A novel method of synthesis of 2,4-diamino-6-arylmethylquinazolines using palladium(0)-catalyzed organozinc chemistry

Full text of DOI:10.1021/jo010536i

7522
J . Org. Chem. 2001, 66, 7522-7526
A Novel Meth od of Syn th esis of
2,4-Dia m in o-6-a r ylm eth ylqu in a zolin es
Usin g P a lla d iu m (0)-Ca ta lyzed Or ga n ozin c
Ch em istr y
Andre Rosowsky* and Han Chen
Dana-Farber Cancer Institute and Department of Biological
Chemistry and Molecular Pharmacology, Harvard Medical
School, Boston, Massachusetts 02115
andre_rosowsky@dfci.harvard.edu
Received May 25, 2001
F igu r e 1. Structures of piritrexim (1), trimethoprim (2),
pyrimethamine (3), and trimetrexate (4).
immunodeficiency syndrome (AIDS).6 A notable struc-
tural feature of 1 is the CH2 bridge between the two
halves of the molecule. This bridge is also present in
trimethoprim (2),7 another lipophilic DHFR inhibitor
widely used for anti-Pc and anti-Tg prophylaxis and
therapy in AIDS patients, usually in combination with
a sulfa drug to enhance the efficacy.8 Two other members
of this class that have been used clinically against these
infections are pyrimethamine (3),7,9 in which the two
halves of the molecule are linked without a CH2 bridge,
and trimetrexate (4),10,11 which contains a CH2NH bridge.
In addition to the fact that it contains a longer bridge, 4
differs from 1 in being a quinazoline as opposed to a
pyrido[2,3-d]pyrimidine. The structures of these four
prototypical examples of clinically active lipophilic anti-
folates are shown in Figure 1.
Although there are a number of examples in the
literature of lipophilic DHFR inhibitors in which the
fused 2,4-diaminopyrimidine ring system and the aryl
side chain are separated by a short O or S bridge, as in
5 and 6,12,13 the only quinazoline antifolates described to
date in which this bridge is CH2 are the 5,6,7,8-tetrahy-
dro derivatives 7.14 In the present paper, we report a
novel and remarkably straightforward method of syn-
thesis of analogues of 7 in which the B-ring is aromatic.
In tr od u ction
Palladium-catalyzed cross-coupling reactions offer a
powerful approach to the creation of a carbon-carbon
bond between an electrophile C-X (e.g., X ) Cl, Br, I,
OTf) and an organometallic species C-M (e.g., M ) Li,
Mg, Zn, B, Si).1 Organozinc reagents are extremely useful
in this context because they can tolerate a wide range of
functionality in the electrophilic partner.2 A large number
of organozinc reagents are available commercially as
standardized solutions in THF or can prepared easily
from organic halides and a highly reactive grade of
metallic zinc (“Rieke zinc”),3 which is likewise com-
mercially available. Thus, organozinc reagents in com-
bination with palladium reagents are advantageous in
the synthesis of complex molecules containing multiple
functional groups, such as natural products. Of particular
note are that the reaction requires only a catalytic
amount of palladium and that, in contrast to the Heck
reaction, the saturated carbon-carbon is generated
directly, without the need to first reduce a double or triple
bond. Thus, palladium-catalyzed cross-coupling reactions
using organozinc reagents are expected to enjoy increas-
ing popularity in organic synthesis and medicinal chem-
istry.
Piritrexim (1),4 a lipophilic inhibitor of the key meta-
bolic enzyme dihydrofolate reductase (DHFR), has been
studied intensively as an anticancer drug5 and, more
recently, was identified as a potent inhibitor of the
enzyme from Pneumocystis carinii (Pc) and Toxoplasma
gondii (Tg), two opportunistic parasites known to be
potentially life-threatening in patients with acquired
(6) Kovacs, J .; Allegra, C. A.; Swan, J . C.; Drake, J . C.; Parrillo, J .
E.; Chabner, B. A.; Masur, H. Antimicrob. Agents Chemother. 1988,
32, 430-433.
(7) For an excellent historical account of the chemical and pharma-
ceutical development of the older lipophilic diaminopyrimidine DHFR
inhibitors pyrimethamine and trimethoprim, see: Roth, B.; Cheng, C.
C. Prog. Med. Chem. 1982, 19, 269-331.
(8) (a) Fischl, M. A.; Dickinson, G. M.; La Voie, L. J . Am. Med. Assoc.
1988, 259, 1185-1189. (b) Medina, I.; Mills, J .; Leoung, G.; Hopewell,
P. C.; Lee, B.; Modin, G.; Benowitz, N.; Wofsy, C. B. N. Engl. J . Med.
1990, 323, 776-782.
(9) Podzamczer, D.; Salazar, A.; J imenez, J .; Consiglio, E.; Santin,
M.; Casanova, A.; Rufi, G.; Gudiol, F. Ann. Intern. Med. 1995, 122,
755-761.
* To whom correspondence should be addressed. Phone: (617) 632-
3117. Fax: (617) 632-2410.
(1) For a comprehensive review of palladium catalysts and their uses
in organic synthesis, see: Tsuji, J . Palladium Reagents and Cata-
lysts: Innovations in Organic Synthesis; Wiley: New York, 1995.
(2) (a) Baba, S.; Negishi, E. J . Am. Chem. Soc. 1976, 98, 6729-6731.
(b) Negishi, E.; King, A. O.; Okukado, N. J . Org. Chem. 1977, 42, 1821-
1823.
(3) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D. J . Org. Chem. 1991, 56,
1445-1453.
(4) Grivsky, E. M.; Lee, S.; Sigel, C. W.; Duch, D. S.; Nichol, C. A.
J . Med. Chem. 1980, 23, 327-329.
(5) Sigel, C. W.; Macklin, A. W.; Woolley, J . L., J r.; J ohnson, N. W.;
Collier, M. A.; Blum, M. R.; Clendeninn, N. J .; Everitt, J . M.; Grebe,
G.; Mackars, A.; Foss, R. G.; Duch, D. S.; Bowers, S. W.; Nichol, C. A.
