Ring-chain tautomerism of 2-aryl-substituted cis- and trans-decahydroquinazolines

Article abstract of DOI:10.1021/jo020070j

In CDCl₃ at 300 K, 2-aryl-substituted cis- and trans-3-isopropyldecahydroquinazolines and trans-3-phenyldecahydroquinazolines proved to be three-component (r¹-o-r²) ring-chain tautomeric mixtures, whereas only ring-closed tautomers could be detected for the 3-methyl-substituted analogues. The proportions of the ring-chain tautomeric forms at equilibrium were strongly influenced by the N-substitutents and the cis-trans ring junction and could be described by the equation log K_x = ρσ + log K_x=H. These are the first examples among 2-aryl-1,3-N,N-heterocycles of a three-component ring-chain tautomeric equilibrium characterized by a Hammett-type equation. The stabilities of the ring-closed forms of cis- and trans-2-aryldecahydroquinazolines and the corresponding 3,1-benzoxazines were found to increase in the following sequence of the heteroatom at position 3: NPh < N-i-Pr < O < NMe.

Full text of DOI:10.1021/jo020070j

Rin g-Ch a in Ta u tom er ism of 2-Ar yl-Su bstitu ted cis- a n d
tr a n s-Deca h yd r oqu in a zolin es
La´szlo´ La´za´r, Aniko´ Go¨blyo¨s, Tama´s A. Martinek, and Ferenc Fu¨lo¨p*
Institute of Pharmaceutical Chemistry, University of Szeged, H-6701 Szeged, POB 121, Hungary
fulop@pharma.szote.u-szeged.hu
Received J anuary 30, 2002
In CDCl3 at 300 K, 2-aryl-substituted cis- and trans-3-isopropyldecahydroquinazolines and trans-
3-phenyldecahydroquinazolines proved to be three-component (r1-o-r2) ring-chain tautomeric
mixtures, whereas only ring-closed tautomers could be detected for the 3-methyl-substituted
analogues. The proportions of the ring-chain tautomeric forms at equilibrium were strongly
influenced by the N-substitutents and the cis-trans ring junction and could be described by the
equation log KX ) Fσ+ + log KX)H. These are the first examples among 2-aryl-1,3-N,N-heterocycles
of a three-component ring-chain tautomeric equilibrium characterized by a Hammett-type equation.
The stabilities of the ring-closed forms of cis- and trans-2-aryldecahydroquinazolines and the
corresponding 3,1-benzoxazines were found to increase in the following sequence of the heteroatom
at position 3: NPh < N-i-Pr < O < NMe.
log KX ) Fσ+ + log KX)H
(1)
In tr od u ction
The structures and reactivities of numerous five- and
six-membered, saturated, N-unsubstituted 1,3-X,N het-
erocycles (X ) O, S, NR) can be characterized by the
ring-chain tautomeric equilibria of the 1,3-X,N hetero-
cycles and the corresponding Schiff bases.1 Studies on the
ring-chain tautomeric equilibria of 2-aryl-substituted
oxazolidines and tetrahydro-1,3-oxazines led to the con-
clusion that the proportion of the ring-closed forms
strongly depends on the electronic character of the
substituent on the aromatic ring. For these compounds,
a linear correlation was found between the log KX values
of the equilibria (KX ) [ring]/[chain]) and the Hammett-
Brown parameters σ+ of the substituents X on the 2-aryl
group both in solution and in the gas phase.1,2 The value
of F in eq 1 was found to be characteristic of the
oxazolidine or tetrahydro-1,3-oxazine ring system and
dependent on the temperature and the nature of the
solvent.1b The scope and limitations of eq 1 were extended
to multicomponent equilibria involving homologous or
regioisomeric 1,3-O,N ring forms in the same tautomeric
mixtures.3
The ring-chain tautomerism of the 1,3-X,N hetero-
cycles can be advantageously exploited in different areas
of organic synthesis. The selectivity of certain transfor-
mations can be explained on the basis of the ring-chain
tautomeric equilibration of the intermediates, followed
by a shift in the equilibrium.5 Oxazolidines and tetrahy-
dro-1,3-oxazines can be used as aldehyde or ketone
sources in the Hantzsch and Pictet-Spengler reactions.6
Ring-chain tautomeric chiral oxazolidines can be applied
for the addition of organometallics or silyl enol ethers in
enantioselective syntheses of chiral amines or â-amino
acids.7 Serine- or threonine-derived oxazolidines and
cysteine-derived thiazolidines (pseudoprolines) are ver-
satile tools with which to overcome various problems in
peptide synthesis and, by virtue of their ring-chain
tautomeric character, serve as reversible protecting
groups of these amino acids.8
(4) (a) Fu¨lo¨p, F.; Mattinen, J .; Pihlaja, K. Tetrahedron Lett. 1988,
29, 5427. (b) Fu¨lo¨p, F.; Mattinen, J .; Pihlaja, K. Tetrahedron 1990,
46, 6545. (c) Vainiotalo, P.; Fu¨lo¨p, F.; Pihlaja, K. Org. Mass Spectrom.
1991, 26, 438. (d) Vainiotalo, P.; Forro´, E.; Fu¨lo¨p, F. ACH - Models in
Chem. 1998, 135, 653.
* Corresponding author. Tel: +36-62-545564; Fax: +36-62-545705.
(1) (a) Valters, R. E.; Flitsch, W. Ring-Chain Tautomerism; Plenum
Press: New York, 1985. (b) Valters, R. E.; Fu¨lo¨p, F.; Korbonits, D.
Adv. Heterocyclic Chem. 1996, 66, 1.
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J ohnson, C. D.; Lewis, C.; McDonell, P. D. Tetrahedron 1985, 41, 5919.
(b) Fu¨lo¨p, F.; Pihlaja, K.; Mattinen, J ., Berna´th, G. J . Org. Chem. 1987,
52, 3821. (c) Vainiotalo, P.; Ronkanen, S.; Fu¨lo¨p, F.; Pihlaja, K.
Tetrahedron 1990, 46, 3683. (d) Fu¨lo¨p, F.; Pihlaja, K.; Neuvonen, K.;
Berna´th, G.; Argay, G.; Ka´lma´n, A. J . Org. Chem. 1993, 58, 1967. (e)
Neuvonen, K.; Fu¨lo¨p, F.; Neuvonen, H.; Koch, A.; Kleinpeter, E.;
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G. Tetrahedron 1997, 53, 1081. (b) Martinek, T.; La´za´r, L.; Fu¨lo¨p, F.;
Riddell, F. G. Tetrahedron 1998, 54, 12887. (c) Star, A.; Fuchs, B. J .
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Chem., Int. Ed. 2000, 39, 2685.
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44, 2993. (b) La´za´r, L.; Fu¨lo¨p, F.; Berna´th, G.; Ka´lma´n, A.; Argay, G.
J . Heterocycl. Chem. 1991, 28, 1213. (c) Andrews, M. D.; Brewster, A.
