Regioselective access to substituted oxindoles via rhodium-catalyzed carbene C-H insertion

Article abstract of DOI:10.1016/j.tet.2009.08.006

Rhodium-catalyzed decomposition of diazoamides followed by insertion of the resulting carbenes into an aromatic C-H bond gives access to substituted oxindoles. The reaction takes place with aromatic rings substituted by either electron-donating or -withdrawing groups at ortho, meta or para positions and the regioselectivity can be controlled by a substitution α to the diazo functionality. In the presence of an ester, the reaction leads to the formation of 2-silyloxyindole-3-carboxylates in 40-85% yields and regioselectivities up to 80% are observed in the case of meta-substituted substrates. This selectivity mainly relies on steric factors and use of a more bulky N,N-diethylamide then affords 2-silyloxyindole-3-carboxamides in 42-91% yields with complete regioselectivity.

Full text of DOI:10.1016/j.tet.2009.08.006

Tetrahedron 65 (2009) 8542–8555
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective access to substituted oxindoles via rhodium-
catalyzed carbene C–H insertion
*
Delphine Gauthier, Robert H. Dodd, Philippe Dauban
Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles, UPR 2301 CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 1 July 2009
Received in revised form 5 August 2009
Accepted 5 August 2009
Available online 11 August 2009
Rhodium-catalyzed decomposition of diazoamides followed by insertion of the resulting carbenes into
an aromatic C–H bond gives access to substituted oxindoles. The reaction takes place with aromatic rings
substituted by either electron-donating or -withdrawing groups at ortho, meta or para positions and the
regioselectivity can be controlled by a substitution
a to the diazo functionality. In the presence of an
ester, the reaction leads to the formation of 2-silyloxyindole-3-carboxylates in 40–85% yields and re-
gioselectivities up to 80% are observed in the case of meta-substituted substrates. This selectivity mainly
relies on steric factors and use of a more bulky N,N-diethylamide then affords 2-silyloxyindole-3-car-
boxamides in 42–91% yields with complete regioselectivity.
Keywords:
Oxindole
Carbene
C–H insertion
Rhodium
Ó 2009 Elsevier Ltd. All rights reserved.
Catalysis
Regioselective
1. Introduction
interestingly, transition metal-catalyzed protocols have recently
emerged that afford a direct access to oxindoles starting from non
Indolic compounds hold a paramount position in the family of
alkaloids and have therefore receivedconsiderableattention from the
synthetic organic and medicinal chemistry communities.1 The com-
parable prominent importance of their oxidized analogs has also re-
cently been acknowledged since oxindoles can be found in a growing
number of natural products and pharmaceutical agents.2 This motif
is present, for example, in the structure of horsfiline,3 spiro-
tryprostatins,4 and welwitindolinones,5 to name but a few. Moreover,
several oxindole-derived compounds have been approved for the
treatment of Parkinson’s disease (Ropinirole),6 arthritis (Tenidap)7 or
renal cell carcinoma (SU11248).8 As a consequence, several strategies
have been devised for the preparation of the oxindole nucleus. Clas-
sical methodologies involve oxidative rearrangements of indoles,1,2a,9
chemical modificationsofisatins,10 radical cyclization,11 and Gassman
synthesis from anilines.12 Not surprisingly, the advent of transition
metal-catalyzed transformations has recently led to the development
of numerous new entries to functionalized oxindoles. These can thus
be obtained either by catalytic intramolecular amidation of haloar-
ortho-substituted anilines18 via a C–H functionalization process.19
Such transformations could greatly simplify the synthesis of oxin-
doles since they circumvent the need to prepare the ortho-haloge-
nated anilines necessary for the aforementioned catalytic reactions.
In the course of a medicinal chemistry program aimed at de-
veloping proteasome inhibitors as new potential antitumor
agents,20 we sought to prepare analogs of TMC-95A 1 (Fig. 1). The
latter isolated from the fermentation broth of Apiospora montagnei
Sacc. TC 1093 is a cyclic peptide displaying potent inhibitory ac-
tivity of the proteasome in the nanomolar range as well as cytotoxic
Highly oxidized
(Z)-1-Propenylamine
L-tryptophan
unit
moiety
O
HO
HO
NH
O
7
6
NH
O
O
N
H
O
1
enes,13 palladium-catalyzed intramolecular -arylation of amides,14
a
20
HO
NH
NH2
Heck-type carbocyclization applied to N-(aryl)-acrylamides15 and
O
19
14
-propynamides16 or catalytic addition to arylisocyanates.17 More
N
H
3-Methyl-2-oxo-
pentanoyl
chain
O
TMC-95A 1
Figure 1. Structure of TMC-95A.
* Corresponding author. Tel.: þ33 (0)1 69 82 45 60; fax: þ33 (0)1 69 07 72 47.
E-mail address: philippe.dauban@icsn.cnrs-gif.fr (P. Dauban).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.006

D. Gauthier et al. / Tetrahedron 65 (2009) 8542–8555
8543
activities against various cancer cell lines.21 Compared to pre-
viously described inhibitors,20 the novelty of TMC-95A lies in its
unique mode of action, i.e., 1 binds non-covalently to the protea-
some active sites via a hydrogen bond network22 as well as in its
structural complexity. In particular, this cyclic tripeptide is cha-
and drugs.33 In particular, Doyle and Durst first recognized the
utility of intramolecular carbene C–H insertions for the preparation
of oxindoles.34 Moody and Padwa then demonstrated the superior
performance of rhodium(II) perfluorocarboxamide as catalyst for
this transformation,35 which was successfully applied to the syn-
theses of convolutamydine C36a and horsfiline.36b In the context of
our planned SAR studies, we decided to enhance the scope of this
reaction studied thus far in a limited number of cases with a par-
ticular emphasis on its regioselectivity, a point that has been
overlooked in preceding work (Scheme 2).
racterized by a highly oxidized
L-tryptophan moiety linked to a ty-
rosine residue by a biaryl bond.
These unusual features have spurred several groups to embark on
synthetic studies that have culminated in the publication of three
total syntheses.23–25 Particular attention has been paid to the prep-
aration of the highly functionalized oxindole part of TMC-95A, which
was found to be accessible via application of a Heck reaction starting
from dibromoaniline derivatives,23,24,26 functional group trans-
formations of isatin25,27 or oxidative rearrangement of indoles.28 In
parallel to these accomplishments, several SAR studies have been
conducted thereby delineating the structural requirements for po-
tent proteasome inhibition.29 Surprisingly, despite several site
modifications, the introduction of substituents on the aromatic part
of the oxindole and the resulting influence on biological activity have
not been investigated so far. It was therefore with the intention of
studying such modifications that we have initiated a program aimed
at developing a versatile access to substituted oxindoles. In order to
avoid the use of ortho-haloaniline derivatives, we have devised
a strategy based on a C–H functionalization process allowing
a straightforward preparation of the expected products (Scheme 1).