NCI Monogr. 1987, 5, 111-120. (c) Laszlo, J .; Brenckman, W. D., J r.;
Morgan, E.; Clendeninn, N. J .; Williams, T.; Currie, V.; Young, C. NCI
Monogr. 1987, 5, 121-125.
(10) (a) Bertino, J . R.; Sawicki, W. L.; Moroson, B. A.; Cashmore,
A. R.; Elslager, E. F. Biochem. Pharmacol. 1979, 28, 1983-1987. (b)
Elslager, E. F.; J ohnson, E. L.; Werbel, L. M. J . Med. Chem. 1983, 26,
1753-1760.
(11) Sattler, F. R.; Frame, P.; Davis, R,; Nichols, L.; Shelton, B.;
Akil, B.; Baugman, R.; Hughlett, C.; Weiss, W.; Boylen, C. T.; van der
Horst, C.; Black, J .; Masur, H.; Feinberg, J . J . Infect. Dis. 1994, 170,
165-172.
(12) Elslager, E. F.; Clarke, J .; J ohnson, J .; Werbel, L. M. Davoll,
J . J . Heterocycl. Chem. 1972, 9, 759-773.
(13) Hynes, J . B.; Ashton, W. T.; Merriman, H. G., III; Walker, F.
C., III. J . Med. Chem. 1974, 17, 682-684.
(14) Rosowsky, A.; Papoulis, A. T.; Forsch, R. A.; Queener, S. F. J .
Med. Chem. 1999, 42, 1007-1017.
10.1021/jo010536i CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/11/2001

Notes
J . Org. Chem., Vol. 66, No. 22, 2001 7523
The key step in the synthesis of these compounds, which
to our knowledge have not been described previously, is
a palladium-catalyzed cross-coupling reaction between
2-amino-5-iodobenzonitrile and arylmethylzinc halides
without protection of the amino group. Ring closure of
the resulting aminonitriles by heating them with chlo-
roformamidine hydrochloride under previously described
dry-fusion conditions15,16 yielded the fully aromatic ana-
logues 8.
erization of chloroformamidine hydrochloride.19 The
MeOH-CHCl3 filtrate at this stage contains the HCl salt
of the diaminoquinazoline as well as the salt of a second
product believed to be a noncyclized amidinonitrile
intermediate.15 As noted earlier,15 further heating under
high vacuum is sometimes required in order to drive the
ring closure to completion, and the exact reaction condi-
tions may vary depending on the reactivity of the amino
nitrile.
1H NMR spectra of 8a -n showed the expected signals
for a 2,4-diamino-6-arylmethylquinazoline, among which
were a singlet at approximately δ 3.9 for H-5 and
doublets at approximately δ 7.1 (J ) 8.4-8.8 Hz) and δ
7.3 (J ) 8.4-8.8 Hz) for H-8 and H-7, respectively.
Signals for the other aromatic protons had chemical shifts
and coupling constants in agreement with the nature and
location of the substituents on the benzyl ring. The
identity of each final product was also confirmed by
microchemical analysis and mass spectrometry.
Yields in the cross-coupling reaction to form the amino
nitriles 10a -n ranged from 43 to 69%, with an average
of 55%. Yields in the ring-closure reaction to form
quinazolines 8a -n ranged from 37 to 60%, with an
average of 47%. Thus, even though the palladium cata-
lyst, solvent, and temperature were not individually
optimized in the cross-coupling reaction and the overall
yield from 2-aminobenzonitrile did not exceed 25%, the
obvious merit of this synthesis is that it involved only
two steps.
As shown in Scheme 1, iodination of 2-aminobenzo-
nitrile with iodine monochloride in glacial AcOH at room
temperature occurred regioselectively at the para position
to give 2-amino-5-iodobenzonitrile (9) in 65% yield as
reported by others.17 When a catalytic amount (0.1 mmol)
of the commercially available reagent [1,1′-bis(diphenyl-
phosphino)ferrocene]dichloropalladium(II)‚CH2Cl2 [(DPPF)-
PdCl2‚H2Cl2]18 was added to a THF solution of the
organozinc halide (5 mmol), a deep yellow color formed
after only a few minutes. Upon addition of a solution of
9 (2 mmol) in THF, followed by heating under reflux for
another 30 min, TLC showed the cross-coupling reaction
to be complete. The resulting amino nitriles 10a -n were
purified by column chromatography on silica gel, and
In summary, the findings reported here suggest that
this simple and potentially versatile method may lend
itself to the synthesis of a large variety of previously
unknown DHFR inhibitors in which an arylmethyl group
is linked directly to the 2,4-diaminoheterocyclic moiety
via a CH2 bridge. Studies along these lines are ongoing
in our laboratory.
1
their identity and purity were established from their H
NMR spectra, which contained the expected singlet at
approximately δ 3.8, along with OMe, NH2, and aromatic
proton peaks consistent with assigned structures.
Sch em e 1
Exp er im en ta l Section
IR spectra were obtained on a Perkin-Elmer model 781
double-beam-recording spectrophotometer. Only peaks with
wavenumbers greater than 1400 cm-1 are reported. 1H NMR
spectra were recorded at 200 MHz on a Varian VX200 instru-
ment or at 400 MHz on a Varian VX400 instrument. TLC
analyses were performed on Whatman MK6F silica gel plates
with UV illumination at 254 nm. Column chromatography was
performed on Baker 7024 flash silica gel (40 µm particle size).
Melting points were measured in Pyrex capillary tubes in a Mel-
Temp ′“Electrothermal”′ apparatus (Fisher Scientific, Pittsburgh,
PA) and are not corrected. Mass spectra in the electron-impact
(EI) or fast-atom-bombardment (FAB) mode were obtained by
staff of the Dana-Farber Cancer Institute Molecular Biology Core
(16) For other reaction conditions under which aminonitriles can
be condensed with chloroformamidine hydrochloride or cyanamide/
pyridine‚HCl, its synthetic equivalent, to obtain various types of di-
and tricyclic 2,4-diaminopyrimidine derivatives, see: (a) Rosowsky A.;
Modest, E. J . J . Org. Chem. 1966, 31, 2607-2613. (b) Rosowsky, A.;
Marini, J . L.; Nadel, M.; Modest, E. J . J . Med. Chem. 1970, 13, 882-
886. (c) Elslager E. F.; J acob, P.; Werbel, L. M. J . Heterocycl. Chem.
