Efficient syntheses of 2,3-disubstituted natural quinazolinones via iridium catalysis

Article abstract of DOI:10.1039/c2ob07178a

Natural products sclerotigenin, pegamine, deoxyvasicinone, mackinazolinone, and rutaecarpine were synthesized. Core quinazolinone structures were constructed via Ir catalysis. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2ob07178a

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Efficient syntheses of 2,3-disubstituted natural quinazolinones via iridium
catalysis†
Jie Fang and Jianguang Zhou*
Received 26th December 2011, Accepted 23rd January 2012
DOI: 10.1039/c2ob07178a
Natural products sclerotigenin, pegamine, deoxyvasicinone,
mackinazolinone, and rutaecarpine were synthesized. Core
quinazolinone structures were constructed via Ir catalysis.
Recently we described1 a one-pot synthesis of 3-unsubstituted
quinazolinones via Ir-catalyzed hydrogen transfer.2 This opera-
tionally convenient methodology avoided any stoichiometric oxi-
dants under base-free conditions. Many naturally occurring
Fig. 1 Naturally occurring quinazolinones.
quinazolinones3 contain 3-substitions (Fig. 1), it is thus our inter-
est to expand the substrate scope using this methodology and
explore the synthesis of these natural products.
Initially, we investigated whether 3-substituted quinazolinones
could be synthesized starting from 2-amino-N-methylbenzamide
2. Screening of conditions (for details, see the ESI†) established
that benzyl alcohol 1 and amide 2 (1 : 1 molar ratio) under the
catalysis of [Cp*IrCl2]2 (Cp* = pentamethyl-cyclopentadienyl)4
gave the best results. As shown in Scheme 1, without acid or
base additives, an excellent yield (97%) of product 3 was
achieved in a shorter reaction time as compared to its 3-unsubsti-
Scheme 1 Synthesis of 3-methyl-2-phenylquinazolin-4(3H)-one.
tuted analog (24 h vs. 36 h).1
The success of this model reaction prompted us to explore the
synthesis of 3-aromatic substituted quinazolinones. Methaqua-
yield of 94% using ammonia in methanol under sealed tube
conditions.7
lone, for example, is a 3-o-tolyl substituted quinazolinone well-
known for its sedative–hypnotic effects.5 Ethanol was employed
Next, we were attracted to the synthesis of biologically impor-
in our synthesis of this compound (Scheme 2). Because of the
low boiling point of ethanol, the conditions of refluxing ethanol
and benzamide 4 (1 : 1 molar ratio) in xylene did not give good
yield of product (conversion <20%) due to loss of the ethanol.
tant quinazolinones with more complex structures. Deoxyvasici-
none8 and mackinazolinone,9 for example, are quinazolinones
fused with pyrrolidine and piperidine, respectively, with anti-
microbial, anti-inflammatory and anti-depressant activities. The
syntheses of deoxyvasicinone10 and mackinazolinone10c,11 have
Ethanol was thus applied as solvent in a sealed tube, and metha-
qualone was isolated in 97% yield under these conditions. Sub-
been widely explored. We were interested in the application of
our methodology to the synthesis of 2-substituted quinazolinone
sequently, N-substituted aminobenzamide 6 was employed under
the same conditions as 4 to give quinazolinone 7 in 89% yield.
The methyl ester group in 6 did not interfere with the quinazoli-
intermediates with an alcohol appendage, such as pegamine, the
subsequent ring closure of which using Mitsunobu conditions12
none formation, testifying to the mildness of our conditions
would form the fused ring systems in these natural products.
without base. After following known procedures6 for bromina-
Pegamine itself is a natural product isolated from Peganum
harmala and exhibits cytotoxic activity.13
tion of 7 to 8, sclerotigenin 9 was synthesized in the excellent
The protocols of synthesis are shown in Scheme 3. The reac-
tions of 2-aminobenzamide (10) with unprotected diols 11a and
11b furnished quinazolinones 12a (pegamine) and 12b, although
with fair yields (12a: 52%, 12b: 57%) under our optimized con-
ditions. A number of mono-protected alcohols of 11a and 11b
were thus tested in the quinazolinone formation reactions.
