One-pot synthesis of N-methylindoles from N-methylanilines and of benzofurans from phenols using transition-metal carbene X-H insertion reactions

Article abstract of DOI:10.1016/j.tet.2009.07.077

Transition-metal carbene X-H insertion reactions (X=N or O) have been employed in the simple conversion of anilines and phenols into indoles and benzofurans, respectively. Thus copper(II) catalyzed N-H insertion reactions of α-diazo-β-ketoesters with N-me

Full text of DOI:10.1016/j.tet.2009.07.077

Tetrahedron 65 (2009) 8995–9001
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
One-pot synthesis of N-methylindoles from N-methylanilines and of benzofurans
from phenols using transition-metal carbene X–H insertion reactions
,
Mark A. Honey a, Alexander J. Blake a, Ian B. Campbell b, Brian D. Judkins b, Christopher J. Moody a
*
a School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
b GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 May 2009
Received in revised form 26 June 2009
Accepted 27 July 2009
Available online 6 August 2009
Transition-metal carbene X–H insertion reactions (X¼N or O) have been employed in the simple con-
version of anilines and phenols into indoles and benzofurans, respectively. Thus copper(II) catalyzed N–H
insertion reactions of
exchange resin gives indoles. In a similar manner, dirhodium(II) catalyzed O–H insertion reactions of
-diazo- -ketoesters with phenols followed by treatment with PPA gives benzofurans.
Ó 2009 Elsevier Ltd. All rights reserved.
a-diazo-b-ketoesters with N-methylanilines followed by treatment with acidic ion-
a
b
1. Introduction
sought to develop a solution-phase, one-pot route to arrays of
indoles, and we report our results herein.
The reaction of anilines with diazocarbonyl compounds is
a known reaction of carbene and metal carbene intermediates, with
the products being derived from an N–H insertion reaction.1,2 The
thermal reaction of ethyl diazoacetate with aniline itself was first
described by Curtius over 100 years ago,3 although nowadays the
reaction is usually carried out in the presence of a metal catalyst,
following Yates’ first report of the copper bronze catalyzed de-
composition of diazoacetophenone in the presence of aniline to
2. Results and discussion
Owing to the wide-ranging biological activity of many natural and
synthetic indoles, this important ring system continues to attract the
attention of synthetic organic chemists.23–26 Among the many routes
to indoles, those which start from a simple aniline derivative are
probably the most useful, since they do not require the presence of an
additional ortho-substituent, such as a halide, as used in the various
transition-metal mediated reactions such as the Larock method. The
Bischler reaction, discovered 100 years ago,27,28 involves the reaction
give a
-anilinoacetophenone in 33% yield.4 Subsequently, reports of
other reactions of anilines with diazocarbonyl compounds catalyzed
by a range of transition-metal complexes, including copper,5–8
rhodium,9–11 rhenium12 and ruthenium,13 followed. We previously
reported the rhodium carbene insertion reaction into the N–H
bond of N-alkylanilines as a key step in a modified Bischler syn-
thesis of indoles,14,15 whilst subsequently Janda and co-workers
have developed a solid-phase variant of this reaction, and applied it
to the synthesis of an array of indoles.16 In continuation of our own
work on carbene N–H insertion reactions in synthesis,17–22 we
of simple anilines with
cyclization of the resulting
In our previously described modification of the Bischler re-
action,14,15 the key
-(N-arylamino)ketone intermediate was
a-haloketones followed by acid catalyzed
a
-(N-arylamino)ketones.
a
obtained by the aforementioned rhodium carbene N–H insertion
reaction, and, after isolation, was subsequently cyclized using
protic or Lewis acids (Scheme 1).
O
R3
R3
Amberlyst® 15
or BF3•Et2O
O
R3
N2
CO2R2
CO2R2
X
X
X
N
R1
CO2R2
NHR1
N
R1
toluene, heat
cat. Rh2(OAc)4
Scheme 1.
Initially we had hoped to exploit the Lewis acidic nature of
dirhodium(II) carboxylates to effect both of the above trans-
formations in a single operation in one pot, but this proved
* Corresponding author. Tel.: þ44 115 846 8500; fax: þ44 115 951 3564.
E-mail address: c.j.moody@nottingham.ac.uk (C.J. Moody).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.077

8996
M.A. Honey et al. / Tetrahedron 65 (2009) 8995–9001
unsuccessful. Likewise, use of scandium triflate, a reagent reported
to mediate carbene N–H insertion reactions,29,30 was also un-
successful, and therefore we resorted to a two-operation, one-pot
method. In the first instance we optimized both steps (cf. Scheme 1)
separately. Thus, methyl 2-diazo-3-oxobutanoate 1 was reacted
with 4-bromo-N-methylaniline in the presence of a range of cata-
lysts in toluene or 1,2-dichloroethane (DCE) to give the N–H in-
sertion product 2 in a range of yields (Table 1). Although dirhodium
catalysts performed satisfactorily, copper(II) trifluoroacetate gen-
erally gave better yields, and therefore was adopted for use in our
one-pot synthesis. The ketone 2 appeared to exist in the enol form
in solution, and in the case of the related compound derived from
methyl 4-(methylamino)benzoate as the aniline component, X-ray
crystallography showed that the compound existed as the enol
form in the solid state also (Fig. 1).
A number of protic acids and Lewis acids have been used to
effect the cyclization of a-(N-arylamino)-ketones or -acetals in the
classical Bischler reaction or in its Nordlander modification,32 and
therefore we screened a range of these in order to optimize the
cyclization of the ketone 2 into the indole, methyl 5-bromo-1,3-
dimethylindole-2-carboxylate. Of the conditions tried, the use of
acidic ion-exchange resin (AmberlystÒ 15) proved bestdother
conditions (FeCl3, AlCl3, Yb(OTf)3, ZnCl2, TFA, p-TsOH) were less
satisfactory.
Application of the optimized conditions to a range of anilines 3
resulted in the formation of indoles 4 (Table 2). Thus, copper(II) tri-
fluoroacetate catalyzed N–H insertion in boiling toluene was fol-
lowed by addition of AmberlystÒ 15 and further heating to give the
indoles 4 in modest to good yields after chromatographic purifica-
tion. The process is tolerant of a range of functional groups on the
aniline, and in the case of the m-substituted aniline derivative 3b,
a mixture of indoles was formed on cyclization with the 6-methoxy-
indole predominating (ca. 3:1). In the case of indole 4j, the use of
dirhodium(II) tetraacetate as catalyst in the first step proved superior.
