Studies on quinazolines. 11. Intramolecular imidate-amide rearrangement of 2-substituted 4-(ω-chloroalkoxy)quinazoline derivatives. 1,3 -O → N shift of chloroalkyl groups via cyclic 1,3-azaoxonium intermediates

Article abstract of DOI:10.1021/jo0263420

The ω-chloroalkylation of 2-substituted quinazo lin-4(3H)-one derivatives 1 and 2 with Br-(CH₂)_n-Cl (n = 2-4) and the intramolecular imidate-amide rearrangement of the alkylated products are described. At room temperature, the 2-phenyl substituent promoted O-alkylation, whereas the less steric 2-benzyl group led to a higher ratio of N-alkylation. The investigation of the O-alkylated products, 4-ω-chloroalkoxyquinazolines, revealed that the migration of ω-chloroethyl and ω-chloropropyl groups from oxygen to nitrogen should be intramolecular via five- and six-membered cyclic 1,3-azaoxonium intermediates, respectively. Competition between rearrangement and nucleophilic substitution results in the formation of 7a,b and 8a,b from the nucleophilic substitution of 4a,b and 6a,b, respectively.

Full text of DOI:10.1021/jo0263420

Stu d ies on Qu in a zolin es. 11.†
In tr a m olecu la r Im id a te-Am id e
Rea r r a n gem en t of 2-Su bstitu ted
of our studies on quinazoline derivatives as R1-adreno-
ceptors,14 we designed and synthesized a series of 2-sub-
stituted 3-(4-arylpiperazinyl)alkylquinazolin-4(3H)-one
derivatives.
There are numerous methods available for the syn-
thesis of quinazolinones and their derivatives.15 Reports
on solid-phase synthesis of related quinazolinones16 are
an additional impetus to explore their multifaceted
importance. We adapted the procedure of direct cyclo-
condensation dehydrogenation17 of anthranilamide with
benzoic anhydride and phenylacetyl chloride to prepare
our starting materials, 2-phenyl- (1) and 2-benzylquinazo-
lin-4(3H)-one (2), respectively.
4-(ω-Ch lor oa lk oxy)qu in a zolin e Der iva tives.
1,3 -O f N Sh ift of Ch lor oa lk yl Gr ou p s via
Cyclic 1,3-Aza oxon iu m In ter m ed ia tes
Grace Shiahuy Chen, Shivaramayya Kalchar,
Chun-Wei Kuo, Chih-Shiang Chang,
Cyril O. Usifoh, and J i-Wang Chern*
School of Pharmacy, College of Medicine, National Taiwan
University, No. 1, Section 1, J en-Ai Road, Taipei 100,
Taiwan, Republic of China
For the preparation of our potential target compounds,
first 1 was treated with ω-chloroethyl bromide in K2CO3/
DMF at room temperature, but unexpectedly it only led
to the O-alkylated product 4a instead of our desired key
intermediate 3a . Nevertheless, when the reaction was
carried out at higher temperature, it was found that the
N-alkylated derivative 3a was the only product. A perusal
of literature indicated that the N-/O-alkylation of het-
erocyclic ambident nucleophiles has been broadly stud-
ied.18 A percentage of about 35:65 for the N-/O-propargyl
products of 1 and no O-alkylation for the corresponding
2-benzyl derivative (2) were reported by two independent
groups.19 To probe this matter, we carried out the
chern@jwc.mc.ntu.edu.tw
Received August 22, 2002
Abstr a ct: The ω-chloroalkylation of 2-substituted quinazo-
lin-4(3H)-one derivatives 1 and 2 with Br-(CH2)n-Cl (n )
2-4) and the intramolecular imidate-amide rearrangement
of the alkylated products are described. At room tempera-
ture, the 2-phenyl substituent promoted O-alkylation, whereas
the less steric 2-benzyl group led to a higher ratio of
N-alkylation. The investigation of the O-alkylated products,
4-ω-chloroalkoxyquinazolines, revealed that the migration
of ω-chloroethyl and ω-chloropropyl groups from oxygen to
nitrogen should be intramolecular via five- and six-mem-
bered cyclic 1,3-azaoxonium intermediates, respectively.