1972, 9, 775-782. (d) Elslager, E. F.; Bird, O. D.; Clarke, J .; Perricone,
S. C.; Worth, S. F. J . Med. Chem. 1972, 15, 1138-1146. (e) Rosowsky,
A.; Chen, K. K. N.; Lin, M. J . Med. Chem. 1973, 16, 191-194. (f)
Ashton, W. T.; Hynes, J . B. J . Med. Chem. 1973, 16, 1233-1237. (g)
Harris, N. V.; Smith, C.; Bowden, K. J . Med. Chem. 1990, 33, 434-
444.
Ring closure of 10a -n to form 8a -n was performed
by heating with chloroformamidine hydrochloride under
conditions we have used in our laboratory in the past,
which involve heating a finely ground mixture of the
reactants in an open pear-shaped flask, without solvent,
at 120-130 °C for 20 min.15 The resultant melt is allowed
to congeal at room temperature and is taken up in MeOH.
Addition of CHCl3 causes precipitation of byproducts
arising from thermally induced self-condensation/polym-
(17) Harris, N. V.; Smith, C.; Bowden, K. Eur. J . Med. Chem. 1992,
27, 7-18.
(18) Hayashi, T.; Konishi, M.; Kobori, Y.; Kumada, M.; Higuchi, T.;
Hirotsu, K. J . Am. Chem. Soc. 1984, 106, 158-163.
(15) Rosowsky, A.; Mota, C. E.; Wright, J . E.; Freisheim, J . H.;
Heusner, J . J .; McCormack, J . J .; Queener, S. F. J . Med. Chem. 1993,
36, 3103-3112.
(19) Self-condensation of chloroformamidine hydrochloride is un-
avoidable in this fusion reaction but is not a problem when an excess
of this reactant is used relative to the aminonitrile.

7524 J . Org. Chem., Vol. 66, No. 22, 2001
Notes
Facility. The palladium catalyst [1,1′-bis(diphenylphosphino)-
ferrocene]dichloropalladium(II)‚CH2Cl2 and other chemicals,
including Rieke-grade active zinc as a suspension in dry THF,
were purchased from Aldrich, Milwaukee, WI. Solutions of 3,4-
dichlorobenzylzinc chloride, 2,5-dimethoxybenzylzinc chloride,
and 3,4,5-trimethoxybenzylzinc chloride in dry THF were pre-
pared and used essentially as described in the literature for other
organozinc reagents3 and were used immediately. Other orga-
nozinc reagents, supplied as 0.5 M solutions in THF in ′“Sure-
Seal”′ bottles, were purchased from Aldrich. The THF used in
the zinc cross-coupling reactions was freshly distilled from Na
benzophenone ketyl under a dry N2 atmosphere. Chloroforma-
midine hydrochloride was prepared from cyanamide in ethereal
HCl as described.17 The amino nitrile intermediates were
checked thoroughly for purity by 1H NMR and TLC (Rf ) 0.24-
0.32 on silica gel using 2:1 hexane-CH2Cl2), but elemental
analyses were obtained only for the quinazoline final products.
Elemental analyses were performed by Robertson Laboratories,
Madison, NJ , and were within (0.4% of theoretical values.
Typ ica l P r oced u r e. Syn th esis of 2,4-Dia m in o-6-ben zyl-
qu in a zolin e (8a ): Step 1. A solution of iodine monochloride
(16.7 g, 0.1 mol) in glacial AcOH (30 mL) was added dropwise
over 15 min to a stirred solution of 2-aminobenzonitrile (11.8 g,
0.1 mol) in glacial AcOH (125 mL) at room temperature. The
mixture was stirred for 3 h and then poured into H2O (1000 mL).
The resulting pinkish-brown solid was filtered, washed with
H2O, and dried in vacuo. Crystallization from 9:1 cyclohexane-
toluene gave 2-amino-5-iodobenzonitrile (9) as translucent plates
(14.9 g, 64%): mp 85-86 °C (lit.17 mp 85-86 °C); 1H NMR
(CDCl3) δ 7.60 (d, J ) 1.6 Hz, 1H, H-6), 7.57 (dd, J ) 9.2, 1.6
Hz, 1H, H-4), 6.53 (d, J ) 9.2 Hz, 1H, H-3), 4.45 (br s, 2H, NH2).
The product was used directly in the next reaction (Step 2).
Step 2. (DPPF)PdCl2‚CH2Cl2 (82 mg, 0.1 mmol) was added
to 0.5 M benzylzinc bromide in dry THF (10 mL, calculated to
contain 5 mmol), and the mixture was stirred at room temper-
ature for 5 min under N2. A solution of 9 (488 mg, 2 mmol) in
dry THF (2 mL) was then added, and the reaction mixture was
heated under reflux and monitored by TLC (silica gel, 2:1 CH2-
Cl2-hexanes). After 30 min, the reaction was quenched by
addition of saturated aqueous NH4Cl (10 mL) followed by
addition of saturated aqueous Na2EDTA (10 mL), and stirring
was continued for another 30 min. The brown mixture was
extracted several times with CH2Cl2, and the combined extracts
were washed with brine, dried over Na2SO4, and evaporated to
dryness under reduced pressure. The residue was purified by
chromatography on silica gel (2:1 CH2Cl2-hexanes) to obtain
7.89 (s, 1H, H-5). In contrast to the majority of the other
diaminoquinazolines described below, the hydrogens on the
4-NH2 group apparently gave a signal at ca. δ 7.2 that was too
broad to be observed. Anal. Calcd for C15H15N4‚0.3H2O: C, 70.46;
H, 5.75; N, 22.16. Found: C, 70.20; H, 5.42; N, 22.28.
2-Am in o-5-(2′-ch lor ob en zyl)b en zon it r ile (10b ). Com-
pound 10b was obtained from 9 (488 mg, 2 mmol) and 2-chlo-
robenzylzinc chloride (0.5 M in THF, 10 mL, 5 mmol) by the
same method as 10a : white powder (272 mg, 62%); mp 79-80
1
°C; H NMR (CDCl3) δ 3.96 (s, 2H, CH2), 4.79 (br s, 2H, NH2),
6.69 (d, J ) 8.8 Hz, 1H, H-3), 7.12-7.19 (m, 5H, aromatic
protons), 7.20 (s, 1H, H-6).