R5
R5
R4
R3
COR1
O
R4
R3
H
O
O
cat. Rh(II)
N
P
R1
N
P
R2
R2
N2
Scheme 2. Intramolecular rhodium-catalyzed carbene C–H insertion for the formation
of oxindoles.
2.2. Synthesis of oxindole 3-carboxylates
We first studied the reactivity of diazomalonamic acid ethyl
esters 9 the preparation of which relies on the acylation of
substituted anilines of type 7 with ethyl 2-diazomalonyl chloride 8
(Scheme 3). The DMB-protected compounds 7 (DMB: 2,4-dime-
thoxybenzyl)36 were in turn isolated in very good yields (generally
greater than 83%) via reductive amination of anilines 6 with 2,4-
dimethoxybenzaldehyde while diazo derivative 8 was prepared by
reaction of triphosgene with commercially available ethyl diazo-
acetate according to a published procedure.37 Acylation of 7a–m
finally occurred in the presence of triethylamine to afford the
expected diazo precursors 9a–m in modest to excellent yields.
In the case 7a and of para- or meta-substituted derivatives 7b–f
and 7j–m, the condensation reaction efficiently takes place in the
presence of either electron-withdrawing or -donating substituents
and allows isolation of the corresponding compounds 9a–f and 9j–m
with yields in the 64–99% range.38 However, acylation of the ortho-
bromo analogs 7g–i proved to be more sluggish probably as a result
of steric hindrance and the corresponding diazos 9g–i were
obtained with non-optimized yields ranging from 22 to 30%.
Compounds 9 were then engaged in the rhodium-catalyzed
transformation into indoles 10 (Table 1). As previously described,35
higher conversions are observed at room temperature in the pres-
ence of rhodium(II) trifluoroacetamide prepared according to a re-
cently published procedure.39 This catalyst, which is more
electrophilic than the classical rhodium(II) acetate, induces the
formation of a metallacarbene the cationic nature of which favors
aromatic substitution.31e,40 Moreover, based on Padwa’s recom-
mendation,35a the oxindoles were isolated as their more stable 2-
silyl enol ethers. In the case of diazoamides 9a–e, the corresponding
2-silyloxyindoles 10a–e are formed in good yields ranging from 68%
to 78% (entries 1–5). The yields appear to weakly depend on elec-
tronic factors. Thus, while the p-trifluoromethyl derivative 10e is
isolated with a yield of 72% (entry 5), the presence of a p-methoxy
group leads to the 5-methoxyindole 10b with a comparable yield of
68% (entry 2). Though the presence of two meta electrondonating
group in substrate 9f should have improved this result, such was not
the case since the corresponding product 10f was isolated in 65%
yield (entry 6). As a possible explanation, the favorable ortho,para-
electronic effects could be counterbalanced by steric factors.
More interestingly, we were very pleased to observe that the
reaction occurs efficiently starting from ortho-bromo derivatives
9g–i (entries 7–9), a key result in the context of the preparation of
TMC-95A analogs because it affords the opportunity to form the
biaryl C1–C20 bond via palladium-catalyzed coupling. Of particular
HO
HO
O
CO2H
NH2
CO2P1
N=P2
HO
X
X
O
OSiR3
N
H
N
P
2
3
Reduction
COR1
X
X
H
O
O
OSiR3
N
P
R1
N
P
C-H
functionalization
H
5
4
Scheme 1. Retrosynthesis of the oxidized tryptophan moiety.
The retrosynthetic disconnection envisaged for the highly oxi-
dized tryptophan moiety 2 first involves an enolate hydroxylation
and condensation of a chiral glycine anion equivalent. The required
aldehyde 3 could in turn be obtained by reduction of a keto de-
rivative 4 (i.e., an ester or an amide), the latter being the product of
a C–H functionalization reaction applied to dicarbonyl compounds
of type 5. However, such a transformation inevitably poses the
problem of regioselectivity with respect to the substitution on the
aryl ring. In this article, we thus present the results of our in-
vestigations directed towards the formation of substituted oxin-
doles involving selective functionalization of a Csp2–H bond.
2. Results and discussion
2.1. Selection of C–H functionalization process
Guided by our recent studies devoted to intermolecular C–H
amination via catalytic nitrene insertion,30 we decided to study the
analogous carbene transfer for the direct functionalization of aro-
matic rings. Such reagents can be efficiently generated by catalytic
decomposition of a diazo compound, the resulting metallacarbene
then inserting into C–H bonds with good yields and selectiv-
ities.31,32 The power of this C–C bond formation is testified by its
application to the total syntheses of natural products, heterocycles,

8544
D. Gauthier et al. / Tetrahedron 65 (2009) 8542–8555
R5
R2
R5
R5
1. Toluene, 18h, reflux
Dean-Stark
Et3N, CH2Cl2
0°C then rt
O
OMe
R4
R3
H
R4
R3
H
R4
R3
H
O
O
+
O
O
2. NaBH4, CH2Cl2/EtOH
0°C then rt
NH2
NH OMe
N
OEt
OMe
R2
R2 DMB N2
9a: 93%
9b: 78%
9c: 99%
9d: 64%
9e: 67%
9f: 83%
9g: 28%
9h: 30%
9i: 22%
9j: 78%
9k: 88%
9l: 90%
9m: 71%
Cl
OEt
6a: R2 = R3 = R4 = R5 = H
7a: 90%
7b: 83%
7c: 96%
7d: 99%
7e: 97%
7f: 93%
7g: 89%
7h: 36%
7i: 95%
7j: 70%
7k: 91%
7l: 96%
7m: 86%
N2
8
6b: R2 = R3 = R5 = H; R4 = OMe
6c: R2 = R3 = R5 = H; R4 = Cl
6d: R2 = R3 = R5 = H; R4 = F
6e: R2 = R3 = R5 = H; R4 = CF3
6f: R2 = R4 = H; R3 = R5 = OMe
6g: R2 = Br; R3 = R4 = R5 = H
6h: R2 = Br; R3 = R5 = H; R4 = F
OMe
6i:
R
2 = Br; R3 = R4 = H; R5 = OMe
2 = R4 = R5 = H; R3 = OMe
6j:
R
6k: R2 = R4 = R5 = H; R3 = OTBDPS
6l:
R
2 = R4 = R5 = H; R3 = F
6m:R2 = R4 = R5 = H; R3 = CF3
Scheme 3. Preparation of diazo compounds 9, precursors of oxindole 3-carboxylates.
