A versatile synthesis of (±)-deoxyfebrifugine, an antimalarial alkaloid analogue, and related compounds

Article abstract of DOI:10.1055/s-2006-926233

The title compound was prepared by a simple route involving Eschenmoser sulfide contraction between 3-(3-bromo-2-oxopropyl)quinazolin-4(3H)-one (11) and piperidine-2-thione (13) followed by chemoselective catalytic hydrogenation. This short but flexible p

Full text of DOI:10.1055/s-2006-926233

LETTER
383
A Versatile Synthesis of ( )-Deoxyfebrifugine, an Antimalarial Alkaloid
Analogue, and Related Compounds
Synthesis
o
of
(
)-Deoxy
s
febrifugin
e
e
ph P. Michael,* Charles B. de Koning, Daniel P. Pienaar
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand, Johannesburg, PO Wits 2050, South Africa
Fax +27(11)7176749; E-mail: jmichael@aurum.wits.ac.za
Received 25 November 2005
total synthesis of febrifugine in recent years,8 largely
sparked by the need to find good synthetic procedures for
making novel analogues having comparable efficacy but
diminished toxicity. Variants with different substitution
Abstract: The title compound was prepared by a simple route in-
volving Eschenmoser sulfide contraction between 3-(3-bromo-2-
oxopropyl)quinazolin-4(3H)-one (11) and piperidine-2-thione (13)
followed by chemoselective catalytic hydrogenation. This short but
flexible procedure also permitted access to N-alkyl analogues, and patterns in both the quinazoline and piperidine moieties
to analogues in which the piperidine ring was replaced by other
have been prepared and tested for antiplasmodial activi-
ty,6,9 and analogues such as 36b and the commercially im-
saturated nitrogen-containing heterocycles.
portant coccidiostat halofuginone (4)9a are promising lead
Key words: alkaloids, enaminones, heterocycles, piperidines,
quinazolines
compounds for further exploration. Although the simpler
synthetic analogue deoxyfebrifugine (5) proved to be in-
ferior to febrifugine in its in vitro antiplasmodial effects,
The quinazoline alkaloids (+)-febrifugine (1) and (+)- it remains an interesting lead compound because it has
isofebrifugine (2) were first reported almost 60 years ago similar antimalarial activity to quinine.10
as metabolites of the Chinese medicinal plant Dichroa
In this paper we describe a short synthesis of ( )-deoxy-
febrifugine (5) by methodology that we believe is versa-
tile enough to permit access to related compounds that can
accommodate significant variation in both heterocyclic
febrifuga.1 The alkaloids were subsequently isolated from
plants of the related genus Hydrangea, including H.
umbellata, H. macrophylla and H. chinense.2 However,
their structural and stereochemical elucidation proved to
portions. This methodology extends our continuing series
be a convoluted affair,3 and it was only as recently as 1999
of investigations into the use of b-acylated enamines
that Kobayashi and co-workers unambiguously demon-
(‘enaminones’ in general) and related compounds as inter-
strated the absolute configurations depicted in Figure 1.4
mediates in alkaloid synthesis.11,12 The fundamental strat-
egy entails a disconnection of generalised targets such as
R
N
O
N
O
6 to enaminone precursors 7, which in general can be
made quite readily by the Eschenmoser sulfide
contraction13 between suitable a-bromoketones 8 and
thiolactams 9, themselves prepared from the correspond-
ing lactams 10 (Scheme 1). It should be apparent that both
building blocks can, in principle, be easily varied.
