N-heterocyclic carbene catalysed oxygen-to-carbon carboxyl transfer of indolyl and benzofuranyl carbonates

Article abstract of DOI:10.1055/s-2008-1077890

The ability of N-heterocyclic carbenes to promote O-to-C carboxyl transfer on a range of indolyl and benzofuranyl carbonates is examined, and the scope and limitations of this process delineated. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1077890

SPECIAL TOPIC
2805
N-Heterocyclic Carbene Catalysed Oxygen-to-Carbon Carboxyl Transfer of
Indolyl and Benzofuranyl Carbonates
O
-to-C Ca
e
rboxyl
T
ran
n
sfer of Indo
n
lyl and Benz
i
ofurany
f
l
Carbon
e
ates r E. Thomson, Andrew F. Kyle, Katherine A. Gallagher, Philip Lenden, Carmen Concellón, Louis C. Morrill,
Andrew J. Miller, Caroline Joannesse, Alexandra M. Z. Slawin, Andrew D. Smith*
EaStCHEM, School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK
Received 29 March 2008
Given the high catalytic efficiency observed using NHCs
Abstract: The ability of N-heterocyclic carbenes to promote O-to-
C carboxyl transfer on a range of indolyl and benzofuranyl carbon-
ates is examined, and the scope and limitations of this process de-
lineated.
as catalysts for O-to-C carboxyl transfer in the oxazolone
series, we sought to probe the ability of NHC 3 to promote
this transformation upon a range of indolyl and benzofura-
nyl derivatives. Herein we delineate our investigations
within this area and showcase the generality and limita-
tions of employing NHC-mediated catalysis in this trans-
formation.
Key words: N-heterocyclic carbene, catalysis, carboxyl transfer
N-Heterocyclic carbenes (NHCs) are versatile and effi-
cient organocatalysts for a plethora of synthetic transfor-
mations.1 Building upon their established use in polarity
reversal or Umpolung techniques,2,3 recent advances have
seen NHCs used for the preparation of homoenolates4 and
enolates,5 as well as applications as catalysts for trifluo-
romethylation,6 cyanosilylation,7 amidation,8 hydroacyla-
tion,9 redox reactions10 and aziridine opening,11 among
others.12 It is widely recognised that the development of
efficient catalytic methodologies for the construction of
all-carbon quaternary stereocentres represents a difficult
challenge in synthetic chemistry. A variety of elegant cat-
alytic asymmetric approaches to this problem have been
developed,13 including Diels–Alder reactions,14 asymmet-
ric alkylations,15 Heck reactions,16 rearrangement
processes17 and desymmetrisation reactions.18 As part of a
research programme concerned with the development of
catalytically efficient methods for the preparation of this
challenging structural motif, we have previously shown
that N-heterocyclic carbene 3 can catalyse the Steglich
rearrangement19 of oxazolyl carbonates to their corre-
sponding 4-carboxyazlactones, a reaction that generates a
C–C bond and a quaternary stereocentre.20,21 A number of
asymmetric variants of this transformation have been de-
veloped,22 and both Fu and Vedejs have extended this pro-
tocol to the asymmetric O-to-C carboxyl transfer of
benzofuranyl and indolyl carbonates using catalysts 1 and
2 to generate 3,3¢-disubstituted oxindole and 3,3¢-benzo-
furanone derivatives respectively.23 Despite high enanti-
oselectivities being observed in these transformations,
reactions in the indolyl series usually required relatively
long reaction times, typically of the order of 48–96 hours,
with 5–10 mol% of catalyst 1 or 2 (Scheme 1), while the
rearrangement of highly substituted benzofuranyl carbon-
ates has proven difficult with TADMAP 2.
NMe2
H
N
N
CPh3
OAc
N
N
N
Ph
Fe
Ph
Ph
Ph
N
1
2
3
Ph
Ph
Ph
OR2
Ph
O
O
O
catalyst
OR2
O
N
N
R1
R1
4, R1 = Me, R2 = C(Me)2CCl3 6, R1 = Me, R2 = C(Me)2CCl3, 98% ee
(1, 5 mol%, CH2Cl2, 35 °C, 48 h)
5, R1 = CO2Ph, R2 = Ph
7, R1 = CO2Ph, R2 = Ph, 90% ee
(2, 10 mol%, Et2O, 4 d)
OR
Bn
Bn
O
O
catalyst
OR
O
O
O
O
8, R = C(Me)2CCl3
10, R = C(Me)2CCl3, 88% ee
(1, 5 mol%, CH2Cl2, 35 °C, 48 h)
11, R = Ph, 92% ee
9, R = Ph
(2, 1 mol%, Et2O, 4 h)
Scheme 1 Catalysts for O-to-C carboxyl transfer of indolyl and
benzofuranyl carbonates
Model Studies: Preparation of Indolyl Substrates
Initial investigations set out to probe the variation in ef-
fectiveness of NHC-mediated catalysis within a series of
indolyl carbonates that differed in bearing either an N-
alkyl or N-phenoxycarbonyl protecting group upon the in-
dole nitrogen. As indolyl carbonates are readily prepared
from the corresponding 3-substituted oxindole, a robust
method for the preparation of N-benzyl-3-methyloxindole
[( )-15] from N-benzylisatin (12) was necessary. Based
upon a literature procedure,22f addition of methylmagne-
sium bromide to N-benzylisatin (12), followed by reduc-
tion of the crude product with tin(II) chloride (2 equiv)
gave, after 90 minutes at 80 °C and at 75% conversion, a
SYNTHESIS 2008, No. 17, pp 2805–2818
x
x.
x
x
.
2
0
0
8
Advanced online publication: 06.08.2008
DOI: 10.1055/s-2008-1077890; Art ID: C03008SS
© Georg Thieme Verlag Stuttgart · New York

2806
J. E. Thomson et al.
SPECIAL TOPIC
50:50 mixture of chloride ( )-14 and desired product ( )- An analogous series of transformations was used to pre-
15. Good conversion (>95%) to exclusively ( )-15 re- pare N-methyl-3-methyloxindole [( )-18] from N-methyl-
quired treatment with excess tin(II) chloride (3 equiv) for isatin (16), giving ( )-18 in 50% yield over two steps.
a prolonged period, giving ( )-15 in 39% yield over two Deprotonation of both N-methyl and N-benzyl-3-methyl-
steps after purification. An authentic sample of chloride oxindoles ( )-15 and ( )-18 with potassium hexamethyl-
( )-14 was prepared from ( )-13 by treatment with thionyl disilazane (KHMDS) and subsequent addition of phenyl
chloride in 83% isolated yield after chromatography, with chloroformate gave the desired indolyl carbonates 19 and
X-ray crystal structure analysis proving unambiguously 20 respectively (Scheme 2). Bisphenoxycarbonyl 22 was
its molecular structure (Figure 1). Reduction of chloride simply prepared by treatment of commercially available
( )-14 with tin(II) chloride (3 equiv) gave only ( )-15, 3-methyloxindole [( )-21] with phenyl chloroformate and
which is consistent with chloride ( )-14 being an interme- triethylamine, giving 22 in 86% yield. Compound 22 was
diate in the preparation of ( )-15 (Table 1).
characterised by X-ray crystal structure analysis, confirm-
ing that O- rather than C-carboxylation had occurred in
this reaction (Figure 2).
Table 1 Preparation of Model Substrate Precursor ( )-15
Me
OH
O
MeMgBr (2 equiv)
THF,
Me
OH
O
Me
SnCl2
(3 equiv)
MeMgBr
(2 equiv)
O
O
N
–78 °C to 0 °C
N
Bn
Bn
12
O
O
O
THF,
N
N
N
AcOH–HCl,
80 °C
( )-13
Me
Me
–78 °C to 0 °C
Me
16
( )-18
SOCl2, r.t.
overnight
83%
( )-17
SnCl2,
AcOH–HCl, 80 °C
50% (2 steps)
KHMDS (1.2 equiv)
THF, –78 °C
Me
Me
Me
Cl
Me
then
O
OCO2Ph
N
N
R
+
PhOCOCl (1.2 equiv)
THF, –78 °C to r.t.
R
O
N
O
N
Bn
Bn
( )-14
( )-15, R = Bn
( )-18, R = Me
19, R = Bn, 56%
20, R = Me, 51%
( )-15
SnCl2 (3 equiv), AcOH–HCl, 80 °C
Me
Me
68%
Et3N (2.2 equiv)
PhOCOCl (2.1 equiv)
THF, r.t.
SnCl2
(equiv)
Time
(h)
Conversion
Product distribution
( )-14:( )-15
O
N
OCO2Ph
CO2Ph
N
(%)a
H
( )-21
22, 86%
2
2
3
1.5
12
75
50:50
Scheme 2 Preparation of model indolyl carbonate derivatives 19,
20 and 22
90
12:88
12
>95
<5:>95 (39%)b
a All product conversions and distributions were judged by 1H NMR
spectroscopic analysis of the crude reaction product.
b Isolated yield of homogeneous product over two steps after chroma-
tography.
Figure 2 Molecular representation of the X-ray crystal structure of
22
Model Studies: N-Protecting Group Effects upon
NHC-Catalysed O-to-C Carboxyl Transfer of Indolyl
Carbonates
Primary studies focused upon probing the ability of the
NHC 3, derived from in situ deprotonation of triazolium
salt 23 (10 mol%) with KHMDS (9 mol%), to promote the
O-to-C carboxyl rearrangement of N-benzyl or N-methyl
Figure 1 Molecular representation of the X-ray crystal structure of
chloride ( )-14 [one of two crystallographically independent mole-
cules showing the major orientation of the disorder at C(3)]
Synthesis 2008, No. 17, 2805–2818 © Thieme Stuttgart · New York

SPECIAL TOPIC
O-to-C Carboxyl Transfer of Indolyl and Benzofuranyl Carbonates
2807
protected carbonates 19 and 20, which proceeded to full treatment of an authentic homogeneous sample of ( )-26
conversion within one hour to give ( )-24 and ( )-25 re- with NHC 3 (9 mol%) furnished a 60:40 mixture of ( )-
spectively. Successively decreasing the catalyst loading 26:( )-27 and diphenyl carbonate (Table 2, entry 4). The
indicated that 1.9 mol% of NHC 3 could be used to pro- product distributions arising from both the crude reaction
mote the desired rearrangement in both cases, giving ( )- mixtures and isolated product mixtures indicate that al-
24 and ( )-25 in 69% and 71% isolated yield respectively though O-to-C carboxyl group rearrangement proceeds
(Scheme 3).
readily in this case, the N-phenoxycarbonyl group is labile
to deprotection both upon silica and exposure to the NHC
3. The formation of diphenyl carbonate as a by-product
presumably requires the in situ generation of phenoxide,
although at the present time a mechanism to account for
this transformation has not been conclusively proven.
Despite these problems, it is clear that NHC 3 promotes
efficiently the O-to-C carboxyl transfer reaction of these
model indolyl carbonate derivatives with good catalytic
efficiency and reasonable reaction times.
N
BF4
Ph
N
N
23 (2 mol%)
KHMDS (1.9 mol%),
THF,
1 h, r.t.
N
OPh
Me
Me
N
N
Ph
O
O
3
OCO2Ph
N
N
R
R
19, R = Bn
20, R = Me
( )-24, R = Bn, 69%
( )-25, R = Me, 71%
Scheme 3 NHC-promoted O-to-C carboxyl transfer of 19 and 20
Similar treatment of biscarbonate 22 with NHC 3 (9
mol%) gave, after complete conversion of 22 (1 h), a
60:40 mixture of C-phenoxycarbonyl ( )-26 and oxindole
( )-27, with chromatographic purification furnishing ( )-
26 in 31% yield and ( )-27 in 69% yield respectively
(Table 2, entry 1). The molecular structure of ( )-27 was
confirmed by X-ray crystallography (Figure 3). Increas-
ing the reaction time to two hours with 9 mol% of NHC 3
gave a 10:90 mixture of ( )-26:( )-27, and allowed the
isolation of diphenyl carbonate as a by-product of this re-
action by chromatography. Decreasing the NHC loading
to 4 mol% gave an 80:20 mixture of ( )-26:( )-27, while
Figure 3 Molecular representation of the X-ray crystal structure of
oxindole ( )-27
Table 2 NHC-Promoted O-to-C Carboxyl Rearrangement of 22
23 (10 mol%), KHMDS (9 mol%)
THF, r.t., 1 h
product ratio ( )-26:( )-27
60:40
N
BF4
N
N
OPh
Me
OPh
Me
Ph
Me
23
KHMDS
O
O
O
O
+
OCO2Ph
CO2Ph
N
N
N
CO2Ph
H
( )-26
( )-27
22
Entry
23
(mol%)
KHMDS
(mol%)
Time
(min)
Product ratioa
( )-26:( )-27
1
2
3
4
10
10
5
9
9
4
9
60
120
60
60:40
10:90
80:20
60:40
10
60
a Product distributions were judged by 1H NMR spectroscopic analysis of the crude reaction mixture.
Synthesis 2008, No. 17, 2805–2818 © Thieme Stuttgart · New York