Among all the protected monoalcohols, e.g., with THP, tosyl,
Chemical and Analytical Development, Suzhou Novartis Pharma
Technology Co. Ltd, Changshu, Jiangsu, China, 215537.
E-mail: jianguang.zhou@novartis.com
†Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data. See DOI: 10.1039/
c2ob07178a
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Scheme 4 Retrosynthesis of 15a and 15b via an intramolecular Ir-cata-
lysed oxidative cyclization as key step.
Scheme 2 Synthesis of methaqualone and sclerotigenin.
Scheme 5 Ir-catalysed intramolecular oxidative cyclization in the
syntheses of 15a and 15b.
the Ir-catalysed quinazolinone synthesis. After deprotection of
the acetyl group under the conditions of K2CO3 in a mixture of
methanol–H2O at room temperature, 12a and 12b were obtained
in high yield (12a: 90%, 12b: 93%). Further transformations of
these 2-substituted quinazolinones with an alcohol appendage,
following the known procedure10d of an intramolecular Mitsu-
nobu reaction, provided natural products deoxyvasicinone and
mackinazolinone in excellent yields (15a: 94%, 15b: 95%).
Although all of our previous examples of quinazolinone
syntheses involved intermolecular reactions between primary
alcohols and o-aminobenzamides, the syntheses of 15a and 15b
offered us the possibility of an intramolecular version of Ir-cata-
lysed cyclization reactions. As shown in Scheme 4, we antici-
pated that intermediates such as 18a and 18b with both alcohol
and aminobenzamide functional groups combined within one
molecule, would undergo hydrogen transfer events (alcohol 18
to aldehyde 17, intramolecular cyclizations to aminal intermedi-
ates 16 followed by dehydrogenation) to produce our final
desired products 15a and 15b.
Scheme 3 Syntheses of deoxyvasicinone and mackinazolinone.
Thus, intermediates 18a and 18b were readily obtained by
reaction of compound 19 with either unprotected 1,4-amino
alcohol 20a or 1,5-amino alcohol 20b in 95% and 94% yield,
respectively, as shown in Scheme 5. For the key intramolecular
oxidative cyclisation reaction, the conditions using 18a in
and acetyl protection, 13a and 13b stood out as the best sub-
strates, giving 14a and 14b in 85% and 93% yield, respectively.
Notably, the acetyl group survived this process under heating,
again demonstrating the mildness of the base-free conditions of
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successful syntheses of natural products sclerotigenin, pegamine,
deoxyvasicinone and mackinazolinone. An intramolecular
version of this reaction was investigated in the synthesis of
deoxyvasicinone and mackinazolinone and showed that TfOH is
a good additive to promote the intramolecular reaction. Further
utilization of mackinazolinone in the synthesis of rutaecarpine
was demonstrated in an efficient manner.
Notes and references
Scheme 6 Synthesis of rutaecarpine.
1 J. Zhou and J. Fang, J. Org. Chem., 2011, 76, 7730. For a subsequent
related report using Ru: A. J. A. Watson, A. C. Maxwell and
J. M. J. Williams, Org. Biomol. Chem., 2012, 10, 240.
2 For recent reviews: (a) K. Fujita and R. Yamaguchi, Synlett, 2005, 4,
560; (b) T. D. Nixon, M. K. Whittlesey and J. M. J. Williams, Dalton
Trans., 2009, 753; (c) M. J. Krische, Angew. Chem., Int. Ed., 2009, 48,
34; (d) G. E. Debereiner and R. H. Crabtree, Chem. Rev., 2010, 110, 681;
(e) T. Suzuki, Chem. Rev., 2011, 111, 1825; (f) J. Choi,
A. H. R. MacArthur, M. Brookhart and A. S. Goldman, Chem. Rev.,
2011, 111, 1761.
3 (a) S. B. Mhaske and N. P. Argade, Tetrahedron, 2006, 62, 9787; (b) For
a recent review on quinazoline alkaloids: M. P. Joseph, Nat. Prod. Rep.,
2008, 25, 166.
