Synthesis of N1,N3-disubstituted formamidrazones via the TMSCl-promoted reaction of isocyanides with thiosemicarbazones

Article abstract of DOI:10.1016/j.tetlet.2012.09.085

A hitherto undescribed TMSCl-promoted reaction of thiosemicarbazones was found to give rare N¹,N³-disubstituted formamidrazones in fair to excellent yields. The scope of this new reaction was investigated and a plausible mechanism proposed.

Full text of DOI:10.1016/j.tetlet.2012.09.085

Tetrahedron Letters 53 (2012) 6540–6543
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Synthesis of N1,N3-disubstituted formamidrazones via the TMSCl-promoted
reaction of isocyanides with thiosemicarbazones
Pakornwit Sarnpitak a, Sergey Tsirulnikov b, Mikhail Krasavin a,
⇑
a Eskitis Institute for Cell and Molecular Therapies, Griffith University, Nathan, Queensland 4111, Australia
b Science and Education Center ‘Innovative Research’, Yaroslavl State Pedagogical University, Yaroslavl 150000, Russia
a r t i c l e i n f o
a b s t r a c t
A hitherto undescribed TMSCl-promoted reaction of thiosemicarbazones was found to give rare N1,N3-
disubstituted formamidrazones in fair to excellent yields. The scope of this new reaction was investigated
and a plausible mechanism proposed.
Article history:
Received 31 July 2012
Revised 14 September 2012
Accepted 20 September 2012
Available online 27 September 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Isocyanide-based multicomponent
reactions
Isocyanide insertion
Lewis acid catalysis
Chlorotrimethylsilane
Formamidrazones
The reaction of an isocyanide with an imine component 1 is key
in the Ugi reaction,1 a prominent four-component reaction that
leads to facile formation of dipeptoid adducts. Oximes 22 and
hydrazones 33 have been successfully utilized as surrogate replace-
ments for the imine component and have provided access to struc-
turally novel, peptidomimetic Ugi-type products (Scheme 1).
Combining an oxime2 or a hydrazone4 motif with isocyanide-inter-
cepting carboxylate functionality in the same reaction component
has been shown to lead to ring-forming reactions with isocyanides,
a strategy exploited extensively for the Ugi reaction itself.5
The use of semicarbazones as components for the Ugi reaction
has been exemplified in the remarkable synthesis of 1,2,4-tria-
zin-1-yl substituted alaninamides by Marcaccini and co-workers.6
However, no account of a thiosemicarbazone reacting with an iso-
cyanide existed in the literature. Intrigued by this void, and
encouraged by the theoretical possibility of the thiocarbamoyl mo-
tif to act, in the absence of a carboxylic acid component, as an
internal isocyanide-intercepting nucleophile, we have investigated
this reaction (Scheme 2).
in dry acetonitrile (the solvent previously found by us8 to provide
optimum results in TMSCl-promoted IMCRs), the model substrate
4 (prepared from p-anisaldehyde and thiosemicarbazide) under-
went, after 3 h at room temperature, full conversion into a new
product that precipitated from the reaction mixture and was
isolated by filtration. Contrary to our expectations of heterocycle
formation (vide supra), 1H and 13C NMR spectroscopic data were
consistent with the structure of 1-(tert-butyl)-4-(4-methoxyben-
zylidene)formamidrazone hydrochloride salt (5a) (Scheme 3).
R4
R2
R2
O
N
N
O
H
N
R1
R1
R1
R3
R1
1
R4
R3NC, R4COOH
R2O
R2O
N
O
N
H
with or without
a Lewis acid
catalyst
N
R3
R2
R1
R4
The use of an acid catalyst/promoter for an isocyanide-based
multicomponent reaction (IMCR) is important. Previously, we
used equimolar amounts of chlorotrimethylsilane (TMSCl) to suc-
cessfully promote various IMCRs.7 This reagent was also chosen
for this study. When treated with TMSCl and tert-butyl isocyanide
2
O
H
N
H
N
R2
N
O
O
N
O
R1
O
3
HN
R3
⇑
Corresponding author. Tel.: +61 7 3735 6041; fax: +61 7 3735 6001.