2808
J. E. Thomson et al.
SPECIAL TOPIC
carboxyl transfer reaction, although carbamate and phos-
phate derivatives are inert.
Probing the Generality of NHC-Mediated O-to-C
Functional Group Transfer of Indolyl Derivatives
Given the product mixtures associated with the rearrange-
ment of N-phenoxycarbonyl protected carbonate 22 with
NHC 3, subsequent studies utilised N-alkyl group protec-
tion of the indole nitrogen and sought to identify the scope
and limitations of this rearrangement process with respect
to both the migrating group and C(3)-substitution. Treat-
ment of N-benzyl-3-methyloxindole [( )-15] with
KHMDS and subsequent derivatisation with dimethylcar-
bamoyl chloride or diphenyl phosphoryl chloride gave the
corresponding indolyl carbamate 28 and phosphate 29 in
good yield. Disappointingly, treatment of either 28 or 29
with NHC 3 (9 mol%) failed to promote rearrangement in
either case,24 returning only starting material after one
hour (Scheme 4).
Figure 4 Molecular representation of the X-ray crystal structure of
34
Table 3 NHC-Promoted O-to-C Carboxyl Transfer of 32–34
KHMDS (1.2 equiv),
Ph
Ph
Me
Me
THF, –78 °C
Et3N then
then
O
MeOCOCl,
PhOCOCl
or PhCOBr
OR2
O
OR
N
R1
N
R1
N
N
ClOCONMe2
or ClPO(OPh)2
THF, –78 °C
Bn
Bn
( )-15
28, R = CONMe2, 85%
29, R = PO(OPh)2, 80%
( )-30, R1 = Bn
( )-31, R1 = Me
32, R1 = Bn, R2 = CO2Me
33, R1 = Bn, R2 = CO2Ph
34, R1 = Me, R2 = CO2Ph
23
KHMDS
(9 mol%)
THF, r.t.
(10 mol%)
N
BF4
Ph
KHMDS
THF, r.t.
N
N
Me
23
R
O
Ph
R2
N
Bn
O
N
R1
Scheme 4 Preparation and attempted NHC-promoted rearrange-
ment of 28 and 29
( )-35, R1 = Bn, R2 = CO2Me
( )-36, R1 = Bn, R2 = CO2Ph
( )-37, R1 = Me, R2 = CO2Ph
Subsequent studies focused predominantly upon the ef-
fect of variation in C(3)-substitution. N-Benzyl- and N-
methyl-3-phenyloxindoles ( )-30 and ( )-31 were pre-
pared by a similar route to that used for ( )-15 and ( )-18
respectively, with derivatisation using methyl or phenyl
chloroformate under standard conditions giving carbon-
ates 32–34 in good yields. X-ray crystal structure analysis
of methyl carbonate 34 confirmed unambiguously that O-
rather than C-carboxylation had occurred under these re-
action conditions (Figure 4). Treatment of N-benzyl pro-
tected carbonates 32 and 33 with NHC 3 (9 mol%) gave
full conversion to ( )-35 and ( )-36 respectively in both
cases, with the structure of ( )-35 confirmed by X-ray dif-
fraction (Figure 5). However, a notable difference in the
reactivity of the methyl and phenyl carbonate derivatives
was observed upon decreasing the catalyst loading, with
phenyl carbonate 33 rearranging readily to give ( )-36
with 1.5 mol% of NHC 3, while methyl carbonate 32 re-
quired 4 mol% of NHC 3 to achieve full reaction conver-
sion to ( )-35 within one hour. Further investigation
showed that N-methyl protected phenyl carbonate 34 re-
quired 4 mol% of NHC 3 to give good conversion to ( )-
37 within one hour (Table 3). ( )-37 was isolated in 74%
yield and further characterised by X-ray crystallographic
analysis (Figure 5). These studies confirm that phenyl car-
bonate derivatives are particularly reactive in this O-to-C
Entry
23
(mol%)
KHMDS
(mol%)
Product
Yield (%)
1
2
3
10
2
9
( )-35
( )-36
( )-37
49
91
74
1.5
4
5
To complete studies within the indolyl series, further
C(3)-substituent modifications utilising N-benzyl indole
protection was investigated. C(3)-Benzyl and C(3)-iso-
propyl substitution was envisaged to probe fully the limi-
tations of this protocol, as the rearrangement of oxazolyl
carbonates with C(3)-a-branched substituents is known to
be difficult with DMAP derivatives.22c Following the
standard protocol outlined above, N-benzylisatin (12) was
converted into N-benzyl-3-benzyl and N-benzyl-3-isopro-
pyloxindoles ( )-40 and ( )-41, respectively. Isolation of
the intermediate 3-hydroxyoxindoles ( )-38 and ( )-39
arising from Grignard addition was achieved by tritura-
tion of the crude reaction mixture with diethyl ether for
characterisation purposes, giving ( )-38 and ( )-39 in
good to moderate yields. In practice, however, the crude
reaction product from the Grignard addition can be re-
Synthesis 2008, No. 17, 2805–2818 © Thieme Stuttgart · New York

SPECIAL TOPIC
O-to-C Carboxyl Transfer of Indolyl and Benzofuranyl Carbonates
2809
one hour, giving ( )-44 in 74% isolated yield (Scheme 6),
the structure of which was confirmed by X-ray crystallo-
graphic analysis (Figure 7).
N
Ph
BF4
Ph
Ph
N
N
CO2Ph
O
Bn
( )-44, 74% yield
23 (2 mol%)
OCO2Ph
KHMDS
(1.5 mol%)
THF, r.t.
N
N
Bn
42
Scheme 6 NHC-promoted O-to-C carboxyl transfer of carbonate 42
Figure 5 Molecular representations of the X-ray crystal structures
of ( )-35 and ( )-37
duced with tin(II) chloride directly to afford the desired 3-
substituted oxindoles in respectable yield over two steps.
Subsequent carbonate formation under standard condi-
tions furnished 42 and 43 in 58% and 56% yield, respec-
tively (Scheme 5). Once again, unambiguous proof of the
O-phenoxycarbonyl linkage within 43 was proven by X-
ray crystal structure analysis (Figure 6).
Figure 7 Molecular representation of the X-ray crystal structure of
( )-44 (only one of two crystallographically independent molecules
shown for clarity)
Treatment of C(3)-benzyl substituted carbonate 42 with
NHC 3 (1.5 mol%) gave complete conversion to 44 within
As expected, the C(3)-isopropyl substituted carbonate 43
proved the most difficult indolyl carbonate substrate to re-
arrange under NHC-mediated catalysis. Treatment of 43
with 4 mol% of NHC 3 gave an 81:19 mixture of the de-
sired C-carboxyl product ( )-45 to oxindole 41 at full con-
version, giving an inseparable 84:16 mixture of ( )-
45:( )-41 after chromatographic purification. Derivatisa-
tion of this 84:16 mixture of ( )-45:( )-41 by treatment
with sodium borohydride and calcium chloride in metha-
nol was investigated to allow full characterisation, giving
a separable 22:62:16 mixture of alcohol ( )-46, methyl es-
ter ( )-47, and oxindole ( )-41, respectively (Scheme 7).
O
R
RMgBr (2 equiv)
OH
O
THF,
–78 °C to 0 °C
O
N
N
Bn
Bn
12
( )-38, R = Bn, 82%
( )-39, R = i-Pr, 37%
SnCl2
(3 equiv)
AcOH–HCl
80 °C
KHMDS (1.2 equiv)
THF, –78 °C
R
R
then
OCO2Ph
O
N
N
PhOCOCl (1.2 equiv)
THF, –78 °C to r.t.
N
Bn
Bn
BF4
N
N
42, R = Bn, 58%
43, R = i-Pr, 56%
Ph
( )-40, R = Bn, 53%
( )-41, R = i-Pr, 46% (2 steps)m
CO2Ph
23
(5 mol%)
+
OCO2Ph
O
O
N
N
N
KHMDS
(4 mol%)
THF, r.t.
Scheme 5 Preparation of indolyl carbonates 42 and 43
Bn
Bn
Bn
( )-45/( )-41 84:16
43
NaBH4, CaCl2
MeOH
CO2Me
OH
+
+
O
O
O
N
N
N
Bn
Bn
( )-47, 67%
Bn
( )-46, 24%
( )-41, 75%
Scheme 7 NHC-promoted O-to-C carboxyl transfer of carbonate 43
(isolated yields of ( )-46 and ( )-47 were calculated based upon the
known 84:16 mixture of ( )-45 and ( )-41, respectively).
Figure 6 Molecular representation of the X-ray crystal structure of
carbonate 43
Synthesis 2008, No. 17, 2805–2818 © Thieme Stuttgart · New York