Table 1
Catalyzed reaction of methyl 2-diazo-3-oxobutanoate
methylaniline
1 with 4-bromo-N-
O
Me
1
Br
O
Br
Me
N
OH
N2
CO2Me
Me
Br
N
Me
2
CO2Me
CO2Me
NHMe
catalyst
so
lvent, reflux
Me
Catalyst
Solvent
Yield 2/%
Rh2(OAc)4
Rh2(OAc)4
Rh2(NHCOC3F7)4
Cu(OTf)2
Cu(OTf)2
Cu(OCOCF3)2
CuCl2
Toluene
DCE
Toluene
Toluene
DCE
Toluene
Toluene
DCE
66
44
65
72
67
84
0
CuCl2
0
InCl3
Sc(OTf)3
Sc(OTf)3
BF3$Et2O
Toluene
Toluene
DCE
19
20
13
0
Table 2
One-pot conversion of N-methylanilines 3 into indoles 4
Toluene
O
R3
R3
N2
CO2R
X
CO2R
X
1. cat. Cu(OCOCF3)2
toluene, reflux
N
NHMe
Me
2. Amberlyst® 15
toluene, reflux
3
4
Compound 3
X
R
R3
Indole 4 X
4
a
Indole 4 yield/%
a
b
2-MeO
3-MeO
Me Me
Me Me
7-MeO
6-MeO
4-MeO
5-Br
5-Cl
5-F
5-NO2
5-MeO
5-CO2Me
5-Me
33
b1 55
b2 19
c
d
e
f
g
h
i
4-Br
4-Cl
4-F
4-NO2
4-MeO
Me Me
Me Me
Me Me
Me Me
Me Me
c
d
e
f
g
h
i
75
80
81
52
30
60
47
50a
36
4-CO2Me Me Me
4-Me
4-NO2
4-Cl
Me Me
Et
Et
f
d
Ph
4-NO2
j
k
4-NO2C6H4 5-Cl
a
In this case dirhodium(II) tetraacetate was used as catalyst in the first step.
We next addressed the synthesis of benzofurans from phenols
using a similar metal carbene based strategy but involving an O–H,
rather than N–H, insertion reaction. Insertion of carbenes or metal
carbenes into O–H bonds is a well known process,33 and a number
of examples involving phenolic components have been reported
both from our own laboratory,34 and by others.35,36 In the case of
O–H insertion, dirhodium(II) carboxylates are usually the catalyst of
choice, and this proved to be true in the current case. No attempt
was made to isolate the intermediate aryloxyketones, which were
cyclized into benzofurans 6 by addition of polyphosphoric acid
(PPA) at 85 ꢀC, following removal of the toluene solvent. The results
are shown in Table 3, and although the yields are for the most part
fairly modest, the method tolerates a range of functional groups in
the starting phenol.
Figure 1. X-ray crystal structure of methyl 2-[N-(4-methoxycarbonylphenyl)-N-
methylamino]-3-oxobutanoate (enol form) prepared by N–H insertion reaction of
methyl 2-diazo-3-oxobutanoate 1 with methyl 4-(methylamino)benzoate.31

M.A. Honey et al. / Tetrahedron 65 (2009) 8995–9001
8997
Table 3
1592, 1491, 1386, 1361, 1345; dH (400 MHz; CDCl3) 12.24 (1H, s,
OH), 7.29 (2H, m, ArH), 6.51 (2H, m, ArH), 3.74 (3H, s, OMe), 3.03
(3H, s, NMe), 1.97 (3H, s, Me); dC (100 MHz; CDCl3) 176.0 (C),
172.2 (C), 148.0 (C), 131.8 (CH), 113.6 (CH), 110.4 (C), 109.1 (C), 51.9
(Me), 39.0 (Me), 17.5 (Me); m/z (ESI) 322 (MNaþ, 100%), 300
(MHþ, 33), 242 (51).
Conversion of phenols 5 into benzofurans 6
O
R3
R3
N2
CO2R
X
CO2R
X
OH
O
1. cat. Rh2(OAc)4
toluene, reflux
2. PPA, 85 °C
3.3. Methyl (2E)-2-[(4-methoxycarbonylphenyl)-
methylamino]-3-hydroxy-2-butenoate
R3 Benzofuran 6 X
6
Benzofuran 6 yield/%
MeO2C
Me
OH
Compound 5
X
R
a
b
c
d
e
f
2-Br
3-MeO
4-Br
4-Cl
4-NO2
4-MeO
Me Me 7-Br
Me Me 6-MeO
Me Me 5-Br
Me Me 5-Cl
Me Me 5-NO2
Me Me 5-MeO
a
b
c
d
e
f
67
19
32
47
26
34
33
53
N
CO2Me
Me
To methyl 2-diazo-3-oxobutanoate (103 mg, 0.725) and
methyl 4-(methylamino)benzoate (100 mg, 0.610 mmol) in dry
toluene (10 mL) was added copper trifluoroacetate hydrate
(2 mol %). The solution was heated at reflux for 2 h. The solvent
was removed under reduced pressure and the residue was sub-
jected to chromatography using ethyl acetate/light petroleum
(1:4) to yield the title compound as a colourless crystalline solid
(135 mg, 80%); mp 140–141 ꢀC. Found: MþHþ, 280.1179.
C14H17NO5þHþ requires 280.1185. nmax (CHCl3)/cmꢁ1 1702, 1652,
1603, 1517, 1440, 1362, 1333, 1267, 1181, 1123, 1107; dH (400 MHz;
CDCl3) 12.27 (1H, s, OH), 7.90 (2H, d, J 9.0 Hz, ArH), 6.61 (2H, d, J
9.0 Hz, ArH), 3.85 (3H, s, OMe), 3.69 (3H, s, OMe), 3.10 (3H, s,
NMe), 1.94 (3H, s, Me); dC (100 MHz; CDCl3) 175.8 (C), 171.8 (C),
167.3 (C), 152.5 (C), 131.35 (CH), 118.5 (C), 111.1 (CH), 110.2 (C),
52.0 (Me), 51.5 (Me), 39.1 (Me), 17.5 (Me); m/z (ESþ) 302 (MNaþ,
6%), 280 (MHþ, 23).
g
d
4-CO2Me Me Me 5-CO2Me
4-Cl Et Ph 5-Cl
g
h
In conclusion we have demonstrated the application of transi-
tion-metal carbene X–H insertion reactions (X¼N or O) in the
simple conversion of anilines and phenols into indoles and ben-
zofurans, respectively.
