Insights into sulfinate formation from tosyl hydrazides

Article abstract of DOI:10.1016/j.tetlet.2011.12.061

Benzylation of 1,2-ditosylhydrazine in DMF under various basic conditions results in a benzyl sulfone via intermediary sulfinate formation, providing new insights and allowing practical conclusions to be drawn. The half-lives of 1,2-ditosylhydrazine and several monotosylated hydrazides with 1,1,3,3-tetramethylguanidine in DMSO have been determined by ¹H NMR spectroscopy and are found to vary from a few minutes to several months. In the course of this work a benzylated, partly detosylated compound has been identified and a 1,1,3,3-tetramethyl guanidine-containing side-product characterized. A contradictory report is also commented on.

Full text of DOI:10.1016/j.tetlet.2011.12.061

Tetrahedron Letters 53 (2012) 1045–1047
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Insights into sulfinate formation from tosyl hydrazides
Ulf Ragnarsson a, , Leif Grehn b
⇑
a Department of Biochemistry and Organic Chemistry, University of Uppsala, Biomedical Center, Box 576, SE-751 23 Uppsala, Sweden
b Medicago AB, Danmark Berga, SE-755 98 Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
Benzylation of 1,2-ditosylhydrazine in DMF under various basic conditions results in a benzyl sulfone via
intermediary sulfinate formation, providing new insights and allowing practical conclusions to be drawn.
The half-lives of 1,2-ditosylhydrazine and several monotosylated hydrazides with 1,1,3,3-tetramethyl-
guanidine in DMSO have been determined by 1H NMR spectroscopy and are found to vary from a few
minutes to several months. In the course of this work a benzylated, partly detosylated compound has
been identified and a 1,1,3,3-tetramethyl guanidine-containing side-product characterized. A contradic-
tory report is also commented on.
Received 1 September 2011
Revised 5 December 2011
Accepted 16 December 2011
Available online 24 December 2011
Keywords:
Half-life determination
Hydrazide cleavage
Nitrogen formation
Sulfinate
Ó 2011 Elsevier Ltd. All rights reserved.
Sulfone
Sulfonyl hydrazides are useful organic reagents of which tosyl
hydrazide (tosyl = 4-methylbenzenesulfonyl) is a typical represen-
tative that has made possible a multitude of diverse manipulations
under mild conditions.1 Prominent are those taking place via
hydrazones and by treatment with bases or reducing agents, lead-
ing to alkenes or deoxygenation products and with the reagent
being converted into benzenesulfinic acid and nitrogen. Other
applications of tosyl hydrazide include a procedure to make sulf-
ones with halides with the evolution of nitrogen2a and as a precur-
sor for diazene.2b Acyl derivatives are frequently required and can
now be prepared with high regioselectivity.3 Fukuyama et al. were
able to trap the nitrogen originating from the reaction of
1,2-ditosylhydrazine (1) with bromoacetates in the presence of
of a contradictory claim discussed below, we decided to explore
the reaction further to rationalize our findings.
The original experiment was performed under mild conditions
similar to those described by Rasmussen.5 Thus, a solution of 1 in
DMF in the presence of two moles of Cs2CO3 was reacted with BnBr
in slight excess (Scheme 1). The addition of Cs2CO3 to the hydra-
zine solution was accompanied by slight gas evolution for more
than an hour. This initially overlooked observation led us to per-
form a series of experiments based on preincubation with base
for various periods of time before BnBr was added, the outcome
of which could easily be determined because products 2 and 3
are both highly crystalline (Table 1).
As demonstrated in entries 1b–1h, the design of these experi-
ments had a drastic effect on the product distribution which could
be monitored conveniently from the benzyl signals of the crude
products. Under appropriate conditions and with enough Cs2CO3,
sulfone 2 was formed exclusively and quite rapidly in essentially
quantitative yield, whereas after only short preincubation, variable
amounts of the hydrazone 3 were also obtained. With lesser base, a
considerable amount of starting material 1 remained. Without pre-
incubation, a maximum yield of 50% of pure 3 was obtained.
As Rasmussen’s work demonstrated a unique effect of cesium
compared to potassium carbonate on alkylation of hydrazines,
we also conducted experiments with anhydrous potassium and so-
dium carbonate with comparable results (entries 2 and 3). Further
benzylation experiments were carried out with triethylamine and
1,1,3,3-tetramethylguanidine (TMG) as base. Triethylamine in
DMF was also found to initiate conversion into 2, although obvi-
ously much more slowly and less completely than in the previous
experiments as demonstrated by the presence of unreacted 1, but
DBU with the formation of diazoacetates.4 An
a-bromomethylke-
tone also furnished the corresponding diazoketone.
