The chemistry of 2H-3,1-benzoxazine-2,4(1H)-dione (isatoic anhydride). XXIV. N-benzylation of isatoic anhydride under mitsunobu conditions

Article abstract of DOI:10.1081/SCC-120003148

Isatoic anhydride is readily alkylated on nitrogen with benzylic alcohols in the presence of triphenylphosphine and diethyl azodicarboxylate. Both electron donating and electron withdrawing groups are tolerated.

Full text of DOI:10.1081/SCC-120003148

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THE CHEMISTRY OF 2H-3,1-BENZOXAZINE-2,4(1H)-
DIONE (ISATOIC ANHYDRIDE). XXIV. N-BENZYLATION OF
ISATOIC ANHYDRIDE UNDER MITSUNOBU CONDITIONS
Gary M. Coppola a
a Department of Metabolic and Cardiovascular Diseases , Novartis Institute for Biomedical
Research , 556 Morris Ave., Summit, NJ, 07901, U.S.A.
Published online: 21 Aug 2006.
To cite this article: Gary M. Coppola (2002) THE CHEMISTRY OF 2H-3,1-BENZOXAZINE-2,4(1H)-DIONE (ISATOIC ANHYDRIDE).
XXIV. N-BENZYLATION OF ISATOIC ANHYDRIDE UNDER MITSUNOBU CONDITIONS, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 32:7, 1009-1013, DOI: 10.1081/SCC-120003148
To link to this article: http://dx.doi.org/10.1081/SCC-120003148
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SYNTHETIC COMMUNICATIONS, 32(7), 1009–1013 (2002)
THE CHEMISTRY OF
2H-3,1-BENZOXAZINE-2,4(1H)-DIONE
(ISATOIC ANHYDRIDE). XXIV.
N-BENZYLATION OF ISATOIC
ANHYDRIDE UNDER MITSUNOBU
CONDITIONS
Gary M. Coppola
Department of Metabolic and Cardiovascular Diseases,
Novartis Institute for Biomedical Research,
556 Morris Ave., Summit, NJ07901
ABSTRACT
Isatoic anhydride is readily alkylated on nitrogen with
benzylic alcohols in the presence of triphenylphosphine and
diethyl azodicarboxylate. Both electron donating and electron
withdrawing groups are tolerated.
Isatoic anhydride (1) and its N-alkyl analogs can be considered an
internally protected and activated form of anthranilic acid. The suscepti-
bility of the C-4 carbonyl to nucleophilic attack has shown this class of
compounds to be extremely versatile intermediates for the preparation of
a wide variety of heterocycles and natural products.1–7
Even though isatoic anhydrides have been known for more than a
century, relatively few methods are known to prepare N-alkyl derivatives.
Simple methylation can be performed with diazomethane,8 however, higher
1009
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1010
COPPOLA
alkyl groups need to be introduced by deprotonation of the N-H of 1 with
bases such as sodium carbonate9 or sodium hydride10 and subsequent alky-
lation with an appropriate alkyl halide or tosylate. Alternatively, the alkyl
group can be incorporated during the construction of the heterocycle by
cyclization of N-alkyl anthranilic acids with phosgene.10,11
In a search for an alternate and mild method for the N-alkylation of
1 which does not involve the use of strong bases, the Mitsunobu reaction
was considered. It is essentially a dehydrative alkylation of an acidic
nucleophile (Nu-H) with an alcohol.12 Classically, the reaction utilizes
the adduct formed between diethyl azodicarboxylate (DEAD) and
triphenylphosphine to activate the alcohol via an oxyphosphonium ion
intermediate which then reacts with the nucleophile in an SN2 process to
furnish the alkylated product. A requirement of this method is that the
acidic hydrogen in Nu-H should have a pKa less than 11 for the reaction to
proceed satisfactorily.13
The pKa value for isatoic anhydride14 is 8.25 which falls within the
acceptable limits of reactivity of the Mitsunobu reaction. Consequently,
when 1 is allowed to react with benzyl alcohol in the presence of triphenyl-
phosphine and DEAD, N-alkylation occurs smoothly and N-benzylisatoic
anhydride (3a) is produced in 75% yield. The aromatic ring of the benzyl
alcohol can accommodate either electron donating or electron withdrawing
groups (e.g., F, Cl, OMe, NO2) to furnish the corresponding substituted
derivatives 3b–e in good yields. In general, the reactions are usually com-
plete within 1 h, however, the 2-nitro derivative 3c requires 18–24 h. In most
cases the products are purified simply by filtration through a pad of silica gel
in order to remove the relatively polar triphenylphosphine oxide by-product.
An added advantage of this type of alkylation is that it is not necessary
to prepare an alkyl halide in instances when they are either not commercially
available or have limited stability. For example, furfuryl chloride or
bromide is not commercially available, although furfuryl alcohol (4) is

