Synthesis of 4H-Benzo[e][1,3]oxazin-4-ones by a Carbonylation–Cyclization Domino Reaction of ortho-Halophenols and Cyanamide

Article abstract of DOI:10.1002/open.201700130

A mild and convenient one-step preparation of 4H-1,3-benzoxazin-4-ones by a domino carbonylation–cyclization process is developed. Readily available ortho-iodophenols are subjected to palladium-catalyzed carbonylative coupling with Mo(CO)₆ and cyanamide, followed by a spontaneous, intramolecular cyclization to afford 4H-1,3-benzoxazin-4-ones in moderate to excellent yields. Furthermore, the scope of the reaction is extended to include challenging ortho-bromophenols. Finally, to highlight the versatility of the developed method, Mo(CO)₆ is successfully replaced with a wide array of CO-releasing reagents, such as oxalyl chloride, phenyl formate, 9-methylfluorene-9-carbonyl chloride, and formic acid, making this an appealing strategy for the synthesis of 4H-benzo[e][1,3]oxazin-4-ones.

Full text of DOI:10.1002/open.201700130

DOI: 10.1002/open.201700130
Synthesis of 4H-Benzo[e][1,3]oxazin-4-ones by a
Carbonylation–Cyclization Domino Reaction of
ortho-Halophenols and Cyanamide
Linda ꢀkerbladh,[b] Shiao Y. Chow,[b] Luke R. Odell,*[b] and Mats Larhed*[a]
A mild and convenient one-step preparation of 4H-1,3-benzox-
azin-4-ones by a domino carbonylation–cyclization process is
developed. Readily available ortho-iodophenols are subjected
to palladium-catalyzed carbonylative coupling with Mo(CO)6
and cyanamide, followed by a spontaneous, intramolecular
cyclization to afford 4H-1,3-benzoxazin-4-ones in moderate to
excellent yields. Furthermore, the scope of the reaction is ex-
tended to include challenging ortho-bromophenols. Finally, to
highlight the versatility of the developed method, Mo(CO)6 is
successfully replaced with a wide array of CO-releasing re-
agents, such as oxalyl chloride, phenyl formate, 9-methylfluor-
ene-9-carbonyl chloride, and formic acid, making this an ap-
pealing strategy for the synthesis of 4H-benzo[e][1,3]oxazin-4-
ones.
1. Introduction
Heterocycles are arguably one of the most important classes of
organic compounds due to their wide range of biological activ-
ities,[1] and there is a constant need for new synthetic methods
for their preparation. Benzoxazines are of particular interest
and have been reported to possess antimicrobial,[2] anticanc-
er,[3,4] and antiplatelet[5,6] activities. However, preparation of this
valuable heterocycle is limited to a handful of synthetic routes
which often require hazardous reagents, cumbersome prepara-
tion of starting materials and reagents or, alternatively, are re-
stricted to electron-withdrawing substituents in the benzene
ring (Scheme 1a–e).[7–12] Palladium-catalyzed carbonylation re-
actions such as aminocarbonylation and cross-coupling reac-
tions have become essential tools for synthesizing heterocycles
and immense effort has been invested in developing safer
methods for handling the toxic carbon monoxide gas.[13–15]
Over the last decade, several non-gaseous CO sources have
been reported both for in situ and ex situ use, for example, for-
mates,[16,17] formamides,[18] aldehydes,[19] formic acid[20] and
Scheme 1. Synthetic procedures for the preparation of benzoxazinones, car-
bonylation–cyclization domino reactions used in the synthesis of 2-amino-
quinazolinones, and the work presented herein.
metal carbonyls such as Mo(CO)6.[21–23] In addition, Pd-catalyzed
decomposition of 9-methylfluorene-9-carbonyl chloride
(COgen)[24] and fluoride-mediated CO release from silacarboxyl-
ic acid[25] enable the use of substoichiometric amounts of CO
as well as the possibility to isotopically label the carbonyl
carbon. Furthermore, base-mediated decomposition of oxalyl
chloride[26] and chloroform[27,28] have been reported as effective
CO-generating strategies for carbonylation chemistry. Notably,
the latter facilitates the preparation of 13C- and 14C-labeled car-
bonyl derivatives.
[a] Prof. M. Larhed
Department of Medicinal Chemistry
Science for Life Laboratory, Uppsala University
SE-751 23 Uppsala (Sweden)
E-mail: mats.larhed@orgfarm.uu.se
[b] L. ꢀkerbladh, Dr. S. Y. Chow, Dr. L. R. Odell
Department of Medicinal Chemistry
Division of Organic Pharmaceutical Chemistry, Uppsala University
SE-751 23 Uppsala (Sweden)
E-mail: luke.odell@orgfarm.uu.se
Supporting Information and the ORCID identification number(s) for the
author(s) of this article can be found under:
We recently reported a novel Mo(CO)6-mediated carbonyla-
tion–cyclization sequence to prepare 2-amino-quinazolin-
4(3H)-ones and 2-aminoquinazolin-4(1H)-ones from ortho-io-
doanilines and cyanamide (Scheme 1 f).[29] As a continuation of
our previous work, we sought to develop an analogous ap-
proach for ortho-halophenols (1 or 3) to give 2-amino-4H-
https://doi.org/10.1002/open.201700130.
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benzo[e][1,3]oxazin-4-ones (2, Scheme 1g). This approach
offers a number of advantages including 1) the use of readily
available starting materials, 2) facile synthesis under low CO
pressures without the use of CO gas, and 3) access to the un-
substituted exocyclic amine.
tuted cyclic structures (2d and 2e, respectively) in 96% and
83% yields, respectively. The bromide was intact and fully or-
thogonal to the iodide under the mild reaction conditions. The
introduction of the strongly electron-withdrawing nitro func-
tionality para to the nucleophilic phenol, resulted only in a
slight reduction in yield (2 f, 77%) compared to other electron-
deficient substrates. This suggests that the phenoxide anion
present under the reaction conditions is a sufficiently strong
nucleophile to counteract the electron-withdrawing properties
of substituents on the aryl ring. Mo(CO)6 has been reported as
a reducing agent of aryl nitro groups at elevated tempera-
tures.[30] However, given that Mo(CO)6 is separated from the
carbonylative reaction mixture and the mild conditions used in
this procedure, nitro substituents can successfully be incorpo-
rated without reduction of the nitro group. 2-Amino-6-(hydrox-
ymethyl)-4H-benzo[e][1,3]oxazin-4-one (2i) was successfully ob-
tained in 84% isolated yield without side reactions taking
place. Electron-rich amino-substituted ortho-iodophenol fur-
nished 2,6-diamino-4H-benzo[e][1,3]oxazin-4-one (2j) and
dibenzyl-protected 2,6-diamino-4H-benzo[e][1,3]oxazin-4-one
(2k) in 94% and 53% isolated yields, respectively. In contrast,
if 2-iodo-5-methoxyphenol was used, a complex reaction mix-
ture was obtained from which the pure compound could not
be isolated. We attribute this result to reduced susceptibility of
the halide towards oxidative addition due to an electron-do-
nating effect from the methoxy group. Finally, Boc-protected
amino-substituted ortho-iodophenol furnished the desired tert-
2. Results and Discussion
Initially, 2-iodophenol (1a) and cyanamide were reacted in
chamber A with Pd(PPh3)4 and triethylamine in 1,4-dioxane
using a bridged two-chamber system,[22] where CO was gener-
ated ex situ from Mo(CO)6 in chamber B at 658C for 20 h. The
reaction afforded full conversion of 1a to 2-amino-4H-benzo[e]
[1,3]oxazin-4-one (2a). Notably, the product was conveniently
isolated by precipitation, affording 2a in 76% yield (Scheme 2).