G.; Crapnell, K. M.; Ibbett, A. J .; J ones, T.; Moloney, M. G.; Prout, K.;
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hedron Lett. 1998, 39, 1199. (b) Higashiyama, K.; Kyo, H.; Takahashi,
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10.1021/jo020070j CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/21/2002
4734
J . Org. Chem. 2002, 67, 4734-4741

Ring-Chain Tautomerism cis- and trans-Decahydroquinazolines
SCHEME 1
The pharmacological and physicochemical properties
of a biologically active compound containing a 1,2- or 1,3-
amino alcohol, a diamine, or an amino thiol moiety or
an oxo group can be influenced by their transformations
to a ring-chain tautomeric prodrug. From the ring-
chain equilibrium of this derivative, the open form
undergoes continuous hydrolysis to give the bioactive
molecule.9
A large number of examples have emerged in recent
years that demonstrate that ring-chain tautomerism
occurs not only among N-unsubstituted saturated 1,3-
O,N heterocycles but also among their 1,3-N,N ana-
logues.1,10,11 On the basis of their ring-chain tautomeric
character, 1,2-disubstituted saturated 1,3-N,N hetero-
cycles can be exploited as intermediates in the selective
functionalization of N-monosubstituted ethylene- or pro-
pylenediamines; the selectivity of the reaction is strongly
influenced by the nature of the substituent at position
2.12 For 2-aryl-substituted imidazolidines, hexahydropy-
rimidines, and 1,2,3,4-tetrahydroquinazolines, similar to
their 1,3-O,N analogues, a Hammett-type linear correla-
tion was found between the ring-chain ratios for the
tautomeric equilibria and the electronic character of the
substituent on the 2-phenyl ring (eq 1).11 For N-substi-
tuted 2-aryl-1,3-N,N heterocycles, the ring-chain tau-
tomeric process and the values of F and log KX)H in eq 1
depend strongly on the steric and electronic characters
of the substituent on the nitrogen. In contrast with the
1,3-O,N analogues, the value of F proved not to be
characteristic of the 1,3-N,N ring system.11
SCHEME 2
As a continuation of previous studies on five- and six-
membered 1,3-N,N heterocycles, our present aim was to
investigate the effects of the substituents and the stere-
ochemisty of the ring junction on the ring-chain tauto-
meric character of some 3-substituted 2-aryldecahydro-
quinazolines for the purpose of refining the scope and
limitations of application of eq 1 among six-membered
1,3-N,N heterocycles.
1).13,14 cis- and trans-2-(Methyl- or isopropyl or pheny-
laminomethyl)cyclohexylamines (9a ,b, 10a ,b, and 11a ,b)
were synthesized by LiAlH4 reduction of the correspond-
ing N-substituted amino carboxamides (6a ,b, 7a ,b, and
8a ,b), which were obtained either by the direct amidation
of amino esters 2a ,b with methylamine13 or via the
N-protected amino acids 3a ,b by using the mixed anhy-
dride method.14
Resu lts a n d Discu ssion
The starting materials for the synthesis of decahy-
droquinazoline model compounds were prepared from cis-
and trans-2-aminocyclohexanecarboxylic acid (1a ,b) by
a combination of standard chemical procedures (Scheme
Model compounds 12-17 were prepared by the reac-
tions of diamines 9-11a ,b with equivalent amounts of
substituted benzaldehydes (Scheme 2). The 1H NMR
spectra of 12-17 revealed that, in CDCl3 solution at 300
K, cis- and trans-3-isopropyl-2-aryldecahydroquinazolines
(14a-g and 15a-g) and trans-3-phenyl-substituted 2-aryl-
decahydroquinazolines (17a -g) participate in three-
component (r1-o-r2) ring-chain tautomeric equilibria,
having both electron-donating and electron-withdrawing
substituents on the 2-phenyl ring. For cis-3-phenyl-2-
aryldecahydroquinazolines (16), ring-chain tautomeric
equilibria could be detected only for compounds bearing
an electron-withdrawing substituent X (16a -c); for the
2-phenyl derivative (16d ) and the compounds with an
electron-donating substituent X on the 2-phenyl ring
(16e-g), only the presence of the open-chain tautomer
was observed. Similar to other N-methyl-substituted six-
(9) (a) N. Bodor, K. B. Sloan, R. J . Little, S. H. Selk, L. Caldwell:
Int. J . Pharmacol. 1982, 10, 165. (b) J ohansen, M.; Bundgaard, H. J .
Pharm. Sci. 1983, 72, 1294. (c) H. T. Nagasawa, D. J . W. Goon, W. P.
Muldoon, R. T. Zera: J . Med. Chem. 1984, 27, 591. (d) Walker, R.;
Massey, M.; Wood, D. M.; Akmal, M. M. Drugs Future 1992, 17, 215.
(e) Walker, R. B.; Dholakia, V. N.; Brasfield, K. L.; Bakhtiar, R. Gen.
Pharmac. 1998, 30, 725.
(10) (a) Moodie, R. B.; Moustras, M. Z.; Read, G.; Sandall, J . P. B.
J . Chem. Res., Synop. 1996, 134. (b) Moodie, R. B.; Moustras, M. Z.;
Read, G.; Sandall, J . P. B. J . Chem. Soc., Perkin Trans. 2 1997, 169.
(c) Pihlaja, K.; Simeonov, M. F.; Fu¨lo¨p, F. J . Org. Chem. 1997, 62, 5080.
(d) Zelenin, K. N.; Alekseyev, V. V.; Ukraintsev, I. V.; Tselinsky, I. V.
Mendeleev Commun. 1997, 111. (e) Zelenin, K. N.; Ukraintsev, I. V.
Org. Prep. Proc. Int. 1998, 30, 109. (f) J outsiniemi, K.; Vainiotalo, P.;
Fu¨lo¨p, F.; La´za´r, L. Rapid Commun. Mass Spectrom. 1998, 12, 876.
(11) (a) Zelenin, K. N.; Alekseyev, V. V.; Ukraintsev, I. V.; Tselinsky,
I. V. Org. Prep. Proc. Int. 1998, 30, 53. (b) La´za´r, L.; Go¨blyo¨s, A.;
Evanics, F.; Berna´th, G.; Fu¨lo¨p, F. Tetrahedron 1998, 54, 13639. (c)
Go¨blyo¨s, A.; La´za´r, L.; Evanics, F.; Fu¨lo¨p, F. Heterocycles 1999, 51,
2431. (d) Go¨blyo¨s, A.; La´za´r, L.; Fu¨lo¨p, F. Tetrahedron 2002, 58, 1011.
(12) (a) Parrinello, G.; Mu¨lhaupt, R. J . Org. Chem. 1990, 55, 1772.
(b) Wang, W.; Liang, T. C.; Zheng, M.; Gao X. Tetrahedron Lett. 1995,
36, 1181. (c) J entgens, C.; Hofmann, R.; Guggisberg, A.; Bienz, S.;
Hesse, M. Helv. Chim. Acta, 1997, 80, 966.
(13) (a) Armarego, W. L. F.; Kobayashi, T. J . Chem. Soc. C 1971,
238. (b) Pihlaja, K.; Fu¨lo¨p, F.; Mattinen, J .; Berna´th, G. Acta Chem.
Scand. 1987, B41, 228. (c) Booth, H.; Khedhair, K. A.; Al-Shirayda, A.
R. Y. Tetrahedron 1988, 44, 1465.
(14) Berna´th, G.; Gera, L.; Go¨ndo¨s, G.; Pa´novics, I.; Ecsery, Z. Acta
Chim. Acad. Sci. Hung. 1976, 89, 61.
J . Org. Chem, Vol. 67, No. 14, 2002 4735

La´za´r et al.
