Reactions of 2-amino-2-thiazolines with isocyanates and isothiocyanates. Chemical and computational studies on the regioselectivity, adduct rearrangement, and mechanistic pathways

Article abstract of DOI:10.1021/jo000618r

2-Amino-2-thiazoline derivatives bearing alkyl or aryl substituents at exocyclic nitrogen have been condensed with different isocyanates and isothiocyanates. The addition occurs at ring endocyclic nitrogen in a regiospecific manner to afford kinetic and enthalpy-favored adducts. The unequivocal assignment of these structures has been confirmed by X-ray diffraction analyses of several compounds. The endo adducts do not rearrange on heating with the sole exception of adducts in which the exocyclic nitrogen remains unsubstituted. Trapping experiments in the presence of other isocyanates or isothiocyanates produce the formation of new endo adducts by acyl exchange in the reaction mixture. Semiempirical PM3 calculations full corroborate the higher stability of endo or exo adducts depending on the substitution pattern. The formation of adducts is compatible with a stepwise reaction mechanism, for which semiempirical transition structures could be located in the potential energy surface, and the global energetics of the process have been determined. The formation of the endo adducts proceeds with a smaller activation barrier.

Full text of DOI:10.1021/jo000618r

8
882
J . Org. Chem. 2000, 65, 8882-8892
Rea ction s of 2-Am in o-2-th ia zolin es w ith Isocya n a tes a n d
Isoth iocya n a tes. Ch em ica l a n d Com p u ta tion a l Stu d ies on th e
Regioselectivity, Ad d u ct Rea r r a n gem en t, a n d Mech a n istic
P a th w a ys†
Mart ´ı n Avalos, Reyes Babiano, Pedro Cintas, Mar ´ı a M. Chavero, Francisco J . Higes,‡
J os e´ L. J im e´ nez, J uan C. Palacios,* and Guadalupe Silvero
Departamentos de Qu ı´ mica Org a´ nica y Qu ´ı mica Inorg a´ nica, Facultad de Ciencias,
Universidad de Extremadura, E-06071 Badajoz, Spain
palacios@unex.es
Received April 24, 2000
2
-Amino-2-thiazoline derivatives bearing alkyl or aryl substituents at exocyclic nitrogen have been
condensed with different isocyanates and isothiocyanates. The addition occurs at ring endocyclic
nitrogen in a regiospecific manner to afford kinetic and enthalpy-favored adducts. The unequivocal
assignment of these structures has been confirmed by X-ray diffraction analyses of several
compounds. The endo adducts do not rearrange on heating with the sole exception of adducts in
which the exocyclic nitrogen remains unsubstituted. Trapping experiments in the presence of other
isocyanates or isothiocyanates produce the formation of new endo adducts by acyl exchange in the
reaction mixture. Semiempirical PM3 calculations full corroborate the higher stability of endo or
exo adducts depending on the substitution pattern. The formation of adducts is compatible with a
stepwise reaction mechanism, for which semiempirical transition structures could be located in
the potential energy surface, and the global energetics of the process have been determined. The
formation of the endo adducts proceeds with a smaller activation barrier.
In tr od u ction
The condensation of isocyanates and isothiocyanates
with amino derivatives constitutes a simple and practical
route for the preparation of diversely functionalized ureas
and thioureas,1 which may serve as potential chemo-
therapeutics. Aryl thioureas such as 1 have been exten-
sively utilized as herbicides and also exhibit antifungical
2
properties. N-Phenyl-N′-(2-thiazolyl)thiourea (2) is an
3
inhibitor of dopamine hydroxylase, the key enzyme that
mediates the conversion of dopamine into norepineph-
rine. Recently, phenethylthiazolyl thioureas (3) have
emerged as a new class of nonnucleoside HIV-1 reverse
transcriptase inhibitors.4
Structures such as 4 have been the subject of enormous
controversy, and the question of the regioselective func-
tionalization of both nitrogen atoms at the 2-aminothia-
zoline moiety has not been definitively settled. The first
thioureido adduct 4 (R ) R′ ) Me, X ) S) or 5 was
isolated by Gabriel as early as 1889 as a byproduct in
the reaction of 2-bromoethylamine with methyl isothio-
*
To whom correspondence should be addressed. Fax: (+34-94)-
2
71149.
†
This work is dedicated respectfully to the memory of Wolfgang
5
cyanate. Later, in 1928, German chemists reported that
phenyl isothiocyanate adds to the endocyclic nitrogen of
Oppolzer and his scientific family of co-workers over the years.
‡
Departamento de Qu ´ı mica Inorg a´ nica. To whom inquiries regard-
ing the X-ray analyses should be addressed.
2
-amino-2-thiazoline (6) to form an adduct (7) which,
(1) (a) Satchell, D. P. N.; Satchell, R. S. In The Chemistry of Sulfur-
6
upon heating, rearranges to the thioureido derivative 8
Containing Functional Groups; Patai, S., Rappoport, Z., Eds.; Wiley;
New York, 1993; Suppl. S, Chapter 12, pp 599-631. (b) Ulrich, H. The
Chemistry and Technology of Isocyanates; Wiley: New York, 1996.
(Scheme 1). Further reinvestigations of this research gave
7
irreproducible and often contradictory results. The selec-
(
2) (a) Behner, O.; Steudel, W. Ger. Offen. DE 2 015 675, 1971;
tive attack at endocyclic or exocyclic nitrogen atoms of 6
as well as the structure of adducts, derived from phenyl
isocyanate and phenyl isothiocyanate, were not clarified
until 1986 when Rasmussen and co-workers pointed out
the strict experimental conditions for rearrangement to
Chem. Abstr. 1972, 76, 46195q. (b) Sumitomo Chemical Co. Ltd., J apan
Kokai Tokkyo Koho J P 82 106 674, 1982; Chem. Abstr. 1982, 97,
1
82402r. (c) Sumitomo Chemical Co. Ltd., J apan Kokai Tokkyo Koho
J P 82 144 205, 1982; Chem. Abstr. 1983, 98, 12930q.
3) (a) J ohnson, G. A.; Boukma, S. J .; Kim, E. G. J . Pharmacol. Exp.
(
Ther. 1970, 171, 80-87. (b) Von Voigtlander, P. F.; Moore, K. E. Proc.
Soc. Exp. Biol. Med. 1970, 133, 817-820.
(4) Cantrell, A. S.; Engelhardt, P.; H o¨ gberg, M.; J askunas, S. R.;
J ohansson, N. G.; J ordan, C. L.; Kangasmets a¨ , J .; Kinnick, M. D.; Lind,
P.; Morin, J . M. J r.; Muesing, M. A.; Nore e´ n, R.; O¨ berg, B.; Pranc, P.;
Sahlberg, C.; Ternansky, R. J .; Vasileff, R. T.; Vrang, L.; West, S. J .;
Zhang, H. J . Med. Chem. 1996, 39, 4261-4274.
(5) Beilsteins Handbuch der Organischen Chemie; J ulius Springer:
Berlin, 1937; Band XXVII, p 361.
(6) Fromm, E.; Kapeller-Adler, R. J ustus Liebigs Ann. Chem. 1928,
467, 240-274.
1
0.1021/jo000618r CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/05/2000

Reactions of 2-Amino-2-thiazolines with Isocyanates
J . Org. Chem., Vol. 65, No. 26, 2000 8883
Sch em e 1
(or 12) or after prolonged heating in solution. This
suggests that these structures should therefore be the
kinetic and thermodynamic control products.
Recently, Sakae and co-workers17 reviewed the reaction
of 2-bromoethylamine with methylisothiocyanate under
mild conditions. Two byproducts, 4 (R ) R′ ) Me, X ) S)
and 5, were isolated and their structures confirmed by
X-ray crystallography. Thermal isomerization of 4 to 5
also was observed.
8
occur. While the X-ray structure of 8 had previously been
9
determined, these authors established the unequivocal
structure of 9 by X-ray diffraction analysis.10 The results
were interpreted by assuming that the kinetic control
adducts 7 and 9 may undergo a facile intramolecular
rearrangement, even at low temperatures and in the solid
state (path a ), and/or dissociate to starting materials with
further recombination at exocyclic nitrogen to yield the
thermodynamically more stable products 8 and 10 (path
b).