E-mail address: m.krasavin@griffith.edu.au (M. Krasavin).
Scheme 1. Imine, oxime, and hydrazine components in the Ugi reaction.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.085

P. Sarnpitak et al. / Tetrahedron Letters 53 (2012) 6540–6543
6541
O
Ph
c-Hex
OH
Ph
O
H2N
HN
O
N
O
c-Hex
HN
O
N
H
N
c-HexNC
base
O
(a)
(b)
N
N
O
N
N
H
OH
O
H2N
Ph
O
NH
NH2
S
NH2
S
tautomerization
?
HN
HN
S
HN
N
N
HN
H+
R2
R2
-C
N
N
H
N+
R2
R1
R1
R1
Scheme 2. An example of using semicarbazones6 (a) and the potential bifunctional character of thiosemicarbazones (b) in reactions with isocyanides.
TMSCl (1.0 equiv.)
O
O
. HCl
S
t-BuNC (1.1 equiv.)
N
N
N
N
H
MeCN, r.t.
87%
H2N
N
H
5a
4
Scheme 3. Model TMSCl-promoted reaction of a thiosemicarbazone with an isocyanide.
Table 1
Formamidrazones 5a–z synthesized in this work
R3
N
R1
N
H
N
R2
5a-z
Product R1
R2 R3
Yield Isolated as (A) free base
(%)
or (B) HCl salt
5a
5b
5c
5d
5e
5f
4-MeOC6H4
H
H
H
H
H
H
H
t-Bu
87
51
46
67
94
B
A
A
A
B
A
A
2-F3CC6H4
2-F3CC6H4
2-F3CC6H4
4-MeOC6H4
2-O2NC6H4
2-O2NC6H4
4-MeOC6H4
MeO2CCH2
Bn
Cyclohexyl
(CH3)3CH2(CH3)2C 63
5g
Cyclohexyl
70
O
*
5h
5i
H
t-Bu
62
A
Figure 1. Single-crystal X-ray structure of compound 5a (ORTEP plot representing
the atoms as thermal ellipsoids at the 50% probability level).
N
N
H
Cyclohexyl
68
58
A
*
*
Single-crystal X-ray analysis9 further confirmed this assignment
(Fig. 1).
5j
H
MeO2CCH2
A
Formamidrazones similar to 5a have rarely appeared in the
literature. They were prepared for the first time in 1968 via the
two-step condensation of benzaldehyde hydrazone with triethyl
orthoformate and various aliphatic amines;10 formamidrazones
have been implicated as valuable synthons for heterocycle synthe-
sis.11 The formamidrazone linkage has also been shown to be cen-
tral to the design of antitubercular compounds.12 Encouraged by
the technically simple and high-yielding preparative access to 5a
depicted in Scheme 3 and by the absence of its analogs in existing
commercially available screening collections,13 we investigated the
scope of this reaction with a range of thiosemicarbazones and iso-
cyanides (Table 1).14 While in some cases the product formamid-
razone hydrochlorides precipitated from the acetonitrile solution
and were isolated conveniently by filtration, in the majority of
the reactions the products were isolated in the free base form,
following aqueous work-up of the reaction mixture with satd aq
NaHCO3, EtOAc extraction, and column chromatography. Free-base
formamidrazones (except for 5b, 5k–l, 5s, and 5u derived from an
aromatic isocyanide) existed as tautomeric mixtures that compli-
cated their NMR spectroscopic characterization. However, they
5k
5l
5m
5n
5o
4-MeC6H4
4-MeOC6H4
2-BrC6H4
3,4-diMeC6H3
3-ClC6H4
H
H
H
H
H
4-MeOC6H4
4-MeOC6H4
Bn
t-Bu
t-Bu
33
40
69
88
90
A
A
A
B
B
H
N
5p
H
H
Cyclohexyl
Bn
90
42
B
*
5q
5r
5s
(CH3)2CHCH2
Ph
Ph
A
A
A
Me t-Bu
Me 4-MeOC6H4
H
N
5t
H
t-Bu
88
29
B
*
*
H
N
5u
H
4-MeOC6H4
A
5v
5w
5x
5y
5z
2-BrC6H4
2-BrC6H4
–(CH2)5–
Me
H
H
MeO2CCH2
Cyclohexyl
t-Bu
A
B
A
A
A
95
50
21
41
Me t-Bu
Cyclohexyl
(CH3)2CHCH2
H

6542
P. Sarnpitak et al. / Tetrahedron Letters 53 (2012) 6540–6543
H
results (possibly due to its protic character and interference with
HNCS scavenging).
