Mechanism insights into an unexpected isomerisation reaction observed during conversion of N-benzyl piperazinones to corresponding N-benzyl thio-piperazinones

Article abstract of DOI:10.1016/j.tetlet.2010.11.096

An interesting and surprising rearrangement was observed during the reaction of 4-N-benzyl piperazinone derivatives with Lawesson's reagent as a thionating agent. Investigation into the possible mechanism responsible for these results is reported herein.

Full text of DOI:10.1016/j.tetlet.2010.11.096

Tetrahedron Letters 52 (2011) 448–452
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Tetrahedron Letters
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Mechanism insights into an unexpected isomerisation reaction observed
during conversion of N-benzyl piperazinones to corresponding N-benzyl
thio-piperazinones
⇑
,
Emanuele Miserazzi , Mario Alessandro Spotti, Roberto Profeta , Simone Spada , Arnaldo Nalin ,
,
⇑
Elisa Moro , Daniele Andreotti
GlaxoSmithKline, Medicines Research Centre, Via A. Fleming 4, 37100 Verona, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
An interesting and surprising rearrangement was observed during the reaction of 4-N-benzyl piperazi-
none derivatives with Lawesson’s reagent as a thionating agent. Investigation into the possible mecha-
nism responsible for these results is reported herein.
Received 20 October 2010
Revised 12 November 2010
Accepted 17 November 2010
Available online 23 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Lawesson reagent
Thioamides
N-Benzyl piperazinones
Mechanism
Red-Ox
N-Benzyl thio-piperazinones
1. Introduction
other methods. During our research activity we were interested
in the conversion of a-amino-amides, in particular piperazinones,
Thioamide is a well known and versatile functional group
widely used in organic chemistry for preparing heteroaromatic
rings1 (Path a Fig. 1), ketones2 by reaction with either alkyl or aryl
organo-lithium compounds (Path b Fig. 1). It can also be relatively
easily converted to the corresponding amine3 (Path c Fig. 1) by
using H2/Ni–Raney. Amongst the several methods available, the
O/S-exchange is the most exploited reaction for preparing
thioamides.4
to the corresponding thio-piperazinone derivatives. This kind of
transformation has been reported in the literature4a,b with very
similar substrates; however, the examples described were charac-
terized by the presence of a protecting group such as N-Boc or N-Cbz
that masked the free lone pair of the piperazinones (Scheme 1).
R
O
In fact, direct treatment of amides4e–i,l with Lawesson’s re-
agent,5 the dimeric anhydride of methoxyphenyl dithiophosphinic
acid-2,4-bis-(p-methoxy pheny)-1,2,3,4-dithiadiphosphetane-2,4-
disulfide, gives rise to the corresponding thioamides; generally
moderate to good yields are reported.
R1
N
R2
Lawesson's Reagent
O
R
NH2
R
Besides the preparation of thioamides the Lawesson’s reagent
has been used extensively also for the conversion of a wide variety
of carbonyl, alcohol, ester, lactone, cyclic peptide derivatives to the
corresponding thio-derivatives and for preparing phosphorous and
sulfur-containing heterocycles,4e which are often inaccessible by
R
Ar
N
H
Ni-Raney
S
N
R1
N
R1
R1
N
N
N
c
R2 = H
a
R2
R2
Ar
R3-Li
R3
b
⇑
O
Corresponding authors. Tel.: +39 045 8219953; fax: +39 045 8218196.
E-mail addresses: Emanuele.Miserazzi@aptuit.com (E. Miserazzi), Daniele.
Andreotti@aptuit.com (D. Andreotti).
R
Present address: Aptuit Medicines Research Centre, Via A. Fleming 4, 37135
Verona, Italy.