Competition between rearrangement and nucleophilic sub-
stitution results in the formation of 7a ,b and 8a ,b from the
nucleophilic substitution of 4a ,b and 6a ,b, respectively.
(8) Matsuno, K.; Ichimura, M.; Nakajima, T.; Tahara, K.; Fujiwara,
S.; Kase, H.; Ushiki, J .; Giese, N. A.; Pandey, A.; Scarborough, R. M.;
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10.1021/jo0263420 CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/14/2003
2502
J . Org. Chem. 2003, 68, 2502-2505

TABLE 1. N- a n d O-Alk yla ted P r od u cts of 2-Su bstitu ted Qu in a zolin -4(3H)-on es
% yielda
percentage
no.
n
R
3
4
5
6
3/4
5/6
1a
1b
1c
2a
2b
2c
2
3
4
2
3
4
Ph
Ph
Ph
CH2Ph
CH2Ph
CH2Ph
2
2
0
77
86
82
3:97
2:98
0:100
72
54
49
4
31
32
95:5
64:36
60:40
a
Yields are given for isolated, purified compounds.
TABLE 2. Rea r r a n gem en t of 2-Su bstitu ted
4-(ω-Ch lor oa lk oxy)qu in a zolin e to 2-Su bstitu ted
3-(ω-Ch lor oa lk yl)qu in a zolin -4(3H)-on e
alkylation of both 1 and 2 with a series of ω-chloroalkyl
bromides (Br-(CH2)n-Cl, n ) 2-4) in K2CO3/DMF at room
temperature, which affords the N- and O-alkylated
products in various yields as depicted in Table 1. Sur-
prisingly, at room temperature the O-alkylation of 1
predominated over the N-alkylation in such a way that
4a -c were the sole products with only a trace or even
none of the N-alkylated products (3a -c). For the alkyl-
ation of 2, 3-(ω-chloroethyl)quinazolin-4(3H)-one (5a ) was
indeed prevalent over the O-alkylated product 6a . Nev-
ertheless, the higher ω-chloroalkyl bromides led to an
increasing amount of 4-alkoxyquinazoline derivatives
(6b,c). Steric hindrance of the 2-substituents of quinazo-
line has been reasoned to hamper the N-alkylation.19a In
addition, Hori and co-worker20 asserted that both the
steric and electronic factors of the 2-substituent should
be involved in the determination of N-/O-alkylation of
4(3H)-quinazolinones. On the basis of our current results,
the steric factor of the alkyl group apparently played a
role in the competition of N- and O-alkylation. The
structures of N- (3, 5) and O-alkylated (4, 6) derivatives
could be distinguished conclusively by the 1H and 13C
NMR and IR spectra. In the NMR spectra, the OCH2
peaks in 4 and 6 are much more downfield compared to
the corresponding peaks of NCH2 in 3 and 5. For
n
R
time
conversion
4a f 3a
4b f 3b
4c f 3c
6a f 5a
6b f 5b
6c f 5c
2
3
4
2
3
4
Ph
Ph
Ph
CH2Ph
CH2Ph
CH2Ph
24 h
7 d
a
18 h
5 d
a
100
100
0
100
100
0
a
Long period.
over 320 °C.22 The rearrangement of alkyl imidates
required even higher temperature than that in Chapman
rearrangement, and its mechanism was proposed to be
intermolecular.23 Alkyl halides and Lewis acids were
reported to catalyze the migration of alkyl groups.24
Alternatively, 2-(ω-chloroethoxy)-1,3,5-trizaines21 and
4-(ω-chloroethoxy)-2H-phthalazin-1-one25 were reported
to undergo uncatalyzed arrangement at temperatures of
110 and 153 °C, respectively. Both series of derivatives
contain a ω-chloroethyl group, and they are analogous
to our system. Therefore, we conducted the inspection on
the rearrangement of 4-(ω-chloroalkoxy)quinazolines 4
and 6.