2810
J. E. Thomson et al.
SPECIAL TOPIC
Table 4 NHC-Promoted O-to-C Carboxyl Rearrangement of 53–56
NHC-Mediated O-to-C Carboxyl Group Transfer of
Benzofuranyl Carbonates
N
BF4
Ph
OR2
R1
R1
Having demonstrated the scope of this NHC-mediated
protocol in the indolyl series, we investigated its exten-
sion to benzofuranyl carbonates. The presence of a C(3)-
branched substituent was again proposed to represent a
significant challenge to the ability of NHC 3 to promote
O-to-C carboxyl transfer in this system. The desired C(3)-
benzyl and C(3)-isopropyl substituted benzofuranones
were prepared following the method of Vedejs,22c with
alkylation of commercially available nitrile 48 and subse-
quent hydrolysis generating ( )-51 and ( )-52 on a multi-
gram scale. Treatment of ( )-51 and ( )-52 with
triethylamine and either phenyl- or methyl chloroformate
gave the desired substrates 53–56 in good isolated yield
(Scheme 8).
N
N
23
O
O
OCO2R2
KHMDS
THF, r.t.
O
O
( )-57, R1 = Bn, R2 = Ph
53, R1 = Bn, R2 = Ph
54, R1 = Bn, R2 = Me
55, R1 = i-Pr, R2 = Ph
56, R1 = i-Pr, R2 = Me
( )-58, R1 = Bn, R2 = Me
( )-59, R1 = i-Pr, R2 = Ph
( )-60, R1 = i-Pr, R2 = Me
Entry
23
(mol%)
KHMDS Product
(mol%)
Yield (%)
1
2
3
4
2
10
5
1.8
9
( )-57
( )-58
( )-59
( )-60
88
80
82
65
4
R1
10
9
NaH
(1.15 equiv)
CN
OMe
CN
a change in product distribution was noted in the indolyl
series with variation of the N-protecting group. The intro-
duction of a C(3)-isopropyl group into both the indolyl
and benzofuranyl skeleton is tolerated using NHC-medi-
ated catalysis, which is indicative of the high reactivity of
NHCs in this reaction manifold. Current studies are fo-
cused upon the preparation and optimisation of chiral
NHCs to develop asymmetric versions of this transforma-
tion and probing new applications of NHCs in asymmetric
catalysis.
THF,0 °C
then BnBr
or i-PrI
OMe
( )-49, R1 = Bn, 93%
( )-50, R1 = i-Pr, 96%
48
HBr (aq)
∆
R1
Et3N (1.4 equiv)
PhOCOCl
R1
OCO2R2
or MeOCOCl
(1.5 equiv), THF,
0 °C to r.t.
O
O
O
( )-51, R1 = Bn, 45%
( )-52, R1 = i-Pr, 61%
Reactions were conducted under an Ar atmosphere using standard
vacuum line techniques and with freshly dried solvents. Room tem-
perature (r.t.) refers to 20–25 °C. In vacuo refers to the use of a
Büchi Rotavapor R-2000 or a Heidolph Laborota 4001 rotary evap-
orator. Petroleum ether (PE), where used, had a boiling range of 40–
60 °C. Flash column chromatography was performed on Kieselgel
60 silica in the solvent system stated. 1H and 13C NMR spectra were
acquired on either a Bruker Avance 300 (300 MHz, 1H; 75.4 MHz,
13C) or Bruker Avance II 400 (400 MHz, 1H; 100 MHz, 13C) spec-
trometer in the deuterated solvent stated. Chemical shift values (d,
ppm) are reported relative to residual solvent peaks. The abbrevia-
tion Ar is used to denote aromatic. Infrared spectra (nmax) were re-
corded on a Perkin–Elmer Spectrum GX FT-IR. Microanalyses
were carried out on a Carlo Erba CHNS analyser. Melting points
were recorded on an Electrothermal apparatus and are uncorrected.
53, R1 = Bn, R2 = Ph, 65%
54, R1 = Bn, R2 = Me, 86%
55, R1 = i-Pr, R2 = Ph, 61%
56, R1 = i-Pr, R2 = Me, 94%
Scheme 8 Preparation of benzofuranyl carbonates 53–56
The O-to-C carboxyl transfer of carbonates 53–56 was
readily promoted upon treatment with 1.8–9 mol% NHC
3, in each case giving good conversion to the desired
products ( )-57–( )-60 within one hour, furnishing ( )-
57–( )-60 in 65–88% isolated yield respectively. The
trends in reactivity noted within this series of reactions
mirrors that observed within the indolyl series, with lower Mass spectrometric (m/z) data was acquired by electrospray ionisa-
tion (ESI), electron impact (EI) or chemical ionisation (CI), either
at the University of St Andrews Mass Spectrometry facility or at the
EPSRC National Mass Spectrometry Service Centre, Swansea.
catalyst loadings of NHC 3 giving full conversion to the
corresponding C-carboxyl products with phenyl rather
than methyl carbonate derivatives. Furthermore, C(3)-a-
Crystallographic data (excluding structure factors) for compounds
branched substituents are readily tolerated but require
( )-14, 22, ( )-27, 34, ( )-35, ( )-37, 43 and ( )-44 have been de-
slightly higher catalyst loadings to achieve full reaction
posited with the Cambridge Crystallographic Data Centre as sup-
conversion within one hour (Table 4).
plementary publication numbers 683081–683088. Copies of the
data can be obtained, free of charge, on application to CCDC, 12
Union Road, Cambridge, CB2 1EZ, UK [fax: +44(1223)336033 or
e-mail: deposit@ccdc.cam.ac.uk]
In conclusion, NHC 3 can promote the O-to-C carboxyl
group rearrangement of indolyl and benzofuranyl carbon-
ates with good catalytic efficiency (1.5–9 mol% of NHC
3) and reasonable reaction times. Variation of carbonate
functionality and C(3)-substitution within the indolyl and
benzofuranyl skeleton is readily accommodated, although
Grignard Addition to Isatins; General Procedure A
To a solution of the desired isatin in THF at –78 °C was slowly add-
ed a solution of Grignard reagent. The resulting solution was stirred
at –78 °C for 10 min, then warmed to 0 °C and stirred for a further
Synthesis 2008, No. 17, 2805–2818 © Thieme Stuttgart · New York

SPECIAL TOPIC
O-to-C Carboxyl Transfer of Indolyl and Benzofuranyl Carbonates
2811
20 min. After this time, sat. aq NH4Cl (5 mL/mmol) was added, fol-
lowed by EtOAc (5 mL/mmol) and the organic phase was removed.
The aqueous phase was extracted into EtOAc (3 × 5 mL/mmol) and
the combined organic fractions were washed with H2O (1 × 5 mL/
mmol) and brine (1 × 5 mL/mmol), dried (MgSO4), filtered and
concentrated.
1H NMR (300 MHz, CDCl3): d = 1.89 (s, 3 H, 3-CH3), 4.81 (ABq,
J = 15.7 Hz, 1 H, CHAHBPh), 4.90 (ABq, J = 15.7 Hz, 1 H,
CHAHBPh), 6.65 (d, J = 7.8 Hz, 1 H, ArH), 7.01 (td, J = 7.5, 1.0 Hz,
1 H, ArH), 7.14 (td, J = 7.8, 1.3 Hz, 1 H, ArH), 7.17–7.28 (m, 5 H,
ArH), 7.36 (dd, J = 7.4, 0.9 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 26.0, 44.0, 61.9, 109.8, 123.5,
123.9, 127.2, 127.9, 129.0, 130.1, 131.1, 135.2, 141.2, 174.6.
MS (CI): m/z (%) = 236.1 (100) [M – Cl]+, 272.1 (65) [M + H]+.
HRMS (CI): m/z [M + H]+ calcd for C16H15NOCl: 272.0842; found:
SnCl2 Reduction; General Procedure B
To a solution of starting material in a mixture of AcOH–HCl (con-
cd) (15:1), was added SnCl2·2H2O and the resulting suspension was
heated at 80 °C overnight. After cooling, the solution was poured
into H2O (10 mL/mmol), extracted into Et2O (3 × 5 mL/mmol) and
the organic fractions combined, washed with aq NaOH (2 M, 2 × 10
mL/mmol), dried (MgSO4), filtered and concentrated in vacuo to
give the desired oxindole after chromatographic purification.
272.0837.
1-Benzyl-3-methyl-2-oxo-2,3-dihydroindole [( )-15]
Following general procedure B, ( )-13 (5.34 g, 21.1 mmol), AcOH
(185 mL), concd HCl (12 mL) and SnCl2·2H2O (14.3 g, 63.3 mmol)
gave, after chromatographic purification (PE–Et2O, 80:20), ( )-15
with spectroscopic data in accordance with the literature.26
Formation of Indol-2-yl Carbonates Using KHMDS; General
Procedure C
Yield: 1.94 g (39% over two steps); yellow solid; mp 112–114 °C
(Lit.26 117–118 °C).
1H NMR (400 MHz, CDCl3): d = 1.53 (d, J = 7.6 Hz, 3 H, 3-CH3),
3.58 (q, J = 7.6 Hz, 1 H, CH), 4.95 (s, 2 H, NCH2Ph), 6.76 (td,
J = 7.8 Hz, 1 H, ArH), 7.03–7.39 (m, 8 H, ArH).
To a stirred solution of KHMDS in toluene (0.5 M, 1.2 equiv) at
–78 °C, was added a solution of the desired oxindole (1 equiv) in
THF at –78 °C. After 30 min the solution was added to a solution of
phenyl chloroformate (1.2 equiv) in THF at –78 °C and the reaction
was warmed slowly to r.t. overnight. After this time, HCl (0.1 M, 10
mL/mmol) was added and the mixture was extracted with Et2O
(3 × 10 mL/mmol). The combined organic phases were washed
with brine (1 × 10 mL/mmol), dried (MgSO4) then concentrated in
vacuo. Chromatographic purification or recrystallisation gave the
desired carbonate.
3-Hydroxy-1,3-dimethyl-2-oxo-2,3-dihydroindole [( )-17]
Following general procedure A, N-methylisatin (16; 2.00 g, 8.44
mmol), THF (40 mL) and methylmagnesium bromide (3.90 mL,
11.8 mmol, 3.0 M in Et2O) gave crude ( )-17 as a dark orange solid
(2.96 g) which was used without further purification.
Formation of Indol-2-yl and Benzofuran-2-yl Carbonates with
Et3N; General Procedure D
To a stirred solution of the desired oxindole or benzofuranone in
THF at 0 °C was added Et3N followed by the selected chlorofor-
mate and the reaction was warmed slowly to r.t. overnight. After
this time, work-up was carried out as described in general procedure
C and subsequent purification gave the desired carbonate.
1,3-Dimethyl-2-oxo-2,3-dihydroindole [( )-18]
Following general procedure B, crude ( )-17 (5.49 g, 30.9 mmol),
AcOH (280 mL), concd HCl (20 mL) and SnCl2·2H2O (13.9 g, 61.7
mmol) gave, after chromatographic purification (PE–Et2O, 70:30),
( )-18 with spectroscopic data in accordance with the literature.27
Yield: 2.50 g (50% over two steps); yellow oil.
1H NMR (400 MHz, CDCl3): d = 1.48 (d, J = 7.6 Hz, 3 H, CH3),
3.21 (s, 3 H, NCH3), 3.43 (q, J = 7.4 Hz, 1 H, H-3), 6.82 (d, J = 7.8
Hz, 1 H, ArH), 7.03–7.08 (m, 1 H, ArH), 7.22–7.30 (m, 2 H, ArH).
Rearrangement of Carbonates; General Procedure E
KHMDS was added to a solution of triazolium salt 23 in THF and
the mixture was stirred at r.t. for 30 min. The desired carbonate was
added, either as a solution in THF or as a solid, and stirred for the
specified time before concentration in vacuo. Chromatographic pu-
rification (silica) gave the desired product.
1-Benzyl-3-methylindol-2-yl Phenyl Carbonate (19)
Following general procedure C, KHMDS (5.00 mL, 2.52 mmol),
oxindole ( )-15 (0.500 g, 2.10 mmol), THF (4.20 mL), phenyl chlo-
roformate (0.320 mL, 2.52 mmol) and THF (4.20 mL) gave, after
chromatographic purification (PE–Et2O, 90:10), carbonate 19 with
spectroscopic data in accordance with the literature.22c
1-Benzyl-3-hydroxy-3-methyl-2-oxo-2,3-dihydroindole [( )-13]
Following general procedure A, N-benzylisatin (12; 5.00 g, 21.1
mmol), THF (100 mL) and methylmagnesium bromide (9.80 mL,
29.5 mmol, 3.0 M in Et2O) gave, after recrystallisation (EtOH), ( )-
13 with spectroscopic data in accordance with the literature.25
Yield: 0.420 g (56%); colourless solid; mp 67–69 °C.
1H NMR (400 MHz, CDCl3): d = 2.20 (s, 3 H, CH3), 5.21 (s, 2 H,
CH2), 7.00–7.17 (m, 7 H, ArH), 7.19–7.25 (m, 3 H, ArH), 7.28–
7.37 (m, 3 H, ArH), 7.48–7.52 (m, 1 H, ArH).
Yield: 2.18 g (41%); yellow solid; mp 146–148 °C.
1H NMR (300 MHz, CDCl3): d = 1.70 (s, 3 H, 3-CH3), 3.14 (s, 1 H,
OH), 4.85 (ABq, J = 15.7 Hz, 1 H, CHAHBPh), 5.00 (ABq, J = 15.7
Hz, 1 H, CHAHBPh), 6.75 (d, J = 7.8 Hz, 1 H, ArH), 7.10 (td,
J = 7.5, 0.9 Hz, 1 H, ArH), 7.23 (td, J = 7.7, 1.3 Hz, 1 H, ArH),
7.27–7.38 (m, 5 H, PhH), 7.45 (dd, J = 7.3, 0.9 Hz, 1 H, ArH).
1,3-Dimethylindol-2-yl Phenyl Carbonate (20)
Following general procedure C, KHMDS (16.8 mL, 8.42 mmol),
oxindole ( )-18 (1.13 g, 7.02 mmol), THF (14 mL), phenyl chloro-
formate (1.06 mL, 8.42 mmol) and THF (14 mL) gave a pale-yellow
solid. NMR analysis of this material indicated that it was a 2:1 mix-
ture of O- and C-carboxylated product. This residue was then tritu-
rated with Et2O and the solid material filtered off to give the desired
carbonate 20 with spectroscopic data in accordance with the litera-
ture.22c
1-Benzyl-3-chloro-3-methyl-2-oxo-2,3-dihydroindole [( )-14]
Thionyl chloride (1.01 mL, 13.8 mmol) was added to ( )-13 (0.500
g, 1.97 mmol) and the resultant solution was stirred at r.t. overnight
before concentration in vacuo. Chromatographic purification (PE–
Et2O, 80:20) gave ( )-14.
Yield: 1.00 g (51%); pale-yellow solid; mp 115–117 °C.
Yield: 0.444 g (83%); yellow solid; mp 76–77 °C.
1H NMR (300 MHz, CDCl3): d = 2.27 (s, 3 H, 3-CH3), 3.67 (s, 3 H,
NCH3), 7.12–7.20 (m, 1 H, ArH), 7.24–7.34 (m, 5 H, ArH), 7.40–
7.49 (m, 2 H, ArH), 7.53–7.58 (m, 1 H, ArH).
IR (KBr): 3032 (C–H), 1730 (C=O), 1613 (Ar C=C), 751 (C–Cl),
697 cm–1 (Ar C–H).
Synthesis 2008, No. 17, 2805–2818 © Thieme Stuttgart · New York