butyl
(2-amino-4-oxo-4H-benzo[e][1,3]oxazin-6-yl)carbamate
(2l) in 64% isolated yield without apparent cleavage of the
carbamate functionality. Overall, both electron-deficient and
electron-rich substrates performed well in the reaction. It is
worth noting that the outcome of the reaction is not exclusive-
ly dependent on electronic properties but also on physical
properties such as solubility; this was illustrated by the differ-
ence in yield of the electronically equivalent 2d (96%) and 2e
(83%).
Scheme 2. Synthesis of 2-amino-4H-benzo[e][1,3]oxazin-4-ones 2a–l from
ortho-iodophenols 1a–l (isolated yields).
To further broaden the generality of the reaction we decided
to develop a viable procedure for reacting ortho-bromophe-
nols. There are few examples in the literature of carbonylative
coupling reactions of ortho-bromophenols, and these reactions
often require harsh conditions and suffer from low yields.[31]
There are, however, reports of palladium-catalyzed aminocar-
bonylations of electron-rich aryl bromides using monodentate
and bidentate phosphine ligands, for example, di(1-adaman-
tyl)-n-butylphosphine (cataCXium A),[32] 1,1’-bis(diphenylphos-
phino)ferrocene (dppf),[22] and bis[(2-diphenylphosphino)phen-
yl] ether (DPEphos).[33] Initial optimization studies were per-
formed using 2-bromophenol (3a) as a standard substrate.
However, it was quickly discovered that the desired product
2a reacted further with cyanamide resulting in the guanidine-
substituted side product 4a along with the desired benzoxazi-
none. We have recently shown by X-ray crystallography that
the corresponding quinazolinone-guanidine side product is
formed in the carbonylation reaction of ortho-iodoanilines with
an excess of cyanamide.[29] Compound 4a was isolated and
subsequently fully characterized; spectral data were in agree-
ment with the proposed structure. We postulated that the
The structure of 2a was confirmed by NMR spectroscopy and
X-ray crystallography (see the Supporting Information). Fur-
thermore, the phenol nucleophile afforded ring closure readily
at 658C, whereas the aniline required higher temperatures for
complete cyclization.
The method was then evaluated for a set of ortho-iodophe-
nols to test the scope and limitations of the reaction
(Scheme 2). Overall, the products were obtained in moderate
to excellent yields and good chemoselectivity was observed
under the mild reaction conditions. The reaction worked well
for electron-deficient ortho-iodophenols and acetyl-substituted
ortho-iodophenol provided the corresponding 6-acetyl-2-
amino-4H-benzo[e][1,3]oxazin-4-one (2b) in 87% isolated yield.
Methyl-ester-substituted ortho-iodophenol furnished the corre-
sponding methyl 2-amino-4-oxo-4H-benzo[e][1,3]oxazine-6-car-
boxylate (2c) without cleavage of the ester functionality in
83% isolated yield. Chloro- and bromo-substituted ortho-iodo-
phenols gave the corresponding 6-chloro- and 6-bromo-substi-
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generation of the desired product is slow from the electron-
rich unsubstituted 2-bromophenol and the resulting large
excess of cyanamide present in the reaction mixture enables
the formation of the guanidine side product. Therefore, 2-
bromo-4-chlorophenol (3b), which is more activated towards
oxidative addition, was used as the standard substrate in the
optimization studies (Table 1). All ligands were found to acti-
entry 7). Next, LiCl[34,35] was added to stabilize the Pd0 species,
however, this favored the formation of 4b, and 2d was isolat-
ed in 11% yield (Table 1, entry 8). We next decided to evaluate
if sodium phenoxide[36] or DMAP[37,38] nucleophiles could accel-
erate the reaction and thereby lower the amount of 4b. How-
ever, addition of sodium phenoxide reduced the conversion of
starting bromide and 4b was obtained as the major product.
In contrast, addition of DMAP maintained a high conversion of
starting material and the desired 2d could be isolated in 58%
yield leading us to continue with the conditions given in
Table 1, entry 5.
Table 1. Optimization of synthesis of 2d from 2-bromo-4-chlorophenol
(3b).[a]
With suitable reaction conditions determined (Table 1,
entry 5), we extended the scope of the reaction to a set of
commercially available ortho-bromophenols (Scheme 3). 2-Bro-
Entry
Ligand
Additive
T
Yield 2d[b]
[8C]
[%]
1
2
3
4
5
6
7
8
9
cataCXium A
–
–
–
–
–
–
–
–
65
65
65
65
65
45
85
65
65
65
trace
trace
10
trace
68
8
36
11
–
[c]
Xantphos
dcpp·BF4
DPEphos
DPEphos
DPEphos
DPEphos
DPEphos
DPEphos
LiCl
NaOPh
DMAP
10
58
[a] Reaction conditions: chamber A: 2-bromo-4-chlorophenol (1 mmol),
cyanamide (1 equiv), Pd(OAc)2 (5 mol%), ligand, Et3N (2 equiv), 1,4-diox-
ane (3 mL), 658C, 20 h; chamber B: Mo(CO)6 (0.8 equiv), DBU (2.4 equiv),
1,4-dioxane (3 mL), 658C, 20 h. [b] Isolated yield. [c] Pd(dppf)Cl2 (5 mol%).
vate the CÀBr bond and facilitated consumption of starting
material (3b) albeit with varying efficiency. Use of neither the
monodentate phosphine ligand cataCXium A and precatalyst
Pd(dppf)Cl2 nor the bidentate phosphine ligand 1,3-bis(dicyclo-
hexylphosphino)propane (dcpp) provided full conversion of
the starting bromide and the guanidine side-product (4b) was
predominantly formed over the desired 2d (Table 1, entries 1–
3). However, if 4,5-bis(diphenylphosphino)-9,9-dimethylxan-
thene (Xantphos) was used as a ligand, 2d could be isolated in
10% yield, although 4b was formed as the major product
(Table 1, entry 4). By changing the ligand to DPEphos the start-
ing material was fully consumed and 2d was formed as the
major product and was isolated in 68% yield (Table 1, entry 5).