TABLE 1. P r op or tion s (%) of Ta u tom er ic F or m s (A-C) in Ta u tom er ic Equ ilibr ia for Cis Com p ou n d s 12, 14, a n d 16
(CDCl3, 300 K)
compd
X
σ+
12A
12B
91.3
12C
14A
14B
14C
16A
83.3
98.4
98.5
16B
16C
a
b
c
d
e
f
p-NO2
m-Br
p-Cl
0.79
0.405
0.114
0
-0.311
-0.778
-1.7
∼0
8.7
27.4
39.8
47.4
55.9
62.5
74.3
88.9
66.6
57.2
48.3
42.8
37.5
25.7
11.1
6.0
3.0
4.3
1.3
∼0
11.4
1.6
1.5
∼0
5.3
∼0
∼0
∼0
∼0
∼0
∼0
H
∼100
p-Me
p-OMe
p-NMe2
∼100
∼100
∼100
∼0
∼0
∼0
g
∼0
∼100
∼0
∼0
∼0
TABLE 2. P r op or tion s (%) of Ta u tom er ic F or m s (A-C) in Ta u tom er ic Equ ilibr ia for Tr a n s Com p ou n d s 13, 15, a n d 17
(CDCl3, 300 K)
compd
X
σ+
13A
13B
13C
15A
15Ba
15Ca
17A
17Bb
17Cb
a
b
c
d
e
f
pNO2
mBr
pCl
0.79
0.405
0.114
0
-0.311
-0.778
-1.7
∼0
∼100
∼0
5.9
15.5
12.2
11.0
17.4
33.6
67.7
89.5
73.7
82.4
85.0
77.7
63.8
32.3
4.6
10.8
5.4
4.0
4.9
2.6
∼0
32.0
64.1
71.9
77.9
88.4
94.5
98.9
54.0
29.3
24.5
18.2
10.3
5.0
14.0
6.6
3.6
3.9
1.3
0.5
∼0
H
pMe
pOMe
pNMe2
g
∼0
∼100
∼0
1.1
The proportions of the ring forms were determined by deconvolution because of the overlapping lines. b The proportions of the tautomeric
a
forms of 17a -f, measured at 233-273 K, were extrapolated to 300 K by using the van’t Hoff equation.
TABLE 3. P r op or tion s (%) of Rin g F or m s (B a n d C) in
Ta u tom er ic Equ ilibr ia for Com p ou n d s 17a -f in CDCl3 a t
233-273 K
the basis of the tautomeric ratios determined at lower
temperatures.15 The decreasing proportions of the ring-
closed tautomers (17B and 17C) with increasing tem-
perature are in good accord with the significant loss of
conformational entropy due to ring formation, which is
indicative of ring-chain tautomerism.
compd 233 K 237 K 241 K 245 K 249 K 253 K 263 K 273 K
17a B 59.3 55.3 55.9 56.0 56.6 57.0 55.6 56.8
17a C 31.9 29.9 28.8 26.4 25.9 24.1 21.8 19.0
17bB 51.2 50.5 50.6 50.6 47.9 47.6 47.3 51.2
17bC 22.0 20.1 18.2 16.7 14.5 12.8
17cB 36.3 36.4 36.6 36.6 35.9 35.4 31.6 30.9
17cC 20.6 18.9 17.3 15.9 14.5 12.3
17d B 29.1 29.6 29.3 28.9 28.7 28.4 25.7 23.2
17d C 14.4 13.1 11.8 10.0 8.7 6.0
17eB 19.2 18.6 19.3 17.7 18.7 17.0 14.1 14.6
a
a
ln KX ) -∆H°/RT + ∆S°/R
(2)
a
a
As a consequence of the very similar NMR spectro-
scopic characteristics of these 2-aryldecahydroquinazo-
lines, with the same N-substituent and stereochemistry
of the ring junction, determination of the relative con-
figuration of the major and minor ring-closed tautomers
and conformational analysis were performed only for the
p-nitrophenyl derivatives 12a -17a (Table 4). Data on
a
a
17eC 16.4 15.4 13.0 11.6
8.5
8.3
3.1
7.0
8.3
2.3
a
a
a
a
a
a
17fB
17fC
9.1
4.4
9.6
4.3
9.4
4.1
9.2
3.7
a
Quantitative integration of the NMR signals was not possible
due to line broadening.
1
12a B and 16a A were chosen to illustrate the H NMR
spectra of the prepared tautomeric compounds (see the
Experimental Section). 2-Aryl substituents did not change
the sequence of the chemical shifts of the characteristic
NCHArN and NdCHAr protons.
membered 2-aryl-1,3-N,N heterocycles,11d for cis- and
trans-3-methyl-2-aryldecahydroquinazolines (12a ,g and
13a ,g), no open-chain tautomeric forms (A) could be
detected. Despite the presence of the electron-donating
p-dimethylamino substituent on the 2-phenyl ring, which
is favorable for the shift of the equilibrium toward the
open tautomer,1 the NMR spectra of 12g and 13g showed
exclusively the presence of ring-closed tautomers.
The proportions of the chain (A) and diastereomeric
ring forms (B and C) of the tautomeric equilibria (KX)
were determined at 300 K by integration of the well-
separated NCHArN (ring) and NdCH (chain) proton
singlets in the 1H NMR spectra of compounds 12-16. For
15, the ratios of the ring-closed tautomers were calculated
by deconvolution because of their partly overlapping
NCHArN singlets (Tables 1 and 2).
For compounds 17, tautomeric ratios (KX) could not be
determined at 300 K because of the fast interconversion
of the tautomeric forms; the signal of the minor ring form
therefore appeared in the 1H NMR spectrum only at
lower temperatures. Values of KX and the ratios of the
ring forms at 300 K for 17 (Tables 2 and 3) were
calculated according to the van’t Hoff equation (eq 2) on
In the EXSY spectra16 of 14a and 15a , there is a
negative cross-peak between the NdCHAr singlet of the
open form and both NCHArN signals of the major and
minor ring forms, while there is no negative cross-peak
between the NCHArN signals of the cyclic tautomers.
This proves the interconversion of the ring-closed tau-
tomers (B and C) through the open-chain form (A). The
relative configurations of the major ring-closed tautomers
of 12a -17a were deduced from the NOESY spectra, in
which the cross-peak for the protons at positions 2 and
8a proves their cis arrangement (B) (Scheme 2). The
same relative configuration of H-2 and H-8a for the major
ring-closed tautomer was found for all the remaining 2-(p-
nitrophenyl)decahydroquinazolines (12a , 13a , 16a , and
17a ). In the ring-chain tautomeric equilibria of the
corresponding 2-aryldecahydro-3,1-benzoxazines (18, 19),
(15) Gu¨nter, H. NMR-Spektroskopie; Georg Thieme Verlag: Stut-
tgart, New York, 1983; p 229.
(16) Macura, S.; Wu¨trich, K.; Ernst, R. R. J . Magn. Reson. 1982,
47, 351.
