Synthesis of 2,3,4-tri-substituted 3,4-dihydroquinazolines via tandem nucleophilic addition/epoxy ring-opening cyclization methodology using N-(2-Oxiranylphenyl)carbodiimides with nucleophiles

Article abstract of DOI:10.3987/COM-10-S(E)66

N-(2-Oxiranylphenyl)carbodiimides, which were synthesized via an aza-Wittig reaction of the corresponding functionalized iminophosphoranes with aromatic and aliphatic isocyanates, underwent O-, S-, C-, or N-nucleophilic addition onto a cumulene, followed by an epoxy ring-opening cyclization with the newly formed NH-nucleophile in a one-pot reaction to furnish 2,3-disubstituted 4-(hydroxymethyl)-3,4-dihydroquinazolines in a highly stereospecific manner. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-10-S(E)66

HETEROCYCLES, Vol. 82, No. 1, 2010
305
HETEROCYCLES, Vol. 82, No. 1, 2010, pp. 305 - 311. © The Japan Institute of Heterocyclic Chemistry
Received, 23rd June, 2010, Accepted, 26th July, 2010, Published online, 27th July, 2010
DOI: 10.3987/COM-10-S(E)66
SYNTHESIS
QUINAZOLINES VIA TANDEM NUCLEOPHILIC ADDITION/EPOXY
RING-OPENING CYCLIZATION METHODOLOGY USING
OF
2,3,4-TRI-SUBSTITUTED
3,4-DIHYDRO-
N-(2-OXIRANYLPHENYL)CARBODIIMIDES WITH NUCLEOPHILES†
Takao Saito,* Tatsuya Ote, Masahiro Shiotani, Hiroko Kataoka, Takashi
Otani, and Noriki Kutsumura
Department of Chemistry, Faculty of Science, Tokyo University of Science,
Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan. tsaito@rs.kagu.tus.ac.jp
Abstract – N-(2-Oxiranylphenyl)carbodiimides, which were synthesized via an
aza-Wittig reaction of the corresponding functionalized iminophosphoranes with
aromatic and aliphatic isocyanates, underwent O-, S-, C-, or N-nucleophilic
addition onto a cumulene, followed by an epoxy ring-opening cyclization with the
newly formed NH-nucleophile in a one-pot reaction to furnish 2,3-disubstituted
4-(hydroxymethyl)-3,4-dihydroquinazolines in a highly stereospecific manner.
We have been interested in the chemistry of functionalized (conjugated) heterocumulenes such as
carbodiimides, and their use as key substrates for the synthesis of nitrogen heterocycles.1 Considerable
advances in the chemistry have been made.2 For examples, the synthetic approaches used included an
aza-Wittig reaction of iminophosphoranes with isocyanates to generate functionalized carbodiimides,
followed by the use of various ring-forming transformations such as (a) electrocyclization,1a-c,3 (b)
intra-1b-d,4 or (c) intermolecular Diels-Alder type reaction,1a,c,5 and (d, e) various types of cyclizations
(various bond-forming reactions, e.g., nucleophilic addition/substitution,1e-g,3a,6 and Pauson-Khand
reaction1h-j,7) in tandem with the heterocumulene functionality and adjacent available functional group, to
furnish nitrogen heterocycles A (Chart 1). Our ongoing program to develop a useful synthetic method
based on this concept of a functionalized carbodiimide-mediated, tandem annulation strategy for
†This paper is dedicated to Professor Dr. Albert Eschenmoser on the occasion of his 85th birthday.

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HETEROCYCLES, Vol. 82, No. 1, 2010
R
X
X
R
X
O
O
N C N
R'
N C N
R2
R1
R2
+
R1
H
N
N C N
R'
Nu-H
(a)
(b)
(c)
R
N
C
N C N R
R
R
X
Nu
(d)
(FG)
(R')
R'
Ph3P
N
+
R'
X
H
I
II
R2
N
R1
N C N
R'
HO
N
H
FG
O C N
cyclic amidine
or guanidine
N R
aza-Wittig
reaction
A
FG
N
Nu
N C N
+
R'
FG
N
C N
R'
III
FG
H
(e)
H
X
X
R''
N
X = N, CH, O
R''
H
HN R'
Scheme 1. Tandem nucleophilic addition
/epoxy ring-opening cyclization
Chart 1. Various tandem cyclization pathways
leading to cyclic amidines or guanidines
heterocyclic synthesis prompted us to seek a suitable new functional group that could play an important
part in the ring-forming reaction in tandem.