isocyanide
N-H
H
N
N
NH2
LA
LA
insertion
N
R3
S
S
According to our mechanistic interpretation, similar reactivity
should be expected of semicarbazones (with respective loss of iso-
cyanic acid). Although the product 5a was indeed isolated as a free
base (following basic work-up and extraction) from the reaction of
the semicarbazone analog of 4, the yield (27%) and abundance of
unwanted side-products were far less appealing. The reasons for
the less efficient reactivity of semicarbazones toward isocyanides,
compared to that of thiosemicarbazones, are not clear at present.
The mechanism presented in Scheme 4 also implies that TMSCl-
promoted insertion of an isocyanide into an H2NCSN–H bond, with
subsequent loss of isothiocyanic acid may be general in nature. We
reacted t-BuNC with unsubstituted thiourea and thiosemicarba-
zide in the presence of 1 equiv of TMSCl. The hydrochlorides of
monosubstituted amidine 6 and formamidrazone 7 were isolated
from the respective reactions by filtration, although the yield of
the former was of little practical value (Scheme 5). Interestingly,
an attempted alternative synthesis of the free-base compound 5a
from monosubstituted formamidrazone 7 (MeCN, p-anisaldehyde,
Et3N, rt, 2 h) led to the conversion of the latter into a complex
product mixture containing only a small amount of the target
material (according to TLC analysis).
In summary, a new TMSCl-promoted reaction of isocyanides
with thiosemicarbazones was shown to provide diversely substi-
tuted formamidrazones in fair to excellent yields for a range of
substrates. Preliminary mechanistic interpretation suggests that
the generality of this reaction extends beyond thiosemicarbazones
and will be further investigated. The potential applications of
N1,N3-disubstituted formamidrazones 5 in heterocycle synthesis
are currently being investigated in our laboratories. The results of
these studies will be reported in due course.
H
N
N
N
R2
C
R2
N
R1
R1
R3
If LA = Me3SiCl:
Me3SiCl
- HNCS
- LA
Me3SiN=C=S
- HCl
H
N
H
N
R2
R3
R2
R3
N
·HCl
N
R1
N
R1
N
Scheme 4. Mechanistic interpretation of the reaction toward formamidrazones
5a–z.
could be ‘locked’ in a single tautomeric form when converted back
into hydrochloride salts for easier characterization.15 The yields of
the precipitated hydrochloride salts were excellent while reactions
requiring aqueous work-up and chromatographic purification pro-
vided the free-base products in yields varying from moderate to
good. Thiosemicarbazones of aromatic aldehydes and ketones gen-
erally provided better yields compared to their aliphatic counter-
parts (5q, 5x–z).
The observed reaction was essentially a condensation of the
hydrazone motif of 4 with the isocyanide, accompanied by a formal
loss of isothiocyanic acid (HNCS). This result can be justified by the
known ability of isocyanides to undergo facile insertion into N–H
bonds (reported under ZnCl2,16 CuCl,17 or Cu2O18 catalysis). More-
over, such isocyanide reactivity has already been exploited for the
preparation of formamidrazones from hydrazines and isocya-
nides.19 Our mechanistic interpretation is presented in Scheme 4.
tert-Butyl isocyanide is expected to insert into the N–H bond of
the Lewis acid activated thisemicarbazone.20 The basic amidine
nitrogen thus installed can subsequently trigger the elimination
of HNCS. The TMSCl present in the reaction mixture in an equimo-
lar amount is then able to scavenge the HNCS whereby an equiva-
lent of HCl is generated leading to the formamidrazone
hydrochloride products.21 The scavenging of HNCS by an equimo-
lar amount of TMSCl and product hydrochloride formation may
essentially drive the reaction forward. For instance, using only
0.2 equiv of TMSCl in MeCN led to proportionally lower conver-
sions and product yields (as determined by 1H NMR spectroscopy).