2-Am in o-5-(3′-ch lor oben zyl)ben zon itr ile (10c). Compound
10c was obtained from 9 (488 mg, 2 mmol) and 3-chlorobenzyl-
zinc chloride (0.5 M in THF, 10 mL, 5 mmol) by the same method
as 10a : white powder (269 mg, 55%); mp 84.5-85.5 °C; 1H NMR
(CDCl3) δ 3.82 (s, 2H, CH2), 4.30 (br s, 2H, NH2), 7.02 (d, J )
8.4 Hz, 1H, H-3), 7.12-7.22 (m, 5H, aromatic protons).
2-Am in o-5-(4′-ch lor ob en zyl)b en zon it r ile (10d ). Com-
pound 10d was obtained from 9 (488 mg, 2 mmol) and 4-chloro-
benzylzinc chloride (0.5 M in THF, 10 mL, 5 mmol) by the same
method as 10a : white powder (243 mg, 59%); mp 91.5-93 °C;
1H NMR (DMSO-d6) δ 3.79 (s, 2H, CH2), 5.87 (br s, 2H, NH2),
6.68 (d, J ) 8.0 Hz, 1H, H-3), 7.11 (d, J ) 8.0 Hz, 1H, H-4), 7.18
(d, J ) 8.4 Hz, 2H, H-2′ and H-6′), 7.20 (s, 1H, H-6), 7.29 (d, J
) 8.4 Hz, 2H, H-3′ and H-5′).
2-Am in o-5-(3′,4′-d ich lor oben zyl)ben zon itr ile (10e). A sus-
pension of active Zn metal in THF (0.76 M, 6.3 mL calculated
to contain 4.8 mmol or a 20% theoretical excess) was placed in
a thoroughly dried three-necked flask that was flushed continu-
ously with
a gentle stream of dry N2. A solution of 3,4-
dichlorobenzyl chloride (790 mg, 4 mmol) in dry THF (2 mL)
was then added slowly to the flask at room temperature, and
the reaction mixture was stirred at 68 °C for 10 h and left to
stand for 3 h to allow the excess Zn metal to settle to the bottom.
The dark-brown solution of organozinc reagent was transferred
via a cannula using gentle N2 pressure into another three-necked
flask, to which was then added dropwise at room temperature
a solution of 9 (244 mg, 1 mmol) in dry THF (1 mL) followed by
a single portion of (DPPF)PdCl2‚CH2Cl2 (41 mg, 0.05 mmol).
Standard workup similar to that used for 10a afforded 10e as a
pale-yellow powder (172 mg, 65%): mp 104-107 °C; 1H NMR
(CDCl3) δ 3.80 (s, 2H, CH2), 4.35 (br s, 2H, NH2), 6.68 (d, J )
8.4 Hz, 1H, H-3), 6.97 (dd, J ) 8.0, 2.0 Hz, 1H, H-6′), 7.11 (s, J
) 8.4 Hz, H-4), 7.16 (s, 1H, H-6), 7.22 (d, J ) 2.0 Hz, 1H, H-2′),
7.35 (d, J ) 8.0 Hz, 1H, H-5′).
2-Am in o-5-(4′-flu or oben zyl)ben zon itr ile (10f). Compound
10f was obtained from 9 (488 mg, 2 mmol) and 4-fluorobenzylzinc
chloride (0.5 M in THF, 10 mL, 5 mmol) by the same method as
10a : pale-yellow powder (275 mg, 51%); mp 105-107 °C; 1H
NMR (CDCl3) δ 3.82 (s, 2H, CH2), 4.32 (br, 2H, NH2), 6.68 (d, J
) 8.8 Hz, 1H, H-3), 6.96-7.00 (m, 2H, H-3′ and H-5′), 7.08-
7.14 (m, 3H, H-4, H-2′, and H-6′), 7.17 (s, 1H, H-6).
2-Am in o-5-(2′-m eth oxyben zyl)ben zon itr ile (10g). Com-
pound 10g was obtained from 9 (610 mg, 2.5 mmol) and
2-methoxybenzylzinc chloride (0.5 M in THF, 10 mL, 5 mmol)
by the same method as 10a : white powder (364 mg, 61%); mp
77.5-78.5 °C; 1H NMR (CDCl3) δ 3.81 (s, 3H, OMe), 3.82 (s, 2H,
CH2), 4.25 (br s, 2H, NH2), 6.64 (d, J ) 8.0 Hz, 1H, H-3), 6.85-
6.88 (m, 2H, H-3′ and H-5′), 7.06 (d, J ) 7.2 Hz, 1H, H-6′), 7.18-
7.23 (m, 3H, H-4′, H-4, and H-6).
2-Am in o-5-(3′-m eth oxyben zyl)ben zon itr ile (10h ). Com-
pound 10h was obtained from 9 (488 mg, 2 mmol) and 3-meth-
oxybenzylzinc chloride (0.5 M in THF, 10 mL, 5 mmol) by the
same method as 10a : white powder (274 mg, 49%); mp 81-82
°C; 1H NMR (CDCl3) δ 3.81 (s, 2H, OMe), 3.82 (s, 2H, CH2), 4.25
(br s, NH2), 6.67 (d, J ) 8.0 Hz, 1H, H-3), 6.68 (s, 1H, H-2′),
6.72-6.77 (m, 2H, H-4′ and H-6′), 7.15 (d, J ) 8.0 Hz, 1H, H-4),
7.19 (s, 1H, H-6), 7.22 (t, J ) 7.6 Hz, 1H, H-5′).
1
10a as a white powder (210 mg, 51%): mp 68-69 °C; H NMR
(DMSO-d6) δ 3.75 (s, 2H, CH2), 5.85 (br s, 2H, NH2), 6.70 (d, J
) 8 Hz, 1H, H-3), 7.13-7.26 (m, 7H, aromatic protons).
