Enols and thioenols of substituted cyanomonothiocarbonylmalonamides: Structures, enolization vs. thioenolization, equilibria and conformations

Article abstract of DOI:10.1039/b717556f

Condensation of organic isothiocyanates with cyanoacetamides gave 24 N- and N′-substituted cyanomonothiocarbonylmalonamides in different tautomeric ratios i.e., amide-thioamides (TMA) R³NHCSCH(CN)CONR ¹R² (12), thioamide-enols of amides (E) R ³NHCSC(CN)=C(OH)NR¹R² (11) or amide-thioenols (TE) R³NHC(SH)=C(CN)CONR¹R² (13). The equilibrium constants (K_thioenol = [TE]/[TMA] and K_enol = [E]/[TMA]) in solution depend on R¹, R², R³ and the solvent. The %(E + TE) for NR¹R² increases in the order NMe₂ < NHMe < NH₂. The (K_thioenol + K_enol) in various solvents follows the order CCl₄ > CDCl₃ > C₆D₆ > THF-d₈ > (CD₃)₂CO > CD₃CN > DMF-d₇ > DMSO-d₆. The δ(OH) values are 16.46-17.43 and the δ(SH) values are 3.87-5.26 ppm in non polar solvents, e.g., CDCl₃ and 6.34-6.97 ppm in THF-d₈ and CD₃CN. An intramolecular O-H...O hydrogen bond leads to the preferred Z-configuration of the enols, and an N-H...O bond stabilizes the thioenols' preferred E-configuration with a non-bonded SH in solution. X-Ray crystallography revealed that systems with high %(E + TE) in solution mostly display the enols 11 in the solid state and systems with lower %(E + TE) in solution display structure 12. The differences in δ(OH), δ(NH), K_enol and crystallographic data for analogous enol and thioenol systems are compared.

Full text of DOI:10.1039/b717556f

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Enols and thioenols of substituted cyanomonothiocarbonylmalonamides:
structures, enolization vs. thioenolization, equilibria and conformations†‡§
Ahmad Basheer and Zvi Rappoport*
Received 13th November 2007, Accepted 18th January 2008
First published as an Advance Article on the web 14th February 2008
DOI: 10.1039/b717556f
Condensation of organic isothiocyanates with cyanoacetamides gave 24 N- and Nꢀ-substituted
cyanomonothiocarbonylmalonamides in different tautomeric ratios i.e., amide–thioamides (TMA)
3
1
2
3
1
2
=
R NHCSCH(CN)CONR R (12), thioamide–enols of amides (E) R NHCSC(CN) C(OH)NR R (11)
3
1
2
=
or amide–thioenols (TE) R NHC(SH) C(CN)CONR R (13). The equilibrium constants (Kthioenol
=
[TE]/[TMA] and Kenol = [E]/[TMA]) in solution depend on R1, R2, R3 and the solvent. The %(E + TE)
for NR1R2 increases in the order NMe2 < NHMe < NH2. The (Kthioenol + Kenol) in various solvents
follows the order CCl4 > CDCl3 > C6D6 > THF-d8 > (CD3)2CO > CD3CN > DMF-d7 > DMSO-d6.
The d(OH) values are 16.46–17.43 and the d(SH) values are 3.87–5.26 ppm in non polar solvents, e.g.,
CDCl3 and 6.34–6.97 ppm in THF-d8 and CD3CN. An intramolecular O–H · · · O hydrogen bond leads
to the preferred Z-configuration of the enols, and an N–H · · · O bond stabilizes the thioenols’ preferred
E-configuration with a non-bonded SH in solution. X-Ray crystallography revealed that systems with
high %(E + TE) in solution mostly display the enols 11 in the solid state and systems with lower %(E +
TE) in solution display structure 12. The differences in d(OH), d(NH), Kenol and crystallographic data
for analogous enol and thioenol systems are compared.
the enol when Y,Yꢀ are not electron-withdrawing groups (EWGs).
Consequently, the acid derivative is much more stabilized than
the enol with a drastic reduction in Kenol compared with those for
simple carbonyl derivatives.6
Our approach to stabilized enols of carboxylic acid derivatives
is by increased stabilization of structure 1b by substituting Cb with
resonatively negative charge EWGs Y and Yꢀ.3,4 The stabilized 1b
is zwitterionic with delocalized positive charge on Ca, X and OH
and negative charge on Cb, Y and Yꢀ. This implies a relatively
long Ca–Cb formal double bond with a significant single bond
character. The acid derivatives are presumably also destabilized
by Y,Yꢀ/CO dipole–dipole repulsion.3b
Introduction
Enols and keto–enol equilibria for mono-carbonyl and 1,3-
dicarbonyl compounds have been extensively investigated over
the last hundred years.1 In contrast, enols of carboxylic acids,
their esters, anhydrides, amides, thioamides or halides have been
scarcely investigated until recently.2 In the last decade we have
extensively investigated these species,3,4 especially the enols of
amides,3a–c,4 which are usually unobservable, i.e., the equilibrium
constant Kenol = [enol]/[amide] is <0.01. The computed Kenol for
acetamide is 10−21.6.5 The reason for this is that mesomeric electron
donation by X stabilizes the acid derivative 2a via contributing
structure 2b which is favored by the negative charge on its oxygen
atom (eqn (1)).
By applying this approach we observed by NMR spectroscopy
ꢀ
=
>100 enols of amides YY C C(OH)NHX (4) either exclusively
or as mixtures with the isomeric amides YꢀYCHCONHX (3) in
solution, and determined the solid structures of >25 enols by X-
ray crystallography. Combinations of Y,Yꢀ for which only the enol
is observed in CDCl3 (Kenol ≥ 50) include amides where YꢀY is
the cyclic diester Meldrum’s acid (MA) moiety,3a Y = CN, Yꢀ =
(1)
CO2R, R = CH3 or CH2CCl3,4d or Y = CO2CH(CF3)2, Yꢀ =
3b
CO2CH2CF3. The Kenol value is low when Y = Yꢀ = CO2Me.3a
A problem is that Y or Yꢀ can serve as an enolization site.
Although ester groups do not compete with an amide, a ketonic
CO at Cb, e.g., in PhNHCOCH(COMe)CO2Et (5),3b serves as an
enolization site. Substituted 2-amidoindandiones can form enol
isomers on both the amide and the ring CO.7
A similar electron donation by X and OH to Ca of the enol
1a creates a negative charge on Cb, which only slightly stabilizes
Department of Organic Chemistry and the Lise Meitner Minerva Center
for Computational Quantum Chemistry, The Hebrew University, Jerusalem
91904, Israel. E-mail: ZR@vms.huji.ac.il
Cyanomalonamides display in solution both the amide 6 and
one of the enols 7or 8 (eqn (2)). The enolic hydrogen forms a strong
intramolecular hydrogen bond to the carbonyl of the second amide
group and apparently migrates rapidly between the two oxygens.8
The Kenol and dH (OH) values in moderate and polar solvents are
relatively high.
