4-
formylbenzylidene)toluenesulfonamide (Table 3, entry 21) as
the product in 76% yield. Generally, aldehydes are more reac-
tive than ketones, since approach of bulky trityl cation is hin-
dered due to the presence of two substituents in ketones. The
reaction of ketones with p-toluenesulfonamide provided the
corresponding N-sulfonyl imines in moderate yields (Table 3,
entries 22 and 23); however, most of the reported methods
were not suitable for the ketones especially enolizable ones.
We suggest that complexes of carbonyl compounds and
triarylmethyl cation (I, II, and III for benzaldehyde) were
formed (Scheme 2). The cationic intermediates I, II, and III
were introduced by Oikawa et al. for the first time (31).
These complexes act as activated carbonyl compound and
then react with p-toluenesulfonamide providing IV, which
converts to V by proton transfer. V dissociates to form an
In general, higher reaction yields were obtained when
benzenesulfonamide
was
used
instead
of
p-
toluenesulfonamide. It was observed that the electronic
properties of the aromatic ring of aromatic aldehydes can af-
fect the reaction. The results showed that electron-donating
substituents improved the reaction yields (Table 3, entries 2,
9, and 10). However, aryl aldehydes possessing electron-
withdrawing groups, generally necessitate longer reaction
times and decrease the reaction yields (Table 3, entries 3, 11,
© 2008 NRC Canada

458
Can. J. Chem. Vol. 86, 2008
Table 3. Preparation of N-sulfonyl imines from sulfonamides and aldehydes as well as ketones
in the presence of DMTrCl in MeCN at 40 °C.
equilibrating mixture of cations as is shown in Scheme 2.
The VI eliminates a proton to give the sulfonylimine prod-
uct, and simultaneously the triarylmethanol is converted to
triarylmethyl chloride. The suggested mechanism is con-
firmed, since the catalyst was completely recovered un-
changed, and no triarylmethanol could be identified after the
completion of the reaction as it could be observed on TLC
by comparison with pure authentic samples. If a base, such
as triethylamine or pyridine (in equimolar amount relative to
DMTrCl), was added to the model reaction preceding to the
addition of DMTrCl, the yield would decrease greatly (9%);
moreover, the DMTrCl was not regenerated and DMTrOH
was obtained instead. We suggest that this is owing to the
ability of base to interfere with the protonation and proton
transfer steps in the mechanism. Increasing the amounts of
base and DMTrCl had negligible effect on the yield. In an-
other experiment, to examine the applicability of another
organo-catalyst for the synthesis of N-sulfonyl imines, the
reaction was performed using the same amount of 2,4,6-
trichloro-1,3,5-triazine instead of DMTrCl and in DMF as the
solvent. The results showed that this catalyst is also able to
perform the reaction (30% yield in 60 min) and emphasize the
role of organo-catalysts for activation carbonyl groups.
In conclusion, this new strategy offers several advantages,
including neutral and mild reaction conditions, short reac-
tion times, high yields of products, low catalyst loading as
well as simple experimental and isolation procedures, which
make it useful for the synthesis of N-sulfonyl imines. The
© 2008 NRC Canada

Khalafi-Nezhad et al.
Table 3 (continued).
459
selected catalyst is found to be highly efficient, easily avail-
able, economical, and recyclable.
General procedure for the synthesis of N-sulfonyl imines
To a mixture of sulfonamide (2 mmol), carbonyl compound
(2 mmol), and MeCN (10 mL) in a 25 mL round-bottomed
flask connected to a reflux condenser was added DMTrCl
(0.25 mmol), and the resulting mixture was stirred at 40 °C
for the times indicated in Table 3. Subsequently, the solvent
was evaporated and to it was added EtOAc (50 mL) and ex-
tracted with saturated solution of NaHSO3 (2 × 50 mL) to re-
move the unreacted carbonyl compound. The organic layer
was dried with MgSO4 and concentrated to 5 mL and to it
was added gradually n-hexane (20–30 mL) and allowed to
stand at room temperature until crystals were formed, which
then was collected by filtration, washed with n-hexane, and
dried. The catalyst was recovered by evaporation of the fil-
trate and subsequent recrystalization in n-hexane.
Experimental
All chemicals were purchased from Merck or Fluka chem-
ical companies. All known compounds were identified by
1
comparison of their melting points, H NMR, and 13C NMR
1
data with the authentic samples. The H NMR (250 MHz)
and 13C NMR (62.5 MHz) were run on a Bruker Avance
DPX-250 FTNMR spectrometer. Mass spectra were re-
corded on a Shimadzu GC MS-QP 1000 EX apparatus.
