Synthesis, Rearrangement, and Hauser Annulation of 3-Isocyanophthalides

Article abstract of DOI:10.1055/s-0034-1380656

3-Isocyanoisobenzofuran-1(3H)-ones (phthalides) were prepared in two steps from the corresponding phthalaldehydic acids. The 3-isocyanoisobenzofuran-1(3H)-ones are readily rearranged to the corresponding 3-cyanoisobenzofuran-1(3H)-ones using triflic anhyd

Full text of DOI:10.1055/s-0034-1380656

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2473–2484
paper
2473
D. Mal et al.
Paper
Synthesis
Synthesis, Rearrangement, and Hauser Annulation of
3-Isocyanophthalides
Dipakranjan Mal*
Ketaki Ghosh
R
Tf2O
2,6-lutidine
0 °C
OH
CN
Soumen Chakraborty
NC
O
CO2Me
base
R
r.t.
X
O
Department of Chemistry, Indian Institute of Technology,
Kharagpur, 721302, India
dmal@chem.iitkgp.ernet.in
X
CO2Me
O
OH
O
7 examples
8 examples
62–80% yields
23–56% yields
12 examples
Received: 27.01.2015
Accepted after revision: 27.03.2015
Published online: 19.05.2015
SO2Ph
CN
O
O
X
DOI: 10.1055/s-0034-1380656; Art ID: ss-2015-z0060-op
X
Abstract 3-Isocyanoisobenzofuran-1(3H)-ones (phthalides) were pre-
pared in two steps from the corresponding phthalaldehydic acids. The
3-isocyanoisobenzofuran-1(3H)-ones are readily rearranged to the cor-
responding 3-cyanoisobenzofuran-1(3H)-ones using triflic anhydride
and 2,6-lutidine, thus enabling the synthesis of 3-cyanoisobenzofuran-
1(3H)-ones without using toxic cyanide. Furthermore their annulation
with Michael acceptors results in direct formation of 1,4-naphthoqui-
nols/1,4-naphthoquinones in moderate yields.
O
O
1
3-(phenylsulfonyl)isobenzofuran-1(3H)-ones
Figure 1 Established Hauser donors
that they can be synthesized without the use of toxic cya-
nides. Furthermore, 3-isocyanoisobenzofuran-1(3H)-ones 2
can be rearranged to 3-cyanoisobenzofuran-1(3H)-ones 1,
as well as be used in multicomponent reactions.6 Herein,
we report the synthesis, rearrangement, and annulation re-
activity of 3-isocyanoisobenzofuran-1(3H)-ones 2.
For the synthesis of 3-isocyanoisobenzofuran-1(3H)-
ones 2, we considered the use of 3-(formylamino)isobenzo-
furan-1(3H)-ones 3 as precursors, since they were expected
to be accessible from phthalaldehydic acids 45c,7 (Scheme
1).
Key words 3-isocyanoisobenzofuran-1(3H)-ones, synthesis, Hauser
annulations, rearrangement, 3-cyanoisobenzofuran-1(3H)-ones
The Hauser annulation1 is an established method for the
regiospecific synthesis of 1,4-dihydroxynaphthalenes in a
one-pot operation from 3-(phenylsulfonyl)isobenzo-
furan-1(3H)-ones and a Michael acceptor (Figure 1). It is
viewed as a domino reaction sequence consisting of ini-
tial lateral deprotonation, Michael addition, followed by
Dieckmann/Claisen cyclization and elimination of the phe-
nylsulfinate ion. The annulation works well when 3-cyano-
isobenzofuran-1(3H)-ones 1 are used in place of sulfonyliso-
benzofuran-1(3H)-ones (Figure 1).2 The efficiency of annu-
lation is significantly improved using lithium tert-butoxide
or lithium hexamethyldisilazanide as the base.3 In many in-
stances, 3-cyanoisobenzofuran-1(3H)-ones 1 in conjunc-
tion with lithium tert-butoxide are the most effective com-
bination for the annulation.4
OH
O
NHCHO
NC
O
X
O
O
X
X
O
O
4
3
2
Scheme 1 Proposed route for the synthesis of 3-isocyanoisobenzofu-
ran-1(3H)-ones
However, all the syntheses of 3-cyanoisobenzofuran-
1(3H)-ones 1 require toxic potassium cyanide or trimethyl-
silyl cyanide,5 and the toxicity of the reagents remains a de-
terrent to their large-scale preparation. Consequently, our
aim was to explore the chemistry of hitherto unknown 3-
isocyanoisobenzofuran-1(3H)-ones 2, since it is conceivable
Initially, a solution of 2-formylbenzoic acid (phthalalde-
hydic acid, 4a, X = H) in benzene was heated with form-
amide in the presence of 4-toluenesulfonic acid to give 3-
(formylamino)isobenzofuran-1(3H)-one (3a, X = H); al-
though the reaction was successful, the yield was ~25%. Fur-
ther studies increased the yield of 3a to 90% by simply heat-
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Synthesis
NHCHO
OH
O
NH2CHO (neat)
80–90 °C, 3 h
O
O
X
X
45–90%
O
4
3
NHCHO
MeO
NHCHO
NHCHO
NHCHO
MeO2C
MeO
O
O
O
O
O
MeO
3c (86%)
O
O
O
3a (90%)
3b (80%)
3d (88%)
MeO
NHCHO
NHCHO
NHCHO
NHCHO
O
O
O
O
O
O
O2N
Br
MeO
MeO
O
O
3e (70%)
Br
3f (86%)
3g (65%)
3h (85%)
NHCHO
NHCHO
NHCHO
O
MeO
O
O
O
O
O
O
O
NHCHO
Br
MeO
MeO
MeO
3j (76%)
MeO
3i (70%)
3k (45%)
3l (62%)
Scheme 2 Synthesis of 3-(formylamino)isobenzofuran-1(3H)-ones from phthalaldehydic acids
ing 4a with neat formamide at 80 °C. The structure was
freshly distilled triethylamine and phosphoryl chloride in
anhydrous tetrahydrofuran at –78 °C and careful workup
furnished the desired 3-isocyanoisobenzofuran-1(3H)-one
(2a) in 65% yield (Scheme 3). The band at 2163 cm–1 in the
IR spectrum clearly indicated the presence of isocyano
group in the compound.
Isocyanide 2a was further characterized chemically by
its reaction with cinnamic acid. As expected,14 it furnished
3-[formyl(3-phenylprop-2-enoyl)amino]isobenzofuran-1(3H)-
one (5) (Scheme 4).
Following the conditions optimized for 2a, 3-isocyano-
isobenzofuran-1(3H)-ones 2a–k were successfully pre-
pared (Scheme 3). For the substrates with methoxy substit-
uents 2b,d,e,g,h, yields of the transformations are greater
than those for substrates containing bromine 2f,i. Surpris-
confirmed by X-ray crystallographic analysis (see the Sup-
1
porting Information). Both H and 13C NMR spectra of 3a
displayed complex splitting pattern due to the presence of
two inseparable cis and trans rotamers in a 1:2 ratio (see
the Supporting Information for analysis of the spectra). Two
sharp IR bands near 1684 and 1763 cm–1 respectively corre-
spond to CHO group and γ-lactone ring. Following the opti-
mized conditions, twelve 3-(formylamino)isobenzofuran-
1(3H)-ones 3a–l were prepared (Scheme 2) from phthalal-
dehydic acids 4 in 45–90% yields. All the synthesized 3-
(formylamino)isobenzofuran-1(3H)-ones have similar NMR
patterns for formylamino units as that of the parent com-
pound 3a.
