Synthesis of 1,4-dihydro-benzo[d][1,3]oxazin-2-ones from phthalides via an aminolysis-Hofmann rearrangement protocol

Article abstract of DOI:10.1016/j.tetlet.2007.10.114

A simple two-step procedure for the conversion of readily available phthalides to the corresponding benzoxazinones was developed. Initial ring-opening aminolysis to form a primary 2-hydroxymethylbenzamide, followed by reaction with bis(trifluoroacetoxy)iodobenzene (BTI) conveniently, provided a variety of 4-substituted benzoxazinones.

Full text of DOI:10.1016/j.tetlet.2007.10.114

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8972–8975
Synthesis of 1,4-dihydro-benzo[d][1,3]oxazin-2-ones from
phthalides via an aminolysis-Hofmann rearrangement protocol
*
´
´
Eliud Hernandez, Jessica M. Velez and Cornelis P. Vlaar
Department of Pharmaceutical Sciences, School of Pharmacy, Medical Sciences Campus, University of Puerto Rico,
San Juan PR 00936, Puerto Rico
Received 28 September 2007; revised 19 October 2007; accepted 22 October 2007
Available online 25 October 2007
Abstract—A simple two-step procedure for the conversion of readily available phthalides to the corresponding benzoxazinones was
developed. Initial ring-opening aminolysis to form a primary 2-hydroxymethylbenzamide, followed by reaction with bis(trifluoro-
acetoxy)iodobenzene (BTI) conveniently, provided a variety of 4-substituted benzoxazinones.
Published by Elsevier Ltd.
Benzoxazinones 2 (1,4-dihydro-benzo[d][1,3]oxazin-2-
ones, Scheme 1) are an important class of compounds
with a benzo-fused heterocyclic ring and form the key
structural element of a variety of biologically active
compounds. For example, Sustivaꢀ (efavirenz) is a
marketed human immunodeficiency virus type 1 (HIV-1)
specific non-nucleoside reverse transcriptase inhibitor
(NNRTI) that contains benzoxazinone core.1 Further-
more, in a recent report a variety of other benzoxazi-
none derivatives were described as potent orally active
nonsteroidal progesterone receptor antagonists with
potential use in contraception or in the treatment of
hormone-dependent cancers.2
O
3a. X = OCCl
3
O
H N OH
2
HN
O
N
R
N
1
X
X
3b. X =
R
2
1
3
R
2
R
3c. X = Cl
1
2
Scheme 1. Generally applied route for the synthesis of
benzoxazinones.
O
(CH3)3Al/
NH4Cl
THF, 50oC
12-16 h
O
H N
O
2
O
OH
BTI
HN
O
R
1
DMF, 0oC
1-4 h
R
R
1
R
1
R
2
2
R
2
4
5
2
In laboratory scale procedures, benzoxazinones are
generally prepared from the corresponding amino
alcohols 1 via reaction with phosgene derivatives such
as triphosgene 3a or 1,10-carbonyldiimidazole 3b. For
the large-scale (15.7 kg) preparation of the heterocyclic
ring system of Sustivaꢀ, the use of the environmentally
unfriendly and extremely toxic and hazardous phosgene
3c has been reported.3 Here, we describe an alternative
procedure for the synthesis of benzoxazinone core via
a two-step process involving the aminolysis of readily
accessible isobenzofuran-1(3H)-ones (phthalides) 4,4
followed by a Hofmann rearrangement reaction.
Scheme 2. Synthesis of benzoxazinones 2 from phthalides 4.
a 3-substituted phthalide 4 was reacted with an in situ
prepared aluminum amide reagent. This resulted in
aminolysis of the aromatic lactone ring to provide the
2-hydroxymethyl substituted benzamide derivative 5.
Subsequent Hofmann rearrangement, most likely via
the isocyanate, provided the desired 4-substituted
benzoxazinone 2. The overall transformation of 4 to 2
can alternatively be visualized as insertion of an N–H
into the bond between the aromatic ring and the
carbonyl group.
The optimized procedure for the process that was
developed is represented in Scheme 2. In the first step,
Initially, the ring-opening aminolysis of phthalides 4 to
the 2-hydroxymethyl-substituted primary benzamides 5
was investigated. Direct reaction of the phthalides with
ammonia (or other primary amines) did not result in
ring-opening of the relatively stable benzolactone ring.