It appears evident from the above results that some
intriguing points of this research have not yet been
elucidated such as the regioselectivity in the attack of
isocyanates and isothiocyanates to N-substituted thia-
zolines and how this substitution pattern affects the
further rearrangement of adducts. Herein, we report an
exhaustive study, corroborated by semiempirical calcula-
tions, on the endo/exo selectivity and the thermal stability
of adducts, and attempts have also been undertaken to
propose a mechanistic pathway consistent with our
experimental observations. These results should certainly
8
11
Given the inherent instability of endo adducts, we
and others1
2,13
have proposed that complex 2-amino-2-
thiazolines derived from carbohydrates form adducts
either with isocyanates or isothiocyanates by selective
attack at exocyclic nitrogen. This rationale was also
extended to the reaction of 2-arylamino-2-thiazolines with
isocyanates and isothiocyanates to form exo adducts such
as 4.14 Recently, this theory had to be retracted by
8
complement those of Rasmussen and his associates,
thereby gaining a further insight into this topic.
determining unequivocally the structure of 11 by X-
diffraction analysis.1
5,16
Remarkably, these compounds
Resu lts a n d Discu ssion
did not undergo rearrangement under the attempted
experimental conditions, either during fusion of neat 11
Syn th esis a n d Str u ctu r a l Ch a r a cter iza tion . The
general preparation of 2-alkyl(aryl)iminothiazolidine hy-
drochlorides 13a -c has been previously reported, and
this can easily be accomplished by reaction of the
1
5
(
7) (a) Cherbuliez, E.; Baehler, B.; J accard, S.; J indra, H.; Weber,
G.; Wyss, G.; Rabinowitz, E. Helv. Chim. Acta 1966, 49, 807-831. (b)
Cherbuliez, E.; Baehler, B.; Espejo, O.; J accard, S.; J indra, H.;
Rabinowitz, J . Helv. Chim. Acta 1966, 49, 2408-2415. (c) Klayman,
D. L.; Maul, J . J .; Milne, G. W. A. Tetrahedron Lett. 1967, 281-284.
d) Klayman, D. L.; Maul, J . J .; Milne, G. W. A. J . Heterocycl. Chem.
968, 5, 517-522. (e) Klayman, D. L.; Milne, G. W. A. Tetrahedron
969, 25, 191-198. (f) Yamamoto, Y.; Yoda, R.; Matsumura, M. Chem.
Pharm. Bull. 1975, 23, 2134-2139. (g) Klayman, D. L.; Woods, T. S.
J . Org. Chem. 1974, 39, 1819-1823. (h) Klayman, D. L.; Woods, T. S.
J . Org. Chem. 1975, 40, 2000-2002. (i) Yamamoto, Y.; Yoda, R.; Sekine,
K. Kyoritsu Yakka Daigaku Kenkyu Nempo 1976, 21, 48-58; Chem.
Abstr. 1976, 87, 135517y. (j) Yamamoto, Y.; Yoda, R.; Koguchi, K.
Kyoritsu Yakka Daigaku Kenkyu Nempo 1978, 23, 38-46; Chem. Abstr.
979, 91, 211309z. (k) Karady, S.; Amato, J . S.; Dortmund, D.; Patchett,
A.; Reamer, R.; Tull, R.; Weinstock, L. Heterocycles 1979, 12, 1199-
202. (l) Mizrakh, L. I.; Polonskaya, L. Yu.; Gvozdetskii, A. N.; Vasil’ev,
A. M. U. S. S. R., SU 1.209.688; Chem. Abstr. 1986, 105, 191068x; (m)
J . Gen. Chem. USSR (Engl. Transl.) 1986, 56, 62-89. (n) Mizrakh, L.
I.; Polonskaya, L. Yu.; Gvozdetskii, A. N. U.S.S.R., SU 1.209.689;
Chem. Abstr. 1986, 105, 208863c.
18
corresponding amines with 2-chloroethyl isothiocyanate.
In our study, we have utilized these compounds as
precursors for the preparation of adducts with isocyan-
ates and isothiocyanates.
(
1
1
As previously mentioned, we have prepared adducts
by condensing 2-aryliminothiazolidines with aryl iso-
15
(
thio)cyanates. These substances have the structure of
N-aryl-2-arylimino-3-thiazolidincarboxamides and car-
bothioamides as in 11 or 12, respectively, which do not
rearrange to their exo counterparts. To ascertain whether
substituents other than aromatic groups influence the
rearrangement of such adducts, the reaction scope has
been extended to include alkyl substituents as well. With
this aim, hydrochlorides 13a -c were reacted with alkyl
or aryl isocyanates and isothiocyanates in pyridine
solution to give, in most cases, crystalline adducts (14
and 15) in good yields. Carbothioamides 14a -d show
spectroscopic data analogous to those of 11, thus confirm-
ing the analogy of these structures. The IR spectra show
1
1
(
8) Rasmussen, C. R.; Villani, F. J . J r.; Mutter, M. S.; Griffin, E. A.
J . Org. Chem. 1986, 51, 1910-1912.
(
(
9) Flippen, J . L.; Karle, I. L. J . Phys. Chem. 1970, 74, 769-773.
10) Rasmussen, C. R.; Villani, F. J . J r.; Griffin, E. A.; Morrison, D.
S.; Olofson, R. A. Acta Crystallogr., Sect. C 1984, 40, 2120-2122.
(
11) (a) Avalos, M.; Babiano, R.; Cintas, P.; Fuentes, J .; J im e´ nez, J .
L.; Palacios, J . C. Heterocycles 1989, 29, 1-4. (b) Avalos, M.; Babiano,
R.; Cintas, P.; J im e´ nez, J . L.; Palacios, J . C. Carbohydr. Res. 1990,
98, 247-258. (c) Avalos, M.; Babiano, R.; Cintas, P.; Fuentes, J .;
J im e´ nez, J . L.; Palacios, J . C. Nucleosides Nucleotides 1990, 9, 137-
-
1
a strong band at ∼1620 cm (CdN stretching) and a
1
-1
weaker one at ∼1550 cm ascribable to the NH bending.
The CdS stretching, however, could not be unequivocally
1
49.
(
12) Ogura, H.; Takeda, K.; Takayanagi, H. Heterocycles 1989, 29,
established since it lies in the region of skeletal absorp-
tions. The fact that the diagnostic NH stretching does
1
171-1177.
19
(13) Fuentes, J .; Moreda, W.; Ortiz, M. C.; Robina, I.; Welsh, C.
Tetrahedron 1992, 48, 6413-6424.
14) Avalos, M.; Babiano, R.; Cintas, P.; J im e´ nez, J . L.; Palacios, J .
C. Heterocycles 1990, 30, 463-469.
15) Avalos, M.; Babiano, R.; Cintas, P.; J im e´ nez, J . L.; Palacios, J .
C.; Valencia, C. Heterocycles 1993, 35, 1237-1246.
16) Dianez, M. J .; Estrada, M. D.; L o´ pez-Castro, A.; P e´ rez-Garrido,
S. Acta Crystallogr., Sect. C 1994, 50, 1640-1642.
(
(17) Sakae, M.; Katsurada, M.; Watanabe, M.; Yoneda, F.; Nishigaki,
S.; Ishida, T. J . Heterocycl. Chem. 1997, 34, 157-160.
(18) (a) Brintzinger, H.; Pfannstiel, K.; Koddebusch, H. Chem. Ber.
1949, 82, 389-399. (b) For a review on haloalkyl isothiocyanates:
Avalos, M.; Babiano, R.; Cintas, P.; J im e´ nez, J . L.; Palacios, J . C.
Heterocycles 1992, 33, 973-1010 and references therein.
(
(

8
884 J . Org. Chem., Vol. 65, No. 26, 2000
Avalos et al.
Sch em e 2
not appear between 3400 and 3300 cm-1 as usual, but
Spectral data of carboxamides 15a -e are equally in
rather as a very weak and broad absorption at ∼3100
accordance with their structures. IR spectra show the
-
1
-1
cm , suggests the participation of the NH group in an
intramolecular hydrogen bonding. This is further con-
firmed by the strong downfield deshielding (11-13 ppm)
of the NH proton. Similar chemical shifts have been
reported for enamines20 and thioureas with intramo-
lecular hydrogen bridges. These noncovalent bonds in
compounds 14 and 15 form quasi six-membered rings,
thus supporting the Z disposition for the CdN bond.
additional amide band at ∼1700-1650 cm . The strong
intramolecular hydrogen bonding also impedes the visu-
alization of the NH stretching, weak and shifted toward
lower wavenumbers. The 13C resonance at ∼151 ppm (Cd
O) is markedly different from that of the CdS group
(∼180 ppm) in carbothioamides, while analogous chemi-
cal shifts are found for the NCdN group (∼158 ppm) and
21
methylene carbons, with a smaller deshielding for NCH
2
as discussed above. Similar resonances for such methyl-
and SCH , respec-
enes (∼49 and ∼26 ppm for NCH
2
2
tively) have been described in other 2-iminothiazolidines
having the exocyclic CdN bond.23 This supports the endo
structures attributed to compounds 15, since such me-
thylenes in the isomeric 2-amino-2-thiazolines, with a
2
3
cocyclic CdN bond, resonate at ∼59 and ∼34 ppm.
