Acyl C→N migration in the thioureidomethylation of 2-(4-methylbenzoyl)cyclohexanone

Article abstract of DOI:10.1070/MC2004v014n01ABEH001866

The thioureidomethylation of the sodium enolate of 2-(4-methylbenzoyl) cyclohexanone 3 with N-(tosylmethyl)thiourea 1a or N-(azidomethyl)thiourea 2 in acetonitrile results in the unexpected formation of N-(4-methylbenzoyl)- N′-[(2-oxocyclohexyl)-methyl]th

Full text of DOI:10.1070/MC2004v014n01ABEH001866

Mendeleev Commun., 2004, 14(1), 31–33
Acyl C®N migration in the thioureidomethylation of
2-(4-methylbenzoyl)cyclohexanone
Anatoly D. Shutalev,*a Nadezhda E. Zhukhlistovab and Galina V. Gurskayac
a Department of Organic Chemistry, M. V. Lomonosov State Academy of Fine Chemical Technology, 117571 Moscow, Russian
Federation. Fax: +7 095 434 8711; e-mail: shutalev@orc.ru
b A. V. Shubnikov Institute of Crystallography, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 1011; e-mail: nez@ns.crys.ras.ru
c V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 095 135 1405; e-mail: gurskaya@genome.eimb.relarn.ru
DOI: 10.1070/MC2004v014n01ABEH001866
The thioureidomethylation of the sodium enolate of 2-(4-methylbenzoyl)cyclohexanone 3 with N-(tosylmethyl)thiourea 1a or
N-(azidomethyl)thiourea 2 in acetonitrile results in the unexpected formation of N-(4-methylbenzoyl)-N'-[(2-oxocyclohexyl)-
methyl]thiourea 6, which was structurally characterised by X-ray diffraction analysis.
Recently, we reported a convenient general synthesis of 5-acyl
and 5-alkoxycarbonyl substituted 4-hydroxyhexahydropyrimidine-
2-thiones from readily available N-(1-tosyl-1-alkyl)thioureas 1
(R = H, alkyl, aryl) or N-(azidomethyl)thiourea 2 (R = H) and
the enolates of acyclic 1,3-diketones and β -oxoesters, respec-
tively.1–3 In contrast, the reaction of 1 and 2 with the enolate of
a cyclic 1,3-diketone such as dimedone gave methylene-bis-
(dimedone) rather than the expected bicyclic pyrimidine-2-
thione.4 No other cyclic 1,3-dicarbonyl compounds, in particular,
those bearing an exocyclic carbonyl group (A), were studied in
this reaction. Based on our previous data, at least three different
reactions can occur in this case to give spiro heterocycles B,
fused heterocycles C and bis-alkylation products D (Scheme 1).
The preliminary structure of the product was determined by
1
IR and H and 13C NMR spectroscopy.¶ These data disagreed
with the expected structures of 4 and 5 containing a 4-hydroxy-
hexahydropyrimidine-2-thione moiety. The absence of this
moiety (see ref. 2,3) followed, in particular, from the character
of absorption at 1500–1700 cm–1 in the IR spectrum of the sub-
stance obtained. Furthermore, the signal of the proton of the
OH group was not observed at 5.80–6.10 ppm (see ref. 2,3) in
the 1H NMR spectrum in [2H6]DMSO.