Table 1
Rhodium-catalyzed carbene C–H insertion for the formation of 2-silyloxyindole-3-carboxylates 10
R5
R5
R5
R4
R3
R4
R3
R4
R3
H
CO2Et
O
CO2Et
OTIPS
5 mol% Rh2(NHCOCF3)4
CH2Cl2, rt, 5h
OEt
TIPSOTf, Et3N
O
O
º
0 C, 15 min
N
N
N
R2
DMB
R2
DMB
R2 DMB N2
9
10
Entry
1
Compound
Product
CO2Et
Yielda
78
%
Entry
8
Compound
Product
CO2Et
Yielda
%
F
9a
9h
40
67
OTIPS
10a
OTIPS
10h
N
N
DMB
Br
DMB
OMe
MeO
Cl
CO2Et
CO2Et
2
3
4
5
6
9b
9c
9d
9e
9f
68
70
71
72
65
9
10
11
12
13
9i
OTIPS
10b
OTIPS
10i
N
N
DMB
Br
DMB
OMe
CO2Et
OTIPS
CO2Et
CO2Et
9j
95 (73:27)
93 (90:10)
93 (73:27)
69 (64:36)
MeO
TBDPSO
F
OTIPS
10j
OTIPS
10j'
N
N
N
DMB
10c
DMB
DMB
OTBDPS
F
CO2Et
OTIPS
CO2Et
CO2Et
9k
9l
OTIPS
10k
OTIPS
10k'
N
N
N
DMB
10d
DMB
DMB
F
F3C
CO2Et
CO2Et
OTIPS
CO2Et
OTIPS
OTIPS
10e
N
N
N
DMB
DMB
DMB
10l
10l'
OMe
CF3
CO2Et
OTIPS
CO2Et
OTIPS
CO2Et
OTIPS
9m
MeO
F3C
N
N
N
DMB
CO2Et
OTIPS
DMB
DMB
10f
10m
10m'
7
9g
85
N
Br
DMB
10g
a
Isolated yields after flash chromatography on SiO2. Values in parentheses indicate the ratio of regioisomers.
note are the isolated yields of 85% and 67% obtained for products
10g,i (entries 7 and 9) since, when compared to the preceding
substrates 9a–f, there is only one C–H bond available for carbene
insertion.
The reaction with substrates 9j–m then allowed us to study the
influence of the substitution on the regioselectivity of the C–H
functionalization. Excellent yields up to 95% were obtained with
these derivatives (entries 10–13). However, contrary to the

D. Gauthier et al. / Tetrahedron 65 (2009) 8542–8555
8545
complete regioselectivity observed with a meta-methoxy sub-
stituted diazoacetamide described in Doyle et al.’s monograph,31b
the meta-methoxy diazo 9j leads to a mixture of indoles 10j,j0 with
a 73:27 ratio in favor of the 6-substituted derivative (entry 10).
These regioisomers are easily distinguishable by 1H NMR. Com-
pound 10j is characterized by a downshielded doublet corre-
Rhodium-catalyzed decomposition of diazos 15 was then in-
vestigated by application of the conditions already used for diazos 9
(Table 2). The N,N-diethyl 2-silyloxyindole-3-carboxamide 16a was
thus obtained with a yield of 88%, better than that observed for the
indole-3-carboxylate 10a (entry 1). More importantly, the meta-
substituted substrates 15j–m led to a single regioisomer thereby
corroborating the influence of steric hindrance on the course of the
reaction. Thus, the 6-OMe 16j, 6-OTBDPS 16k, 6-F 16l, and 6-CF3 16m
indole derivatives were isolated in 88, 91, 72, and 42% yields, re-
spectively (entries 2–5). These results clearly indicate that the
regioselective formation of substituted oxindoles via C–H function-
alization is indeed possible by carefully choosing the substitution
pattern on the precursor. A bulky amide is likely to favor reaction at
the para position with electron-donating groups, 6-substituted in-
doles 16j,k being isolated with better yields when compared to
products 10j,k. However, the same sterically demanding substitution
appears to have a different influence on the reactivity in the presence
of electron-withdrawing groups. Inhibition of C–H insertion at the
ortho-position is indeed suggested by comparing the results
obtained in the cases of fluoro derivatives 10l and 16l, and of tri-
fluoromethyl compounds 10m and 16m. Yields are roughly the same
for the para-adducts (70% vs 72% and 44% vs 42%) while formation of
the ortho-isomer is no longer observed in the case of the amide.
sponding to H4
(w3.0 Hz) is smaller than that of H7 in isomer 10j0 (w8.0 Hz). This
result can be attributed to either the nature of the substituent - to
(d 7.9 ppm) while the coupling constant for H7
a
the diazo or a ligand effect since the above mentioned complete
regioselectivity was observed starting from a diazoacetamide in the
presence of Rh2(OAc)4.31b Such an influence of the diazo sub-
stitution and the rhodium(II) catalyst on the regio- and chemo-
selectivity is well known and documented in several previous
reports.31e,f,40 Replacement of the methoxy group by a bulkier tert-
butyldiphenylsilyloxy group significantly improves the regiose-
lectivity, a higher ratio of 90:10 in favor of the 6-silyloxy regioisomer
10k being recorded (entry 11). This observation tends to prove that
the course of the reaction can be controlled by steric factors. How-
ever, electronic effects also play an important role as suggested by
the replacement of the m-methoxy group by the less sterically de-
manding fluorine atom that leads to the same proportion, i.e., 73:27,
of regioisomers 10l,l0 (entry 12). Finally, the presence of the m-tri-
fluoromethyl group in diazo 9m induces a decrease of reactivity and
also of selectivity (entry 13).
Table 2
Rhodium-catalyzed carbene C–H insertion for the formation of 2-silyloxyindole-3-
carboxamides 16
2.3. Synthesis of oxindole 3-carboxamides
5 mol%
Rh2(NHCOCF3)4
R
CONEt2
H
Based on the postulated influence of steric effects, we then
planned to improve the regioselectivity of the carbene C–H in-
sertion by studying the case of more sterically demanding diazo-
amides. We thus turned our attention to N,N-diethylamide
derivatives of type 15 that can in principle be reduced under mild
conditions via hydrozirconation using Cp2Zr(H)Cl.41 Isolation of
these starting materials required the initial preparation of diazo-
malonamyl chloride 14 synthesized from diketene in four steps and
40% overall yield (Scheme 4).42 Condensation of the latter with
anilines 7 then afforded the expected diazo compounds 15 in ex-
cellent yields greater than 90%.