Having established of the synthesis of the 3-(formylami-
no)isobenzofuran-1(3H)-ones 3, we undertook their con-
version into the proposed isocyanides 2. Exploratory stud-
ies with the parent 3-(formylamino)isobenzofuran-1(3H)-
one (3a) involved a number of dehydrating agents [ i.e.,
POCl3, Py;8 CBr4, Ph3P, Et3N; Cl3COCO2CCl3, Et3N;9 POCl3,
i-Pr2NH;10 PhOPOCl2, Et3N;11 TMSCN, MsOH, Et3N; Burgess
reagent;12 Tf2O, Et3N13]. Among the reagents examined, the
Burgess reagent and triflic anhydride/triethylamine provid-
ed 2a (X = H), but in very low yields; in all other cases, in-
tractable mixtures were obtained. However, the use of
ingly,
3-(formylamino)-6-nitroisobenzofuran-1(3H)-one
(3f) could not be converted into its isocyanide under these
conditions. Perhaps, nitro group induced increased acidity
of C3–H of the isocyanide thus resulting in its dimerization
or polymerization. This explanation seems to be in line
with observations that the halogenated 3-isocyanoisoben-
zofuran-1(3H)-ones 2f and 2i are relatively unstable. These
halogenated 3-isocyanoisobenzofuran-1(3H)-ones substan-
tially polymerize at room temperature on standing for a
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Synthesis
NC
O
NHCHO
POCl3, Et3N, THF
–78 °C
X
O
O
X
35–70%
O
3
2
NC
MeO
NC
NC
O
NC
O
MeO2C
MeO
O
O
O
O
MeO
O
O
2a (65%)
2b (60%)
2c (64%)
2d (70%)
NC
O
NC
O
MeO
NC
NC
O
O
MeO
Br
MeO
O
O
MeO
MeO
O
O
2e (66%)
2f (40%)
2g (60%)
2h (65%)
Br
NC
NC
O
O
MeO
O
O
NC
Br
O
O
MeO
MeO
2j (35%)
2i (42%)
2k (60%)
Scheme 3 3-Isocyanoisobenzofuran-1(3H)-ones from 3-(formylamino)isobenzofuran-1(3H)-ones
long time (~7 d), whereas sterically crowded 3-isocyano-4-
methoxyisobenzofuran-1(3H)-one is highly stable at room
temperature.
nized several bases (Table 1) for improvement of the yields.
Among the bases examined lithium tert-butoxide and sodi-
um hydride were found to be quite attractive.
Ph
Table 1 Scrutiny of Bases and Solvents in the Annulation Reaction of
3-Isocyanoisobenzofuran-1(3H)-one (2a) and Methyl Acrylate
OHC
NC
O
toluene, N2
reflux, 3 h
N
COOH
O
Entry
Conditions
Yield (%)
O
55%
1
2
3
4
5
6
7
8
LiOt-Bu, THF, –78 °C to r.t., 8 h
LiOt-Bu, LiCl, –78 °C to r.t., 6–7 h
KOt-Bu, DMSO, r.t., 30 min
KOt-Bu, THF, –78 °C to r.t., 8 h
NaH, THF, –78 °C to r.t., 8 h
DBU, MeCN, 0 °C to r.t., 7 h
LDA, THF, –78 °C to r.t., 7 h
LiHMDS, THF, –78 °C to r.t., 7 h
46
O
36
O
5
2a
Scheme 4 Reaction of 2a with cinnamic acid
mixture
35
38
Next, we explored the reactivity of the 3-isocyanoiso-
benzofuran-1(3H)-ones towards the Hauser annulation.
Since the 3-isocyanoisobenzofuran-1(3H)-ones are suscep-
tible to polymerization at room temperature, they were not
used as limiting reagents in the annulation; they were used
in excess, but at the end of the reaction no starting material
recovered. The parent 3-isocyanoisobenzofuran-1(3H)-one
(2a) first reacted with methyl acrylate in the presence of
lithium tert-butoxide in tetrahydrofuran at –78 °C; the ex-
pected product, methyl 1,4-dihydroxynaphthalene-2-car-
boxylate (6)15 was obtained in 31% yield. We briefly scruti-
polymer
polymer
polymer
Substrate variation resulted in seven annulation prod-
ucts with moderate yields (Table 2). Annulation of 2a with
methyl crotonate similarly provided the corresponding ae-
rial oxidized product 716 in 36% yield (Scheme 5). The
deprotonated isocyanide A undergoes Michael addition fol-
lowed by Dieckmann cyclization to give B which collapses
to diketone C. Proton abstraction via base of C resulted in
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2473–2484

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Synthesis
aromatized product D which on aerial oxidation furnished
compound 7. In case of cyclohexenone as the acceptor, ex-
pected product 8,16 contaminated with its dehydrogenated
form, was isolated. With cyclohexadienone 9, the yield of
the annulation product 1017 was 23%. Expectedly, the prod-
uct 1118 was obtained from 1,4-naphthoquinone in 35%
yield. Hauser annulation reaction of 2a with naphthalenone
Table 2 Annulation Reactions with 3-Isocyanoisobenzofuran-1(3H)-one (2a) or 3-Cyanoisobenzofuran-1(3H)-one (1a)
Entry
Acceptor
Product
Yield (%)
From 2a
From 1ab
OH
1
31
36
68
CO2Me
CO2Me
OH
O
615
2
3
4
5
73
75
88
58
CO2Me
CO2Me
O
716
OH
46
23
35
O
OH
O
O
816
OMe
O
O
O
OH
OH
1017
9
O
OH
OH
O
O
OH
OH
OH
O
1118
97b
OMe
6
7
56
48
O
O
O
1319
12
14
88b
OH
O
O
O
1519
a Refers to isolated yields.
b From cited reference.
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Synthesis
Ot-Bu
O
CN
NC
O
O
H
H
– LiNC
CO2Me
CO2Me
CO2Me
O
O
O
A
B
C
O
O
OH
OH
[O]
CO2Me
CO2Me
D
7
Scheme 5 Mechanism of annulation of isocyanide 2a with methyl crotonate
12 and spiro[naphthalene-1(2H),2′-oxiran]-2-one 14 pro-
duced angucycline (13)19 and 5-(hydroxymethyl)angucy-
cline (15)19 in 56 and 48% yields, respectively.
at 150 °C; we attempted flash vacuum pyrolysis (FVP) of 2a
without success. We then examined Lewis acid catalyzed
rearrangements following the studies of glycosyl isocya-
nides. Different Lewis acids15 [e.g., ZnI2, Cu(OAc)2, AlCl3,
FeCl3, TMSOTf, TBDMSCl, PdCl2] and bases [e.g., DBU,
Ag2CO3] in various solvents were used for the rearrange-
ment of 2a, but all these attempts were unsuccessful in pro-
ducing the desired 3-cyanoisobenzofuran-1(3H)-one (1a).