Mass spectra have also been performed to elucidate the
structure and fragmentation pattern of compounds 14
and 15. The intensities and the abundance of molecular
ions are both enhanced by the use of an appropriate
counterion (samples were treated with NaI solution) and
ionization matrix using the fast-atom-bombardment mass
spectrometry (FABMS). The peaks M + 1 and M + 23
could easily be detected in most spectra. As described for
similar compounds,7
f,11b
the fragmentation patterns arise
mainly from two decomposition routes (Scheme 2). Path
2
4
a takes place through a McLafferty-type fragmentation
while route b involves the cleavage between the hetero-
cyclic nitrogen and the (thio)carbonyl group. Both of them
originate the most abundant peaks, which undergo
subsequent fragmentations. In general, the most abun-
dant peak is attributable to the isocyanate or isothiocy-
anates coming from the McLafferty fragmentation. It
should be noted that structures with alkyl groups on both
exocyclic nitrogen atoms (e.g., 14c, 14d ) fragment mainly
following the pathway a , with M + 1 as the most
abundant peak. The regioisomeric exo adducts, if present,
would give a similar fragmentation pattern.7
The methylene protons adjacent to the heterocyclic
nitrogen are more deshielded than those vicinal to the
sulfur atom (∆δ
H
∼1.6 ppm). This deshielding should be
attributed to the anisotropy of the thiocarbonyl group,
close to that methylene and in opposite position to the
hydrogen bonding. This is also evidenced by replacing
the CdS group for the carbonyl, which causes a smaller
deshielding between both methylenes (∆δ
H
∼1.1 ppm for
d
carboxamides 15) and in full agreement with the lesser
2
2
anisotropic effect of the CdO group. Similar conclusions
can be extracted from the 13C NMR spectra. In particular,
chemical shifts of the heterocyclic carbons are analogous
to those of other 2-iminothiazolidines.15,23
In addition, the structure of carboxamide 15a has been
25
unequivocally determined by X-ray diffractometry,
which confirms the unifying character of endo adducts
in this type of reactions. Single-crystal X-ray data (Sup-
porting Information, Figure S1) reveal the same structure
as that suggested by the NMR parameters. The five-
membered ring is slightly twisted from an envelope
(
19) Nakanishi, K.; Solomon, P. H. Infrared Absorption Spectroscopy;
Holden-Day: San Francisco, 1977; p 50.
20) G o´ mez-S a´ nchez, A.; Borrachero, P.; Bellanato, J . Carbohydr.
Res. 1984, 135, 101-106.
21) (a) Merkel, W.; Ried, W. Chem. Ber. 1973, 106, 471-483. (b)
Ried, W.; Merkel, W.; M o¨ ssinger, O. Liebigs Ann. Chem. 1973, 1362-
371. (c) Sudha, L. V.; Sathyanarayana, D. N. J . Chem. Soc., Perkin
Trans. 2 1986, 1647-1650.
22) J ackman, L. M.; Sternhell, S. Applications of NMR Spectroscopy
in Organic Chemistry; Pergamon Press: Oxford, 1969; p 378.
23) Soh a´ r, P.; Feh e´ r, G.; Toldy, L. Org. Magn. Reson. 1978, 11,
-11.
(
(
(24) Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric
Identification of Organic Compounds; J ohn Wiley: New York, 1981;
p. 15.
(25) Authors have deposited atomic coordinates for compounds 10
(CCDC-138647) and 15a (CCDC-138648) with the Cambridge Crystal-
lographic Data Centre. The coordinates can be obtained, on request,
from the Director, Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge, CB2 1EZ, U.K.
1
(
(
9

Reactions of 2-Amino-2-thiazolines with Isocyanates
J . Org. Chem., Vol. 65, No. 26, 2000 8885
conformation. Atoms C3 and C2 are 0.218 and 0.314 Å
above and below the plane of atoms S, C(1), and N(1),
respectively. The angle between the planes of both phenyl
groups is 62.6°. The molecules are linked by intramo-
lecular hydrogen bonds between N(3)-H(3a) and N(2)
being the length N(3)‚‚‚N(2) 2.698(2) Å and the angle
N(3)-H(3a)-N(2) 138.5(1)°.
Sch em e 3
For comparative purposes, the X-ray diffraction analy-
sis of compound 10 has also been accomplished, and a
view with the crystallographic numbering scheme is
shown in the Supporting Information (Figure S2). Al-
though the structure of its thioanalogue 8 was estab-
Sch em e 4
9
lished in 1970 by X-ray crystallography, in that time the
tautomeric composition of 8 could not be distinguished.
Compound 10 is a rearranged product with a cocyclic
C-N double bond, which evidences the rapid rearrange-
ment of adducts having no alkyl or aryl substituent at
exocyclic nitrogen. The thiazoline moiety appears in an
envelope conformation in which the carbon atom C(3) is
placed 0.392 Å above the plane occupied by the other four
atoms of the ring. The X-ray crystal structure is consis-
tent wich a structure of thiazoline and not of iminothia-
zolidine. The C(1)-N(endo) bond distance (1.262 Å)
corresponds to a double bond, and it is shorter than the
observed C(1)-N(exo) separation (1.378 Å). There is an
intramolecular hydrogen bonding between N(3)-H(6)
and N(1) [N(3)‚‚‚N(1) 2.716(2) Å; N(3)-H(6)-N(1) 136.6-
Ta ble 1. Tr a p p in g Exp er im en ts of Ad d u cts 11 a n d 12
a ,b
w ith Som e Iso(th io)cya n a tes
4
6 4 6 4
-MeC H - 4-MeC H -
compd PhNCO PhNCS
NCO
NCS
MeNCO MeNCS
1
1
1
2
+
c
+
+
c
+
+
+
-
-
a
In refluxing benzene. b Signs + and - indicate positive and
negative tests, respectively. c Not determined.
of a sample subjected to prolonged refluxing consists of
a ∼1:1 mixture of the iminothiazolidine and MeNCS. The
regioisomeric exo adduct, however, could not be detected.
These results are consistent with a dissociation/recom-
bination process as depicted in Scheme 3.
(1)°]. The molecules are also linked by intermolecular
N(2)-H(5)‚‚‚O hydrogen bonds [N(2)‚‚‚O 2.821(2) Å;
N(2)-H(5)-O 171.4(1)°]. Selected bond length and bond
angles for 10 and 15a are recolleted in the Supporting
Information (Table S1).
Volatile isocyanates or isothiocyanates, such as MeNCS
or MeNCO,27 can be partly eliminated on heating, yield-
ing an equimolar amount of the free iminothiazolidine.
With nonvolatile isocyanates or isothiocyanates (e.g.,
PhNCO), the recombination path is essentially complete
It is noteworthy that the solid-state structure of 10
differs considerably from that of its thioanalogue 8. The
s-trans,s-trans conformation found for the phenyl-
ureido moiety in the crystalline structure of 10 should
be attributed to the intramolecular hydrogen bonding
N-H‚‚‚N(endo), stronger than the intramolecular non-
1
and the H NMR spectrum of the recovered material is
coincidental with that of the starting endo adduct. The
preceding experiments indicate that endo adducts bear-
ing alkyl or aryl substituents at the iminic nitrogen atom
do not rearrange at all.
Tr a p p in g Exp er im en ts. To get further evidence on
a dissociation/recombination mechanism, trapping ex-
periments have also been achieved. When an endo adduct
is heated in the presence of an equimolar amount of
another isocyanate or isothiocyanate, the reaction mix-
ture may eventually contain a new adduct in which the
latter isocyanate or isothiocyanate may replace the
former (Scheme 4).28
bonded interaction S‚‚‚O (1,5-intra mode), which has its
origin in n(CdO) f σ*(C-S) orbital overlap effect.26 In stark
contrast, the intramolecular 1,5-type S‚‚‚S interaction
should largely be responsible for the preferential s-cis
arrangement of 8 in the solid state, as evidenced by the
short intramolecular distance (3.0 Å) between the two
9
sulfur atoms (rvw(S) ) 1.85 Å).
Isom er iza tion Exp er im en ts. To ascertain whether
2
-iminothiazolidine derivatives with N-substituents other
Adducts 11 and 12 were refluxed with different alkyl
and aryl iso(thio)cyanates, and reaction mixtures were
analyzed by TLC and NMR spectroscopy. Results are
summarized in Table 1, indicating the cases in which the
thiazolidine ring was captured by the added heterocu-
mulene. Table 2 collets the energetics of these transfor-
mations evaluated by PM3 calculations (vide infra).
Thus, the resulting crude of 11 plus PhNCO consisted
than hydrogen at exocyclic nitrogen are susceptible to
rearrange upon heating, some carbothioamides and car-
boxamides were melt or refluxed in benzene solution.
After cooling and/or solvent evaporation, the resulting
1
residues were dissolved in CDCl
NMR.
3
and monitored by H
We have learned that adducts in which both exocyclic
nitrogen atoms bear aryl substituents do not isomerize
1
to exo adducts.15 Similarly, adducts 15d and 15e did not
of a 3:2 mixture (by H NMR integration) of adducts 11
undergo the rearrangement to exo adducts. Thus, 15d
was recovered unaffected and gave a clear H NMR
spectrum, and 15e showed a minor decomposition to the
starting alkyliminothiazolidine without evidencing the
formation of an exo adduct.
1
(27) Methyl isocyanate is believed to be the main hazardous agent
released in the sadly famous Bhopal incident. For an excellent chemical
investigation of this issue see: D’Silva, T. D. J .; Lopes, A.; J ones, R.
L.; Singhawangcha, S.; Chan, J . K. J . Org. Chem. 1986, 51, 3781-
3
788.
28) (a) Klayman and co-workers once described the replacement of
(
In the case of carbothioamide 14c, with an alkyl
PhNCO by 1-naphthyl isothiocyanate in the exo adduct derived from
2-amino-2-thiazoline (ref 7d). (b) Similar replacement in 2-amino-2-
oxazolines derivatives were described: Bosc, J . J .; J arry, C.; Ouhabi,
J .; Laguerre, M.; Carpy, A. Can. J . Chem. 1996, 74, 1341-1347. (c)
For other acyl groups rearrangement: Kaugars, G.; Martin, S. E.;
Nelson, S. J .; Watt, W. Heterocycles 1994, 38, 2593-2603.