3. Experimental
3.1. General procedures
Commercially available reagents were used throughout without
purification unless otherwise stated. Light petroleum refers to the
fraction with bp 40–60 ꢀC. Ether refers to diethyl ether. Analytical
thin layer chromatography was carried out on aluminium backed
plates coated with silica gel, and visualized under UV light at 254
and/or 360 nm. Column chromatography was carried out on silica
gel unless otherwise stated. Fully characterized compounds are
chromatographically homogeneous. Infrared spectra were recorded
in the range 4000–600 cmꢁ1. NMR spectra were recorded at 300,
400 and 500 MHz (1H frequencies, corresponding 13C frequencies
75, 100 and 125 MHz). Chemical shifts are quoted in parts per
million and are referenced to residual H in the deuterated solvent
as the internal standard. In the 13C NMR spectra, signals corre-
sponding to CH, CH2, or CH3 groups are assigned from DEPT. High
and low resolution mass spectra were recorded on a time-of-flight
mass spectrometer.
3.4. Synthesis of indoles 4
3.4.1. General method. To methyl 2-diazo-3-oxobutanoate
1
(92 mg, 0.645 mmol) and the N-methylaniline 3 (0.537 mmol) in
toluene (10 mL) was added copper(II) trifluoroacetate hydrate
(2 mol %). The reaction mixture was heated at reflux for 2 h.
AmberlystÒ 15 (300 mg) was added, and the mixture was heated
at reflux overnight. The solvent was removed under reduced
pressure and the residue was subjected to chromatography to give
the indole 4.
3.4.1.1. Methyl 7-methoxy-1,3-dimethylindole-2-carboxylate 4a.
Me
CO2Me
N
3.2. Methyl (2E)-2-[(4-bromophenyl)methylamino]-3-
hydroxy-2-butenoate 2
Me
OMe
Br
Me
N
OH
To methyl 2-diazo-3-oxobutanoate (0.124 g, 0.873 mmol) and 2-
methoxy-N-methylaniline (0.100 g, 0.729 mol) in toluene (10 mL)
was added copper trifluoroacetate hydrate (2 mol %). The reaction
mixture was heated at reflux for 2 h. AmberlystÒ 15 (0.300 g) was
added and the resultant mixture was heated at reflux overnight.
Work up as above gave the title compound as a colourless solid
(56 mg, 33%); mp 62–64 ꢀC (lit.,15 mp 61–63 ꢀC); nmax (CHCl3)/cmꢁ1
2951, 2837, 1694, 1574, 1496, 1458, 1399, 1372, 1352, 1324, 1274,
1152, 1105, 1047; dH (400 MHz; CDCl3) 7.26 (1H, dd, J 7.6, 0.8 Hz,
ArH), 7.03(1H, t, J 7.6 Hz, ArH), 6.73 (1H, d, J 7.6 Hz, ArH), 4.31 (3H, s,
NMe), 3.95 (3H, s, OMe), 3.94 (3H, s, OMe), 2.53 (3H, s, Me); dC
(100 MHz; CDCl3) 163.4 (C), 148.0 (C), 129.16 (C), 129.17 (C), 125.7
(C),120.8 (C),119.8 (CH),113.2 (CH),105.4 (CH), 55.5 (Me), 51.3 (Me),
35.0 (Me), 11.0 (Me).
CO2Me
Me
To methyl 2-diazo-3-oxobutanoate 1 (92 mg, 0.648 mmol) and
4-bromo-N-methylaniline (100 mg, 0.537 mmol) in dry toluene
(10 mL) was added copper trifluoroacetate (2 mol %). The solution
was heated at reflux for 2 h. The solvent was removed under
reduced pressure and the residue was subjected to chromatog-
raphy using ethyl acetate/light petroleum (1:5) to yield the title
compound as an off-whiteþcrystalline solid (135 mg, 84%); mp
133–135 ꢀC. Found: MþNa , 322.0051. C12H1479BrNO3þNaþ re-
quires 322.0049. nmax (CHCl3)/cmꢁ1 2954, 2881, 2817, 1651, 1616,

8998
M.A. Honey et al. / Tetrahedron 65 (2009) 8995–9001
3.4.1.2. Methyl 6-methoxy-1,3-dimethylindole-2-carboxylate 4b1 and
methyl 4-methoxy-1,3-dimethylindole-2-carboxylate 4b2.
3.4.1.5. Methyl 5-fluoro-1,3-dimethylindole-2-carboxylate 4e.
Me
F
OMe
Me
Me
CO2Me
N
CO2Me
CO2Me
Me
N
N
MeO
Me
Me
To methyl 2-diazo-3-oxobutanoate (0.140 g, 0.959 mmol) and 4-
fluoro-N-methylaniline (0.100 g, 0.800 mmol) in toluene (10 mL)
was added copper trifluoroacetate hydrate (2 mol %). The reaction
mixture was heated at reflux for 2 h. AmberlystÒ 15 (0.300 g) was
added, and the mixture heated at reflux overnight. Work up as above
gave the title compound as a colourless solid (134 mg, 81%); mp 107–
108 ꢀC. Found: C, 64.9; H, 5.4; N, 6.3. C12H12FNO2 requires C, 65.2; H,
5.5; N, 6.3%. Found: MþHþ, 222.0929. C12H12FNO2þHþ requires
222.0930. nmax (CHCl3)/cmꢁ1 2952, 1704, 1625, 1490, 1461, 1400,
1385, 1368. 1122, 1105, 908; dH (400 MHz; CDCl3) 7.27 (2H, m, ArH),
7.11 (1H, td, J 9.0, 2.4 Hz, ArH), 3.99 (3H, s, OMe), 3.96 (3H, s, NMe),
2.53 (3H, s, Me); dC (100 MHz; CDCl3) 163.3 (C), 157.7 (d, J 236.5 Hz,
CF), 135.4 (C), 127.1 (d, J 10.0 Hz, C), 126.7 (C), 120.2 (d, J 6.0 Hz, C),
114.3 (d, J 27.2 Hz, CH), 111.1 (d, J 9.1 Hz, CH), 104.9 (d, J 22.1 Hz, CH),
51.5 (Me), 32.3 (Me), 10.8 (Me); m/z (ESI) 222 (MHþ, 22%).