† Presented in part in the 11th Kyushu International Symposium on
Physical Organic Chemistry (KISPOC XI), Fukuoka, September 12–15,
2005
‡ CCDC reference numbers 667545–667551. For crystallographic data in
CIF or other electronic format see DOI: 10.1039/b717556f
§ Electronic supplementary information (ESI) available: Tables S1–S6
(spectral and analytical data). See DOI: 10.1039/b717556f
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Kenol = [E]/[TMA], Kthioenol = [TE]/[TMA],
Ktotal = ([E] + [TE])/[TMA]
In the present work we replaced one carbonyl group in 6
by a thiocarbonyl group, obtaining cyanomonothiocarbonyl-
malonamides R3NHCSCH(CN)CONR1R2, in order to investigate
the following goals: (i) to extend the scope of stable enols of
amides with a b-thioamido group; (ii) to study the intramolecular
competition between amide and thioamide enolization sites as a
function of R1–R3; (iii) to probe the role of hydrogen bonding on
the configuration and conformation of the enols and thioenols;
(iv) to determine the solid state structure of these species, and
whether it is the same as in solution.
(4)
Solid state structures
Solid state structures of eight systems were determined by X-ray
diffraction.‡ Four of them display the enol structures 11h–11k. 11h
and 11i were crystallized from EtOAc and 11j was crystallized from
EtOAc under nitrogen. Fig. 1a displays the ORTEP drawing of 11j
which shows both intramolecular O–H · · · S and intermolecular
CN · · · H–N hydrogen bonds. The four derivatives 12d (Fig. 1b),
12f, 12k, 12v display amide structures. 12d, 12f and 12v were
crystallized from CDCl3.
Table 1 gives selected crystallographic data for enols 11h–11j.
Data for 11k, which was crystallized from CDCl3, was reported
earlier.10c The differences between the relevant parameters for the
four compounds are small, considering the standard deviations.
Results
Synthesis
The 24 “formal”9 cyanomonothiocarbonylmalonamides 11/
12/13 (a–x) were prepared by reacting the anion of a substituted
cyanoacetamide (9) with an organic isothiocyanate (10) (eqn
(3)). The products are the amide–thioamide (TMA, 12), the
enol (E, 11) and/or the thioenol (TE, 13), or a mixture. Three
equilibrium constants are defined: Kenol, Kthioenol and Ktotal (eqn (4)).
Compounds, 12e,10a 12h,10b 12k,10c 11k,10c 11o,10d 11p10e,f and 12r11
were prepared previously. The stereochemistries of 11 and 13 are
discussed below. Compounds 11/12/13 are much more reactive
than 6/7/8. Several of them react on crystallization in a variety of
ways, mostly to give heterocyclic compounds.11
˚
The C(1)–O(1) bond lengths of 1.301–1.307 A, the C(2)–C(4) bond
˚
˚
of 1.402–1.417 A, the small difference of ≤ 0.011 A between the
bond lengths of C(1)–C(2) and C(2)–C(3) for the three compounds,
˚
=
and the doubly bonded C S moiety (1.687–1.700 A), indicate a
highly delocalized enol structure. The variable O–H bond length
˚
of 0.98–1.18 A is in line with the difficulty in locating hydrogens
by X-ray diffraction. The O · · · S non-bonding distance of 2.836–
˚
=
2.865 A, and the non-linear C S · · · H–O hydrogen bond of
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System 11k/12k/13k, R3 = Me was crystallized either as the
amide 12k or as the enol 11k, depending on the solvent polarity.10c
Structures in solution. NMR spectra and Kenol values in solution
1H and 13C NMR spectra were recorded for 11/12/13 in several
solvents. Selected 1H spectral parameters are given in Table 3 and
the complete data are in Table S1. The 13C NMR data are in Table
S2 in the supplementary data.§
On dissolving a sample of the X-ray analyzed crystals of either
11 or 12 or the formal9 TMA, the substituent- and solvent-
dependent spectra of the tautomeric system 11 (E)/12 (TMA)/13
(TE) were instantaneously observed. The composition did not
change with time, i.e., equilibria between the various species is
rapidly established, as found for other enols of amides.3,4
Both the E and TE species can a priori exist in both E and
Z configurations. For the analogous 7/8 only the isomer whose
enolic OH is intramolecularly hydrogen bonded to the cis amido
carbonyl is usually observed.8 The linear CN cannot form an
intramolecular CN · · · H–O hydrogen bond and the isomer with
the cis-CN/OH configuration is not observed.
For all enols 11 the d(OH) signals at >16 ppm in CDCl3 indicate
the presence of hydrogen bonding. Most derivatives (except for
NR1R2 = NMe2, R3 = Alk) also showed a relatively high field
singlet at ca. 3.9–7.0 ppm ascribed to a non-hydrogen bonded SH
group of 13.
Fig. 1 ORTEP drawing of (a) 11j and (b) 12d (thermal ellipsoids scaled
to include 50% probability).
Fig. 2a displays the low field region of a CDCl3 solution of
formal9 t-BuNHCSCH(CN)CONHMe 12n. The lowest field very
narrow doublet at d 16.88 is ascribed to the hydrogen bonded
OH signal of 11, by analogy with many systems.3,4 There are two
relatively sharp NH signals for each species, with reliable position
and integration for assignment and for determination of the Kenol
values; e.g., the signals at d 6.55 and 6.05 with 99% intensities of
the d(OH) are the NH signals of 11. The NH signals at d 11.61 and
5.81 with 40 1% intensity of d(OH), are ascribed to 13. Its SH
signal almost overlaps the amide CH signal at d 4.79. The signals
of 12 at d 8.75 and 7.05 have 81% intensity of d(OH).
˚
1.70–1.93 A indicate a weaker hydrogen bond than the O · · · H–
O bond in enols 7/8.8 Bond angles around the C(1)–C(2) bond
are 120
5◦ (Table 1), and their sum of 359.8–360.0◦ indicate
planarity around C(2). The structures are dimeric: one cyano
nitrogen in each molecule is intermolecularly hydrogen bonded
to the amide H–N–CO of a second molecule. These bonds cause
˚
1
a C(4)–N(2) bond elongation from 1.136–1.137 A for the Csp ≡N
bond12 to 1.148–1.151 A. The non-bonding N · · · N (N belongs
to a second molecule) and H · · · N# distances, the N–H bond
lengths and the N(1)–H · · · N(2)# angles indicate an asymmetric
and bent intermolecular hydrogen bond.
#
#
˚
1
The H NMR spectrum in DMSO-d6 displays only the CH,
CSNH and CONH signals of 12n at d 5.13, 8.00 and 9.77 ppm,
respectively (Fig. 2b). In the 13C NMR spectrum in CDCl3
(Fig. 2c), three pairs of signals appear in the high ppm region:
Fig. 1b, Table 2 and the ESI§ give structural data for the amides
=
12d, 12f and 12v and of the “amide” part of 12r (see below; those
at ca. d 185 for the C S groups of 11n and 12n, at d 172 and 168
of 12k was reported earlier10c), with normal bond lengths: C O
for Ca of the 11n and 13n, and at d 162 and 164 for the C O signals
=
=
˚
˚
˚
=
1.228–1.236 A, C S 1.646–1.659 A, C≡N 1.129–1.137 A and
of 13n and 12n. The coupled Cb signals are singlets at 66.7 (11n)
and 70.7 (13n) ppm and a doublet at 56.1 ppm for 12n. Simpler
1H NMR spectra are observed for systems 11a–g/12a–g/13a–g,
having only three NH signals; e.g., for 11c/12c/13c the d(NH)
values resemble those observed in Fig. 2a. The separated CH and
SH signals are at 5.49 and 4.50 ppm, respectively.