1
substituent at the iminic nitrogen, the H NMR spectrum
(26) Nagao, Y.; Hirata, T.; Goto, S.; Sano, S.; Kakehi, A.; Iizuka,
K.; Siro, M. J . Am. Chem. Soc. 1998, 120, 3104-3110.

8
886 J . Org. Chem., Vol. 65, No. 26, 2000
Avalos et al.
Ta ble 2. Rea ction En th a lp ies for Tr a p p in g Exp er im en ts
Sch em e 5
∆
HRa
entry
R
X
R1
Y
(kcal mol-1)
1
2
3
4
5
6
7
Ph
Ph
Ph
Ph
Ph
Me
Me
S
S
S
O
O
S
Ph
O
O
S
-20.45
-19.56
-1.21
Me
Me
Me
Me
Ph
S
+19.24
+0.89
O
O
O
-18.79
-0.63
O
Me
a
Determined by PM3 calculations.
and 12, evidencing that the starting adduct releases
PhNCS and 2-phenyliminothiazolidine being the latter
trapped by the isocyanate (Table 2, entry 1). The proton
spectrum shows two NH resonances, at 14.06 and 12.00
ppm, characteristic of both adducts, and different reso-
The reaction was unsuccessful in pyridine solution as
well as in a mixture of pyridine-Et N under reflux since
3
deprotonation could not be achieved. However, treatment
of N,N′-diphenylurea with NaH in THF solution and
subsequent dropwise addition of 2-chloroethyl isothiocy-
anate afforded a crystalline, chromatographically homo-
geneous compound having the same spectral data of the
nances for the NCH
In the presence of 4-MeC
2
groups (∆δ ) 0.52 ppm, vide supra).
NCS, the resulting spectra
6
H
4
consisted of two and very similar signal sets attributable
to adducts 11 and 14a .
On the contrary, reaction of 11 with MeNCO led almost
1
rearranged compound 12. Furthermore, H NMR spectra
1
13
exclusively to the formation of 15c. The H and C NMR
spectra of the crude reaction were identical to those of
an authentical sample of 15c. Neither the deshielded
of 12 were obtained by performing the reaction in THF-
d at -20 °C, immediately recording the spectra at that
8
probe temperature, and then at regular intervals from
that temperature to ambient temperature. NMR spectra
verified the presence of 12 whereas resonances ascribable
to the protons of 16 could not be identified.
NCH
2
methylene (at ∼4.9 ppm) nor the thiocarbonyl
resonance (at ∼180 ppm) could be detected, thus discard-
ing the recombination pathway with PhNCS. This result
evidences the greater stability of isocyanate-based ad-
ducts than those derived from isothiocyanates (Table 2,
entry 2). The reaction of 11 with MeNCS gave a mixture
Th eor et ica l R a t ion a liza t ion . By far the experi-
mental results of the reactions of 2-amino-2-thiazo-
lines (or their tautomeric 2-iminothiazolidines) with
isocyanates or isothiocyanates can be summarized as
follows: (a) adducts with isocyanates are more stable
than those of isothiocyanates; (b) the attack of hetero-
cumulenes occurs regiospecifically at endocyclic nitrogen
to give the endo adducts as the kinetically favored
products; (c) if the exocyclic nitrogen is unsubstituted,
the endo adducts rearrange to form the exo ones; (d) no
rearrangement occurs if the exocyclic nitrogen is substi-
∼
1:3 of adducts 11 and 14b. This also agrees with the
enhanced stability of adducts derived from alkyl isothio-
cyanates with respect to their aromatic counterparts
(Table 2, entry 3).
Experiments with 12 gave positive results with isocy-
anates only and failed with isothiocyanates (Table 2,
entry 4 and inverse of entry 1). The crude reaction of 12
6 4
plus 4-MeC H NCO consisted of an almost 1:1 mixture
of 12 and 15b. Again, the reaction of 12 with MeNCO
29
tuted. A theoretical study using PM3 semiempirical
1
afforded the adduct 15c. In this case, however, the H
calculations was accomplished to justify the reactivity
and regiochemical outcome as well as the stability of
adducts. It is fair to say that related studies on the
reaction of 2-amino-2-oxazolines with isocyanates and
isothiocyanates have also been carried out at a semi-
NMR spectrum also detected a second byproduct, N,N′-
dimethylurea (δNH ) 4.43 ppm, δCH3 ) 2.79 ppm),
generated presumably by reaction of MeNCO with traces
of moisture.
To test whether the dissociative pathway also works
with adducts containing alkyl substituents, compound
28b
empirical level too.
(
a ) Ad d u ct F or m a tion . The first issue to be ad-
dressed concerns the energetic profile of reactions of
-iminothiazolidine derivatives with iso(thio)cyanates.
1
5d was subjected to the aforementioned conditions in
the presence of 4-MeC
both adducts, 15d and 15f.
6
H
4
NCO to give a ∼1:2 mixture of
2
Energetics data of semiempirical calculations (PM3)
collected in Table 3 indicate the higher stability of
adducts derived from isocyanates than their sulfur
counterparts. Likewise, reactions with alkyl isocyanates
or isothiocyanates usually yield more stable adducts than
The preceding experiments prove once again that endo
adducts derived from N-alkyl- or aryliminothiazolidines
and isocyanates or isothiocyanates are the kinetic and
thermodynamic control products without further ten-
dency to isomerize. This does not mean, at least a priori,
that exo adducts cannot be obtained by an indirect
method. It is known that heterocyclic NH groups can be
efficiently acylated by haloalkyl isothiocyanates in the
presence of base.1 Accordingly, we reasoned that iso-
meric structures 16 could be obtained from N,N′-di-
phenylurea and 2-chloroethyl isothiocyanate, thus form-
ing a transient 2-chloroethylthiourea that cyclizes in-
with aryl ones.
When a DFT calculation (B3LYP/6-31G*)30 of a pair
of representative isocyanate and isothiocyanate adducts
8b
(29) Stewart, J . J . P. J . Comput. Chem. 1989, 10, 209-220.
(30) (a) Parr, R. G.; Yang, W. Density Funtional Theory of Atoms
and Molecules; Oxford University Press: Oxford, 1989. (b) Becke, A.
D. J . Chem. Phys. 1993, 98, 5648-5652. (c) Lee, C.; Yang, W.; Parr,
R. Phys. Rev. B 1988, 37, 785-789. (d) Baerends, E. J .; Gritsenko, O.
V. J . Phys. Chem. A 1997, 101, 5383-5403.
N
tramolecularly by a S 2 pathway (Scheme 5).

Reactions of 2-Amino-2-thiazolines with Isocyanates
J . Org. Chem., Vol. 65, No. 26, 2000 8887
Ta ble 3. Rea ction En th a lp ies for Ad d u cts F or m a tion
Ta ble 5. Rela tive Sta bilities (k ca l m ol-1) of Com p ou n d s
2
9-39
compd
a
b
c
2
3
31
32
9a
0
0.00
+3.08
+3.56
-3.61
-1.35
+0.49
+0.49
-1.48
-1.48
-3.77
-3.77
0.00
+3.51
+4.10
-3.66
-1.86
+0.37
+0.30
-0.92
-2.15
-3.26
-2.67
0.00
+3.39
+4.12
-3.87
-1.42
-0.52
+1.12
-1.88
-1.76
-3.60
-2.87
HRa
∆
R1
(kcal mol-1)
R
X
3
3
H
H
H
Me
Me
Me
Ph
Ph
Ph
H
H
O
O
O
O
O
O
O
O
O
S
S
S
S
S
S
S
S
S
-20.59
-17.79
-17.15
-24.81
-22.19
-21.60
-23.38
-20.52
-21.41
-3.00
0.47
34
35
36
37
38
39
Me
Ph
H
Me
Ph
H
Me
Ph
H
Me
Ph
H
Me
Ph
H
Me
Ph
a
Energies are abitrarily referred to this structure.
26-28, and in fact, the simulated study provided the
alternative structures 22-24, respectively.
H
H
1.73
Me
Me
Me
Ph
Ph
Ph
-7.52
-4.03
-2.81
-5.69
-2.17
-0.96
a
Determined by PM3 calculations.
Ta ble 4. Rela tive Sta bility (k ca l m ol-1) of Ad d u cts 18-25
X
18 a
19
20
21
22
23
24
25
S
O
0.00 +3.56 +3.08 +0.49 -1.48 -3.61 -3.77 -1.35
0.00 +4.17 +3.37 +1.68 -2.46 -2.64 -3.92 -0.16
a
Energies are arbitrarily referred to this structure.
1
(
R ) R ) Me; Table 3) was developed, the same order of
Table 4 collects the potential energy differences of
compounds 18-25, referred arbitrarily to 18, which were
determined with the PM3 Hamiltonian. These data
reveal that exo adducts 22-25 are more stable than the
endo structure 18, whereas structures 19-21 are ener-
getically disfavored. The energy differences between the
structures of endo and exo adducts lie in the average
range ∼1.5-4.0 kcal mol , which justifies the rearrange-
ment of the former to the more stable exo adducts.