Next, we attempted to circumvent the formation of the guani-
dine side product by altering the reaction temperature to 45
and 858C. By doing so, we hoped to either 1) suppress the nu-
cleophilic attack leading to 4b at the lower temperature, or
2) increase the reaction rate for the oxidative addition step at
elevated temperature and thereby reduce the concentration of
cyanamide present in the reaction mixture after the product
had formed. Unfortunately, the formation of 4b was observed
despite the reduction in temperature and the starting material
was not fully consumed in contrast to the reaction at 658C
(Table 1, entry 6). At 858C the starting material was fully con-
sumed, nonetheless 4b was the major product (Table 1,
Scheme 3. Synthesis of 2-amino-4H-benzo[e][1,3]oxazin-4-ones 2a, 2d, and
2m-q from ortho-bromophenols 3a–g (isolated yields).
mophenol (1a) was fully consumed, however the side reac-
tions took precedence, leading to the formation of the guani-
dine adduct as the major product and the desired 2a was iso-
lated in 20% yield. In contrast, the electron-poor chloro-substi-
tuted ortho-bromophenol gave the desired 2d as major prod-
uct which could be isolated in 68% yield. This correlation
became even more clear with a comparison of the reactions of
fluoro-substituted analogues (3c–e). Among these substrates,
3c has almost no electron-withdrawing effect on the bromo
position, and thus the corresponding 2m was obtained in
21% yield. In contrast, 3d is activated for oxidative addition,
providing 2n in 34% isolated yield. The difluoro-substituted
3e gave the corresponding 2-amino-6,7-difluoro-4H-benzo[e]
[1,3]oxazin-4-one (2o) in 45% isolated yield. The strongly elec-
tron-withdrawing nitrile-substituted ortho-bromophenol 3 f re-
turned the desired product 2p in 90% isolated yield and 2-
bromo-4-methylphenol (3g) afforded 2q in 46% yield.
Overall, the ortho-bromophenols afforded lower yields than
the analogous iodides and the reaction towards electron-poor
halides was clearly favored. Nonetheless, this is one of the first
examples of palladium-catalyzed carbonylation of ortho-bro-
mophenols that typically prove challenging.
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To verify that the reaction proceeds via the proposed N-cya-
nobenzamide intermediate 5, phenol 1a was protected with a
para-methoxybenzyl (PMB) group according to standard proce-
dures, yielding PMB-protected compound 6 in 62% isolated
yield (Scheme 4). Compound 6 was then treated with cyana-
Table 2. Evaluation of various CO sources.[a–c]
Entry
CO source
T
[8C]
Pmax
[bar]
TPmax
[min]
Yield
[%]
[d]
1
2
3
4
5
6
7
8
9
10
Mo(CO)6
65
85
65
65
65
80
65
80
80
80
2.3
2.4
atm[f]
2.5
3.1
3.1
2.9
2.7
6.3
3.5
40
20
–
20 h
22 h
21
3
108
39
76
69
68
–
67
75
79
61
–
[d]
Mo(CO)6
Oxalyl chloride[d]
Phenyl formate[e]
Phenyl formate[d]
COgen[d]
MePh2SiCOOH[d]
[d]
CHCl3
[e]
CHCl3
Formic acid[d]
15
75
[a] Pmax: maximum pressure achieved; TPmax: time required to reach Pmax
.
[b] See the Supporting Information for full experimental conditions.
[c] Isolated yields. [d] Ex situ. [e] In situ. [f] CO collected in and distributed
using a balloon.
Scheme 4. Mechanistic studies for the formation of 2a from 1a. Reaction
conditions: a) 4-methoxybenzylbromide, K2CO3, DMF, 508C, 5 h; b) NH2CN,
Pd(PPh3)4, Et3N, Mo(CO)6, DBU, 1,4-dioxane, 658C, 20 h; c) TFA, CH2Cl2, 08C to
RT, 1 h.
chloroform[27,28] (Table 2, entry 8) resulted in the slow release of
CO (TPmax =22 h and 108 min, respectively), which caused in-
creased formation of guanidine side-product and thus a de-
crease in yield of 2a. Unfortunately, neither phenyl formate
nor hydrolysis of chloroform were successful in situ and no
product was detected (Table 2, entries 5 and 9). Both palladi-
um-catalyzed release of CO from COgen[24] and fluoride-medi-
ated decarbonylation of silacarboxylic acid[25] proved efficient
and compatible for ex situ use (Table 2, entries 6 and 7). Finally,
ex situ introduction of CO by dehydration of formic acid by sul-
furic acid[20] gave 2a in equivalent yield (Table 2, entry 10).
The results in Table 2 show that the method developed
herein could be easily paired with a variety of ex situ CO surro-
gates. Depending on the aim of the chemistry, for example,
cheap and readily available precursors, solid shelf-stable CO
sources, or isotopic labeling, the reported method provides an
mide under the carbonylative conditions described in
Scheme 2. Pleasingly, this afforded the corresponding PMB-pro-
tected cyanobenzamide 7 in 45% isolated yield. It is worth
noting that the deprotected and cyclized benzoxazinone prod-
uct 2a was also generated and isolated in 14% yield after the
carbonylation step. The benzyl ether 7 was cleaved using stan-
dard acidic conditions, which gave a mixture of O-debenzylat-
ed cyanobenzamide 5 and cyclized 2a. The crude mixture was
carried forward without further purification and was heated
with Et3N in 1,4-dioxane at 658C to complete the cyclization in
80% isolated yield over two steps.
The field of non-gaseous carbonylation reactions has flour-
ished over the last decade with the development of several
novel CO sources that have eradicated the need to use cum-
bersome CO gas.[39,40] The main focus has been to identify and
develop cheap, easy to handle and convenient reagents that
can be used for carbonylations, including isotopic labeling. To
assess if the method developed herein was viable with previ-
ously reported CO surrogates we replaced Mo(CO)6 as the CO
source in both ex situ (two-chamber system[22]) and in situ
(single vial) reactions (Table 2). For each CO surrogate, the in-
ternal pressure was monitored over the course of the CO-re-
leasing reaction as a means to follow CO generation (see the
Supporting Information for details). Ex situ use of Mo(CO)6 at
65 and 858C generated a yield of 76% and 69% respectively
(Table 2, entries 1 and 2) with moderately rapid release of CO
to relatively high internal pressures. Secondly, CO was deliv-
ered from a balloon following ex situ generation from oxalyl
chloride,[26] returning 2a in 68% yield (Table 2, entry 3). At at-
mospheric pressure a slight decrease in yield was observed
and the same outcome was noted for prolonged CO-release
times (Table 2, entries 3, 5 and 8). CO generated from phenyl
formate[17] ex situ (Table 2, entry 5) and alkaline hydrolysis of
attractive synthetic route to
a variety of 4H-benzo[e]
[1,3]oxazin-4-ones (2a–q).