O
OH
O
N
N
N
H
N
H
(+)-febrifugine R = OH (1)
deoxyfebrifugine R = H (5)
(+)-isofebrifugine (2)
OH
N
Br
Cl
O
N
O
O
R2
R2
( )n
N
N
N
N
( )n
N
N
O
O
H
H
N
N
O
O
N
N
halofuginone (4)
3
R1
O
R1
O
6
7
Figure 1
R2
N
R2
( )n
N
O
( )n
Both alkaloids are potent antimalarial agents that appear
to act in a novel manner by potentiating the production of
NO in macrophages.5 (+)-Febrifugine in particular is one
to two orders of magnitude more effective than chloro-
quine in its antimalarial effects against Plasmodium para-
sites,4b,6 but its clinical use is precluded by severe
gastrointestinal irritation and emetic effects.1d,7 Neverthe-
less, there has been a substantial renewal of interest in the
O
+
Br
N
O
N
R1
S
R1
10
9
8
Scheme 1
Our route to deoxyfebrifugine (Scheme 2) began with a
novel preparation of 3-(3-bromo-2-oxopropyl)quinazolin-
4(3H)-one (11). This compound was previously featured
in a synthesis of deoxyfebrifugine by Takeuchi et al.,10
who prepared it by alkylating quinazolin-4(3H)-one (12)
SYNLETT 2006, No. 3, pp 0383–0386
1
5.
0
2.
2
0
0
6
Advanced online publication: 06.02.2006
DOI: 10.1055/s-2006-926233; Art ID: D35505ST
© Georg Thieme Verlag Stuttgart · New York

384
J. P. Michael et al.
LETTER
with bromoacetone, and then brominating the kinetically ‘oscillation of the double bond’ (sic), one of the proposed
generated silyl enol ether of the alkylated product with N- alternative structures being the conjugated enaminone
bromosuccinimide. Our shorter, more economical route to tautomer 17b with an exocyclic double bond.21
11 simply involved treating 1214 with potassium carbon-
ate and a threefold excess of 1,3-dibromoacetone15 in dry
N,N-dimethylformamide at room temperature for two
hours. Although the desired product 11 was obtained in a
yield of only 66%, the procedure is both convenient and
suitable for large-scale operation; furthermore, unreacted
dibromoacetone can be recovered from the reaction
mixture by distillation.
H
N
N
O
N
O
16
H
H
N
O
N
O
OEt
OEt
17a
17b
N
N
O
i
Figure 2
Br
N
N
66%
H
O
O
Conversion of enaminone 15 into deoxyfebrifugine re-
quires a chemoselective reduction of the conjugated C=C
bond. We have in the past been able to reduce the double
bond of related vinylogous amides selectively with lithi-
um aluminium hydride under carefully controlled condi-
tions without affecting the carbonyl group.22 As one might
have expected, however, this reagent also partially re-
duced the quinazolinone unit of 15, as did milder hydride
reducing agents such as sodium cyanoborohydride or so-
dium triacetoxyborohydride. We eventually achieved the
desired reduction by catalytic hydrogenation at three
atmospheres over platinum dioxide in methanol contain-
ing aqueous hydrochloric acid solution (8.5 M). The
product was initially obtained as the bis(hydrochloride)
salt, which, after neutralisation, exhaustive extraction of
the free base and recrystallisation, yielded ( )-deoxy-
febrifugine (5) in an overall yield of 58%. The IR and 1H
NMR spectra agreed well with those reported by Takeuchi
et al.;10 in addition, we report a 13C NMR spectrum of 5
for the first time.23 It is worth noting that Baker et al. were
able to reduce the putative tetrahydropyridine 16 under
similar conditions to those described above; their yield of
deoxyfebrifugine bis(hydrochloride) was 66%.20
11
12
Br–
N
H
N+
O
ii
S
N
N
H
S
O
13
14
64% from 13
iii
H
N
O
H
N
N
O
N
iv
58%
O
N
N
O
5
15
Scheme 2 Reagents and conditions: i) BrCH2COCH2Br (3 equiv),
K2CO3, DMF, r.t., 2 h; ii) THF, r.t., 48 h; iii) N-methylpiperidine (2.5
equiv), PPh3 (2.5 equiv), MeCN, r.t., 18 h; iv) H2 (3 atm), PtO2 (cat.),
MeOH–aq HCl (8.5 M), r.t., 6 h, then aq K2CO3.
