One-Pot Synthesis and Conformational Features of N,N′-Disubstituted Ketene Aminals

Article abstract of DOI:10.1021/jo0352528

N,N′-Disubstituted ketene aminals are bioisosteres of thioureas and are useful building blocks in many synthetic operations. A convenient one-pot synthesis of N,N′-disubstituted ketene aminals from activated methylene compounds and isothiocyanates is desc

Full text of DOI:10.1021/jo0352528

On e-P ot Syn th esis a n d Con for m a tion a l
F ea tu r es of N,N′-Disu bstitu ted Keten e
Am in a ls
SCHEME 1. On e-P ot Syn th esis of
N,N′-Disu bstitu ted Keten e Am in a ls
†
Yan Shi,* J ing Zhang, Nyeemah Grazier,
Philip D. Stein, Karnail S. Atwal, Sarah C. Traeger,
Sharon P. Callahan, Mary F. Malley,
Michael A. Galella, and J ack Z. Gougoutas*
The Bristol-Myers Squibb Pharmaceutical Research
Institute, P.O. Box 5400, Princeton, New J ersey 08543-5400
yan.shi@bms.com
difficult to obtain or involve high temperature and the
generation of noxious mercaptans.
Received August 27, 2003
During our investigation of the synthesis of thiourea
bioisosteres, we have previously demonstrated that 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
Abstr a ct: N,N′-Disubstituted ketene aminals are bioisos-
teres of thioureas and are useful building blocks in many
synthetic operations. A convenient one-pot synthesis of N,N′-
disubstituted ketene aminals from activated methylene
compounds and isothiocyanates is described. Most of these
aminals exist in rotameric equilibrium around the central
CdC bonds in solution, and the rotamers are stabilized by
intramolecular hydrogen bonding both in solution and in
solid states.
8
(
EDCI) is an efficient thiocarbonyl activating agent in
9
the synthesis of N,N′-disubstituted cyanoguanidines,
1
0
acylguanidines, sulfamoylguanidines, and sulfonyl-
guanidines.11 In this report, we disclose the EDCI-
assisted one-pot synthesis of N,N′-disubstituted ketene
aminals from activated methylene compounds and isothio-
3
cyanates. We also consider the conformational features
of these aminals.
As shown in Scheme 1, N,N′-disubstituted ketene
aminals could be synthesized via two routes starting from
the reaction of an isothiocyanate with a nucleophilic
reagent, followed by the displacement of resulting thio
group by another nucleophile. In the first route (Method
N,N′-Disubstituted ketene aminals are useful building
blocks in many synthetic operations, especially as the
1
intermediates for construction of heterocyclic com-
2
pounds. They are also of general interest in medicinal
and agricultural chemistry because they are possible
bioisosteres of thioureas but with extra sites in the ketene
that can be derivatized. Like N,N′-disubstituted thio-
ureas, their biologic activities rely on the stereochemistry
of aminals because of possible syn/anti rotameric confor-
mations. Typically, the synthesis of N,N′-disubstituted
ketene aminals involves the stepwise or simultaneous
(4) (a) Rudorf, W.-D.; Koch, K.; Augustin, M. J . Prakt. Chem. 1977,
319, 545. (b) Rudorf, W.-D.; K o¨ ditz, J .; Henze, N.; Tersakian, A.
Phosphorous, Sulfur, Silicon Relat. Elem. 1995, 107, 87. (c) Singh, O.
M.; J unjappa, H.; Ila, H. J . Chem. Soc., Perkin Trans. 1 1997, 23, 3561.
(d) Shishoo, C. J .; Devani, M. B.; Bhadti, V. S.; Ananthan, S.; Ullas,
G. V. J . Chem. Res. Synop. 1985, 375. (e) Hojo, M.; Masuda, R.; Okada,
E.; Yamamoto, H.; Morimoto, K.; Okada, K. Synthesis 1990, 195. (f)
Elvidge, J . A.; J udson, P. N.; Percival, A.; Shah, R. J . Chem. Soc.,
Perkin Trans. 1 1983, 8, 1741. (g) Huang, Z.-T.; Liu, Z.-R. Synth.