Figure 1. Formation and some application of thioamides.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.096

E. Miserazzi et al. / Tetrahedron Letters 52 (2011) 448–452
449
O
O
R
O
R
O
Lawesson's Reagent
N
N
R = t-But, Bn
N
S
a
2
Expected
O
N
N
H
N
H
S
N
H
N
H
1
O
Scheme 1. Conversion of N-Cbz and N-Boc protected piperazinone to correspond-
ing thiopiperazinone.
b
O
The presence of even reactive functions such as nitro, halogen
and amino groups however does not complicate the thionation
process.4,5 Though, on some particular substrates the use of thio-
nating agents can give unexpected results.4m,n To the best of our
knowledge only a limited number of thionation examples7 are re-
ported in the presence of a secondary or tertiary free nitrogen at
the alpha position to the amide as in the case of 4-N-Benzyl piper-
azinone (1). Two similar mechanisms for the thionation of carbonyl
groups have been proposed4f,6 to proceed via four-membered ring,
1,3,2-oxathiaphosphetane derivatives (Fig. 2) and it is reasonable
to assume that conversion of secondary and tertiary amides to
thioamides also proceeds through a similar Wittig-type intermedi-
ate. The first example we investigated is reported in Scheme 2, the
commercially available 4-(phenylmethyl)-2-piperazinone (1) was
heated in toluene at 80 °C in the presence of (1 equiv) Lawesson’s
reagent.8 Although the compound isolated in moderate yield
showed the right molecular mass unexpectedly, a more careful
1H NMR examination revealed that the structure of the obtained
compound was consistent with the isomer 3 rather than 2 as de-
rived from chemical shifts and NOE results.
N
S
N
4
3
Obtained
N
H
N
H
Scheme 2. Reagents and conditions: (a) toluene, Lawesson’s reagent 1 equiv, 3 h,
Y = 43%; (b) toluene, Lawesson’s reagent 1 equiv, 3.5 h, Y = 35%.
S
a
b
N
N
N
1
O
S
N
N
N
5
6
7
~3:2 mixture
Scheme 3. Reagents and conditions: (a) DMF, NaH 1.5 equiv, 1-propyl bromide
2 equiv, from 0 °C 1 h to 25 °C O/N, Y = 61%; (b) toluene, Lawesson’s reagent 1 equiv,
80 °C 3 h. Y(6) = 28%, Y(7) = 19%.
Intrigued by this result the reaction was repeated and moni-
tored with time via LCMS, we then noticed at the beginning of
the reaction the formation of two peaks with the same molecular
weight of the thioamides (likely 2 and 3) but after a few hours only
one peak remains corresponding to compound 3. To further inves-
tigate and support this result we decided to submit compound 4 to
the same reaction conditions.
O
Reaction of 4 with Lawesson’s reagent gave the corresponding
thioamide 3 in moderate yield and the analytical data confirmed
the formation of the same thioamide 3 from both experiments. In
order to verify whether a scrambling of the N-benzyl group of 1
and 4 could explain this unexpected convergent isomerisation to-
wards isomer 3 we decided to prepare the N,N0-bis-alkylated piper-
azinone 5 as reported in Scheme 3. In this case we obtained the
two thioamide isomers 6 and 7 in 28% and 19% yields, respectively.
Therefore, this result rules out the possibility that formation of 3
S
P
P
S
S
S
Lawesson's reagent
O
S
P+
S
2
R
R1
R2
O
O
O
S
R1
N
R2
1,3,2-oxathiaphosphetanes derivatives
R
Cl
R1
R2
Y
S
R1
b
a
Y
P
N
N
P
X
N
X = O, Y = S
or
X = S, Y = O
X
O
R2
N
H
9
11
N
H
N
H
O
S
8
O
O
c
S
P+
O
N
N
S
O
10
12
R
R1
R2
N
H
O
N
H
S
S
R1
N
R2
Figure 2. General mechanism of thionation via Wittig-like intermediate.
Scheme 4. Reagents and conditions: (a) CH3CN, benzyl methyl amine 1 equiv,
K2CO3 2 equiv, 80 °C, 3 h, Y = 73%; (b) toluene, Lawesson’s reagent 1 equiv, 80 °C,
14 h, Y = 71%; (c) toluene, Lawesson’s reagent 1 equiv, 80 °C, 20 h, Y = 45%.

450
E. Miserazzi et al. / Tetrahedron Letters 52 (2011) 448–452
starting from the two intermediates 1 and 4 could be due to a sim-
ple scrambling of the benzyl group; an event more subtle and
deserving of a deeper investigation was clearly occurring during
this reaction.
mechanism involved in this rearrangement. In this regard we
thought that at least two possible pathways, A and B, could be
deemed as reported in Figure 3 to support the obtained results.