Spectroscopic data and the results of elemental analysis were
consistent with the structures of two isomeric compounds,
N-acylthiourea 6 and 10-membered cyclic thioureide 7. However,
it was impossible to choose 6 or 7 unambiguously on the basis
of the data obtained. This choice in favour of N-(4-methyl-
benzoyl)-N'-[(2-oxocyclohexyl)methyl]thiourea 6 was made by
a single crystal X-ray diffraction study.††
R
Z
O
O
HN
NH2
O
M
R1
NH2
Figure 1 shows the X-ray structure of compound 6 and the
numbering of atoms. A characteristic feature of 6 is a planar
structure of its thioureidomethyl fragment connecting phenyl
and cyclohexane rings. The hydrogen atom of the N(1)–H
R
S
O
R1
HN
A
1, 2
S
†
Compound 1a was prepared by the reaction of N-(hydroxymethyl)-
A
thiourea6 with p-toluenesulfinic acid in water at 20 °C according to a
published procedure.5 Crude product 1a obtained in this reaction was
used without further purification. 1H NMR (Bruker DPX 300, 300.13 MHz,
[2H6]DMSO) d: 8.36 (unsolved br. t, 1H, NH), 7.77 (br. s, 1H, NH in
NH2), 7.70 (d, 2H, Carom, J 8.1 Hz), 7.43 (d, 2H, Carom, J 8.1 Hz), 7.16
(br. s, 1H, NH in NH2), 5.17 (br. d, 2H, CH2, J ~ 5 Hz), 2.40 (s, 3H,
Me). 13C NMR (Bruker DPX 300, 75.48 MHz, [2H6]DMSO) d: 183.97
(C=S), 144.54 [C(4) in Ts], 134.79 [C(1) in Ts], 129.75 [C(3) and C(5)
in Ts], 128.51 [C(2) and C(6) in Ts], 64.81 (CH2), 21.13 (Me). IR
(Shimadzu IR 435, Nujol, n/cm–1): 3392, 3291, 3180 (ν N–H), 3077,
3041 (ν Carom–H), 1608, 1548 [NH–C(S)–NH2], 1271 (ν as SO2), 1133
(ν s SO2), 802 (δ Carom–H).
R1
R
OH
R1
O
R
O
R
O
O
OH
R1
O
R1
HN
NH
HN
NH
O
D
S
S
B
C
1 Z = Ts, R = H, alkyl, aryl
2 Z = N3, R = H
R1 = alkyl, aryl; M = K, Na
Compound 2 was synthesised according to a modified method:2
a
mixture of N-(hydroxymethyl)thiourea6 (13.34 g, 125.7 mmol), NaN3
(13.89 g, 213.7 mmol) and water (40 ml) was cooled to –10 °C and
treated dropwise under stirring with a solution of conc. HCl (18.0 ml,
21.24 g, 209.7 mmol) in water (20 ml) for 10 min (all operations for the
synthesis of 2 should be carried out in a hood). The flask was closed with
a glass stopper, and the reaction mixture was stirred at room temperature
for 2 h. Then seed crystals of 2 were added to the solution obtained
(otherwise crystallization begins later). Immediately abundant white pre-
cipitate of 2 starts to separate out. The reaction mixture was additionally
stirred at room temperature for 4.5 h, allowed to stand at the same
temperature for 14 h, and cooled to +5 °C. The solid was collected by
filtration, washed with ice water and light petroleum and dried to afford
13.25 g (80.4%) of 2, which was used without further purification.
1H NMR (Bruker DPX 300, 300.13 MHz, [2H6]DMSO) d: 8.33 (br. s,
1H, NH), 7.62 (br. s, 2H, NH2), 4.89 (br. s, 2H, CH2). 13C NMR (Bruker
DPX 300, 75.48 MHz, [2H6]DMSO) d: 184.68 (C=S), 59.14 (CH2). IR
(Shimadzu IR 435, Nujol, n/cm–1): 3357, 3263, 3164, 3048 (ν NH),
2082 (ν N3), 1608, 1568 [NH–C(S)–NH2], 1348, 1273, 1221.
Scheme 1
Here, we report on the reactivity of N-(tosylmethyl)thiourea
1a (R = H)† and N-(azidomethyl)thiourea 2† towards the sodium
enolate of 2-(4-methylbenzoyl)cyclohexanone generated by the
treatment of corresponding CH acid 3 with one equivalent of
sodium hydride in dry acetonitrile (Scheme 2).
Using thin layer chromatography,‡ we found that the reaction
of 1a with an equimolar amount of the sodium enolate of 3 in
acetonitrile at room temperature results in the disappearance of
1a in a short time (~7 h). According to TLC, the reaction mix-
ture mainly consists of starting CH acid 3 and a new low polar
product. A mixture of these compounds in a 40:60 ratio (1H
NMR spectroscopy data) was isolated after the evaporation of
the solvent in a vacuum followed by the successive treatment
of the residue with light petroleum, a saturated aqueous NaHCO3
solution and chloroform. The resulting mixture was separated
by the extraction of CH acid 3 with boiling hexane.§
‡
TLC was performed on Silufol UV-254 silica gel plates using chloro-
form or chloroform–methanol (9:1, v/v) as an eluent; the plates were
visualised with iodine vapour.