Compound 11 was then treated with piperidine-2-thione
(13)16 in dry tetrahydrofuran. When precipitation of the S-
alkylated product 14 appeared to be complete, the solvent
was removed and replaced by acetonitrile, in which the
salt is moderately soluble. Treatment with triphenylphos-
phine as thiophile and N-methylpiperidine as base, in ac-
cordance with the procedure of Honda and Kimura,17
effected the expected sulfide contraction to give enamin-
one 15 in 64% yield.18 The hydrogen-bonded Z geometry
of this product was apparent from the chemical shift of the
CH2 signal adjacent to the double bond (dH = 2.39 ppm);
anisotropic deshielding by the carbonyl group in related E
enaminones generally causes a downfield shift of about
0.5 ppm.13a The geometry was confirmed by X-ray crys-
tallography.19 Interestingly, 15 may not be a new com-
pound. One of the intermediates in Baker’s 1952 synthesis
of deoxyfebrifugine20 was assigned the tetrahydropyri-
dine structure 16 (Figure 2); but our experience suggests
that the tautomer 15 with the conjugated exocyclic double
bond is a more likely structure. The earlier publication, of
course, included no spectroscopic characterisation; but
the melting points of the products are comparable.18 Baker
et al. themselves postulated that a related tetrahydropyri-
dine, assigned the structure 17a, fails to undergo hydro-
genation in neutral solution because it is stabilised by
To support our contention that our approach is versatile
enough for preparing analogues of febrifugine, we also
performed the Eschenmoser condensation of 11 with a
range of thiolactams 18a–e of varying ring sizes
(Figure 3). The Z enaminones 19a–e were formed in
yields of 50–59% (Table 1); only for the thirteen-mem-
bered product 19e (n = 8) was a lower yield (37%) ob-
tained. To our knowledge, the only other reported
febrifugine analogues in which the piperidine ring has
been replaced by rings of other sizes are the pyrrolidine
congeners prepared over fifty years ago by Baker’s
team.24 With piperidine-2-thiones 20a–c bearing alkyl
substituents on nitrogen, triethylamine was used as the
base instead of N-methylpiperidine; the Eschenmoser re-
action proceeded more easily, and the yields of products
21a–c were generally better. In these cases the products
were found to have the E configuration,19 presumably for
steric reasons and because hydrogen bonding to the carbo-
nyl group is not possible.
Synlett 2006, No. 3, 383–386 © Thieme Stuttgart · New York

LETTER
Synthesis of (±)-Deoxyfebrifugine
385
Disappointingly, all attempts to reduce the enaminone
products 19 chemoselectively under the conditions de-
scribed for deoxyfebrifugine either failed or gave mix-
tures of over-reduced products. By contrast, the N-alkyl
enaminones 21 were readily hydrogenated in acidic meth-
anol to give the N-substituted deoxyfebrifugines 22a–c in
good yield (81%, 70% and 86%, respectively).
References and Notes
(1) (a) Jang, C. S.; Fu, F. Y.; Wang, C. Y.; Huang, K. C.; Lu, G.;
Chou, T. C. Science 1946, 103, 59. (b) Koepfli, J. B.; Mead,
J. F.; Brockman, J. A. Jr. J. Am. Chem. Soc. 1947, 69, 1837.
(c) Kuehl, F. A. Jr.; Spencer, C. F.; Folkers, K. J. Am. Chem.
Soc. 1948, 70, 2091. (d) Koepfli, J. B.; Mead, J. F.;
Brockman, J. A. Jr. J. Am. Chem. Soc. 1949, 71, 1048.
(e) Koepfli, J. B.; Brockman, J. A. Jr.; Moffat, J. J. Am.
Chem. Soc. 1950, 72, 3323.
(2) (a) Ablondi, F.; Gordon, S.; Morton, J. II; Williams, J. H. J.