CH2Cl2, rt
O
O
R
then
TIPSOTf, Et3N, 0 C
OTIPS
N
NEt2
N
DMB
°
DMB
H
N2
16
15
Entry
Compound
Product
Yielda
88
%
CONEt2
1
2
3
4
15a
OTIPS
16a
N
DMB
CONEt2
MeO
TBDPSO
F
15j
15k
15l
88
91
72
OTIPS
16j
N
DMB
SO2N3
CONEt2
O
OTIPS
16k
O
O
O
O
Et2NH, Et3N
N
AcHN
NEt2
DMB
O
NEt2
CONEt2
Toluene/MeOH
0ºC
Et3N
N2
CH3CN
rt
11: 95%
12: 94%
OTIPS
16l
N
N
DMB
O
O
O
Triphosgene
NaOMe, MeOH
0ºC
CONEt2
12
NEt2
Cl
NEt2
5
15m
F3C
42
Pyridine
Toluene
OTIPS
16m
N2
13: 98%
N2
14: 46%
DMB
0ºC then rt
a
Isolated yields after flash chromatography on SiO2.
3. Conclusion
H
H
14, Et3N, CH2Cl2
O
O
0ºC then rt
Rhodium-catalyzed carbene aromatic C–H insertion has been
found to occur in moderate to very good yields in the presence of
either electron-donating or -withdrawing groups. ortho, meta, and
para Substitutions are well tolerated. More importantly, the re-
action can take place with very high regioselectivity in the case of
meta-substituted starting materials. This selectivity can be fine-
tuned by carefully choosing the substituents. In this context, while
the importance of electronic effects was previously highlighted,31b
we have demonstrated that steric hindrance plays a key role in
R
N
NEt2
R
NH OMe
DMB N2
15a: 91%
15j: 95%
15k: 97%
15l: 99%
15m: 97%
7a: R = H
OMe
7j: R = OMe
7k: R = OTBDPS
7l: R = F
7m: R = CF3
Scheme 4. Preparation of acyl chloride 14 and diazos compounds 15.

8546
D. Gauthier et al. / Tetrahedron 65 (2009) 8542–8555
directing the C–H insertion to a selected position. Work is now in
progress to apply these results to the preparation of highly oxidized
tryptophan moieties for incorporation into the structure of cyclic
tripeptides analogous to TMC-95A.
127.9 (4C), 110.5, 108.5, 106.7, 26.7 (3C), 19.7; IR (neat, cmꢁ1): 3377,
3069, 3044, 2955,1617,1461,1389,1111, 820;HRMS(ESþ)m/z [MþH]þ
calcd for C22H26NOSi: 348.1784; found: 348.1786.
4.4. General procedure (A) for the synthesis of 2,4-
dimethoxybenzyl-protected compounds 7
4. Experimental
4.1. General methods
4.4.1. N-(2,4-Dimethoxybenzyl)aniline (7a). A solution of aniline 6a
(0.752 mL, 8.25 mmol, 1 equiv) and 2,4-dimethoxybenzaldehyde
(1.40 g, 8.42 mmol, 1.02 equiv) in toluene (10 mL) was stirred at
165 ꢀC for 18 h in a 50 mL flask equipped with a Dean–Stark water
trap. After cooling to room temperature, the solvent was removed
under reduced pressure and the crude imine was re-dissolved
in CH2Cl2/EtOH (10 mL, 1:1). Sodium borohydride (0.487 g,
12.87 mmol, 1.6 equiv) was slowly added to the solution cooled at
0 ꢀC and the reaction mixture was allowed to stir for 12 h. The re-
action mixture was then poured into ice. Concd HCl and 5 M NaOH
were added successively until the pH of the mixture was, re-
spectively, acidic and basic. The mixture was then transferred to
a separatory funnel and the layers separated. The aqueous portion
was extracted with CH2Cl2 (3ꢂ). The combined organic fractions
were then dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by flash column chromatography on silica
gel (heptane/EtOAc, 7/3) to give 7a (1.81 g, 90%) as a white solid;
Melting points (mp [ꢀC]), measured in capillary tubes, are un-
corrected. IR spectra were recorded on an FT-IR spectrometer.1H,13
C
and 19F NMR spectra were recorded at ambient temperature on
a Bruker spectrometer at 300 MHz or 500 MHz, in CDCl3 unless
otherwise stated. Chemical shifts (d) are reported in parts per mil-
lion with reference to CDCl3 (1H: 7.27, 13C: 77.00). The following
abbreviations are used for the proton spectra multiplicities: s: sin-
glet, d: doublet, t: triplet, q: quartet, qu: quintuplet, hep: heptuplet,
m: multiplet, br: broad. Coupling constants (J) are reported in hertz
(Hz). The carbon bearing the diazo group (C]N2) was not detected
on the 13C NMR spectra. Mass spectra were obtained using elec-
trospray ionization and a Time of Flight analyzer (ESI-MS) for high
resolution mass spectra (HRMS). The reactions were performed
under an atmosphere of dry nitrogen in flame-dried glassware and
were monitored by thin-layer chromatography (TLC) analysis using
silica gel (60 F254) plates. The compounds were visualized by UV
irradiation and/or with a solution of p-anisaldehyde (5%) in ethanol/
H2SO4/AcOH (90/5/1) or a solution of ninhydrin (2% in ethanol).
Column chromatography was performed on silica gel 60 (230–
400 mesh, 0.040–0.063 mm) at medium pressure (300 mbar). All
solvents were freshly distilled when required. Elemental analyses
were performed at the ICSN, CNRS, Gif-sur-Yvette, France.
mp 99–100 ꢀC. 1H NMR (300 MHz, CDCl3)
d
7.19 (d, J¼8.2 Hz, 1H),
7.15–7.12 (m, 2H), 6.70–6.63 (m, 3H), 6.47 (d, J¼2.3 Hz, 1H), 6.42
(dd, J¼8.2, 2.3 Hz, 1H), 4.24 (br s, 2H), 4.03 (br s, 1H), 3.82 (s, 3H),
3.78 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 160.4, 158.6, 148.7, 129.9,
129.3 (2C), 120.0, 117.5, 113.3 (2C), 104.1, 98.9, 55.6 (2C), 43.4; IR
(neat, cmꢁ1): 3370, 2939, 1601, 1504, 1433, 1319, 1254, 1206, 1130,
1034, 747; HRMS (ESþ) m/z [MþNa]þ calcd for C15H17NO2Na:
266.1157; found: 266.1144.
4.2. 2-Bromo-5-methoxyaniline 6i43
4.4.2. N-(2,4-Dimethoxybenzyl)-4-methoxyaniline (7b)36b. Compound
7b was prepared according to the general procedure (A) reported for
7a starting from 4-methoxyaniline 6b (1.02 g, 8.25 mmol, 1 equiv)
and 2,4-dimethoxybenzaldehyde (1.40 g, 8.42 mmol, 1.02 equiv).