Next, we have tried to rationalize the influence of
substituents at exocyclic nitrogen atoms on the stability
of adducts. With this aim, different substitution patterns
have been considered for frameworks 29-41.
stability was observed, validating our semiempirical
results.31
(
b) Ad d u ct Rea r r a n gem en t. Second, the conforma-
tional or tautomeric stability of adducts should be
analyzed. With this goal, a series of simplified models,
also applicable to oxazoline derivatives, have been com-
puterized semiempirically. In the case of endo adducts,
not only the conformer 18 should be considered, but also
-1
7, 19, and 20, despite X-ray diffraction data,8
,15,16
1
support a Z stereochemistry for the CdN double bond,
and the intramolecular hydrogen bridge causes an s-trans
disposition around the N-CX bond. This intramolecular
bonding cannot be established in the alternative s-cis
conformer 17. Furthermore, the PM3 calculations could
not locate any minimum for the latter structure, which
evolved into 18. Table 4 also shows that the E isomers
1
9 and 20 are appreciably less stable than 18.
Table 5 summarizes the energy differences for com-
pounds 29-39, evidencing the greater stability of exo
adducts 32, 33, and 36-39 with respect to their endo
counterparts 29-31.2 Again, no minima were obtained
for 40 and 41 at this theory level, and both structures
evolved into 32.
For exo adducts, eight possible structures have been
8b
considered (21-28). Structures 23-26 are geometrically
compatible with an intramolecular hydrogen bonding,
while the tautomeric forms 21 and 22 exhibit the skeletal
9
These results clearly corroborate the experimental
disposition of the exo adduct 8 and 23 that of 10, both
7
i
works by Yamamoto and co-workers, who demonstrated
of them determined by X-ray analysis. As before, theo-
retical calculations were unable to locate minima for
the transformation of the structure 29b into 32b, and
8
by Rasmussen et al., who pointed out the easy rear-
) -24.52 kcal mol-1, X ) O and -19.14 kcal
31) DFT results: ∆H
R
-1
rangement of 9 (structure 29c) to the exo adduct 10
(structure 32c).
(
mol , X ) S.

8
888 J . Org. Chem., Vol. 65, No. 26, 2000
Avalos et al.
Ta ble 6. Rela tive Sta bility (k ca l m ol-1) of Com p ou n d s
4
2-50
compd
a
b
c
d
e
f
4
4
4
4
4
4
4
4
5
2a
3
4
5
6
7
8
9
0
0.00
+4.77
+4.36
+2.59
+5.16
+6.39
+6.39
+2.59
+2.59
0.00
+4.78
+4.48
+2.82
+4.54
+6.59
+6.28
+2.82
+5.66
0.00
0.00
+3.34
+3.35
+4.49
+7.24
+5.54
+5.54
+6.00
+6.00
0.00
+3.00
+3.33
+5.86
+7.10
+7.48
+5.36
+4.42
+5.80
0.00
+4.18
+6.17
+7.51
+8.79
+8.59
+6.91
+5.96
+5.59
+4.45
+4.63
+2.86
+5.16
+6.39
+6.42
+3.65
+4.31
a
Energies are abitrarily referred to this structure.
Ta ble 7. Rela tive Sta bility (k ca l m ol-1) of Str u ctu r es
1-54
5
When the exocyclic nitrogen atom of the heterocycle is
also substituted, the computational estimation of energies
differs considerably from the above results, as evidenced
in Table 6 for model compounds 42-50. Structures as
compd
a
b
c
1
3
6-39 cannot be adopted when R * Η and were ruled
5
5
5
5
1a
2
3
0.00
0.00
+3.02
+4.55
0.00
-0.01
-1.48
-0.01
0.00
+0.35
-0.12
-0.21
out.
4
a
Energies are abitrarily referred to this structure.
Sch em e 6
equivalent to a [(2σ + 2π) + 2π] ene reaction from a
formal standpoint. The second possibility is a stepwise
mechanism involving the intermediacy of dipolar species
The search for true minima in the case of 49a , 49b,
(Scheme 6).
and 50a resulted in the location of the corresponding
adducts 45. The endo adducts 42 become both the kinetic
and thermodynamic control products with no tendency
to convert into exo adducts. Thus, compounds 12 and 15c
In a concerted mechanism, the formation of endo
adducts arises from 2-amino-2-thiazoline tautomers while
the 2-iminothiazolidine forms lead to exo adducts. This
pathway suggests an explanation for the reversibility
observed in adducts of 2-amino-2-thiazoline with phenyl
isocyanate or isothiocyanate and the McLafferty-type
fragmentation24 (a retro-ene process) of adducts detected
by mass spectrometry.
First, the relative stability of the possible conformers
and tautomers of 2-amino-2-thiazoline and its N-methyl
and N-phenyl derivatives was examined. A PM3 semi-
empirical calculation on structures 51-54 is shown in
Table 7.
(
structures 42f and 42e, respectively) do not undergo
rearrangement after prolonged heating. Substances with
alkyl substituents on the nitrogen atom attached to C-2
do not rearrange either as evidenced by the experiments
of Yamamoto and co-workers7 with structure 42b and
those of the present work.
f,7i
(
c) Regioch em istr y. Th e Mech a n istic P a th w a ys.
It would be desirable to have an additional assessment
of the endo regiospecificity observed in this type of
reactions. The postulates of the frontier molecular orbital
The reactive tautomers capable of undergoing a peri-
cyclic mechanism (Scheme 6) should be 51 and 53. It
(
FMO) theory offer a simple, often satisfactory, approach
to evaluate the regioselectivity of numerous organic
reactions.32 This might also give some insight into the
reaction outcome. There are two possible scenarios. The
adducts could have been formed by a concerted pericyclic
mechanism with a six-electron cyclic transition state (TS),
(
32) (a) Fleming, I. Frontier Orbitals and Organic Chemical
Reactions; Wiley: New York, 1976. (b) Gilchrist, T. L.; Storr, R. C.
Organic Reactions and Orbital Symmetry; Cambridge University
Press: London, 1979.

Reactions of 2-Amino-2-thiazolines with Isocyanates
J . Org. Chem., Vol. 65, No. 26, 2000 8889
Sch em e 7
Ta ble 8. Hea t of F or m a tion (k ca l m ol-1) a n d Bon d
Dista n ces (Å) for th e En d o Ad d u ct P r ocess
should also be noted that 51 (or 52) become the most
stable tautomers when R ) H, whereas the iminothia-
zolidines 53 and 54 are energetically favored if R ) Me
or Ph, respectively. Bearing this in mind, our next target
was to evaluate the energy of FMOs of the heterocycles
and heterocumulenes (Table S2).
entry
51b MeNCO TS1
I
TS2
42b
1
2
3
4
5
6
7
8
∆Hf
20.14 -18.56 11.67 2.88 6.63 -20.61
dNendo‚‚‚C(O)
2.09 1.52 1.50
1.30 1.35 1.37
1.82 1.69 1.43
1.02 1.06 1.25
1.39 1.35 1.33
1.33 1.38 1.40
2.72 2.55 2.50
1.46
1.42
1.01
1.90
1.30
1.44
2.70
dN(CO)‚‚‚C(O)
dN(CO)‚‚‚H
dNexo‚‚‚H
dC2‚‚‚Nexo
dC2‚‚‚Nendo
dNexo‚‚‚N(CO)
1.26
Energy values for HOMOs/LUMOs of reactants allow
1.00
1.42
1.31
us the determination of ∆E
1
) HOMOheterocycle
-
-
A
LUMOheterocumulene and ∆E
2
)
HOMOheterocumulene
3
2
LUMOheterocycle, according to the FMO approach.
simple inspection of data obtained (see Supporting In-
formation) reveals that ∆E < ∆E in most cases, and
Ta ble 9. Hea t of F or m a tion (k ca l m ol-1) a n d Bon d
Dista n ces (Å) for th e Exo Ad d u ct P r ocess
1
2
this leads to consider the HOMOheterocycle/LUMOheterocumulene
interaction as prevalent, although figures for phenyl
isocyanate and phenyl isothiocyanate result in compa-
entry
53b MeNCO TS1
I
TS2
45b
1
2
3
4
5
6
7
8
∆Hf
18.66 -18.56 11.89 5.07 8.99 -17.49
dNexo‚‚‚C(O)
dN(CO)‚‚‚C(O)
dN(CO)‚‚‚H
dNendo‚‚‚H
dC2‚‚‚Nendo
2.06 1.54 1.51
1.30 1.35 1.37
1.83 1.69 1.41
1.02 1.05 1.25
1.42 1.37 1.35
1.31 1.36 1.38
2.69 2.51 2.50
1.47
1.42
1.02
1.89
1.32
1.42
2.68
rable magnitudes of ∆E
1
2
and ∆E .