Org. Chem. 1952, 17, 14. (b) Hutchings, E. L.; Gordon, S.;
Ablondi, F.; Wolf, C. F.; Williams, J. H. J. Org. Chem. 1952,
17, 19. (c) Kato, M.; Inaba, M.; Itahana, H.; Ohara, E.;
Nakamura, K.; Uesato, S.; Inouye, H.; Fujita, T.
H
N
N
O
( )n
N
( )n
N
S
H
O
18a–e n = 0, 2, 3, 4, 8
19a–e n = 0, 2, 3, 4, 8
Shoyakugaku Zasshi 1990, 44, 288; Chem. Abstr. 1991, 115,
64012f. (d) Khalil, A. T.; Chang, F.-R.; Lee, Y.-H.; Chen,
C.-Y.; Liaw, C.-C.; Ramesh, P.; Yuan, S.-S. F.; Wu, Y.-C.
Arch. Pharm. Res. 2003, 26, 15.
N
O
N
N
N
R
S
(3) Takeuchi, Y.; Harayama, T. Trends Heterocycl. Chem.
2001, 7, 65.
R
O
20a–c R = Me, Bn, CH2CH2CN
21a–c R = Me, Bn, CH2CH2CN
(4) (a) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H.
Tetrahedron Lett. 1999, 40, 2175. (b) Kobayashi, S.; Ueno,
M.; Suzuki, R.; Ishitani, H.; Kim, H.-S.; Wataya, Y. J. Org.
Chem. 1999, 64, 6833.
N
O
N
N
R
(5) (a) Murata, K.; Takano, F.; Fushiya, S.; Oshima, Y. J. Nat.
Prod. 1998, 61, 729. (b) Murata, K.; Takano, F.; Fushiya,
S.; Oshima, Y. Biochem. Pharm. 1999, 58, 1593.
(6) (a) Hirai, S.; Kikuchi, H.; Kim, H.-S.; Begum, K.; Wataya,
Y.; Tasaka, H.; Miyazawa, Y.; Yamamoto, K.; Oshima, Y.
J. Med. Chem. 2003, 46, 4351. (b) Kikuchi, H.; Tasaka, H.;
Hirai, S.; Takaya, Y.; Iwabuchi, Y.; Ooi, H.; Hatakeyama,
S.; Kim, H.-S.; Wataya, Y.; Oshima, Y. J. Med. Chem. 2002,
45, 2563. (c) Takeuchi, Y.; Koike, M.; Azuma, K.;
Nishioka, H.; Abe, H.; Kim, H.-S.; Wataya, Y.; Harayama,
T. Chem. Pharm. Bull. 2001, 49, 721. (d) Takaya, Y.;
Tasaka, H.; Chiba, T.; Uwai, K.; Tanitsu, M.; Kim, H.-S.;
Wataya, Y.; Miura, M.; Takeshita, M.; Oshima, Y. J. Med.
Chem. 1999, 42, 3163; and references cited therein.
(7) Edeson, J. F. B.; Wilson, T. Trans. R. Soc. Trop. Med. Hyg.
1955, 49, 543.
(8) For recent syntheses of optically active or racemic
febrifugine, see the following: (a)Takeuchi, Y.; Oshige, M.;
Azuma, K.; Abe, H.; Harayama, T. Chem. Pharm. Bull.
2005, 53, 868. (b) Ashoorzadeh, A.; Caprio, V. Synlett
2005, 346. (c) Katoh, M.; Matsune, R.; Nagase, H.; Honda,
T. Tetrahedron Lett. 2004, 45, 6221. (d) Huang, P.-Q.; Wei,
B.-G.; Ruan, Y.-P. Synlett 2003, 1663. (e) Sugiura, M.;
Hagio, H.; Hirabayashi, R.; Kobayashi, S. Synlett 2001,
1225. (f) Ooi, H.; Urushibara, A.; Esumi, T.; Ibabuchi, Y.;
Hatakeyama, S. Org. Lett. 2001, 3, 953. (g) Sugiura, M.;
Kobayashi, S. Org. Lett. 2001, 3, 477. (h) Okitsu, O.;
Suzuki, R.; Kobayashi, S. J. Org. Chem. 2001, 66, 809.