Flash column chromatography on silica gel (heptane/EtOAc, 7/3)
afforded 7b (1.87 g, 83%) as a white solid; mp 72–73 ꢀC. 1H NMR
To a solution of 4-bromo-3-nitroanisole (3.45 g, 14.87 mmol,
1 equiv) in ethanol (50 mL) were added iron powder (2.48 g,
44.48 mmol, 6.2 equiv) and concd HCl (8.15 mL, 8.28 mmol,
1.2 equiv). After 3 h of reflux, the mixture was cooled to room
temperature and Na2CO3 was added by portions until gas evolution
ceased. After filtration over Celite, the filtrate was extracted with
Et2O and the combined organic fractions were washed with H2O and
a saturated solution of NaCl. The organic layer was then dried over
Na2SO4, filtered, and concentrated in vacuo. The residual oil was
purified by distillation under vacuum (bp 130–135 ꢀC; 0.3 mbar) to
give 6i (2.63 mg, 88%) as a yellow oil. 1H NMR (300 MHz, CDCl3)
(300 MHz, CDCl3)
d
7.17 (d, J¼8.2 Hz,1H), 6.75 (dd, J¼8.9, 3.5 Hz, 2H),
6.61 (dd, J¼8.9, 3.5 Hz, 2H), 6.45 (d, J¼2.4 Hz, 1H), 6.40 (dd, J¼8.2,
2.4 Hz, 1H), 4.18 (s, 2H), 3.89 (s, 1H), 3.81 (s, 3H), 3.73 (s, 3H), 3.71 (s,
3H); 13C NMR (75 MHz, CDCl3)
d 160.4, 158.7, 152.4, 142.9, 130.0,
120.1,115.0 (2C),114.8 (2C),104.1, 98.8, 56.0, 55.6 (2C), 44.5; IR (neat,
cmꢁ1) 3371, 2955, 2835, 1614, 1586, 1505, 1462, 1235, 1210, 1130,
1029, 813; HRMS (ESþ) m/z [MþH]þ calcd for C16H20NO3: 274.1443;
found: 274.1431.
d
7.26 (d, J¼8.7 Hz,1H), 6.30 (d, J¼2.8 Hz,1H), 6.21 (dd, J¼8.7, 2.8 Hz,
1H), 4.00 (s, 2H), 3.72 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 160.2,
145.0, 133.0, 105.7, 101.5, 100.7, 55.5; IR (neat, cmꢁ1) 3466, 3370,
3000, 2961, 1574, 1299, 1262, 1170, 1147, 1047, 778; HRMS (ESþ) m/z
[MþH]þ calcd for C7H979BrNO: 201.9868; found: 201.9866; calcd for
C7H981BrNO: 203.9847; found: 203.9846.
4.4.3. 4-Chloro-N-(2,4-dimethoxybenzyl)aniline (7c). Compound 7c
was prepared according to the general procedure (A) reported for 7a
starting from 4-chloroaniline 6c (1.05 g, 8.25 mmol,1 equiv) and 2,4-
dimethoxybenzaldehyde (1.40 g, 8.42 mmol, 1.02 equiv). Flash col-
umn chromatography on silica gel (heptane/EtOAc, 8/2) afforded 7c
(2.20 g, 96%) as a white solid; mp 52–53 ꢀC. 1H NMR (500 MHz,
4.3. 3-(tert-Butyldiphenylsilyloxy)aniline 6k
To a solution of 3-aminophenol (750 mg, 6.90 mmol, 1 equiv) in
acetonitrile (12.5 mL) were added dropwise, under argon, distilled
Et3N (6.0 mL, 42.80 mmol, 6.2 equiv) and tert-butylchlorodi-
phenylsilane (2.2 mL, 8.30 mmol, 1.2 equiv). After 4 h of reflux, the
mixture was cooled to room temperature and concentrated in vacuo.
TheresiduewasthendissolvedinCH2Cl2 andthesolutionwaswashed
with H2O, dried over Na2SO4, filtered, and concentrated in vacuo. The
residue was purified by flash column chromatography on silica gel
(heptane/EtOAc, 8/2) to give 6k (1.40 g, 58%) as a yellow oil. 1H NMR
CDCl3)
d
7.14 (d, J¼8.2 Hz, 1H), 7.07 (dd, J¼2.1, 8.8 Hz, 2H), 6.54 (dd,
J¼8.8, 2.1 Hz, 2H), 6.46 (d, J¼2.4 Hz, 1H), 6.41 (dd, J¼8.2, 2.4 Hz, 1H),
4.20 (s, 2H), 4.05 (br s, 1H), 3.81 (s, 3H), 3.78 (s, 3H); 13C NMR
(75 MHz, CDCl3)
d 160.5, 158.6, 147.1, 129.8, 129.1 (2C), 122.0, 119.4,
114.4 (2C), 104.1, 98.9, 55.6 (2C), 43.5; IR (neat, cmꢁ1): 3387, 2940,
1615,1585,1401,1261,1176,1093,1027, 844; HRMS (ESþ) m/z [MþH]þ
calcd for C15H1735ClNO2: 278.0948; found: 278.0964. Anal. Calcd for
C15H16ClNO2: C, 64.87; H, 5.81; N, 5.04. Found: C, 64.71; H, 5.89; N,
5.01.