3. Conclusions
We have developed a low-pressure, gas-free, one-step carbon-
ylation method for the synthesis of 4H-benzo[e][1,3]oxazin-4-
ones from readily available ortho-halophenols and cyanamide
that involves a palladium-catalyzed carbonylation–cyclization
sequence. The reaction products are readily isolated by precipi-
tation and the reaction occurs under mild conditions with
good substrate compatibility. Additionally, the protocol was
further extended to include ortho-bromophenols as substrates.
Finally, the versatility of the reaction was demonstrated by re-
placing Mo(CO)6 with a variety of ex situ CO-releasing reagents,
including introduction of CO with a balloon at atmospheric
pressure, with retained product yields.
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reaction mixture was stirred at À788C for 30 min and then the
cold bath was removed and the reaction mixture was stirred at RT
for 2 h. The reaction was quenched by the addition of water
(50 mL) and acetic acid (10 mL). The aqueous layer was extracted
with CH2Cl2 (2ꢂ50 mL) and the combined organic layers were
dried over MgSO4 and concentrated under reduced pressure. The
crude mixture was purified by silica gel column chromatography
using pentane/EtOAc (1:1) to give 1i as a white solid (304 mg,
Experimental Section
General Information
Analytical thin-layer chromatography (TLC) was performed on silica
gel 60 F254 plates and visualized with UV light. Flash column chro-
matography was performed on silica gel 60 (40–63 mm). 1H, 13C,
and 19F NMR spectra were recorded at 400, 100 and 377 MHz, re-
spectively. The chemical shifts for H, 13C and 19F NMR spectra are
1
1
60%). H NMR (400MHz, [D6]DMSO): d=10.14 (s, OH), 7.60 (d, J=
referenced to tetramethylsilane according to residual solvent sig-
nals, a sealed capillary filled with CFCl3 was used as an internal ref-
erence in 19F NMR (1H: CD3OD at 3.31 ppm, CDCl3 at 7.26 ppm and
[D6]DMSO at 2.50 ppm; 13C: CD3OD at 49.0 ppm, CDCl3 at 77.0 ppm
and [D6]DMSO at 39.5 ppm; 19F: CFCl3 at 0.0 ppm). The data are re-
ported as (s=singlet, brs=broadened singlet, d=doublet, t=trip-
let, q=quartet, or m=multiplet, coupling constant(s), integral).
Analytical HPLC–MS was performed using electrospray ionization
(ESI) and a C18 column (50ꢂ3.0 mm, 2.6 mm particle size, 100 ꢀ
pore size) with CH3CN/H2O in 0.05% aqueous HCOOH as mobile
phase at a flow rate of 1.5 mLminÀ1. Analysis of purity by LC was
performed using a gradient of 5–100% CH3CN/H2O in 0.05% aque-
ous HCOOH as mobile phase at a flow rate of 1.5 mLminÀ1 for
5 min, unless otherwise stated, on a C18 column. High-resolution
molecular masses were determined on a mass spectrometer
equipped with an ESI source and time-of-flight (TOF) mass
analyzer.
2.1 Hz, 1H), 7.11 (dd, J=8.2, 2.1 Hz, 1H), 6.82 (d, J=8.2 Hz, 1H),
5.06 (t, J=5.8 Hz; OH), 4.34 ppm (d, J=5.2 Hz, 2H); 13C NMR
(100MHz, [D6]DMSO): d=155.3, 137.0, 135.2, 128.0, 114.6, 84.1,
61.8 ppm; HRMS (ESI-TOF): m/z: calcd for C7H6IO2: 248.9413
[MÀH]À; found: 248.9420; LC purity (254 nm): >98%.
4-(Dibenzylamino)-2-iodophenol (1k)
4-Amino-2-iodoaniline (250 mg, 1.06 mmol) and benzaldehyde
(0.32 mL, 3.2 mmol) were dissolved in MeOH (5 mL) and acetic acid
(0.18 mL, 3.1 mmol) was added. The reaction mixture was stirred at
RT for 30 min, cooled to 08C and NaBH3CN (174 mg, 2.77 mmol)
was added. The reaction was allowed to warm from 08C to RT and
stirred for 48 h. The reaction was quenched with saturated aq
NaHCO3 (30 mL) and then extracted with EtOAc (3ꢂ50 mL). The
combined organic layers were washed with brine (50 mL), dried
over Na2SO4, filtered and concentrated under reduced pressure.
The crude mixture was purified by silica gel column chromatogra-
phy using pentane/EtOAc (20:1) to yield 1k as a pale purple solid
(239 mg, 54%). 1H NMR (400MHz, CDCl3): d=7.36–7.30 (m, 4H),
7.29–7.21 (m, 6H), 7.06 (s, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.68 (m,
1H), 4.75 (s; OH), 4.52 ppm (s, 4H); 13C NMR (100MHz, CDCl3): d=
147.0, 144.9, 138.4, 128.8, 127.2, 127.0, 122.5, 116.0, 115.3, 86.6,
55.1 ppm; HRMS (ESI-TOF): m/z: calcd for C20H19INO: 416.0511
[M+H]+; found: 416.0506; LC purity (254 nm): 95%
Synthesis of ortho-Iodophenol Precursors 1
4-Chloro-2-iodophenol (1d)
Prepared following a literature procedure[41] to give a white solid
(618 mg, 47%). Compound 1d is known,[41] and spectral data were
in agreement with the proposed structure and matched those re-
ported in the literature.
4-Bromo-2-iodophenol (1e)
tert-Butyl (4-Hydroxy-3-iodophenyl)carbamate (1l)
Prepared following a modified literature procedure[41] to give a
white solid (1.05 g, 66%). Compound 1e is known,[42] and spectral
data were in agreement with the proposed structure and matched
those reported in the literature.
4-Amino-2-iodophenol (250 mg, 1.06 mmol) and di-tert-butyl car-
bonate (232 mg, 1.06 mmol) were dissolved in anhydrous THF and
stirred at RT for 4 h. The reaction mixture was concentrated and
the crude material was purified by silica gel column chromatogra-
phy using pentane/EtOAc (5:1) to yield 1l as an off-white solid
(317 mg, 89%). 1H NMR (400MHz, CDCl3): d=7.77 (brs, 1H), 7.10
(dd, J=8.8, 2.7 Hz, 1H), 6.86 (m, 1H), 6.39 (brs, 1H), 5.43 (brs, 1H),
1.50 ppm (s, 9H); 13C NMR (100MHz, CDCl3): d=153.2, 151.4, 132.3,
129.1, 121.7, 114.9, 85.3, 80.9, 28.5 ppm; HRMS (ESI-TOF): m/z:
calcd for C11H13INO3: 333.9940 [MÀH]À; found: 333.9948; LC purity
(254 nm): 98%.