(i) Takeuchi, Y.; Azuma, K.; Takakura, K.; Abe, H.; Kim,
H.-S.; Wataya, Y.; Harayama, T. Tetrahedron 2001, 57,
1213. (j) For syntheses published prior to 2001, see the
references cited in the preceding.
O
22a–c R = Me, Bn, CH2CH2CN
Figure 3
Table 1 Eschenmoser Sulfide Contraction between 3-(3-Bromo-2-
oxopropyl)quinazolin-4(3H)-one (11) and Thiolactams 18 or 20
Reactant
18a
n or R
Product
19a
Yield (%)
n = 0
59
55
58
50
37
58
72
73
18b
n = 2
19b
19c
18c
n = 3
18d
n = 4
19d
19e
18e
n = 8
20a
R = Me
R = Bn
R = CH2CH2CN
21a
20b
21b
21c
20c
In conclusion, we have demonstrated that a variety of feb-
rifugine analogues can be prepared by a novel procedure
that has the virtues of simplicity and flexibility. Applica-
tions to the enantioselective synthesis of febrifugine itself,
as well as to related hydroxylated analogues, are currently
being investigated.
(9) (a) Jiang, S.; Zeng, Q.; Gettayacamin, M.; Tungtaeng, A.;
Wannaying, S.; Lim, A.; Hansukjariya, P.; Okunji, C. O.;
Zhu, S.; Fang, D. Antimicrob. Agents Chemother. 2005, 49,
1169. (b) Chien, P.-L.; Cheng, C. C. J. Med. Chem. 1970, 13,
867. (c) Fishman, M.; Cruickshank, P. A. J. Med. Chem.
1970, 13, 155. (d) Baker, B. R.; Schaub, R. E.; Joseph, J. P.;
McEvoy, F. J.; Williams, J. H. J. Org. Chem. 1953, 18, 133;
and references cited therein.
Acknowledgment
This work was supported by grants from the National Research
Foundation, Pretoria (grant number 2053652) and the University of
the Witwatersrand. We are grateful to Mr. R. Mampa and Mr. T. van
der Merwe for recording NMR spectra and mass spectra, respec-
tively.
(10) Takeuchi, Y.; Tokuda, S.; Takagi, T.; Koike, M.; Abe, H.;
Harayama, T.; Shibata, Y.; Kim, H.-S.; Wataya, Y.
Heterocycles 1999, 51, 1869.
Synlett 2006, No. 3, 383–386 © Thieme Stuttgart · New York

386
J. P. Michael et al.
LETTER
(11) Review: Michael, J. P.; de Koning, C. B.; Gravestock, D.;
Hosken, G. D.; Howard, A. S.; Jungmann, C. M.; Krause, R.
W. M.; Parsons, A. S.; Pelly, S. C.; Stanbury, T. V. Pure
Appl. Chem. 1999, 71, 979.
(12) Michael, J. P.; de Koning, C. B.; van der Westhuyzen, C. W.
Org. Biomol. Chem. 2005, 3, 836; and references cited
therein.
(20) (a) Baker, B. R.; Querry, M. V.; Schaub, R. E.; Williams, J.
H. J. Org. Chem. 1952, 17, 58. (b) For an alternative
synthesis of ( )-deoxyfebrifugine from the same group, see:
Baker, B. R.; Querry, M. V.; Kadish, A. F.; Williams, J. H.
J. Org. Chem. 1952, 17, 52.
(21) Baker, B. R.; Schaub, R. E.; Querry, M. V.; Williams, J. H.
J. Org. Chem. 1952, 17, 97.
(13) (a) Roth, M.; Dubs, P.; Götschi, E.; Eschenmoser, A. Helv.
Chim. Acta 1971, 54, 710. (b) Shiosaki, K. In
(22) Ghirlando, R.; Howard, A. S.; Katz, R. B.; Michael, J. P.