Finally, reaction with 2,6-lutidine followed by triflic anhy-
dride at 0 °C gave 3-cyanoisobenzofuran-1(3H)-one (1a) in
very good yield (Scheme 6).
It appears from Tables 1 and 2 and earlier studies20 that
further improvement in the efficiency of the annulations
can be made by rigorous examination of the base and reac-
tion conditions.
To complement the efficiency of 3-isocyanoisobenzofu-
ran-1(3H)-ones 2 as Hauser donors, we thought of their re-
arrangement to 3-cyanoisobenzofuran-1(3H)-ones 1, al-
ready proven for their efficacy. Isomerization of organic iso-
cyanides to their cyanides is generally conducted by
thermal processes or metal salt catalyzed reactions.21 Ther-
mogravimetric analysis (TGA) of the parent 3-isocyanoiso-
benzofuran-1(3H)-one (2a) showed an endothermic peak
The reaction was also carried out with combinations of
several bases (pyridine, 2,6-lutidine, 2,4,6-collidine, Et3N)
with different acid anhydrides (TFAA, Tf2O). While 2,6-luti-
dine with trifluoroacetic anhydride resulted in 1a in trace
2,6-lutidine
NC
CN
Tf2O, CH2Cl2
0 °C
X
O
X
O
62–76%
O
O
2
1
MeO
CN
O
MeO
CN
O
CN
O
CN
O
MeO
O
O
O
MeO
O
1d (72%)
1a (76%)
1b (80%)
1c (65%)
CN
O
CN
O
CN
O
MeO2C
O
O
CN
MeO
O
O
O
MeO
MeO
MeO
1h (62%)
1e (62%)
1f (68%)
1g (72%)
Scheme 6 Rearrangement of 3-isocyanoisobenzofuran-1(3H)-ones to 3-cyanoisobenzofuran-1(3H)-ones
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2473–2484

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D. Mal et al.
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Synthesis
amounts, 2,4,6-collidine with triflic anhydride gave 1a in
35% yield. However, 2,6-lutidine a better base giving 1a in
76% yield (Table 3). The reaction was also carried out with
trifluoroacetic anhydride and 2,6-lutidine, but 1a was ob-
tained in trace amounts only.
1(3H)-one 1 (Scheme 7). The failure of the isomerization of
4-toluenesulfonylmethyl isocyanide, tert-butyl isocyanide,
or ethyl isocyanoacetate indirectly supports the mecha-
nism. The initial loss of the isocyanide from the substrates
to form the corresponding carbenium (cf. 17) is not pro-
moted by any group/atom.
In conclusion, the 3-isocyanoisobenzofuran-1(3H)-ones
were prepared in two simple steps from phthalaldehydic
acids. The 3-isocyanoisobenzofuran-1(3H)-ones can be re-
arranged to the established 3-cyanoisobenzofuran-1(3H)-
ones using triflic anhydride and 2,6-lutidine. This prepara-
tion of 3-cyanoisobenzofuran-1(3H)-ones is free from the
use of toxic cyanides. Moreover, the 3-isocyanoisobenzofu-
ran-1(3H)-ones undergo Hauser annulation with Michael
acceptors in low yields. Their efficacy in the annulation has
been compared with those of established 3-cyanoisobenzo-
furan-1(3H)-ones.
Table 3 Scrutiny of Bases and Solvents in the Rearrangement of 3-Iso-
cyanoisobenzofuran-1(3H)-one (2a) to 3-Cyanoisobenzofuran-1(3H)-
one (1a)
Entry
Conditions
Yield(%)
1
2
3
4
5
6
Et3N, TFAA, 0 °C, 10 h
0
0
Et3N, Tf2O, 0 °C, 10 h
pyridine, Tf2O, 0 °C, 10 h
2,6-lutidine, TFAA, 0 °C
2,6-lutidine, Tf2O, 0 °C, 6 h
2,4,6-collidine, Tf2O, 0 °C, 10 h
0
trace
76
35
Melting points are uncorrected. IR spectra were recorded on a Ther-
mo Nicolet Nexus 870 FT-IR spectrophotometer using KBr pellets.
Only the characteristic, strong and medium IR bands are presented.
1H and 13C NMR spectra of the samples in the indicated solvents were
recorded on a 200 MHz or 400 MHz spectrometer (Bruker) with re-
sidual CHCl3 and DMSO-d6 as the internal standard. Mass spectra
were taken using a VG Autospec M mass spectrometer. Dry solvents
used for reactions were purified, before use, according to standard
protocols. All solvents for chromatography were distilled prior to use.
Columns were prepared with silica gel (60–120 or 230–400 mesh).
Under the optimized conditions, 3-isocyanoisobenzofu-
ran-1(3H)-ones 2a,c–e,g,h,j,k underwent smooth rear-
rangement to 3-cyanoisobenzofuran-1(3H)-ones 1a–
h
5c,22,29 (Scheme 6). To further extend the scope of the reac-
tion and gain insight into the mechanism, we examined the
reactivity of isocyanides, such as 4-toluenesulfonylmethyl
isocyanide (TosMIC), tert-butyl isocyanide, ethyl isocyano-
acetate, and phenyl isocyanide, under these conditions. In-
terestingly, these isocyanides resisted rearrangement to
their corresponding cyano derivatives. In some cases, in-
tractable mixtures of products were obtained.
The mechanism of this isomerization can be explained
as follows. Triflic anhydride reacts first with 3-isocyanoiso-
benzofuran-1(3H)-one 2 to produce activated nitrenium
ion 16, which then fragments into oxacarbenium ion 17
and triflyl cyanide (18). Cyanide ion, generated from triflyl
cyanide by the reaction with 2,6-lutidine, then attacks the
oxacarbenium ion 17 to furnish 3-cyanoisobenzofuran-
Annulation Reaction 6–8,10,11,13,15; General Procedure
To a stirred solution of LiOt-Bu (3.20 mmol) in THF (10 mL) at –78 °C
(CHCl3–liq N2 bath) under an inert atmosphere was added a solution
of isocyanophthalide (1.0 mmol) in THF (5 mL). The resulting yellow-
ish solution was stirred at –78 °C for 25 min, after which a solution of
a Michael acceptor (1.0–1.5 equiv unless otherwise stated) in THF (5
mL) was added. The cooling bath was removed after ca. 1 h at –78 °C
and the mixture was brought to r.t. over a period of 1 h and stirred for
a further 2–6 h. The reaction was then quenched with 10% aq NH4Cl
(15 mL) and the resulting solution was concentrated. The residue was
C
C
SO2CF3
CF3SO3
N
N
(CF3SO2)2O
i)
X
O
O
O
X
X
+
N
C
SO2CF3
18
CF3SO3
O
O
O
2
16
17
CN
O
N
• •
X
CN
ii)
+
N
C
SO2CF3
N
18
O
O
X
SO2CF3
1
CF3SO3
O
17
Scheme 7 Proposed mechanism for the isomerization of isocyanides to cyanides
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2473–2484

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D. Mal et al.
Paper
Synthesis
diluted with EtOAc (50 mL) and the layers were separated. The aque-
ous layer was extracted with EtOAc (3 × 25 mL). The combined ex-
tracts were washed with H2O (15 mL) and brine (15 mL), dried (anhyd
Na2SO4), and concentrated under reduced pressure. The crude prod-
uct was purified by column chromatography (silica gel) or by recrys-
tallization to obtain the pure product.