1.26
The AO coefficients at endocyclic nitrogen of 2-amino-
-thiazoline derivatives are very similar to those of
-iminothiazolidines at their exocyclic nitrogen, so that
2
2
1.00
1.45
1.29
dC2‚‚‚Nexo
the exclusive or preferential formation of endo adducts
cannot be rationalized in terms of the FMO theory
assumptions (Table S3).
dNendo‚‚‚N(CO)
carried out on a simplified reaction of both tautomers of
-methylamino-2-thiazoline (51b and 53b) with methyl
As mentioned above, a stepwise process should not be
ruled out. Bosc and co-workers have rationalized the endo
addition of aryl isocyanates to 2-amino-2-oxazolines based
on the higher reactivity index of endocyclic nitrogen
atom.33 The reactivity index is defined as electronic
density of an atom in the HOMO, in other words,
2
isocyanate (Scheme 7). However, attempts to locate
the transition structures of the concerted path were
unsuccessful.
The energetics of the stepwise reactions of tautomers
5
1b and 53b with MeNCO have been calculated and two
HOMO
2
2
(c
i
i
) being c the AO coefficient of the atom consid-
TSs and one dipolar intermediate have to be considered
in each case (Tables 8 and 9, entry 1). The intrinsic
reaction coordinate (IRC)34 calculations demonstrate in
both cases that TS1 and TS2 connect the reactant and
the products with the dipolar intermediate (I).
Figures 1 and 2 displays the optimized geometries for
the four transition structures and the two intermediates
for endo and exo stepwise pathways. In both cases, the
process occurs after the initial nucleophilic attack of the
azomethine nitrogen to the isocyanate group leading to
relatively early transition states on the reaction coordi-
nates (Tables 8 and 9, entry 2).
Dihedral angles collected in Table 10 represent a
strong evidence supporting the quasi-planar geometries
of TS1, TS2, and the intermediate I for both endo and
exo processes. The frontal approach of thiazoline to the
isocyanate is a consequence of the nuclephilic attack of
ered. Although the computation was achieved with a
simple CNDO/2 method, this result explains the selective
attack of an isocyanate at the endocyclic nitrogen.
However, the higher PM3 calculation of 2-amino-2-
thiazolines gives similar reactivity indexes at endocyclic
and exocyclic nitrogen atoms. Given the dipolar character
of intermediates in a stepwise addition, not only the
orbital contribution but also the Coulombic interactions
must be added to the energy balance, being favored the
attack from the more negative center of the heterocycle
to the positive center of the heterocumulene. However,
the consideration of this parameter could not differentiate
between endo and exo approaches.
The evaluation of the energy changes, e.g. activation
and reaction energies, for the concerted and stepwise
reactions has also been performed. Calculations were
2
the unshared pair of the sp -hybridized nitrogen atom.
(33) (a) Bosc, J . J .; Forfar, I.; J arry, C.; Ouhabi, J .; Leger, J . M.;
Carpy, A. Arch. Pharm. (Weinheim) 1990, 323, 561-566. (b) J arry, C.;
Forfar, I.; Thomas, J .; Leger, J . M.; Laguerre, M. Heterocycles 1993,
(34) (a) Fukui, K. Acc. Chem. Res. 1981, 14, 363-368. (b) Head-
Gordon, M.; Pople, J . A. J . Chem. Phys. 1988, 89, 5777-5786.
3
6, 2465-2473.

8
890 J . Org. Chem., Vol. 65, No. 26, 2000
Avalos et al.
F igu r e 1. Atomic charges of transition structures and intermediate for endo adduct process.
F igu r e 2. Atomic charges of transition structures and intermediate for exo adduct process.
Ta ble 10. Dih ed r a l An gles (Deg) of TSs a n d In ter m ed ia tes for th e En d o a n d Exo Ad d u ct P r ocesses
endo
exo
angle
TS1
I
TS2
angle
TS1
I
TS2
N(CO)-C(O)-Nendo-C2
C(O)-Nendo-C2-Nexo
Nendo-C2-Nexo-H
-2.7
-12.4
15.7
1.2
-2.0
1.8
-14.8
-10.8
-4.0
N(CO)-C(O)-Nexo-C2
C(O)-Nexo-C2-Nendo
Nexo-C2-Nendo-H
-18.6
-11.0
25.5
0.0
0.0
0.0
0.0
-10.4
5.8
-1.4
-1.0
C2-Nexo-H-C(O)
2.7
0.5
-1.0
C2-Nendo-H-C(O)
6.0
This situation contrasts with the well-known “two-plane
orientation complex” which precedes the bond-forming
and bond-breaking processes of a pericyclic reaction.
amino-2-thiazoline or its tautomer during the addition
reaction.
The endo addition exhibits two energetic barriers of
-
1
Both TSs also feature close N-C bond lengths (2.06
and 2.09 Å), thereby suggesting a similar nucleophilic
character at the azomethine nitrogen atoms. Likewise,
the isocyanate moiety remains practically unaffected in
both TSs as evidenced by the bond angle N-C-O of
about 160° (the bond angle N-C-O at the methyl
isocyanate is 168.3°).
10.1 and 3.8 kcal mol , respectively, to afford 42b in a
-
1
slightly exothermic process (22.2 kcal mol ). It should
be noted the relatively low energy barriers assuming
that the transformation occurs with charge separation.
Nevertheless, both the positive and negative charges at
the dipolar zwitterion are largely delocalized through
their neighboring atoms. Concerning the exo addition,
yielding 45b, the process is less exothermic as well (∼17.9
Nevertheless, in the intermediates where the N-C
bond is almost completely formed (1.52-1.54 Å), the
carbonyl carbon of the isocyanate possesses a trigonal
geometry. A key structural feature of intermediates and
TSs is the hydrogen bonding interaction between the
nitrogen atoms of both fragments. The intramolecular
bond distances Nendo(exo)‚‚‚N(CO) are predicted to be e2.72
Å (Tables 8 and 9, entry 8), in agreement with the values
found for 10 and 15a by X-ray analyses.
-
1
kcal mol ) via two close activation barriers of 11.8 and
-
1
3
.9 kcal mol . Again, the endo approach is both kinetic
and thermodynamically favored.
Con clu d in g Rem a r k s
The preceding results constitute an in-depth explora-
tion on the reactivity of 2-amino-2-thiazolines toward
isocyanates and isothiocyanates and the rearrangement
of the resulting adducts. The endo regiospecificity ob-
served appears to be a general and unifying rule for these
five-membered heterocycles having two nonequivalent
amidine-type nitrogen atoms, which enables selective
functionalizations. Additional and interesting examples
also illustrate this tendency in other heterocyclic systems,
even with aromatic character. Thus, 2-hydrazino-2-
thiazoles (55) react with isocyanates to give the deriva-
tives 56, in which the attack occurs at the exocyclic NH
group.35 This is however consistent with an attack at the
The reaction does not stop after the nucleophilic
attack: proton transfer occurs in the second step. When
the transition state is reached the NH‚‚‚N distances are
1
.25 and ∼1.42 Å for each structure. The bond angle
N-H-N (∼134°) is compatible with an almost planar
transition state (Table 10).
The progression of bond lengths C-N f CdN and
CdN f C-N at the stationary points through the
reaction coordinate (Tables 8 and 9, entries 6 and 7) does
reflect the structural variation experienced by 2-methyl-

Reactions of 2-Amino-2-thiazolines with Isocyanates
J . Org. Chem., Vol. 65, No. 26, 2000 8891
Sch em e 8a
Sch em e 9a
a
Reagents: (i) ClCONCS or EtOCONCS.
more nucleophilic endo nitrogen atom followed by sub-
sequent rearrangement to the exocyclic position of an
unsubstituted 2-aminoheterocycle. Similarly, 3-amino-
a
Reagents: (i) MeCNO, Me2SO or MeCN, 0-25 °C, NEt3; (ii)
3
6
1
,2,4-triazoles (57, X ) CH) or 5-amino-1,2,3,4-tetra-
37
MeNCS; (iii) NaNO2, 2 M HCl, rt.
zoles (57, X ) N) react with iso(thio)cyanates and
alkylating agents38 at a ring nitrogen to give endo adducts
clarifies the misassignment of structures attributed
to numerous isomers in the past, particularly those
with biological properties. Thus, it is well-known that
isocyanates and isothiocyanates are powerful carbamoyl-
ating and thiocarbamoylating agents and their interac-
tion with amino groups of macromolecules are relevant
in understanding the process of carcinogenesis and its
clinical treatment.41
(58) that underwent rearrangement to 59 on raising the
temperature.
Exp er im en ta l Section
Gen er a l Meth od s. All melting points were determined on
a capillary apparatus and are uncorrected. Solid-state IR
spectra were recorded in KBr pellets and oily samples as
1
13
obtained. H and C NMR spectra were recorded at 200 and
0.3 MHz, respectively. Chemical shifts were reported in ppm
5
1
3
(δ) using Me
4
Si as internal standard. The multiplicity of
C
7
g,39
Not only 2-amino-2-thiazoline
but also 2-amino-2-
NMR spectra was determined by DEPT measurements. FAB
mass spectrometry was performed using Xe (and/or Ar) atoms
having a kinetic energy equivalent to 7 kV at an accelerating
voltage of 4 kV. Determinations were made by adding sodium
ions in the form of sodium iodide; and glycerol, 1-thioglycerol,
and 3-nitrobenzyl alcohol were used as the matrix solution.