Tetrahedron 1984, 40, 2879.
Comprehensive Organic Synthesis, Vol. 2; Trost, B. M., Ed.;
Pergamon Press: Oxford, 1991, 865–892.
(14) von Niementowski, S. J. Prakt. Chem. 1895, 51, 564.
(15) Weygand, F.; Schmied-Kowarzik, V. Chem. Ber. 1949, 82,
333.
(16) Brillon, D. Synth. Commun. 1990, 20, 3085.
(17) Honda, T.; Kimura, M. Org. Lett. 2000, 2, 3925.
(18) Synthesis of 3-[(3Z)-2-Oxo-3-(piperidin-2-
ylidene)propyl]quinazolin-4 (3H)-one (15).
(23) Synthesis of ( )-Deoxyfebrifugine (5).
Enaminone 15 (190 mg, 0.671 mmol) was dissolved in a
mixture of MeOH (15 mL) and aq HCl (8.5 N, 0.20 mL). The
solution was stirred over pre-hydrogenated PtO2·xH2O
(Adams catalyst, 26 mg) under H2 gas (3 atm) for 6 h. After
filtering through Celite®, the solvent was removed under
reduced pressure and the residue was triturated with EtOH–
MeOH (5:1), cooled down and left to precipitate overnight in
the freezer. After filtering, the precipitate was identified as
the dihydrochloride salt of ( )-deoxyfebrifugine, 5·2HCl
(138 mg, 58%), mp 218–221 °C (decomp.) [lit. mp 228–
230 °C (decomp.)20]. 1H NMR (300 MHz, D2O): d = 8.65 (1
H, s, H-2), 8.28 (1 H, d, J = 8.1 Hz, H-5), 8.04 (1 H, m, H-
6), 7.74–7.83 (2 H, m, H-7 and H-8), 5.20 (2 H, s,
O=CCH2N), 3.70 (1 H, m, J = 7.1 Hz, NCH), 3.05–3.49 (4
H, m, ring NCH2 and O=CCH2CH), 1.92–2.11 (3 H, m,
A mixture of 3-(3-bromo-2-oxopropyl)quinazolin-4 (3H)-
one (11, 395 mg, 1.41 mmol) and piperidine-2-thione (13,
163 mg, 1.41 mmol) in dry THF (30 mL) was stirred at r.t.
for 48 h until salt precipitation was complete. After
evaporation of the solvent in vacuo, dry MeCN (25 mL),
triphenylphosphine (PPh3, 0.92 g, 3.5 mmol) and 1-
methylpiperidine (0.44 mL, 3.5 mmol) were sequentially
added to the residue. Stirring was continued at r.t. for another
18 h. After evaporation of the solvent in vacuo, the residue
was dissolved in CH2Cl2 (50 mL) and extracted with aq HCl
(2 M, 3 × 20 mL). The combined aqueous extracts were
washed with CH2Cl2 (10 mL), then made basic with concd
aq NH3 solution. Extraction with CH2Cl2 (3 × 15 mL) was
followed by washing of the combined organic extracts with
brine (10 mL). Drying (Na2SO4), filtering and evaporation to
dryness yielded crude product as a light brown solid, which
was purified by column chromatography (EtOAc–hexane,
4:1) to afford 15 as a colourless solid (254 mg, 64%), mp
167.5–170 °C (from EtOAc–hexane) (lit. mp of the putative
tautomer 16,20 167–170 °C; 176–178 °C after
recrystallisation). MS: m/z calcd for C16H17N3O2: 283.1321;
found: 283.1326 [M+]. IR (CHCl3): nmax = 2948, 2869, 1673