1-Oxo-1,3-dihydronaphtho[1,2-c]furan-3-carbonitrile (1g)
Following the general procedure using 2k (100 mg, 0.48 mmol),
CH2Cl2 (15 mL), and 2,6-lutidine (0.11 mL, 0.96 mmol); 0 °C, 15 min,
followed by Tf2O (0.15 mL, 0.96 mmol). Workup as for 1e with purifi-
cation by column chromatography gave 1g (72 mg, 72%) as a white
solid; mp 123–125 °C.
1H NMR (400 MHz, CDCl3): δ = 8.94 (d, J = 8.4 Hz, 1 H), 8.31 (d, J = 8.4
Hz, 1 H), 8.05 (d, J = 8.4 Hz, 1 H), 7.81 (t, J = 7.4 Hz, 1 H), 7.75 (t, J = 7.6
Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 6.16 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 168.0, 143.4, 137.5, 134.5, 130.3,
129.1, 129.0, 128.9, 123.7, 119.6, 118.3, 114.0, 65.6.
3-(Formylamino)isobenzofuran-1(3H)-ones 3a–l; General Proce-
dure
A stirred solution of a phthalaldehydic acid 4 (6.00 mmol) dissolved
in neat formamide (3 mL/mmol) was heated for 4 h (unless otherwise
stated) at 80–100 °C with an argon balloon fitted with a condenser.
The reaction was monitored by TLC. When the reaction was complete,
the mixture was extracted with EtOAc (3 × 40 mL) and the combined
organic extracts were washed with brine (6 × 20 mL) and dried
(Na2SO4). Removal of the solvent gave a residue that was purified by
column chromatography (60–120 mesh size, CH2Cl2–MeOH, 95:5) or
by recrystallization (MeOH).
HRMS (ES+): m/z [M + H]+ calcd for C13H8NO2: 210.0556; found:
210.0559.
3-Isocyanoisobenzofuran-1(3H)-one (2a)
Following the general procedure using 3a (500 mg, 2.8 mmol), THF
(20 mL), and Et3N (1.2 mL, 8.4 mmol) then POCl3 (0.35 mL, 3.6 mmol).
Purification by column chromatography gave 2a (290 mg, 65%) as a
yellow solid; mp 60–62 °C.
3-Isocyanoisobenzofuran-1(3H)-ones 2a–k; General Procedure
To a stirred solution of 3-(formylamino)isobenzofuran-1(3H)-one 3,
dissolved in dry THF (8 mL/mmol) was added freshly distilled Et3N (5
equiv) at –78 °C and the mixture was stirred for 10 min. Then freshly
distilled POCl3 (1.3 equiv) was added to the mixture at –78 °C and the
mixture was maintained this temperature for a further 0.5 h and then
allowed to reach r.t. and stirred for 1.5 h (TLC monitoring). When the
starting material had been consumed, the mixture was quenched
with aq NaHCO3. Solvent was evaporated under reduced pressure, the
residue was extracted with Et2O (3 × 30 mL), and the combined ex-
tracts were washed with H2O (2 × 20 mL) and brine. After removal of
Et2O, the resulting residue was purified by column chromatography.
IR (KBr): 2163, 1792, 1723, 1561, 1465, 1054, 1011, 747 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.94 (d, J = 7.2 Hz, 1 H), 7.86 (t, J = 7.4
Hz, 1 H), 7.63–7.45 (m, 2 H), 6.53 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 166.7, 164.9, 142.7, 135.7, 131.9,
126.2, 124.7, 122.9, 78.3.
HRMS (ES+): m/z [M + H]+ calcd for C9H6NO2: 160.0399; found:
160.0401.
3-Isocyano-5-methoxyisobenzofuran-1(3H)-one (2b)
Following the general procedure using 3b (300 mg, 1.45 mmol), THF
(15 mL), Et3N (0.6 mL, 4.35 mmol), and POCl3 (0.2 mL, 1.88 mmol). Pu-
rification by column chromatography gave 2b (165 mg, 60%) as a yel-
low solid; mp 63–65 °C.
3-Cyanoisobenzofuran-1(3H)-ones 1a–h; General Procedure
To a stirred solution of 3-isocyanoisobenzofuran-1(3H)-one 2 dis-
solved in dry CH2Cl2 (10 L/mol) at 0 °C was added 2,6-lutidine (2
equiv) and the mixture was stirred for 20 min at 0 °C. Tf2O (2 equiv)
was added then dropwise at this temperature. The resulting mixture
was stirred for 6 h at r.t. The reaction was quenched with 1 M HCl and
extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts
were washed with H2O (20 mL) and brine (20 mL). Purification was
performed by column chromatography or by preparative TLC.
IR (KBr): 2322, 1724, 1621, 1435, 1285, 1140, 750 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.84 (d, J = 8.8 Hz, 1 H), 7.18 (dd, J = 2,
8.4 Hz, 1 H), 7.12 (d, J = 2 Hz, 1 H), 6.42 (s, 1 H), 3.96 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.6, 166.1, 165.1, 145.9, 128.0,
119.4, 116.9, 107.0, 77.9, 56.5.
HRMS (ES+): m/z [M + H]+ calcd for C10H8NO3: 190.0505; found:
190.0510.
4,5-Dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-carbonitrile
(1e)
Methyl 3-Isocyano-7-methoxy-1-oxo-1,3-dihydroisobenzofuran-
5-carboxylate (2c)
Following the general procedure using 2h (100 mg, 0.45 mmol),
CH2Cl2 (15 mL), and 2,6-lutidine (0.10 mL, 0.91 mmol); 0 °C, 15 min,
followed by Tf2O (0.14 mL, 0.91 mmol). Work up used 1 M HCl (1 × 10
mL), and the CH2Cl2 extracts were washed with H2O (3 × 10 mL) and
brine (1 × 10 mL). Removal of CH2Cl2 under reduced pressure gave a
residue that was purified by column chromatography to give 1e (62
mg, 62%) as a white solid; mp 120–122 °C.
1H NMR (200 MHz, CDCl3): δ = 7.30 (d, J = 3.6 Hz, 2 H), 5.96 (s, 1 H),
4.13 (s, 3 H), 3.95 (s, 3 H).
13C NMR (50 MHz, CDCl3): δ = 165.1, 164.5, 148.8, 135.1, 120.1, 117.7,
116.5, 113.2, 64.0, 62.7, 57.0.
Following the general procedure using 3c (356 mg, 1.34 mmol), THF
(15 mL), Et3N (0.6 mL, 4.03 mmol), and POCl3 (0.16 mL, 1.74 mmol).
Purification by column chromatography gave 2c (212 mg, 64%) as a
yellow solid; mp 72–74 °C.
IR (KBr): 2320, 1758, 1718, 1612, 1440, 1336, 1244, 1106, 1051, 769
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.89 (s, 1 H), 7.77 (s, 1 H), 6.48 (s, 1 H),
4.09 (s, 3 H), 4.01 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 165.4, 164.7, 163.8, 158.5, 145.1,
139.1, 115.3, 115.1, 114.7, 77.5, 56.7, 53.1.