Commun. 1989, 943. (h) Rudorf, W.-D.; Schierhorn, A.; Augustin, M.
Tetrahedron 1979, 35, 551. (i) Rudorf, W.-D.; Koch, K.; Augustin, M.
J . Prakt. Chem. 1981, 323, 637. (j) Thomas, A.; Vishwakarma, J . N.;
Apparao, S.; Ila, H.; J unjappa, H. Tetrahedron 1988, 44, 1667. (k)
Gompper, R.; T o¨ pfl, W. Chem. Ber. 1962, 95, 2871.
3
displacement of both methylthio groups of ketene
dithioacetals4
,2d
or the displacement of 2,2-dihalovinyl
5
cyano or ketone compounds by nucleophilic amines.
However, these procedures usually lead to a mixture of
mono- and disubstituted products and are only useful for
the synthesis of symmetric N,N′-disubstituted products.
Alternative methods involve the reaction of activated
(5) (a) Ichikawa, J .; Kobayashi, M.; Yokota, N.; Noda, Y.; Minami,
T. Tetrahedron 1994, 50, 11637. (b) Hashimoto, N.; Kawano, Y.; Morita
K. J . Org. Chem. 1970, 35, 828. (c) Soulen, R. L.; Kundiger, D. G.;
Searles, S., J r.; Sanchez, R. A. J . Org. Chem. 1967, 32, 2661. (d)
Yatasishin, A. A.; Bodnarchuk, N. D. Zh. Org. Khim. 1979, 15, 1381.
(6) Hartke, K. Angew. Chem., Int. Ed. Engl. 1964, 3, 640.
(7) (a) Maas, G.; Feith, B. Synth. Commun. 1984, 14, 1073. (b)
Kantlehner, W.; Greiner, U. Liebigs Ann. Chem. 1990, 965. (c)
Kantlehner, W.; Mergen, W. W.; Haug, E. Liebigs Ann. Chem. 1983,
290. (d) Karlsson, S.; Sandstr o¨ m, J . Acta Chem. Scand. 1978, 32, 141.
(e) Kantlehner, W. Synthesis 1979, 343. (f) Bredereck, H.; Berdereck,
K. Chem. Ber. 1961, 94, 2278. (g) Ericsson, E.; Sandstr o¨ m, J .;
Wennerbeck, I. Acta Chem. Scand. 1970, 24, 3102. (h) Ericsson, E.;
Marnung, T.; Sandstr o¨ m, J .; Wennerbeck, I. J . Mol. Struct. 1975, 24,
373. (i) Kantlehner, W.; J aus, H.; Kienitz, L.; Bredereck, H. Liebigs
Ann. Chem. 1979, 2096.
(8) Similar uses have also been described by others. For example:
(a) Poss, M. A.; Iwanowicz, E.; Reid, J . A.; Lin, J .; Gu, Z. Tetrahedron
Lett. 1992, 33, 5933. (b) Schneider, S. E.; Bishop, P. A.; Salazar, M.
A.; Bishop, O. A.; Anslyn, E. V. Tetrahedron 1998, 54, 15063.
(9) Atwal, K. S.; Ahmed, S. Z.; O’Reilly, B. C. Tetrahedron Lett. 1989,
30, 7313.
6
methylene compounds with isothioamide or formami-
7
dinium salts. All of these methods require the avail-
ability of necessary starting materials, which are often
†
Current address: Novartis Pharmaceutical Corporation, One
Health Plaza, East Hanover, NJ 07936.
(
1) J unjappa, H.; Ila, H.; Asokan, C. V. Tetrahedron 1990, 46, 5423.
(2) (a) Shishoo, C. J .; Devani, M. B.; Bhadti, V. S.; Ananthan, S.;
Ullas, G. V. Tetrahedron Lett. 1984, 25, 1291. (b) Su, M.; Liu, Y.; Ma,
H.; Ma, Q.; Wang, Z.; Yang, J .; Wang, M. Chem. Commun. 2001, 960.
(
(
c) Kumar, A.; Aggarwal, V.; Ila, H.; J unjappa, H. Synthesis 1980, 748.
d) Tominaga, Y.; Michioka, T.; Moriyama, K.; Hosomi, A. J . Heterocycl.