Microanalyses were performed on a PerkinElmer 240-B
microanalyzer. Melting points were recorded on a Büchi B-
545 apparatus in open capillary tubes.
© 2008 NRC Canada

460
Can. J. Chem. Vol. 86, 2008
Table 3 (concluded).
aIsolated yield.
bMolar ratio of TsNH2/terphtalaldehyde is 2:1.
cMolar ratio of TsNH2/terphtalaldehyde is 1:1.
Acknowledgements
Scheme 2. The proposed mechanism for the condensation of sul-
fonamides with carbonyl compounds.
We are grateful to the Shiraz University Research Coun-
cils for financial support of this work.
References
1. (a) S.M. Weinreb. Top. Curr. Chem. 190, 131 (1997);
(b) M. Gohain. Synlett, 2097 (2003); (c) R. Bloch. Chem. Rev.
98, 1407 (1998).
2. (a) J. Sisko and S.M. Weinreb. Tetrahedron Lett. 30, 3037
(1989); (b) D.L. Boger, W.L. Corbett, T.T. Curran, and
A.M. Kasper. J. Am. Chem. Soc. 113, 1713 (1991).
3. O. Garcia-Mancheno, R. Gomez-Arrayas, and J. C. Carretero. J.
Am. Chem. Soc. 126, 456 (2004); and refs. cited therein.
4. (a) M.J. Melnick, A.J. Freyes, and S.M. Weinreb. Tetrahedron
Lett. 29, 3891 (1988); (b) K. Yamada, H. Fujihara, Y. Yamamoto,
Y. Miwa, T. Taba, and K. Tomioka. Org. Lett. 3509 (2002);
(c) V. Aggarwal, E. Alonso, M. Ferrar, and S.E. Spey. J. Org.
Chem. 67, 2335 (2002); (d) T. Soeta, K. Nagai, H. Fujihara,
M. Kuriyama, and K. Tomioka, J. Org. Chem. 68, 9723
(2003); (e) P. Wipf, C. Kendall, and C.R. Stephenson. J. Am.
Chem. Soc. 125, 761 (2003); (f) M. Gunter and H.-J. Gais. J.
Org. Chem. 68, 8037 (2003); (g) H.-K. Yim and H.N.C. Wong.
J. Org. Chem. 69, 2892 (2004).
5. (a) M. Hojo, C. Murakami, A. Fujii, and A. Hosomi. Tetrahe-
dron Lett. 40, 911 (1999); (b) H. Nisikori, R. Yoshihara, and
A. Hosomi, Synlett, 561 (2003).
6. K.-I. Yamada, H. Fujihara, Y. Yamamoto, Y. Miwa, T. Taga,
and K. Tomioka. Org. Lett. 3509 (2002).
7. M. Yamanaka, A. Nishida, and M. Nakagwa. Org. Lett. 159
(2002).
8. (a) R. Hori, T. Aoayama, and T. Shoiri. Tetrahedron Lett. 41,
9455 (2000); (b) L.G. Arini, A. Sinclair, P. Szeto, and
R. A. Stockan. Tetrahedron Lett. 45, 1589 (2004).
9. B.M. Trost and M. Christopher. J. Org. Chem. 56, 6468 (1991).
10. (a) A. Hasaninejad and H. Sharghi. Phosphorus Sulfur Silicon
Relat. Elem. 182, 873 (2007); (b) A. Hasaninejad and A. Zare.
J. Sulfur Chem. 28, 357 (2007); (c) E. Zieglere and W. Ruef.
Z. Naturforsch. 30B, 946 (1975).
11. K.Y. Lee, C.C. Lee, and J.N. Kim. Tetrahedron Lett. 44, 1231
(2003); and refs. cited therein.
© 2008 NRC Canada

Khalafi-Nezhad et al.
461
12. R.N. Ram and A.A. Khan. Synth. Commun. 31, 841 (2001).
13. G.D. Artman, A. Bartolozzi, R.W. Franck, and S.M. Weinreb.
Synlett, 232 (2001).
14. D.L. Boger and W.L. Corbett. J. Org. Chem. 57, 4777 (1992).
15. J. Wolfe and J.E. Ney. Org. Lett. 4607 (2003).
16. T. Jin, G. Feng, M. Yang, and T. Li. Synth. Commun. 34, 1277
(2004).