Prompted by the work of Rasmussen,5 and in continuation of
our earlier work on tosyl hydrazides,6 we made an attempt to ben-
zylate 1 and obtained a mixture of two components that could be
resolved easily by chromatography. The major component proved
to be benzyl 4-methylphenylsulfone (2, Ts–Bn7), identified without
comments by Rooney et al. as a minor product in the reaction be-
tween BnCl and tosyl hydrazide.8 Following chromatography on
silica gel with dichloromethane we obtained minor amounts of
the previously described hydrazone 3 (Table 1, entry 1a).9 Inspec-
tion of the literature indicated that formation of hydrazones such
as 3 had not been described under similar conditions, and because
⇑
Corresponding author. Tel.: +46 18 471 45 55.
E-mail addresses: Ulf.Ragnarsson@biorg.uu.se, u.ragnarsson.018301116@teli
a.com (U. Ragnarsson).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.061

1046
U. Ragnarsson, L. Grehn / Tetrahedron Letters 53 (2012) 1045–1047
Table 1
Attempted benzylation experiments with 1
Entry
Basea
Reagent ratiob
Preincubation/reaction time (h)
Yieldc
Other products (%)
1a
1b
1c
1d
1e
1f
1g
1h
2
A
A
A
A
A
A
A
A
B
C
D
D
E
1:2:2.2
1:2:2.2
1:2:2.2
1:2:2.2
1:2:2.2
1:1:2.2
1:0.5:2.2
1:1:1.1
1:2:2.2
1:2:2.2
1:2:2.2
1:2:2.2
1:2:2.2
1:2:2.2
1:2:2.2
1:2:1.1
1:1:1.1
1:1:1
—/2
0.106/59d
0/92
17d (3)
—
24/2
3/0.5
0.2/2
0/2
<0.003/93
0.158/58d
0.470/45d
0.013/83
<0.001/38
0/52
—
27d (3)
50d (3)
3/0.5
3/0.5
24/2
24/2
24/2
24/2
0.1/2
0.2/2
0.2/2
3/0.5
3/0.5
0.2/0.5
1/0.5
—
40 (1)
—
—
0/92
3
<0.003/92
<0.005/49d
0.348/23d
0/89
0/88
0/92
—
4a
4b
5
<1 (3); 22 (1)
15d (3); 42 (1)
—
—
—
—
6
F
7a
7b
7c
7d
G
G
G
G
0/48
0/45e
55e (1)
50e (1)
0/50e
a
b
c
Bases are abbreviated: A = Cs2CO3, B = K2CO3, C = Na2CO3, D = Et3N, E = TMG, F = TMG + DMSO, G = KOtBu.
All experiments were performed with 1 mmol of 1 in 4 mL of DMF (except 6); compound 1: base: BnBr molar ratio.
Crude product 4.85/4.29 ppm (CDCl3) or 5.00/4.62 ppm [(CD3)2SO] proton signal ratio/yield of recrystallized 2 (%).
After chromatography and crystallization.
d
e
By NMR spectroscopy.
Cs2CO3
BnBr
of 2, featuring complete reduction of the tosyl and nitrogen forma-
tion via an intermediate of the tosyldiazene type is depicted in
Scheme 2. Interestingly, the authors claimed they could treat a
DMSO solution of 1 with NaOD/D2O and reverse its effect with
HCl and also noted that sodium ethoxide gave rise to sodium p-tol-
uenesulfinate on standing.12 It has also been stated that 1 is soluble
in aqueous sodium hydroxide and the author concluded that this
would prove the position of the tosyl groups.13
Wessig and Henning have reported the reaction of 1 with
1 equiv each of KOtBu and BnBr in DMF and obtained the mono-
benzyl derivative, Ts(Bn)N–NHTs, in a 70% yield.14 Since this claim
would disprove our findings about the effect of bases, including
even much weaker ones, on 1, we decided to perform a few exper-
iments with 1 and KOtBu under similar conditions (entries 7a–d).