Scheme 1 depicts our new strategy. A nucleophile initially adds to the cumulene carbon of the
(2-oxyranylphenyl)carbodiimide I to give the intermediate II, the newly formed NH-nucleophilic center,
which subsequently attacks the epoxy ring resulting in a ring-opening cyclization in a permitted 6-exo-tet
manner to produce 4-(hydroxymethyl)dihydroquinazoline III. Herein, we report the results of this new
synthetic approach to dihydroquinazolines having a !-amino-alcohol unit.
First, the key substrates 6-7, epoxy-carbodiimides bearing a variety of substituents (R, R1, R2), were
prepared from o-aminobenzyl alcohol (1) according to the route shown in Scheme 2.
O
O
O
R1
R2
R1
R2
OH
OH
N3
R1
R2
O
H
H
H
(a)
(c), (d)
or (e)
(f)
(g)
(b)
PPh3
NH2
N3
N
N C NR
N3
6(trans): R1 = CO2Et, R2 = H
7(trans): R1 = Ph, R2 = H
7(cis): R1 = H, R2 = Ph
1
2
3
4
5
(a) i) NaNO2/aq.HCl, 1 h; ii) NaN3, 1 h/aq.HCl, 0 °C, 64%
(b) PCC, rt, 2 h/CH2Cl2, 94% (c) ClCH2CO2Et, Na/EtOH, rt, 4 h, 99%
(d) BnBr, tetrahydrothiophene, K2CO3/MeCN, rt, 3 d, 80% (e) i) PhCH=PPh3, ii) mCPBA
(f) Ph3P/CH2Cl2, 96% (g) R-NCO/CH2Cl2, 0 °C-rt, 1-4 h, 88-99%
Scheme 2. Preparation of the oxiranylcarbodiimides 6-7
Oxiranylcarbodiimides 6-7 obtained in this way were allowed to react initially with alcohol nucleophiles;
the results are summarized in Table 1. The reaction with methanol or o-chlorophenol in the presence of
the corresponding sodium alcoholate or phenolate proceeded slowly to afford the dihydroquinazolines 9

HETEROCYCLES, Vol. 82, No. 1, 2010
307
and 10/10’ in good to moderate yields (Table 1, runs 1–6).8 The presence of the base is necessary because
the reaction without the base did not proceed even at 110 °C for 10 h. We believe that the reaction is
initiated by nucleophilic addition onto the cumulene bond to form the intermediate 8, followed by the
intramolecular nucleophilic attack at the proximal epoxy ring by the newly formed amine nucleophile,
with simultaneous epoxy ring-opening to produce the dihydroquinazolines 9 and 10/10’. The exclusive
formation of the erythro-isomer from trans-6/7 and threo-isomer from cis-7ꢀconfirms that the
Table 1. Reaction of carbodiimides 6-7 with O-, S- and C-nucleophiles to give dihydroquinazolines 9-14
R1
O
R1