4736 J . Org. Chem., Vol. 67, No. 14, 2002

Ring-Chain Tautomerism cis- and trans-Decahydroquinazolines
TABLE 4. Selected Ch a r a cter istic 1H Ch em ica l Sh ifts
(p p m , δTMS ) 0 P p m ) a n d Cou p lin g Con sta n ts (Hz) for
Com p ou n d s 12a -17a
SCHEME 3
compd H-2 H-4eq H-4ax H-4a H-8a 3J (4eq,4a) 3J (4ax,4a)
12a B
12a C
13a B
3.81 2.87 2.42 1.60 3.05
4.07 2.70 2.63 1.67 2.80
3.88 2.97 2.02 1.45 2.27
2.01
5.29
3.53
b
3.53
<1
11.08
b
14a Aa 8.39 2.46 2.36 1.79 3.61
14a B
14a C
4.39 2.81 2.59 1.67 3.02
4.58 3.16 2.62 1.66 2.96
2.27
b
b
3.27
b
b
15a Aa 8.39 2.40 2.54 1.33 3.10
15a B
15a C
4.44 2.97 2.18 1.39 2.28
5.04 2.85 2.54 1.32 3.08
3.53
3.02
7.55
b
<1
b
9.06
11.58
5.79
b
5.38
b
16a Aa 8.35 3.06 2.92 1.98 3.66
16a B
16a C
5.90 3.32 3.20 1.70 3.20
5.03 3.67 3.35 2.22 3.72
17a Aa,c 8.38 2.98 2.87 2.05 3.07
17a Bc 5.94 3.63 2.81 1.45 2.28
17a Cc 5.06 3.51 2.75 1.63 2.47
3.27
3.02
11.58
11.33
a
The protons of the open form (A) are numbered according to
the corresponding protons of the quinazoline ring forms (B and
C). Coupling constants were not available due to overlapping of
SCHEME 4
b
the lines and the low proportion of the tautomeric form at
equilibrium. c Data from the spectra run at 253 K.
the major ring-closed tautomeric form also had cis-
arranged H-2 and H-8a.2b
The configuration of the azomethine double bond was
determined by observing the intensity of the NOE
interaction between H-2 and H-8a in model compounds
that contain the open tautomeric form in a higher
proportion (16a and 17a ). A high-intensity NOESY cross-
peak could be detected for both compounds, which sug-
gests the E configuration of the CdN double bond and
shows that the H(8a)-C(8a)-N(1)-C(2) torsion angle is
within the region of (60°.
The data in Tables 1 and 2 indicate that the propor-
tions of the diastereomeric ring-closed tautomers in the
equilibria, which are proportional to the relative stabili-
ties of these ring forms, are greatly influenced by the
relative configurations of the chiral centers. In an at-
tempt to find a relationship between the relative stability
and the predominant conformation of the ring epimers,
a conformational analyis of cis- and trans-3-isopropyl-2-
(p-nitrophenyl)decahydroquinazolines (14a and 15a ) was
performed by using NMR and modeling methods. An
earlier conformational analysis on decahydroquinazoline
derivatives led to the conclusion that cis-fused derivatives
could exist in two interconvertible chair-chair conforma-
tions (N-in or N-out), the equilibrium of which was
strongly dependent on the substitution of the nitrogen
at position 1. For 1-unsubstituted cis-decahydroquinazo-
lines, the conformational equilibrium is shifted predomi-
nantly toward the N-in conformer, while the 1-methyl
cis derivative can be characterized by a predominant
N-out conformation.13c,17
can be detected from H-2 to H-4ax and H-8a, which is
evidence of a predominantly equatorial aryl group, in
accordance with its steric demand. On the basis of these
results, it can be concluded that the major ring-closed
tautomer 14a B predominantly occupies an N-in confor-
mation (Scheme 3). The low relative concentration of the
minor ring-closed tautomer 14a C did not facilitate the
extraction of useful NMR data and therefore a standard
conformational search procedure18 was carried out to find
the lowest energy conformation. The resulting structure
(Scheme 3) of 14a C shows an N-out conformation with
the sterically demanding aryl group in the equatorial
position. The energy difference between 14a B and 14a C,
estimated from the average ring-ring tautomeric ratio,
is approximately 6.6 kJ /mol. The steric repulsion between
H-4ax and H-5ax and between H-2 and H-7ax in 14C may
account for the observed stability difference.
The major trans ring-annelated diastereomer 15a B
exhibits a vicinal coupling constant (3J (H-4a, H-4eq) )
3.53 Hz and 3J (H-4a, H-4ax) ) 9.06 Hz) and NOE
interaction (H-2-H-4ax, H-2-H-8a) pattern, which is in
accordance with the expected conformation with the aryl
group in an equatorial position (Scheme 4). The residual
amount of the minor component in the sample made
molecular modeling necessary. The conformational search
for the minor epimer 15a C indicated a chair-chair
conformation in which the aryl group has an axial
The conformation for 14a B (major ring form) can
readily be determined by analysis of the crucial NMR
spectral parameters. The coupling constants of the
signals of the protons at positions 4a and 4 are similar,
3
3J (H-4eq, H-4a) ) 2.27 Hz and J (H-4ax, H-4a) ) 3.27
Hz, and low, which suggests an equatorial orientation of
H-4a relative to the heterocyclic ring. NOE interactions
(17) (a) Armarego, W. L. F.; Reece, P. A. J . Chem. Soc., Perkin Trans.
1 1974, 2313. (b) Fu¨lo¨p, F.; Berna´th, G.; Pihlaja, K. Adv. Heterocycl.
Chem. 1998, 69, 349.
(18) Martinek, T.; Riddell, F. G.; Wilson, C. F. J . Chem Soc., Perkin
Trans. 2 2000, 2192.
J . Org. Chem, Vol. 67, No. 14, 2002 4737

La´za´r et al.
withdrawing substituents on the 2-phenyl ring favor the
ring-closed tautomer. The slopes for 3-substituted 2-aryl-
decahydroquinazolines (14, 15, and 17) lie within a wider
range (0.51-1.21) than those for the corresponding
2-aryldecahydro-3,1-benzoxazines (18 and 19: 0.55-0.64)
and, similarly as for other 2-aryl-1,3-N,N heterocycles
exhibiting ring-chain tautomerism, the value of F is not
characteristic of the ring system. The stereochemistry of
the ring junction does not seem to influence the value of
F: cis- and trans-3-isopropyl-2-aryldecahydroquinazolines
have very similar values of F (0.51 and 0.57). The
considerable differences in the values of F for equilibria
containing C-2 epimeric ring forms (17B-17A and 17C-
17A) indicate that the rates of the alternative ring-
closures (A f B or A f C) of the open form are also
influenced by the aromatic substituent. The substituent
on the nitrogen exerted a similar effect on the value of F
to that found for 3-isopropyl- and 3-phenyl-substituted
2-aryl-1,2,3,4-tetrahydroquinazolines:11d the value of F
was somewhat higher for the 3-phenyl derivatives for the
equilibria involving either the major (15B-17B) or the
minor (15C-17C) ring forms.
F IGURE 1. Plots of log K (in CDCl3) for 14B ([), 15B (9),
15C (2), 17B (b), and 17C (O) vs Hammett-Brown parameter
σ+.
orientation (Scheme 4). The axial position of the 2-aryl
group explains the lower stability (∆G ) 2.9 kJ /mol) of
15a C as compared with 15a B.
When eq 1 was applied to the log KX values, good linear
correlations were obtained vs the Hammett-Brown
parameter σ+ of the substituent X on the 2-phenyl group
for compounds 14, 15, and 17 (Figure 1 and Table 5),
which are the first examples among 2-aryl-1,3-N,N
heterocycles of three-component ring-chain tautomeric
processes characterized by a Hammett-type correlation.
