Transnitrosation from a stable thionitrate to an amine with concomitant formation of a sulfenic acid

Article abstract of DOI:10.1080/17415993.2013.794801

The reaction of a stable thionitrate bearing a bowl-shaped steric protection group with dibutylamine resulted in nitrosation of the amine with concomitant formation of a sulfenic acid, presenting the experimental evidence for the proposed mechanism of the reaction of thionitrates with amines.

Full text of DOI:10.1080/17415993.2013.794801

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Transnitrosation from a stable
thionitrate to an amine with
concomitant formation of a sulfenic
acid
Kei Gotoa, Shuhei Yoshikawaa, Taku Ideuea & Shohei Sasea
a Department of Chemistry, Graduate School of Science and
Engineering, Tokyo Institute of Technology, Tokyo, 152-8551, Japan
Published online: 14 May 2013.
To cite this article: Kei Goto, Shuhei Yoshikawa, Taku Ideue & Shohei Sase (2013) Transnitrosation
from a stable thionitrate to an amine with concomitant formation of a sulfenic acid, Journal of
Sulfur Chemistry, 34:6, 705-710, DOI: 10.1080/17415993.2013.794801
To link to this article: http://dx.doi.org/10.1080/17415993.2013.794801
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Journal of Sulfur Chemistry, 2013
Vol. 34, No. 6, 705–710, http://dx.doi.org/10.1080/17415993.2013.794801
SHORT COMMUNICATION
Transnitrosation from a stable thionitrate to an amine with
concomitant formation of a sulfenic acid
Kei Goto*, Shuhei Yoshikawa, Taku Ideue and Shohei Sase
Department of Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology,
Tokyo 152-8551, Japan
(Received 15 March 2013; final version received 8 April 2013)
The reaction of a stable thionitrate bearing a bowl-shaped steric protection group with dibutylamine resulted
in nitrosation of the amine with concomitant formation of a sulfenic acid, presenting the experimental
evidence for the proposed mechanism of the reaction of thionitrates with amines.
Keywords: thionitrate; nitrosation; N-nitrosoamine; sulfenic acid; steric protection
1. Introduction
Thionitrates (RSNO2) have been attracting increasing attention as key intermediates in the bioac-
tivation of organic nitrates (RONO2), such as nitroglycerin and isosorbide nitrates, which are
known to exert a vasodilator effect through the transformation to nitric oxide (NO) (1–4). Many
investigators have proposed that a cysteine residue (CysSH) in the active site of an enzyme medi-
ates this bioactivation of RONO2, and that a cysteine thionitrate (CysSNO2) is formed as the
initial intermediate, which produces NO through some chemical transformation. However, the
mechanism for this biotransformation of organic nitrates to NO has not been elucidated yet. From
such viewpoints, there has been a growing interest in chemical transformation processes from
thionitrates to other nitrogen species. Although thionitrates are usually rather labile because of
ready bimolecular decomposition, fundamental chemical properties of this species were inten-
sively studied by Oae and Shinhama (5), Oae et al. (6–8), Kim and Kim (9) and Kim et al. (10).
They examined the reaction of thionitrates with nitrogen nucleophiles, and reported that t-butyl
thionitrate (t-BuSNO2, 1) serves as a diazotizing reagent of arylamines (6–8). As the plausible
mechanism for the first stage of the diazotizing reaction, transnitrosation from a sulfenyl nitrite
(RS-ONO) (11, 12), a tautomeric form of a thionitrate, to an amine to produce the corresponding
*Corresponding author. Email: goto@chem.titech.ac.jp
Dedicated to the memory of Professor Alessandro Degl’Innocenti.
© 2013 Taylor & Francis