Derivatives 4 and 6 were heated in CH3CN at reflux
to explore the possibility of rearrangement, and the
results are depicted in Table 2. The 4-(ω-chloroethoxy)-
quinazolines 4a and 6a were rearranged completely to
the corresponding N-alkylated derivatives 3a and 5a ,
respectively, in less a day, and the 4-(ω-chloropropoxy)-
1
instance, the OCH2 of 4a is 4.96 and 66.3 ppm in the H
and 13C NMR, respectively, whereas the NCH2 of 3a is
at 4.35 and 47.1 ppm, respectively. Furthermore, 3 and
5 showed strong peaks at about 1670 cm-1 indicating a
CdO stretch of quinazolin-4(3H)-one.
Our preceding results showed that at room tempera-
ture the ω-chloroethylation of 1 only led to 4a , whereas
at higher temperature it led to the N-alkylated product
3a . We assumed that a rearrangement might be involved
in our case. A survey of literature indicated that aryl,
alkyl, or allyl groups of imidates could migrate from
oxygen to nitrogen.21 The uncatalyzed thermal rear-
rangement of aryl imidates via 1,3-O f N shift, the so-
called Chapman rearrangement, needed a temperature
of over 200 °C. This degenerate rearrangement was also
reported on the quinazoline system at a temperature of
(22) (a) Shine, H. J .; Park, K. H.; rownawell, M. L.; Filippo, J . S.
J r. J . Am. Chem. Soc. 1984, 106, 7077. (b) Newman, A. H.; Bevan, K.;
Bowery, N.; Tortella, F. C. J . Med. Chem. 1992, 35, 4135. (c) Scherrer,
R. A.; Beatty, H. R. J . Org. Chem. 1972, 37, 1681.
(23) Wiberg, K.; Shryne, T. Kinter, R. J . Am. Chem. Soc. 1957, 79,
3160.
(24) Challis, B. C.; Frenkel, A. D. Chem. Commun. 1972, 303.
(25) Pring, B. G.; Swahn, C. Acta Chem. Scand. 1973, 27, 1891.
(20) Hori, M.; Ohtaka, H. Chem. Pharm. Bull. 1993, 41, 1114.
(21) The Chemistry of Amidines and Imidates; Patai, S., Rappoport,
Z., Eds.; J ohn Wiley & Sons: Chichester, 1991; Vol. 2.
J . Org. Chem, Vol. 68, No. 6, 2003 2503

SCHEME 1
SCHEME 2
ized, and even the X-ray crystal structures have been
solved.26c As a result of these stable 1,3-azaoxonium
intermediates, the noncatalyzed intramolecular arrange-
ments of ω-chloroethyl and ω-chloropropyl could be
carried out at such low temperature. Obviously, the
rearrangements of 4-(ω-chlorobutoxy)quinazolines 4c and
6c were hampered as a result of the restricted formation
of a seven-membered cyclic intermediate. Our current
results lend some support to the fact that the intra-
molecular two-step mechanism via the cyclic 1,3-azaoxo-
nium intermediate for the O f N degenerate arrange-
ment is involved in ω-chloroalkyl groups.