N-(4-Hydroxy-3-iodophenyl)acetamide (1g)
Acetic anhydride (0.10 mL, 1.1 mmol) was added to a solution of 4-
amino-2-iodophenol (250 mg, 1.06 mmol) in absolute ethanol
(5 mL) and the reaction mixture was stirred at RT for 1 h. The reac-
tion mixture was concentrated to give a brown residue, which was
purified using silica gel column chromatography pentane/EtOAc
1
(4:1) to give 1g as a brown solid (184 mg, 62%). H NMR (400MHz,
Method A: General Procedure for the Synthesis of 2-Amino-
4H-benzo[e][1,3]oxazin-4-ones 2a–l from ortho-Iodophenols
1a–l
CD3OD): d=7.90 (d, J=2.5 Hz, 1H), 7.31 (dd, J=8.7, 2.5 Hz, 1H),
6.76 (d, J=8.7 Hz, 1H), 2.08 ppm (s, 3H); 13C NMR (400MHz,
CD3OD): d=171.3, 154.9, 132.9, 132.4, 123.0, 115.3, 83.9, 23.5 ppm;
HRMS (ESI-TOF): m/z: calcd for C8H9INO2: 277.9678 [M+H]+; found:
277.9671; LC purity (254 nm): 95%.
To the reaction chamber (chamber A) of an oven-dried, bridged
two-chamber system[22] was added ortho-iodophenol (1.0 mmol),
cyanamide (50 mg, 1.2 mmol) and Pd(PPh3)4 (58 mg, 5 mol%).
Mo(CO)6 (211 mg, 0.8 mmol) was added to the CO-generation
chamber (chamber B).[43] The two chambers were capped with gas-
tight caps, and the atmosphere was exchanged for nitrogen. 1,4-
Dioxane (3 mL) was added through the septa into each chamber,
followed by the addition of Et3N (0.28 mL, 2 mmol) into chamber A
and DBU (0.36 mL, 2.4 mmol) into chamber B. The two-chamber
4-(Hydroxymethyl)-2-iodophenol (1i)
Methyl 4-hydroxy-3-iodobenzoate (562 mg, 2.02 mmol) was dis-
solved in anhydrous CH2Cl2 (50 mL) under inert conditions and
cooled to À788C. Then, diisobutylaluminum hydride (7.0 mL,
7.0 mmol, 1m in heptane) was added dropwise over 15 min. The
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system was immediately heated with vigorous stirring in a heating
block at 658C for 20 h. After 20 h, the reaction mixture in cham-
ber A was poured into iso-hexane (30 mL) and collected by filtra-
tion. The solid was washed with water (10 mL) and EtOAc (10 mL)
to give the pure compound.
2-Amino-6-chloro-4H-benzo[e][1,3]oxazin-4-one (2d)
Method A: Tan solid (189 mg, 96%). Method B: Gray solid (110 mg,
68%). Rf =0.23 (SiO2, 5% MeOH/CH2Cl2 +Et3N); 1H NMR (400MHz,
CD3OD): d=7.95 (d, J=2.6 Hz, 1H), 7.70 (dd, J=8.8, 2.6 Hz, 1H),
7.35 ppm (d, J=8.8 Hz, 1H); 13C NMR (100 MHz, [D6]DMSO) d=
165.0, 159.7, 152.1, 133.9, 129.2, 125.7, 118.5, 118.2 ppm; HRMS
(ESI-TOF): m/z: calcd for C8H6ClN2O2: 197.0118 [M+H]+; found:
197.0111; LC purity (254 nm): >98%.
Method B: General Procedure for the Synthesis of 2-Amino-
4H-benzo[e][1,3]oxazin-4-ones 2a, 2d, and 2m–q from
ortho-Bromophenols 3a–g
2-Amino-6-bromo-4H-benzo[e][1,3]oxazin-4-one (2e)
To the reaction chamber (chamber A) of an oven-dried, bridged
two-chamber system[22] was added ortho-bromophenol (1.0 mmol),
cyanamide (42 mg, 1.0 mmol), Pd(OAc)2 (11 mg, 5 mol%) and DPE-
phos (32 mg, 6 mol%). Mo(CO)6 (211 mg, 0.8 mmol) was added
into the CO-generation (chamber B). The two chambers were
capped with gastight caps, and the atmosphere was exchanged
for nitrogen. 1,4-Dioxane (3 mL) was added through the septa into
each chamber, followed by the addition of Et3N (0.28 mL, 2 mmol)
into chamber A and DBU (0.36 mL, 2.4 mmol) into chamber B. The
two-chamber system was immediately heated and vigorously
stirred in a heating block at 658C for 20 h. After 20 h, the reaction
mixture in chamber A was poured into iso-hexane (30 mL) and col-
lected by filtration. The solid was washed with water (10 mL) and
EtOAc (10 mL) to give the pure compound.
Method A: Tan solid (197 mg, 83%). Rf =0.23 (SiO2, 5% MeOH/
CH2Cl2 +Et3N); H NMR (400MHz, [D6]DMSO/CD3OD 3:1) d=7.94 (d,
J=2.6 Hz, 1H), 7.79 (dd, J=8.8, 2.5 Hz, 1H), 7.26 ppm (d, J=8.8 Hz,
1H); 13C NMR ([D6]DMSO): d=164.8, 159.6, 152.5, 136.7, 128.7,
118.9, 118.5, 116.9 ppm; HRMS (ESI-TOF): m/z: calcd for C8H6BrN2O2:
240.9613 [M+H]+; found: 240.9612; LC purity (254 nm): 97%.
1
2-Amino-6-nitro-4H-benzo[e][1,3]oxazin-4-one (2 f)
Method A: Pale yellow solid (166 mg, 77%). Rf =0.20 (SiO2, 5%
1
MeOH/CH2Cl2 +Et3N); H NMR (400 MHz, [D6]DMSO) d=8.55 (d, J=
2.8 Hz, 1H), 8.53 (brs, 1H; NH), 8.48 (dd, J=9.0, 2.9 Hz, 1H), 8.44
(brs, 1H; NH), 7.57 ppm (d, J=9.1 Hz, 1H); 13C NMR (100MHz,
[D6]DMSO): d=164.7, 159.6, 157.2, 144.1, 128.8, 122.2, 117.9,
117.6 ppm; HRMS (ESI-TOF): m/z: calcd for C8H6N3O4: 208.0358
[M+H]+; found: 208.0357; LC purity (254 nm): >98%.
2-Amino-4H-benzo[e][1,3]oxazin-4-one (2a)
Method A: Tan solid (128 mg, 76%). Method B: Tan solid (34 mg,
20%). Rf =0.29 (SiO2, 5% MeOH/CH2Cl2 +Et3N); m.p. 256–2578C;
1H NMR (400MHz, CD3OD): d=8.00 (dd, J=7.8, 1.7 Hz, 1H), 7.71
(ddd, J=8.7, 7.3, 1.7 Hz, 1H), 7.41 (m, 1H), 7.34 ppm (dd, J=8.3,
1.0 Hz, 1H); 13C NMR (100MHz, [D6]DMSO): d=166.0, 159.8, 153.4,
134.1, 126.6, 125.2, 117.1, 115.7 ppm; HRMS (ESI-TOF): m/z: calcd
for C8H7N2O2: 163.0508 [M+H]+; found: 163.0503; LC purity
(254 nm): >98%.