ISATOIC ANHYDRIDE. XXIV
1011
inexpensive. Alkylation of 1 with 4 under Mitsunobu conditions affords
N-furfurylisatoic anhydride (5) in 79% yield.
Efforts are currently underway to investigate the scope of this alkyla-
tion using a variety of primary and secondary alcohols in addition to the use
of polymer-supported reagents.
EXPERIMENTAL
Melting points were determined on a Thomas-Hoover Uni-melt
apparatus and were uncorrected. IR spectra were obtained on a Nicolet
Magna-550 spectrometer. 1H-NMR spectra were recorded on a Bruker
ARX-300 or Bruker DPX-300 instrument, and chemical shifts were relative
to internal Me4Si. 13C-NMR spectra were recorded at 75.48 MHz. The
described reactions were not optimized.
General Procedure for N-Alkylation of Isatoic Anhydride
To a stirred solution of 326 mg (2 mmol) of 1, 524 mg (2 mmol) of
triphenylphosphine and 2 mmol of the benzylic alcohol 2 in 15 ml of tetra-
hydrofuran were added dropwise a solution of 348 mg (2 mmol) of diethyl
azodicarboxylate in 0.5 ml of tetrahydrofuran. The mixture was stirred at
room temperature for 1 h, then the solvent was removed under reduced
pressure. The residue was filtered through a pad of silica gel using methylene
chloride to elute the product 3 which was then crystallized from methylene
chloride/MTBE.
3a: (R¼H), 75% yield, m.p. 138–140ꢀC (lit.10 m.p. 140–142ꢀC). IR
1
(CH2Cl2): 1784, 1730, 1608 cmꢁ1; H-NMR (CDCl3): d 8.16 (d, J ¼ 8 Hz,

1012
COPPOLA
1H), 7.63 (m, 1H), 7.40–7.20 (m, 5H), 7.06 (d, J ¼ 8.5 Hz, 1H), 5.30 (s, 2H);
13C-NMR (CDCl3): d 158.37, 148.47, 141.36, 137.26, 134.38, 130.78, 129.12
(2 carbons), 128.10, 126.58 (2 carbons), 124.17, 114.77, 111.76, 48.48.
3b: (R¼2-Cl), 57% yield, m.p. 165–167ꢀC (lit.10 m.p. 165–167ꢀC). IR
1
(CH2Cl2): 1786, 1733, 1609 cmꢁ1; H-NMR (CDCl3): d 8.20 (d, J ¼ 8 Hz,
1H), 7.65 (t, 1H), 7.47 (d, J ¼ 8 Hz, 1H), 7.35–7.15 (m, 3H), 7.04 (d,
J ¼ 8.5 Hz, 1H), 6.93 (d, J ¼ 8.5 Hz, 1H), 5.41 (s, 2H); 13C-NMR (CDCl3):
d 158.18, 148.37, 141.08, 137.45, 132.50, 131.47, 130.93, 130.04, 129.79,
127.54, 126.68, 124.42, 114.60, 111.78, 46.14.
3c: (R¼2-NO2), 54% yield, m.p. 208–211ꢀC (lit.10 m.p. 211–213ꢀC).
1
IR (CH2Cl2): 1787, 1734, 1608 cmꢁ1; H-NMR (CDCl3): d 8.25 (t, 2H),
7.71–7.50 (m, 3H), 7.34 (t, 1H), 7.18 (d, J ¼ 8 Hz, 1H), 6.91 (d, J ¼ 8 Hz,
1H), 5.74 (s, 2H); 13C-NMR (CDCl3): d 157.95, 148.12, 147.59, 141.07,
137.58, 134.52, 131.23, 130.19, 129.02, 126.70, 126.15, 124.70, 114.25,
111.82, 46.66.
3d: (R¼3-F), 83% yield, m.p. 133–136ꢀC (lit.10 m.p. 133–136ꢀC). IR
1
(CH2Cl2): 1785, 1732, 1608 cmꢁ1; H-NMR (CDCl3): d 8.19 (d, J ¼ 8 Hz,
1H), 7.66 (t, 1H), 7.39–7.25 (m, 5H), 7.12–6.90 (m, 4H), 5.30 (s, 2H).
3e: (R¼4-OCH3), 28% yield, m.p. 134–137ꢀC (lit.10 m.p. 138–139ꢀC).
IR (CH2Cl2): 1783, 1730, 1609 cmꢁ1; 1H-NMR (CDCl3): d 8.16 (d, J ¼ 8 Hz,
1H), 7.65 (t, 1H), 7.30–7.24 (m, 3H), 7.17 (d, J ¼ 8.5 Hz, 1H), 6.88 (d,
J ¼ 8.5 Hz, 2H), 5.24 (s, 2H), 3.78 (s, 3H); 13C-NMR (CDCl3): d 159.40,
158.40, 148.49, 141.41, 137.16, 130.84, 128.18 (2 carbons), 126.35, 124.10,
114.73, 114.50 (2 carbons), 111.85, 55.31, 48.04.
5: 79% yield, m.p. 139–140ꢀC (lit.10 m.p. 141–143ꢀC). IR (CH2Cl2):
1
1784, 1735, 1609 cmꢁ1; H-NMR (CDCl3): d 8.16 (d, J ¼ 8 Hz, 1H), 7.77 (t,
1H), 7.49 (d, J ¼ 8 Hz, 1H), 7.38–7.25 (m, 2H), 6.47 (m, 1H), 6.36 (m, 1H),
5.25 (s, 2H); 13C-NMR (CDCl3): d 158.23, 148.09, 147.83, 142.81, 141.22,
137.21, 130.84, 124.22, 114.47, 111.73, 110.82, 109.97, 41.43.
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ISATOIC ANHYDRIDE. XXIV
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Received in the USA April 4, 2001