706 K. Goto et al.
Figure 1. Stable thionitrate and sulfenic acid bearing a bowl-shaped substituent.
N-nitrosoamine and sulfenic acid (RSOH) was proposed (Scheme 1) (7). In the reported reactions
(6–8), however, the formation of the sulfenic acid was not confirmed because of its instability
(13). For the verification of the chemical process depicted in Scheme 1, a molecular system that
can stabilize both thionitrate and resulting sulfenic acid is required. We have been investigating the
stabilization of chalcogen-containing reactive species by taking advantage of bowl-shaped molec-
ular cavities (14–21), and previously reported the synthesis and isolation of the stable thionitrate
2 (18) and sulfenic acid 3 (20) bearing a dendrimer-type steric protection group, a Bpq group
(Figure 1). Here, we report the experimental demonstration of the nitrosation of an amine with a
thionitrate accompanied by the formation of a sulfenic acid.
Scheme 1. Proposed mechanism for the reaction of a thionitrate with an amine.
2. Results and discussion
Thionitrate 2 bearing a Bpq group was synthesized according to the procedure we previously
reported (18). Since the crystal structure of 2 was not determined, X-ray crystallographic analysis
was performed with the single crystals of 2 obtained by recrystallization from chloroform/hexane
(Figure 2). The selected bond lengths and angles are summarized in Table 1. In the literature,
there have been only two examples of crystallographic analysis of thionitrates: the triarylmethyl-
substituted thionitrate 4 (16) reported by us and the aromatic thionitrate 5 (22) reported by Itoh
−
et al. (Figure 3). The S N bond length of 2 is 1.7898(17)Å, which is similar to that of the aromatic
derivative 5 and slightly longer than that of the aliphatic derivative 4 (Table 1).
Thenitrosatingabilityofthionitrate 2 wasexaminedbythereactionwithasecondaryamine.The
treatment of a degassed CDCl3 solution of thionitrate 2 with three equivalents of dibutylamine at
roomtemperatureresultedintheformationofthecorrespondingsulfenicacid 3asthemainproduct
with concomitant formation of N-nitrosodibutylamine in 66% and 70% yields, respectively, as
estimated by 1H NMR spectroscopy (Scheme 2). In addition to sulfenic acid 3, sulfenamide 6 was
formed as the minor product in 26% yield. This is the first demonstration of the transformation of a
thionitrate and an amine to the corresponding sulfenic acid and N-nitrosoamine. Usually, sulfenic

Journal of Sulfur Chemistry 707
Figure 2. ORTEP drawing of 2 (50% probability). Hydrogen atoms and solvents are omitted for clarity.
Table 1. Selected bond lengths and angles for 2, 4 and 5.
2
4 (16)
5 (22)
Bond lengths (Å)
S(1)–N(1)
N(1)–O(1)
N(1)–O(2)
C(1)–S(1)
1.7898 (17)
1.213 (2)
1.2180 (19)
1.7651 (15)
1.746 (9)
1.239 (9)
1.229 (9)
1.789 (6)
1.795 (2)
1.228 (3)
1.215 (3)
1.764 (2)
Bond angles (◦)
S(1)–N(1)–O(1)
S(1)–N(1)–O(2)
O(1)–N(1)–O(2)
C(1)–S(1)–N(1)
113.28 (13)
120.25 (12)
126.44 (17)
100.47 (7)
119.7 (9)
114.1 (9)
126.2 (11)
107.9 (5)
113.48 (18)
121.19 (17)
125.3 (2)
99.75 (10)
Figure 3. Crystallographically analyzed thionitrates.
acids are very unstable due to rapid bimolecular decomposition (13), and in the reported reactions
utilizing thionitrate 1 only the corresponding thiosulfonate, t-BuSO2S(t-Bu), was obtained (6–8).
By utilizing the bowl-shaped substituent, which can stabilize both thionitrate and sulfenic acid,
the elementary chemical process depicted in Scheme 1 was unambiguously demonstrated. During
the reaction, the formation of the sulfenyl nitrite, BpqS-ONO (7), which is a tautomeric form of
thionitrate 2, was not detected. Theoretical reports predicted that sulfenyl nitrite forms (RS-ONO)
would be much higher in energy than thionitrate forms (RS-NO2) (11, 12). The tautomeric form
7 is considered to be a transient species if generated.