(300 MHz, CDCl3)
(m, 1H), 6.21–6.14 (m, 3H), 3.43 (br s, 2H), 1.08 (s, 9H); 13C NMR
(75 MHz, CDCl3) 156.8, 147.6, 135.7 (4C), 133.4 (2C), 130.0 (2C), 129.9,
d 7.73–7.70 (m, 4H), 7.41–7.35 (m, 6H), 6.87–6.81
4.4.4. N-(2,4-Dimethoxybenzyl)-4-fluoroaniline (7d). Compound 7d
was prepared according to the general procedure (A) reported for
d

D. Gauthier et al. / Tetrahedron 65 (2009) 8542–8555
8547
7a starting from 4-fluoroaniline 6d (0.92 g, 8.25 mmol, 1 equiv) and
2,4-dimethoxybenzaldehyde (1.40 g, 8.42 mmol, 1.02 equiv). Flash
column chromatography on silica gel (heptane/EtOAc, 7/3) afforded
7d (2.13 g, 99%) as a beige solid; mp 66–67 ꢀC. 1H NMR (300 MHz,
silica gel (heptane/EtOAc, 7/3) afforded 7h (1.01 g, 36%) as a white
solid; mp 44–45 ꢀC. 1H NMR (300 MHz, CDCl3)
2.7 Hz, 1H), 7.17 (d, J¼8.2 Hz, 1H), 6.90 (dt, J¼8.2, 2.7 Hz, 1H), 6.61
(dd, J¼8.8, 4.9 Hz, 1H), 6.51 (d, J¼1.8 Hz, 1H), 6.45 (dd, J¼8.2, 1.8 Hz,
1H), 4.65 (br s, 1H), 4.30 (s, 2H), 3.85 (s, 3H), 3.80 (s, 3H); 13C NMR
d
7.21 (dd, J¼7.9,
CDCl3)
6.46 (d, J¼2.3 Hz, 1H), 6.42 (dd, J¼8.3, 2.3 Hz, 1H), 4.19 (s, 2H), 3.81
(s, 3H), 3.78 (s, 3H); 13C NMR (75 MHz, CDCl3)
160.5, 158.7, 156.1
d
7.16 (d, J¼8.2 Hz,1H), 6.89–6.81 (m, 2H), 6.60–6.53 (m, 2H),
(75 MHz, CDCl3)
d
160.5, 158.5, 154.5 (d, J¼238.2 Hz), 142.1, 129.5,
d
119.4 (d, J¼25.2 Hz), 118.9, 115.0 (d, J¼21.4 Hz), 112.0 (d, J¼7.7 Hz),
(d, J¼235.0 Hz), 144.9, 130.0, 119.7, 115.7 (d, J¼22.0 Hz, 2C), 114.2 (d,
109.1 (d, J¼9.9 Hz), 104.0, 98.8, 55.4 (2C), 43.7; 19F NMR (282 MHz,
J¼7.7 Hz, 2C), 104.1, 98.9, 55.6 (2C), 44.2; 19F NMR (282 MHz, CDCl3)
CDCl3)
d
ꢁ127.18; IR (neat, cmꢁ1) 3405, 2936,1613,1587,1503,1264,
d
ꢁ128.34; IR (neat, cmꢁ1) 3366, 2960, 1607, 1589, 1510, 1466, 1207,
1206, 1155, 1033, 795; HRMS (ESþ) m/z [MþH]þ calcd for
1130, 1036, 828; HRMS (ESþ) m/z [MþH]þ calcd for C15H17FNO2:
C15H1679BrFNO2: 340.0348; found: 340.0322.
262.1243; found: 262.1240.
4.4.9. 2-Bromo-N-(2,4-dimethoxybenzyl)-5-methoxyaniline
(7i). Compound 7i was prepared according to the general procedure
(A) reported for 7a starting from 2-bromo-5-methoxyaniline 6i
(1.67 g, 8.25 mmol,1 equiv) and 2,4-dimethoxybenzaldehyde (1.40 g,
8.42 mmol, 1.02 equiv). Flash column chromatography on silica gel
(heptane/EtOAc, 7/3) afforded 7i (2.76 g, 95%) as a yellow oil. 1H NMR
4.4.5. N-(2,4-Dimethoxybenzyl)-4-(trifluoromethyl)aniline (7e). Com-
pound 7e was prepared according to the general procedure (A)
reported for 7a starting from 4-(trifluoromethyl)aniline 6e (1.33 g,
8.25 mmol, 1 equiv) and 2,4-dimethoxybenzaldehyde (1.40 g,
8.42 mmol, 1.02 equiv). Flash column chromatography on silica gel
(heptane/EtOAc, 6/4) afforded 7e (2.49 g, 97%) as a white solid; mp
(300 MHz, CDCl3)
d
7.28 (dd, J¼8.7 Hz,1H), 7.17 (d, J¼8.2 Hz,1H), 6.48
79–80 ꢀC. 1H NMR (300 MHz, CDCl3)
d
7.37 (d, J¼8.7 Hz, 2H), 7.15 (d,
(dd, J¼8.2, 2.3 Hz, 1H), 6.44 (d, J¼8.2 Hz, 1H), 6.27 (d, J¼2.9 Hz, 1H),
J¼8.1 Hz, 1H), 6.62 (d, J¼8.7 Hz, 2H), 6.48 (d, J¼2.3 Hz, 1H), 6.43 (dd,
J¼8.1, 2.3 Hz, 1H), 4.37 (br s, 1H), 4.27 (br s, 2H), 3.83 (s, 3H), 3.79 (s,
6.14 (dd, J¼8.7, 2.9 Hz, 1H), 4.78 (br s, 1H), 4.30 (s, 2H), 3.84 (s, 3H),
3.78 (s, 3H), 3.72 (s, 3H); 13C NMR (75 MHz, CDCl3)
d 160.4, 160.3,
3H); 13C NMR (75 MHz, CDCl3)
d
160.7, 158.6, 150.9, 129.8, 126.7 (q,
158.5,146.1,132.5,129.6,119.0,104.1,102.7,101.2, 98.7, 98.6, 55.4 (3C),
43.0; IR (neat, cmꢁ1) 3405, 2933, 2832, 1587, 1504, 1454, 1285, 1205,
1155, 1034, 822; HRMS (ESþ) m/z [MþNa]þ calcd for
C16H1879BrNO3Na: 374.0368; found: 374.0384.
J¼3.3 Hz, 2C), 125.3 (q, J¼268.1 Hz), 119.0, 118.9 (q, J¼33.5 Hz), 112.3
(2C), 104.1, 98.9, 55.6 (2C), 43.0; 19F NMR (282 MHz, CDCl3)
d
ꢁ61.50; IR (neat, cmꢁ1) 3387, 2923, 1613, 1509, 1463, 1325, 1258,
1151, 1094, 822; HRMS (ESꢁ) m/z [MꢁH]ꢁ calcd for C16H15F3NO2:
310.1055; found: 310.1042. Anal. Calcd for C16H16F3NO2: C, 61.73; H,
5.18; N, 4.50. Found: C, 61.83; H, 5.47; N, 4.38.
4.4.10. N-(2,4-Dimethoxybenzyl)-3-methoxyaniline (7j). Compound
7j was prepared according to the general procedure (A) reported for
7a starting from 3-methoxyaniline 6j (1.02 g, 8.25 mmol, 1 equiv)
and 2,4-dimethoxybenzaldehyde (1.40 g, 8.42 mmol, 1.02 equiv).