N-(2-Amino-4-oxo-4H-benzo[e][1,3]oxazin-6-yl)acetamide (2g)
Method A: Brown solid (111 mg, 96%). Rf =0.17 (SiO2, 5% MeOH/
CH2Cl2 +Et3N); 1H NMR (400MHz, CD3OD): d=8.12 (d, J=2.6 Hz,
1H), 7.96 (dd, J=9.0, 2.6 Hz, 1H), 7.30 (d, J=9.0 Hz, 1H), 2.15 ppm
(s, 3H); 13C NMR (100MHz, [D6]DMSO): d=168.8, 166.5, 160.2,
149.4, 136.8, 125.3, 117.6, 116.5, 116.2, 24.3 ppm; HRMS (ESI-TOF):
m/z: calcd for C10H10N3O3: 220.0722 [M+H]+; found: 220.0729; LC
purity (254 nm): >98%.
6-Acetyl-2-amino-4H-benzo[e][1,3]oxazin-4-one (2b)
2-Amino-6-phenyl-4H-benzo[e][1,3]oxazin-4-one (2h)
Method A: Tan solid (178 mg, 87%). Rf =0.26 (SiO2, 5% MeOH/
1
Method A: Off-white solid (209 mg, 89%). Rf =0.46 (SiO2, 5%
MeOH/CH2Cl2 +Et3N); 1H NMR (400MHz, [D6]DMSO): d=8.23 (brs,
1H; NH, exchanges with deuterium), 8.16 (brs, 1H; NH, exchanges
with deuterium), 8.08 (d, J=2.4 Hz, 1H), 7.98 (dd, J=8.6, 2.4 Hz,
1H), 7.74–7.64 (m, 2H), 7.54–7.45 (m, 2H), 7.46–7.37 ppm (m, 2H);
13C NMR (100MHz, [D6]DMSO): d=166.0, 159.8, 153.0, 138.7, 137.2,
132.4, 129.2, 127.8, 126.7, 124.1, 117.5, 116.5 ppm; HRMS (ESI-TOF):
m/z: calcd for C14H11N2O2: 239.0821 [M+H]+; found: 239.0814; LC
purity (254 nm): 98%.
CH2Cl2 +Et3N); H NMR (400MHz, [D6]DMSO/CD3OD 3:1) d=8.43 (d,
J=2.2 Hz, 1H), 8.20 (dd, J=8.7, 2.3 Hz, 1H), 7.39 (d, J=8.6 Hz, 1H),
2.59 ppm (s, 3H); 13C NMR (100MHz, [D6]DMSO): d=196.4, 165.5,
159.6, 156.3, 133.6, 133.4, 127.2, 117.0, 116.5, 26.7 ppm; HRMS (ESI-
TOF): m/z: calcd for C10H9N2O3: 205.0613 [M+H]+; found: 205.0615;
LC purity (254 nm): >98%.
Methyl 2-Amino-4-oxo-4H-benzo[e][1,3]oxazine-6-carboxylate
(2c)
2-Amino-6-(hydroxymethyl)-4H-benzo[e][1,3]oxazin-4-one (2i)
Method A: Off-white solid (185 mg, 83%). Rf =0.26 (SiO2, 5%
MeOH/CH2Cl2 +Et3N); H NMR (400MHz, [D6]DMSO): d=8.41 (d, J=
1
Method A: Tan solid (163 mg, 84%). Rf =0.14 (SiO2, 5% MeOH/
CH2Cl2 +Et3N); 1H NMR (400MHz, CD3OD): d=7.98 (d, J=2.1 Hz,
1H), 7.71 (dd, J=8.5, 2.2 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 4.67 ppm
(s, 2H); 13C NMR (100MHz, [D6]DMSO): d=166.6, 160.2, 152.7,
140.0, 132.6, 124.5, 117.1, 115.8, 62.5 ppm; HRMS (ESI-TOF): m/z:
calcd for C9H9N2O3: 193.0613 [M+H]+; found: 193.0607; LC purity
(254 nm): >98%.
2.2 Hz, 1H), 8.36 (brs, 1H; NH), 8.28 (brs, 1H; NH), 8.20 (dd, J=8.6,
2.3 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 3.89 ppm (s, 3H); 13C NMR
(100 MHz, [D6]DMSO): d=165.3, 165.1, 159.6, 156.4, 134.4, 128.0,
126.4, 117.2, 116.7, 52.4 ppm; HRMS (ESI-TOF): m/z: calcd for
C10H9N2O4: 221.0562 [M+H]+; found: 221.0572; LC purity (254 nm):
95%.
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1
13C NMR (100 MHz, [D6]DMSO): d=164.6, 159.8, 152.8 (dd, JCF
=
=
2,6-Diamino-4H-benzo[e][1,3]oxazin-4-one (2j)
1
253.5 Hz, 2JCF =14.8 Hz), 150.0–149.8 (m, 1C), 147.0 (dd, JCF
Method A: Brown solid (175 mg, 94%). Rf =0.23 (SiO2, 5% MeOH/
CH2Cl2 +Et3N); 1H NMR (400MHz, CD3OD): d=7.20 (dd, J=2.8,
0.5 Hz, 1H), 7.09 (dd, J=8.8, 0.5 Hz, 1H), 7.04 ppm (dd, J=8.8,
2.7 Hz, 1H); 13C NMR (100MHz, [D6]DMSO): d=166.7, 159.8, 146.2,
144.9, 120.2, 117.5, 115.9, 108.6 ppm; HRMS (ESI-TOF): m/z: calcd
for C8H8N3O2: 178.0617 [M+H]+; found: 178.0609; LC purity
(254 nm): 95%.
246.3 Hz, 2JCF =13.3 Hz), 114.8–113.8 (m, 2C), 106.1 ppm (d, J=
21.8 Hz); 19F NMR (377 MHz, CD3OD): d=À128.2, À141.7 ppm;
HRMS (ESI-TOF): m/z: calcd for C8H5F2N2O2: 199.0319 [M+H]+;
found: 199.0317; LC purity (254 nm): >98%.
2-Amino-4-oxo-4H-benzo[e][1,3]oxazine-6-carbonitrile (2p)
Method B: Gray solid (161 mg, 90%). Rf =0.27 (SiO2, 5% MeOH/
1
CH2Cl2 +Et3N); H NMR (400MHz, [D6]DMSO): d=8.37–8.16 (m, 3H),
2-Amino-6-(dibenzylamino)-4H-benzo[e][1,3]oxazin-4-one (2k)
8.09 (m, 1H), 7.50 ppm (m, 1H); 13C NMR (100MHz, [D6]DMSO): d=
164.1, 159.3, 155.8, 137.1, 131.3, 117.9, 117.50, 117.47, 107.9 ppm;
HRMS (ESI-TOF): m/z: calcd for C9H6N3O2: 188.0460 [M+H]+;
found: 188.0463; LC purity (254 nm): 97%.