Similarly, inefficient (albeit not negligible) conversions were
achieved using other Lewis acid promoters (0.2 equiv): Yb(OTf)3,
InCl3, Sc(OTf)3, Zn(OTf)2 as well as concentrated HCl. This attests
to the unique character of TMSCl as a promoter in this reaction.
Reactions in acetonitrile provided the best results,22 but acceptable
product yields could be achieved in dichloromethane and THF
while running the reactions in methanol led to markedly poorer
Acknowledgments
Mikhail Krasavin acknowledges the support from the Griffith
University (New Researcher Grant 2012, project 215586). Dr. Hoan
Vu of the Eskitis Institute is thanked for high-resolution mass spec-
trometry measurements.
References and notes
1. Ugi, I.; Meyr, R.; Fetzer, U.; Steinbrückner, C. Angew. Chem. 1959, 71, 386.
2. (a) Basso, A.; Banfi, L.; Guanti, G.; Riva, R.; Riu, A. Tetrahedron Lett. 2004, 45,
6109–6111; (b) Basso, A.; Banfi, L.; Guanti, G.; Riva, R. Tetrahedron Lett. 2005,
46, 8003–8006.
3. (a) Krasavin, M.; Bushkova, E.; Parchinsky, V.; Shumsky, A. Synthesis 2010, 933–
942; (b) Bushkova, E. E.; Parchinsky, V. Z.; Krasavin, M. Mol. Divers. 2010, 14.
493-399..
4. Krasavin, M.; Parchinsky, V.; Shumsky, A.; Konstantinov, I.; Vantskul, A.
Tetrahedron Lett. 2010, 51, 1367–1370.
5. Ivachtchenko, A. V.; Ivanenkov, Ya. A.; Kysil, V. M.; Krasavin, M.; Ilyin, A. P. Russ.
Chem. Rev. 2010, 79, 787–817.
6. Sañudo, M.; Marcaccini, S.; Basurto, S.; Torroba, T. J. Org. Chem. 2006, 71, 4578–
4584.
7. (a) Krasavin, M.; Tsirulnikov, S.; Nikulnikov, M.; Kysil, V.; Ivachtchenko, A.
Tetrahedron Lett. 2008, 49, 5241–5243; (b) Krasavin, M.; Shkavrov, S.;
Cl
Si
S
NH2
H
t-BuNC
Cl
Si
TMSCl
H
N
N
S
R
H
N
S
N
N
·HCl
NH
R
N
H
NH2
dry MeCN
r.t., 16 h
R
- TMSNCS
C
R
N
6
, R = H, 6%
7, R = NH2, 67%
Scheme 5. Reactions of thiourea and thiosemicarbazone with t-BuNC promoted by TMSCl.

P. Sarnpitak et al. / Tetrahedron Letters 53 (2012) 6540–6543
6543
Parchinsky, V.; Bukhryakov, K. J. Org. Chem. 2009, 74, 2627–2629; (c)
Tsirulnikov, S.; Kysil, V.; Ivachtchenko, A.; Krasavin, M. Synth. Commun. 2010,
40, 111–119; (d) Tsirulnikov, S.; Dmitriev, D.; Krasavin, M. Synlett 2010, 1935–
1938.