◦
˚
C(1)–C(2) 1.535–1.543 A. The 107.6–113.6 angles around C2
indicate an sp3 carbon. The structures are “polymeric” where the
=
C O carbonyl is intermolecularly hydrogen bonded to the H–N–
=
C S of another molecule.
Crystallization of 12r from CD3CN gave an associate with
an “apparent” amide structure 12r intermolecularly hydrogen
bonded via one water molecule to 3,5-bis(isopropylamino)-
[1,2]dithiolane-4-carbonitrile (Fig. 1 in ref. 11). The C(1)–C(2),
C(2)–C(3) and C(2)–C(4) bonds of 12r are shorter, and the C(1)–
O(1), C(3)–N(3) and C(4)–N(2) bonds are longer, than those of
The d(OH), d(SH) and d(CH) for selected R3NHCSCH(CN)-
CONR1R2 systems in several solvents where all three species are
observed are given in Table 3. In all the solvents and for all R’s
d(OH) is at 16.46–17.43, d(SH) is at 3.87–6.97 and d(CH) is at
4.09–5.79. Changes due to combinations of R1, R2 and R3 are not
systematic. The highest d(OH) and d(SH) values are in THF-d8 or
C6D6, for each group.
=
the other amides (Table 2). The H–N–C S is intramolecularly
=
hydrogen bonded to the C O group with an N–H bond length
˚
˚
=
=
and O · · · H and O · · · N distances of 0.82(2) A, 2.01(2) A and
In the dC values of the C S, C O, Ca(11), Ca(13), C≡N and
Cb signals for the three isomers of all systems soluble in CDCl3
(Table S3 in the ESI§), each isomer displays pairs of low field
◦
˚
2.667(2) A, respectively, and an OHN angle of 137.7(17) . It was
suggested that the species is a radical derived from 12r.11
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3
1
2
3
=
Table 1 Selected crystallographic data (bond lengths, hydrogen bond distances and angles) for the enols R NHCSC(CN) C(OH)NR R 11h–11j, (R =
Ph, p-An(p-MeOC6H4), 1-Np) at room temperaturea
Compound
11h (R3 = Ph)b
11i (R3 = p-An)
11j (R3 = 1-Np)
˚
Bond length/A
C(1)–C(2)
C(1)–N(1)
C(1)–O(1)
C(2)–C(3)
C(3)–N(3)
C(3)–S(1)
C(2)–C(4)
C(4)–N(2)
1.426(2), 1.425(2)
1.318(2), 1.317(2)
1.301(2), 1.302(2)
1.427(2), 1.427(2)
1.352(2), 1.345(2)
1.693(1), 1.700(1)
1.415(2), 1.414(2)
1.151(2), 1.149(2)
1.06(3), 1.05(3)
1.424(5)
1.314(4)
1.301(4)
1.427(4)
1.346(4)
1.687(3)
1.402(5)
1.151(4)
1.18(5)
1.412(3)
1.319(3)
1.307(2)
1.423(3)
1.344(3)
1.694(2)
1.417(3)
1.148(3)
0.98(3)
O(1)–H(O1)
S(1) · · · H(O1)
1.85(3), 1.84(3)
2.857(1), 2.849(1)
0.82(2), 0.77(2)
1.70(5)
2.836(3)
0.83(3)
1.93(3)
2.865(2)
0.87(2)
O(1) · · · S(1)
N(1)–H(N1)
N(3)–H(N3)
0.75(2), 0.76(2)
2.23(2), 2.30(2)
2.999(2), 2.975(2)
0.83(4)
0.78(2)
N(2) · · · H(N1)c
N(1) · · · N(2)c
Bond angle/◦
O(1)–C(1)–C(2)
O(1)–C(1)–N(1)
N(1)–C(1)–C(2)
C(1)–C(2)–C(3)
C(1)–C(2)–C(4)
C(4)–C(2)–C(3)
C(2)–C(3)–S(1)
N(3)–C(3)–S(1)
C(2)–C(3)–N(3)
C(2)–C(4)–N(2)
C(1)–O(1)–H(O1)
O(1)–H · · · S(1)
N(1)–H(N1) · · · N(2)c
2.23(4)#1
2.976(5)#1
2.14(2)#2
2.947(3)#2
122.7(1), 123.0(1)
115.3(1), 115.3(1)
122.0(1), 121.7(1)
124.9(1), 125.1(1)
116.1(1), 116.3(1)
118.9(1), 118.6(1)
123.7(1), 122.9(1)
120.5(1), 120.3(1)
115.8(1), 116.7(1)
178.5(2), 179.3(2)
108(2), 104(2)
122.5(3)
115.4(3)
122.2(3)
124.9(3)
116.0(3)
119.0(3)
123.1(3)
119.8(3)
117.1(3)
179.3(5)
104(2)
122.9(2)
115.3(2)
121.8(2)
125.1(2)
116.7(2)
118.0(2)
124.2(2)
119.2(2)
116.7(2)
178.4(3)
107(2)
156(2), 160(2)
150(2), 151(2)
161(3)
158(2)
151(3)#1
153(2)#2
a Measured at 173(1) K. b Two independent molecules. c Symmetry transformations used to generate equivalent atoms: #1, −x + 2, −y + 1, −z + 1; #2, −x,
−y + 1, −z + 1.
Table 2 Selected crystallographic data for the amides R3NHCSCH(CN)CONR1R2 [12d, 12f, 12v, 12r (associated with a heterocycle)] at room
temperaturea
Compound
12d (R3 = Me)
12f (R3 = i-Pr)
12v (R3 = i-Pr)
12r (R3 = i-Pr)
˚
Bond length/A
C(1)–C(2)
C(1)–N(1)
C(1)–O(1)
C(2)–C(3)
C(3)–N(3)
C(3)–S(1)
C(2)–C(4)
C(4)–N(2)
1.535(6)
1.315(5)
1.236(5)
1.540(5)
1.308(5)
1.646(4)
1.456(7)
1.129(6)
0.98
1.542(2)
1.310(2)
1.229(2)
1.544(2)
1.315(2)
1.659(1)
1.467(2)
1.137(2)
0.98
1.543(6)
1.333(6)
1.228(5)
1.524(6)
1.300(7)
1.646(5)
1.460(7)
1.133(6)
0.98
1.447(2)
1.340(2)
1.253(2)
1.425(2)
1.333(2)
1.713(2)
1.418(2)
1.149(2)
—
C(2)–H(C2)
N(3)–H(N3)
H(N3) · · · O(1)b
N(3) · · · O(1)b
Bond angle/◦
O(1)–C(1)–C(2)
O(1)–C(1)–N(1)
N(1)–C(1)–C(2)
C(1)–C(2)–C(3)
C(1)–C(2)–C(4)
C(4)–C(2)–C(3)
C(2)–C(3)–S(1)
N(3)–C(3)–S(1)
C(2)–C(3)–N(3)
C(2)–C(4)–N(2)
N(3)–H(N3) · · · (O1)b
0.81(5)
0.82(2)
0.65(5)
0.82(2)
2.01(2)c
2.667(2)c
2.07(5)#1
2.871(5)#1
2.15(2)#2
2.910(2)#2
2.45(5)#3
3.064(5)#3
118.8(4)
123.9(4)
117.3(4)
111.6(3)
109.9(4)
109.5(3)
121.0(3)
124.4(3)
114.6(4)
176.1(5)
172(5)#1
119.7(1)
122.7(1)
117.6(1)
112.3(1)
108.2(1)
107.7(1)
119.06(9)
126.9(1)
114.05(1)
177.7(2)
154(2)#2
122.6(5)
124.2(5)
112.9(4)
107.6(4)
110.2(4)
113.6(4)
120.8(4)
125.8(4)
113.1(4)
175.8(5)
158(7)#3
122.4(2)
119.0(2)
118.6(2)
124.9(1)
116.6(1)
118.5(1)
120.5(1)
121.4(1)
118.1(1)
174.9(2)
138(2)c
a Measured at 173(1) K. b Symmetry transformations used to generate equivalent atoms: #1 x − 1, −y + 1/2, z − 1/2; #2 x, −y + 1/2, z + 1/2; #3 x, −y +
2, z + 1/2. c The N–H is intramolecularly hydrogen bonded to oxygen O(1).