Step 3. A finely ground mixture of 10a (60 mg, 0.29 mmol)
and chloroformamidine hydrochloride (132 mg, 1.16 mmol) was
placed in a 10 mL pear-shaped flask, which was immersed in
an oil bath and triturated continuously with a glass rod while
being heated to 120 °C (internal temperature) under a gentle
stream of N2 as described.15 After 20 min, the reaction mixture
was cooled to room temperature, the resulting glassy solid was
dissolved in MeOH (0.75 mL), and the solution was diluted with
CHCl3 (12 mL) and chilled at 0 °C for 1 h. The solid precipitate
was collected, washed with CHCl3, and discarded. This solid
consisted mainly of byproducts arising from self-condensation
of the chloroformamidine, whereas the pooled filtrates contained
the HCl salt of the desired product, along with a variable amount
of the salt of the intermediate noncyclized amidinonitrile. To
ensure complete ring closure, excess i-Pr2NH (0.5 mL) was added
to the filtrate to neutralize the acid, the mixture was concen-
trated to dryness on a rotary evaporator, and the solid residue
was heated for 1.5 h at 70 °C under high vacuum (0.1 Torr).
The crude product was then dissolved in boiling MeOH, and the
solution was treated with a small amount of decolorizing carbon
(Darco) and hot filtered through a bed of Celite. When the filtrate
became cool, it was basified to pH 10 with ammonia, and the
precipitate was collected. Recrystallization from MeOH-H2O
afforded 8a as a white crystalline solid (32 mg, 44%): mp 220-
222 °C; MS m/z 251.4, calcd 251.3 (M + 1); IR (KBr) ν 3340,
3170, 1620, 1570, 1510, 1450, 1400 cm-1; 1H NMR (DMSO-d6) δ
3.92 (s, 2H, CH2), 5.84 (br s, 2H, 2-NH2), 7.13 (d, J ) 8.6 Hz,
1H, H-8), 7.16-7.35 (m, ca. 6H, H-7 and other aromatic protons),
2-Am in o-5-(4′-m eth oxyben zyl)ben zon itr ile (10i). Com-
pound 10i was obtained from 9 (488 mg, 2 mmol) and 4-meth-
oxybenzyl chloride (0.5 M in THF, 10 mL, 5.0 mmol) by the same
method as 10a : white powder (239 mg, 43%); mp 72.5-73.5 °C;
1H NMR (CDCl3) δ 3.79 (s, 5H, CH2 and OMe), 4.28 (br s, NH2),
6.66 (d, J ) 8.4 Hz, 1H, H-3), 6.83 (d, J ) 8.4 Hz, 2H, H-3′ and
H-5′), 7.05 (d, J ) 7.6 Hz, 2H, H-2′ and H-6′), 7.14 (d, J ) 8.4
Hz, 1H, H-4), 7.17 (s, 1H, H-6).

Notes
2-Am in o-5-(2′,5′-d im eth oxyben zyl)ben zon itr ile (10j). 2,5-
J . Org. Chem., Vol. 66, No. 22, 2001 7525
chloroformamidine hydrochloride (456 mg, 4 mmol) at 130 °C
for 15 min: white needles (107 mg, 37%); mp 224-225 °C; MS
m/z 285.1, calcd 285.8 (M + 1); IR (KBr) ν 3340, 3160, 1615,
Dimethoxybenzylzinc chloride was prepared from 2,5-dimethoxy-
benzyl chloride (746 mg, 4 mmol) and reactive metallic zinc
suspension (0.76 M in THF, 6.3 mL, 4.8 mmol). The supernatant
was transferred via a cannula into a solution of 9 (366 g, 1.5
mmol) in THF at room temperature, followed by addition of a
(DPPF)PdCl2‚CH2Cl2 (62 mg, 0.075 mmol) in one portion. After
the usual workup, 10j was obtained as a pale-yellow powder (280
mg, 69%): mp 90-92 °C; 1H NMR (CDCl3) δ 3.74 (s, 3H, OMe),
3.76 (s, 3H, OMe), 3.80 (s, 2H, CH2), 4.66 (br s, 2H, NH2), 6.63
(d, J ) 2.8 Hz, 1H, H-6′), 6.70 (d, J ) 8.4 Hz, 1H, H-3), 6.72 (dd,
J ) 9.0 Hz, J ) 2.8 Hz, 1H, H-4′), 6.80 (d, J ) 9.0 Hz, 1H, H-3′),
7.19 (d, J ) 8.4 Hz, 1H, H-4), 7.22 (s, 1H, H-6).
2-Am in o-5-(3′,4′-dim eth oxyben zyl)ben zon itr ile (10k). Com-
pound 10k was obtained from 9 (488 mg, 2 mmol) and 3,4-
dimethoxybenzylzinc chloride (0.5 M in THF, 10 mL, 5.0 mmol)
by the same method as 10a : yellow oil (247 mg, 46%); 1H NMR
(CDCl3) δ 3.79 (s, 2H, CH2), 3.83 (s, 3H, OMe), 3.86 (s, 3H, OMe),
4.21 (br s, NH2), 6.65-6.82 (m, 4H, H-3, H-2′, H-5′, and H-6′),
7.15 (d, J ) 8.4 Hz, 1H, H-4), 7.17 (s, 1H, H-6).
1
1565, 1510, 1490, 1450, 1400 cm-1; H NMR (DMSO-d6) δ 4.02
(s, 2H, CH2), 5.89 (br s, 2-NH2), 7.12 (d, J ) 8.8 Hz, 1H, H-8),
7.19 (br s, 2H, 2-NH2), 7.25 (d, J ) 8.4 Hz, 2H, H-2′ and H-6′),
7.32 (d, J ) 8.8 Hz, 1H, H-7), 7.34 (d, J ) 8.4 Hz, 2H, H-3′ and
H-5′), 7.88 (s, 1H, H-5). Anal. Calcd for C15H13N4Cl‚0.2H2O: C,
62.48; H, 4.68; N, 19.43; Cl, 12.29. Found: C, 62.52; H, 4.56; N,
19.63; Cl, 12.32.