Both pathways were supposed to go through pseudo-symmetric
intermediates A and B which can evolve towards the formation
of the tertiary thioamides 6 and 7. The main difference between
the two possible pathways consists in the different roles played
by the carbon backbone of the glycine-amide moiety.
In case of Path A the rearrangement can be considered as an
internal red-ox reaction where the two carbons of the glycine-
amide fragment whilst maintaining their relative positions are
swapping their relative oxidation levels. On the contrary, in the
case of Path B the oxidation levels of these two carbons do not
change throughout the rearrangement but they are swapping their
relative positions. In order to shed some light on the possible
mechanism of such a rearrangement, via Path A or B, intermediates
1 (13C) and 16 (13C) enriched with isotope 13C at the position two of
the piperazinones were prepared (Scheme 5).
Prompted by these results another two examples, 9 and 10,
were prepared as depicted in Scheme 4, for testing under the same
reaction conditions. Compounds 9 and 10 can be considered as the
open versions of the N-benzyl-piperazinones 1 and 4, respectively.
When these compounds were reacted with the Lawesson’s reagent
in toluene at 80 °C, although longer reaction time was needed (14–
20 h instead of 3 h), the corresponding thioamides 11 and 12 were
isolated in 45% and 71%, respectively, without observing any isom-
erisation. This result might suggest that the corresponding open
version of the transition state responsible for the isomerisation of
1 towards the tertiary thioamide 3, likely the thermodynamically
more stable product, cannot be achieved starting from 9 and the
O/S exchange mediated by the Lawesson’s reagent proceeds as ex-
pected to give 11 instead of 12.
Although apparently limited to the piperazinone case, these re-
sults elicited our interest to understand more about the possible
In fact, we envisaged the possibility of discriminating between
these two possible paths by analysing the reaction products via
R1
N
N
O
R2
Path B
Path A
R1
N
R1
N+
O
O
X
R1
N
S
P
P
N
N
S
S
S
Y
OH
R2
R2
P
N
S
O
X =O, Y=S
or
X = S, Y= O
R2
R1
X
O
Y
N
P
B
S
N
O
R2
O
R1
N
R1
R1
R2
N
A
O
S
S
R1 and R2 = H
S
R1 and R2 = H
N
N
P
P
+
O
S
N
N+
N
S
N
S
O
R2
R2
R2
R1
R2 = H
R2 = H
Mixture of isomers
O
R1
R1
N
OH
P
S
N
S
P
S
O
S
HO
N
N
Single isomer
OH
S
R1
Y
R1
R1
P
S
O
N
P
N
S
N
S
X
N
H
O
N
H
N
H
Figure 3. Paths A and B, and the proposed pseudo-symmetric intermediates.

E. Miserazzi et al. / Tetrahedron Letters 52 (2011) 448–452
451
O
O
O
13C
13C
O
13C
O
N
O
a
c)
N
S
a) b)
N
N
HN
NH
1(13C)
O
3(13C)
13C
13C
N
H
N
H
O
O
13
14
15
N
N
N
N
b
N
N
N
N
S
d)
e)
N
13C
13C
13C
13C
13C
O
S
O
N
O
H
16(13C)
1 : 1 ratio
1(13C)
16(13C)
18(13C)
17(13C)
Scheme 5. Reagents and conditions: (a) dioxane, HCl 4 N in dioxane, 25 °C, O/N; (b)
(i) MeOH, TEA 1.05 equiv, benzaldehyde 1.0 equiv at 0 °C for 30 min then 25 °C, 3 h;
(ii) NaBH4 1.3 equiv, 0 °C 30 min then 25 °C, 1.5 h Y = 69%; (c) THF, K2CO3 3 equiv,
bromoacetonitrile 1.1 equiv, 10 h reflux, Y = 90%; (d) MeOH, H2, Ni/Raney, 50 psi,
60 °C, 3 h, Y = 82%; (e) DMF, benzyl bromide 1.2 equiv, NaH 1.3 equiv, 0 °C 1 h,
Y = 69%.
Scheme 6. Reagents and conditions: (a) toluene, Lawesson’s reagent 1 equiv, 2.0 h,
Y = 65%; (b) toluene, Lawesson’s reagent 1 equiv, 2 h, Y = 30%.