To methyl 2-diazo-3-oxobutanoate (120 mg, 0.875 mmol) and
4-chloro-N-methylaniline (100 mg, 0.729 mmol) in toluene (10 mL)
was added copper trifluoroacetate hydrate (2.5 mol %). The reaction
mixture was heated at reflux for 2 h. AmberlystÒ 15 (300 mg) was
added and the mixture was heated at reflux overnight. Work up as
above gave (i) methyl 6-methoxy-1,3-dimethylindole-2-carboxyl-
ate 4b1 as a colourless crystalline solid (94 mg, 55%); mp 94–95 ꢀC
(lit.,15 93–94 ꢀC); dH (400 MHz; CDCl3) 7.54 (1H, d, J 8.8 Hz, ArH),
6.83 (1H, dd, J 8.8, 2.0 Hz, ArH), 6.73 (1H, d, J 2.0 Hz, ArH), 3.97 (3H,
s, OMe), 3.94 (3H, s, OMe), 3.91 (3H, s, NMe), 2.56 (3H, s, Me); and
(ii) methyl 4-methoxy-1,3-dimethylindole-2-carboxylate 4b2
(32 mg, 19%); mp 89–90 ꢀC (lit.,15 mp 90–92 ꢀC); dH (400 MHz;
CDCl3) 7.24 (1H, t, J 8.0 Hz, ArH), 6.92 (1H, d, J 8.4 Hz, ArH), 6.45 (1H,
d, J 7.6 Hz, ArH), 3.96 (3H, s, OMe), 3.94 (3H, s, OMe), 3.93 (3H, s,
NMe), 2.79 (3H, s, Me).
3.4.1.6. Methyl 1,3-dimethyl-5-nitroindole-2-carboxylate 4f.
3.4.1.3. Methyl 5-bromo-1,3-dimethylindole-2-carboxylate 4c.
Me
Me
O2N
Br
CO2Me
N
CO2Me
N
Me
Me
To methyl 2-diazo-3-oxobutanoate (0.37 g, 2.60 mmol) and N-
methyl-4-nitroaniline (0.300 g, 2.00 mmol) in toluene (25 mL) was
added copper trifluoroacetate hydrate (11.6 mg, 0.04 mmol). The
reaction mixture was heated at reflux for 150 min. AmberlystÒ 15
(0.300 g) was added. The resultant mixture was heated at reflux
overnight. Work up as above gave the title compound as a yellow solid
(0.26 g, 52%); mp 179–181 ꢀC (lit.,15 mp 178–180 ꢀC). Found: C, 58.1;
H, 4.9; N, 11.0. C12H12N2O4 requires C, 58.1; H, 4.9, N, 11.3%. nmax
(CHCl3)/cmꢁ1 3683, 2927, 2400, 1698, 1624, 1492, 1459, 1402, 1385,
1298, 1268, 1128, 1107, 1039; dH (400 MHz; CDCl3) 8.65 (1H, d, J
2.1 Hz, H-4), 8.22 (1H, dd, J 9.3, 2.1 Hz, H-6), 7.38 (1H, d, J 9.0 Hz, H-7),
4.05 (3H, s, OMe), 3.99 (3H, s, NMe), 2.62 (3H, s, Me); dC (100 MHz;
CDCl3) 162.7 (C), 141.6 (C), 140.9 (C), 127.8(C), 126.3 (C), 123.0 (C),
120.2 (CH), 118.4 (CH), 110.2 (CH), 51.9 (Me), 32.7 (Me), 10.8 (Me).
To methyl 2-diazo-3-oxobutanoate (92 mg, 0.645 mmol) and 4-
bromo-N-methylaniline (100 mg, 0.537 mmol) in toluene (10 mL)
was added copper trifluoroacetate hydrate (2 mol %). The reaction
mixture was heated at reflux for 2 h. AmberlystÒ 15 (300 mg) was
added, and the mixture was heated at reflux overnight. Work up as
above gave the title compound as a colourless solid (121 mg, 75%);
mp 91–93 ꢀC. Found: MþHþ, 303.9940. C12H1279BrNO2þNaþ re-
quires 303.9944. nmax (CHCl3)/cmꢁ1 2952, 1704, 1464, 1445, 1401,
1365, 1134, 1109; dH (400 MHz; CDCl3) 7.80 (1H, s, H-4), 7.42(1H, dd,
J 8.8, 2.0 Hz, H-6), 7.22 (1H, d, J 8.8 Hz, H-7), 3.99 (3H, s, NMe), 3.96
(3H, s, OMe), 2.54 (3H, s, Me); dC (100 MHz; CDCl3) 163.2 (C), 137.3
(C), 128.6 (C), 128.1 (CH), 123.2 (C), 119.8 (CH), 112.8 (C), 111.6 (CH),
110.0 (C), 51.5 (Me), 32.2 (Me), 10.7 (Me); m/z (ESI) 282 (MHþ, 8%).
3.4.1.4. Methyl 5-chloro-1,3-dimethylindole-2-carboxylate 4d.
3.4.1.7. Methyl 5-methoxy-1,3-dimethylindole-2-carboxylate 4g.
Me
Me
Cl
MeO
CO2Me
N
CO2Me
N
Me
Me
To methyl 2-diazo-3-oxobutanoate (0.120 g, 0.847 mmol) and 4-
chloro-N-methylaniline (0.100 g, 0.706 mmol) in toluene (10 mL)
was added copper trifluoroacetate hydrate (2 mol %). The reaction
mixture was heated at reflux for 2 h. AmberlystÒ 15 (0.300 g) was
added, and the mixture was heated at reflux overnight. Work up as
above gave the title compound as a colourless solid (0.134 g, 80%);
mp 65–67 ꢀC (lit.,15 mp 64–66 ꢀC); nmax (CHCl3)/cmꢁ1 2952, 1704,
1467, 1445, 1366, 1134, 1110, 871; dH (400 MHz; CDCl3) 7.62 (1H, s,
H-4), 7.26 (2H, m, ArH), 3.97 (3H, s, NMe), 3.96 (3H, s, OMe), 2.53
(3H, s, Me); dC (100 MHz; CDCl3) 163.2 (C), 137.0 (C), 127.9 (C), 125.9
(C), 125.6 (CH), 125.4 (C), 120.0 (CH), 111.2 (CH), 110.0 (C), 51.5 (Me),
32.2 (Me), 10.7 (Me).