Chem. 1990, 27, 1217. (e) Aggarwal, V.; Ila, H.; J unjappa, H. Synthesis
983, 147.
3) (a) Stein, P. D.; Shi, Y.; O’Connor, S. P.; Li, C. PCT Int. Appl.
1
(
WO 0196331, 2001. (b) D o¨ rwald, F. Z.; Hansen, J . B. PCT Int. Appl.
WO 9850344, 1998. (c) Hansen, J . B.; Tagmose, T. M.; Mogensen, J .
P.; D o¨ rwald, F. Z.; J ørgensen, A. S. PCT Int. Appl. WO 0027805, 2000.
(10) Zhang, J .; Shi, Y.; Stein, P.; Atwal, K.; Li, C. Tetrahedron Lett.
2002, 43, 57.
(d) Barzen, R.; Schunack, W. Arch. Pharm. (Weinheim, Ger.) 1982, 315,
6
80. (e) J udson, P. N.; White, C. R. H. Eur. Pat. Appl. EP 10396, 1980.
(11) Zhang, J .; Shi, Y. Tetrahedron Lett. 2000, 41, 8075.
1
0.1021/jo0352528 CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/09/2003
1
88
J . Org. Chem. 2004, 69, 188-191

TABLE 1. Syn th esis of N,N′-Disu bstitu ted Keten e
Am in a ls (Sch em e 1)
SCHEME 2. Solu tion Con for m a tion of
N,N′-Disu bstitu ted Keten e Am in a ls
thiocarbonyl activating reagent and the requisite amine
(
)
Method B). Intermediate 6a (R ) cyano, R
1
) Ph, EWG
CO Me) was synthesized from methyl cyanoacetate
2
sodium anion and phenyl isothiocyanate. The formation
of intermediate 6a was monitored by LC-MS or TLC
analysis, which showed complete conversion of the start-
ing phenyl isothiocyanate to 6a in 30 min at 60 °C. After
cooling to room temperature, the reaction mixture was
treated with n-butylamine and EDCI to provide 5a in
9
1% yield. As expected, we found that mercury(II)
1
3
chloride and 2-chloro-1-methylpyridinium iodide (Mu-
1
4
kaiyama’s reagent ) are also capable of converting
intermediate 6a to 5a in 59% and 37% yields, respec-
tively. This route appears to be general for a variety of
activated methylene compounds as shown in Table 1. It
should be noted that even acetophenone participates in
the reaction to provide 5f in good yield (55%).
a
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene. b All compounds were
purified by silica gel column chromatography and characterized
1
13
by H NMR, C NMR, and elemental analysis. All yields are
isolated yields.
Ketene aminals have been known to have fairly low
A), the intermediate thiourea could be condensed with
an activated methylene anion to afford the N,N′-disub-
stituted ketene aminal with the assistance of a thiocar-
bonyl activating reagent. Since it has been reported that
activated methylene compounds can react with isothio-
rotational barriers around the CdC bond as a result of
the push-pull effect of their substituents,1
5,4f,7g
and a
recent report suggests that derivatives of Meldrum’s acid
(Scheme 2) also should undergo rapid rotation about
7
6
the CdC bond at room temperature, giving rise to NMR
signals from one average structure.16 Spectral studies on
compounds prepared in the present investigation indi-
cated that they exist in the enamino form with strong
intramolecular hydrogen binding. The IR spectra (KBr)
strongly indicated a hydrogen-bonded NH stretching
amide, we first investigated the reaction of a thiourea
3
a (R
1
) Ph, R ) n-Bu) with methyl cyanoacetate 4a .