Analytical TLC was developed on precoated plates with silica
gel Merck 60 GF254 of 2 mm thickness. Elemental analyses
were performed by the Servicio de Microan a´ lisis, Universidad
de Extremadura. Reagents were purchased from commercial
suppliers or prepared by literature methods. CAUTION:
2-chloroethyl isothiocyanate1 is a potential carcinogenic agent
and should be handled with extreme care. All reactions
involving isocyanates and isothiocyanates should be conducted
in a well-ventilated hood.
selenazoline, 2-amino-5,6-dihydro-4H-1,3-thiazine,7g and
7
g
2
-amino-2-oxazolines (62)33b react with the highly reac-
tive ethoxycarbonyl isothiocyanate to give exclusively
adducts resulting from an endo addition (60 or 63).
However, the reaction with benzoyl isothiocyanate pro-
duces a mixture of endo and exo adducts (Scheme 8).7h
Remarkably, a recent synthesis of the antitumor drug
Temozolomide (67)40 clearly illustrates the differential
reactivity of endo and exo positions toward heterocumu-
lenes (Scheme 9). The key step in this synthesis is the
reaction of 65 with methyl isocyanate, which gives
selectively the ureido precursor 66. However, the thio-
analogue, thiotemozolomide (68), could not be obtained
as the condensation of 65 with methyl isothiocyanate took
place at the exo position, presumably by an in situ
rearrangement of the endo adduct, affording 69.
8a
Com p u ta tion a l Meth od s. Semiempirical calculations on
reactants, transition structures, and reaction products were
performed using the PM3 method from the Gaussian 94
29
42
package of programs. All stationary points were located on
In summary, the present study provides a reasonable
interpretation of this type of reactivity and outlines
some mechanistic considerations. Moreover, this survey
the potential energy surfaces and characterized by frequency
calculations according to the number of negative vibrational
frequencies.43 The corresponding geometries were subse-
quently refined by minimizing the energy with full optimiza-
(
35) Berg, S. S.; Toft, M. P. Eur. J . Med. Chem.-Chim. Ther. 1975,
0, 268-272.
36) Hirata, T.; Wood, H. B. J r.; Driscoll, J . S. J . Chem. Soc., Perkin
Trans. 1 1973, 1209-1212.
37) Denny, G. H.; Cragoe, E. J ., J r.; Rooney, C. S.; Springer, J . P.;
Hirshfield, J . M.; McCauley, J . A. J . Org. Chem. 1980, 45, 1662-1665.
38) Selectivity with electrophiles other than iso(thio)cyanates may
1
(41) (a) Ames, B. N. Science 1979, 204, 587-593. (b) Montgomery,
J . A. Acc. Chem. Res. 1986, 19, 293-300. (c) Silverman, R. B. The
Organic Chemistry of Drug Design and Drug Action; Academic Press:
San Diego, 1992; pp 251-254.
(
(
(42) (a) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith, T.; Petersson,
G. A.; Montgomery, J . A.; Raghavachari, K.; Al-Laham, M. A.;
Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.; Cioslowski, J .;
Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala,
P. Y.; Chen, W.; Wong, M. M.; Andres, J . L.; Replogle, E. S.; Gomperts,
R.; Martin, R. L.; Fox, D. J .; Binkley, J . S.; Defrees, D. J .; Baker, J .;
Stewart, J . P.; Head-Gordon, M.; Gonzalez, C.; Pople, J . A. Gaussian
94, Revision D.1; Gaussian, Inc.: Pittsburgh, PA, 1995. (b) Frisch, M.
J .; Frisch, Æ.; Foresman, J . B. Gaussian 94 User’s Reference; Gaussian,
Inc.: Pittsburgh, PA, 1994-1996.
(
be markedly different. However, alkylation of 2-amino-2-thiazoline with
Michael acceptors occurs with complete endo regioselection yielding
stable adducts; see: Kaugars, G.; Martin, S. E.; Nelson, S. J .; Watt,
W. Heterocycles 1994, 38, 2593-2603.
(
39) Capuano, L.; Schrepfer, H. J . Chem. Ber. 1971, 104, 3039-3047.
These authors reported a structure arising from attack to the exocyclic
7
g
nitrogen, which was later corrected by Klayman et al.
40) (a) Wang, Y.; Stevens, M. F. G.; Thomson, W. T.; Shutts, B. P.
(
J . Chem. Soc., Perkin Trans. 1 1995, 2783-2787. (b) Wang, Y.; Lowe,
P. R.; Thomson, W. T.; Clark, J .; Stevens, M. F. G. J . Chem. Soc., Chem.
Commun. 1997, 363-364.
(43) McIver, J . W.; Komornicki, A. J . Am. Chem. Soc. 1972, 94,
2625-2633.

8
892 J . Org. Chem., Vol. 65, No. 26, 2000
Avalos et al.
tion of all geometric variables (bond lengths, bond angles, and
dihedral angles).
48.9, 25.7, 20.8. Anal. Calcd for C17
N, 13.50. Found: C, 65.52; H, 5.44; N, 13.21.
H
16
N
3
OS: C, 65.78; H, 5.19;
Gen er al P r epar ation of (Z)-2-Alkyl(ar yl)im in o-N-alkyl-
(Z)-2-P h en ylim in o-N-m eth yl-3-th ia zolid in eca r boxa m -
id e (15c): 70% yield from 13a and MeNCO; mp 129-131 °C;
(
a r yl)th ia zolid in eca r both ioa m id es (14a -d ). To a solution
-
1
of the corresponding 2-alkyl- or 2-phenyliminothiazolidine
IR (KBr) 3080, 3000-2800, 1600, 1585, 1535, 760, 680 cm
;
1
5
1
hydrochlorides (13a -c, 1.0 mmol) in pyridine (2 mL) was
added the alkyl(aryl) isothiocyanate (1.0 mmol), and the
reaction mixture was kept at room temperature for 24 h. Then,
H NMR (CDCl
J ) 7.0 Hz, 2H), 3.09 (t, J ) 7.0 Hz, 2H), 2.89 (d, J ) 4.7 Hz,
3H); 13C NMR (CDCl
) δ 158.0, 154.2, 149.7, 129.1, 124.5,
121.3, 48.9, 26.5, 25.8. Anal. Calcd for C11 OS: C, 56.14;
3
) δ 9.40 (bs, 1H), 7.38-6-91 (m, 5H), 4.29 (t,
3
it was poured into ice-water and extracted with CH
2
Cl
2
. The
13 3
H N
combined organic extracts were washed with 3 N hydrochloric
acid, a saturated aqueous solution of sodium hydrogencarbon-
H, 5.56; N, 17.85. Found: C, 56.25; H, 5.36; N, 17.47.
(Z)-2-[(2,2-Dim eth oxy)eth yl]im in o-N-p h en yl-3-th ia zo-
lid in eca r boxa m id e (15d ): 86% yield from 13b and PhNCO;
mp 63-64 °C; IR (KBr) 3080-2840, 1685, 1635, 1600, 1560,
ate, and water, dried over anhydrous MgSO
to give the title compounds as homogeneous oils or crystals.
Z)-2-P h e n ylim in o-N -(4-t olyl)-3-t h ia zolid in e ca r b o-
th ioa m id e (14a ): 80% yield from 13a and 4-MeC NCS; mp
19-121 °C; IR (KBr) 3000-2700, 1600, 1540, 815, 730,
4
, and evaporated
-
1
1
1
500, 1450, 1360, 1300, 1185, 1075, 960, 745, 690 cm ; H
NMR (CDCl ) δ 12.31 (bs, 1H), 7.52-7.04 (m, 5H), 4.66 (t, J )
.6 Hz, 1H), 4.29 (t, J ) 7.0 Hz, 2H), 3.45 (d, J ) 5.6 Hz, 2H),
(
H
4
3
6
5
1
6
4
1
3
-
1
1
3.43 (s, 6H), 3.20 (t, J ) 7.0 Hz, 2H); C NMR (CDCl
51.1, 138.5, 128.9, 123.2, 119.5, 103.2, 55.6, 53.4, 48.3, 25.9.
Anal. Calcd for C14 S: C, 54.35; H, 6.19; N, 13.58.
Found: C, 54.00; H, 6.27; N, 13.32.
Z)-N-P h en yl-2-(1-p r op yl)im in o-3-th ia zolid in eca r box-
3
) δ 158.1,
90 cm ; H NMR (CDCl
3
) δ 13.90 (s, 1H), 7.42-6.97 (m, 9H),
1
.90 (t, J ) 7.0 Hz, 2H), 3.16 (t, J ) 7.0 Hz, 2H), 2.34 (s, 3H);
1
3
19 3 3
H N O
C NMR (CDCl
29.3, 125.2, 125.1, 121.3, 54.9, 24.8, 21.1. Anal. Calcd for
: C, 62.32; H, 5.23; N, 12.83. Found: C, 62.45; H,
.41; N, 12.67.