2,4-Diam in o-6-(3′,4′-dich lor oben zyl)qu in azolin e (8e). Com-
pound 8e was obtained from 10e (172 mg, 0.65 mmol) and
chloroformamidine hydrochloride (298 mg, 2.6 mmol) at 130 °C
for 15 min: white needles (78 mg, 37%); mp 150-151 °C; MS
m/z 319.2, calcd 319.2 (M + 1); IR (KBr) ν 3310, 3180, 1620,
1
1560, 1510, 1470, 1445, 1400 cm-1; H NMR (DMSO-d6) δ 3.93
(s, 2H, CH2), 5.89 (br s, 2H, 2-NH2), 7.12 (d, J ) 8.4 Hz, 1H,
H-8), 7.19 (br s, 2H, 4-NH2), 7.22 (d, J ) 8.4 Hz, 1H, H-6′), 7.35
(d, J ) 8.4 Hz, 1H, H-7), 7.51 (s, 1H, H-2′), 7.54 (d, J ) 7.6 Hz,
1H, H-5′), 7.87 (s, 1H, H-5). Anal. Calcd for C15H12N4Cl2‚
0.1H2O: C, 56.13; H, 3.83; N, 17.45; Cl, 22.09. Found: C, 56.21;
H, 3.73; N, 17.27; Cl, 21.83.
2-Am in o-5-(3′,5′-dim eth oxyben zyl)ben zon itr ile (10l). Com-
pound 10l was obtained from 9 (244 mg, 1 mmol) and 3,5-
dimethoxybenzylzinc chloride (0.5 M in THF, 5 mL, 2.5 mmol)
by the same method as 10a : pale-yellow powder (158 mg, 59%);
2,4-Dia m in o-6-(4′-flu or oben zyl)qu in a zolin e (8f). Com-
pound 8f was obtained from 10f (150 mg, 0.56 mmol) and
chloroformamidine hydrochloride (255 mg, 2.24 mmol) at 120
°C for 30 min: white needles (97 mg, 65%); mp 214-216 °C;
MS m/z 269.2, calcd 269.3 (M + 1); IR (KBr) ν 3310, 3180, 1610,
1550, 1500, 1440, 1400 cm-1; 1H NMR (DMSO-d6) δ 3.93 (s, 2H,
CH2), 5.86 (br, 2-NH2), 7.08-7.14 (m, 3H, H-3′, H-5′, and H-8),
7.18 (br s, 2H, 4-NH2), 7.25-7.28 (m, 2H, H-2′ and H-6′), 7.32
(d, J ) 8.4 Hz, 1H, H-7), 7.88 (s, 1H, H-5). Anal. Calcd for
C15H13N4F: C, 67.15; H, 4.88; N, 20.88; F, 7.08. Found: C, 66.98;
H, 5.03; N, 20.81; F, 7.16.
2,4-Dia m in o-6-(2′-m eth oxyben zyl)qu in a zolin e (8g). Com-
pound 8g was obtained from 10g (190 mg, 0.8 mmol) and
chloroformamidine hydrochloride (365 mg, 3.2 mmol) at 120 °C
for 20 min: pale-yellow solid (127 mg, 57%); mp 214-215 °C;
MS m/z 281.4, calcd 281.3 (M + 1); IR (KBr) ν 3340, 3180, 1610,
1560, 1500, 1450, 1400 cm-1; 1H NMR (DMSO-d6) δ 3.79 (s, 3H,
OMe), 3.89 (s, 2H, CH2), 6.18 (br s, 2H, 2-NH2), 6.85 (t, J ) 7.2
Hz, 1H, H-5′), 6.96 (d, J ) 8.4 Hz, 1H, H-3′), 7.05 (d, J ) 7.2 Hz,
1H, H-6′), 7.13 (d, J ) 8.4 Hz, 1H, H-8), 7.18 (t, J ) 7.6 Hz, 1H,
H-4′), 7.34 (d, J ) 8.4 Hz, 1H, H-7), 7.43 (br s, 2H, 4-NH2), 7.89
(s, 1H, H-5). Anal. Calcd for C16H16N4O: C, 68.55; H, 5.73; N,
19.99. Found: C, 68.34; H, 5.58; N, 20.09.
1
mp 105-107 °C; H NMR (CDCl3) δ 3.76 (s, 8H, CH2, 3′-OMe,
and 5′-OMe), 4.31 (br s, NH2), 6.29-6.32 (m, 3H, H-2′, H-4′, and
H-6′), 6.68 (d, J ) 8.2 Hz, 1H, H-3), 7.14 (d, J ) 8.2 Hz, 1H,
H-4), 7.19 (s, 1H, H-6).
2-Am in o-5-(3′,4′,5′-tr im eth oxyben zyl)ben zon itr ile (10m ).
3,4,5-Trimethoxybenzylzinc chloride was prepared from 3,4,5-
trimethoxybenzyl chloride (867 mg, 4 mmol) and reactive metal-
lic zinc suspension (0.76 M in THF, 6.3 mL, 4.8 mmol). The
supernatant was transferred via a cannula into a solution of 9
(244 g, 1 mmol) in THF at room temperature, followed by
addition of (DPPF)PdCl2‚CH2Cl2 (41 mg, 0.05 mmol) in one
portion. After the usual workup, 10m was obtained as a pale-
yellow oil (127 mg, 43%): 1H NMR (CDCl3) δ 3.78 (s, 2H, CH2),
3.81 (s, 6H, 3′-OMe and 5′-OMe), 3.82 (s, 3H, 4′-OMe), 4.28 (br
s, NH2), 6.30 (s, 2H, H-2′ and H-6′), 6.69 (d, J ) 8.4 Hz, 1H,
H-3), 7.16 (d, J ) 8.4 Hz, 1H, H-4), 7.19 (s, 1H, H-6).
2-Am in o-5-(2′-n a p h th ylm eth yl)ben zon itr ile (10n ). Com-
pound 10n was obtained from 9 (488 mg, 2 mmol) and 2-naph-
thylmethylzinc chloride (0.5 M in THF, 10 mL, 5 mmol) by the
same method as 10a : pale-yellow oil (327 mg, 63%); 1H NMR
(CDCl3) δ 4.01 (s, 2H, CH2), 4.35 (br s, NH2), 6.68 (d, J ) 8.0
Hz, 1H, H-3), 7.18 (d, J ) 8.0 Hz, 1H, H-4), 7.24 (s, 1H, H-6),
7.45-7.49 (m, 3H, H-4′, H-5′ and H-8′), 7.59 (s, 1H, H-1′), 7.76-
7.82 (m, 3H, H-3′, H-6′, and H-7′).