1074 | Org. Biomol. Chem., 2008, 6, 1071–1082
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=
C O and Ca signals of 13 are at 164.80–169.38 ppm (13k at
173.26 ppm). The C≡N signals are doublets (J = 9.5–11.0 Hz)
at 113.85–114.64 ppm for 12 and at 117.93–120.04 ppm for 11,
and are singlets at 120.21–121.78 ppm for 13. The coupled Cb
signals are doublets at 50.15–58.65 ppm (J = 139.2–143.2 Hz) for
12, and the Cb signals are singlets for 11 and 13 at 65.93–68.09 and
69.82–73.04 ppm, respectively.
Substituent and solvent effects
The substituents R1–R3 have an effect on the distribution of
the three species, and the derived Kenol for R1R2NCOCH-
(CN)CSNHR3 in different solvents at rt is given in Table 4.
For NMe2 systems the %(12) in CDCl3 is much higher for the
aliphatic R3 = Alk, when 13 is not observed, than when R3 = Ph,
p-An, 1-Np, where 13 is present in 16–29%. When R3 = Ph, p-An,
%(11) > %(13), whereas the %(11 + 13) is higher when R3 = 1-
Np, but the %(13) slightly exceeds the %(11). A similar trend was
observed for other NR1R2 systems (Table 4). The effects of R1–R3
on the % and the K’s of the various species are shown in Table 4.
The %(11 + 13) increases by successively replacing the Me groups
in NR1R2 by hydrogens, as was observed for the 7/8/9 system and
in calculations.8 Thus, for R3 = Alk, the %(12) is 88–96%, 22–37%
and 7–24% for NR1R2 = NMe2, NHMe and NH2, respectively,
and a similar trend was found for R3 = Ar. Systematically, Kenol
>
Kthioenol for R3 = Alk, Ph. In both CDCl3 and THF-d8, 12 is the
major species for the NMe2 derivative, a minor component for
NHMe and is absent for the NH2 derivative. For the NHMe and
NH2 derivatives 11h/12h/13h and 11o/12o/13o, the %(13)/%(11)
in CDCl3 is ca. 1.1 and 1.5, respectively. However, in THF-d8
K
enol/Kthioenol = 11 for NHMe, and 49 for NH2 when R3 = Ph. For
11h–n/12h–n/13h–n, the %(11) decreased on increasing the bulk
of R3: Me (71) > Et (68) ≈ i-Pr (66) > t-Bu (45) ≈ Ph (46) > p-An
(43) > 1-Np (31). The %(12) and %(13) increase on increasing the
steric effect according to t-Bu > i-Pr ≈ Et > Me (Table 4).
The percentage of enolization and thioenolization decreases on
increasing the solvent polarity from CCl4 to DMSO-d6 (Table 4),
as found earlier for enols of amides.3,4,8 In the highly polar DMSO-
d6 and DMF-d7, and also for several systems in CD3CN, only 12 is
observed. The highest %(13) for all systems is in CDCl3. In CDCl3
and CCl4, Kthioenol resembles or is higher than Kenol for aromatic
R’s. In the other solvents Kenol > Kthioenol
.
Discussion
Comparison of the solid state structures of 6/7/8 and 11/12/13
The X-ray solid state structures of three analogous pairs of the
=
two series can be compared: (i) i-PrNH(C Z)CH(CN)CONMe2
(I), in which Z = O, S have amide structures with small bond
˚
Fig. 2 1H NMR spectra for the 11n/12n/13n system: (a) OH, NH, CH
and SH regions (inset Me and t-Bu signals) in CDCl3 at rt; (b) in DMSO-d6
at rt. Only 12n is observed, and no signals are at <10 ppm. (c) 13C NMR
spectrum in CDCl3 at rt.
length differences (DOS = 0.003–0.0096 A) between Z = O and
Z = S. For I in CDCl3, Z = O is 80% enol and Z = S is 12% enol;
=
(ii) PhNH(C Z)CH(CN)CONHMe (II), in which Z = O displays
=
an amide structure, whereas for Z S it crystallized as an enol,
although in CDCl3 the %(enol) is 90% (Z = O) and 46% (Z = S);
=
=
=
signals with similar intensities. For 12 the C S and C O signals
are at 183.16–187.67 ppm and 158.78–162.37 ppm, respectively;
(iii) p-AnNH(C Z)CH(CN)CONHMe (III), in which Z = O, S
are both enols, with small bond length differences (DOS = 0.004–
˚
˚
=
for 11 the C S and Ca(E) are at 184.75–189.88 ppm and 170.41–
0.03 A). The C(1)–C(2) bond lengths of 1.401 A for Z = O and
˚
=
=
173.26 ppm, respectively. Mostly, d(C S, 11) > d(C S, 12). The
1.422 A for Z = S indicate a lower single bond character for the
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Table 3 Selected 1H NMR d values (in ppm) for 11/12/13 systems in several solvents at room temperature
Compound
R3
Solvent
d(OH) (E, 11)
d(CH) (TMA, 12)
d(SH) (TE, 13)
11a/12a/13a
11b/12b/13b
11c/12c/13c
Ph
p-An
1-Np
CDCl3
CDCl3
CCl4
CDCl3
C6D6
16.64
16.61
16.56
16.64
17.29
16.89
16.52
16.85
17.09
16.85
16.85
17.12
16.86
16.83
17.11
16.79
16.59
16.64
16.68
16.57
16.88
17.43
16.61
16.46
16.66
17.02
16.82
17.11
16.64
16.94
17.09
17.31
5.33
5.33
5.01
5.49
5.09
5.79
5.65
5.05
5.03
5.05
4.94
5.01
4.58
4.53
4.29
4.50
4.27
5.17
5.11
4.45
6.89
6.80
4.36
4.85
4.55
4.34
6.97
6.34
4.55
4.54
5.84
4.47
4.79
5.44
4.47
5.22
4.88
3.87
4.70
6.35
5.26
4.63
4.83
4.90
THF-d8
CD3CN
CDCl3
THF-d8
CD3CN
CDCl3
THF-d8
CD3CN
CDCl3
THF-d8
CD3CN
CDCl3
CDCl3
CDCl3
CCl4
CDCl3
C6D6
CDCl3
CDCl3
CDCl3
C6D6
11h/12h/13h
11i/12i/13i
11j/12j/13j
Ph
p-An
1-Np
5.01
a
5.30
5.36
4.88
4.87
4.85
4.21
4.79
11k/12k/13k
11l/12l/13l
11m/12m/13m
11n/12n/13n
Me
Et
i-Pr
t-Bu
4.09
a
11o/12o/13o
11r/12r/13r
11s/12s/13s
Ph
i-Pr
t-Bu
4.68
4.75
4.29
5.17
5.04
4.83
4.81
4.79
4.86
11t/12t/13t
Ph
CDCl3
THF-d8
CDCl3
CDCl3
CDCl3
CDCl3
11u/12u/13u
11v/12v/13v
11w/12w/13w
11x/12x/13x
i-Pr
i-Pr
t-Bu
t-Bu
a The CH or other signals of the TMA were not observed.