2812
J. E. Thomson et al.
SPECIAL TOPIC
1-Benzyl-3-methylindol-2-yl Dimethylcarbamate (28)
3-Methyl-1-phenoxycarbonylindol-2-yl Phenyl Carbonate (22)
Following general procedure D, 3-methyloxindole ( )-21 (1.50 g,
10.2 mmol), THF (30 mL), Et3N (3.10 mL, 22.4 mmol) and phenyl
chloroformate (2.70 mL, 21.6 mmol) gave, after trituration (PE), the
product 22, with spectroscopic data in accordance with the litera-
ture.22c
To a stirred solution of oxindole ( )-15 (0.200 g, 0.850 mmol) in
THF (1.70 mL) at –78 °C was added KHMDS (2.05 mL, 1.02
mmol) followed by dimethylcarbamoyl chloride (0.0820 mL, 0.900
mmol) and the reaction warmed slowly to r.t. overnight. After this
time, H2O (2 mL) was added and the organic phase was extracted
with Et2O (3 × 2 mL). The organic extracts were combined, washed
with HCl (0.1 M, 1 × 6 mL), sat. aq NaHCO3 (1 × 6 mL) and brine
(1 × 6 mL), dried (MgSO4) then concentrated in vacuo. Chromato-
graphic purification (PE–Et2O, 25:75) gave carbamate 28.
Yield: 3.40 g (86%); pale-yellow solid; mp 93–96 °C.
1H NMR (300 MHz, CDCl3): d = 2.28 (s, 3 H, 3-CH3), 7.10–7.25
(m, 3 H, ArH), 7.29–7.56 (m, 10 H, ArH), 8.14–8.19 (m, 1 H, ArH).
Yield: 0.222 g (85%); colourless solid; mp 135–136 °C.
Phenyl 1-Benzyl-3-methyl-2-oxo-2,3-dihydroindole-3-carboxy-
late [( )-24]
Following general procedure E, KHMDS (0.018 mL, 0.0090 mmol,
1.9 mol%), triazolium salt 23 (0.0030 g, 0.0090 mmol, 2.0 mol%),
THF (0.4 mL) and carbonate 19 (0.17 g, 0.46 mmol) gave, after 1 h
and chromatographic purification (PE–Et2O, 60:40), ( )-24 with
spectroscopic data in accordance with the literature.22c
IR (KBr): 3053 (C–H), 2930 (C–H), 1739 (C=O), 1645 (Ar C=C),
1266 (C–O), 731 (C–H), 695 cm–1 (C–H).
1H NMR (300 MHz, CDCl3): d = 2.11 (s, 3 H, 3-CH3), 2.90 [s, 3 H,
N(CH3)2], 2.93 [s, 3 H, N(CH3)2], 5.07 (s, 2 H, CH2), 7.21–7.00 (m,
8 H, ArH), 7.45–7.42 (m, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 7.9, 37.0, 34.5, 46.4, 97.5, 109.7,
119.0, 119.8, 121.6, 127.1, 127.5, 127.7, 129.0, 132.8, 138.1, 140.2,
153.6.
Yield: 0.12 g (69%); colourless oil.
1H NMR (400 MHz, CDCl3): d = 1.76 (s, 3 H, CH3), 4.77 (ABq,
J = 15.8 Hz, 1 H, CHAHBPh), 5.09 (ABq, J = 15.8 Hz, 1 H,
CHAHBPh), 6.69 (d, J = 7.8 Hz, 1 H, ArH), 6.90 (d, J = 7.6 Hz, 2 H,
ArH), 7.01 (td, J = 7.6, 0.7 Hz, 1 H, ArH), 7.10–7.22 (m, 5 H, ArH),
7.22–7.31 (m, 5 H, ArH).
MS (EI+): m/z (%) = 309 (100) [M + H]+.
HRMS (EI+): m/z [M + H]+ calcd for C19H21N2O2: 309.1598; found:
309.1595.
1-Benzyl-3-methylindol-2-yl Diphenyl Phosphate (29)
Phenyl 1,3-Dimethyl-2-oxo-2,3-dihydroindole-3-carboxylate
[( )-25]
Following general procedure E, KHMDS (0.014 mL, 0.0070 mmol,
1.9 mol%), triazolium salt 23 (0.0020 mg, 0.0070 mmol, 2 mol%),
THF (0.3 mL) and carbonate 20 (0.10 g, 0.35 mmol) gave, after 1 h
and chromatographic purification (PE–Et2O, 50:50), ( )-25 with
spectroscopic data in accordance with the literature.22c
To a stirred solution of oxindole ( )-15 (0.200 g, 0.85 mmol) in
THF (1.70 mL) at –78 °C was added KHMDS (2.05 mL, 1.02
mmol) followed by diphenyl phosphoroyl chloride (0.170 mL,
0.900 mmol) and the reaction warmed slowly to r.t. overnight. After
this time, H2O (2 mL) was added and the organic phase was extract-
ed with Et2O (3 × 2 mL). The organic extracts were combined,
washed with 0.1 M HCl (1 × 6 mL), sat. aq NaHCO3 (1 × 6 mL) and
brine (1 × 6 mL), dried (MgSO4) then concentrated in vacuo. Chro-
matographic purification (PE–Et2O, 25:75) gave phosphate 29.
Yield: 0.071 g (71%); colourless solid; mp 93–95 °C.
1H NMR (400 MHz, CDCl3): d = 1.77 (s, 3 H, 3-CH3), 3.30 (s, 3 H,
NCH3), 6.90–6.96 (m, 3 H, ArH), 7.11–7.21 (m, 2 H, ArH), 7.28–
7.40 (m, 4 H, ArH).
Yield: 0.320 g (80%); colourless oil.
IR (thin film): 3061 (C–H), 2900 (C–H), 1301 (P=O), 1627 (Ar
C=C), 1185 (C–O), 951 (P–O–C), 739 (C–H), 688 cm–1 (C–H).
1H NMR (300 MHz, CDCl3): d = 2.21 (d, J = 2.1 Hz, 3 H, 3-CH3),
5.11 (s, 2 H, CH2), 6.88–6.90 (m, 2 H, ArH), 7.00–7.19 (m, 16 H,
ArH), 7.40–7.44 (m, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 7.7, 45.8, 95.9 (d, J = 3.0 Hz),
109.7, 119.0, 120.0, 120.3 (d, J = 3.9 Hz), 122.0, 126.0, 126.6,
126.9, 127.4, 128.7, 130.0, 132.1, 137.4, 138.1 (d, J = 7.7 Hz),
150.5 (d, J = 7.3 Hz).
31P NMR (121 MHz, CDCl3): d = –16.
MS (CI+): m/z (%) = 470 (100) [M + H]+.
Diphenyl 3-Methyl-2-oxo-2,3-dihydroindole-1,3-dicarboxylate
[( )-26]
Following general procedure E, KHMDS (0.116 mL, 0.0581 mmol,
9 mol%), triazolium salt 23 (0.0176 g, 0.0645 mmol, 10 mol%),
THF (2.5 mL) and carbonate 22 (0.250 g, 0.645 mmol) gave, after
1 h, a 60:40 mixture of ( )-26:( )-27. Subsequent chromatographic
purification (PE–Et2O, 90:10→50:50), afforded ( )-26 (0.077 g,
31%) as a yellow oil with spectroscopic data in accordance with the
literature,22c and ( )-27 (0.119 g, 69%) as an orange solid.
1H NMR (400 MHz, CDCl3): d = 1.90 (s, 3 H, CH3), 6.94–7.01 (m,
2 H, ArH), 7.17–7.50 (m, 11 H, ArH), 8.05 (d, J = 8.1 Hz, 1 H,
ArH).
HRMS (CI+): m/z [M + H]+ calcd for C28H25NO4P: 470.1521;
found: 470.1520.
Phenyl-3-methyl-2-oxoindole-3-carboxylate [( )-27]
Mp 220–223 °C.
1-Benzyl-2-oxo-3-phenyl-2,3-dihydroindole [( )-30]
Following general procedure B, crude 1-benzyl-3-hydroxy-2-oxo-
3-phenyl-2,3-dihydroindole (1.99 g, 6.33 mmol), AcOH (56 mL),
concd HCl (4 mL) and SnCl2·2H2O (2.86 g, 12.7 mmol) gave, after
chromatographic purification (PE–Et2O, 80:20), ( )-30 with spec-
troscopic data in accordance with the literature.28
IR (KBr): 3083 (N–H), 1755 (C=O), 1708 (C=O), 1192 (C–O), 745
cm–1 (Ar C–H).
1H NMR (300 MHz, CDCl3): d = 1.73 (s, 3 H, 3-CH3), 6.88–6.92
(m, 3 H, ArH), 7.01–7.29 (m, 6 H, ArH), 8.16 (br s, 1 H, NH).
13C NMR (75 MHz, CDCl3): d = 19.6, 55.1, 110.1, 121.1, 122.2,
123.2, 126.3, 129.2, 129.7, 130.3, 142.2, 150.0, 168.4, 175.3.
Yield: 1.42 g (75% over two steps); yellow solid; mp 108–110 °C
(Lit.28 115–116 °C).
1H NMR (400 MHz, CDCl3): d = 4.63 (s, 1 H, H-3), 4.83 (ABq,
J = 15.6 Hz, 1 H, CHAHBPh), 4.93 (ABq, J = 15.6 Hz, 1 H,
CHAHBPh), 6.71 (d, J = 7.8 Hz, 1 H, ArH), 6.94 (td, J = 7.6, 0.9 Hz,
1 H, ArH), 7.08–7.30 (m, 12 H, ArH).
MS (ESI+): m/z (%) = 290.1 (100) [M + Na]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C16H13NO3Na: 290.0793;
found: 290.0792.
Synthesis 2008, No. 17, 2805–2818 © Thieme Stuttgart · New York