The shift in the tautomeric equilibrium toward the open-
chain tautomer meant that a linear correlation could not
be calculated for the few plots for compounds 16.
The linear regression analysis data in Table 5 show
that, as customary among 2-aryl-1,3-X,N heterocycles,1,11
the value of F is positive in each case; i.e. electron-
Both the substituent on the nitrogen and the cis-trans
ring junction gave rise to marked effects on the value of
the intercept. To characterize the effects of the annelated
ring on the stability of the ring form, a substitution effect
parameter (cs) was calculated as the difference in the
intercepts for the given 2-aryldecahydroquinazolines and
the corresponding 2-arylhexahydropyrimidines (20 and
21) bearing the same substituent on the nitrogen. This
TABLE 5. Lin ea r Regr ession Da ta on Com p ou n d s 14, 15, 17, cis- a n d tr a n s-2-Ar yld eca h yd r o-3,1-ben zoxa zin es (18 a n d
19) a n d 3-Su bstitu ted 2-Ar ylh exa h yd r op yr im id in es (20 a n d 21)
no. of
points
correlation
coefficient
substitution
heteroatom
effect (ch)b
equilibrium
slopea (F)
intercepta
effect (cs)b
14A h 14B
15A h 15B
15A h 15C
17A h 17B
17A h 17C
18A h 18Bc
18A h 18Cc
19A h 19Bc
19A h 19Cc
20A h 20Bd
21A h 21Bd
7
7
6
7
6
7
7
7
7
6
7
0.51(2)
0.57(8)
0.71(10)
0.85(5)
1.21(9)
0.60(2)
0.60(6)
0.55(6)
0.64(3)
0.77(3)
0.42(3)
-0.06(4)
0.72(16)
-0.43(12)
-0.59(10)
-1.39(11)
0.66(3)
-0.45(12)
1.12(12)
-0.69(6)
-1.04(4)
-1.28(6)
0.994
0.957
0.952
0.985
0.988
0.998
0.978
0.973
0.995
0.997
0.988
0.98
2.00
0.85
0.69
-0.11
0.81
-0.30
1.27
-0.54
0
-0.72
-0.40
0.26
-1.71
-0.70
0
0
0
0
-0.89
-1.13
0
a
b
Standard deviations are given in parentheses. Relative ring stability constant: see the text. c For compounds 18 and 19 (ref 2b),
tautomeric ratios were remeasured and the linear regression analysis was performed separately for the equilibria involving C-2 epimeric
d
ring forms. Data from ref 11d.
4738 J . Org. Chem., Vol. 67, No. 14, 2002

Ring-Chain Tautomerism cis- and trans-Decahydroquinazolines
kind of relative ring stability constant was introduced
earlier for the saturated 2-aryl-1,3-O,N heterocycles
bearing substituents at positions 4-6.1b,2b Positive values
of cs mean a more stable ring form relative to the
corresponding 2-arylhexahydropyrimidine. The values of
phenyl-2-aryldecahydroquinazolines (17), three-compo-
nent ring-chain tautomeric equilibria characterized by
a Hammett-type equation have been detected for the first
time among 2-aryl-1,3-N,N heterocyles.
cs indicate that the annelated ring had a considerable
stabilizing effect on the ring form for 14B, 15B, 15C, and
17B, but not for 17C. This effect is entropy-driven, since
the annelated ring decreases the flexibility of the C(4a)-
C(8a) bond and preorganizes the Schiff base to form the
heterocyclic ring; however, the stabilization is compen-
sated by the N-substituents. The destabilization may be
due to 1,3 steric interactions; it was more pronounced
for the N-isopropyl-substituted derivatives (14 and 15)
than for the N-phenyl compounds (17). For 3-isopropyl-
and 3-phenyldecahydroquinazolines, the trans-annelated
cyclohexane ring (15B: cs ) 2.00) had a higher stabilizing
effect than that of the cis ring junction (14B: cs ) 0.98).
The lack of a stabilizing substituent effect in the cis-3-
phenyldecahydroquinazolines (16) led to a nearly quan-
titative shift in the equilibria toward the open-chain
tautomers (16A).
The effect of the substituted nitrogen atom at position
3 on the stability of the ring-closed tautomeric form can
be expressed by a heteroatom effect parameter (ch), which
is calculated as the difference in intercept for the given
2-aryldecahydroquinazoline and the corresponding 2-aryl-
decahydro-3,1-benzoxazine (18B,C and 19B,C).11b-d The
value of ch refers to the stability difference of the given
1,3-O,N and 1,3-N,N heterocycles. Earlier studies on the
2-aryl-substituted six-membered 1,3-N,N and 1,3-O,N
heterocycles concluded that replacement of the hetero-
cyclic oxygen with nitrogen leads to a significant stabi-
lization of the ring form.11a,d However, the data in Table
5 demonstrate that the ring form for compounds 14B,
15B, 17B, and 17C is less stable than that for the
corresponding decahydrobenzoxazine. Since the ring-
chain tautomeric equilibria of cis- and trans-3-methyl-
substituted decahydroquinazolines (12 and 13) are ap-
preciably shifted toward the ring-closed tautomer, the
stabilities of the ring-closed forms of cis- and trans-2-
aryldecahydroquinazolines and the corresponding 3,1-
benzoxazines increase in the following sequence of the
heteroatom at position 3: NPh < NiPr < O < NMe. This
trend suggests that the destabilization effect of the
N-substituents is related to their steric demand influenc-
ing the conformational energy.
Exp er im en ta l Section
1H NMR spectra (400 MHz) were recorded at 300 K.
Chemical shifts are given in δ (ppm) relative to TMS (CDCl3)
or to TSP (D2O) as internal standards; multiplicities were
recorded as s (singlet), d (doublet), dd (double doublet), ddd
(double double doublet), dt (double triplet), t (triplet), m
(multiplet), or om (overlapping multiplet). For the equilibria
to be established in tautomeric compounds,2,11 the samples
were dissolved in CDCl3 and the solutions were allowed to
stand at ambient temperature for 1 day before the 1H NMR
spectra were run. The number of scans was usually 64.
The conformational search protocol was performed by using
the INSIGHTII environment and the CDISCOVER molecular
mechanics program. For the calculations, the cvff force field
was utilized.
Compounds 3a ,b14 and 6a ,b13b were prepared according to
known procedures.
Gen er a l Meth od for th e P r ep a r a tion of cis- a n d tr a n s-
N-Isop r op yl- a n d N-P h en yl-2-(ben zyloxyca r bon yla m i-
n o)cycloh exa n eca r boxa m id es (4a ,b a n d 5a ,b). To a stirred
and cooled (ice-salt bath) suspension of cis- or trans-2-
(benzyloxycarbonylamino)cyclohexanecarboxylic acid (3a ,b)
(2.77 g, 0.01 mol) and triethylamine (1.01 g, 0.01 mol) in dry
toluene (100 mL) was added dropwise ethyl choroformate (1.08
g, 0.01 mol) at a rate low enough to keep the internal
temperature below -10 °C. After 15 min, a solution of
isopropylamine or freshly distilled aniline (0.01 mol) in dry
CH2Cl2 (10 mL) was added dropwise to the mixture, the
internal temperature being kept below -10 °C. Stirring was
continued for 30 min with cooling and for 30 min without, and
the mixture was then heated slowly to reflux and refluxed for
5 min. The mixture was allowed to cool and washed with
saturated aqueous NaHCO3 solution (2 × 50 mL) and water
(80 mL) after the addition of CHCl3 (200 mL). The combined
organic phases were dried (Na2SO4) and evaporated under
reduced pressure to give a white crystalline residue, which was
filtered off, washed with Et2O, and recrystallized from i-Pr2O-
EtOAc.