Flash column chromatography on silica gel (heptane/EtOAc, 7/3)
afforded 7j (1.58 g, 70%) as a white solid; mp 73–74 ꢀC. 1H NMR
4.4.6. N-(2,4-Dimethoxybenzyl)-3,5-dimethoxyaniline (7f). Compound
7f was prepared according to the general procedure (A) reported for 7a
starting from 3,5-dimethoxyaniline 6f (1.26 g, 8.25 mmol,1 equiv) and
2,4-dimethoxybenzaldehyde (1.40 g, 8.42 mmol, 1.02 equiv). Flash
column chromatography on silica gel (heptane/EtOAc, 6/4) afforded 7f
(2.33 g, 93%) as a pale-yellow solid; mp 71–72 ꢀC. 1H NMR (300 MHz,
(300 MHz, CDCl3)
d
7.20 (d, J¼8.2 Hz, 1H), 7.06 (t, J¼8.0 Hz, 1H), 6.45
(d, J¼2.3 Hz, 2H), 6.43 (dd, J¼8.2, 2.3 Hz, 1H), 6.28–6.24 (m, 2H),
6.21 (t, J¼2.2 Hz, 1H), 4.23 (s, 2H), 3.82 (s, 3H), 3.79 (s, 3H), 3.75 (s,
CDCl3)
2.3 Hz, 1H), 5.86–5.83 (m, 3H), 4.20 (s, 2H), 4.03 (br s, 1H), 3.81 (s, 3H),
3.78 (s, 3H), 3.72 (s, 6H); 13C NMR (75 MHz, CDCl3)
161.9 (2C), 160.4,
d
7.17 (d, J¼8.3 Hz, 1H), 6.44 (d, J¼2.3 Hz, 1H), 6.40 (dd, J¼8.3,
3H); 13C NMR (75 MHz, CDCl3)
d 160.8, 160.2, 158.4, 149.9, 129.9,
129.7, 119.7, 106.3, 103.9, 102.4, 99.1, 98.6, 55.4 (2C), 55.1, 43.1; IR
(neat, cmꢁ1) 3380, 2962, 1603, 1576, 1505, 1462, 1207, 1129, 1035,
827; HRMS (ESþ) m/z [MþH]þ calcd for C16H20NO3: 274.1443;
found: 274.1438. Anal. Calcd for C16H19NO3: C, 70.31; H, 7.01; N,
5.12. Found: C, 70.21; H, 7.09; N, 4.93.
d
158.6,150.6,130.0,119.9,104.2, 98.8, 92.1 (2C), 89.9, 55.6 (2C), 55.3 (2C),
43.3; IR (neat, cmꢁ1) 3414, 2948,1611,1588,1505,1462,1286,1201,1172,
1146, 1130, 1042, 808; HRMS (ESþ) m/z [MþH]þ calcd for C17H22NO4:
304.1549; found: 304.1524.
4.4.11. 3-(tert-Butyldiphenylsilyloxy)-N-(2,4-dimethoxybenzyl)ani-
line (7k). Compound 7k was prepared according to the general
procedure (A) reported for 7a starting from 3-(tert-butyldiphenyl-
silyloxy)aniline 6k (2.87 g, 8.25 mmol, 1 equiv) and 2,4-dimethoxy-
benzaldehyde (1.40 g, 8.42 mmol, 1.02 equiv). Flash column
chromatography on silica gel (heptane/EtOAc, 7/3) afforded 7k
(3.74 g, 91%) as a white solid; mp 100–101 ꢀC. 1H NMR (500 MHz,
4.4.7. 2-Bromo-N-(2,4-dimethoxybenzyl)aniline (7g). Compound
7g was prepared according to the general procedure (A) reported
for 7a starting from 2-bromoaniline 6g (1.42 g, 8.25 mmol,
1 equiv) and 2,4-dimethoxybenzaldehyde (1.40 g, 8.42 mmol,
1.02 equiv). Flash column chromatography on silica gel (heptane/
EtOAc, 6/4) afforded 7g (2.36 g, 89%) as a pale-yellow solid; mp
47–48 ꢀC. 1H NMR (500 MHz, CDCl3)
d
7.39 (dd, J¼7.8, 1.3 Hz, 1H),
CDCl3)
d
7.72–7.70 (m, 4H), 7.40–7.32 (m, 6H), 7.02 (d, J¼8.2 Hz, 1H),
7.15 (d, J¼8.3 Hz, 1H), 7.14–7.09 (m, 1H), 6.66 (dd, J¼8.2, 1.1 Hz, 1H),
6.53 (dt, J¼7.8, 1.1 Hz, 1H), 6.46 (d, J¼2.3 Hz, 1H), 6.42 (dd, J¼8.3,
2.3 Hz, 1H), 4.78 (br s, 1H), 4.30 (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H);
6.84 (t, J¼7.9 Hz, 1H), 6.42 (d, J¼2.1 Hz, 1H), 6.35 (dd, J¼8.2, 2.1 Hz,
1H), 6.17 (dd, J¼7.9, 1.5 Hz, 1H), 6.13 (dd, J¼1.5, 1.2 Hz, 1H), 6.10 (dd,
J¼7.9, 1.2 Hz, 1H), 4.03 (s, 2H), 3.87 (br s, 1H), 3.78 (s, 3H), 3.77 (br s,
13C NMR (75 MHz, CDCl3)
d
160.5, 158.6, 145.3, 132.5, 129.6, 128.6,
3H), 1.08 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 160.3, 158.6, 156.8,
119.2, 117.9, 112.1, 110.1, 104.1, 98.9, 55.6 (2C), 43.3; IR (neat, cmꢁ1
)
149.8, 135.7 (4C), 133.6 (2C), 130.0, 129.9 (2C), 129.7, 127.8 (4C),
119.9, 109.2, 106.8, 104.8, 104.0, 98.7, 55.6, 55.5, 43.3, 26.8 (3C), 19.7;
IR (neat, cmꢁ1) 3385, 2854, 1608, 1588, 1506, 1463, 1262, 1187, 1132,
696; HRMS (ESþ) m/z [MþNa]þ calcd for C31H35NO3SiNa: 520.2284;
found: 520.2233.
3412, 2932, 1583, 1503, 1415, 1320, 1237, 1206, 1132, 1072, 928;
HRMS (ESþ) m/z [MþNa]þ calcd for C15H1679BrNO2Na: 344.0262;
found: 343.9991; calcd for C15H1681BrNO2Na: 346.0242; found:
345.9873.