As with TMG, in our hands, KOtBu gave instant nitrogen evolution
and furnished, after preincubation, exclusively 2 in a 92% yield
(with 2.2 equiv of BnBr) and a 48% yield (with 1.1 equiv of BnBr),
respectively, in the presence of 2 equiv of base. On the contrary,
with only 1 equiv of this base, 50–55% of the starting material re-
mained together with 2 at the end of the reaction. From a mecha-
nistic point of view this implies that the postulated intermediate
above, HN@N–Ts, is deprotonated preferentially to 1 when the
H
H
Bn
N N
PhCH
N N
Ts Ts
Ts Bn
2
+
DMF
Ts
1
3
Scheme 1. Initial attempt at benzylation of 1.
still testifying to the instability of 1 to bases. Interestingly, TMG
immediately gave rapid nitrogen evolution lasting for about
5 min, quickly allowing benzylation to be initiated, and furnished
2 in essentially quantitative yield. Identical results were obtained
with this base in DMSO instead of DMF. Thus, with TMG the prein-
cubation time required for complete conversion of 1 into 2 could
be significantly reduced (entries 5 and 6).
The use of TMG as a base provided a simple method to monitor
directly the preincubation step in DMSO by 1H NMR spectroscopy.
In this way it could be demonstrated that a 0.1 M solution of 1 with
2.5 equiv of TMG at room temperature had, within about 25 min,
been completely converted into the TMG salt of the corresponding
sulfinic acid, 4-CH3–C6H4–SO2H. Furthermore, by monitoring rele-
vant signals every two minutes and fitting the data to a second or-
der reaction equation, the half-life of 1 was calculated to be less
than 1.5 min (for more details see Supplementary data). This reac-
tivity to base seems to be unique for a compound of the present
type. The sulfinate solution appeared to be stable for several
weeks.
Sulfinate salts are ambient nucleophiles that undergo alkylation
on sulfur and they are therefore useful precursors of sulfones.10
Fukuyama et al. found small amounts of a by-product (<5%) on
treatment of 1 with an excess of DBU in THF at 0 °C which was
characterized as a sulfone.4 A reasonable rationale for the forma-
tion of 2 is that deprotonation of 1 by the base initiates an elimina-
tion reaction with the generation of sulfinate and eventual
extrusion of nitrogen, the rate of which varies with the strength
of the base. If BnBr is added before this step is completed, compet-
ing N-benzylation takes place. Subsequent elimination of one tosyl
as a sulfinate leads to partly oxidized product 3, otherwise a
remarkably smooth and clean S-benzylation occurs. Mechanistic
studies on substrates for the McFadyen–Stevens reaction11 of the
1-benzenesulfonyl-2-benzoyl-hydrazine type have been pub-
lished.12 By analogy, a postulated mechanism for the formation
Scheme 2. Postulated mechanism for the formation of 2 and 3.

U. Ragnarsson, L. Grehn / Tetrahedron Letters 53 (2012) 1045–1047
1047
Table 2
Substrate stability of 1-X1-2-X2-hydrazides toward TMG
Entry
X
X1
X2
Product:substrate ratio/timea (selected data)
Estimated half-lifeb
1
2
3
4
5
4
5
6
7
1
Ts
Ts
Ts
Ts + Boc
Ts
H
Boc
Z
H
Ts
0.76/1.8; 1.48/8.7
0.86/171; 1.20/219
0.94/227; 1.15/266
See discussion in the text
For details, see Supplementary data
4
190
240
n.d.
<1.5 min
a
0.1 mmol Substrate in (CD3)2SO (ca. 590 lL) + 1.25 equiv TMG at RT; measured (always Ts–Me, in several cases also aromatic Ts signals) sulfinate product: substrate ratio
by 1H NMR spectroscopy/days.
b
Days (by linear interpolation).
supply of base is limited. As no product other than 2 could be iso-
lated in these experiments we conclude that the claim of Wessig
and Henning is not correct.
(8), formally by substitution on the Boc-carbonyl group. It remains
to be demonstrated that similar compounds can be made in the
same way.
The half-lives of the other compounds as determined in Table 2
together with 1 span a range of more than 5 orders of magnitude,
of which 3–3.5 refer to the introduction of the second tosyl group.
The dramatic behavior of 1 toward bases as reflected in Table 1 and
illustrated visually by the evolution of nitrogen as described above
are interesting in this perspective.