To methyl 2-diazo-3-oxobutanoate (0.100 g, 0.873 mmol) and 4-
methoxy-N-methylaniline (0.100 g, 0.729 mmol) in toluene (10 mL)
was added copper trifluoroacetate hydrate (2.5 mol %). The reaction
mixture was heated at reflux for 2.5 h. AmberlystÒ 15 (0.300 g) was
added and the mixture heated at reflux overnight. Work up as
above gave the title compound as an off-white crystalline solid
(0.10 g, 30%); mp 81–83 ꢀC (lit.,15 mp 81–82 ꢀC); nmax (CHCl3)/cmꢁ1
3683, 2927, 2400, 1698, 1624, 1492, 1459, 1402, 1385, 1298, 1268,
1128, 1107, 1039; dH (400 MHz; CDCl3) 7.27 (1H, m, ArH), 7.06 (2H,
m, ArH), 4.00 (3H, s, OMe), 3.96 (3H, s, OMe), 3.90 (3H, s, NMe), 2.58
(3H, s Me); dC (100 MHz; CDCl3) 163.5 (C), 154.1 (C), 134.4 (C), 127.1

M.A. Honey et al. / Tetrahedron 65 (2009) 8995–9001
8999
(C), 119.9 (C), 116.8 (CH), 111.0 (CH), 100.8 (CH), 55.8 (Me), 51.3 (Me),
32.2 (Me), 10.9 (Me).
0.025 mmol). The reaction mixture was heated at reflux for 2 h.
AmberlystÒ 15 (300 mg) was added and the mixture heated at
reflux overnight. The solution was allowed to cool to room tem-
perature and the solvent was removed under reduced pressure. The
sample was loaded in dichloromethane onto a silica cartridge (50 g)
and purified using a 0–50% ethyl acetate/cyclohexane solvent sys-
tem over 40 min. The resultant yellow solid was recrystallized from
methanol to yield the title compound as light yellow crystalline
needles (162 mg, 50%), mp 122–123 ꢀC (lit.,37 mp not given); nmax
(CHCl3)/cmꢁ1 1693, 1609, 1519, 1335, 1251, 1092; dH (400 MHz;
CDCl3) 8.52 (1H, d, J 2.3 Hz, H-4), 8.27 (1H, dd, J 9.3, 2.3 Hz, H-6),
7.50–7.40 (6H, m, ArH), 4.24–4.19 (2H, q, J 7.0 Hz, OCH2Me), 4.14
(3H, s, NMe), 1.09–1.05 (3H, t, J 7.1 Hz, OCH2Me); dC (100 MHz;
CDCl3) 161.9 (C), 142.6 (C), 140.5 (C), 133.0 (C), 130.2 (CH), 128.1
(CH), 127.7 (CH), 126.6 (C), 126.0 (C), 125.1 (C), 120.3 (CH), 119.3
(CH), 118.5 (C), 110.4 (CH), 61.1 (CH2), 32.6 (Me), 13.6 (Me).
3.4.1.8. Dimethyl 1,3-dimethyl-1H-indole-2,5-dicarboxylate 4h.
Me
MeO2C
CO2Me
N
Me
To methyl 2-diazo-3-oxobutanoate (103 mg, 0.726 mmol) and
methyl 4-(methylamino)benzoate (100 mg, 0.605 mmol) in toluene
(10 mL) was added copper trifluoroacetate hydrate (2 mol %). The
reaction mixture was heated at reflux for 2 h. AmberlystÒ 15
(300 mg) was added, and the resultant mixture heated at reflux
overnight. Work up as above gave the title compound as an off-
white solid (94 mg, 60%); mp 128–129 ꢀC. Found: MþNaþ,
284.0899. C14H15NO4þNaþ requires 284.0893. nmax (CHCl3)/cmꢁ1
2952, 2844,1705,1614,1574,1547, 1445, 1370,1317, 1300,1151, 1114;
dH (400 MHz; CDCl3) 8.45 (1H, s, H-4), 8.01 (1H, d, J 8.8 Hz, H-6),
7.32 (1H, d, J 8.8 Hz, H-7), 4.00 (3H, s, NMe), 3.97 (3H, s, OMe), 3.95
(3H, s, OMe), 2.60 (3H, s, Me); dC (100 MHz; CDCl3) 167.8 (C), 163.1
(C), 140.9 (C), 126.7 (C), 126.2 (C), 126.1 (CH), 124.1 (CH), 122.3 (C),
121.8 (C), 109.7 (CH), 52.0 (Me), 51.6 (Me), 32.4 (Me), 10.8 (Me); m/z
(ESI) 284 (MNaþ, 100%), 262 (MHþ, 33), 203 (2).
3.4.1.11. Ethyl 5-chloro-1-methyl-3-(4-nitrophenyl)-
indole-2-carboxylate 4k.
NO2
Cl
CO2Et
N
3.4.1.9. Methyl 1,3,5-trimethylindole-2-carboxylate 4i.
Me
Me
Me
To 4-chloro-N-methylaniline (142 mg, 1 mmol) and ethyl 2-di-
azo-3-(4-nitrophenyl)-3-oxopropanoate (290 mg, 1.1 mmol) in
toluene (5 mL) was added copper trifluoroacetate hydrate (7 mg,
0.025 mmol). The reaction mixture was heated to 110 ꢀC and stirred
for 2 h. AmberlystÒ 15 (300 mg) was added and heated under reflux
overnight. The reaction mixture was cooled and filtered. The sol-
vent was removed under reduced pressure and the resultant oil
purified over a silica cartridge (20 g) using a solvent gradient of
0–50% ethyl acetate/cyclohexane. The crude product was recrys-
tallized from methanol to give the title compound as a yellow
crystalline solid (129 mg, 36%); mp 108–109 ꢀC.Found: C, 60.3; H,
4.1; N, 7.7. C18H15ClN2O4 requires C, 60.3; H, 4.2; N, 7.8%. Found:
MþHþ, 359.0797. C18H1535ClN2O4þHþ requires 359.0799. nmax
(CHCl3)/cmꢁ1 2976, 1701, 1594, 1512, 1485, 1463, 1384, 1345, 1278,
1257, 1242, 1181; dH (400 MHz; CDCl3) 8.31 (2H, d, J 8.8 Hz, ArH),
7.59 (2H, d, J 8.8 Hz, ArH), 7.46 (1H, d, J 1.6 Hz, H-4), 7.39 (1H, d, J
8.8 Hz, H-7), 7.37 (1H, dd, J 8.8, 1.8 Hz, H-6), 4.23 (2H, q, J 7.0 Hz,
OCH2Me), 4.10 (3H, s, NMe), 1.10 (3H, t, J 7.2 Hz, OCH2Me); dC
(100 MHz; CDCl3) 161.7 (C), 146.9 (C), 141.5 (C), 136.7 (C), 131.2 (C),
127.3 (C), 126.8 (C), 126.3 (C), 126.2 (CH), 123.1 (CH), 121.1 (CH),
120.0 (CH), 111.7 (CH), 61.1 (CH2), 32.4 (Me), 13.8 (Me); m/z (ESI) 717
(2MþHþ, 100%), 359 (MHþ, 45).