– 31 –

Mendeleev Commun., 2004, 14(1), 31–33
group and the O(41) atom form a strong intramolecular hydro-
gen bond,‡‡ the geometrical parameters of which are shown in
Figure 1. The hydrogen atom of the N(1)–H group is located
(within the limits of 0.01 Å) in the plane of non-hydrogen
atoms of the acylthiourea moiety. As a result, the second flat
six-membered ring that includes the atoms O(41), C(4), N(3),
C(2) and N(1) and the hydrogen atom of the N(1)–H group is
C(45)
C(47)
C(46)
C(41)
O(41)
C(4)
C(44)
O(52)
C(43)
C(42)
N(3)
C(52)
N(1)
C(53)
§
Synthesis of 6: a 50 ml round-bottom flask fitted with a magnetic
C(54)
C(55)
C(5)
C(51)
C(56)
C(2)
stirring bar and calcium chloride drying tube was charged with NaH
(0.133 g, 5.55 mmol) and dry acetonitrile (10 ml). Compound 3 (1.202 g,
5.56 mmol) was added in one portion with stirring, and the resulting
mixture was stirred with protection from air moisture at room tempera-
ture up to the finishing of hydrogen evolution (about 2 h). To the resulting
suspension of sodium enolate of 3 was added thiourea 1a (1.358 g,
5.56 mmol) and dry acetonitrile (7 ml). The flask was sealed with a glass
stopper, and the reaction mixture was stirred at room temperature for
7 h. The solvent was removed under a reduced pressure, and the residue
was treated with light petroleum (6 ml) at room temperature for 1 h.
After decanting the light petroleum, a saturated aqueous solution of
NaHCO3 (3 ml) was added, and the gummy substance obtained was
rubbed up to complete solidification. The precipitate was filtered, washed
with cold water and light petroleum and dried. The solid obtained
(1.499 g) was treated with chloroform (30 ml); the solution was filtered
from an insoluble residue and vacuum evaporated to dryness. Then,
hexane (3 ml) was added; the precipitate was collected by filtration and
dried to give a mixture (0.838 g) of compounds 6 (33.7% according to
1H NMR spectroscopy data) and 3 (60:40). The mixture obtained was
extracted with boiling hexane (6×5 ml). The hexane solution contained
mainly CH acid 3, and the insoluble residue was pure compound 6
(0.398 g, 23.6%). Mp 110–111 °C (ethanol). Found (%): C, 63.63; H,
6.17; N, 8.87. Calc. for C16H20N2O2S (%): C, 63.13; H, 6.62; N, 9.20.
S
Figure 1 Molecular structure of compound 6 and the intramolecular
hydrogen bond N(1)–H···O(41). Parameters of the hydrogen bond: N(1)···
O(41) 2.673(2) Å, H(N1)···O(41) 2.00(2) Å, the angle N(1)–H···O(41) is
equal to 139(2)°.
simulated in the molecule of 6. A similar presence of an intra-
molecular hydrogen bond in the ureide fragment is observed in
the structure of N-benzoyl-N'-(5-phenyl-1,3,4-oxadiazol-2-yl)-
urea.8
Thus, the main direction of the reaction of N-(tosylmethyl)-
thiourea 1a with the sodium enolate of CH acid 3 in acetonitrile
is the formation of N-(4-methylbenzoyl)-N'-[(2-oxocyclohexyl)-
methyl]thiourea 6. The yield of isolated compound 6 on the
basis of reacted thiourea 1a was relatively low and in various
experiments did not exceed 24% (yield of crude 6 was about
34% according to 1H NMR spectroscopy data). Note that a
significant quantity of charged CH acid 3 (about 22%) did not
react and it was recovered after the treatment of reaction
mixtures. Apparently, it is caused by partial transformation of
nucleophilic sodium enolates of 3 in the loose CH acid under
the action of thioureide 6 with rather high NH acidity.§§
The reaction of N-(azidomethyl)thiourea 2 with 3 (NaH,
acetonitrile, 20 °C) provided analogous results. Thioureide 6 was
isolated in 14% yield as the principal product of the reaction.