708 K. Goto et al.
Scheme 2. Reaction of thionitrate 2 with dibutylamine.
It was reported that thionitrate 1 reacts with octylamine to produce the corresponding sulfe-
namide, t-BuSNH(n-C8H17) (7). Similarly, the reaction of thionitrate 2 with benzylamine in
CDCl3 at room temperature afforded sulfenamide 8 (17) in 89% yield (Scheme 3), and no appre-
ciable formation of any other products deriving from 2 and benzylamine was observed. These
results indicate that substitution at the sulfur atom of thionitrates predominates in the reaction
with primary alkylamines.
Scheme 3. Reaction of thionitrate 2 with benzylamine.
3. Conclusion
Nitrosation of an amine with a thionitrate accompanied by the formation of a sulfenic acid was
demonstrated experimentally for the first time by taking advantage of a bowl-shaped molecular
cavity. The present results would provide useful chemical information for the elucidation of
the behavior of thionitrate intermediates in the bioactivation process of organic nitrates. Further
investigations on the nitrosating ability of thionitrates are currently in progress.
4. Experimental
All synthetic experiments were performed under argon atmosphere. Chloroform and chloroform-
d were distilled over CaH2 prior to use. Reagents were purchased from commercial sources and
used as received. 1H NMR spectra were recorded on a JEOL JNM-AL400 or a JEOL LAMBDA-
400, and the chemical shifts of 1H are referenced to the residual proton signal of CDCl3 (δ 7.25).
13C NMR spectra were measured on a JEOL ECX-400, and the chemical shifts are referenced to
the signal of CDCl3 (δ 77.0). Mass spectra were obtained with a JEOL JMS-700 (FAB, matrix:
m-nitrobenzyl alcohol).
4.1. Reaction of thionitrate 2 with dibutylamine
A solution of thionitrate 2 (9.6 mg, 10 μmol) in CDCl3 (0.5 mL) was placed into a 5 mm o/d NMR
tube and degassed via freeze-pump-thaw cycles. To the solution was added a degassed solution of
dibutylamine in CDCl3 (0.14 M, 0.22 mL, 31 μmol). The resulting solution was degassed again via
freeze-pump-thaw cycles and sealed in the NMR tube. The reaction was monitored by 1H NMR
spectroscopy, anditwasfoundthatthionitrate 2 wastotallyconsumedafter1 hatroomtemperature
to afford sulfenic acid 3 (66%), sulfenamide 6 (26%), and N-nitrosodibutylamine (70%).All yields
1
were estimated by H NMR spectroscopy. Sulfenamide 6 of analytical purity was obtained by
recrystallization from hexane. 6: colorless solid, m.p. 239–240◦C. 1H NMR (400 MHz, CDCl3)
δ 0.69 (t, J = 7.0 Hz, 6H), 1.00–1.11 (m, 32H), 1.15 (d, J = 7.2 Hz, 24H), 2.36 (t, J = 6.0 Hz,
4H), 2.89 (sept, J = 7.2 Hz, 8H), 6.97 (t, J = 1.6 Hz, 2H), 7.20 (d, J = 7.6 Hz, 8H), 7.25 (d,
J = 1.6 Hz, 4H), 7.28–7.35 (m, 4H), 7.36–7.41 (m, 3H); 13C NMR (98.5 MHz, CDCl3) δ 13.81

Journal of Sulfur Chemistry 709
(q), 19.81 (t), 24.01 (q), 24.44 (q), 29.54 (t), 30.38 (d), 55.91 (t), 122.48 (d), 127.78 (d), 128.36
(d), 129.29 (d), 129.71 (d), 130.18 (d), 134.21 (s), 139.22 (s), 139.64 (s), 142.26 (s), 146.86 (s),
148.26 (s); LRMS (FAB, positive) m/z 1030 (M+). Anal. Calcd for C74H95NS: C, 86.20; H, 9.50;
N, 1.06; S, 3.26. Found: C, 86.24; H, 9.29; N, 1.36; S, 3.11.
4.2. Reaction of thionitrate 2 with benzylamine
To a solution of thionitrate 2 (13.9 mg, 14.7 μmol) in chloroform (1 mL) was added benzylamine
(80 μL, 0.73 mmol), and the solution was stirred at room temperature for 6 h. After the removal
of the solvent and excess of amine in vacuo, the resulting solid was washed with hexane to afford
sulfenamide 8 (13.2 mg, 13.1 μmol, 89%) (17) as colorless crystals.
4.3. X-ray crystallography
Single crystals of 2·0.5C6H14 were grown in their chloroform/hexane solutions. The intensity
data were collected at 120 K on a Rigaku/MSC Mercury CCD diffractometer with graphite-
monochromated MoKα radiation (λ = 0.71069 Å). The structures were solved by the direct
method and refined by full-matrix least squares on F2 using SHELXL 97 (23). The non-hydrogen
atoms were refined anisotropically. The hydrogen atoms were idealized using the riding mod-
els. Crystallographic data for 2·0.5C6H14: C69H84NO2, M = 991.43, monoclinic, space group
P-1, a = 11.9733(9), b = 15.5347(11), c = 17.6554(13) Å, α = 71.621(4)◦, β = 81.836(4)◦,
γ = 75.274(3)◦, V = 3007.2(4) Å3, Z = 2, Dcalcd = 1.095 g cm−3, 20,667 measured reflec-
tions, 10,354 independent, 719 parameters. R1 = 0.0474 (I > 2σ(I)), wR2 = 0.1471 (all data).
Goodness-of-fit on F2 = 1.107. Crystallographic data for the structure of 2·0.5C6H14 have been
deposited with the Cambridge Crystallographic Data Centre, CCDC No. 926333.
Acknowledgements
This work was partly supported by Grants-in-Aid for The Global COE Program for Education and Research Center for
Emergence of New Molecular Chemistry and for Scientific Research on Innovative Areas “Molecular Activation Directed
toward Straightforward Synthesis” from the Ministry of Education, Culture, Sports, Science and Technology, Japan.
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