CO2Me
N
Me
To methyl 2-diazo-3-oxobutanoate (157 mg, 1.10 mmol) and
N-methyl-4-toluidine (121 mg, 1.00 mmol) in toluene (10 mL)
was added copper trifluoroacetate hydrate (8 mg, 0.025 mmol).
The reaction mixture was heated to 110 ꢀC for 2 h. AmberlystÒ 15
(300 mg) was added and the reaction mixture heated under
reflux overnight. The mixture was cooled to room temperature
and filtered. The filtrate was concentrated under reduced pres-
sure and the resultant solid loaded onto a silica cartridge (20 g)
and purified using a gradient of 0–50% ethyl acetate/cyclohexane
over a period of 30 min. The crude produce recrystallized from
methanol to yield the title compound as a colourless crystalline
solid (101 mg, 47%); mp 34–36 ꢀC. Found: MþHþ, 218.1171.
C13H15NO2þHþ requires 218.1181. nmax (CHCl3)/cmꢁ1 2918, 1699,
1530, 1443, 1403, 1379, 1354, 1265, 1249, 1193, 1183; dH
(400 MHz; CDCl3) 7.45 (1H, s, H-4), 7.25 (1H, d, J 8.5 Hz, H-7), 7.21
(1H, dd, J 8.5, 1.3 Hz, H-6), 3.99 (3H, s, NMe), 3.95 (3H, s, OMe),
2.58 (3H, s, Me), 2.48 (3H, s, ArMe); dC (100 MHz; CDCl3) 163.6
(C), 137.4 (C), 128.9 (C), 127.2 (CH), 124.9 (C), 122.5 (C), 120.2 (C),
120.0 (CH), 109.7 (CH), 51.3 (Me), 32.1 (Me), 21.4 (Me), 10.8 (Me);
m/z (ESI) 218 (MHþ, 33%), 217 (Mþ, 20), 186 (100).
3.5. Synthesis of benzofurans 6
3.5.1. General method. To methyl 2-diazo-3-oxobutanoate (157 mg,
1.10 mmol) and the phenol 5 (1.00 mmol) in toluene (0.5 mL) under
an atmosphere of nitrogen was added rhodium(II) acetate dimer
(11 mg, 0.025 mmol). The reaction mixture was heated to 110 ꢀC for
2 h. The mixture was allowed to cool to room temperature and the
solvent removed under reduced pressure. Polyphosphoric acid
(300 mg) was pre-heated to 85 ꢀC and added to the crude reaction
mixture. The viscous mixture was stirred at 85 ꢀC overnight. The
reaction mixture was cooled to 0 ꢀC and water (20 mL) was added.
The organic material was extracted with methyl tert-butyl ether
(3ꢂ30 mL) and neutralized with sodium hydrogen carbonate. The
organic layer was dried over MgSO4 and the suspension was filtered
3.4.1.10. Ethyl 1-methyl-5-nitro-3-phenylindole-2-carboxylate 4j.
Ph
O2N
CO2Et
N
Me
To a solution of N-methyl-4-nitroaniline (152 mg, 1 mmol) and
ethyl 2-diazo-3-oxo-3-phenylpropanoate (263 mg, 1.200 mmol) in
toluene (2 mL), stirred under an atmosphere of nitrogen at room
temperature was added rhodium(II) acetate dimer (11.05 mg,

9000
M.A. Honey et al. / Tetrahedron 65 (2009) 8995–9001
and the filtrate concentrated under reduced pressure. The residue
was purified over a silica cartridge (20 g) using a solvent gradient of
0–50% ethyl acetate/cyclohexane over a period of 20 min.
for 2 h. The mixture was allowed to cool to room temperature
and the solvent removed under reduced pressure. Poly-
phosphoric acid (300 mg) was pre-heated to 85 ꢀC and added to
the crude reaction mixture. The viscous mixture was stirred at
85 ꢀC overnight. The reaction mixture was cooled to 0 ꢀC and
distilled water (20 mL) added. Work up as above gave the title
compound as a colourless crystalline solid (86 mg, 32%); mp 83–
84 ꢀC (MeOH) (lit.,39 mp not given). Found: MþHþ, 268.9806.
C11H979BrO3þHþ requires 268.9813. nmax (CHCl3)/cmꢁ1 3675,
2988, 2902, 1720, 1440, 1364, 1310, 1147; dH (400 MHz; CDCl3)
7.77 (1H, d, J 2.0 Hz, H-4), 7.54 (1H, dd, J 8.8, 2.0 Hz, H-6), 7.42
(1H, d, J 8.8 Hz, H-7), 3.99 (3H, s, OMe), 2.56 (3H, s, Me); dC
(100 MHz; CDCl3) 160.5 (C), 153.0 (C), 130.9 (C), 130.8 (CH), 125.0
(C), 123.8 (CH), 120.0 (C), 116.3 (C), 113.7 (CH), 52.2 (Me), 9.3
(Me); m/z (ESI) 269 (MHþ, 100%).
3.5.1.1. Methyl 7-bromo-3-methylbenzofuran-2-carboxylate 6a.
Me
CO2Me
O
Br
To methyl 2-diazo-3-oxobutanoate (157 mg, 1.10 mmol) and 2-
bromophenol (173 mg, 1.00 mmol) in toluene (0.5 mL) under an
atmosphere of nitrogen was added rhodium(II) acetate dimer
(11 mg, 0.025 mmol). The reaction mixture was heated at reflux for
3 h. The resultant solution was allowed to cool and the solvent
removed under reduced pressure. Polyphosphoric acid (300 mg)
was pre-heated to 85 ꢀC and added to the residue. The mixture was
stirred at 85 ꢀC overnight. The reaction mixture was cooled to 0 ꢀC
and diluted with distilled water (20 mL). Work up as above gave the
title compound as a colourless solid (181 mg, 67%); mp 99–101 ꢀC.