2
When the reaction was conducted in the presence of
EDCI and triethylamine in methylene dichloride, the
product 5a was isolated in only 5% yield even after
refluxing for 24 h. However, when DBU was employed
as the base, compound 5a was obtained in 80% yield after
heating at 80 °C in DMF for 1 h. Similar results were
obtained when mercury(II) chloride was employed as the
thiocarbonyl activating agent (55%). This method appears
to be general for highly activated methylene compounds,
as shown in Table 1. For example, (phenylsulfonyl)-
acetonitrile reacts with thiourea 3b smoothly to afford
-
1
vibration at 3240-3330 cm . The carbonyl stretching
vibration in these compounds was merged with bands
-1
around and below 1600 cm , reflecting the characteristic
conjugation effect of the aminal group and strong in-
1
tramolecular hydrogen bonding. The H NMR of com-
pound 5b showed only one set of signals in either CDCl
or DMSO-d , indicating it is either a single stereoisomer
3
6
or it has a very low rotational barrier around the CdC
5
b in 80% yield after 1 h at 80 °C (entry b). The reaction
bond.17 Although its stereochemistry about the ketene
of less activated methylene compounds with thioureas
requires sodium hydride as the base (entries c-f). For
example, 2-cyano-N,N-dimethyl-acetamide reacts with
thiourea 3c to afford 5c in 70% yield when sodium
hydride is used, compared to a 20% yield with DBU.
Alternatively, the isothiocyanate could first be con-
densed with an activated methylene anion to afford the
intermediate thioamide anion 6,12 which provides the
N,N′-disubstituted ketene aminal by the action of a
(13) (a) Klaus, P. Z. Chem. 1975, 15, 146. (b) Kim, K. S.; Qian, L.
Tetrahedron Lett. 1993, 34, 7677.
(
14) (a) Shibanuma, T.; Shiono, M.; Mukaiyama, T. Chem. Lett.
977, 575. (b) Yong, Y. F.; Kowalski, J . A.; Lipton, M. A. J . Org. Chem.
1997, 62, 1540.
15) (a) Sandstr o¨ m, J . Topics Stereochem. 1983, 14, 83. (b) Walter,
1
(
W.; Meyer, H.-W. Liebigs Ann. Chem. 1975, 36. (c) Mitamura, S.;
Takaku, M.; Nozaki, H. Bull. Chem. Soc. J pn. 1974, 47, 3152.
(16) Bernhardt, P. V.; Koch, R.; Moloney, D. W. J .; Shtaiwi, M.;
Wentrup, C. J . Chem. Soc., Perkin Trans. 2 2002, 515.
(
3
17) The results from low temperature (10 to -40 °C in CDCl ) NMR
(12) Darr e´ , F.; Lamazou e` re, A. M.; Sotiropoulos, J . Bull. Soc. Chim.
experiments are not conclusive because complex spectra arise from
Fr. 1975, 829.
C-N bond rotamers.
J . Org. Chem, Vol. 69, No. 1, 2004 189

F IGURE 1. The molecular conformation and hydrogen bonding (dashed bonds) in the solvated crystal structures of 5d (right)
and 5e (solvent molecules not shown). The angle of twist about the CdC bond is 10° and 3°, respectively, and the NCN angle is
1
21° in both.
double bond is not known, the conformation of the aminal
group was determined to be syn-anti by observing com-
mon NOE correlations to the aniline N-H proton from
SCHEME 3. P ossible Con for m a tion s of Am in a ls
both the N-CH
aniline ring from
DMSO-d (Scheme 2). For compounds 5a , 5c, 5e, and
f, our NMR experiments in CDCl at room temperature
2
protons and the ortho protons of the
1
a
H PSNOESY experiment in
1
8
6
5
3
indicated distinct, intramolecularly hydrogen bonded Z
and E isomers. For example, the two N-H protons of 5a
showed four resonances at 10.54, 9.05, 6.65, and 4.95
ppm. While the two downfield signals can be assigned to
the N-H protons that form hydrogen bonds with the
carbonyl oxygen, the two upfield signals are due to N-H
6
DMSO-d , most likely because of the disruption of the
internal hydrogen bonds.