SPECIAL TOPIC
O-to-C Carboxyl Transfer of Indolyl and Benzofuranyl Carbonates
2813
1-Methyl-2-oxo-3-phenyl-2,3-dihydroindole [( )-31]
IR (KBr): 3052 (C–H), 2925 (C–H), 1777 (C=O), 1619 (Ar C=C),
1601 (Ar C=C), 1249 (C–O), 1138 (C–O), 748 cm–1 (Ar C–H).
1H NMR (400 MHz, CDCl3): d = 3.65 (s, 3 H, N-CH3), 6.99–7.03
(m, 2 H, ArH), 7.09–7.30 (m, 7 H, ArH), 7.37–7.42 (m, 2 H, ArH),
7.56–7.59 (m, 2 H, ArH), 7.74 (d, J = 8.0 Hz, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 28.6, 29.8, 103.3, 109.4, 119.8,
120.6, 120.8, 122.3, 124.7, 126.4, 126.7, 128.4, 128.9, 129.7, 132.7,
133.0, 138.7, 150.8.
To a solution of crude 3-hydroxy-1-methyl-2-oxo-3-phenyl-2,3-di-
hydroindole (4.49 g, 18.7 mmol) in anhydrous CH2Cl2 (40 mL) at
0 °C was added triethylsilane (5.96 mL, 37.4 mmol) followed by
BF3·OEt2 (4.74 mL, 37.4 mmol). The reaction mixture was stirred
at 0 °C for 20 min and then allowed to warm slowly to r.t. overnight.
The reaction was quenched with sat. aq NaHCO3 (40 mL) and, once
gas evolution had subsided, extracted with CH2Cl2 (3 × 40 mL).
The organic extracts were combined, washed with H2O (1 × 40 mL)
and brine (1 × 40 mL), dried (MgSO4) and concentrated in vacuo.
Chromatographic purification (PE–Et2O, 90:10) afforded ( )-31
with spectroscopic data in accordance with the literature.29
MS (CI+): m/z (%) = 344.1 (70) [M + H]+.
HRMS (CI+): m/z [M + H]+ calcd for C22H18NO3: 344.1287; found:
344.1293 (+1.8 ppm).
Yield: 2.50 g (60% over two steps); pale-yellow solid; mp 116–
118 °C (Lit.30 118–119 °C).
1H NMR (300 MHz, CDCl3): d = 3.30 (s, 3 H, N-CH3), 4.65 (s, 1 H,
H-3), 6.94 (d, J = 7.8 Hz, 1 H, ArH), 7.11 (t, J = 7.5 Hz, 1 H, ArH),
7.20–7.26 (m, 3 H, ArH), 7.30–7.40 (m, 4 H, ArH).
Methyl 1-Benzyl-2-oxo-3-phenyl-2,3-dihydroindole-3-carboxy-
late [( )-35]
Following general procedure E, KHMDS (0.10 mL, 0.050 mmol, 9
mol%), triazolium salt 23 (0.015 mg, 0.056 mmol, 10 mol%), THF
(2 mL) and carbonate 32 (0.20 g, 0.56 mmol) gave, after 1 h and
chromatographic purification (PE–Et2O, 80:20), compound ( )-35.
1-Benzyl-3-phenylindol-2-yl Methyl Carbonate (32)
Following general procedure D, oxindole ( )-30 (1.00 g, 3.34
mmol), THF (15 mL), Et3N (0.510 mL, 3.68 mmol) and methyl
chloroformate (0.270 mL, 3.55 mmol) gave, after chromatographic
purification (PE–Et2O, 90:10), carbonate 32.
Yield: 0.098 g (49%); colourless solid; mp 140–142 °C.
IR (KBr): 2952 (C–H), 1746 (C=O), 1720 (C=O), 1609 (Ar C=C),
1232 (C–O), 696 cm–1 (Ar C–H).
1H NMR (300 MHz, CDCl3): d = 3.69 (s, 3 H, OCH3), 4.75 (ABq,
J = 15.8 Hz, 1 H, CHAHBPh), 4.95 (ABq, J = 15.8 Hz, 1 H,
CHAHBPh), 6.68–6.71 (m, 1 H, ArH), 7.01–7.07 (m, 1 H, ArH),
7.14–7.30 (m, 11 H, ArH), 7.35–7.39 (m, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 44.1, 53.4, 64.1, 109.9, 123.1,
126.0, 127.1 (× 2), 127.7, 128.0, 128.4, 128.7, 128.8, 129.6, 135.4,
135.8, 143.5, 169.8, 173.1.
Yield: 1.67 g (93%); pale-yellow gum.
IR (thin film): 3059 (C–H), 3032 (C–H), 2957 (C–H), 2925 (C–H),
1781 (C=O), 1619 (C=C), 1244 (C–O), 1213 (C–O), 700 cm–1 (Ar
C–H).
1H NMR (300 MHz, CDCl3): d = 3.64 (s, 3 H, OCH3), 5.19 (s, 2 H,
CH2Ph), 7.07–7.27 (m, 9 H, ArH), 7.34–7.40 (m, 2 H, ArH), 7.52–
7.56 (m, 2 H, ArH), 7.72–7.78 (m, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 46.2, 56.2, 103.7, 110.0, 119.8,
120.9, 122.5, 125.1, 126.4, 126.9, 127.7, 128.4, 128.9 (× 2), 132.4,
133.0, 136.7, 138.8, 152.6.
MS (ESI+): m/z (%) = 380.0 (100) [M + Na]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C23H19NO3Na: 380.1263;
found: 380.1268 (+1.3 ppm).
MS (ESI+): m/z (%) = 380.1 (100) [M + Na]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C23H19NO3Na: 380.1263;
Phenyl 1-Benzyl-2-oxo-3-phenyl-2,3-dihydroindole-3-carboxy-
late [( )-36]
Following general procedure E, KHMDS (0.028 mL, 0.014 mmol,
1.5 mol%), triazolium salt 23 (0.0050 mg, 0.019 mmol, 2.0 mol%),
THF (0.4 mL) and carbonate 33 (0.40 g, 0.96 mmol) gave, after 1 h
and subsequent chromatographic purification (PE–Et2O, 90:10),
( )-36.
found: 380.1256 (–1.8 ppm).
1-Benzyl-3-phenylindol-2-yl Phenyl Carbonate (33)
Following general procedure D, oxindole ( )-30 (1.50 g, 5.02
mmol), THF (23 mL), Et3N (0.770 mL, 5.52 mmol) and phenyl
chloroformate (0.670 mL, 5.32 mmol) gave, after recrystallisation
(CH2Cl2–MeOH), carbonate 33.
Yield: 0.36 g (91%); colourless solid; mp 85–87 °C.
IR (KBr): 3061 (C–H), 3032 (C–H), 2936 (C–H), 1768 (C=O),
1714 (C=O), 1608 (Ar C=C), 1189 (C–O), 752 (C–H), 695 cm–1 (Ar
C–H).
1H NMR (300 MHz, CDCl3): d = 4.86 (ABq, J = 15.8 Hz, 1 H,
CHAHBPh), 5.15 (ABq, J = 15.8 Hz, 1 H, CHAHBPh), 6.84–6.87 (m,
1 H, ArH), 7.05–7.09 (m, 2 H, ArH), 7.19–7.54 (m, 15 H, ArH),
7.61–7.65 (m, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 44.2, 64.4, 110.2, 121.2, 123.3,
126.0, 126.3, 126.7, 127.2, 127.8, 128.2, 128.6, 128.8, 128.9, 129.5,
130.0, 135.4, 143.7, 150.6, 167.8, 172.7.
Yield: 1.82 g (87%); pale-yellow solid; mp 116–118 °C.
IR (KBr): 3060 (C–H), 3033 (C–H), 2925 (C–H), 1793 (C=O),
1620 (C=C), 1228 (C–O), 1192 (C–O), 742 (Ar C–H), 700 cm–1 (Ar
C–H).
1H NMR (300 MHz, CDCl3): d = 5.30 (s, 2 H, CH2Ph), 6.72–6.77
(m, 2 H, ArH), 7.09–7.28 (m, 12 H, ArH), 7.38–7.44 (m, 2 H, ArH),
7.59–7.63 (m, 2 H, ArH), 7.74–7.80 (m, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 46.2, 103.8, 110.0, 119.8, 120.5,
120.9, 122.6, 125.0, 126.5, 126.6, 126.9, 127.8, 128.4, 128.9 (× 2),
129.6, 132.4, 132.9, 136.6, 138.7, 150.2, 150.7.
MS (ESI+): m/z (%) 442.1 (100) [M + Na]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C28H21NO3Na: 442.1419;
MS (CI): m/z (%) = 420.2 (100) [M + H]+.
HRMS (CI): m/z [M + H]+ calcd for C28H22NO3: 420.1600; found:
found: 442.1422 (+0.7 ppm).
420.1589 (–2.5 ppm).
Phenyl 1-Methyl-2-oxo-3-phenyl-2,3-dihydroindole-3-carboxy-
late [( )-37]
Following general procedure E, KHMDS (0.058 mL, 0.029 mmol,
4 mol%), triazolium salt 23 (0.010 g, 0.036 mmol, 5 mol%), THF
(1.6 mL) and carbonate 34 (0.25 g, 0.73 mmol) gave, after 1 h and
chromatographic purification (PE–Et2O, 60:40), ( )-37.
1-Methyl-3-phenylindol-2-yl Phenyl Carbonate (34)
Following general procedure D, oxindole ( )-31 (0.600 g, 2.69
mmol), THF (7 mL), Et3N (0.390 mL, 2.96 mmol) and phenyl chlo-
roformate (0.360 mL, 2.85 mmol) gave, after chromatographic pu-
rification (PE–Et2O, 90:10), carbonate 34.
Yield: 0.19 g (74%); colourless oil.
Yield: 0.757 g (82%); pale-yellow solid; mp 78–80 °C.
Synthesis 2008, No. 17, 2805–2818 © Thieme Stuttgart · New York