*
Corresponding author. Tel.: +1 787 758 2525; fax: +1 787 767
2796; e-mail: cvlaar@rcm.upr.edu
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.10.114

E. Herna´ndez et al. / Tetrahedron Letters 48 (2007) 8972–8975
8973
The aluminum amide reagent Me3Al-HNR2ÆHCl,
formed by mixing trimethylaluminum with an amine
hydrochloride, has been reported to be useful for the
aminolysis of non-cyclic esters to give primary, second-
ary, or tertiary amides.5 Analogous reagents prepared
in situ from DIBAL-H/NR2ÆHCl6 or from Me2AlCl/
HNR2ÆHCl have been used similarly. It was reported
that when NH4Cl was used as the amine source, a three-
fold excess of the aluminum amide reagent was required
to obtain acceptable conversion of starting material,
which we also observed in the current experiments.5
As shown in Table 1 (entries 1 and 2), aminolysis of
the unsubstituted phthalide 4a with the latter two
reagents resulted in only moderate yields of the desired
product. The best yield of 5a was obtained by heating
4a for 12–16 h at 50 ꢁC in THF with the reagent
prepared from Me3Al/NH4Cl. The same reaction also
proceeded at ambient temperature, but did not go to
completion resulting in low yield (entry 4). Despite the
relative stability of the benzo-fused lactone ring, in the
presence of three equivalents of the aluminum amide
reagent, the aminolysis proceeded satisfactorily. The
successful conditions established in entry 3 were utilized
for aminolysis of the substituted phthalides 4b–f. The
isolated yields of substituted 2-hydroxymethylbenz-
amides 5b–f are represented in Table 3 and are shown
to be in the 71–81% range.11
We first examined the Hofmann rearrangement of the
unsubstituted 2-hydroxymethylbenzamide 5a with BTI
in a variety of solvents. When the reaction was carried
out in THF or acetone, consumption of the starting
material 5a required several hours and the desired
benzoxazinone 2a was obtained in only moderate yields
(Table 2). In acetonitrile, a slight increase in reaction
yield was observed. However, when the reaction was
performed in DMF, starting material 5a was consumed
within 1 h and benzoxazinone 2a could be isolated in a
yield of 90%. Therefore, as standard reaction conditions
for Hofmann rearrangement of a-substituted 2-hydroxy-
methyl-benzamides 5b–f, we utilized 1.05 equiv of
BTI in DMF at 0 ꢁC for 1 h. The isolated yields of the
corresponding benzoxazinones 2a–f are represented in
Table 3.12
As is demonstrated in Table 3, the selected reaction con-
ditions provide for the successful conversion of a variety
of a-substituted 2-hydroxymethylbenzamides 5a–f to
their corresponding benzoxazinones 2a–f. The reaction
occurred smoothly to provide the desired cyclic carba-
mates in yields of 61–90%. The unsubstituted product
2a (entry 1) was obtained in the highest yield, possibly
due to the strong nucleophilic character of the primary
alcohol. Entries 2–5 show that the Hofmann rearrange-
ment and benzoxazinone formation proceed readily with
various substituted (hetero)aromatic or aliphatic
groups. The reaction of the sterically hindered 3,3-disub-
stituted tertiary alcohol 5f with BTI required 4 h to pro-
duce the carbamate 5f in 61% yield. It should be noted
that in some, but not all cases (seemingly especially in
acidic conditions), the 2-hydroxymethylbenzamides 5
are prone to lactonization, upon which the correspond-
ing phthalides 2 are regenerated. As this might lead to
loss of material during purification of 5, we demon-
strated that the conversion of 5e to 2e, without column
chromatographic purification of intermediate 4e, pro-
vided a good combined yield (70%) of 2e.
With a series of 2-hydroxymethylbenzamide derivatives
5 now available, attention was turned to their conver-
sion into the benzoxazinones 2. The classical procedure
for the Hofmann rearrangement converts a primary car-
boxamide via an isocyanate to an amine using an alka-
line solution of bromine.7 However, compounds 5
contain primary or secondary benzylic hydroxyl groups
that are very labile in these standard oxidative reaction
conditions. Therefore, a much milder reagent would be
required for the potential rearrangement of 5 to 2 and
we chose to investigate the relatively mildly oxidizing
polyvalent iodine compounds.8 As a precedent, the syn-
thesis of a variety of benzo-fused five-membered ring 2-
benzoxazolones was shown to be formed by reaction of
2-hydroxybenzamides with PhI(OAc)2 in basic metha-
nolic solution.9 Similarly, the reaction of non-aromatic
c-hydroxybutyramides with PhI(OCOCF3)2 (BTI) pro-
vided 2-oxazolidinones in excellent yield.10 However,
the presence of sensitive benzylic hydroxyl groups and
the formation of a larger six-membered ring fused to a
benzene group as in 2 provide an additional challenge.