latter. For III in CDCl3, Z = O is 90% enol, and Z = S is 43% enol.
We conclude that there is no correlation between the %(enol) in
solution and the structure of the crystallized species. The data are
reported in Table S4 in the ESI.§
are for saturated systems, and for triarylethenols the O–H BDE
is ca. 80 kcal mol−1.19 Extensive calculations17 for the CH3CH X
=
systems (X = S, O) show that thioenolization (DH = −5.5–8 kcal
mol−1) is always favored over enolization (DH = 5–17 kcal mol−1).
−1
=
For (CH3)2C X, the D(DH) value is 8.8 kcal mol at B3LYP/6–
31G**. In less extensive calculations D(DH) = 8–11 kcal mol−1.20
=
=
Enolization on C O vs. thioenolization on C S
These large differences do not apply for intramolecular compet-
=
=
itive enolization in an O C–CH–C S system. Our systems are
A main theme of this work is the intramolecular competition
=
=
the first where such competition involves C O and C S sites of
=
=
between enolization on C O and thioenolization on C S. Both
processes have been previously compared in terms of both
intermolecular and intramolecular competition as shown below.
For single enolization sites thioenolization is qualitatively much
more facile than enolization. Simple thioenols are observable
species13 but the corresponding enols are usually unobservable.6
Recent measurements illustrate this point: Kthioenol/Kenol = ≥106,
amides and thioamides. A competitive intermolecular enolization
on esters strongly favors the C S site.
thioxoketones R C( O)CHRC( S)R (R , R = Alk, Ar), the
situation is more complex. The many techniques used to determine
whether enolization or thioenolization is preferred gave different
answers.22 Complications arise from the simultaneous presence of
15,21
=
However, for 1,3-
ꢀ
ꢀꢀ
ꢀ
ꢀꢀ
22
=
=
4
6
5
14
=
thioxoketone, cis (with an O–H · · · S C hydrogen bond) and trans
=
ca. 10 , 10 and 10 when X = S, O for Ph2CHC( X)Ph, 9-
15
16a
=
enols, and cis (with a S–H · · · O C hydrogen bond) and trans
=
=
C( X)OMe-fluorenes, mesityl-C( X)Me and benzo[b]-2,3-
16b
thioenols. The observation of only one NMR (OH/SH) signal at rt
is ascribed to a rapid prototropic equilibrium between few species,
especially the cis enol and thioenol, which average the NMR
signals. Indeed, in a low temperature dynamic NMR study22h
both species plus a minor percentage of the non-hydrogen bonded
Z-thioenol were observed. The large intermolecular preference
of enolization over thioenolization had disappeared, presum-
ably due to a counter-effect of intramolecular O–H · · · S and
=
dihydrothiophene-2-( X).
The higher extent of thioenolization is ascribed17 to the much
−1 18
=
=
weaker C S bond than the C O bond (115 vs. 177 kcal mol ),
which is not compensated by the smaller C–S and S–H bond
energies than those of C–O and O–H bonds (61, 82, 88 and
110 kcal mol−1).18 From these values thioenolization is 7 kcal
mol−1 more favored than the enolization, as reflected in the
experimental values. However, these O–H and S–H bond energies
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Table 4 Effect of R1, R2, R3 and the solvent on Kenol, Kthioenol and Ktotal for 11/12/13 systemsa
Compound
R3
Ph
Solvent
% 12
% 11
% 13
Ktotal
0.67
Kenol
0.40
0.10
0.04
0.38
0.06
Kthioenol
11a/12a/13a
CDCl3
THF-d8
CD3CN
CDCl3
THF-d8
CD3CN
CCl4
60
91
96
61
94
97
33
44
58
86
92
94
88
96
92
96
72
88
97
89
96
100
4
24
9
4
23
6
3
35
27
28
12
7
5
12
4
8
4
28
12
3
11
4
16
0
0
16
0
0
32
29
14
2
1
1
0
0
0
0
0
0
0
0
0
0
50
7
8
53
5
8
69
9
6
12
7
0
0
10
0
0
11
0
0
12
7
18
0
0
60
2
61
0
10
10
23
0
0
37
5
6
7
0
0
24
0
27
0
48
0
0.27
0
0
0.25
0
0
0.97
0.66
0.24
0.02
0.01
0.01
0
0
0
0
0
0
0
0
0
0.10
0.04
0.63
0.06
0.03
2.03
1.27
0.72
0.16
0.09
0.06
0.14
0.05
0.09
0.05
0.039
0.14
0.03
0.13
0.04
11b/12b/13b
11c/12c/13cb
p-An
0.03
1-Np
1.06
0.61
0.48
0.14
0.08
0.05
0.14
0.05
0.09
0.05
0.39
0.14
0.03
0.13
0.04
≤0.02
11.50
3.81
1.45
11.73
3.8
CDCl3
C6D6
THF-d8
(CD3)2CO
CD3CN
CDCl3
THF-d8
CDCl3
THF-d8
CCl4
11d/12d/13dc
11e/12e/13ec
11f/12f/13fc
Me
Et
i-Pr
CDCl3
THF-d8
CCl4
11g/12g/13gc
11h/12h/13h
11i/12i/13i
11j/12j/13j
t-Bu
Ph
CDCl3
THF-d8
CDCl3
THF-d8
CD3CN
CDCl3
THF-d8
CD3CN
CDCl3
THF-d8
(CD3)2CO
CD3CN
CDCl3
THF-d8
CD3CN
CDCl3
THF-d8
CD3CN
CDCl3
THF-d8
CD3CN
CCl4
0
≤0.02
≤0.02
12.50
0.36
0.21
14.16
0.27
0.21
46
74
54
43
75
53
31
76
65
55
71
66
33
68
62
30
66
53
23
74
62
45
34
11
40
98
39
100
66
90
70
83
33
9
24.00
4.17
1.66
25.89
4.07
1.58
19
38
4
20
39
0
p-An
1-Np
1.37
≥50
15
29
33
22
34
67
22
38
70
23
47
77
14
31
37
66
89
0
5.66
2.43
2.08
3.54
1.97
0.50
3.64
1.62
0.44
3.35
1.13
0.30
6.19
2.23
1.64
0.51
0.12
5.04
2.23
1.70
3.23
1.97
0.50
3.14
1.62
0.44
2.87
1.13
0.30
5.32
2.02
1.18
0.51
0.12
0.62
0.20
0.38
0.31
0
0
0.50
0
11k/12k/13k
11l/12l/13l
Me
Et
0
0.48
0
11m/12m/13m
11n/12n/13nb
i-Pr
t-Bu
0
0.87
0.21
0.46
0
C6D6
CDCl3
THF-d8
CD3CN
CDCl3
THF-d8
CDCl3
THF-d8
CDCl3
C6D6
CDCl3
THF-d8
CD3CN
CDCl3
THF-d8
CD3CN
CDCl3
THF-d8
CD3CN
CDCl3
THF-d8
CDCl3
THF-d8
CDCl3
THF-d8
0
11o/12o/13o
Ph
≥50
0
0
0
24
0
≥50
≥50
≥50
11p/12p/13p
11q/12q/13q
11r/12r/13r
11s/12s/13sb
p-An
1-Np
i-Pr
3.17
2.75
0.42
t-Bu
≥50
7
14.12
10.6
5.01
0.49
0.16
2.06
0.92
3.15
0.64
0.18
6.16
0.25
1.35
0.11
1.69
5.01
3.53
0
0
0.69
0.17
0.12
0.32
0
0
2.29
0
0.86
0
2.46
0
17
67
54
31
49
23
61
85
11
80
31
90
20
17
5.01
0.49
0.86
2.23
1.04
3.47
0.64
0.18
8.45
0.25
2.21
0.11
4.15
5.01
11t/12t/13t
11u/12u/13u
Ph
64
45
70
39
15
65
20
42
10
32
83
i-Pr
11v/12v/13vc
11w/12w/13wc
11x/12x/13xc
i-Pr
t-Bu
t-Bu
a For all systems only 12 was observed in DMSO-d6. b Only 12 was observed in DMF-d7. c Only 12 was observed in CD3CN.