(s, quinazolinone C=O), 1607 (s, enaminone C=O), 1578,
1526, 1474 cm–1. 1H NMR (300 MHz, CDCl3): d = 11.11 (1
H, br s, NH), 8.31 (1 H, d, J = 8.3 Hz, H-5), 8.04 (1 H, s, H-
2), 7.71–7.78 (2 H, m, H-7 and H-8), 7.45–7.51 (1 H, m, H-
6), 4.93 (1 H, s, NC=CH), 4.64 (2 H, s, O=CCH2), 3.32 (2 H,
dt, J = 5.7, 2.3 Hz, ring NCH2), 2.39 (2 H, t, J = 6.2 Hz,
NCCH2), 1.67–1.81 (4 H, m, 2 × ring CH2). 13C NMR: d =
186.0 (enaminone C=O), 166.5 (NC=CH), 161.1
1.5 × ring CH2), 1.59–1.75 (3 H, m, 1.5 × ring CH2). 13
C
NMR (50 MHz, D2O): d = 204.4, 163.5, 151.7, 144.6, 139.2,
132.0, 129.4, 125.9, 122.5, 58.2, 54.7, 47.6, 45.1, 30.7, 24.3,
24.0. The salt was dissolved in sat. K2CO3 solution (5 mL),
and the resulting solution was extracted with EtOAc (3 × 10
mL). The combined extracts were dried (MgSO4), filtered
and evaporated in vacuo to give the free base as a cream-
coloured solid which could be repeatedly recrystallised from
EtOAc–hexane to afford ( )-deoxyfebrifugine (5) in
quantitative yield from the hydrochloride salt; colourless
needles, mp 127.5–129 °C (lit.10 mp 139–141 °C; lit.20 138–
140 °C). MS: m/z calcd for C16H20N3O2: 286.1556; found:
286.1559 [MH+]. IR (film) nmax = 3063 (w), 2930 (m), 2854
(w), 1729 (m), 1677 (s), 1613 (s), 1563 (w), 1474 (m) cm–1.
1H NMR (300 MHz, CDCl3): d = 8.28 (1 H, d, J = 8.1 Hz, H-
5), 7.89 (1 H, s, H-2), 7.72–7.80 (2 H, m, H-7 and H-8), 7.51
(1 H, dt, J = 7.3, 1.4 Hz, H-6), 4.84 (1 H, d, J = 17.4 Hz,
O=CCHaHbN), 4.73 (1 H, d, J = 17.4 Hz, O=CCHaHbN),
3.04 (2 H, 2 × m, NCH and O=CCHaHbCH), 2.64–2.67 (3 H,
m, ring NCH2 and O=CCHaHbCH), 2.11 (1 H, br s, NH),
1.80 (1 H, br d, ring CHaHb), ca. 1.64, 1.40, 1.23 (2 H, 2 H,
1 H, 3 × m, remaining ring CH2). 13C NMR: d = 202.1,
160.9, 148.2, 146.2, 134.5, 127.6, 127.4, 126.7, 121.8, 54.8,
52.7, 47.7, 46.7, 32.7, 26.0, 24.5. FAB-MS: m/z (%) = 286
(25) [MH+], 180 (5), 154 (100), 136 (74), 124 (9), 120 (13),
115 (5), 107 (26). The 1H NMR spectroscopic data agree
with those reported in the literature.10
(quinazolinone C=O), 148.3, 147.2, 134.1, 127.4, 127.0,
126.8, 122.1, 90.2 (NC=CH), 52.4 (O=CCH2), 41.1 (ring
NCH2), 28.5, 21.9, 18.9. MS (EI): m/z (%) = 283 (9) [M+],
255 (2), 220 (3), 124 (100), 82 (4), 55 (3).
(19) Results of a more extensive crystallographic survey that
includes 15 and representative examples of compounds 19
and 21 will be published elsewhere.
(24) (a) Baker, B. R.; Schaub, R. E.; Williams, J. H. J. Org.
Chem. 1952, 17, 109. (b) Baker, B. R.; Schaub, R. E.;
Williams, J. H. J. Org. Chem. 1952, 17, 116.
Synlett 2006, No. 3, 383–386 © Thieme Stuttgart · New York