1:1 ratio due to the pseudo-symmetry of the molecule which gives
rise to the formation of a symmetric intermediate A as depicted in
Figure 4.
13C NMR (Fig. 4); expecting a 1:1 mixture of 17 (13C) and 18 (13C)
in case of Path A whilst only 18 (13C) would be obtained in case of
Path B. We were pleased to see that in both cases reacting 1 (13C)
and 16 (13C) with Lawesson’s reagent the 13C NMR data of the iso-
lated products pointed in the same direction with both being con-
sistent with Path A, Scheme 6.
At this point we could assume that formation of intermediate A
in Figure 4 could be obtained through the steps highlighted in Fig-
ure 3 Path A, where the process remains reversible till reaching the
pseudo-symmetric intermediate A (pending on the nature of R1
and R2). In case of R1 and R2 are different from H a mixture of both
possible thioamides is obtained whilst in case R2 = H intermediate
A irreversibly evolves towards a single product, again the tertiary
thioamide.
In fact, 13C NMR of 3 (13C) showed an intense peak at 57.49 ppm
consistent with the presence of a 13CH2 and not a 13C(S)N. As a fur-
ther evidence of the presence of 13CH2 the 1H NMR showed at
ꢀ4.12 ppm a doublet with a broad JCH = 140.13 Hz. The products
17 (13C)/18 (13C) isolated from reaction of 16 (13C) showed the
13C evenly distributed (two intense 13C NMR peaks at
196.68 ppm and 64.81 ppm) on both positions suggesting that
the O/S exchange reaction proceeds through a variation of the oxi-
dation level of the two carbons reaching, in this particular case, a
2. Conclusions
We have here reported an unexpected isomerisation reaction
observed during conversion of 4-N-benzyl piperazinone
derivatives to the corresponding thioamides via O/S exchange
Internal red-ox potential exchange between carbon isotopes
A
N
N
S
N
N
O
N
N
S
S
S
Path A
P
O
N
18(13C)
17(13C)
N
O
Swap of positions between carbon isotopes
16(13C)
B
N
N
S
O
S
N
P
Path B
13C
S
O
N
=
18(13C)
Figure 4. Possible outcomes from paths A and B using labelled 13C piperazinone derivatives.

452
E. Miserazzi et al. / Tetrahedron Letters 52 (2011) 448–452
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currently limited to the piperazinone template, preliminary mech-
anistic aspects of such isomerisation have been investigated by
preparing suitable 13C labelled piperazinones. The data obtained
suggest that this rearrangement could go through formation of
an intermediate A-like (Figs. 3 and 4) involving an internal
red-ox process and a possible chemical path has been proposed
in Figure 3 to rationalize the results observed.
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8. Typical experimental procedures for thioamides formation:
Acknowledgements
To a solution of the amide 1 (1 g, 5.26 mmol) in toluene (20 ml), Lawesson’s
reagent (2.13 g, 5.26 mmol) was added portionwise.
We are grateful Dr. Carla Marchioro and her Analytical Chemis-
try Department in Verona for the experimental collaboration and
in particular to Dr. Ornella Curcuruto for High Resolution Mass
generation and to Dr. Luca Rovatti for the effective LCMS support.
The mixture was heated at 80 °C and the reaction progress was monitored by
LCMS. After 3 h the mixture was evaporated to dryness and then dissolved in
200 ml of dichloromethane.
The organic phase was washed with saturated bicarbonate solution (100 ml),
water (100 ml), dried over sodium sulfate and evaporated. The oily material was
purified by flash chromatography eluting with DCM/MeOH from 100/0 to 95/5)
to give 540 mg of 3 as a brownish solid (Y = 45%).
1-(phenylmethyl)-2-piperazinethione (3).
Supplementary data
1H NMR (400 MHz, DMSO-d6): d (ppm) 2.95–3.02, (s, 2H); 3.25–3.30, (t, 2H);
3.78–3.82 (s, 2H); 5.22–5.27, (s, 2H), 7.25–7.40 (m, 5H).
13C NMR (100 MHz, DMSO-d6): d (ppm) 41.1, 48.2, 55.0, 58.3, 127.0, 127.2,
129.1, 138.5, 199.1.