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O · · · H–S hydrogen bonds of different strengths, whose magni-
tudes were disputed.23
b-Oxothioacetamides, which were also investigated by NMR,
ꢀ
ꢀ
ꢀꢀꢀ
=
=
are written as the enols R C(OH) CRC( S)NR R , displaying
only one (presumably OH) signal at d 14.2–15.2.24
Structures of enols 11 and thioenols 13 in solution
Potential enol and thioenol structures (Chart 1 and 2) are the Z-syn
=
thioenol 14 with an S–H · · · O C bond and a Z-syn enol 18 with
=
an O–H · · · S C hydrogen bond. In both the two double bonds
are in an s-syn arrangement. These 6-membered ring structures are
analogous to the most stable structures for the cyanomalonamides
7/88 where the NR1R2 and NHR moieties are not involved in
=
hydrogen bonding. Rotation around the C–C( X) bond (X = O, S)
gives the Z-anti structures with an S–H · · · NR1R2 hydrogen bond
for 15 or an O–H · · · NHR3 bond for 19. Formal rotation around
=
the C C bond generates the E-isomers. In the E-syn enol, if the
1
2
=
cis-NR R to the C S contains no hydrogen there is no hydrogen
Chart
carbonylmalonamides.
2
Possible structures for the enols of cyanomonothio-
1
2
=
bond, but if R and/or R = H, an N–H · · · S C hydrogen bond
exists in 20. Since in all the cyanomonothiocarbonylmalonamides
the thioamide nitrogen carries one hydrogen, there is an N–
=
H · · · O C hydrogen bond in the E-syn thioenol 16. An N–H · · · N
of the various configurations/conformations of 14–21 arising
from the contribution of the hydrogen bonds, we assume that
bond exists in both the E-anti enol and thioenol isomers (17 and
21) and if R1 and/or R2 = H, there are several options for such a
bond. Consequently, the combination of dipole–dipole attraction
and repulsion interactions, and different hydrogen bonds in the
various structures, make it difficult to unequivocally determine the
structure in solution. The solid state structure is not necessarily
identical to that in solution and analogy with 7/8 is useless since
=
the C S · · · H–N and the S–H · · · N hydrogen bonds are weaker
=
than the C O · · · H–N and O–H · · · N bonds.
A valuable probe is the difference in the two d(N–H) values for
each species when R1 or R2 = H. We expect a large difference when
only one, low field hydrogen participates in a hydrogen bond and
a relatively small difference when both N–H bonds do not form
hydrogen bonds. Analysis shows that the N–H bond is involved
in hydrogen bonding for the E-anti enol and thioenol and for the
E-syn thioenols. If R1 = H, a large value is also predicted for the
E-syn enol.
=
=
the C O → C S change affects the nature of the hydrogen bond.
=
In 12 there are intramolecular N–H · · · O C bonds if one of the
R groups = H.
When R1 = R2 = Me each species displays only one NH signal:
at d 12.14–13.19 for 13, at d 10.45–11.13 (R3 = Ar) and 8.65–9.00
(R3 = Alk) for 12, and at d = 8.33–8.49 (R3 = Ar) and 6.81–7.26
(R3 = Alk) for 11 (Table 5). When R1 = H, R2 = Me, the order
of d values is retained, but each species display two signals. The
Dd(N–H) values of 4.20–7.08 for 13 > Dd 2.97–3.52 (R3 = Ar)
and 1.69–2.50 (R3 = Alk) for 12 > Dd 1.59–2.17 (R3 = Ar) and
0.27–1.16 (R3 = Alk) for 11 (Table 5). For R1 = R2 = H, Dd =
6.19–7.21 for 13, 2.50 for 12 and 1.13–2.76 for 11.
Consequently, the large Dd values for 13 indicate an E-
configuration (16 or 17) and the significantly lower Dd values
for 11 indicate a Z configuration (18 or 19). This conclusion is
consistent with the d(OH) of >16.5 ppm (Table 3) observed for
other hydrogen bonded enols,3,4,8 and hence 18 is the preferred con-
=
formation for the enol; e.g., for enols ArNHC(OH) C(CN)CO2R
=
(R CF3CH2 and (CF3)2CH),4c d(OH) for the Z-isomers is mostly
at d 13.2–14.5, and moves 2–3 ppm to a higher field for the E-
isomers. The NH values are at ca. d 8.3–10.0 for the Z-enols and
at d 10.2–10.9 for the E-enols.
Chart
1
Possible structures for the thioenols of cyanomonothio-
carbonylmalonamides.