HRMS (ES+): m/z [M + H]+ calcd for C12H10NO5: 248.0559; found:
248.0562.
HRMS (ES+): m/z [M + H]+ calcd for C11H10NO4: 220.0611; found:
220.0615.
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Synthesis
3-Isocyano-4-methoxyisobenzofuran-1(3H)-one (2d)
3-Isocyano-6,7-dimethoxyisobenzofuran-1(3H)-one (2h)
Following the general procedure using 3d (400 mg, 1.93 mmol), THF
(17 mL), Et3N (0.8 mL, 5.7 mmol), and POCl3 (0.24 mL, 2.5 mmol). Pu-
rification by column chromatography gave 2d (255 mg, 70%) as a yel-
low solid; mp 81–83 °C.
Following the general procedure using 3j (600 mg, 2.23 mmol), THF
(10 mL), Et3N (0.99 mL, 7.1 mmol), and POCl3 (0.28 mL, 2.89 mmol).
Purification by column chromatography gave 2h (150 mg, 65%) as a
yellow solid; mp 63–65 °C.
IR (KBr): 2356, 1723, 1576, 1445, 1060, 101121, 740 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.35 (s, 2 H), 6.39 (s, 1 H), 4.01 (s, 3 H),
3.93 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.65 (t, J = 7.8 Hz, 1 H), 7.48 (d, J = 7.4
Hz, 1 H), 7.24 (d, J = 8 Hz, 1 H), 6.44 (s, 1 H), 3.99 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.5, 154.6, 148.8, 135.1, 120.0,
117.3, 116.5, 77.4, 62.7, 57.6.
HRMS (ES+): m/z [M + H]+ calcd for C11H10NO4: 220.0611; found:
13C NMR (100 MHz, CDCl3): δ = 166.7, 164.2, 154.8, 133.8, 129.8,
126.4, 117.4, 116.8, 76.9, 56.1.
220.0615.
HRMS (ES+): m/z [M + H]+ calcd for C10H8NO3: 190.0505; found:
190.0509.
4,6-Dibromo-3-isocyano-5,7-dimethoxyisobenzofuran-1(3H)-one
(2i)
3-Isocyano-7-methoxyisobenzofuran-1(3H)-one (2e)
Following the general procedure using 3i (350 mg, 0.9 mmol), THF
(10 mL), Et3N (0.37 mL, 2.7 mmol), and POCl3 (0.11 mL, 1.17 mmol).
Purification by column chromatography gave 2i (135 mg, 42%) as a
yellow solid; mp 63–65 °C.
Following the general procedure using 3e (450 mg, 2.17 mmol), THF
(15 mL), Et3N (0.9 mL, 6.5 mmol), and POCl3 (0.3 mL, 2.8 mmol). Puri-
fication by column chromatography gave 2e (270 mg, 66%) as a yellow
solid; mp 70–72 °C.
IR (KBr): 2300, 1727, 1610, 1452, 1292, 1189, 756, 556 cm–1
.
IR (KBr): 2320, 1726, 1619, 1452, 1292, 1140, 756 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.27 (s, 1 H), 4.17 (s, 3 H), 4.02 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.7, 162.7, 162.0, 157.5, 142.9,
1H NMR (400 MHz, CDCl3): δ = 7.76 (t, J = 8 Hz, 1 H), 7.23 (d, J = 7.6 Hz,
1 H), 7.09 (d, J = 8.4 Hz, 1 H), 6.42 (s, 1 H), 4.01 (s, 3 H).
139.3, 118.2, 114.1, 77.8, 63.4, 61.3.
HRMS (ES+): m/z [M + H]+ calcd for C11H8Br2NO4: 375.8821; found:
13C NMR (100 MHz, CDCl3): δ = 165.0, 164.8, 159.0, 145.4, 138.2,
114.3, 113.8, 112.2, 77.5, 56.6.
375.8824, 375.8827, 377.8806.
HRMS (ES+): m/z [M + H]+ calcd for C10H8NO3: 190.0505; found:
190.0510.
1-Isocyano-4-methoxy-6,7,8,9-tetrahydronaphtho[1,2-c]furan-
3(1H)-one (2j)
6-Bromo-3-isocyanoisobenzofuran-1(3H)-one (2f)
Following the general procedure using 3k (450 mg, 1.7 mmol), THF
(15 mL), Et3N (0.72 mL, 5.1 mmol), and POCl3 (0.21 mL, 2.21 mmol)
with workup as for 2h. Purification by column chromatography gave
pure 2j (146 mg, 35%) as a yellow solid; mp 65–67 °C.
Following the general procedure using 3g (250 mg, 0.9 mmol), THF
(10 mL), Et3N (0.4 mL, 2.9 mmol), and POCl3 (0.11 mL, 1.17 mmol). Pu-
rification by column chromatography gave 2f (93 mg, 40%) as a yellow
solid; mp 63–65 °C.
IR (KBr): 2322, 1717, 1621, 1522, 1435, 1332, 1300, 1285, 1140, 750
IR (KBr): 2326, 1710, 1655, 1529, 1435, 1386, 1300, 1278, 1143, 708
cm–1
.
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.27 (s, 1 H), 6.79 (s, 1 H), 3.95 (s, 3 H),
2.91–2.87 (m, 4 H), 2.04–1.79 (s, 4 H).
13C NMR (100 MHz, CDCl3): δ = 165.9, 156.5, 154.0, 148.7, 142.1,
123.9, 113.8, 109.3, 77.65, 56.14, 30.46, 24.22, 22.19, 22.07.
HRMS (ES+): m/z [M + H]+ calcd for C14H14NO3: 244.0974; found:
244.0980.
1H NMR (400 MHz, CDCl3): δ = 6.52 (s, 1 H), 7.65 (d, J = 8.2 Hz, 1 H),
8.00 (d, J = 8.2 Hz, 1 H), 8.13 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 169.6, 154.7, 145.3, 137.2, 128.7,
127.8, 123.9, 123.1, 77.8.
HRMS (ES+): m/z [M + H]+ calcd for C9H5BrNO2: 237.9504; found:
237.9508 and 239.9488.
3-Isocyanonaphtho[1,2-c]furan-1(3H)-one (2k)
3-Isocyano-4,6-dimethoxyisobenzofuran-1(3H)-one (2g)
Following the general procedure using 3l (550 mg, 2.41 mmol), THF
(15 mL), Et3N (1.01 mL, 7.26 mmol), and POCl3 (0.3 mL, 2.21 mmol)
with workup as for 2h. Purification by column chromatography gave
2k (300 mg, 60%) as a yellow solid; mp 63–65 °C.
Following the general procedure using 3h (500 mg, 2.1 mmol), THF
(15 mL), Et3N (0.88 mL, 6.3 mmol), and POCl3 (0.26 mL, 2.73 mmol).
Purification by column chromatography gave 2g (278 mg, 60%) as a
yellow solid; mp 72–74 °C.
IR (KBr): 2322, 1717, 1621, 1522, 1435, 1332, 1300, 1285, 1140, 750
IR (KBr): 2360, 1785, 1720, 1561, 1535, 1455, 1050, 865, 747 cm–1
1H NMR (400 MHz, CDCl3): δ = 6.92 (d, J = 2 Hz, 1 H), 6.75 (d, J = 1.8
Hz, 1 H), 6.38 (s, 1 H), 3.95 (s, 3 H), 3.88 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 167.2, 164.9, 164.1, 155.7, 127.7,
123.4, 106.1, 99.6, 77.2, 56.4, 56.3.