R2
O
R1
HO
R2
H
H
Nu-H
H
R2
NR
NHR
N C NR
Nu
N
N C
6(trans): R1 = CO2Et, R2 = H
7(trans): R1 = Ph, R2 = H
7(cis): R1 = H, R2 = Ph
Nu
a: R = Ph
b: R = allyl
8
9-14
Carbo-
Run diimide R1
Base
(equiv)
MeONa (0.1)
Reaction
Conditions
rt, 3 d, CH2Cl2
rt, 48 h, CH2Cl2
rt, 2 h, CH2Cl2
Producta
(Yield/%)
9a (61)
R2
H
R
Ph
Nu-H
MeOH
1
6a
CO2Et
CO2Et
CO2Et
Ph
2
6b
H
H
H
H
allyl
Ph
MeOH
MeONa (0.2)
Na (1.0)
MeONa (0.1)
Na (1.0)
MeONa (0.1)
Et3N (1.0)
Et3N (1.0)
-
9b (37)
3
6a
o-ClPhOH
MeOH
9c (54)
4
7a
Ph
10a (66)
10b (44)
10’a (85)
11a (82)
11b (67)
11c (96)
12a (82)
12b (85)
12’a (90)
13a (98)
13b (60)
14a (76)
14’a (89)
0 °C"rt, 5 d, CH2Cl2
0 °C"rt, 5 d, CH2Cl2
0 °C"rt, 6 h, MeOH
0 °C, 1 h, CH2Cl2
5
7a
Ph
Ph
o-ClPhOH
MeOH
6
7a(cis)
6a
H
Ph Ph
7
CO2Et
CO2Et
CO2Et
Ph
H
H
H
H
H
Ph
C12H25SH
C12H25SH
PhSH
8
6b
allyl
Ph
0 °C, 10 min, CH2Cl2
0 °C, 10 min, CH2Cl2
0 °C"rt, 1 h, CH2Cl2
0 °C"rt, 24 h, CH2Cl2
0 °C"rt, 2 h, MeOH
!78"!40 °C, 1 h, THF
9
6a
10
11
12
13
14
15
16
7a
Ph
C12H25SH
PhSH
Et3N (1.0)
-
7a
Ph
Ph
7a(cis)
6a
H
Ph Ph
C12H25SH
NCCH2CO2Et
Et3N (1.0)
NaH (1.0)
CO2Et
CO2Et
Ph
H
H
H
Ph
Ph
Ph
6a
MeCOCH2COMe NaH (1.0) !78˚C"rt, 2 h, THF
7a
NCCH2CO2Et
NCCH2CO2Et
NaH (1.0)
NaH (1.0)
!78"0 °C, 10 min, THF
!78 °C "rt, 30 min, THF
7a(cis)
H
Ph Ph
a A prime mark for the products 10’ and 12’ denotes threo-isomer. For the others (9-12), erythro-isomers.
intramolecular nucleophilic substitution in the epoxy ring-opening process proceeded with complete
inversion of the stereogenic center at the epoxy-2-position. Similarly, the oxiranylcarbodiimides 6-7 also

308
HETEROCYCLES, Vol. 82, No. 1, 2010
reacted with dodecanethiol and benzenethiol to afford the dihydroquinazolines 11 and 12/12’
stereospecifically in good yields (runs 7–12).8 It is noteworthy that the reaction with benzenethiol
proceeded even in the absence of an amine base (Et3N) (runs 9 and 11). The reaction with carbon
nucleophiles was also examined. Treatment with Grignard reagents RMgBr (R = Me, n-Hex, Ph) or
enolate anions derived from acetonitrile and acetophenone failed. However, reaction with stable enolate
anions derived from 1,3-diketones successfully resulted in the formation of the expected C-attacking
quinazoline products 13 and 14/14’ (runs 13–16).