Method A: Pale yellow solid (92 mg, 53%). 1H NMR (400MHz,
[D6]DMSO): d=7.86 (brs, 2H, NH), 7.36–7.31 (m, 4H), 7.29–7.21 (m,
6H), 7.11 (m, 1H), 7.03–6.98 (m, 2H), 4.75 ppm (s, 4H); 13C NMR
(100MHz, [D6]DMSO): d=166.4, 159.8, 145.6, 145.1, 138.4, 128.6,
126.8, 126.5, 118.7, 117.4, 116.2, 107.4, 54.6 ppm; HRMS (ESI-TOF):
m/z: calcd for C22H20N3O2: 358.1556 [M+H]+; found: 358.1559; LC
purity (254 nm): 97%.
2-Amino-6-methyl-4H-benzo[e][1,3]oxazin-4-one (2q)
Method B: Gray solid (84 mg, 46%). Rf =0.41 (SiO2, 5% MeOH/
1
CH2Cl2 +Et3N); H NMR (400MHz, [D6]DMSO): d=8.07 (brs, 1H; NH,
exchanges with deuterium), 8.03 (brs, 1H; NH, exchanges with
deuterium), 7.67 (m, 1H), 7.49 (m, 1H), 7.21 (d, J=8.4 Hz, 1H),
2.36 ppm (s, 3H); 13C NMR (100MHz, [D6]DMSO): d=166.2, 159.8,
151.5, 134.8, 134.5, 126.3, 116.8, 115.5, 20.3 ppm; HRMS (ESI-TOF):
m/z: calcd for C9H9N2O2: 177.0664 [M+H]+; found: 177.0661; LC
purity (254 nm): >98%.
tert-Butyl (2-amino-4-oxo-4H-benzo[e][1,3]oxazin-6-yl)carba-
mate (2l)
Method A: Off-white solid (126 mg, 64%). Rf =0.32 (SiO2, 5%
MeOH/CH2Cl2 +Et3N); 1H NMR (400MHz, CD3OD) d=7.99 (d, J=
2.7 Hz, 1H), 7.79 (dd, J=9.1, 2.7 Hz, 1H), 7.26 (d, J=9.0 Hz, 1H),
1.53 ppm (s, 9H); 13C NMR (100MHz, [D6]DMSO): d=166.1, 159.8,
152.8, 148.5, 136.6, 124.1, 117.2, 116.0, 114.7, 79.4, 28.1 ppm; HRMS
(ESI-TOF): m/z: calcd for C13H16N3O4: 278.1141 [M+H]+; found:
278.1151; LC purity (254 nm): >98%.
Characterization of Side Product 2-(4-Oxo-4H-benzo[e]
[1,3]oxazin-2-yl)guanidine (4a)
To the reaction chamber (chamber A) of an oven-dried, bridged
two-chamber system[22] was added ortho-bromophenol (0.12 mL,
0.99 mmol), cyanamide (44 mg, 1.1 mmol), Pd(OAc)2 (11 mg,
5 mol%) and DPEphos (38 mg, 7 mol%). Mo(CO)6 (215 mg,
0.8 mmol) was added into the CO-generation chamber (cham-
ber B). The two chambers were capped with gastight caps, and the
atmosphere was exchanged for nitrogen. 1,4-Dioxane (3 mL) was
added through the septa into each chamber, followed by the addi-
tion of Et3N (0.28 mL, 2.0 mmol) into chamber A and DBU (0.36 mL,
2.4 mmol) into chamber B. The two-chamber system was immedi-
ately heated and vigorously stirred in a heating block at 658C for
20 h. After 20 h, the reaction mixture in chamber A was poured
into iso-hexane (30 mL) and the resulting precipitate was filtered
off. The filtrate was concentrated under reduced pressure and puri-
fied by silica gel column chromatography using a gradient of 1–
5% MeOH in CH2Cl2 containing 1% Et3N. The combined pure frac-
tions were concentrated under reduced pressure, dissolved in
CH2Cl2 (10 mL) and washed with 0.1% aq HCl (2ꢂ10 mL) and
water (10 mL) to remove excess Et3N. The organic phase was dried
over Na2SO4, filtered and concentrated under reduced pressure to
yield 4a as a white solid (19 mg, 9%). 1H NMR (400MHz, CDCl3/
CD3OD 1:3): d=8.03 (dd, J=8.0, 1.8 Hz, 1H), 7.45 (m, 1H), 7.02–
6.93 ppm (m, 2H); 13C NMR (100MHz, [D6]DMSO): d=166.6, 159.4,
157.4, 135.2, 130.9, 119.7, 117.2, 116.8, 116.0 ppm; HRMS (ESI-TOF):
m/z: calcd for C9H7N4O2: 203.0569 [MÀH]À; found: 203.0574; LC
purity (254 nm): 97%.
2-Amino-7-fluoro-4H-benzo[e][1,3]oxazin-4-one (2m)
Method B: Gray solid (38 mg, 21%). Rf =0.35 (SiO2, 5% MeOH/
1
CH2Cl2 +Et3N); H NMR (400MHz, [D6]DMSO): d=8.21 (brs, 1H; NH,
exchanges with deuterium), 8.16 (brs, 1H; NH, exchanges with
deuterium), 7.93 (m, 1H), 7.36–7.15 ppm (m, 2H); 13C NMR
(100MHz, [D6]DMSO): d=165.3, 164.9 (d, 1JCF =251.0 Hz), 159.7,
154.5 (d, 3JCF =14.0 Hz), 129.2 (d, 3JCF =10.7 Hz), 114.1 (d, JCF
=
4
2.8 Hz), 113.0 (d, 2JCF =22.5 Hz), 103.3 ppm (d, 2JCF =26.2 Hz);
19F NMR (377 MHz, CD3OD): d=À103.6 ppm; HRMS (ESI-TOF): m/z:
calcd for C8H6FN2O2: 181.0413 [M+H]+; found: 181.0407; LC purity
(254 nm): 95%.
2-Amino-6-fluoro-4H-benzo[e][1,3]oxazin-4-one (2n)
Method B: Gray solid (56 mg, 34%). Rf =0.32 (SiO2, 5% MeOH/
1
CH2Cl2 +Et3N); H NMR (400MHz, [D6]DMSO): d=8.22 (brs, 1H; NH
exchanges with deuterium), 8.16 (brs, 1H; NH exchanges with deu-
terium), 7.64–7.49 (m, 2H), 7.41 ppm (m, 1H); 13C NMR (100MHz,
[D6]DMSO): d=165.5, 160.0, 158.7 (d, 1JCF =242.9 Hz), 149.8 (d,
4JCF =1.8 Hz), 121.7 (d, 2JCF =24.8 Hz), 118.4 (d, 3JCF =7.1 Hz), 118.3
(d, 3JCF =8.0 Hz), 111.9 ppm (d, 2JCF =23.8 Hz); 19F NMR (377 MHz,
CD3OD): d=À117.0 ppm; HRMS (ESI-TOF): m/z: calcd for
C8H6FN2O2: 181.0413 [M+H]+; found: 181.0410; LC purity
(254 nm): >98%.