2,4-Dia m in o-6-(3′-m eth oxyben zyl)qu in a zolin e (8h ). Com-
pound 8h was obtained from 10h (238 mg, 1 mmol) and
chloroformamidine hydrochloride (456 mg, 4 mmol) at 120 °C
for 20 min: pale-yellow needles (124 mg, 60%); mp 207-209 °C;
MS m/z 281.4, calcd 281.3 (M + 1); IR (KBr) ν 3415, 3350, 3110,
With the exception of minor adjustments in the amounts of
MeOH and CHCl3 used in the crystallization step, the following
2,4-diaminoquinazolines were prepared from amino nitriles
10b-10n and chloroformamidine hydrochloride as described for
8a (see above).
1
1650, 1600, 1550, 1500, 1425 cm-1; H NMR (DMSO-d6) δ 3.71
(s, 3H, OMe), 3.89 (s, 2H, CH2), 6.03 (br s, 2-NH2), 6.75 (d, J )
7.2 Hz, 1H, H-4′ or H-6′), 6.80 (d, J ) 7.2 Hz, 1H, H-4′ or H-6′),
6.81 (s, 1H, H-2′), 7.13 (d, J ) 8.8 Hz, 1H, H-8), 7.19 (t, J ) 7.6
Hz, 1H, H-5′), 7.32 (br s, 2H, 4-NH2), 7.37 (d, J ) 8.4 Hz, 1H,
H-7), 7.82 (s, 1H, H-5). Anal. Calcd for C16H16N4O: C, 68.55; H,
5.73; N, 19.99. Found: C, 68.34; H, 5.91; N, 19.91.
2,4-Dia m in o-6-(2′-ch lor oben zylqu in a zolin e (8b). Com-
pound 8b was obtained from 10b (180 mg, 0.74 mmol) and
chloroformamidine hydrochloride (340 mg, 3 mmol) at 130 °C
(internal) for 30 min: white needles (79 mg, 38%); mp 221-222
°C; MS m/z 285.2, calcd 285.8 (M + 1); IR (KBr) ν 3400, 3180,
1610, 1550, 1500, 1430 cm-1; 1H NMR (DMSO-d6) δ 4.04 (s, 2H,
CH2), 5.88 (br s, 2-NH2), 7.11 (s, J ) 8.0 Hz, 1H, H-8), 7.18 (br
s, 4-NH2), 7.20-7.24 (m, 4H, H-3′, H-4′, H-5′, and H-6′), 7.43 (d,
2,4-Dia m in o-6-(4′-m eth oxyben zyl)qu in a zolin e (8i). Com-
pound 8i was obtained from 10i (238 mg, 1 mmol) and chloro-
formamidine hydrochloride (456 mg, 4 mmol) at 120 °C for 20
min: pale-yellow needles (124 mg, 60%); mp 207-209 °C; MS
m/z 281.4, calcd 281.2 (M + 1); IR (KBr) ν 3420, 3340, 3120,
1600, 1560, 1500, 1400 cm-1; 1H NMR (DMSO-d6) δ 3.70 (s, 3H,
OMe), 3.86 (s, 2H, CH2), 5.87 (br s, 2H, 2-NH2), 6.84 (d, J ) 8.0
Hz, 2H, H-3′ and H-5′), 7.10 (d, J ) 8.4, 1H, H-8), 7.14 (d, J )
8.0 Hz, 2H, H-2′ and H-6′), 7.18 (br s, 2H, 4-NH2), 7.27 (d, J )
8.8 Hz, 1H, H-7), 7.87 (s, 1H, H-5). Anal. Calcd for C16H16N4O:
C, 68.55; H, 5.73; N, 19.99. Found: C, 68.62; H, 5.53; N, 20.12.
2,4-Dia m in o-6-(2′,5′-d im eth oxyben zyl)qu in a zolin e (8j).
Compound 8j was obtained from 10j (120 mg, 0.45 mmol) and
chloroformamidine hydrochloride (204 mg, 1.8 mmol) at 120 °C
for 20 min: white crystals (65 mg, 46%); mp 190-192 °C; MS
m/z 311.2, calcd 311.4 (M + 1); IR (KBr) ν 3360, 3180, 1610,
1560, 1490, 1440, 1400 cm-1; 1H NMR (DMSO-d6) δ 3.64 (s, 3H,
OMe), 3.73 (s, 3H, OMe), 3.85 (s, 2H, CH2), 5.81 (br s, 2H,
2-NH2), 6.65 (d, J ) 3.2 Hz, 1H, H-6′), 6.73 (dd, J ) 9.0, 3.2 Hz,
1H, H-4′), 6.88 (d, J ) 9.0 Hz, 1H, H-3′), 7.10 (d, J ) 8.6, 1H,
J
) 8.0 Hz, 1H, H-7), 7.88 (s, 1H, H-5). Anal. Calcd for
C15H13N4Cl‚0.3H2O: C, 62.09; H, 4.72; N, 19.31; Cl, 12.21.
Found: C, 62.40; H, 4.65; N, 19.32; Cl, 11.84.
2,4-Dia m in o-6-(3′-ch lor ob en zylq u in a zolin e (8c). Com-
pound 8c was obtained from 10c (107 mg, 0.44 mmol) and
chloroformamidine hydrochloride (201 mg, 1.76 mmol) at 120
°C for 30 min: white needles (52 mg, 41%); mp 242-243 °C;
MS m/z 285.1, calcd 285.8 (M + 1); IR (KBr) ν 3440, 3200, 1620,
1565, 1510, 1470 cm-1; 1H NMR (DMSO-d6) δ 3.98 (s, 2H, CH2),
5.92 (br s, 2-NH2), 7.11 (d, J ) 8.4 Hz, 1H, H-8), 7.16-7.27 (m,
4H, H-2′, H-4′, H-5′, and H-6′), 7.21 (br s, 2H, 4-NH2), 7.34 (d, J
) 8.4 Hz, 1H, H-7), 7.88 (s, 1H, H-5). Anal. Calcd for C15H13N4-
Cl‚0.2H2O: C, 62.48; H, 4.68; N, 19.43; Cl, 12.29. Found: C,
62.32; H, 4.64; N, 19.38; Cl, 12.56.