Z)-2-P h en ylim in o-N-m eth yl-3-th ia zolid in eca r both io-
a m id e (14b): 73% yield from 13a and MeNCS; mp 116-117
3
) δ 179.2, 159.0, 148.4, 136.3, 136.1, 129.4,
1
(
17 17 3 2
C H N S
a m id e (15e): 60% yield from 13c and PhNCO; mp 65-67 °C;
IR (KBr) 3080-2800, 1690, 1635, 1600, 1565, 1500, 1450, 755,
5
(
-
1
1
6
3
90 cm ; H NMR (CDCl ) δ 12.41 (bs, 1H), 7.49-7.04 (m,
-
1
1
5H), 4.25 (t, J ) 7.0 Hz, 2H), 3.24 (t, J ) 6.8 Hz, 2H), 3.17 (t,
°
(
C; IR (KBr) 3000-2800, 1600, 1550, 770, 690 cm ; H NMR
CDCl ) δ 12.02 (bs, 1H), 7.39-6.92 (m, 5H), 4.83 (t, J ) 7.0
Hz, 2H), 3.19 (d, J ) 4.6 Hz, 3H), 3.12 (t, J ) 7.0 Hz, 2H);
NMR (CDCl ) δ 177.8, 158.7, 129.0, 123.3, 120.8, 54.9, 32.2,
5.1. Anal. Calcd for C11 : C, 52.56; H, 5.27; N, 16.11.
Found: C, 51.78; H, 5.46; N, 16.02.
Z)-2-[(2,2-Dim eth oxy)eth yl]im in o-N-m eth yl-3-th ia zoli-
J ) 7.0 Hz, 2H), 1.73 (m, J ) 6.9, 6.8 Hz, 2H), 1.04 (t, J ) 6.9
3
Hz, 3H); 13C NMR (CDCl
) δ 156.1, 151.3, 138.5, 128.8, 123.1,
3
1
3
C
1
19.6, 56.7, 48.0, 25.7, 24.2, 12.1. Anal. Calcd for C13
OS: C, 59.28; H, 6.51; N, 15.95. Found: C, 59.27; H, 6.53; N,
5.81.
Isom er iza tion Exp er im en ts. Meth od A. A flask charged
17 3
H N -
3
2
13 3 2
H N S
1
(
with pure endo adduct (0.5 mmol) was heated until complete
melting and held there for 5 min. The flask was removed from
din ecar both ioam ide (14c): 52% yield from 13b and MeNCS;
mp 94-95 °C; IR (KBr) 3120, 3000-2800, 1620, 1555, 1370,
the oil bath, and the melt was extracted into CDCl
analyzed by NMR spectroscopy.
3
and
1
1
1
2
2
1
290, 1250, 1190, 1135, 1085, 1060 cm-1; H NMR (CDCl
3
) δ
2.31 (bs, 1H), 4.75 (t, J ) 7.0 Hz, 2H), 4.57 (t, J ) 5.5 Hz,
Meth od B. A solution of the endo adduct (0.5 mmol) was
refluxed in benzene (3.0 mL) for 24 h. The reaction mixture
was cooled to room temperature, the solvent evaporated, and
H), 3.40 (s, 6H), 3.38 (d, J ) 5.5 Hz, 2H), 3.16 (t, J ) 7.0 Hz,
1
3
H), 3.13 (d, J ) 4.5 Hz, 3H); C NMR (CDCl ) δ 180.7, 158.6,
3
03.2, 56.2, 54.2, 53.6, 32.0, 25.2. Anal. Calcd for
: C, 41.04; H, 6.51; N, 15.95. Found: C, 40.98;
H, 6.49; N, 15.96.
Z)-N-Met h yl-2-(1-p r op yl)im in o-3-t h ia zolid in eca r b o-
th ioa m id e (14d ): 45% yield from 13c and MeNCS; oil; IR
the residue dissolved in CDCl
NMR spectroscopy.
3
and immediately monitored by
9 17 3 2 2
C H N O S
Tr a p p in g E xp er im en t s. An equimolar mixture of endo
adduct (0.5 mmol) and an appropriate isocyanate or isothio-
cyanate (0.5 mmol) in benzene (5.0 mL) was refluxed for 24 h.
The reaction mixture was cooled to room temperature, the
(
(
neat) 3120, 3000-2800, 1610, 1545, 1440, 1420, 1355, 1320,
-
1 1
1
4
7
2
5
3
275, 1230, 850, 730 cm ; H NMR (CDCl ) δ 12.50 (bs, 1H),
benzene evaporated, and the residue dissolved in CDCl
characterized by NMR spectrometry.
3
and
.72 (t, J ) 7.0 Hz, 2H), 3.19 (t, J ) 6.8 Hz, 2H), 3.14 (t, J )
.0 Hz, 2H), 3.13 (d, J ) 4.4 Hz, 3H), 1.65 (m, J ) 7.1 Hz,
R ea ct ion of N,N′-Dip h en ylu r ea w it h 2-Ch lor oet h yl
Isoth iocya n a te. To a suspension of NaH (60% dispersion in
mineral oil, 3.0 mmol) in dry THF (10 mL) was added dropwise
a solution of N,N′-diphenylurea (0.42 g, 2.0 mmol) in dry THF
H), 0.96 (t, J ) 7.3 Hz, 3H); 13C NMR (CDCl
) δ 180.8, 156.7,
3
8 15 3 2
6.8, 53.9, 31.8, 25.1, 23.8, 11.8. Anal. Calcd for C H N S :
C, 62.70; H, 9.86; N, 27.42. Found: C, 62.52; H, 9.56; N, 27.69.
Gen er al P r epar ation of (Z)-2-Alkyl(ar yl)im in o-N-alkyl-
(30 mL), and the reaction mixture was stirred at 0 °C (external
(
a r yl)-3-th ia zolid in eca r boxa m id es (15a -e). To a solution
bath) for 1 h. Then, 2-chloroethyl isothiocyanate (0.3 mL, 3.0
mmol) was added and the stirring slurry was allowed to warm
to room temperature. After 1 h, it was diluted with brine (30
mL), the ethereal layer separated, and the aqueous phase
of the corresponding 2-alkyl or 2-phenyliminothiazolidine
1
5
hydrochlorides (13a -c, 1.0 mmol) in pyridine (2 mL), the
alkyl(aryl) isocyanate (1.0 mmol) was added and the reaction
mixture was kept at room temperature for 24 h. Then, it was
poured into ice-water and the resulting solid filtered, washed
with cold water, and recrystallized from 96% aqueous ethanol.
extracted with CH
extracts were dried and concentrated to give 12 (0.3 g, 44%).
NMR Mon itor in g in THF -d . To a suspension of NaH
2
Cl
2
(3 × 20 mL). The combined organic
8
(
Z)-2-P h en ylim in o-N-(3-m eth oxyph en yl)-3-th iazolidin e-
(60% dispersion in mineral oil, 0.2 mmol) in THF-d (0.5 mL)
8
ca r boxa m id e (15a ): 76% yield from 13a and 3-MeOC
6
H
4
-
was added N,N′-diphenylurea (0.02 g, 0.09 mmol) in THF-d8
(0.5 mL), and the reaction mixture was kept at -20 °C for 24
h. Then, it was filtered, and cold (-20 °C) 2-chloroethyl
isothiocyanate was added (13 µL, 0.14 mmol). NMR spectra
were recorded at 15-min intervals from -20 to +20 °C.
NCO; mp 135-136 °C; IR (KBr) 3080-2900, 2820, 1690, 1615,
1
590, 1560, 1290, 1280, 1230, 1210, 1050, 860, 765, 695 cm-1
;
1
H NMR (CDCl
3
) δ 12.01 (bs, 1H), 7.42-6-61 (m, 9H), 4.38
1
3
(
t, J ) 7.1 Hz, 2H), 3.80 (s, 3H), 3.17 (t, J ) 7.1 Hz, 2H);
C
NMR (CDCl ) δ 160.1, 158.4, 150.8, 149.1, 139.3, 129.5, 129.2,
3
Ack n ow led gm en t. We thank the Spanish Direcci o´ n
de Investigaci o´ n Cient ´ı fica y T e´ cnica (PB98-0997) and
the Junta de Extremadura-Fondo Social Europeo (IPR98-
A065 and IPR99-C032) for financial support. G.S.
thanks J unta de Extremadura for a fellowship.
1
24.9, 121.5, 112.3, 109.6, 105.5, 55.3, 48.9, 25.6. Anal. Calcd
for C17 : C, 62.37; H, 5.23; N, 12.83. Found: C, 61.99;
H, 5.28; N, 12.75.
Z)-2-P h en ylim in o-N-(4-tolyl)-3-th ia zolid in eca r boxa m -
id e (15b): 70% yield from 13a and 4-MeC NCO; mp 129-
31 °C; IR (KBr) 3060-2800, 1685, 1610, 1600, 1580, 1550,
280, 1230, 1190, 810, 760, 740, 690 cm-1; 1H NMR (CDCl
) δ
1.87 (bs, 1H), 7.41-6-99 (m, 9H), 4.38 (t, J ) 7.1 Hz, 2H),
17 3 2 2
H N O S
(
6
H
4
1
1
1
3
1
Su p p or t in g In for m a t ion Ava ila b le: X-ray acquisition
data, Figures S1 and S2, and Tables S1-S4. This material is
available free of charge via the Internet at http://pubs.acs.org.
3
1
3
.15 (t, J ) 7.1 Hz, 2H), 2.30 (s, 3H); C NMR (CDCl
3
) δ 158.3,
50.9, 149.2, 135.4, 133.2, 129.4, 129.2, 124.8, 121.5, 120.0,
J O000618R