The most likely reaction pathway follows the Hofmann
rearrangement as induced by BTI, Scheme 3. Reaction
of the 2-hydroxymethylbenzamide 5 with BTI leads to
the formation of the rate-limiting step intermediate
6.8b Breakdown of 6 leads to the formation of 7 and
the isocyanate group is rapidly trapped by the free
hydroxyl group to produce the intramolecular cycliz-
ation carbamate 2.
In summary, we have developed a simple two-step pro-
cedure to synthesize benzoxazinones from phthalides via
Table 1. Yield of 5a after aminolysis of 4a with aluminum amide
reagents
Entry
Methoda
Temperature (ꢁC)
Yield (%)
1
2
3
4
DIBAL-H/NH4Clb
Me2AlCl/NH4Clc
Me3Al/NH4Cld
Me3Al/NH4Cl
45
50
50
rt
60
56
78
22
Table 2. Influence of solvent on the yield of 2a from the reaction of 5a
with BTI
Entry
Solvent
Yielda (%)
1
2
3
4
THF
36
58
66
90
a The aluminum amide reagents were prepared in situ in THF
following the reported procedure. A threefold excess of the reagent
was used for each of the reactions.
Acetone
Acetonitrile
DMF
b DIBAL-H 1.5 M in toluene.
a All reactions were carried out with 1.05 equiv BTI at 0 ꢁC and
monitored by TLC until all 5a had been consumed.
c Me2AlCl 1.0 M in hexane.
d Me3Al 2.0 M in hexane.

8974
E. Herna´ndez et al. / Tetrahedron Letters 48 (2007) 8972–8975
Table 3. Synthesis of benzoxazinones 2 from phtalides 4 via 2-hydroxymethylbenzamides 5
Entry Phthalidea Yieldb (%) Benzoxazinone
2-Hydroxymethylbenzamide
Timec (h) Yieldc (%)
2a
2b
2c
O
4a
O
5a
5b
5c
H N
2
O
OH
O
HN
HN
O
O
1
2
78
77
1
1
90
78
O
O
4b
H N
2
O
OH
O
O
O
H N
2
O
O
4c
4d
O
O
OH
OH
O
O
HN
HN
O
O
3
4
81
76
1
1
68
70
OCH
3
OCH
3
OCH
3
2d
5d
H N
2
N
N
N
2e
2f
O
O
4e
4f
O
O
5e
5f
H N
2
O
O
OH
OH
O
O
HN
HN
O
O
5
6
80
71
1
4
77
61
H N
2
CH
O
3
CH
3
CH
3
O
O
a Prepared according to Ref. 4c.
b Isolated yield of 5 from 4; reaction conditions: 3.0 equiv (CH3)3Al/NH4Cl, THF, 50 ꢁC, 12–16 h.
c Isolated yield of 2 from 5; reaction conditions: 1.05 equiv BTI in DMF at 0 ꢁC for time provided.
Acknowledgments
F C
O
I
3
H
N
H N
2
O
O
O
OH
PhI(OCOCF )
OH
We gratefully acknowledge the financial support of this
work by INDUNIV and RCMI Grant #G12RR03051.
We also thank Bristol-Myers-Squibb, Humacao, and
the University of Puerto Rico at Humacao for use of
their NMR facilities.
3 2
R
1
R
Ph
1
R
2
R
2
6
5
O
O
C
H
R
HN
O
N
O
R
2
1
1
R
R
2
7
2
Supplementary data
Scheme 3. Reaction pathway for the formation of benzoxazinones 2.
Supplementary data include NMR and MS-data of com-
pounds 5b–f and 2b–f. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.10.114.