The synthesis of 6 proceeds, apparently, through a stage
of the initial formation of thioureidomethylation product 8,
which predominantly undergoes cyclization into 1-hydroxy-1-
(4-methylphenyl)-3-thioxo-2,4-diazaspiro[5.5]undecane-7-one
4.¶¶ The latter spontaneously turns into thioureide 6 after
¶
1
Spectroscopic data for 6. H NMR (Bruker DPX 300, 300.13 MHz,
[2H6]DMSO) d: 11.17 (s, 1H, NH–C=O), 11.06 (br. t, 1H, NH–CH2,
3JNH,CH 5.3 Hz), 7.83 (d, 2H, C(2)H and C(6)H in 4-MeC6H4, J 7.8 Hz),
7.31 (d, 2H, C(3)H and C(5)H in 4-MeC6H4, J 7.8 Hz), 3.72 (t, 2H,
N–CH2, 3JCH,CH 6.2 Hz, 3JNH,CH 5.3 Hz), 2.86 (m, 1H, CH–C=O), 2.32–
2.53 (m, 1H, Hax in CH2–C=O, the signals partly overlapped with the
signals of Me protons and residual protons of the solvent), 2.37 (s, 3H,
2
Me), 2.18–2.29 (m, 1H, Heq in CH2–C=O, J 13.4 Hz), 1.94–2.12 and
1.32–1.86 (2m, 2H and 4H, respectively, CH2CH2CH2). 13C NMR
(Bruker DPX 300, 75.48 MHz, [2H6]DMSO) d: 211.89 (C=O), 180.24
(C=S), 167.89 (NH–C=O), 143.48 [C(4) in 4-MeC6H4], 129.27 [C(1) in
4-MeC6H4], 129.04 [C(2) and C(6) in 4-MeC6H4], 128.64 [C(3) and C(5)
in 4-MeC6H4], 48.73 (CH–C=O), 44.55 (CH2–N), 41.42 (CH2–C=O),
31.23 (CH2CHC=O), 27.22 (CH2CH2C=O), 24.16 (CH2CH2CH2C=O),
21.14 (Me). IR (FT-IR Bruker ‘Equinox 55/S’, KBr pellet, n/cm–1): 3251
(ν NH), 3049 (ν Carom–H), 1712 (ν C=O), 1672 (amide-I), 1612 (ν C=C),
1560, 1520, 1500 (amide-II, thioamide-II), 1257, 1163, 746.
O
Z
R
S
NaH
O
H N
NH
H N
NH
O
2
2
– NaZ
†† Crystal data. The triclinic single crystals of 6 belong to space group
P1, a = 10.787(2), b = 10.565(2), c = 8.273(2) Å, a = 106.09(1)°, b =
= 104.08(1)°, g = 101.66(1)°, V = 841.1(3) Å3, Z = 2, dcalc = 1.202 g cm–3;
C16H20N2O2S, M = 304.40. Intensities of 2786 independent reflections
were measured with a Syntex P21 four-circle diffractometer (CuKα
radiation, graphite monochromator, q/2q scanning technique, qmin = 4.41°,
R
O
S
1a, 2
3
8
1a Z = Ts
2 Z = N
3
O
q
max = 63.68°), 2521 reflections have I > 2s(I). The absorption correction
was introduced by the semiempirical method using a transmission curve.
The structure was solved by the direct method; non-hydrogen atoms
were refined by the full-matrix least-squares procedure in the anisotropic
approximation. The coordinates of all hydrogen atoms were located from
the difference electron-density maps and refined by the least-squares
procedure isotropically. The final value of the discrepancy factor R = 0.041
was calculated for 2521 reflections with I > 2s(I) (R = 0.044 for 2786
independent reflections). All calculations were performed using the
SHELX97 program.7
OH
R
NH
O
R
OH
HN
HN
NH
S
S
4
5
R = 4-MeC H
6
4
Atomic coordinates, bond lengths, bond angles and thermal param-
eters have been deposited at the Cambridge Crystallographic Data Centre
(CCDC). These data can be obtained free of charge via www.ccdc.cam.uk/
conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336 033; or deposit@ccdc.cam.ac.uk).