4a : yield 2.75 g (86%); mp 129-130 °C; 1H NMR (CDCl3) δ
1.08 (d, 3H, J ) 6.6 Hz, CH3), 1.08 (d, 3H, J ) 6.6 Hz, CH3),
1.40 (m, 2H, (CH2)4), 1.50-1.78 (om, 5H, (CH2)4), 2.01 (m, 1H,
(CH2)4), 2.53 (m, 1H, COCH), 3.87 (m, 1H, NCH), 4.04 (m, 1H,
NCH(CH3)2), 5.08 (s, 2H, OCH2), 5.44 (br s, 1H, NH), 5.68 (br
s, 1H, NH), 7.27-7.37 (om, 5H, C6H5). Anal. Calcd for
C
18H26N2O3: C, 67.90; H, 8.23; N, 8.80. Found: C, 67.72; H,
8.15; N, 8.69.
4b: yield 1.20 g (38%); mp 201-202 °C; 1H NMR (CDCl3) δ
1.03 (d, 3H, J ) 6.6 Hz, CH3), 1.06 (d, 3H, J ) 6.6 Hz, CH3),
1.13-1.51 (om, 4H, (CH2)4), 1.75 (m, 2H, (CH2)4), 1.98 (m, 2H,
(CH2)4), 2.27 (m, 1H, COCH), 3.51 (m, 1H, NCH), 4.02 (m, 1H,
NCH(CH3)2), 5.02 (d, 1H, NH, J ) 8.6 Hz), 5.08(s, 2H, OCH2),
5.78 (br s, 1H, NH), 7.33 (m, 5H, C6H5). Anal. Calcd for
Con clu sion s
In conclusion, the ring-chain tautomerism of cis-
and trans-3-substituted-2-aryldecahydroquinazolines is
strongly dependent on the substituents on the nitrogen
and on the cis-trans ring junction. Compounds with a
small N-substituent (Me) exist exclusively in the ring-
closed form, independent of the stereochemistry of the
ring junction. Compounds with larger N-substituents (iPr
or Ph) participate in three-component ring-chain tau-
tomeric mixtures involving diastereomeric ring-closed
forms besides the open-chain tautomer. In all cases, H-2
and H-8a of the major ring form (B) are cis-arranged.
The ratios of the ring-closed tautomers were higher for
the trans compounds. For the cis- and trans-3-isopropyl-
2-aryldecahydroquinazolines (14 and 15) and trans-3-
C
18H26N2O3: C, 67.90; H, 8.23; N, 8.80. Found: C, 67.69, H,
8.08; N, 8.68.
5a : yield 2.86 g (81%); mp 169-172 °C (lit.14 mp 172-173
1
°C); H NMR (CDCl3) δ 1.45 (m, 2H, (CH2)4), 1.57-1.70 (om,
3H, (CH2)4), 1.84 (m, 2H, (CH2)4), 2.07 (m, 1H, (CH2)4), 2.80
(m, 1H, COCH), 3.99 (m, 1H, NCH), 5.08 (s, 2H, OCH2), 5.55
(d, 1H, J ) 6.7 Hz, NH), 7.10 (t, 1 H, J ) 7.4 Hz, C6H5), 7.28-
7.32 (om, 7H, C6H5), 7.46 (d, 2H, J ) 7.9 Hz, C6H5), 7.55 (br s,
1H, NH).
5b: yield 1.17 g (33%); mp 217-218 °C; 1H NMR (CDCl3) δ
1.15-1.85 (om, 6H, (CH2)4), 1.99 (m, 1H, (CH2)4), 2.10 (m, 1H,
(CH2)4), 2.52 (m, 1 H, COCH), 3.66 (m, 1 H, NCH), 4.98-5.13
(om, 3H, OCH2, NH), 7.08 (t, 1H, J ) 7.4 Hz, C6H5), 7.18-
7.32 (om, 7H, 2 × C6H5), 7.48 (d, 2H, J ) 7.7 Hz, C6H5). Anal.
J . Org. Chem, Vol. 67, No. 14, 2002 4739

La´za´r et al.
TABLE 6. P h ysica l Da ta on Deca h yd r oqu in a zolin es 12-17
δ NdCHAr
chain (A)
δ NCHArN
ring (B)
δ NCHArN
ring (C)
compd
mp (°C)
formula
MW
12a
12g
13a
13g
14a
14b
14c
14d
14e
14f
14g
15a
15b
15c
15d
15e
15f
15g
16a
16b
16c
16d
16e
16f
16g
17a
17b
17c
17d
17e
17f
17g
50-53a
55-57a
oil
C15H21N3O2
C17H27N3
275.35
273.43
275.35
273.43
303.41
337.31
292.86
258.41
272.44
288.44
301.48
303.41
337.31
292.86
258.41
272.44
288.44
301.48
337.43
371.33
326.87
292.43
306.46
322.46
335.50
337.43
371.33
326.87
292.43
306.46
322.46
335.50
3.81
3.59
3.88
3.67
4.39
4.23
4.25
4.26
4.23
4.22
4.25
4.44
4.24
4.26
4.27
4.25
4.23
4.19
5.90
5.89
5.89
5.88
5.87
5.88
4.06
C
15H21N3O2
78-81a
oil
C17H27N3
C
C
C
C
C
C
17H25N3O2
17H25BrN2
17H25ClN2
17H26N2
18H28N2
18H28N2O
8.39
8.22
8.25
8.29
8.25
8.22
8.16
8.39
8.18
8.24
8.28
8.18
8.20
8.13
8.35
8.21
8.19
8.30
8.24
8.22
8.16
8.38b
8.21b
8.24b
8.30b
8.26b
8.21b
8.14
4.58
4.39
4.43
4.42
oil
oil
oil
oil
oil
58-60a
100-103a
oil
C19H31N3
C17H25N3O2
5.04
4.31
4.32
4.37
4.29
4.27
C
C
C
C
C
C
C
C
C
C
17H25BrN2
17H25ClN2
17H26N2
18H28N2
18H28N2O
19H31N3
20H23N3O2
20H23BrN2
20H23ClN2
20H24N2
oil
oil
oil
oil
oil
oil
oil
oil
5.03
oil
62-63a
oil
C21H26N2
C
C
C
21H26N2O
22H29N3
20H23N3O2
oil
oil
oil
5.94b
5.85b
5.86b
5.93b
5.91b
5.89b
5.88
5.06b
4.88b
4.89b
4.90b
4.89b
4.84b
C20H23BrN2
C20H23ClN2
C20H24N2
C21H26N2
C21H26N2O
C22H29N3
83-85a
77-80a
68-70a
92-93a
83-85a
a
b
Recrystallized from n-hexane. From the spectra run at 253 K.
Calcd for C21H24N2O3: C, 71.57; H, 6.86; N, 7.95. Found: C,
71.34; H, 6.63; N, 7.82.