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SPECIAL TOPIC
1-Benzyl-2-oxo-3-isopropyl-2,3-dihydroindole [( )-41]
Following general procedure B, crude ( )-39 (3.56 g, 12.7 mmol),
AcOH (120 mL), concd HCl (8 mL) and SnCl2·2H2O (8.57 g, 38.0
mmol) gave, after chromatographic purification (PE–Et2O, 90:10),
( )-41 with spectroscopic data in accordance with the literature.33
IR (thin film): 3061 (C–H), 2937 (C–H), 1763 (C=O), 1720 (C=O),
1609 (Ar C=C), 1187 (C–O), 750 (Ar C–H), 736 cm–1 (Ar C–H).
1H NMR (400 MHz, CDCl3): d = 3.13 (s, 3 H, NCH3), 6.86 (d,
J = 7.8 Hz, 1 H, ArH), 6.88–6.92 (m, 2 H, ArH), 7.05–7.14 (m, 2 H,
ArH), 7.18–7.29 (m, 5 H, ArH), 7.32–7.38 (m, 3 H, ArH), 7.48–
7.51 (m, 1 H, ArH).
Yield: 1.55 g (46% over two steps); crimson oil.
13C NMR (75 MHz, CDCl3): d = 26.9, 64.1, 109.1, 121.2, 123.2,
126.1, 126.3, 126.5, 128.0, 128.5, 128.7, 129.5, 130.1, 135.5, 144.6,
150.6, 167.7, 172.4.
MS (EI): m/z (%) = 343.1 (10) [M]+.
HRMS (EI): m/z [M]+ calcd for C22H17NO3: 343.1208; found:
1H NMR (300 MHz, CDCl3): d = 0.93 [d, J = 7.0 Hz, 3 H,
CH(CH3)2], 1.12 [d, J = 7.0 Hz, 3 H, CH(CH3)2], 2.51–2.63 [m,
1 H, CH(CH3)2], 3.47 [d, J = 3.5 Hz, 1 H, C(3)H], 4.79 (ABq,
J = 15.6 Hz, 1 H, NCHAHBPh), 5.03 (ABq, J = 15.6 Hz, 1 H,
NCHAHBPh), 6.68–6.73 [m, 1 H, C(7)H], 6.97–7.03 (m, 1 H, ArH),
7.12–7.20 (m, 1 H, ArH), 7.21–7.32 (m, 6 H, ArH).
343.1211 (+0.7 ppm).
1,3-Dibenzylindol-2-yl Phenyl Carbonate (42)
1,3-Dibenzyl-3-hydroxy-2-oxo-2,3-dihydroindole [( )-38]
Following general procedure A, N-benzylisatin 12 (3.50 g, 14.8
mmol), THF (60 mL) and benzylmagnesium bromide (8.12 mL,
16.2 mmol, 2.0 M in THF) gave, after trituration with Et2O, ( )-38
with spectroscopic data in accordance with the literature.31
Yield: 3.97 g (82%); pale-yellow solid; mp 164–165 °C (Lit.31 188–
190 °C).
1H NMR (300 MHz, CDCl3): d = 3.30 (ABq, J = 12.7 Hz, 1 H,
CHAHBPh), 3.43 (ABq, J = 12.7 Hz, 1 H, CHAHBPh), 4.45 (ABq,
J = 16.0 Hz, 1 H, NCHAHBPh), 5.00 (ABq, J = 16.0 Hz, 1 H,
NCHAHBPh), 6.42–6.46 [m, 1 H, C(7)H], 6.69–6.74 (m, 2 H, ArH),
6.93–6.98 (m, 2 H, ArH), 7.04–7.24 (m, 8 H, ArH), 7.35–7.40 (m,
1 H, ArH).
Following general procedure C, KHMDS (6.50 mL, 3.25 mmol),
oxindole ( )-40 (0.850 g, 2.71 mmol), THF (8 mL), phenyl chloro-
formate (0.410 mL, 3.26 mmol) and THF (5 mL) gave, after recrys-
tallisation (Et2O–hexane), carbonate 42.
Yield: 0.680 g (58%); colourless solid; mp 97–99 °C.
IR (KBr): 3062 (C–H), 3029 (C–H), 2933 (C–H), 1778 (C=O),
1623 (Ar C=C), 1495 (Ar C=C), 1225 (C–O), 1198 (C–O), 742
cm–1 (Ar C–H).
1H NMR (300 MHz, CDCl3): d = 4.03 (s, 2 H, CCH2Ph), 5.21 (s,
2 H, NCH2Ph), 6.85–6.92 (m, 2 H, ArH), 6.96–7.04 (m, 1 H, ArH),
7.05–7.30 (m, 15 H, ArH), 7.32–7.38 (m, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 29.8, 46.5, 101.2, 110.0, 120.0,
120.5, 121.0, 122.5, 124.8, 126.5, 127.0, 127.1, 128.1, 128.8, 129.1,
129.3, 130.0, 132.9, 137.3, 139.7, 140.5, 150.9, 151.1.
1-Benzyl-3-hydroxy-2-oxo-3-isopropyl-2,3-dihydroindole [( )-
39]
Following general procedure A, N-benzylisatin 12 (4.00 g, 16.9
mmol), THF (65 mL) and isopropylmagnesium chloride (9.28 mL,
18.6 mmol, 2.0 M in THF) gave, after trituration with Et2O, ( )-39.
MS (CI): m/z (%) = 314.2 (100) [M + H – CO2Ph]+, 434.2 (34) [M
+ H]+.
HRMS (ESI+): m/z [M + H]+ calcd for C29H24NO3: 434.1751; found:
434.1751 (+0.1 ppm).
Yield: 1.77 g (37%); pale-yellow solid; mp 142–144 °C.
IR (KBr): 3366 (O–H), 3030 (C–H), 2966 (C–H), 1699 (C=O),
1616 (Ar C=C), 1466 (Ar C=C), 1181 (C–O), 754 cm–1 (Ar C–H).
1-Benzyl-3-isopropylindol-2-yl Phenyl Carbonate (43)
Following general procedure C, KHMDS (14.0 mL, 7.00 mmol),
( )-41 (1.55 g, 5.84 mmol), THF (14.5 mL), phenyl chloroformate
(0.880 mL, 7.00 mmol) and THF (9 mL) gave, after recrystallisation
(Et2O–hexane), carbonate 43.
1H NMR (300 MHz, CDCl3): d = 0.80 [d, J = 6.8 Hz, 3 H,
CH(CH3)2], 1.13 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 2.32 [sept, J = 6.8
Hz, 1 H, CH(CH3)2], 2.70 (s, 1 H, OH), 4.74 (ABq, J = 15.6 Hz,
1 H, NCHAHBPh), 5.03 (ABq, J = 15.6 Hz, 1 H, NCHAHBPh),
6.71–6.76 [m, 1 H, C(7)H], 7.01–7.08 (m, 1 H, ArH), 7.18–7.25 (m,
1 H, ArH), 7.25–7.33 (m, 5 H, ArH), 7.37–7.41 (m, 1 H, ArH).
Yield: 1.26 g (56%); colourless solid; mp 86–89 °C.
IR (KBr): 3064 (C–H), 2961 (C–H), 2926 (C–H), 1792 (C=O),
1622 (Ar C=C), 1466 (Ar C=C), 1225 (C–O), 1194 (C–O), 740
cm–1 (Ar C–H).
1H NMR (400 MHz, CDCl3): d = 1.45 [d, J = 7.1 Hz, 6 H,
CH(CH3)2], 3.21 [sept, J = 7.1 Hz, 1 H, CH(CH3)2], 5.25 (s, 2 H,
NCH2Ph), 7.04–7.25 (m, 8 H, ArH), 7.27–7.41 (m, 5 H, ArH),
7.69–7.73 (m, 1 H, ArH).
13C NMR (100 MHz, CDCl3): d = 22.4, 25.1, 46.0, 107.8, 109.8,
119.7, 120.2, 120.6, 121.9, 125.0, 126.6, 126.8, 127.6, 128.9, 129.7,
132.7, 137.1, 137.6, 150.9, 151.08.
13C NMR (75 MHz, CDCl3): d = 16.0, 16.5, 36.2, 43.9, 79.3, 109.3,
122.9, 124.8, 127.4, 127.7, 128.6, 128.8, 129.5, 135.6, 143.2, 178.7.
MS (EI+): m/z (%) = 91.1 (100) [CH2Ph]+, 238.2 (28) [M –
CH(CH3)2]+, 281.2 (27) [M]+, 282.3 (5) [M + H]+.
HRMS (ESI+): m/z [M + NH4]+ calcd for C18H23N2O2: 299.1754;
found: 299.1759 (+1.8 ppm).
1,3-Dibenzyl-2-oxo-2,3-dihydroindole [( )-40]
Following general procedure B, ( )-38 (2.00 g, 6.07 mmol), AcOH
(58 mL), concd HCl (3.7 mL) and SnCl2·2H2O (4.10 g, 18.2 mmol)
gave, after chromatographic purification (PE–Et2O, 90:10), ( )-40
with spectroscopic data in accordance with the literature.32
MS (ESI+): m/z (%) = 408.2 (100) [M + Na]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C25H23NNaO3: 408.1576;
found: 408.1579 (+0.9 ppm).
Yield: 1.00 g (53%); pale-yellow solid; mp 93–95 °C (Lit.32 98–
99 °C).
Phenyl 1,3-Dibenzyl-2-oxo-2,3-dihydroindole-3-carboxylate
[( )-44]
1H NMR (300 MHz, CDCl3): d = 3.14 [dd (ABX), J = 8.1 Hz,
JA–B = 13.6 Hz, 1 H, CHAHBPh], 3.51 (dABq, J = 4.4 Hz, JA–
B = 13.6 Hz, 1 H, CHAHBPh), 3.85 [dd, J = 4.4, 8.1 Hz, 1 H, C(3)H],
4.64 [dd (ABX), J = 15.8 Hz, 1 H, NCHAHBPh], 5.04 (ABq,
J = 15.8 Hz, 1 H, NCHAHBPh), 6.55 [d, J = 7.8 Hz, 1 H, C(7)H],
6.90–7.00 (m, 4 H, ArH), 7.06–7.17 (m, 3 H, ArH), 7.19–7.24 (m,
6 H, ArH).
Following general procedure E, KHMDS (0.0210 mL, 0.0107
mmol, 1.5 mol%), triazolium salt 23 (0.00390 g, 0.0143 mmol, 2
mol%), THF (0.55 mL) and carbonate 42 (0.310 g, 0.715 mmol)
gave, after 1 h and chromatographic purification (PE–Et2O, 90:10),
( )-44.
Yield: 0.228 g (74%); colourless solid; mp 104–105 °C.
Synthesis 2008, No. 17, 2805–2818 © Thieme Stuttgart · New York