28.2. HRMS m/z (M+H+) calcd for C13H20N3O 234.1601, found 234.1595.
Compound 5eÁHCl—Grey solid, mp = 173–175 °C (dec) 1H NMR (500 MHz,
DMSO-d6) d 13.40 (br s, 1H, HCl), 9.72 (dd, J = 13.0, 7.5 Hz, 1H, amidine CH),
8.43 (s, 1H, Ar-CH@N), 8.19 (d, J = 13.0 Hz, 1H, c-HexNH), 7.90 (d, J = 8.5 Hz, 2H,
4-MeOC6H4), 7.06 (d, J = 8.5 Hz, 2H, 4-MeOC6H4), 3.84 (s, 3H, OMe), 3.49–3.55
(m, 1H, c-Hexyl CH–NH), 1.88–1.92 (m, 2H), 1.76–1.81 (m, 2H), 1.61–1.65 (m,
1H), 1.52 (ddd, J = 24.5, 12.5, 2.5 Hz, 2H), 1.23–1.32 (m, 2H), 1.08–1.15 (m, 1H);
13C NMR (125 MHz, DMSO-d6) d 161.1, 157.0, 154.5, 149.4, 129.2, 114.0, 55.7,
55.3, 54.3, 31.6, 30.6. HRMS m/z (M+H+) calcd for C15H22N3O 260.1757, found
260.1746. Compound 5hÁHCl—Beige hygroscopic solid, mp = 116–120 °C
8. S.A. Tsirulnikov, Reactions of N,N-dinucleophiles with carbonyl compounds
and isocyanides, Dissertation, The Zelinsky Institute of Organic Chemistry,
Moscow, 2010.
9. Crystallographic data (excluding structure factors) for structure 5a have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 894123. Copies of the data can be obtained free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK. [Fax:
+44 (0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
10. Neunheoffer, H.; Hennig, H. Chem. Ber. 1968, 101, 3947–3951.
11. Alves, M. J.; Booth, B. L.; Freitas, A. P.; Proença, M. F. J. R. P. J. Chem. Soc., Perkin
Trans. 1 1992, 913–917; (b) Katritzky, A. R.; Huang, T.-B.; Voronkov, M. V. J. Org.
Chem. 2000, 65, 2246–2248.
12. (a) Vavríková, E.; Polanc, S.; Kocevar, M.; Horváti, K.; Bosze, S.; Stolaríková, I.;
Vávrová, K.; Vinsová, J. Eur. J. Med. Chem. 2011, 46, 4937–4945; (b) Jampilek, J.;
Reckova, Z.; Imramovsky, A.; Raich, I.; Vinsova, J.; Dohnal, J. Curr. Org. Chem.
2008, 12, 667–674; (c) Imramovsky, A.; Polanc, S.; Vinsova, J.; Kocevar, M.;
Jampilek, J.; Reckova, Z.; Kaustova, J. Bioorg. Med. Chem. 2007, 15, 2551–2559.
13. Compounds synthesized in this work have been deposited with the
Queensland Compound Library (Griffith University) and are available for
collaborative discovery projects.
(broad); 1H NMR (500 MHz, DMSO-d6)
d 13.64 (br s, 1H, HCl), 9.65 (d,
J = 13.5 Hz, 1H, amidine CH), 8.57 (s, 1H, 2-furyl-CH@N), 8.20 (d, J = 13.5 Hz,
1H, t-BuNH), 7.99 (s, 1H, 2-furyl), 7.25 (d, J = 3.2 Hz, 1H, 2-furyl), 6.74 (m, 1H,
2-furyl), 1.39 (s, 9H, t-Bu); 13C NMR (125 MHz, DMSO-d6) d 147.2, 146.9, 146.5,
142.4, 117.6, 112.3, 54.7, 28.1. HRMS m/z (M+H+) calcd for C10H16N3O
194.1288, found 194.1280. Compound 5nÁHCl—White solid, mp = 144–
146 °C. 1H NMR (500 MHz, DMSO-d6)
d 13.62 (br s, 1H, HCl), 9.57 (d,
J = 13.8 Hz, 1H, amidine CH), 8.58 (s, 1H, Ar-CH@N), 8.23 (d, J = 13.8 Hz, 1H,
t-BuNH), 7.71 (d, J = 7.9 Hz, 1H, Ar), 7.69 (s, 1H, Ar), 7.26 (d, J = 7.9 Hz, 1H, Ar),
2.29 (s, 6H), 1.42 (s, 9H, t-Bu); 13C NMR (125 MHz, DMSO-d6) d 153.5, 147.1,
140.3, 136.4, 129.6, 129.4, 129.0, 125.6, 54.7, 28.2, 19.0, 18.7. HRMS m/z
(M+H+) calcd for C14H22N3 232.1808, found 232.1806. Compound 5oÁHCl—
Beige solid, mp = 157-159 °C (dec). 1H NMR (500 MHz, DMSO-d6) d 13.79 (br s,
1H, HCl), 9.78 (d, J = 13.7 Hz, 1H, amidine CH), 8.64 (s, 1H, Ar-CH@N), 8.28 (d,
J = 13.7 Hz, 1H, t-BuNH), 8.15 (s, 1H, Ar), 7.89 (d, J = 7.6 Hz, 1H, Ar), 7.60 (m, 1H,
Ar), 7.54 (t, J = 7.8 Hz, 1H, Ar), 1.44 (s, 9H, t-Bu); 13C NMR (125 MHz, DMSO-d6)
d 151.8, 147.7, 134.2, 133.2, 130.8, 130.2, 127.3, 126.7, 54.9, 28.2; HRMS m/z
(M+H+) calcd for C12H17ClN3 238.1106, found 238.1105.