HRMS (ES+): m/z [M + H]+ calcd for C11H10NO4: 220.0611; found:
220.0617.
.
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.89 (d, J = 8.4 Hz, 1 H), 8.28 (d, J = 8.4
Hz, 1 H), 8.02 (d, J = 8.4 Hz, 1 H), 7.80–7.69 (m, 3 H), 6.57 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 167.1, 165.4, 144.1, 137.5, 134.7,
130.2, 129.0, 128.9, 128.7, 123.9, 119.9, 118.4, 78.2.
HRMS (ES+): m/z [M + H]+ calcd for C13H8NO2: 210.0556; found:
210.0562.
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Synthesis
N-(3-Oxo-1,3-dihydroisobenzofuran-1-yl)formamide (3a)
N-(7-Methoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)formamide
(3d)
Following the general procedure using 4a (1 g, 6.7 mmol) and form-
amide (10 mL) at 80 °C for 3 h. Workup used EtOAc (3 × 60 mL), H2O (3
× 20 mL), and brine (20 mL) to give 3a (1.06 g, 90%) as a white solid;
mp 112–115 °C.
Following the general procedure using 3-hydroxy-4-methoxyisoben-
zofuran-1(3H)-one25 (600 mg, 3.33 mmol) and formamide (10 mL) at
100 °C for 3 h. Workup used EtOAc (3 × 60 mL), H2O (3 × 20 mL), and
brine (20 mL) followed by column chromatography to give 3d (605
mg, 88%) as a white solid; mp 132–134 °C.
IR (KBr): 1763, 1684, 1515, 1394, 1063 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ (mixture of rotamers) = 9.37 (d, J =
9.2 Hz, 2 H, trans), 9.03 (t, J = 10.4 Hz, 1 H, cis), 8.47 (d, J = 10.4 Hz, 1
H, cis), 8.28 (s, 2 H, trans), 7.87–7.65 (m, 6 H, cis + trans), 7.105 (d, J =
9.6 Hz, 1 H, trans), 6.97 (d, J = 10.0 Hz, 1 H, cis).
13C NMR (100 MHz, DMSO-d6): δ = 169.1, 165.9, 162.8, 146.4, 145.9,
135.3, 135.2, 131.1, 130.9, 126.9, 126.8, 125.2, 125.2, 124.3, 124.0,
85.2, 79.5.
IR (KBr): 3312, 2908, 2857, 1560, 1442, 1233, 710 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ (mixture of rotamers) = 8.89 (d, J =
9.2 Hz, 2 H, trans), 8.65 (d, J = 8.8 Hz, 2 H, cis), 8.29–8.25 (m, 3 H, cis +
trans), 8.13 (s, 2 H, trans), 7.50 (t, J = 8 Hz, 3 H, cis + trans), 7.23 (d, J =
8 Hz, 6 H, cis + trans), 6.39 (d, J = 9.2 Hz, 2 H, trans), 6.10 (d, J = 8 Hz, 1
H, cis), 3.84 (s, 6 H, cis + trans).
13C NMR (100 MHz, DMSO-d6): δ = 168.9, 163.5, 160.6, 155.0, 133.5,
133.0, 131.7, 128.9, 117.4, 117.3, 116.2, 115.9, 81.9, 85.9, 85.8.
HRMS (ES+): m/z [M + H]+ calcd for C9H8NO3: 178.0505; found:
178.0509.
HRMS (ES+): m/z [M + H]+ calcd for C10H10NO4: 208.0611; found:
208.0620.
N-(6-Methoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)formamide
(3b)
N-(4-Methoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)formamide
(3e)
Following the general procedure using 3-hydroxy-5-methoxyisoben-
zofuran-1(3H)-one23 (500 mg, 2.78 mmol) and formamide (10 mL) at
80 °C for 4 h. Workup used EtOAc (3 × 60 mL), H2O (3 × 20 mL), and
brine (20 mL) followed by column chromatography to give 3b (460
mg, 80%) as a white solid; mp 102–104 °C.
Following the general procedure using 3-hydroxy-7-methoxyisoben-
zofuran-1(3H)-one (500 mg, 2.77 mmol) and formamide (10 mL) at
100 °C for 12 h. Workup used EtOAc (3 × 60 mL), H2O (3 × 20 mL), and
brine (20 mL) followed by column chromatography to give 3e (400
mg, 70%) as a white solid; mp 126–128 °C.
IR (KBr): 3312, 2908, 2857, 1560, 1442, 1233, 713 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ (mixture of rotamers) = 9.34 (d, J =
9.2 Hz, 2 H, trans), 8.99 (t, J = 10.8 Hz, 1 H, cis), 8.44 (t, J = 10.8 Hz, 1 H,
cis), 8.27 (s, 2 H, trans), 7.76 (d, J = 9.6 Hz, 3 H, cis + trans), 7.23–7.14
(m, 5 H, cis + trans), 7.00 (d, J = 9.6 Hz, 2 H, trans), 6.86 (d, J = 10.4 Hz,
1 H, cis), 3.87 (s, 6 H, cis + trans).
13C NMR (100 MHz, DMSO-d6): δ = 165.7, 165.0, 162.6, 149.2, 126.8,
126.7, 118.9, 118.4, 118.3, 108.1, 107.9, 84.3, 78.5, 86.6.
IR (KBr): 3312, 2908, 2857, 1560, 1442, 1233, 710 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ (mixture of rotamers) = 9.31 (d, J =
9.2 Hz, 2 H, trans), 8.98 (d, J = 8.8 Hz, 2 H, cis), 8.45 (d, J = 10.8 Hz, 1 H,
cis), 8.29 (s, 2 H, trans), 7.78 (t, J = 8 Hz, 3 H, cis + trans), 7.26–7.12 (m,
6 H, cis + trans), 6.95 (d, J = 9.2 Hz, 2 H, trans), 6.85 (d, J = 8 Hz, 1 H,
cis), 3.95 (s, 6 H, cis + trans).
13C NMR (100 MHz, DMSO-d6): δ = 166.5, 165.7, 162.6, 158.2, 148.9,
137.5, 115.6, 115.3, 113.8, 113.3, 83.6, 77.9, 56.4.
HRMS (ES+): m/z [M + H]+ calcd for C10H10NO4: 208.0611; found:
208.0618.
HRMS (ES+): m/z [M + H]+ calcd for C10H10NO4: 208.0611; found:
208.0620.
Methyl 3-(Formylamino)-7-methoxy-1-oxo-1,3-dihydroisobenzo-
furan-5-carboxylate (3c)
N-(5-Nitro-3-oxo-1,3-dihydroisobenzofuran-1-yl)formamide (3f)
Following the general procedure using methyl 3-hydroxy-7-methoxy-
1-oxo-1,3-dihydroisobenzofuran-5-carboxylate24 (500 mg, 2.10
mmol) and formamide (10 mL) at 100 °C for 6 h. Workup used EtOAc
(3 × 60 mL), H2O (3 × 20 mL), and brine (20 mL) followed by column
chromatography to give 3c (478 mg, 86%) as a yellowish solid; mp
133–135 °C.