2,4-Dia m in o-6-(4′-ch lor oben zyl)qu in a zolin e (8d ). Com-
pound 8d was obtained from 10d (243 mg, 1 mmol) and

7526 J . Org. Chem., Vol. 66, No. 22, 2001
Notes
H-8), 7.15 (br s, 2H, 4-NH2), 7.35 (dd, J ) 8.6, 2.0 Hz, 1H, H-7),
7.84 (d, J ) 2.0 Hz, 1H, H-5). Anal. Calcd for C17H18N4O2‚
0.3H2O: C, 64.66; H, 5.94; N, 17.74. Found: C, 64.62; H, 5.71;
N, 17.74.
2,4-Diam in o-6-(3′,4′,5′-tr im eth oxyben zyl)qu in azolin e (8m ).
Compound 8m was obtained from 10m (82 mg, 0.28 mmol) and
chloroformamidine hydrochloride (125 mg, 1.1 mmol) at 120 °C
for 15 min: white crystals (47 mg, 49%); mp 219-221 °C; MS
m/z 341.2, calcd 341.4 (M + 1); IR (KBr) ν 3380, 3180, 1620,
1560, 1500, 1450, 1400 cm-1; 1H NMR (DMSO-d6) δ 3.59 (s, 3H,
4′-OMe), 3.71 (s, 6H, 3′-OMe and 5′-OMe), 3.84 (s, 2H, CH2),
5.83 (br s, 2H, 2-NH2), 6.54 (s, 2H, H-2′ and H-6′), 7.10 (d, J )
8.6 Hz, 1H, H-8), 7.14 (br s, 2H, 4-NH2), 7.35 (dd, J ) 8.6, 2.0
Hz, 1H, H-7), 7.88 (s, 1H, H-5). Anal. Calcd for C18H20N4O3‚
0.3H2O: C, 62.52; H, 6.00; N, 16.20. Found: C, 62.14; H, 5.90;
N, 16.13.
2,4-Diam in o-6-(2-n aph th ylm eth yl)qu in azolin e (8n ). Com-
pound 8n was obtained from 10n (172 mg, 0.66 mmol) and
chloroformamidine hydrochloride (300 mg, 2.64 mmol) at 120
°C for 20 min: white crystals (90 mg, 45%); mp 256-257 °C;
MS m/z 301.3, calcd 301.4 (M + 1); IR (KBr) ν 3340, 3180, 1615,
1565, 1510, 1445, 1400 cm-1; 1H NMR (DMSO-d6) δ 4.04 (s, 2H,
CH2), 5.86 (br s, 2H, 2-NH2), 7.09 (d, J ) 8.2 Hz, 1H, H-8), 7.15
(br s, 2H, 4-NH2), 7.33-7.46 (m, 4H, H-4′, H-5′, H-8′, and H-7),
7.70 (s, 1H, H-1′), 7.78-7.85 (m, 3H, H-3′, H-6′, and H-7′), 7.93
(d, J ) 2.0 Hz, 2H, H-5). Anal. Calcd for C19H16N4‚0.3H2O: C,
74.63; H, 5.47; N, 18.32. Found: C, 74.27; H, 5.37; N, 18.52.
2,4-Dia m in o-6-(3′,4′-d im eth oxyben zyl)qu in a zolin e (8k ).
Compound 8k was obtained from 10k (120 mg, 0.45 mmol) and
chloroformamidine hydrochloride (204 mg, 1.8 mmol) at 120 °C
for 20 min: white crystals (61 mg, 43%); mp 215-217 °C; MS
m/z 311.2, calcd 311.4 (M + 1); IR (KBr) ν 3350, 3180, 1610,
1550, 1500, 1440, 1400 cm-1; 1H NMR (DMSO-d6) δ 3.70 (s, 3H,
OMe), 3.71 (s, 3H, OMe), 3.85 (s, 2H, CH2), 5.85 (br s, 2H,
2-NH2), 6.70 (dd, J ) 8.2 Hz, 1.8 Hz, 1H, H-6′), 6.84 (dd, J ) 1.8
Hz, 1H, H-2′), 6.86 (d, J ) 8.2 Hz, 1H, H-5′), 7.11 (d, J ) 8.6,
1H, H-8), 7.18 (br s, 2H, 4-NH2), 7.33 (dd, J ) 8.6 Hz, 1.8 Hz,
1H, H-7), 7.88 (d, J ) 1.8 Hz, 1H, H-5). Anal. Calcd for
C17H18N4O2‚0.3H2O: C, 64.66; H, 5.94; N, 17.74. Found: C,
64.35; H, 5.70; N, 17.78.
2,4-Dia m in o-6-(3′,5′-d im eth oxyben zyl)qu in a zolin e (8l).
Compound 8l was obtained from 10l (120 mg, 0.45 mmol) and
chloroformamidine hydrochloride (204 mg, 1.8 mmol) at 120 °C
for 20 min: white crystals (57 mg, 41%); mp 230-232 °C; MS
m/z 311.2, calcd 311.4 (M + 1); IR (KBr) ν 3360, 3160, 1610,
1560, 1490, 1450, 1400 cm-1; 1H NMR (DMSO-d6) δ 3.69 (s, 6H,
OMe), 3.84 (s, 2H, CH2), 5.84 (br s, 2H, 2-NH2), 6.31 (t, J ) 2.4
Hz, 1H, H-4′), 6.39 (d, J ) 2.4 Hz, 2H, H-2′ and H-6′), 7.11 (d, J
) 8.6 Hz, 1H, H-8), 7.17 (br s, 2H, 4-NH2), 7.34 (dd, J ) 8.6, 2.0
Hz, 1H, H-7), 7.88 (d, J ) 2.2 Hz, 1H, H-5). Anal. Calcd for
C17H18N4O2: C, 65.79; H, 5.85; N, 18.05. Found: C, 65.53; H,
5.67; N, 18.12.
Ack n ow led gm en t. This work was supported by
Grant RO1-AI-29904 from the National Institute of
Allergy and Infectious Disease, NIH, DHHS.
J O010536I