an aminolysis-Hofmann rearrangement procedure. For
the difficult aminolysis of the benzolactone ring, in situ
prepared aluminum amide reagents were successfully
employed. For the Hofmann rearrangement, BTI was
selected and shown to be sufficiently mild to not oxidize
the benzylic alcohol groups. Instead the hydroxyl group
reacted with the intermediate isocyanate to form the
desired six-membered ring benzoxazinones. The method
can potentially be applied to available phthalide
libraries.4e
References and notes
1. Patel, M.; Ko, S. S.; McHugh, R. J.; Markwalder, J. A.;
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E. Herna´ndez et al. / Tetrahedron Letters 48 (2007) 8972–8975
8975
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(5.0 mmol) of phthalide 4a was added and the reaction
heated to 50 ꢁC for 18 h upon which all starting material
had disappeared (confirmed by TLC). The reaction
mixture was carefully quenched by addition of water
(10 mL) while maintaining the temperature at 0 ꢁC. The
mixture was partitioned between 10 mL of the aqueous
phase and 20 mL of EtOAc. The aqueous phase was
washed with EtOAc (3 · 20 mL). The organic phases were
combined and dried over MgSO4, filtered and concen-
trated by rotary evaporation. The residue was purified by
flash chromatography with a solvent mixture of hexane–
EtOAc (1:1) to yield 2-(hydroxymethyl)benzamide 4a as a
white solid in a yield of 78% (3.90 mmol, 0.59 g).
Rf = 0.18. 1H NMR (DMSO-d6, 400 MHz) d 4.79 (d,
J = 5.7 Hz, 2H), 5.13 (t, J = 5.7 Hz, 1H), 7.30 (t,
J = 7.4 Hz, 1H) 7.43–7.50 (m, 3H), 7.53 (d, J = 7.6 Hz,
1H), 7.86 (s, 1H); 13C (DMSO-d6, 100 MHz) d 61.2, 126.5,
127.41, 127.64, 129.6, 134.9, 140.4, 170.6; LRGC-MS m/z
[M]+ 151. HRESIMS m/z calcd for [C8H9NO2+H]+
152.0706, found 152.0703.
3. Pierce, M. E.; Choudhury, A.; Lawrence, R.; Radesca, L.
A. U.S. Patent # 5,932,726, 1999.
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Baker, R. J. Tetrahedron 1983, 3, 1991–1999; (d) Sibi, M.
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55, 588–597.
12. 1,4-Dihydro-benzo[d][1,3]oxazin-2-one 2a: In
a 50 mL
round bottom flask was added 2-(hydroxymethyl)benz-
amide 5a (3.00 mmol, 0.454 g) and dissolved in 12 mL of
DMF. The solution was cooled at 0 ꢁC and covered with
aluminum paper. To the solution, BTI (3.15 mmol, 1.35 g)
was added in one portion and the resulting mixture stirred
for 1 h at 0 ꢁC and monitored by TLC which indicated
disappearance of the starting material. The mixture was
allowed to reach room temperature and 20 mL EtOAc was
added. The organic phase was washed with NaHSO3
(2 · 10 mL). The resulting aqueous phase was washed with
EtOAc (3 · 10 mL). The combined organic phases were
washed with brine, dried with Na2SO4, filtered and
concentrated by rotary evaporation. The residue was
purified by flash chromatography with a first wash
with hexane to remove iodobenzene, and then with a
mixture of hexane–EtOAc (3:1) to give benzoxazinone
2a as a white solid in a yield of 90% (2.70 mmol, 0.403 g).
5. Levin, J. I.; Turos, E.; Weinreb, S. M. Synth. Commun.
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6. Huang, P.-Q.; Zheng, X.; Deng, X.-M. Tetrahedron Lett.
2001, 42, 9039–9041.
7. Hofmann, A. W. Ber. 1881, 14, 2725.
8. (a) Zhdankin, V. V.; Stang, P. Chem. Rev. 2002, 102,
2523–2584; (b) Moriarty, R. M.; Chany, C. J., II; Prakash,
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42, 1449–1452.
11. General procedure: 2-Hydroxymethylbenzamide 5a: In a
50 mL three neck round bottom flask, 0.80 g (15.0 mmol)
of dry, finely ground NH4Cl was added followed by 10 mL
of THF under a nitrogen atmosphere. The flask was
immersed in an ice-water bath and 7.5 mL (15.0 mmol) of
(CH3)3Al (2.0 M in Toluene) was added dropwise. The
ice-water bath was removed and the reaction mixture
stirred for 2 h at room temperature. Then, 0.67 g
Rf = 0.47. 1H NMR (CDCl3, 400 MHz)
d 5.35 (s,
2H), 6.90 (d, J = 7.9 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H),
7.11 (d, J = 7.2 Hz, 1H), 7.28 (t, J = 7.4 Hz, 1H), 9.15 (s,
1H); 13C NMR (CDCl3, 100 MHz), d 68.7, 114.2, 117.8,
123.3, 124.2, 129.2, 135.5. LRGC-MS m/z [M]+ 149.
HRESIMS m/z calcd for [C8H7NO2+H]+ 150.0550, found
150.0551.