SPECIAL TOPIC
O-to-C Carboxyl Transfer of Indolyl and Benzofuranyl Carbonates
2815
IR (KBr): 3060 (C–H), 3033 (C–H), 2933 (C–H), 1759 (C=O),
1721 (C=O), 1613 (Ar C=C), 1491 (Ar C=C), 1193 (C–O), 742
cm–1 (Ar C–H).
1H NMR (400 MHz, CDCl3): d = 3.72 (ABq, J = 13.4 Hz, 1 H,
CHAHBPh), 3.78 (ABq, J = 13.4 Hz, 1 H, CHAHBPh), 4.63 (ABq,
J = 16.1 Hz, 1 H, NCHAHBPh), 4.95 (ABq, J = 16.1 Hz, 1 H,
NCHAHBPh), 6.42–6.46 [m, 1 H, C(7)H], 6.67–6.72 (m, 2 H, ArH),
6.94–7.25 (m, 13 H, ArH), 7.32–7.38 (m, 2 H, ArH), 7.49–7.53 (m,
1 H, ArH).
Methyl 1-Benzyl-2-oxo-3-isopropyl-2,3-dihydroindole-3-car-
boxylate [( )-47]
IR (thin film): 2964 (C–H), 1745 (C=O), 1715 (C=O), 1610 (Ar
C=C), 1466 (Ar C=C), 1259 (C–O), 750 cm–1 (Ar C–H).
1H NMR (300 MHz, CDCl3): d = 0.85 [d, J = 6.9 Hz, 3 H,
CH(CH3)2], 1.16 [d, J = 6.9 Hz, 3 H, CH(CH3)2], 2.86 [sept, J = 6.9
Hz, 1 H, CH(CH3)2], 3.74 (s, 3 H, OCH3), 4.93 (ABq, J = 15.7 Hz,
1 H, NCHAHBPh), 4.98 (ABq, J = 15.7 Hz, 1 H, NCHAHBPh),
6.71–6.75 [m, 1 H, C(7)H], 7.02–7.09 (m, 1 H, ArH), 7.17–7.25 (m,
1 H, ArH), 7.25–7.37 (m, 6 H, ArH).
13C NMR (100 MHz, CDCl3): d = 17.2, 17.3, 34.8, 43.8, 52.9, 63.2,
109.1, 122.7, 124.1, 127.3, 127.60, 127.63, 128.7, 128.8, 135.7,
143.2, 169.8, 173.4.
13C NMR (75 MHz, CDCl3): d = 39.2, 43.8, 61.1, 109.9, 121.3,
122.8, 123.8, 126.2, 126.6, 127.0 (× 2), 127.3, 128.1, 128.7, 129.4
(× 2), 130.4, 134.3, 134.8, 143.6, 150.5, 168.1, 173.1.
MS (CI): m/z (%) = 314.2 (68) [M + H – CO2Ph]+, 434.2 (100) [M
+ H]+, 451.2 (50) [M + NH4]+.
MS (ESI+): m/z (%) = 346.2 (100) [M + Na]+.
HRMS (ESI+): m/z [M + NH4]+ calcd for C29H27N2O3: 451.2016;
HRMS (ESI+): m/z [M + Na]+ calcd for C20H21NO3Na: 346.1419;
found: 451.2008 (–1.7 ppm).
found: 346.1412 (–2.1 ppm).
Phenyl 1-Benzyl-2-oxo-3-isopropyl-2,3-dihydroindole-3-car-
boxylate [( )-45]
2-(2-Methoxyphenyl)-3-phenylpropiononitrile [( )-49]
2-Methoxyphenyl acetonitrile (48; 2.00 g, 13.6 mmol) was added in
a single portion to a stirred slurry of NaH (0.626 g, 15.6 mmol, 60%
wt in mineral oil) in DMF (3 mL) and stirred at r.t. for 1 h. The so-
lution was then cooled to 0 °C, benzyl bromide (1.62 mL, 13.6
mmol) was added, and the mixture warmed slowly to r.t. overnight.
The solution was quenched with sat. aq NH4Cl (50 mL), H2O (50
mL) was added and the mixture was extracted with Et2O (3 × 50
mL). The organic extracts were combined, dried (MgSO4) and con-
centrated in vacuo to give nitrile ( )-49, which was used without
further purification.
Following general procedure E, KHMDS (0.046 mL, 0.023 mmol,
4 mol%), triazolium salt 23 (0.0079 g, 0.029 mmol, 5 mol%), THF
(1.11 mL) and carbonate 43 (0.222 g, 0.576 mmol) gave, after 1 h
and chromatographic purification (PE–Et2O, 90:10), an inseparable
84:16 mixture of ( )-45:( )-41 (estimated by 1H NMR) as a colour-
less solid (0.172 g).
1H NMR (400 MHz, CDCl3): d = 0.93 [d, J = 6.8 Hz, 3 H,
CH(CH3)2], 1.27 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 2.96 [sept, J = 6.8
Hz, 1 H, CH(CH3)2], 4.93 (ABq, J = 15.7 Hz, 1 H, NCHAHBPh),
5.04 (ABq, J = 15.7 Hz, 1 H, NCHAHBPh), 6.74–6.77 [m, 1 H,
C(7)H], 7.00–7.04 (m, 2 H, ArH), 7.06–7.11 (m, 1 H, ArH), 7.20–
7.37 (m, 9 H, ArH), 7.42–7.45 (m, 1 H, ArH).
Yield: 2.99 g (93%); yellow oil.
1H NMR (300 MHz, CDCl3): d = 3.04–3.10 (m, 2 H, CH2Ph), 3.85
(s, 3 H, OCH3), 4.39–4.45 (m, 1 H, CHCN), 6.88–7.40 (m, 9 H,
ArH).
1-Benzyl-3-(hydroxymethyl)-2-oxo-3-isopropyl-2,3-dihydroin-
dole [( )-46]
2-(2-Methoxyphenyl)-3-methylbutyronitrile [( )-50]
NaBH4 (0.0400 g, 1.06 mmol) was added to a suspension of a 84:16
mixture of ( )-45:( )-41 (0.121 g) and CaCl2 (0.0590 g, 0.530
mmol) in anhydrous MeOH (1 mL), cooled to 0 °C and stirred at
this temperature for 2 h. The reaction was then allowed to warm to
r.t. and stirred overnight before concentration in vacuo. 3 N citric
acid was added dropwise until pH 2–3 before extracting with
CH2Cl2 (3 × 20 mL). The organic extracts were combined, dried
(Na2SO4) and concentrated in vacuo to give, after chromatography
(PE–Et2O, 90:10), ( )-46 as a colourless solid (0.0200 g, 24%) and
( )-47 (0.0600 g, 67%) as a colourless gum. Unreacted ( )-41 was
also recovered from the reaction mixture (0.0104 g, 75%).
2-Methoxyphenyl acetonitrile (48; 2.00 g, 13.6 mmol) was added in
a single portion to a stirred slurry of NaH (0.626 g, 15.6 mmol, 60%
wt in mineral oil) in DMF (3 mL) and stirred at r.t. for 1 h. The so-
lution was then cooled to 0 °C, 2-iodopropane (1.36 mL, 13.6
mmol) was added, and the mixture was warmed slowly to r.t. over-
night. The solution was quenched with sat. aq NH4Cl (50 mL), H2O
(50 mL) was added and the mixture was extracted with Et2O (3 × 50
mL). The organic extracts were combined, dried (MgSO4) and con-
centrated in vacuo to give nitrile ( )-50, which was used without
further purification.
Yield: 2.30 g (96%); pale-yellow oil.
IR (thin film): 2970 (C–H), 1750 (C≡N), 1620 cm–1 (C=C).
1H NMR (400 MHz, CDCl3): d = 0.99 [m, 6 H, (CH3)2], 2.08 [m,
1 H, CH(CH3)2], 3.73 (s, 3 H, OCH3), 4.03 (d, J = 6.4 Hz, 1 H,
CHCN), 6.78–6.97 (m, 2 H, ArH), 7.16–7.30 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 18.8, 20.9, 29.7, 39.0, 55.5, 110.7,
120.3, 120.7, 123.6, 129.2, 129.3, 156.2.
MS (ESI+): m/z (%) = 212.1 (100) [M + Na]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C12H15NONa: 212.1051;
Mp 137–140 °C.
IR (KBr): 3424 (O–H), 2964 (C–H), 1695 (C=O), 1611 (Ar C=C),
1466 (Ar C=C), 1177 (C–O), 697 cm–1 (Ar C–H).
1H NMR (300 MHz, CDCl3): d = 0.72 [d, J = 6.9 Hz, 3 H,
CH(CH3)2], 1.11 [d, J = 6.9 Hz, 3 H, CH(CH3)2], 2.32–2.42 (m,
1 H, OH), 2.54 [sept, J = 6.9 Hz, 1 H, CH(CH3)2], 3.79–3.88 (m,
1 H, CH2OH), 4.02–4.14 (m, 1 H, CH2OH), 4.91 (ABq, J = 15.7
Hz, 1 H, NCHAHBPh), 4.97 (ABq, J = 15.7 Hz, 1 H, NCHAHBPh),
6.72–6.78 [m, 1 H, C(7)H], 7.00–7.08 (m, 1 H, ArH), 7.15–7.34 (m,
7 H, ArH).
13C NMR (75 MHz, CDCl3): d = 17.3, 17.5, 31.2, 43.7, 57.6, 65.5,
109.2, 122.5, 123.9, 127.3, 127.6, 128.3, 128.7, 128.8, 135.8, 143.8,
180.0.
found: 212.1047 (+1.9 ppm).
3-Benzyl-2-oxo-2,3-dihydrobenzofuran [( )-51]
Nitrile ( )-49 (4.60 g, 20.5 mmol) was poured onto aq HBr (48%,
100 mL) and heated to reflux for 5 d. The reaction was then cooled
0 °C, and excess acid was neutralised by slow addition of 3 M aq
NaOH, then extracted with Et2O (3 × 75 mL). The organic layers
were combined, dried (MgSO4) and concentrated in vacuo to give,
after chromatographic purification (PE–Et2O, 90:10), benzofura-
MS (ESI+): m/z (%) = 318.2 (100) [M + Na]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C19H21NO2Na: 318.1470;
found: 318.1465 (–1.5 ppm).
Synthesis 2008, No. 17, 2805–2818 © Thieme Stuttgart · New York

2816
J. E. Thomson et al.
SPECIAL TOPIC
none ( )-51 with spectroscopic data in accordance with the litera-
Yield: 4.10 g (61%); pale-yellow oil.
ture.34
IR (thin film): 2968 (C–H), 1797 (C=O), 1653 (C=C), 1225 (C–O),
746 cm–1 (Ar C–H).
Yield: 2.09 g (45%); pale-orange oil.
1H NMR (300 MHz, CDCl3): d = 2.95 (dd, J = 13.7, 9.0 Hz, 1 H,
CHAHBPh), 3.43 (dd, J = 13.7, 4.8 Hz, 1 H, CHAHBPh), 3.93 (dd,
J = 9.0, 4.8 Hz, 1 H, CHCH2Ph), 6.66–7.43 (m, 9 H, ArH).
1H NMR (400 MHz, CDCl3): d = 0.95 [d, J = 6.9 Hz, 3 H,
CH(CH3)2], 1.23 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 2.93 [sept, J = 6.8
Hz, 1 H, CH(CH3)2], 7.01–7.05 (m, 2 H, ArH), 7.18 (d, J = 8.1 Hz,
1 H, ArH), 7.21–7.27 (m, 2 H, ArH), 7.33–7.43 (m, 3 H, ArH), 7.47
(dd, J = 1.0 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 21.7, 24.3, 108.7, 111.4, 120.5,
120.7, 122.9, 124.1, 126.8, 128.0, 129.8, 147.8, 149.8, 150.6, 150.9.
2-Oxo-3-isopropyl-2,3-dihydrobenzofuran [( )-52]
Nitrile ( )-50 (17.4 g, 91.9 mmol) was poured onto aq HBr (48%,
500 mL) and heated to reflux for 5 d. The reaction was then cooled
0 °C, and excess acid was neutralised by slow addition of 10 M aq
NaOH, then extracted with Et2O (3 × 250 mL). The organic layers
were combined, dried (MgSO4) and concentrated in vacuo to give,
after chromatographic purification (PE–Et2O, 90:10), benzofura-
none ( )-52.
MS (ESI+): m/z (%) = 319.1 (100) [M + Na]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C18H16O4Na: 319.0946;
found: 319.0942 (–1.3 ppm).
Methyl 3-Isopropylbenzofuran-2-yl Carbonate (56)
Following general procedure D, benzofuranone ( )-52 (3.17 g, 18.0
mmol), THF (40 mL), Et3N (3.73 mL, 27.0 mmol) and methyl chlo-
roformate (2.07 mL, 27.0 mmol) gave, after chromatographic puri-
fication (PE–Et2O, 95:5), carbonate 56.
Yield: 9.86 g (61%); pale-yellow oil.
IR (thin film): 3010 (C–H), 1820 cm–1 (C=O).
1H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 6.9 Hz, 3 H, CH3), 1.01
(t, J = 6.9 Hz, 3 H, CH3), 2.41 [sept, J = 6.9, 3.6 Hz, 1 H,
CH(CH3)2], 3.56 [d, J = 3.9 Hz, 1 H, C(3)H], 7.00–7.10 (m, 2 H,
ArH), 7.18–7.27 (m, 2 H, ArH).
13C NMR (75 MHz, CDCl3): d = 18.5, 19.4, 31.4, 49.7, 110.6, 123.9,
124.6, 126.1, 128.8, 154.1, 176.5.
MS (ESI+): m/z (%) = 199.1 (100) [M + Na]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C11H12O2Na: 199.0735;
Yield: 3.96 g (94%); colourless oil.
IR (thin film): 2965 (C–H), 1650 (C=C), 1247 cm–1 (C–O).
1H NMR (400 MHz, CDCl3): d = 1.29 [d, J = 7.2 Hz, 6 H,
CH(CH3)2], 2.98 [sept, J = 7.2 Hz, 1 H, CH(CH3)2], 3.88 (s, 3 H,
OCH3), 7.03–7.13 (m, 2 H, ArH), 7.30–7.32 (m, 1 H, ArH), 7.49–
7.51 (m, 1 H, ArH).
found: 199.0732 (–1.8 ppm).
13C NMR (100 MHz, CDCl3): d = 21.6, 24.1, 56.4, 108.2, 111.2,
120.3, 122.7, 123.8, 127.9, 148.0, 149.7, 152.6.
3-Benzylbenzofuran-2-yl Phenyl Carbonate (53)
MS (CI+): m/z (%) = 234.1 (75) [M]+, 235.1 (40) [M + H]+.
HRMS (CI+): m/z [M + H]+ calcd for C13H15O4: 235.0970; found:
Following general procedure D, benzofuranone ( )-51 (2.00 g, 8.92
mmol), THF (50 mL), Et3N (1.87 mL, 13.0 mmol) and phenyl chlo-
roformate (1.68 mL, 13.0 mmol) gave, after chromatographic puri-
fication (hexane–Et2O, 95:5), carbonate 53 with spectroscopic data
in accordance with the literature.22c
235.0968 (–1.0 ppm).
Phenyl 3-Benzyl-2-oxo-2,3-dihydrobenzofuran-3-carboxylate
[( )-57]
Yield: 2.01 g (65%); off-white solid; mp 78–80 °C.
Following general procedure E, KHMDS (0.0520 mL, 0.0260
mmol, 1.8 mol%), triazolium salt 23 (0.00800 g, 0.0290 mmol, 2
mol%), THF (5 mL) and carbonate 53 (0.500 g, 1.45 mmol) gave,
after 1 h and chromatographic purification (PE–Et2O, 90:10), ( )-57
with spectroscopic data in accordance with the literature.22c
1H NMR (400 MHz, CDCl3): d = 4.02 (s, 2 H, CH2Ph), 7.17 (td,
J = 7.5, 1.0 Hz, 1 H, ArH), 7.20–7.33 (m, 10 H, ArH), 7.39–7.45
(m, 3 H, ArH).
3-Benzylbenzofuran-2-yl Methyl Carbonate (54)
Yield: 0.440 g (88%); colourless solid; mp 106–108 °C.
1H NMR (300 MHz, CDCl3): d = 3.63 (s, 2 H, CH2Ph), 6.85–7.40
(m, 14 H, ArH).
Following general procedure D, benzofuranone ( )-51 (4.00 g, 17.8
mmol), THF (100 mL), Et3N (3.73 mL, 27.0 mmol) and methyl
chloroformate (2.07 mL, 27.0 mmol) gave, after chromatographic
purification (PE–Et2O, 90:10), carbonate 54.
Methyl 3-Benzyl-2-oxo-2,3-dihydrobenzofuran-3-carboxylate
[( )-58]
Following general procedure E, KHMDS (0.12 mL, 0.060 mmol, 9
mol%), triazolium salt 23 (0.019 g, 0.070 mmol, 10 mol%), THF (5
mL) and carbonate 54 (0.20 g, 0.71 mmol) gave, after 1 h and chro-
matographic purification (PE–Et2O, 90:10), ( )-58.
Yield: 4.32 g (86%); yellow oil.
IR (thin film): 1704 (C=O), 1444 (C=C), 1250 (C–O), 749 cm–1 (Ar
C–H).
1H NMR (300 MHz, CDCl3): d = 4.00 (s, 3 H, OCH3), 4.10 (s, 2 H,
CH2Ph), 7.25–7.44 (m, 8 H, ArH), 7.52–7.56 (m, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 28.5, 56.4, 101.8, 111.2, 120.1,
123.1, 124.2, 126.5, 128.5, 128.57, 128.64, 138.4, 149.8, 150.0,
152.4.
MS (ESI+): m/z (%) = 305.0 (100) [M + Na]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C17H14O4Na: 305.0790;
Yield: 0.16 g (80%); pale-yellow oil.
IR (thin film): 2965 (C–H), 1762 (C=O), 1630 cm–1 (Ar C=C).
1H NMR (400 MHz, CDCl3): d = 3.58 (ABq, J = 13.6 Hz, 1 H,
CHAHBPh), 3.62 (ABq, J = 13.6 Hz, 1 H, CHAHBPh), 3.76 (s, 3 H,
OCH3), 6.87–6.93 (m, 3 H, ArH), 7.06–7.14 (m, 3 H, ArH), 7.18
(td, J = 7.6, 1.0 Hz, 1 H, ArH), 7.25–7.30 (m, 1 H, ArH), 7.35–7.38
(m, 1 H, ArH).
found: 305.0796 (+2.1 ppm).
Phenyl 3-Isopropylbenzofuran-2-yl Carbonate (55)
13C NMR (100 MHz, CDCl3): d = 40.4, 53.6, 60.0, 110.9, 124.3,
Following general procedure D, benzofuranone ( )-52 (4.00 g, 22.7
mmol), THF (40 mL), Et3N (4.75 mL, 34.0 mmol) and phenyl chlo-
roformate (4.28 mL, 34.0 mmol) gave, after chromatographic puri-
fication (hexane–Et2O, 95:5), carbonate 55.
124.4, 125.8, 127.4, 128.2, 130.0, 130.1, 133.4, 153.4, 168.2, 172.8.
MS (ESI+): m/z (%) = 305.1 (100) [M + Na]+.
HRMS (ESI+): m/z [M + Na]+ calcd for C17H14O4Na: 305.0790;
found: 305.0787 (–1.0 ppm).
Synthesis 2008, No. 17, 2805–2818 © Thieme Stuttgart · New York