Found: MþHþ, 268.9806. C11H979BrO3þHþ requires 268.9813. nmax
(CHCl3)/cmꢁ1 2950, 1710, 1604, 1439, 1356, 1288, 1210, 1134; dH
(400 MHz; CDCl3) 7.61 (1H, d, J 7.8 Hz, ArH), 7.57 (1H, d, J 7.8 Hz,
ArH), 7.19 (1H, t, J 7.8 Hz, ArH), 4.00 (3H, s, OMe), 2.59 (3H, s, Me); dC
(100 MHz; CDCl3) 160.5 (C), 141.5 (C), 130.7, 130.2 (C), 126.4 (C),
124.4 (CH), 120.2 (CH), 104.9 (C), 71.9, 52.1 (Me), 9.5 (C); m/z (ESI)
269 (MHþ, 53%).
3.5.1.4. Methyl 5-chloro-3-methylbenzofuran-2-carboxylate 6d.
Me
Cl
CO2Me
O
To methyl 2-diazo-3-oxobutanoate (157 mg, 1.10 mmol) and 4-
chlorophenol (129 mg, 1.00 mmol) in toluene (0.5 mL) under an
atmosphere of nitrogen was added rhodium(II) acetate dimer
(11 mg, 0.025 mmol). The reaction mixture was heated to 110 ꢀC for
2 h. The mixture was allowed to cool to room temperature and the
solvent removed under reduced pressure. Polyphosphoric acid
(300 mg) was pre-heated to 85 ꢀC and added to the crude reaction
mixture. The viscous mixture was stirred at 85 ꢀC overnight. The
reaction mixture was cooled to 0 ꢀC and distilled water (20 mL) was
added. Work up as above gave the title compound as a light orange
solid (105 mg, 47%); mp 86–87 ꢀC (EtOH) (lit.,40 mp 95–95.8 ꢀC).
Found: MþHþ, 225.0314. C11H935ClO3þHþ requires 225.0318. nmax
(CHCl3)/cmꢁ1 2951, 1730, 1713, 1602, 1581, 1446, 1358, 1308, 1278,
1224, 1145, 1132, 1100; dH (400 MHz; CDCl3) 7.60 (1H, d, J 2.0 Hz, H-
4), 7.46 (1H, d, J 8.8 Hz, H-7), 7.40 (1H, dd, J 8.8, 2.1 Hz, H-6), 3.99
(3H, s, OMe), 2.56 (3H, s, Me); dC (100 MHz; CDCl3) 160.5 (C), 152.7
(C), 141.9 (C), 130.3 (C), 129.0 (C), 128.1 (CH), 125.2 (C), 120.7 (CH),
113.3 (CH), 52.1 (Me), 9.3 (Me).
3.5.1.2. Methyl 6-methoxy-3-methylbenzofuran-2-carboxylate 6b.
Me
CO2Me
O
MeO
To methyl 2-diazo-3-oxobutanoate (157 mg, 1.100 mmol) and 3-
methoxyphenol (124 mg, 1 mmol) in toluene (0.5 mL) under ni-
trogen was added rhodium(II) acetate dimer (11 mg, 0.025 mmol).
The reaction mixture was heated at reflux for 2 h. The resultant
solution was allowed to cool and the solvent removed under re-
duced pressure. Polyphosphoric acid (300 mg) was pre-heated to
85 ꢀC and added to the residue. The mixture was stirred at 85 ꢀC
overnight. The reaction mixture was cooled to 0 ꢀC and diluted with
distilled water (20 mL). Work up as above gave the title compound
as an off-white solid (41 mg, 19%); mp 80–81 ꢀC (lit.,38 mp 90 ꢀC).
Found: MþHþ, 221.0810. C12H12O4þHþ requires 221.0814. nmax
(CHCl3)/cmꢁ1 2948, 2343, 2327, 2310, 1698, 1620, 1599, 1497, 1428,
1361, 1312, 1271, 1235, 1189, 1152, 1130; dH (400 MHz; CDCl3) 7.49
(1H, d, J 8.5 Hz, H-4), 7.02 (1H, d, J 2.3 Hz, H-7), 6.94 (1H, dd, J 8.5,
2.3 Hz, H-5), 3.97 (3H, s, OMe), 3.87 (3H, s, OMe), 2.57 (3H, s, Me); dC
(100 MHz; CDCl3) 160.8 (CH), 155.7 (C), 140.1 (C), 126.4 (C), 122.4
(C), 121.4 (CH), 116.5 (C), 113.3 (CH), 95.6 (CH), 55.7 (Me), 51.8 (Me),
9.4 (Me); m/z (EIþ) 221 (MHþ, 100%), 220 (Mþ, 18).
3.5.1.5. Methyl 3-methyl-5-nitrobenzofuran-2-carboxylate 6e.
Me
O2N
CO2Me
O
To methyl 2-diazo-3-oxobutanoate (157 mg, 1.1 mmol) and 4-
nitrophenol (139 mg, 1 mmol) in toluene (0.5 mL) under an atmo-
sphere of nitrogen was added rhodium(II) acetate dimer (11 mg,
0.025 mmol). The reaction vessel was sealed and heated to 110 ꢀC
for 2 h. The reaction mixture was allowed to cool to ambient
temperature and the solvent removed under reduced pressure.
Polyphosphoric acid (300 mg) was heated to 85 ꢀC for 30 min and
added to the crude reaction mixture. The viscous solution was
stirred at 85 ꢀC overnight. The reaction mixture was cooled in an ice
bath and distilled water (20 mL) was added. Work up as above gave
the title compound as a yellow solid (60 mg, 26%); mp 120–122 ꢀC
(MeOH) (lit.,41 mp 147–148.5 ꢀC); nmax (CHCl3)/cmꢁ1 2110, 2957,
2925, 1726, 1525, 1435, 1336, 1287, 1223, 1146; dH (400 MHz; CDCl3)
8.60 (1H, d, J 2.3 Hz, H-4), 8.37 (1H, dd, J 9.1, 2.3 Hz, H-6), 7.65 (1H, d,
J 9.1 Hz, H-7), 4.02 (3H, s, OMe), 2.66 (3H, s, Me); dC (100 MHz;
CDCl3) 160.0 (C), 156.9 (C), 144.4 (C), 143.6 (C), 129.4 (C), 126.2 (C),
123.2 (CH), 118.0 (CH), 111.8 (CH), 52.4 (Me), 9.3 (Me).