Characterization of Side Product 2-(6-Chloro-4-oxo-4H-
benzo[e][1,3]oxazin-2-yl)guanidine (4b)
2-Amino-6,7-difluoro-4H-benzo[e][1,3]oxazin-4-one (2o)
Method B: Gray solid (91 mg, 45%). Rf =0.35 (SiO2, 5% MeOH/
CH2Cl2 +Et3N); 1H NMR (400MHz, [D6]DMSO): d=8.15 (brs, 2H;
NH2, exchanges with deuterium), 7.79 (m, 1H), 7.57 ppm (m, 1H);
To the reaction chamber (chamber A) of an oven-dried, bridged
two-chamber system[22] was added 2-bromo-4-chlorophenol
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(208 mg, 1.00 mmol), cyanamide (43 mg, 1.0 mmol), Pd(OAc)2
(11 mg, 5 mol%) and CataCXium A (55 mg, 15 mol%). Mo(CO)6
(215 mg, 0.8 mmol) was added into the CO-generation chamber
(chamber B). The two chambers were capped with gastight caps,
and the atmosphere was exchanged for nitrogen. 1,4-Dioxane
(3 mL) was added through the septa into each chamber, followed
by the addition of Et3N (0.28 mL, 2.0 mmol) into chamber A and
DBU (0.36 mL, 2.4 mmol) into chamber B. The two-chamber system
was immediately heated and vigorously stirred in a heating block
at 658C for 20 h. After 20 h, the reaction mixture in chamber A was
poured into iso-hexane (30 mL) and the resulting precipitate was
filtered off. The filtrate was concentrated under reduced pressure
and purified by silica gel column chromatography using a gradient
of 1–5% MeOH in CH2Cl2 containing 1% Et3N. The combined pure
fractions were concentrated under reduced pressure, dissolved in
CH2Cl2 (10 mL) and extracted with 0.1% aq HCl (2ꢂ10 mL) to
remove excess Et3N. Compound 4b precipitated out in the acidic
aqueous phase and was filtered off and dissolved in EtOAc. The or-
ganic phase was dried over Na2SO4, filtered and concentrated
under reduced pressure to yield 4b as a yellow solid (20 mg, 8%).
1H NMR (400MHz, [D6]DMSO): d=8.92 (brs, 1H), 7.68 (d, J=2.9 Hz,
1H), 7.46 (brs, 1H), 7.20 (dd, J=8.8, 2.9 Hz, 1H), 6.68 (d, J=8.8 Hz,
1H), 4.11 ppm (brs, 2H); 13C NMR (100MHz, [D6]DMSO): d=171.6,
166.1, 163.0 (detected by HMBC), 132.8, 128.7, 124.7, 120.5 (two
signals overlapping, confirmed by HMBC), 119.2 ppm; HRMS (ESI-
TOF): m/z: calcd for C9H6ClN4O2: 237.0179 [MÀH]À; found:
237.0184; LC purity (254 nm): >98%.
1H), 7.39–7.32 (m, 2H), 7.19–7.11 (m, 2H), 7.01–6.92 (m, 2H), 5.17
(s, 2H), 3.84 ppm (s, 2H); 13C NMR (100MHz, CDCl3, 508C): d=
164.0, 160.8, 157.5, 135.7, 133.2, 129.9, 126.5, 122.4, 118.4, 115.0,
113.7, 106.9, 72.4, 55.5 ppm; HRMS (ESI-TOF): m/z: calcd for
C16H13N2O3: 281.0926 [MÀH]À; found: 281.0918; LC purity (254 nm):
>98%.
Deprotection of Compound 7 and Cyclization to Benzoxazi-
none 2a
TFA (0.10 mL, 1.3 mmol) was added to a solution of compound 7
(37 mg, 0.13 mmol) in dichloromethane (3 mL) on an ice bath. The
reaction mixture was stirred at RT for 1 h and then concentrated
and co-evaporated with toluene (3ꢂ5 mL) to give a brown residue.
The crude residue was dissolved in 1,4-dioxane (3 mL) followed by
the addition of Et3N (0.02 mL, 0.1 mmol) and the resulting solution
was stirred at 658C for 3 h. The crude mixture was purified by silica
gel column chromatography using a gradient of 0–5% MeOH/
CH2Cl2 to yield 2a as a white solid (17 mg, 80%).
Acknowledgements
The authors thank Magnus Fagrell (Fagrell Produktutveckling AB,
Sweden) for technical support with the pressure measurements
and Dr. Lisa D. Haigh (Imperial College London, UK) and Alfred
Svan (Uppsala University) for assistance with accurate mass de-
termination. The research was supported by Uppsala University.
Synthesis of 4-Methoxybenzyl 2’-Iodophenyl Ether (6)
1-(Bromomethyl)-4-methoxybenzene (0.41 mL, 2.8 mmol) was
added to
a
stirred suspension of 2-iodophenol (565 mg,
Conflict of Interest
2.57 mmol) and potassium carbonate (1.80 g, 13 mmol) in DMF.
The reaction mixture was stirred at 508C for 5 h. The crude mixture
was separated between diethyl ether and water and the organic
phase was washed with water (2ꢂ15 mL) and brine (3ꢂ15 mL)
consecutively to remove DMF. The organic phase was dried over
MgSO4, filtered and concentrated to yield 6 as a tan solid (543 mg,
62%). Compound 6 is known[44] and spectral data were in agree-
ment with the proposed structure and matched those reported in
the literature.
The authors declare no conflict of interest.
Keywords: 4H-benzo[e][1,3]oxazin-4-ones
domino reactions · halophenols · heterocycles
· carbonylation ·
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Received: July 10, 2017
Revised manuscript received: July 24, 2017
Version of record online && &&, 2017
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ꢁ 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
These are not the final page numbers! ÞÞ

FULL PAPERS
L. ꢀkerbladh, S. Y. Chow, L. R. Odell,*
M. Larhed*
The domino effect: Sequential carbony-
lative coupling of ortho-halophenols
with cyanamide followed by intramolec-
ular cyclization can be used to conven-
iently prepare 4H-benzo[e][1,3]oxazin-4-
ones. Moreover, the methodology is ap-
plicable to several readily available CO-
releasing reagents making this a highly
attractive synthetic route to a variety of
4H-benzo[e][1,3]oxazin-4-ones.
&& – &&
Synthesis of 4H-Benzo[e][1,3]oxazin-4-
ones by a Carbonylation–Cyclization
Domino Reaction of ortho-
Halophenols and Cyanamide
&
ChemistryOpen 2017, 00, 0 – 0
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10
ꢁ 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!