Following the general procedure using 3-hydroxy-6-nitroisobenzofu-
ran-1(3H)-one26 (850 mg, 4.35 mmol) and formamide (15 mL) at 100
°C for 6 h. Workup used EtOAc (3 × 60 mL), H2O (3 × 20 mL), and brine
(20 mL) followed by column chromatography to give pure 3f (830 mg,
86%) as a white solid; mp 123–125 °C.
IR (KBr): 3312, 2908, 2857, 1560, 1442, 1233, 710.
IR (KBr): 3310, 2900, 2857, 1560, 1447, 1252, 708 cm–1
.
1
H NMR (400 MHz, DMSO-d6): δ (mixture of rotamers) = 9.33 (d, J =
1H NMR (400 MHz, DMSO-d6): δ (mixture of rotamers) = 9.45 (d, J =
9.2 Hz, 2 H, trans), 9.06 (t, J = 10.8 Hz, 1 H, cis), 8.64–8.59 (m, 3 H, cis
+ trans), 8.53–8.47 (m, 3 H, cis + trans), 8.30, 8.28 (2 × s, 3 H, cis +
trans), 8.00 (d, J = 8 Hz, 1 H, cis), 7.93 (d, J = 8.4 Hz, 2 H, trans), 7.18 (d,
J = 8.8 Hz, 2 H, trans), 7.12 (d, J = 10.4 Hz, 1 H, cis).
9.4 Hz, 2 H, trans), 8.95 (t, J = 10.6 Hz, 1 H, cis), 8.42 (d, J = 10.8 Hz, 2
H, cis), 8.21 (s, 2 H, trans), 7.72 (s, 1 H, cis + trans), 7.63 (d, J = 2.2 Hz, 5
H, cis + trans), 7.01 (d, J = 9 Hz, 2 H, trans), 6.89 (d, J = 10.0 Hz, 1 H,
cis), 3.99 (s, 3 H, cis + trans), 3.91 (s, 3 H, cis + trans).
13C NMR (100 MHz, DMSO-d6): δ = 169.1, 165.5, 164.0, 163.9, 162.5,
156.2, 156.1, 129.7, 126.1, 125.6, 105.8, 99.6, 83.7, 79.8, 78.0, 66.3,
56.8, 56.7.
13C NMR (100 MHz, DMSO-d6): δ = 179.8, 166.2, 165.9, 162.8, 151.9,
153.3, 149.8, 129.9, 129.8, 128.6, 128.6, 126.2, 125.7, 120.2, 120.2,
85.4, 79.9, 79.5.
HRMS (ES+): m/z [M + H]+ calcd for C12H12NO6: 266.0665; found:
HRMS (ES+): m/z [M + H]+ calcd for C9H7N2O5: 223.0356; found:
266.0669.
223.0360.
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Synthesis
N-(5-Bromo-3-oxo-1,3-dihydroisobenzofuran-1-yl)formamide
N-(4,5-Dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)form-
(3g)
amide (3j)
Following the general procedure using 6-bromo-3-hydroxyisobenzo-
furan-1(3H)-one27 (350 mg, 1.54 mmol) and formamide (7 mL) at 100
°C for 6 h. Workup used EtOAc (3 × 60 mL), H2O (3 × 20 mL), and brine
(20 mL) followed by column chromatography to give 3g (252 mg, 65%)
as a yellow solid; mp 88–90 °C.
Following the general procedure using opianic acid (1 g, 4.76 mmol)
and formamide (15 mL) at 120 °C for 6 h. Workup used EtOAc (3 × 60
mL), H2O (3 × 20 mL), and brine (20 mL) followed by column chroma-
tography to give 3j (855 mg, 76%) as a white solid; mp 152–154 °C.
IR (KBr): 3320, 2890, 2855, 1567, 1452, 1234, 710, 694 cm–1
.
IR (KBr): 3312, 2908, 2857, 1560, 1442, 1233, 708 cm–1
.
1H NMR (200 MHz, DMSO-d6): δ (mixture of rotamers) = 9.27 (d, J =
9.2 Hz, 2 H, trans), 8.92 (t, J = 10.8 Hz, 1 H, cis), 8.42 (d, J = 10.8 Hz, 1
H, cis), 8.26 (s, 2 H, trans), 7.49 (d, J = 8.4 Hz, 3 H, cis + trans), 7.28 (t, J
= 9.4 Hz, 3 H, cis + trans), 6.94 (d, J = 9.4 Hz, 2 H, trans), 6.78 (d, J = 10
Hz, 1 H, cis), 3.90 (s, 3 H, cis + trans), 3.86 (s, 3 H, cis + trans).
13C NMR (50 MHz, DMSO-d6): δ = 166.6, 166.3, 165.9, 162.8, 153.9,
153.8, 147.5, 147.4, 138.9, 138.6, 120.7, 119.4, 119.3, 119.1, 84.0, 79.8,
78.2, 62.2, 57.4.
1H NMR (400 MHz, DMSO-d6): δ (mixture of rotamers) = 9.32 (d, J =
9.2 Hz, 2 H, trans), 8.96–8.81 (m, 3 H, cis + trans), 8.46 (t, J = 9.2 Hz, 1
H, cis), 8.23, 8.21, 8.13 (3 × s, 2 H, cis + trans), 7.94 (s, 2 H, trans),
7.95–7.91 (m, 2 H, cis + trans), 7.63 (dd, J = 9.2 Hz, 8 Hz, 2 H, cis +
trans), 7.07–6.91 (m, 3 H, cis + trans).
13C NMR (100 MHz, DMSO-d6): δ = 167.7, 167.1, 165.9, 162.8, 146.9,
145.6, 138.0, 137.9, 131.5, 129.9, 129.6, 129.4, 129.4, 128.3, 127.9,
127.8, 126.7, 126.5, 126.2, 123.9, 85.3, 84.7, 79.7, 79.3.
HRMS (ES+): m/z [M + H]+ calcd for C11H12NO5: 238.0716; found:
238.0726.
HRMS (ES+): m/z [M + H]+ calcd for C9H7BrNO3: 255.9610; found:
255.9615.
N-(1-Oxo-1,3-dihydronaphtho[1,2-c]furan-3-yl)formamide (3l)
N-(5,7-Dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)form-
amide (3h)
Following the general procedure using 3-hydroxy-3H-naphtho[1,2-
c]furan-1-one (500 mg, 2.5 mmol) and formamide (8 mL) at 120 °C for
3 h; Workup used EtOAc (3 × 60 mL), H2O (3 × 20 mL), and brine (20
mL) followed by column chromatography to give 3l (350 mg, 62%) as a
light yellow solid; mp 126–128 °C.
Following the general procedure using 3-hydroxy-4,6-dimethoxyiso-
benzofuran-1(3H)-one28 (600 mg, 2.85 mmol) and formamide (10
mL) at 100 °C for 6 h. Workup used EtOAc (3 × 60 mL), H2O (3 × 20 mL),
and brine (20 mL) followed by column chromatography to give 3h
(580 mg, 85%) as a white solid; mp 132–133 °C.