3.5.1.3. Methyl 5-bromo-3-methylbenzofuran-2-carboxylate 6c.
Me
Br
CO2Me
O
To methyl 2-diazo-3-oxobutanoate (157 mg, 1.100 mmol) and
4-bromophenol (173 mg, 1 mmol) in toluene (0.5 mL) under an
atmosphere of nitrogen was added rhodium(II) acetate dimer
(11 mg, 0.025 mmol). The reaction mixture was heated to 110 ꢀC

M.A. Honey et al. / Tetrahedron 65 (2009) 8995–9001
9001
3.5.1.6. Methyl 5-methoxy-3-methylbenzofuran-2-carboxylate 6f.
compound as a colourless solid (158 mþg, 53%); mp 91–92 ꢀC (MeOH)
(lit.,43 mp 105–106 ꢀC). Found: MþH , 301.0625. C17H1335ClO3þHþ
requires 301.0631. nmax (CHCl3)/cmꢁ1 3661, 2987, 2902, 1720, 1371,
1272, 1261, 1226, 1145; dH (400 MHz; CDCl3) 7.58–7.43 (8H, m, ArH),
4.36 (2H, q, J 7.0 Hz, OCH2Me), 1.29 (3H, t, J 7.1 Hz, OCH2Me); dC
(100 MHz; CDCl3) 159.5 (C), 152.8 (C), 141.3 (C), 130.0 (C), 129.9 (CH),
129.7 (C), 129.6 (C), 128.7 (CH), 128.6 (C), 128.3 (CH), 128.3 (CH),
121.6 (CH), 113.4 (CH), 61.5 (CH2), 14.1 (Me); m/z (ESI) 323 (MNaþ,
42%), 301 (MHþ, 70), 255 (100).
Me
MeO
CO2Me
O
To methyl 2-diazo-3-oxobutanoate (157 mg, 1.10 mmol) and 4-
methoxyphenol (124 mg, 1.00 mmol) in toluene (0.5 mL) under an
atmosphere of nitrogen was added rhodium(II) acetate dimer
(11 mg, 0.025 mmol). The reaction vessel was sealed and heated to
110 ꢀC for 2 h. The reaction mixture was allowed to cool to ambient
temperature and the solvent removed under reduced pressure.
Polyphosphoric acid (300 mg) was heated to 85 ꢀC and added to the
crude reaction mixture. The viscous solution was stirred at 85 ꢀC
overnight. The reaction mixture was cooled in an ice bath and dis-
tilled water (20 mL) was added. Work up as above gave the title
compound as an off-white solid (75 mg, 34%); mp 82–83 ꢀC (MeOH)
(lit.,42 mp 88–89 ꢀC); nmax (CHCl3)/cmꢁ1 2959,1710,1589,1480,1430,
1366, 1321, 1292, 1233, 1185, 1147; dH (400 MHz; CDCl3) 7.44 (1H, d, J
9.0 Hz, H-7), 7.07 (1H, dd, J 9.0, 2.5 Hz, H-6), 7.01 (1H, d, J 2.5 Hz, H-4),
3.99 (3H, s, OMe), 3.88 (3H, s, OMe), 2.58 (3H, s, Me); dC (100 MHz;
CDCl3) 160.8 (C), 156.2 (C), 149.4 (C), 141.3 (C), 129.4 (C), 125.8 (C),
117.6 (CH), 112.8 (CH), 102.2 (CH), 55.8 (Me), 51.9 (Me), 9.3 (Me).
Acknowledgements
We thank the EPSRC and GlaxoSmithKline for support of this
work under the Array Chemistry Programme.
References and notes
1. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic Methods for Organic
Synthesis with Diazo Compounds; John Wiley: New York, NY, 1998.
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9. Aller, E.; Buck, R. T.; Drysdale, M. J.; Ferris, L.; Haigh, D.; Moody, C. J.; Pearson,
N. D.; Sanghera, J. B. J. Chem. Soc., Perkin Trans. 1 1996, 2879–2884.
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3.5.1.7. Dimethyl 3-methylbenzofuran-2,5-dicarboxylate 6g.
Me
MeO2C
CO2Me
O
14. Moody, C. J.; Swann, E. Synlett 1998, 135–136.
15. Bashford, K. E.; Cooper, A. L.; Kane, P. D.; Moody, C. J.; Muthusamy, S.; Swann, E.
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5258.
To methyl 2-diazo-3-oxobutanoate (157 mg, 1.100 mmol) and
methyl 4-hydroxybenzoate (152 mg, 1 mmol) in toluene (0.5 mL)
under an atmosphere of nitrogen was added rhodium(II) acetate
dimer (11 mg, 0.025 mmol). The reaction vessel was sealed and
heated to 110 ꢀC for 2 h. The reaction mixture was allowed to cool to
ambient temperature and the solvent removed under reduced
pressure. Polyphosphoric acid (300 mg) was heated to 85 ꢀC and
added to the crude reaction mixture. The viscous solution was
stirred at 85 ꢀC for 1 h. The mixture was cooled to room tempera-
ture and ice cold water (20 mL) was added. Work up as above gave
the title compound as a colourless solid (81 mg, 33%); mp 144–
145 ꢀC (MeOH). Found: MþHþ, 249.0759. C13H12O5þHþ requires
249.0763. nmax (CHCl3)/cmꢁ1 2969, 1713, 1596, 1434, 1290, 1223,
1145; dH (400 MHz; CDCl3) 8.40 (1H, d, J 1.7 Hz, H-4), 8.17 (1H, dd, J
8.8, 1.7 Hz, H-6), 7.58 (1H, d, J 8.8 Hz, H-7), 4.01 (3H, s, OMe), 3.97
(3H, s, OMe), 2.64 (3H, s, Me); dC (100 MHz; CDCl3) 166.8 (C), 160.5
(C), 156.8 (C), 142.0 (C), 129.2 (CH), 129.1 (C), 126.2 (C), 125.7 (C),
123.8 (CH), 112.1 (CH), 52.3 (Me), 52.2 (Me), 9.3 (Me); m/z (ESI) 249
(MHþ, 100%).
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Union Road, Cambridge, CB21EZ, UK; fax: þ44 1223 336 033; or deposit@ccdc.
cam.ac.uk) CCDC 743574.
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To ethyl 2-diazo-3-oxo-3-phenylpropanoate (240 mg, 1.100 mmol)
and 4-chlorophenol (129 mg, 1 mmol) in toluene (0.5 mL) under an
atmosphere of nitrogen was added rhodium(II) acetate dimer (11 mg,
0.025 mmol) and heated to 110 ꢀC for 3 h. The reaction mixture was
allowed to cool to ambient temperature and the solvent removed
under reduced pressure. Polyphosphoric acid (300 mg) was heated
to 85 ꢀC and added to the crude mixture. The viscous solution was
stirred at 85 ꢀC overnight. The mixture was cooled to 0 ꢀC and ice
cold water (20 mL) was added. Work up as above gave the title