Although derivatives 4 and 6 were not our expected
intermediates, all of the ω-chloroalkylated derivatives
3-6 were subjected to undergo nucleophilic substitution
with 4-(2-methoxyphenyl)piperazine to provide the cor-
responding arylpiperazinyl-substituted quinazoline and
quinazolinone derivatives. As expected, the nucleophilic
substitution of 3 and 5 furnished the corresponding 3-[4-
(2-methoxyphenyl)piperazin-1-yl]alkylquinazolin-4(3H)-
ones 7 and 8, respectively, in good yields (Scheme 2). To
our surprise, the nucleophilic substitution of 4 and 6
under the same condition gave not only the nucleophilic
substituted products 9 and 10, respectively, but also 7
and 8, respectively, which should come from 3 and 5 in
different extent as can be seen in Table 3. The 4-(ω-
chloroethoxy)quinazolines (4a , 6a ) exceptionally resulted
in 7a and 8a , respectively, as the sole products in
percentages of 88% and 100%, respectively. For the
ω-chloropropoxyquinazolines (4b, 6b), the direct substi-
tution products (9b, 10b) predominated over the rear-
ranged products (7b, 8b) resulting in ratios of 95:5 and
93:7, respectively. For the longer side chain ω-chloro-
butoxy-substituted derivatives 4c and 6c, it led to only
the direct substitution products 9c and 10c, respectively.
Even after prolonged reflux, no rearranged product was
found except for decomposition. It appears that the
formation of 7 and 8 during the nucleophilic substitution
of 4 and 6, respectively, should result from the rear-
rangement of the O-alkylated derivatives to the more
thermodynamic stable N-alkylated ones, then followed
by the nucleophilic substitution.
quinazolines 4b and 6b also accomplished the rearrange-
ment to 3b in 7 days and 5b in 5 days, respectively.
However, the rearrangement was not feasible for the
4-(ω-chlorobutoxy)quinazolines 4c and 6c, even after a
prolonged period at reflux. Further, the rearrangements
of 4c and 6c were examined in a higher boiling solvent,
DMF, to see the achievability at higher temperature. In
DMF, there was no reaction at 80 °C but there was
decomposition to a complicated mixture without the
expected rearranged product at 120 °C. In regard to
2-substituents, the 2-phenyl group prolonged the rear-
rangement in comparison to the 2-benzyl group, likely
as a result of the steric hindrance. In addition, 4a could
also be rearranged completely to the corresponding 3a
at room temperature in 4 days. It appeared that higher
temperature speeded up the rate of rearrangement, and
our results were coherent with the reported result25 in
which the rearrangement was 85% completed in boiling
DMF after 4 h.
Evidently, the low migration temperature of ω-chloro-
alkyl groups indicated that the mechanism should be
different from those intermolecular rearrangements of
alkyl groups. An intramolecular mechanism has been
postulated on the basis of the rearrangement of ω-chloro-
ethoxy-substituted 1,3,5-trizaines and 2H-phthalazin-1-
one.21,25 Our current results further ascertained the
migration of ω-chloroalkyl groups being accomplished via
an intramolecular mechanism since only ω-chloroethyl
and ω-chloropropyl groups could migrate from oxygen to
nitrogen rather than the ω-chlorobutyl group.
As illustrated in Scheme 1, the O f N shift of the
chloroethyl and chloropropyl groups could proceed by an
intramolecular two-step mechanism via the five- and six-
membered cyclic 1,3-azaoxonium intermediates, respec-
tively. Aube´ et al.26 have reported that a series of five-
and six-membered 1,3-azaoxonium ions, also called imi-
nium ethers, existed and could be isolated as tetra-
fluoroborate salts. The authors also reported that the
structures of these iminium ethers have been character-
(26) (a) Gracias, V.; Milligan, G. L.; Aube´, J . J . Am. Chem. Soc. 1995,
117, 8047. (b) Gracias, V.; Milligan, G. L.; Aube´, J . J . Org. Chem. 1996,
61, 10. (c) Forsee, J . E.; Aube´, J . J . Org. Chem. 1999, 64, 4381. (d)
Smith, B. T.; Gracias, V.; Aube´, J . J . Org. Chem. 2000, 65, 3771.