4 K. Fujita, S. Furukawa and R. Yamaguchi, J. Organomet. Chem., 2002,
649, 289.
refluxing xylene (concentration = 0.5 M) under [Cp*IrCl2]2 cata-
lysis (2.5 mol%) only afforded product 15a in 35% yield. We
observed several byproducts resulting from intermolecular reac-
tions under these conditions. We reasoned that acid additives
would accelerate the intramolecular cyclizations from 17a to 16a
and thus increase the yield of 15a. Another factor to inhibit the
intermolecular byproduct formations will be the more dilute con-
centration of 18a. Among the acid additives (AcOH, TfOH,
H2SO4 and TFA), and concentrations of 18a in xylene (0.25 M,
0.125 M, 0.062 M and 0.031 M) screened, the combination of
10 mol% of TfOH with 18a concentration of 0.125 M in
refluxing xylene gave the best yield of 15a (68%). Under similar
unoptimized reaction conditions, the analog 15b was obtained
in lower yield of 47% even with a higher catalyst loading
(5 mol%).
5 A. H. Amin, D. R. Mehta and S. S. Samarth, Prog. Drug Res., 1970, 14,
218.
6 D. R. Harrison, P. D. Kennewell and J. B. Taylor, J. Heterocycl. Chem.,
1977, 14, 1191.
7 A low yield of 38% was reported for the same transformation: A. Witt
and J. Bergman, J. Heterocycl. Chem., 2002, 39, 351.
Both deoxyvasicinone 15a14 and mackinazolinone 15b11b
have been utilized for the synthesis of rutaecarpine 22. As an
example, a literature procedure was followed to transform macki-
nazolinone (15b) to rutaecarpine.11b As shown in Scheme 6,
compound 15b reacted with diazonium salt of aniline generated
in situ to give the corresponding hydrazone 21 in 97% yield.
Further Fisher-indole synthesis from 21 led to rutaecarpine (22)
smoothly in 94% yield.
8 (a) A. H. Amin and D. R. Mehta, Nature, 1959, 183, 1317;
(b) D. R. Mehta, J. S. Naravane and R. M. Desai, J. Org. Chem., 1963,
28, 445; (c) M. P. Jain, S. K. Koul, K. L. Dhar and C. K. Atal, Phyto-
chemistry, 1980, 19, 1880; (d) A. Al-Shamma, S. Drake, D. L. Flynn, L.
A. Mitscher, Y. H. Park, G. S. R. Rao, A. Simpson, J. K. Swayze,
T. Veysoglu and S. T. S. Wu, J. Nat. Prod., 1981, 44, 745.
9 (a) S. R. Johns and J. A. Lamberton, Chem. Commun. (London), 1965,
267; (b) J. S. Fitzgerald, S. R. Johns, J. A. Lamberton and A.
H. Redcliffe, Aust. J. Chem., 1966, 19, 151.
10 For examples: (a) A. V. Lygin and A. de Meijere, Org. Lett., 2009, 11,
389; (b) C. Zhang, C. K. De, R. Mal and D. Seidel, J. Am. Chem. Soc.,
2008, 130, 416; (c) J.-F. Liu, P. Ye, K. Sprague, K. Sargent, D. Yohannes,
C. M. Baldino, C. J. Wilson and S.-C. Ng, Org. Lett., 2005, 7, 3363;
(d) S. B. Mhaske and N. P. Argade, J. Org. Chem., 2001, 66, 9038.
11 For examples: (a) S. B. Mhaske and N. P. Argade, Tetrahedron, 2004, 60,
3417; (b) J. Kokosi, I. Hermecz, G. Szasz and Z. Meszaros, Tetrahedron
Lett., 1981, 22, 4861; (c) T. Kametani, T. Higa, C. V. Loc, M. Ihara,
M. Koizumi and K. Fukumoto, J. Am. Chem. Soc., 1976, 98, 6186.
12 O. Mitsunobu, Synthesis, 1981, 1.
Conclusions
We expanded our substrate scope and synthesized 2,3-disubsti-
tuted quinazolinones via Ir-catalyzed oxidative cyclisations
between primary alcohols and N-substituted o-aminobenzamides.
This reaction utilized an air and water stable Ir catalyst under
base-free conditions and without stoichiometric external oxi-
dants. Good functional group tolerance was demonstrated in the
13 Z. Z. Ma, Y. Hano, T. Nomura and Y. J. Chen, Heterocycles, 1999, 51,
1883.
14 J. Kokosi, G. Szasz and I. Hermecz, Tetrahedron Lett., 1992, 33, 2995.
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