IR: 3310, 2900, 2857, 1560, 1447, 1252, 725, 708 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ (mixture of rotamers) = 8.84–8.78
(m, 3 H, cis + trans), 8.39–8.31 (m, 3 H, cis + trans), 8.21–8.13 (m, 3 H,
cis + trans), 7.89 (t, J = 9.0 Hz, 2 H, trans), 7.79–7.67 (m, 2 H, cis +
trans), 6.82 (d, J = 10.8 Hz, 1 H, cis), 6.71 (d, J = 10.8 Hz, 2 H, trans),
6.55 (d, J = 10.8 Hz, 1 H, cis).
13C NMR (100 MHz, DMSO-d6): δ = 170.0, 169.7, 169.4, 149.7, 148.6,
147.9, 136.3, 136.2, 136.1, 134.3, 129.8, 129.7, 129.5, 128.7, 128.6,
128.6, 128.2, 128.1, 123.3, 122.3, 121.8, 121.3, 121.1, 121.0, 120.9,
98.0, 91.8, 89.1.
IR (KBr): 3320, 2890, 2855, 1567, 1452, 1234, 710, 694 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ (mixture of rotamers) = 9.24 (d, J =
9.2 Hz, 2 H, trans), 8.92 (t, J = 10.8 Hz, 1 H, cis), 8.42 (d, J = 10.8 Hz, 1
H, cis), 8.22 (s, 2 H, trans), 6.96–6.84 (m, 8 H, cis + trans), 3.84 (s, 6 H,
cis + trans).
13C NMR (100 MHz, DMSO-d6): δ = 169.1, 165.5, 164.0, 163.9, 162.5,
156.3, 156.2, 129.7, 126.1, 125.7, 105.9, 99.6, 83.8, 79.8, 78.0, 60.4,
56.8, 56.7.
HRMS (ES+): m/z [M + H]+ calcd for C11H12NO5: 238.0716; found:
HRMS (ES+): m/z [M + H]+ calcd for C13H10NO3: 228.0661; found:
238.0762.
228.0670.
N-(5,7-Dibromo-4,6-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-
1-yl)formamide (3i)
3-[Formyl(3-phenylprop-2-enoyl)amino]isobenzofuran-1(3H)-
one (5)29
Following the general procedure using 4,6-dibromo-3-hydroxy-5,7-
dimethoxyisobenzofuran-1(3H)-one (350 mg, 0.95 mmol) and forma-
mide (5 mL) at 100 °C for 4 h. Workup used EtOAc (3 × 60 mL), H2O (3
× 20 mL), and brine (20 mL) followed by column chromatography to
give 3i (265 mg, 70%) as a yellowish solid; mp 126–128 °C.
To a solution of 2a (30 mg, 0.19 mmol) dissolved in dry toluene (5 mL)
in a round-bottom flask fitted with a N2 balloon was added cinnamic
acid (14 mg, 0.09 mmol). The mixture was heated at 110 °C for 3 h.
After complete disappearance of 2a, toluene was removed under re-
duced pressure. The residue was extracted with EtOAc (3 × 10 mL),
and the combined organic extracts were washed with H2O (20 mL)
and brine (20 mL). The residue was purified by column chromatogra-
phy to provide 5 (31 mg, 55%) as a yellow oil.
1H NMR (200 MHz, CDCl3): δ = 9.25 (s, 1 H), 8.01–7.51 (m, 10 H), 6.81
(d, J = 15.2 Hz, 1 H), 6.52 (s, 1 H).
13C NMR (50 MHz, CDCl3): δ = 209.9, 166.3, 153.3, 150.0, 149.4, 138.4,
IR (KBr): 3310, 2900, 2857, 1560, 1447, 1252, 725, 708 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ (mixture of rotamers) = 9.26 (d, J =
9.2 Hz, 2 H, trans), 8.86 (t, J = 9.0 Hz, 1 H, cis), 8.49 (d, J = 10.8 Hz, 1 H,
cis), 8.28, 8.27 (2 s, 3 H, cis + trans), 6.89–6.85 (m, 3 H, cis + trans),
3.98 (s, 6 H, cis + trans), 3.87 (s, 6 H, cis + trans).
13C NMR (100 MHz, DMSO-d6): δ = 165.8, 164.9, 164.4, 162.6, 160.6,
160.4, 156.1, 147.6, 146.8, 117.4, 117.2, 116.2, 115.9, 108.1, 107.7,
84.4, 79.8, 79.7, 79.5, 79.2, 78.9, 63.2, 61.5.
136.3, 129.8, 128.5, 127.4, 127.2, 125.3, 124.8, 121.5, 115.7, 108.0.
Methyl 1,4-Dihydroxynaphthalene-2-carboxylate (6)15
HRMS (ES+): m/z [M + H]+ calcd for C11H10Br2NO5: 393.8926; found:
Following the general procedure using 2a (159 mg, 1 mmol), methyl
acrylate (95 mg, 1.1 mmol), LiOt-Bu (256 mg, 3.2 mmol), and THF (7
mL). Purification by column chromatography gave pure 6 (67 mg,
31%) as a yellow solid; mp 193–195 °C.
393.8928, 395.8910.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2473–2484

2483
D. Mal et al.
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 11.55 (s, 1 H), 8.40 (d, J = 8.4 Hz, 1 H),
8.13 (d, J = 8.4 Hz, 1 H), 7.68–7.55 (m, 2 H), 7.11 (s, 1 H), 5.04 (br s, 1
H), 3.98 (s, 3 H).
Acknowledgment
We gratefully acknowledge CSIR, DST, New Delhi for financial sup-
port. K.G. and S.C. are thankful to UGC and CSIR for their fellowships,
New Delhi for research fellowship and contingency grant. We are also
thankful to DST-FIST for assistance in establishing NMR and X-ray fa-
cility.
Methyl 3-Methyl-1,4-dioxo-1,4-dihydronaphthalene-2-carboxyl-
ate (7)16
Following the general procedure using 2a (159 mg, 1 mmol), methyl
crotonate (110 mg, 1.1 mmol), LiOt-Bu (256 mg, 3.2 mmol), and THF
(12 mL) afforded 7 (82 mg, 36%) as a light yellow solid; mp 96–98 °C.
1H NMR (200 MHz, CDCl3): δ = 8.37 (d, J = 8.4 Hz, 1 H), 8.04 (d, J = 8.2
Supporting Information
Supporting information for this article is available online at
Hz, 1 H), 7.70–7.44 (m, 2 H), 3.99 (s, 3 H), 2.52 (s, 3 H).
http://dx.doi.org/10.1055/s-0034-1380656.
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9,10-Dihydroxy-3,4-dihydroanthracen-1(2H)-one (8)16
Following the general procedure using 2a (159 mg, 1 mmol), cyclo-
hex-2-en-1-one (106 mg, 1.1 mmol), LiOt-Bu (256 mg, 3.2 mmol),
and THF (12 mL) afforded 8 (105 mg, 46%) as a yellow solid; mp 172–
174 °C.
1H NMR (200 MHz, CDCl3): δ = 13.85 (s, 1 H), 8.39 (d, J = 8.2 Hz, 1 H),
8.04 (d, J = 8.4 Hz, 1 H), 7.68–7.45 (m, 2 H), 2.95 (t, J = 8.0 Hz, 2 H),
2.76–2.59 (m, 2 H), 2.40 (t, J = 8.0 Hz, 2 H).
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