(m, 1H, COCH), 2.91 (ddd, 1H, J ) 10.58, 10.83, 4.28 Hz,
NCH), 7.06 (t, 1 H, J ) 7.40 Hz, C6H5), 7.29 (t, J ) 7.9 Hz,
2H, C6H5), 7.55 (d, 2H, J ) 7.9 Hz, C6H5), 9.55 (br s, 1H,
CONH). Anal. Calcd for C13H18N2O: C, 71.53; H, 8.31; N,
12.83. Found: C, 71.29; H, 8.08; N, 12.60.
Gen er a l Meth od for th e P r ep a r a tion of cis- a n d tr a n s-
N-Isop r op yl- a n d N-P h en yl-2-a m in ocycloh exa n eca r box-
a m id es (7a ,b a n d 8a ,b). The appropriate N-substituted cis-
or trans-2-(benzyloxycarbonylamino)cyclohexanecarboxamide
(4a ,b or 5a ,b) (0.01 mol) was suspended in 33% hydrobromic
acid in acetic acid (12 mL), and the mixture was allowed to
stand at room temperature for 1 h with occasional shaking.
The crystalline hydrobromide salt of 7a ,b or 8a ,b that was
formed was filtered off and dissolved in ice-cold water (75 mL).
The solution was made alkaline with 10% NaOH and extracted
with EtOAc (5 × 50 mL). The combined organic phases were
dried over Na2SO4 and evaporated under reduced pressure.
The crystalline residue was recrystallized from EtOH.
Gen er a l Meth od for th e P r ep a r a tion of cis- a n d tr a n s-
2-(Meth yl-, Isop r op yl-, or P h en yla m in om eth yl)cyclo-
h exyla m in es (9a ,b, 10a ,b, a n d 11a ,b). To a stirred suspen-
sion of LiAlH4 (2.28 g, 0.06 mol) in dry THF (50 mL) was added
dropwise a solution of the appropriate amide (6a ,b, 7a ,b, or
8a ,b) (0.02 mol) in dry THF (20 mL). The mixture was stirred
and refluxed for 4 h and then cooled, and the excess of LiAlH4
was decomposed by addition of a mixture of water (4.5 mL)
and dry THF (30 mL). The inorganic salts were filtered off
and washed with EtOAc (3 × 75 mL). The combined organic
filtrate and washings were dried over Na2SO4 and evaporated
under reduced pressure to give crude diamines as oily (9a ,b
and 10a ,b) or crystalline (11a ,b) products.
1
7a : yield 1.44 g (78%); mp 83-86 °C; H NMR (CDCl3) δ
1.14 (d, 6H, J ) 6.5 Hz, CH(CH3)2), 1.29-1.68 (om, 7H, (CH2)4),
1.74 (br s, 2H, NH2) 1.83 (m, 1H, (CH2)4), 2.31 (m, 1H, COCH),
3.28 (m, 1H, NCH), 4.06 (m, 1H, NCH(CH3)2), 7.80 (br s, 1H,
CONH). Anal. Calcd for C10H20N2O: C, 65.18; H, 10.94; N,
15.20. Found: C, 64.92; H, 10.73; N, 14.96.
The crude diamines were purified by distillation (9a ,b and
10a ), by column chromatography on silica by using a mixture
of CHCl3 and MeOH (1:1) as eluent (11a ), or as hydrochloride
salts (10b and 11b).
7b: yield 1.56 g (85%); mp 105-108 °C; 1H NMR (CDCl3) δ
1.08-1.52 (om, 12H, CH(CH3)2, (CH2)4, NH2) 1.73 (m, 3H,
(CH2)4), 1.80-1.90 (om, 2H, (CH2)4, COCH), 2.92 (ddd, 1H, J
) 7.32, 11.58, 4.03 Hz, NCH), 4.09 (m, 1H, NCH(CH3)2) 5.92
(br s, 1H, CONH). Anal. Calcd for C10H20N2O: C, 65.18; H,
10.94; N, 15.20. Found: C, 64.95; H, 10.72; N, 15.01.
8a : yield 1.84 g (84%); mp 122-124 °C (lit.14 mp 143-144
°C); 1H NMR (CDCl3) : 1.36-1.73 (om, 7H, (CH2)4), 1.84 (br s,
2H, NH2), 1.98 (m, 1H, (CH2)4), 2.50 (m, 1H, COCH), 3.36 (m,
1H, NCH), 7.05 (t, 1H, J ) 7.4 Hz, C6H5), 7.29 (t, 2H, J ) 8.36
Hz, C6H5), 7.58 (d, 2H, J ) 8.44 Hz, C6H5), 11.31 (br s, 1H,
CONH).
9a : yield 1.55 g (54%); bp 82-90 °C (6 mmHg). The 1H NMR
data on the product correspond to the literature13c data.
1
9b: yield 2.30 g (81%); bp 80-85 °C (4 mmHg); H NMR
(CDCl3) δ 0.92-1.30 (om, 5H, (CH2)4), 1.62-1.84 (om, 4H,
(CH2)4, CCH), 2.38-2.60 (om, 4H, NCH, CH3), 2.50 (dd, 1H, J
) 5.9, 11.6 Hz, NCH2), 2.71 (dd, 1H, J ) 5.6, 11.6 Hz, NCH2).
Anal. Calcd for C8H18N2: C, 67.55; H, 12.76; N, 19.69. Found:
C, 67.36; H, 12.95; N, 19.48.
10a : yield 2.56 g (75%); bp 85-89 °C (2-3 mmHg); 1H NMR
(CDCl3) δ 1.05 (d, 6H, J ) 6.3 Hz, CH(CH3)2), 1.20-1.68 (om,
12H, (CH2)4, CCHC, NH2, NH), 2.47 (dd, 1H, J ) 6.6, 11.5 Hz,
NCH2), 2.62 (dd, 1 H, J ) 7.4, 11.5 Hz, NCH2), 2.75 (m, 1 H,
8b: yield 1.90 g (87%); mp 108-110 °C; 1H NMR (CDCl3) δ
1.13-1.55 (om, 6H, (CH2)4, NH2), 1.77 (m, 2H, (CH2)4), 2.15
4740 J . Org. Chem., Vol. 67, No. 14, 2002

Ring-Chain Tautomerism cis- and trans-Decahydroquinazolines
CH(CH3)2), 3.11 (m, 1 H, NCH). Anal. Calcd for C10H22N2: C,
appropriate diamine (9-11a ,b, 3 mmol) in absolute MeOH (20
mL) was added an equivalent amount of aromatic aldehyde
(for liquid aldehydes, a freshly distilled sample was used), and
the mixture was allowed to stand at ambient temperature for
1 h. The solvent was evaporated off, and the evaporation was
repeated after the addition of toluene (10 mL). The oily
products were dried in a vacuum desiccator for 24 h. The NMR
spectra proved that the purities of these compounds were
greater than 95%. The crystalline products were filtered off
and recrystallized. All of the recrystallized new compounds
(12a ,g, 13g, 14g, 15a , and 17c-g) gave satisfactory data on
elemental analysis (C, H, N (0.3%). The physical data for
compounds 12-17 are listed in Table 6.
70.53; H, 13.02; N, 16.45. Found: C, 70.36; H, 12.75; N, 16.19.