The low field d(SH) signals at 4.3–4.8 in CDCl3 (Table 3)
are consistent with a non-hydrogen bonded SH group in the E-
thioenols. Since an N–H · · · O is a stronger hydrogen bond than
an N–H · · · N bond, the structure should be E-syn 16. The d
of 6.3–6.9 for the NHMe derivatives in CD3CN and THF-d8 is
=
In our systems the nitrogen adjacent to the C S is connected to
=
one hydrogen and only in the E-syn enols is there no C S · · · H–
N bond when R1, R2 = H. In analysing the relative stabilities
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consistent with intermolecular hydrogen bonds of the SH with
the hydrogen bond accepting solvents. Indeed, in b-thioxoesters
Experimental section
1
2
General methods, NMR and analytical data
=
=
HSC(R ) CHCO2R the intramolecular S–H · · · O C hydrogen
bonded Z-isomer displays d(SH) at 5.68–8.19 ppm, which is at
ca. d 3.80 for the E-isomer.22a A structure related to 20 with a
“free” SH group was detected earlier in solution.22h,l
Melting points, 1H and 13C NMR and IR spectra were measured as
described previously.2f All the commercial precursors and solvents
were purchased from Aldrich.
d values are relative to Me4Si. J values aregiven in Hz. Analytical
data, mps and yields are given in Table S6 in the ESI.§
Comparison of d(OH) and Kenol values of the enols 11 and 7/8
A qualitative comparison between the 11/12/13 and 6/7/8
systems show, in CDCl3, a 0.69–1.69 ppm lower field d(OH)
Reaction of N,N-dimethylcyanoacetamide with phenyl, p-anisyl,
1-naphthyl, methyl, ethyl, isopropyl and tert-butyl isothiocyanates
to form 11a–g/12a–g/13a–g
=
in the latter, ascribed to a better O–H · · · O C than an O–
=
H · · · S C hydrogen bond. Kenol and Ktotal values are significantly
=
higher for 6/7/8. The ratios for PhNH(C Z)CH(CN)CONRMe
The procedure for isopropyl isothiocyanate was also used with the
other isothiocyanates.
(Z = O, S) are >10-fold higher for R = Me than for R =
H (4.01–4.5 for R3 = Alk and 0.77–0.78 for R3 = Ar). For
To a suspension of Na (0.25 g, 11 mmol) in dry THF (50 mL)
was added N,N-dimethylcyanoacetamide (1.12 g, 10 mmol) and
the mixture was stirred overnight giving a white precipitate. A
solution of isopropyl isothiocyanate (1.08 mL, 10 mmol) in dry
THF (20 mL) was added dropwise to the stirred mixture over
20 min. After stirring overnight at rt the dissolved white precipitate
gave a yellow solution. The solvent was evaporated, the remaining
Na salt was dissolved in DMF (5 mL) and the solution was added
slowly to a cold 2 N HCl solution (100 mL). The formed yellowish
precipitate was filtered, washed with cold water (30 mL) and dried
in air to give 1.96 g (92%) of 12f, mp 147–9 ◦C. Anal. calcd
for C9H15N3OS: C, 50.70; H, 7.04; N, 19.72; found: C, 50.30; H,
7.06; N, 19.42%. Crystals for X-ray diffraction were obtained by
keeping a solution of 12f in THF-d8 or CDCl3 at rt for 2–3 weeks.
Detailed NMR spectra of 11f/12f and the analogous preparation
and spectra of 11c are given in the ESI.§ Spectral data, mps, yields
and analyses are given in Tables 3, S1–S3 and S6.
=
i-PrNH(C Z)CH(CN)CONHPr-i the ratio is 2.57. Hence, the
extent of enolization is strongly structure-dependent. The corre-
sponding data are reported in Table S5 in the ESI.§
Solvent and substituent effects on Kenol and Kthioenol
Kenol and Kthioenol are strongly solvent- and substituent-dependent
(Table 4). Kenol values increase on decreasing the solvent polarity,
following the order CCl4 > CDCl3 > C6D6 > THF-d8
>
(CD3)2CO > CD3CN > DMF-d7 > DMSO-d6. The same trend
was observed for Kthioenol, except that CDCl3 > CCl4. In contrast
with compounds 6/7/8, where the NHMe and NH2 derivatives
display the enol in DMSO-d6,8 for compounds 11/12/13, 12 is the
exclusive tautomer in DMSO-d6.
For a constant NHR3, both Kenol and Kthioenol decrease for NR1R2
in the order NH2 > NHMe > NMe2. Thus, for 11h–j/12h–
j/13h–j and 11o–p/12o–p/13o–p, 13 predominates in CDCl3, and
12 predominates for 11a–g/12a–g/13a–g systems. Moreover, for
NMe2 systems no 13 was observed for R3 = Alk and a small
to moderate %(13) was observed when R3 = Ar. The %(13) for
NHMe and NH2 systems was independent of R3.
Reaction of N-methylcyanoacetamide with phenyl, p-anisyl,
1-naphthyl, methyl, ethyl, isopropyl and tert-butyl isothiocyanates
to form 11h–n/12h–n/13h–n
The procedure is demonstrated for phenyl isothiocyanate. Very
small Na pieces (0.25 g, 11 mmol) were added to an N-
methylcyanoacetamide (0.98 g, 10 mmol) solution in dry THF
(50 mL) under nitrogen. The mixture was stirred for 48 h until
complete Na disappearance, giving a white precipitate in an
orange solution. A solution of phenyl isothiocyanate (1.2 mL,
10 mmol) in dry THF (20 mL) was added dropwise over 30 min
and during 6 h reflux the precipitate dissolved to give a dark
orange solution. Removal of the solvent left the brown salt
[PhNHCSC(CN)CONHMe]−Na+. dH (400 MHz, 298 K, DMSO-
d6): 2.61 (3H, d, J = 4.5, NMe), 6.94 (1H, t, J = 7.8, p-H), 7.21
(2H, t, J = 7.8, m-H), 7.79 (2H, d, J = 7.2, o-H), 13.20 (1H, s,
NH). dC (100.133 MHz, 298 K, DMSO-d6): 26.43 (q, J = 136.7,
Me), 76.76 (s, C[anion]), 122.18 (d, J = 160.4), 122.75 (d, J =
162.4), 125.56 (s, CN), 128.32 (d, J = 161.1), 142.26 (s), 169.66 (s,
Conclusions
3
=
=
Replacing one C O with a C S group in R NHCOCH(CN)-
CONR1R2 leads to seven changes: (i) both enolization and
thioenolization are observed in solution. (ii) The intramolecular
O–H · · · O hydrogen bonded Z-enol structures in the 6/8 and
11/13 systems are analogous, whereas the thioenol structure
has the E-configuration, no intramolecular H-bonded SH group
and an intramolecularly N–H · · · O H-bonded moiety. (iii) d(OH)
values in 7 are at a lower field than in analogs 11. (iv) Kenol values
for 11/12/13 are lower than in 6/7/8. (v) The thioenol 13 is less
stable than enol 11 for S C-N-Alk-substituted systems, but the
stabilities are much closer and even slightly reversed for N-aryl
systems. An increased number of N–H bonds adjacent to the C O
strongly increases the Kthioenol and Kenol values. (vi) Compounds
11/12/13 are more reactive, giving an array of different reactions.11
(vii) The intramolecular hydrogen bond strengths are important
in determining the structures of the enols and thioenols and the
differences between them.
=
=
=
=
C O), 185.96 (s, C S).
The salt was dissolved in DMF (5 mL) and the orange solution
was added dropwise to a cold 2 N HCl solution (100 mL). The
yellow precipitate was filtered, washed with cold water (200 mL)
and dried in air to give 1.87 g (80%) of 11h, mp 153–5 ◦C. Anal.
calcd for C11H11N3OS: C, 56.65; H, 4.72; N, 18.03; found: C, 56.72;
1080 | Org. Biomol. Chem., 2008, 6, 1071–1082
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H, 4.86; N, 17.79%. Crystals for X-ray diffraction were obtained
by slow evaporation of the EtOAc solution at rt.