Consequently, an intramolecular mechanism involving
1,3-azaoxonium clarified why the nucleophilic substitu-
2504 J . Org. Chem., Vol. 68, No. 6, 2003

SCHEME 3
TABLE 3. N- a n d O-[4-(2-Meth oxyp h en yl)p ip er a zin -1-
yl]a lk yl P r od u cts fr om Nu cleop h ilic Su bstitu tion of
2-Su bstitu ted 4-(ω-Ch lor oa lk oxy)qu in a zolin es
ω-chloropropyl groups from oxygen to nitrogen in imi-
date-amide rearrangement proceeds via an intramolecu-
lar mechanism involving cyclic 1,3-azaoxonium interme-
diates. Only five- and six-membered rings of 1,3-
azaoxonium ions are feasible. Furthermore, the formation
rate of a five-membered cyclic 1,3-azaoxonium ion is
much faster than the reaction rate of nucleophilic sub-
stitution. On the other hand, the formation of a six-
membered cyclic 1,3-azaoxonium ion is slower compared
to the nucleophilic substitution.
Exp er im en ta l Section
Gen er a l P r oced u r e for 3-6. To a stirred mixture of
2-substituted quinazoline 1 or 2 (4.5 mmol) and potassium
carbonate (4.5 mmol) in DMF (10 mL) was added dropwise the
appropriate bromochloroalkane (6.7 mmol) at room temperature
for 24-48 h. The reaction was quenched by water (25 mL) and
extracted with ethyl acetate (25 mL × 2). The combined organic
extracts were washed with brine (25 mL × 3), dried by Na2SO4,
and evaporated under reduced pressure. The residue was then
purified by column chromatograph over silica gel eluting with
ethyl acetate/hexane ) 1/4.
Gen er a l P r oced u r e for 7-10. A mixture of appropriate
alkylated product (1 mmol), Na2CO3 (2 mmol), and N-(2-
methoxyphenyl)piperazine (2 mmol) was heated in dry CH3CN
(10 mL) at reflux for 24-48 h. The reaction mixture was then
concentrated in vacuo, and the residue was extracted with CH2-
Cl2 (20 mL × 2). The combined organic layers were washed with
brine, dried over Na2SO4, and concentrated to give the crude
product, which was purified by column chromatography over
silica gel eluting with CH2Cl2/MeOH ) 99/1 or ethyl acetate/
hexane ) 1/2.
% yielda
percentage
n
R
7
9
8
10
7/9
8/10
4a
4b
4c
6a
6b
6c
2
3
4
2
3
4
Ph
Ph
Ph
68
4
0
9
88:12
5:95
0:100
72
80b
CH2Ph
CH2Ph
CH2Ph
74
6
0
0
100:0
7:93
0:100
76
74b
a
b
Yields given for isolated, purified compounds. Diisopropyl
ethylamine was used. If Na2CO3 was used, the yields of 9c and
10c were 28% and 18%, respectively.
tion of 4 and 6 with arylpiperazine gave the direct
substitution and arrangement products in different pro-
portions (Table 3). It is the competing result of rear-
rangement and nucleophilic substitution. For the ω-chloro-
ethyl derivatives 4a and 6a , the five-membered cyclic 1,3-
azaoxonium intermediates were formed straightforwardly
before the substitution took place. The distal end of the
N-O tether could be attacked by either arylpiperazine
directly or by chloride anion first and then substitution
to provide 7a and 8a (Scheme 3). For the ω-chloropropyl
derivatives 4b and 6b, the nuclophilic substitution took
place before the formation of six-membered cyclic 1,3-
azaoxonium intermediates, resulting the high ratio of 9b
and 10b, respectively.
Rea r r a n gem en ts of 4 a n d 6. A solution of 4 or 6 (1 mmol)
in dry CH3CN (10 mL) was heated at reflux for 2 h to 10 days,
giving 3 or 5, respectively, in quantitative yield. Analytically
pure product was recrystallized from ethyl acetate/hexane.
Ack n ow led gm en t. This work was financially sup-
ported by the National Health Research Institutes of
the Republic of China (Grant NHRI-EX91-8918BL).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
In summary, our current results provide further sup-
ports that the migration of both ω-chloroethyl and
J O0263420
J . Org. Chem, Vol. 68, No. 6, 2003 2505