1
11a : yield 2.90 g (71%); mp 44-46 °C; H NMR (CDCl3) δ
1.29 (m, 1H, (CH2)4), 1.37-1.71 (om, 7H, (CH2)4), 1.80 (m, 1H,
CCH), 3.02 (dd, 1H, J ) 6.3, 12.5 Hz, NCH2), 3.14-3.21 (om,
2 H, NCH2, NCH), 6.61 (d, 2H, J ) 7.8 Hz, C6H5), 6.67 (t, 1H,
J
C
) 7.3 Hz, C6H5), 7.16 (m, 2 H, C6H5). Anal. Calcd for
13H20N2: C, 76.42; H, 9.87; N, 13.71. Found: C, 76.21; H,
9.65; N, 13.59.
Crude diamines 10b and 11b were converted to crystalline
dihydrochloride salts by treatment of their ethanolic solutions
(10 mL) with an excess of 22% ethanolic HCl and Et2O. The
crystalline dihydrochlorides were filtered off and recrystallized
from MeOH-Et2O.
1H NMR Sp ectr oscop ic Da ta for (4a r ,2c,8a c)-3-Meth yl-
2-(4-n itr op h en yl)d eca h yd r oqu in a zolin e (12a B) a n d cis-
N-(4-Nitr oben zyliden e)-2-(ph en ylam in om eth yl)cycloh ex-
yla m in e (16a A) in CDCl3. The protons of the open form (A)
are numbered according to the corresponding protons of the
quinazoline ring form (B) (δ in ppm, multiplicity, couplings
in Hz, and assignment, respectively, in parentheses).
12a B: 1.31 (m, 1H, (CH2)4), 1.27 (m, 1H, (CH2)4), 1.49 (m,
1H, (CH2)4), 1.55 (m, 1H, (CH2)4), 1.59 (m, 1H, (CH2)4), 1.63
(m, 1H, CCH), 1.75 (m, 1H, (CH2)4), 1.78 (m, 1H, (CH2)4), 1.86
(s, 3H, CH3), 2.43 (dd, 1H, J ) 3.5, 11.6 Hz, NCH2), 2.88 (dd,
1H, J ) 2.0, 11.6 Hz, NCH2), 3.05 (m, 1H, NCH), 3.81 (s, 1H,
CH), 7.65 (d, 2H, J ) 8.5 Hz, C6H4), 8.21 (d, 2H, J ) 8.7 Hz,
C6H4).
16a A: 1.47 (m, 1H, (CH2)4), 1.51 (m, 1H, (CH2)4), 1.63 (m,
1H, (CH2)4), 1.73 (m, 2H, (CH2)4), 1.82 (m, 2H, (CH2)4), 1.85
(m, 1H, (CH2)4), 1.99 (m, 1H, CCH), 2.93 (dd, 1H, J ) 5.8, 12.3
Hz, NCH2), 3.10 (dd, 1H, J ) 7.8, 12.3 Hz, NCH2), 3.66 (bs,
1H, NCH), 6.52 (d, 2H, J ) 8.1 Hz, C6H5), 6.65 (t, 1H, J ) 6.6
Hz, C6H5), 7.11 (t, 2H, J ) 7.6 Hz, C6H5), 7.89 (d, 2H, J ) 8.5
Hz, C6H4), 8.26 (d, 2H, J ) 8.5 Hz, C6H4), 8.35 (s, 1H, NHd
CH).
10b‚2HCl: yield 3.84 g (79%); mp 200-203 °C; 1H NMR
(D2O) δ 1.17-1.56 (om, 10 H, CH(CH3)2, (CH2)4), 1.80 (m, 2H,
(CH2)4), 1.98 (m, 2H, (CH2)4), 2.08 (m, 1H, CCH), 3.03 (dd, 1H,
J ) 10.4, 12.6 Hz, NCH2), 3.14 (ddd, 1H, J ) 4.0, 10.3, 10.6
Hz, NCH), 3.29 (dd, 1 H, J ) 3.3, 12.7 Hz, NCH2), 3.47 (m, 1
H, CH(CH3)2). Anal. Calcd for C10H24Cl2N2: C, 49.38; H, 9.95;
N, 11.52. Found: C, 49.22; H, 9.78; N, 11.36.
11b‚2HCl: yield 4.81 g (87%); mp 193-195 °C; 1H NMR
(D2O) δ 1.14-1.44 (om, 4H, (CH2)4), 1.71 (m, 2H, (CH2)4), 1.88-
2.05 (om, 3H, (CH2)4, CCH), 3.09 (dt, 1H, J ) 3.9, 10.3 Hz,
NCH), 3.39 (dd, 1H, J ) 10.1, 12.8 Hz, NCH2), 3.57 (dd, 1H, J
) 3.7, 12.8 Hz, NCH2), 7.35-7.53 (om, 5H, C6H5). Anal. Calcd
for C13H22Cl2N2: C, 56.32; H, 8.00; N, 10.10. Found: C, 56.06;
H, 7.85; N, 9.88.
Pure diamine bases 10b and 11b were obtained from the
above dihydrochlorides by alkaline treatment (20% NaOH),
extraction (CH2Cl2), and evaporation under reduced pressure.
The free bases were dried in a vacuum desiccator for 24 h
before the further transformations.
10b: 1H NMR (CDCl3) δ 0.92-1.32 (om, 6 H, (CH2)4), 1.04
(d, 3 H, J ) 6.3 Hz, CH3), 1.05 (d, 3 H, J ) 6.3 Hz, CH3), 1.60-
1.87 (om, 7H, NH2, NH, (CH2)4), 2.42 (dt, 3.8, 10.2 Hz, 1H,
NCH), 2.52 (dd, 1H, J ) 5.8, 11.4 Hz, NCH2), 2.69-2.78 (om,
1H, NCH2, CH(CH3)2). Anal. Calcd for C10H22N2: C, 70.53; H,
13.02; N, 16.45. Found: C, 70.36; H, 12.84; N, 16.22.
11b: mp 38-39 °C; 1H NMR (CDCl3) δ 0.98-1.39 (om, 5H,
(CH2)4), 1.69 (m, 2H, (CH2)4), 1.69 (m, 2H, (CH2)4), 1.75-1.84
(om, 2H, (CH2)4, CCH), 2.44 (dt, 1H, J ) 4.0, 10.3 Hz, NCH),
3.04 (dd, 1H, J ) 5.5, 12.2 Hz, NCH2), 3.21 (dd, 1H, J ) 6.2,
12.2 Hz, NCH2), 6.61 (d, 2H, J ) 7.7 Hz, C6H5), 6.66 (t, 1H, J
) 7.3 Hz, C6H5), 7.15 (m, 2H, C6H5). Anal. Calcd for C13H20N2:
C, 76.42; H, 9.87; N, 13.71. Found: C, 76.27; H, 9.63; N, 13.48.
Gen er a l Meth od for th e Syn th esis of 3-Su bstitu ted
2-Ar yld eca h yd r oqu in a zolin es 12-17. To a solution of the
Ack n ow led gm en t. We thank the Hungarian Re-
search Foundation (OTKA Nos. T034901 and T030452)
for financial support and the Hungarian Academy of
Sciences, Biological Research Centre, for providing the
molecular modeling facilities.
Su p p or tin g In for m a tion Ava ila ble: Table of -∆H°/R
and -∆S°/R for compounds 17a -f. This material is available
free of charge via the Internet at http://pubs.acs.org.
J O020070J
J . Org. Chem, Vol. 67, No. 14, 2002 4741