Any request to the CCDC for data should quote the full literature citation
and CCDC reference number 223321. For details, see ‘Notice to Authors’,
Mendeleev Commun., Issue 1, 2004.
O
R
O
O
H
HN
NH
HN
N
O
S
S
R
‡‡ According to 1H NMR spectroscopy data, this intramolecular hydrogen
bond also occurs in solutions of 6. Indeed, when turning from a solution
in CDCl3 to a solution in [2H6]DMSO the expected significant downfield
shift of NH protons in the NH–C=O fragment of 6 occurs (from d 8.91
to 11.17 ppm), while the chemical shift of NH protons in the NH–CH2
fragment does not change (d 11.06 ppm in both solvents).
6
7
Scheme 2
§§ For example, the five-membered cyclic thioureide 2-thiohydantoine
has pKa 8.51 (water, 25 °C) due to the deprotonation of the N(3)H
group.9
– 32 –

Mendeleev Commun., 2004, 14(1), 31–33
3
4
5
A. D. Shutalev and V. A. Kuksa, Khim. Geterotsikl. Soedin., 1997, 105
[Chem. Heterocycl. Compd. (Engl. Transl.), 1997, 33, 91].
A. D. Shutalev and E. A. Kishko, Khim. Geterotsikl. Soedin., 2000, 70
[Chem. Heterocycl. Compd. (Engl. Transl.), 2000, 36, 62].
A. D. Shutalev, E. A. Kishko, N. V. Sivova and A. Yu. Kuznetsov,
Molecules, 1998, 3, 100.
H. Staudinger and K. Wagner, Makromol. Chem., 1954, 12, 168.
G. M. Sheldrick, SHELX97. Program for the Solution and Refinement
of the Crystal Structures, University of Göttingen, Germany, 1997.
Li Zhong, Zhu Zhixiang, Song Gonghua, Qian Xuhong and Sun Jie,
J. Chem. Research (S), 1999, 66.
cleaving the C(1)–C(6) bond of the hexahydropyrimidine ring
under the reaction conditions. Thus, the transformation 8 ® 6
can be considered as the C®N migration of the 4-methyl-
benzoyl group.†††
This study was supported in part by a President grant for
leading scientific schools (no. 1781.2003.4).
6
7
8
References
1
A. D. Shutalev and V. A. Kuksa, Khim. Geterotsikl. Soedin., 1993,
1698 [Chem. Heterocycl. Compd. (Engl. Transl.), 1993, 29, 1470].
A. D. Shutalev and V. A. Kuksa, Khim. Geterotsikl. Soedin., 1995, 97
[Chem. Heterocycl. Compd. (Engl. Transl.), 1995, 31, 86].
9
M. J. Blais, O. Enea and G. Berthon, Thermochim. Acta, 1977, 20, 335.
10 A. D. Shutalev, E. A. Kishko and S. G. Alekseeva, Khim. Geterotsikl.
Soedin., 1999, 839 [Chem. Heterocycl. Compd. (Engl. Transl.), 1999,
35, 750].
2
¶¶ This preferable direction of heterocyclization is unexpected because of
a well-known fact of greater reactivity of aliphatic ketones in comparison
with aromatic ones in reactions with nucleophiles. Recently, we found2
that the reaction of 1a, 2 with benzoylacetone (NaH, acetonitrile, 20 °C)
results in the exclusive formation of 5-benzoyl-4-hydroxy-4-methyl-
hexahydropyrimidine-2-thione, which is a heterocyclization product
with the participation of an acetyl group rather than a benzoyl group in
the initial product of benzoylacetone thioureidomethylation.
††† Earlier, an analogous base-catalysed transformation was found in the
series of 5-acyl-4-hydroxyhexahydropyrimidine-2-thiones.10
Received: 21st November 2003; Com. 03/2192
– 33 –