5 mmol) reacted with t-butyl isothiocyanate (0.58 mL, 5 mmol)
to yield 1.29 (87%) of 11x, mp 147–8 ◦C (dec.). The spectral and
analytical data are in Tables 3, S1–S3 and S6.
Attempts to obtain the 1-naphthyl derivative, 11j, gave a product
in 89% yield, mp 158–60 ◦C. However, crystallization from EtOAc
at rt gave a 5-membered ring compound resulting from an
oxidation reaction, apparently by air oxygen.11 Crystallization
from EtOAc under nitrogen revealed the enol structure 11j.
Compounds 11i, 11l–n were obtained similarly. The reaction of
11n and the spectra of the 11n/12n/13n obtained, and spectral
and analytical data of all the compounds are given in Tables 3,
S1–S3 and S6.
Crystal data
˚
12d: C21H33N9O3S3, M = 555.74, monoclinic, a = 14.6537(11) A,
◦
◦
˚
˚
b = 14.1922(11) A, c = 14.9966(12) A, a = 90 , b = 108.8310(10) ,
◦
3
˚
c = 90 , U = 2951.9(4) A , T = 295(1) K, space group P2(1)/c,
Z = 4, 29 673 reflections collected, 5779 independent reflections
[R(int) = 0.0635]. The final wR(F2) = 0.1972 [I > 2r(I)]. 12f:
˚
C9H15N3OS, M = 213.30, monoclinic, a = 7.3690(4) A, b =
◦
◦
◦
˚
˚
15.9322(8) A, c = 10.1036(5) A, a = 90 , b = 98.6260(10) , c = 90 ,
Reaction of cyanoacetamide with phenyl, p-anisyl, 1-naphthyl,
isopropyl and tert-butyl isocyanates to form 11o–s/12o–s/13o–s
3
˚
U = 1172.79(10) A , T = 295(1) K, space group P2(1)/c, Z = 4,
12 869 reflections collected, 2557 independent reflections [R(int) =
0.0210]. The final wR(F2) = 0.1003 [I > 2r(I)]. 12v: C20H21N3OS,
The procedure for all the derivatives is similar. To a heated solution
of cyanoacetamide (0.84 g, 10 mmol) in dry THF (100 mL) at
60 ◦C was added Na (0.25 g, 11 mmol) and the mixture was
stirred at 60 ◦C for 4 days, giving a white precipitate. The organic
isothiocyanate (10 mmol) in dry THF (30 mL) was added dropwise
during 30 min at rt. The mixture was refluxed for 48 h and then
stood at rt for 1 h to give a brown solution and a white precipitate
which was filtered and washed with dry ether giving the salt
[R3NHCSC(CN)CONH2]−Na+. The salt solution in DMF (5 mL)
was added dropwise to a cold 2 N HCl solution (100 mL), the
solid obtained was filtered, washed with cold water (500 mL) and
dried in air or in vacuum to give the pure product. Attempts to
crystallize the products gave different heterocycles.11 Their spectral
and analytical data are given in Tables 3, S1–S3 and S6.
˚
˚
M = 351.46, monoclinic, a = 12.321(2) A, b = 18.376(3) A, c =
◦
◦
◦
3
˚
˚
9.3465(16) A, a = 90 , b = 116.339(3) , c = 90 , U = 1896.5(6) A ,
T = 295(1) K, space group Cc, Z = 4, 10 385 reflections collected,
4082 independent reflections [R(int) = 0.1157]. The final wR(F2) =
0.0973 [I > 2r(I)]. 11h: C11H11N3OS, M = 233.29, triclinic, a =
◦
˚
˚
˚
9.4637(5) A, b = 9.9527(6) A, c = 13.2117(8) A, a = 81.3100(10) ,
◦
◦
3
˚
b = 79.1780(10) , c = 68.9710(10) , U = 1136.10(11) A , T =
295(1) K, space group P–1, Z = 4, 12 684 reflections collected,
4900 independent reflections [R(int) = 0.0172]. The final wR(F2) =
0.1267 [I > 2r(I)]. 11i: C12H13N3O2S, M = 263.31, monoclinic,
◦
˚
◦
˚
˚
a = 10.5904(6) A, b = 26.0342(14) A, c = 9.6563(5) A, a = 90 ,
◦
3
˚
b = 99.0470(10) , c = 90 , U = 2629.2(2) A , T = 295(1) K,
space group P2(1)/c, Z = 8, 30 522 reflections collected, 6255
independent reflections [R(int) = 0.0845]. The final wR(F2) =
0.1344 [I > 2r(I)]. 11j: C15H13N3OS, M = 283.34, monoclinic, a =
Reaction of N-isopropylcyanoacetamide with phenyl and isopropyl
isothiocyanates to form 11t and 11u
◦
˚
˚
˚
4.9892(4) A, b = 19.2928(14) A, c = 14.7103(12) A, a = 90 , b =
◦
◦
3
˚
99.0450(10) , c = 90 , U = 1398.34(18) A , T = 295(1) K, space
group P2(1)/n, 15 798 reflections collected, 3056 independent
reflections [R(int) = 0.0569]. The final wR(F2) = 0.0865 [I > 2r(I)].
12r: C8.50H14N3OS1.50, M = 222.32, orthorhombic, a = 8.4053(5)
The procedure resembles that of the reaction of N-
methylcyanoacetamide with phenyl isothiocyanate. 11t, mp 128–
30 ◦C, was prepared from N-isopropyl cyanoacetamide (1.26 g,
10 mmol) and phenyl isothiocyanate (1.2 mL, 10 mmol) in
80% yield. 11u, mp 157–8 ◦C, was prepared from N-isopropyl
cyanoacetamide (1.26 g, 10 mmol) and isopropyl isothiocyanate
(1.07 mL, 10 mmol) in 74% yield. The spectral and analytical data
are in Tables 3, S1–S3 and S6
◦
◦
˚
˚
˚
˚
A, b = 14.8272(9) A, c = 18.2296(11) A, a = 90 , b = 90 , c =
◦
3
90 , U = 2271.9(2) A , T = 293(1) K, space group P2(1)2(1)2(1),
Z = 8, 26 066 reflections collected, 4961 independent reflections
[R(int) = 0.0344]. The final wR(F2) = 0.0689 [I > 2r(I)].
Acknowledgements
Reaction of N-benzhydrylcyanoacetamide with isopropyl and
t-butyl isothiocyanates to form 12v and 12w
We are indebted to the Israel Science Foundation for support, and
to Dr Shmuel Cohen for the X-ray structure determination.
The procedure resembles the reaction of N,N-dimethylcyano-
acetamide with isopropyl isothiocyanate. The isopropyl derivative
11v (0.78 g, 89%), mp 162–4 ◦C, was obtained by reacting N-
benzhydrylcyanoacetamide (0.625 g, 2.5 mmol) with isopropyl
isothiocyanate (0.27 mL, 2.5 mmol). Crystals of 12v for X-ray
diffraction were obtained after long-term standing in CDCl3.
The t-butyl derivative 12w (0.67 g, 73%), mp 166–8 ◦C, was
obtained from N-benzhydrylcyanoacetamide (0.625 g, 2.5 mmol)
and t-butyl isothiocyanate (0.29 mL, 2.5 mmol). The spectral and
analytical data are in Tables 3, S1–S3 and S6.
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