14. General procedure for the preparation of formamidrazones 5a–z:
A
magnetically stirred suspension (solution) of an aldehyde or ketone
thiosemicarbazone (1 mmol) in dry MeCN (15 mL) was treated with TMSCl
(1 mmol) and stirred for 10 min. Next the isocyanide (1.1 mmol) was added,
the reaction flask was purged with argon and the mixture stirred at rt until the
reaction was complete (3–16 h, as judged by the disappearance of the starting
material according to TLC analysis). Solid products that precipitated from the
reaction mixtures (5a, 5e, 5n–p, 5t, 5w) were filtered off, washed with Et2O,
and air-dried to provide analytically pure formamidrazone hydrochlorides. In
all other cases the mixture was diluted with EtOAc (50 mL), washed with satd
aq NaHCO3, dried over anhydrous MgSO4, filtered, and concentrated to provide
the crude product. The latter was purified by column chromatography on silica
gel using an appropriate gradient of EtOAc in hexanes or MeOH in CH2Cl2 to
provide analytically pure free base formamidrazones.
16. Davis, T. L.; Yelland, W. E. J. Am. Chem. Soc. 1937, 59, 1998–1999.
17. Saegusa, T.; Ito, Y.; Kobayashi, S.; Hirota, K.; Yoshioka, H. Tetrahedron Lett. 1966,
7, 6121–6124.
18. Saegusa, T.; Murase, I.; Ito, Y. Tetrahedron 1971, 27, 3795–3801.
19. Jacobsen, P. Acta Chem. Scand. B 1976, 30, 847–852.
20. 1H NMR monitoring of the reaction depicted in Scheme 3 (in CD3CN) revealed
that the signals corresponding to the starting thiosemicarbazone 4 broadened
on addition of TMSCl (indicating some degree of interaction between these
reagents), but remained unchanged for at least 1 h, until t-BuNC was added.
21. On completion of the reaction, the 1H NMR (500 MHz, CD3CN) spectral signal
15. Characterization data for representative formamidrazone hydrochlorides:
Compound 5aÁHCl—White solid, mp = 162–164 °C. 1H NMR (500 MHz, DMSO-
d6) d 13.25 (br s, 1H, HCl), 9.51 (d, J = 13.5 Hz, 1H, amidine CH), 8.49 (s, 1H, Ar-
CH@N), 8.19 (d, 1H, J = 13.5 Hz, t-BuNH), 7.92 (d, J = 8.0 Hz, 2H, 4-MeOC6H4),
7.05 (d, J = 8.0 Hz, 2H, 4-MeOC6H4), 3.84 (s, 3H, OMe), 1.42 (s, 9H, t-Bu); 13C
NMR (125 MHz, DMSO-d6) d 161.6, 152.9, 146.8, 129.9, 124.5, 113.8, 54.9, 54.5,
corresponding to the TMS group experienced a slight downfield shift
(0.37 ? 0.46 ppm) that was consistent with the conversion of TMSCl into the
thioisocyanatotrimethylsilane implicated in the proposed mechanism.
22. Acetonitrile is able to form a complex with TMSCl—see, for example: Olsson, L.;
Ottosson, C.-H.; Cremer, D. J. Am. Chem. Soc. 1995, 117, 7460–7479. which may
attenuate the Lewis acidity of the latter.