Supplementary data (key experimental procedures, compound
characterizations and selected NMR spectra) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.11.096.
HRMS calculated for [C11H14N2S]; [M+H]+: m/z 207.0956, found m/z 207.0992.
1-(phenylmethyl)-2-piperazinethione-3-13C (3(13C));
1H NMR (400 MHz, CDCl3): d (ppm) 3.11–3.23 (q, 2H), 3.28–3.40 (t, 2H), 3.90–
4.35 (d, J = 140.13 Hz, 2H), 5.30–5.40 (s, 2H), 7.32–7.41 (m, 5H). 13C NMR
(100 MHz, DMSO-d6): d (ppm) 42.15, 48.74, 55.84, 57.49, 127.38, 127.63, 128.49.
HRMS (ES+) calculated for [13CC10H14N2S] [M+H]+: m/z 208.0990, found m/z
208.0992
References and notes
1-(phenylmethyl)-4-propyl-2-piperazinethione (6);
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1H NMR (400 MHz, CDCl3): d (ppm) 0.84 (3H, t, J = 7.50 Hz) 1.44 (2H, s) 2.28 (2H,
t, J = 7.50 Hz) 2.63 (2H, t, J = 5.42 Hz) 3.33 (2H, t, J = 5.42 Hz) 3.69 (2H, s) 5.23
(2H, s) 7.16–7.32 (5H, m).
HRMS calculated for [C14H20N2S]; [M+H]+: m/z 249.1425, found m/z 249.1429.
4-(phenylmethyl)-1-propyl-2-piperazinethione (7);
1H NMR (400 MHz, CDCl3): d (ppm) 0.92–1.00 (t, 3H), 1.66–1.84 (m, 2H), 2.67–
2.78 (t, 2H), 3.42–3.49 (t, 2H), 3.52–3.56 (s, 2H), 3.66–3.73 (s, 2H), 3.82–3.93 (m,
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HRMS calculated for [C14H20N2S]; [M+H]+: m/z 249.1425, found m/z 249.1429.
N-Methyl-2-methyl(phenylmethyl)amino]ethanethioamide (11);
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3.35–3.38 (s, 2H), 3.53–3.57 (s, 2H), 7.23–7.29 (t, 1H), 7.30–7.36 (t, 2H), 7.37–
7.42 (d, 2H), 9.69–9.95 (brs, 1H). 13C NMR (100 MHz, DMSO-d6): d (ppm) 30.5,
41.8, 60.9, 67.2, 126.6, 128.1, 129.0, 138.2, 199.3.
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HRMS calculated for [C11H16N2S]; [M+H]+: m/z 209.1112, found m/z 209.1110.
N-Methyl-2-(methylamino)-N-(phenylmethyl) ethanethioamide (12);
1H NMR (500 MHz, DMSO-d6): d (ppm) 2.32–2.38 (s, 3H), 3.21–3.24 (s, 3H),
3.64–3.69 (m, 2H), 5.27–5.31 (s, 2H), 3.52–3.56 (s, 2H), 3.66–3.73 (s, 2H), 3.82–
3.93 (m, 2H), 7.24–7.47 (m, 5H)
HRMS calculated for [C11H16N2S]; [M+H]+: m/z 209.1112, found m/z 209.1109.
1,4-bis(phenylmethyl)-2-piperazinethione-3-13C (17(13C)) and 1,4-bis(phenylmethyl)-
2-piperazinethione-2-13C (18(13C));
1H NMR (400 MHz, CDCl3): d (ppm) 2.64–2.84 (m, 4H), 3.35–3.46 (t, 4H), 3.53–3.62
(t, 4H), 3.63–4.03 (d, 2H), 3.80–3.85 (d, 2H), 5.24–5.38 (t, 4H), 7.29–7.41 (m, 20H).
13C NMR (100 MHz, CDCl3): d (ppm) 48.86, 48.87, 49.30, 56.47, 61.05, 61.07, 61.09,
64.81, 127.61, 127.98, 128.18, 128.51, 128.85, 129.08, 135.01, 136.57, 196.68.
HRMS calculated for [13CC17H20N2S]; [M+H]+: m/z 298.1459, found m/z 298.1455.