Table 2. Reaction of carbodiimides 6-7 with N-nucleophiles to give dihydroquinazolines 16-19
R1
R1
O
R1
R2
O
R1
HO
HO
R2
R2
H
H
R3
R4 N H
H
H
R2
NR3
a
NR
N R3
+
NHR
N C NR
N
b
C
N
N
N R
N R3
R4
R4
6(trans): R1 = CO2Et, R2 = H
7(trans): R1 = Ph, R2 = H
7(cis): R1 = H, R2 = Ph
H
(R4 = H)
via a
16/18
via b
15
17/19
Carbo-
diimide
7a(cis)
R3
Reaction
Conditions
Producta
(Yield/%)
16’a (78)
Run
1
R1
H
R2
Ph
R
R4N-H
pyperidine
Ph
0 °C, 10 min, CH2Cl2
0 °C, 10 min, CH2Cl2
0 °C, 1 h, CH2Cl2
0 °C, 10 min, CH2Cl2
0 °C, 1 h, CH2Cl2
0 °C, 1 h, CH2Cl2
0 °C, 10 min, CH2Cl2
rt, 2 h, CH2Cl2
16b (33) b
16c (75)
16d (66)
17e (42) b
2
3
7b
Ph
H
H
H
H
H
Ph
Ph
Ph
H
H
H
H
H
H
allyl
pyperidine
allylNH2
allylNH2
allylNH2
c-HexNH2
allylNH2
allylNH2
c-HexNH2
allylNH2
7c
Ph
p-Tol
4
7d
Ph
p-ClPh
c-Hex
allyl
Ph
5
7e
Ph
6
7f
Ph
16f [=17e] (64)
16’g (93)
7
7a(cis)
7e(cis)
7f(cis)
6a
H
8
H
c-Hex
allyl
Ph
17’e (99)
9
H
16’f [=17’e] (72)
18a (99)
0 °C, 30 min, CH2Cl2
rt, 10 min, CH2Cl2
10
11
12
13
14
15
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
6a
Ph
c-HexNH2 rt, 30 min, CH2Cl2
PhNH2
c-HexNH2 rt, 1 h, CH2Cl2
18b (85)
6b
allyl
allyl
c-Hex
p-ClPh
19a [=18a] (30)
18c (45)
114 °C, 3 h, toluene
6b
6c
allylNH2
allylNH2
rt, 3 h, CH2Cl2
19c [=18c] (60)
18d (80)
6d
rt, 10 min, CH2Cl2
a A prime mark for the products 16’ and 17’ denotes threo-isomer. For the others (16-19), erythro-isomers.
b Yield for the reaction performed in one-pot from corresponding azide 4.
The carbodiimides 7a(cis) and 7b reacted rapidly with a secondary amine, piperidine, at 0 °C for 10 min
to give the corresponding dihydroquinazolines 16’a and 16b, respectively, in fairly good yield (Table 2,

HETEROCYCLES, Vol. 82, No. 1, 2010
309
runs 1–2). The reaction apparently proceeded through the guanidine intermediate 15, in which an epoxy
ring-opening cyclization via path “a” by NHR attack was involved. The reaction of carbodiimides 7c, 7d
and 7a(cis) (R = aryl) and 7f and 7f(cis) (R = allyl) with a primary amine (R4 = H: allyl amine, cyclohexyl
amine) also produced the corresponding quinazolines 16c, d, f and 16’f, g similarly via the path “a” in 15
with the ambidentate nucleophilic guanidines (runs 3, 4, 6, 7 and 9). In contrast, the reaction of
carbodiimides 7e and 7e(cis) bearing a bulky substituent (R = cyclohexyl group) with a less bulky allyl
amine yielded quinazolines 17e and 17’e via the alternative path “b” by NHR3 attack in 15 (runs 5 and 8).
Similarly, the reaction of trans-[(3-ethoxycarbonyloxyran-2-yl)phenyl]carbodiimides 6a-d with a primary
amine (allyl amine, cyclohexyl amine, aniline) resulted in the formation of quinazolines 18 or 19 (runs
10–15). The preferred formation of either 16/18 or 17/199 may be ascribed principally to the steric
hindrance of the NHR(R3) group rather than to its nucleophilicity,10 if the allyl group is relatively bulkier
than a phenyl group under the conditions in 15.
In summary, we have developed the functionalized carbodiimide-mediated tandem nucleophilic addition
/epoxy ring-opening cyclization method for stereospecific synthesis of 2,3-disubstituted
4-(hydroxymethyl)-3,4-dihydroquinazolines.