SPECIAL TOPIC
O-to-C Carboxyl Transfer of Indolyl and Benzofuranyl Carbonates
2817
Phenyl 3-Isopropyl-2-oxo-2,3-dihydrobenzofuran-3-carboxy-
late [( )-59]
Following general procedure E, KHMDS (0.14 mL, 0.068 mmol, 4
mol%), triazolium salt 23 (0.023 g, 0.084 mmol, 5 mol%), THF (5
mL) and carbonate 55 (0.50 g, 1.7 mmol) gave, after 1 h and chro-
matographic purification (PE–Et2O, 90:10), ( )-59.
Angew. Chem. Int. Ed. 2002, 41, 1743. (e) Kerr, M. S.;
Read de Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124,
10298. (f) Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc.
2004, 126, 8126. (g) Reynolds, N. T.; Read de Alaniz, J.;
Rovis, T. J. Am. Chem. Soc. 2004, 126, 9518. (h) Myers,
M. C.; Bharadwaj, A. R.; Milgram, B. C.; Scheidt, K. A.
J. Am. Chem. Soc. 2005, 127, 14675. (i) Suzuki, Y.; Toyota,
T.; Imada, F.; Sato, M.; Miyashita, A. Chem. Commun.
2003, 1314.
Yield: 0.41 g (82%); colourless oil.
IR (thin film): 2970 (C–H), 1813 (C=O), 1756 (C=O), 1190 (C–O),
754 cm–1 (Ar C–H).
1H NMR (400 MHz, CDCl3): d = 0.88 [d, J = 7.0 Hz, 3 H,
CH(CH3)2], 1.13 [d, J = 7.0 Hz, 3 H, CH(CH3)2], 2.83 [sept, J = 7.0
Hz, 1 H, CH(CH3)2], 6.96–7.40 (m, 9 H, ArH).
13C NMR (75 MHz, CDCl3): d = 17.3, 17.4, 35.7, 62.8, 111.0, 121.2,
124.6, 124.8, 126.0, 126.5, 129.6, 130.2, 150.4, 153.7, 166.4, 171.7.
(4) For select examples, see: (a) Burstein, C.; Glorius, F.
Angew. Chem. Int. Ed. 2004, 43, 6205. (b) Sohn, S. S.;
Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126,
14370. (c) Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905.
(5) For the direct formation of enolates from ketenes, see:
(a) Duguet, N.; Campbell, C. D.; Slawin, A. M. Z.; Smith, A.
D. Org. Biomol. Chem. 2008, 6, 1108. (b) Zhang, Y.-R.;
He, L.; Wu, X.; Shao, P.-L.; Ye, S. Org. Lett. 2008, 10, 277.
(6) Song, J. J.; Tan, Z.; Reeves, J. T.; Gallou, F.; Yee, N. K.;
Senanayake, C. H. Org. Lett. 2005, 7, 2193.
(7) (a) Song, J. J.; Gallou, F.; Reeves, J. T.; Tan, Z.; Yee, N. K.;
Senanayake, C. H. J. Org. Chem. 2006, 71, 1273.
(b) Suzuki, Y.; Abu Bakar, M. D.; Muramatsu, K.; Sato, M.
Tetrahedron 2006, 62, 4227. (c) Kano, T.; Sasaki, K.;
Konishi, T.; Mii, H.; Maruoka, K. Tetrahedron Lett. 2006,
47, 4615.
MS (ESI): m/z (%) = 391.1 (100) [M + Na]+.
HRMS (ESI): m/z [M + Na]+ calcd for C18H16O4Na: 319.0946;
found: 319.0943 (–1.0 ppm).
Methyl 3-Isopropyl-2-oxo-2,3-dihydrobenzofuran-3-carboxy-
late [( )-60]
Following general procedure E, KHMDS (0.384 mL, 0.192 mmol,
9 mol%), triazolium salt 23 (0.058 g, 0.213 mmol, 10 mol%), THF
(5 mL) and carbonate 56 (0.500 g, 2.13 mmol) gave, after 1 h and
chromatographic purification (PE–Et2O, 90:10), ( )-60.
(8) (a) Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129,
13796. (b) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007,
129, 13798.
Yield: 0.323 g (65%); colourless oil.
(9) Chan, A.; Scheidt, K. A. J. Am. Chem. Soc. 2006, 128, 4558.
(10) (a) Zeitler, K. Angew. Chem. Int. Ed. 2005, 44, 7506.
(b) Reynolds, N. T.; Rovis, T. J. Am. Chem. Soc. 2005, 127,
16406. (c) Sohn, S. S.; Bode, J. W. Angew. Chem. Int. Ed.
2006, 45, 6021.
(11) (a) Sun, X.; Ye, S.; Wu, J. Eur. J. Org. Chem. 2006, 4787.
(b) Wu, J.; Sun, X.; Ye, S.; Sun, W. Tetrahedron Lett. 2006,
47, 4813.
(12) (a) Fukada, Y.; Maeda, Y.; Kondo, K.; Aoyama, T. Chem.
Pharm. Bull. 2006, 54, 397. (b) Song, J. J.; Tan, Z.; Reeves,
J. T.; Yee, N. K.; Senanayake, C. H. Org. Lett. 2007, 9, 1013.
(13) For a review, see: Douglas, C. J.; Overman, L. E. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 5363.
(14) (a) Corey, E. J. Angew. Chem. Int. Ed. 2002, 41, 1650.
(b) Maruoka, K. In Catalytic Asymmetric Synthesis, 2nd ed.;
Ojima, I., Ed.; Wiley-VCH: New York, 2000, 467–491.
(c) Kozmin, S. A.; Iwama, T.; Huang, Y.; Rawal, V. H.
J. Am. Chem. Soc. 2002, 124, 4628. (d) Ryu, D. H.; Corey,
E. J. J. Am. Chem. Soc. 2003, 125, 6388. (e) Evans, D. A.;
Wu, J. J. Am. Chem. Soc. 2003, 125, 10162.
(15) (a) O’Donnell, M. J. In Catalytic Asymmetric Synthesis, 2nd
ed.; Ojima, I., Ed.; Wiley-VCH: New York, 2000, 727–755.
(b) Trost, B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96,
395. (c) Hodous, B. L.; Fu, G. C. J. Am. Chem. Soc. 2002,
124, 1578. (d) d’Angelo, J.; Desmaële, D.; Dumas, F.;
Guingant, A. Tetrahedron: Asymmetry 1992, 3, 459.
(e) Trost, B. M.; Jiang, C. J. Am. Chem. Soc. 2001, 123,
12907. (f) Austin, J. F.; Kim, S.-G.; Sinz, C. J.; Xiao, W.-J.;
MacMillan, D. W. C. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 5482. (g) Bella, M.; Kobbelgaard, S.; Jørgensen, K. A.
J. Am. Chem. Soc. 2005, 127, 3670.
(16) (a) Dounay, A. B.; Overman, L. E. Chem. Rev. 2003, 103,
2945. (b) Donde, Y.; Overman, L. E. In Catalytic
Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley-VCH:
New York, 2000, 675–697. (c) Lebsack, A. D.; Link, J. T.;
Overman, L. E.; Stearns, B. A. J. Am. Chem. Soc. 2002, 124,
9008.
IR (thin film): 2969 (C–H), 1811 (C=O), 1748 (C=O), 1187 (C–O),
749 cm–1 (Ar C–H).
1H NMR (400 MHz, CDCl3): d = 0.85 [d, J = 6.8 Hz, 3 H,
CH(CH3)2], 1.10 [d, J = 6.8 Hz, 3 H, CH(CH3)2], 2.80 [sept, J = 6.8
Hz, 1 H, CH(CH3)2], 3.75 (s, 3 H, OCH3), 7.10–7.14 (m, 1 H, ArH),
7.16–7.21 (m, 1 H, ArH), 7.33–7.38 (m, 2 H, ArH).
13C NMR (100 MHz, CDCl3): d = 17.1, 17.3, 35.6, 53.3, 62.5, 110.7,
124.45, 124.47, 126.1, 129.8, 153.4, 168.2, 172.0.
MS (CI): m/z (%) = 175.1 (100) [M – COOMe]+, 235.1 (13) [M +
H]+.
HRMS (CI): m/z [M + H]+ calcd for C13H15O4: 235.0970; found:
235.0972 (+0.7 ppm).
Acknowledgment
The authors would like to thank the Royal Society for a University
Research Fellowship (A.D.S.) and a Summer Studentship (K.A.G.),
the EPSRC (C.C. and C.J.), EaStCHEM and the University of St
Andrews (J.E.T. and A.J.M.), and AstraZeneca (Research Support
Grant) for funding (L.C.M.).
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Synthesis 2008, No. 17, 2805–2818 © Thieme Stuttgart · New York

2818
J. E. Thomson et al.
SPECIAL TOPIC
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Synthesis 2008, No. 17, 2805–2818 © Thieme Stuttgart · New York