Ts-NHNH2 Ts-NHNH-Boc Ts-NHNH-Z
4
5
6
In the initially mentioned method to prepare sulfones,2a the
authors reacted tosyl hydrazide (4) and alkyl or activated aryl ha-
lides in boiling ethanol with sodium acetate as the base. The reac-
tion required an excess of halide and base and typical reaction
times of 3–24 h to go to completion. Interestingly, the authors
claimed that in addition to tosyl, some of the halides were also re-
duced. For comparison with 1, we investigated the stability of 4 to-
ward TMG in DMSO (Table 2, entry 1) and found that it also
decomposed into sulfinate, exclusively, but with a half-life of a
few days instead of minutes, suggesting 1 as a more reactive, much
milder alternative to 4 in this context. It should be pointed out that
a large number of sulfonyl analogs of 1 have also been described.15
Introduction of a Boc-group on tosyl hydrazide-N2 5 had an
opposite effect in comparison with that of a second tosyl. Com-
pound 516a only reacted very slowly to give a sulfinate (entry 2).
This result was corroborated for its Z-analog 616b which exhibited
similar reactivity (entry 3). In these measurements with 5 and 6,
over several months, the observed chemical shifts drifted to a var-
iable degree toward lower field, least for Ts–Me, and most for the
Ts-3,5-proton signals ( 0.008 and 0.028 ppm, respectively), but
the conversions into sulfinate seemed to take place without detect-
able intermediates and were completely selective.
Acknowledgment
This work was initiated with funds from Magn. Bergvalls Stift-
else and is gratefully acknowledged.
Supplementary data
Supplementary data (starting materials and synthetic proce-
dures used, NMR and HRMS spectral data, primary kinetic data
for 1) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.12.061.
References and notes
1. For a recent summary on applications of tosyl hydrazide, see: Chamberlin, A.
R., ; Sheppeck, J. E., II; Goess, B.; Lee, C. In Paquette, L. A., Crich, D., Fuchs, P. L.,
Molander, G. A., Eds.; Encyclopedia of Reagents for Organic Synthesis;
Chichester: Wiley, 2009; 12, pp 9634–9645. 2nd ed.
2. (a) Ballini, R.; Marcantoni, E.; Petrini, M. Tetrahedron 1989, 45, 6791; (b) Pasto,
D. J.; Taylor, R. T. Org. React. 1991, 40, 91.
3. Namba, K.; Shoji, I.; Nishizawa, M.; Tanino, K. Org. Lett. 2009, 11, 4970. and
references therein.
4. Toma, T.; Shimokawa, J.; Fukuyama, T. Org. Lett. 2007, 9, 3195.
5. Rasmussen, L. K. J. Org. Chem. 2006, 71, 3627.
6. (a) Ragnarsson, U.; Grehn, L.; Koppel, J.; Loog, O.; Tšubrik, O.; Bredikhin, A.;
Mäeorg, U.; Koppel, I. J. Org. Chem. 2005, 70, 5916. and references therein; (b)
Ragnarsson, U. Chem. Soc. Rev. 2001, 30, 205.
7. It should be pointed out that for the sake of simplicity in this Letter Ts is used as
an abbreviation for 4-CH3C6H4SO2 independent of its state of oxidation or
charge.
Ts-NNH2 Ts-NNH2
NMe2
CO-N C
Boc
NMe2
7
8
8. Rooney, C. S.; Cragoe, E. J., Jr.; Porter, C. C.; Sprauge, J. M. J. Med. Pharm. Chem.
1962, 5, 155.
9. Keith, J. M.; Gomez, L. J. Org. Chem. 2006, 71, 7113.
10. See for example: Simpkins, N. S. Sulfones in Organic Synthesis; Pergamon Press:
Oxford, 1993.
11. Mosettig, E. Org. React. 1954, 8, 232.
12. Matin, S. B.; Craig, J. C.; Chan, R. P. K. J. Org. Chem. 1974, 39, 2285.
13. Jennings, K. F. J. Chem. Soc. 1957, 1172.
14. Wessig, P.; Henning, H.-G. Liebigs Ann. Chem. 1991, 983.
15. Bartmann, E. A. Synthesis 1993, 490.
16. (a) Ragnarsson, U.; Grehn, L.; Maia, H. L. S.; Monteiro, L. S. J. Chem. Res. 2000, (S)
6; (M) 129.; (b) Grehn, L.; Nyasse, B.; Ragnarsson, U. Synthesis 1997, 1429; (c)
Grehn, L.; Ragnarsson, U. Tetrahedron 1999, 55, 4843.
Interestingly, substrate 716c with a Boc-group on the tosyl
hydrazide-N1 reacted rather differently with TMG than the other
compounds studied in Table 2 (entry 4). After about two days the
substrate was no longer detectable and at least two products had
formed. The major product was isolated from a small-scale pre-
parative experiment (for details see Supplementary data). Based
on spectroscopic data it was tentatively assigned a structure of a
semicarbazide that had incorporated TMG, Ts–N(NH2)–CO–TMG