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J.-H. Zeng, H. Fujii, N. Abe, and A. Kakehi, Heterocycles, 2006, 67, 337; (c) C. Shi, Q. Zhang, and
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1
8. The structures 9-14 were determined spectroscopically. 12a (Table 1, run 10): Colorless oil; H
NMR (CDCl3, 500.0 MHz) " 0.87 (t, J = 6.9 Hz, 3H), 1.25-1.35 (m, 18H), 1.56-1.63 (m, 2H), 2.44
(brs, 1H, OH), 2.93 (ddd, J = 6.9, 8.1, 12.9 Hz, 1H), 3.19 (ddd, J = 6.6, 8.1, 12.9 Hz, 1H), 4.55 (d, J
= 6.8 Hz, 1H, H-4), 4.75 (d, J = 6.8 Hz, 1H, CH-O), 6.64-6.66 (m, 2H, Ar), 6.72 (d, J = 7.4 Hz, 1H,
Ar), 6.99 (dt, J = 1.2, 7.4 Hz, 1H, Ar), 7.13-7.15 (m, 3H, Ar), 7.21 (d, J = 7.8 Hz, 1H, Ar), 7.26-7.35
(m, 6H, Ar). 13C NMR (CDCl3, 125.6 MHz) " 14.1 (CH3), 22.6 (CH2), 28.9 (CH2), 29.1 (CH2), 29.1
(CH2), 29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2), 29.6 (CH2), 31.3 (CH2), 31.8 (CH2), 69.7 (CH,
C-4), 74.2 (CH, C-O), 122.0 (C), 123.2 (CH, Ar), 123.8 (CH, Ar), 126.7 (CH, Ar), 127.0 (2CH, Ph),
127.1 (CH, Ar), 127.4 (2CH, Ph), 127.9 (CH, Ar), 128.2 (2CH, Ph), 128.7 (2CH, Ph), 128.8 (CH,
Ar), 140.3 (C, Ph), 142.6 (C, Ph), 143.9 (C), 158.7 (C). IR (neat): 3401, 3062, 2923, 2854, 2360,
1527, 1481, 1257 cm-1. ESI-MS: Calcd for C33H43N2OS (M + H)+ 515.3096, found 515.3107. 12’a
(Table 1, run 12): Colorless oil; 1H NMR (CDCl3, 600.1 MHz): " 0.87 (t, J = 7.0 Hz, 3H), 1.25-1.30
(m, 16H), 1.35-1.39 (m, 2H), 1.62-1.67 (m, 2H), 2.72 (brs, 1H, OH), 2.94 (ddd, J = 6.8, 8.2, 12.9 Hz,
1H), 3.24 (ddd, J = 6.3, 8.2, 13.0 Hz, 1H), 4.62 (d, J = 8.4 Hz, 1H, H-4), 4.69 (d, J = 8.4 Hz, 1H,
CH-O), 6.12 (d, J = 7.4 Hz, 1H), 6.75 (ddd, J = 2.0, 6.5, 7.4 Hz, 1H, Ar), 7.02 (d, J = 7.0 Hz, 2H, Ph),
13
7.17-7.23 (m, 6H, Ar), 7.31 (dd, J = 7.5, 8.0 Hz, 2H, Ph), 7.46 (d, J = 7.8 Hz, 2H, Ph). C NMR
(CDCl3, 150.9 MHz): " 14.1 (CH3), 22.7 (CH2), 28.9 (CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (CH2),
29.5 (CH2), 29.6 (CH2), 29.6 (CH2), 29.7 (CH2), 31.3 (CH2), 31.9 (CH2), 69.8 (CH, C-4), 74.3 (CH,
C-O), 122.0 (C), 123.2 (CH, Ar), 123.8 (CH, Ar), 126.7 (CH, Ar), 127.0 (2CH, Ph), 127.1 (CH, Ar),
127.4 (2CH, Ph), 127.9 (CH, Ar), 128.2 (2CH, Ph), 128.7 (2CH, Ph), 128.8 (CH, Ar), 140.0 (C, Ph),

HETEROCYCLES, Vol. 82, No. 1, 2010
311
142.4 (C, Ph), 144.8 (C), 157.3 (C). IR (neat): 3216, 3062, 2923, 2854, 2360, 1527, 1481, 1257 cm-1.
ESI-MS: Calcd for C33H42N2NaOS (M + Na)+ 537.2916, found 537.2909.
9. The structures 16-19 were determined spectroscopically (in particular, the observedꢀcorrelation for
NOESY and HMBC measurements between H-4/HC(Ar-N(3)) and H-4/C-N(3), respectively).
10. Similar observations and arguments have been reported. See lit.1f and G. Blanco, N. Segui, J. M.
Quintela, C. Peinador, M. Chas, and R. Toba, Tetrahedron, 2006, 62, 11124.