17. F.A. Davis, J. Lamendola, U. Nadir, E.W. Kluger,
T.C. Sedergran, T.W. Panunto, R. Billmers, R. Jenkins,
I.J. Turchi, W.H. Watson, J.S. Chen, and M. Kimura. J. Am.
Chem. Soc. 102, 2000 (1980).
(2007); (b) A. Hasaninejad, A. Zare, H. Sharghi, M. Shekouhy,
R. Khalifeh, A. Salimi Beni, and A.R. Moosavi Zare. Can. J.
Chem. 85, 416 (2007); (c) A. Zare, A. Hasaninejad, A. Khalafi-
Nezhad, A.R. Moosavi Zare, A. Parhami, and G.R. Nejabat.
Arkivoc, i, 58 (2007); (d) A. Khalafi-Nezhad, A. Parhami,
M.N. Soltani Rad, M.A. Zolfigol, and A. Zare. Tetrahedron
Lett. 48, 5219 (2007); (e) A. Zare, A. Hasaninejad, A. Khalafi-
Nezhad, A.R. Moosavi Zare, and A. Parhami. Arkivoc, xiii, 105
(2007); (f) A. Hasaninejad, A. Zare, H. Sharghi, K. Niknam,
and M. Shekouhy. Arkivoc, xiv, 39 (2007); (g) A. Zare,
A. Hasaninejad, A. Khalafi-Nezhad, A. Parhami, and
A.R. Moosavi Zare. J. Iran. Chem. Soc. 5, 100 (2008).
28. A. Milenkovic, F. Fache, R. Faure, and M. Lemaire. Synth.
Commun. 29, 1535 (1999).
29. F. Chelma, V. Hebbe, and J-F. Normant. Synthesis, 75 (2000).
30. D.L. Borger and W.L. Corbett. J. Org. Chem. 57, 4777 (1992).
31. M. Oikawa, H. Yoshizaki, and S. Kusumoto. Synlett, 757 (1998).
32. Spectral data for unknown compound, 4-methyl-N-{(E)-[4-((E)
{[(4-methylphenyl)sulfonyl]imino}methyl)phenyl]methylidene}ben-
zenesulfonamide (1t): Pale yellow crystals, mp 109–110 °C.
1H NMR (DMSO-d6, ppm) δ: 2.36 (s, 6H), 7.28 (d, 4H, J =
7.5 Hz), 7.76 (d, 4H), 8.01 (d, 4H, J = 7.5 Hz), 9.31 (s, 2H).
13C NMR (DMSO-d6) δ: 21.8, 124.7, 128.7, 137.9, 140.2,
141.6, 145.7, 172.5. MS m/z: 349 [M+ – CH3C6H4]. Anal.
calcd. for C22H20N2O4S2: C, 59.98; H, 4.58; N, 6.36. Found:
C, 60.17; H, 4.35; N, 6.58.
18. J.L.G. Ruano, J. Aleman, M.B. Cid, and A. Parra. Org. Lett.
179 (2005).
19. A. Vass, J. Dudas, and R. S. Varma. Tetrahedron Lett. 40, 4951
(1999).
20. G.I. Georg, G.C.B. Harriman, and S.A. Peterson. J. Org.
Chem. 60, 7366 (1995).
21. (a) F.A. Davis and S.G. La. J. Org. Chem. 53, 5004 (1988);
(b) S.L. Jain. V.B. Sharma, and B. Sain. Mol. Catal. A: Chem.
239, 92 (2005).
22. Z. Li, X. Ren, P. Wei, H. Wan, Y. Shi, and P. Ouyang. Green
Chem. 8, 433 (2006).
23. (a) J.C. Barros. Synlett, 2115 (2005); (b) K.P. Haval. Synlett,
2156 (2006); (c) T. Kundu. Synlett, 498 (2006).
24. W.E. Bachmann. Org. Synth. Coll. 3, 841 (1955).
25. T.W. Green and P.G.M. Wuts. Protective groups in organic
synthesis. 3rd ed. John Wiley and Sons, New York. 1999.
26. T. Mukaiyama and S. Kobayashi. J. Organomet. Chem. 382,
39 (1990).
33. K-C. Yamada, Y. Yamamoto, and K. Tomioka. Org. Lett, 5,
1797 (2003).
27. (a) A. Zare, A. Hasaninejad, A.R. Moosavi Zare, A. Parhami,
H. Sharghi, and A. Khalafi-Nezhad. Can. J. Chem. 85, 438
© 2008 NRC Canada