15b,20
By contrast, 5d prefers a single configuration in both
1
5
15
3 3
CDCl and CD CN. The results of N HMBC, N HMQC,
2
1
and NOE experiments are consistent with the hydrogen-
bonded E configuration observed in a single crystal
protons not associated with hydrogen bonds. The N-CH
2
(Figure 1).
protons also showed two broad peaks at 2.96 and 2.78
ppm, which are assigned to stereoisomers 5a -Z and 5a -E
In general, N,N′-disubstituted ketene aminals can have
four extreme C-N rotameric conformations (ss, as, sa,
and aa) as defined in Scheme 3. Each intramolecular
hydrogen bond (NH-X or NH-Y) necessarily requires
an antiperiplanar (a) rotameric conformation.
1
(
(
ratio ∼1:1.3) on the basis of H COSY NMR experiments
Scheme 2). Similarly, 5e exists as a (∼2.3:1) mixture of
3
Z and E isomers in CDCl , but only the E isomer is
present in a single crystal (Figure 1).19 This apparently
is the first reported observation of distinct rotameric
isomers for N,N′-disubstituted ketene aminals.
2
2
A survey of the Cambridge Structural Database (CSD)
revealed 19 examples of N,N′-disubstituted ketene ami-
nals having acyclic C-N bonds, and most of them favor
the sa (or as) conformation (16 out of 19 examples; see
Supporting Information). All examples have the potential
to form at least one intramolecular hydrogen bond
involving an NH, and we note several correlations
between their chemical structures and solid-state con-
formations: (a) Despite the potential to form two
Except for 5f, distinct isomers were not observed
in strongly coordinating solvents such as CD CN or
3
(18) The rotamers observed for 5c are not due to the rotation of the
amide bond since only one resonance is observed for methyl groups on
the amide nitrogen.
(
19) H-bond distances designate O‚ ‚ ‚N separation (Å). For 5d ,
colorless rods from CH Cl /hexanes: T ) -70 °C, a ) 23.1020(6), b )
2
2
1
1.9057(3), c ) 19.4958(5), â ) 105.563(1), V ) 163.4(2), C2/c, Z ) 8,
R ) 0.13, R
w
) 0.21 for 2477 observed intensities at with I g 3σ(I).
(20) It has been shown by AM1 calculation that the rotation barriers
of Meldrum’s acid derivatives decrease dramatically in a dielectric filed
(e ) 40) as the result of a much more effective stabilization of the
zwitterionic transition state. See ref 16.
The crystals are unstable at room temperature, and the solvent
positions were poorly defined and partially occupied. Only the chlorine
position for the CH
CH Cl
5.10(1), â ) 83.93(1), γ ) 71.38(1), V ) 1182.6(3), P1bar, Z ) 2, R )
.08, R ) 0.13 for 3166 observed intensities at with I g 3σ(I), mp
2
Cl
2
site was obvious. For 5e, colorless prisms from
1
5
2
2
: T ) -40 °C, a ) 10.100(1), b ) 10.539(1), c ) 12.136(2), R )
(21) N HMBC and HMQC NMR experiments correlate the non-
hydrogen bonded N-H (s, 6.97 ppm) and the 2′-H (7.27 ppm) of the
4′-chlorophenyl group to the same nitrogen (95.0 ppm), and the
hydrogen bonded N-H (s, 11.15 ppm) and tert-butyl group to the other
nitrogen (129.7 ppm). The NOE observed between N-H proton (6.97
ppm) of aniline and t-butyl group protons indicates it is the E
stereoisomer.
7
0
1
w
10-40 °C. Crystallographic data (excluding structure factors) for the
above compounds have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication nos. CDC-212560
(
5d ) and -212561 (5e). Copies of the data can be obtained free of charge
upon application to CCDC, 12 Union Road, Cambridge CB21EZ, U.K.
Fax: (+44)1223-336-033. E-mail: deposit@ccdc.cam.ac.uk).
(22) Allen, F. H.; Kennard, O. Chem. Des. Autom. News 1993, 8, pp
1, 31-37, Version 524.
(
1
90 J . Org. Chem., Vol. 69, No. 1, 2004

intramolecular hydrogen bonds and maintain an es-
sentially planar conformation, all but 1 of the 10 ex-
amples are instead twisted more than 70° about rela-
tively long (1.45-1.49 Å) CdC bonds and adopt sa or ss
conformations without any intramolecular hydrogen
disubstituted ketene aminals from activated methylene
compounds and isothiocyanates. Most of these aminals
exist in rotameric equilibrium around the central CdC
bonds in solution, and the rotamers are stabilized by
intramolecular hydrogen bonding both in solution and
in solid states.
2
bonds. The sole exception (X ) 2-benzothiazole, Y ) NO ,
R
1
) R
) Ph)23 has an almost planar aminal with two
2
intramolecular hydrogen bonds and the rare, sterically
Exp er im en ta l Section
demanding aa conformation. It therefore appears that
unfavorable steric interactions between R and R in aa
1 2
conformation outweigh the two stabilizing intramolecular
hydrogen bonds for most of these compounds. (b) The
Gen er a l P r oced u r e for Meth od A. To a solution of an
isothiocyanate 1 (1.0 mmol) in dry DMF (2 mL) was added an
amine 2 (1.0 mmol). After 20 min of stirring, sodium hydride
(95%, 38 mg, 1.5 mmol) or DBU (1.5 mmol) was added under
nitrogen. The mixture was stirred for 5 min, and an activated
methylene compound 4 (1.5 mmol) and EDCI (288 mg, 1.5 mmol)
were added in that order. The reaction was heated to 80 °C for
a period of 1-12 h. After cooling to room temperature, the
reaction was quenched with water and extracted with ethyl
acetate (3 × 5 mL). The organic phase was washed with
saturated sodium chloride aqueous solution and dried over
magnesium sulfate. The solvent was removed to give a crude
product. Purification of the crude product on a silica gel column
with 20-50% EtOAc in hexanes provided pure 5.
Gen er a l P r oced u r e for Meth od B. To a solution of an
activated methylene compound 4 (1.5 mmol) in dry DMF (2 mL)
was added sodium hydride (95%, 38 mg, 1.5 mmol) under
nitrogen. After 5 min of stirring, an isothiocyanate 1 (1.0 mmol)
was added. The mixture was stirred for 30 min at 60 °C. An
amine 2 (1.5 mmol) and EDCI (288 mg, 1.5 mmol) were added
in that order. The reaction was heated to 80 °C for a period of
remaining 9 examples have the potential to form one
intramolecular hydrogen bond. All but one24 of the them
are only slightly twisted (<6°) with correspondingly
shorter CdC bonds (1.39-1.42 Å), and the intramolecular
hydrogen bonds are evident. Examples 5d and 5e fall into
this category (with a CdC length of 1.428 and 1.426 Å,
and a twist angle of 10° and 3°, respectively). Interest-
1 2
ingly, 5e is the first example with an aa (R , R ) alkyl,
aryl) conformation and only one stabilizing intramolecu-
lar hydrogen bond. All of the other examples in this
category have a sa (or as) conformation. (c) No aa
1 2
conformation is known when both R and R are alkyl,
probably because of unfavorable steric factors. In con-
trast, all rotameric conformations have been reported
when R and R are either aryl or one is aryl.
1 2
In conclusion, we have demonstrated two efficient
1
-12 h. After cooling to room temperature, the reaction was
quenched with water and extracted with ethyl acetate (3 × 5
mL). The organic phase was washed with saturated aqueous
sodium chloride solution and dried over magnesium sulfate. The
solvent was removed to give a crude product. Purification of the
crude product on a silica gel column with 20-50% EtOAc in
hexanes provided pure 5.
routes (Methods A and B) for the synthesis of N,N′-
(
23) Another example of an aminal with an aa solid-state conforma-
tion has been reported recently. Its structure is shown below (See ref
6).
1
Ack n ow led gm en t. We thank Dr. Vikram A. Roong-
ta for helpful discussions about NMR experiments.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for Schemes 1, full characterization of compounds 5a -f,
X-ray crystallographic files for 5d and 5e, and structural
information and references of 19 compounds obtained from
CSD. This material is available free of charge via the Internet
at http://pubs.acs.org.
(
24) In the solid state, this aminal is severely twisted (66°) about
the long (1.47 Å) CdC bond and forms no intramolecular hydrogen
bond, its structure is shown below (also see Supporting Information).
J O0352528
J . Org. Chem, Vol. 69, No. 1, 2004 191