4.4.8. 2-Bromo-N-(2,4-dimethoxybenzyl)-4-fluoroaniline
(7h). Compound 7h was prepared according to the general pro-
cedure (A) reported for 7a starting from 2-bromo-4-fluoroaniline
6h (1.57 g, 8.25 mmol, 1 equiv) and 2,4-dimethoxybenzaldehyde
(1.40 g, 8.42 mmol, 1.02 equiv). Flash column chromatography on
4.4.12. N-(2,4-Dimethoxybenzyl)-3-fluoroaniline (7l). Compound 7l
was prepared according to the general procedure (A) reported for
7a starting from 3-fluoroaniline 6l (0.92 g, 8.25 mmol, 1 equiv) and
2,4-dimethoxybenzaldehyde (1.40 g, 8.42 mmol, 1.02 equiv). Flash
column chromatography on silica gel (heptane/EtOAc, 7/3) afforded

8548
D. Gauthier et al. / Tetrahedron 65 (2009) 8542–8555
7l (2.07 g, 96%) as a beige solid; mp 77–78 ꢀC. 1H NMR (300 MHz,
CDCl3)
7.16 (d, J¼8.2 Hz, 1H), 7.04 (br q, J¼7.5 Hz, 1H), 6.47 (d,
J¼2.4 Hz, 1H), 6.43 (d, J¼8.2, 2.4 Hz, 1H), 6.41–6.32 (m, 3H), 4.21 (s,
2H), 3.81 (s, 3H), 3.78 (s, 3H); 13C NMR (75 MHz, CDCl3)
164.3 (d,
(75 MHz, CDCl3) d 161.0, 160.5, 159.5, 158.6, 158.5, 135.5, 131.0, 128.4
d
(2C), 117.8, 114.3 (2C), 104.3, 98.5, 61.5, 55.6 (2C), 55.4, 48.9, 14.5; IR
(neat, cmꢁ1) 3083, 2934, 2113,1720,1613,1505,1287,1246,1207,1101,
834; HRMS (ESþ) m/z [MþNa]þ calcd for C21H23N3O6Na: 436.1485;
found: 436.1495.
d
J¼242.6 Hz), 160.6, 158.6, 150.3 (d, J¼10.4 Hz), 130.3 (d, J¼10.4 Hz),
129.9, 119.3, 109.2, 104.1, 103.8 (d, J¼31.8 Hz), 99.9 (d, J¼25.3 Hz),
98.9, 55.6 (2C), 43.3; 19F NMR (282 MHz, CDCl3)
d
ꢁ113.00; IR (neat,
4.5.3. Ethyl 3-(N-(4-chlorophenyl)-N-(2,4-dimethoxybenzyl)amino)-
2-diazo-3-oxopropanoate (9c). Compound 9c was prepared accord-
ing to the general procedure (B) reported for 9a starting from
4-chloro-N-(2,4-dimethoxybenzyl)aniline 7c (628 mg, 2.26 mmol,
1 equiv), distilled Et3N (1.49 mL, 10.60 mmol, 4.7 equiv), and ethyl 2-
diazomalonyl chloride 8 (400 mg, 2.26 mmol, 1 equiv). Flash column
chromatography on silica gel (heptane/EtOAc, 7/1) afforded 9c
(934 mg, 99%) as a yellow solid; mp 97–98 ꢀC. 1H NMR (300 MHz,
cmꢁ1) 3377, 2935, 1614, 1583, 1505, 1434, 1336, 1252, 1205, 1142,
1041, 819; HRMS (ESþ) m/z [MþH]þ calcd for C15H17FNO2:
262.1243; found: 262.1237.
4.4.13. N-(2,4-Dimethoxybenzyl)-3-(trifluoromethyl)aniline
(7m). Compound 7m was prepared according to the general pro-
cedure (A) reported for 7a starting from 3-trifluoromethylaniline
6m (1.33 g, 8.25 mmol, 1 equiv) and 2,4-dimethoxybenzaldehyde
(1.40 g, 8.42 mmol, 1.02 equiv). Flash column chromatography on
silica gel (heptane/EtOAc, 7/3) afforded 7m (2.20 g, 86%) as a white
CDCl3)
d
7.19 (d, J¼8.3 Hz, 1H), 7.14 (dd, J¼8.7, 2.0 Hz, 2H), 6.96 (dd,
J¼8.7, 2.0 Hz, 2H), 6.33 (dd, J¼8.3, 2.3 Hz, 1H), 6.26 (d, J¼2.3 Hz, 1H),
4.83 (s, 2H), 3.95 (q, J¼7.1 Hz, 2H), 3.67 (s, 3H), 3.51 (s, 3H), 1.05 (t,
solid; mp 88–89 ꢀC. 1H NMR (300 MHz, CDCl3)
1H), 7.21 (d, J¼8.4 Hz, 1H), 6.92–6.86 (m, 2H), 6.78–6.74 (m, 1H),
6.51 (d, J¼2.1 Hz, 1H), 6.47 (dd, J¼8.4, 2.1 Hz, 1H), 4.38 (br s, 1H),
4.29 (s, 2H), 3.86 (s, 3H), 3.83 (s, 3H); 13C NMR (75 MHz, CDCl3)
d
7.27 (br d, J¼7.9 Hz,
J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 161.6, 161.1, 160.5, 158.3,
141.5, 132.2, 130.7, 128.9 (2C), 127.9 (2C), 117.2, 104.3, 98.3, 61.4, 55.3,
55.1, 48.9, 14.3; IR (neat, cmꢁ1) 2936, 2120, 1713, 1614, 1491, 1367,
1285, 1207, 1098, 833; HRMS (ESþ) m/z [MþNa]þ calcd for
C20H2035ClN3O5Na: 440.0989; found: 440.0997.
d
160.6, 158.7, 148.7, 131.4 (q, J¼31.3 Hz), 130.1, 129.7, 124.4 (q,
J¼271.7 Hz), 119.1, 116.1, 113.9 (q, J¼2.2 Hz), 109.4 (q, J¼4.4 Hz),
104.2, 98.9, 55.6 (2C), 43.2; 19F NMR (282 MHz, CDCl3)
d
ꢁ62.86; IR
4.5.4. Ethyl 2-diazo-3-(N-(2,4-dimethoxybenzyl)-N-(4-fluorophenyl)-
amino)-3-oxopropanoate(9d). Compound 9d was prepared according
to the general procedure (B) reported for 9a starting from N-(2,4-
dimethoxybenzyl)-4-fluoroaniline 7d (590 mg, 2.26 mmol, 1 equiv),
distilled Et3N (1.49 mL, 10.60 mmol, 4.7 equiv), and ethyl 2-diazo-
malonyl chloride 8 (400 mg, 2.26 mmol, 1 equiv). Flash column
chromatography on silica gel (heptane/EtOAc, 7/3) afforded 9d
(neat, cmꢁ1) 3405, 2930, 1609, 1504, 1436, 1276, 1153, 1108, 1033,
788; HRMS (ESꢁ) m/z [MꢁH]ꢁ calcd for C16H15F3NO2: 310.1055;
found: 310.1045. Anal. Calcd for C16H16F3NO2: C, 61.73; H, 5.18; N,
4.50. Found: C, 61.24; H, 5.24; N, 4.39.
4.5. General procedure (B) for the synthesis of the
diazomalonamic acid ethyl esters 9
(580 mg, 64%) as a yellow oil. 1H NMR (300 MHz, CDCl3)
d 7.25 (d,
J¼8.4 Hz, 1H), 7.06–7.00 (m, 2H), 6.96–6.88 (m, 2H), 6.40 (dd, J¼8.4,
2.3 Hz, 1H), 6.31 (d, J¼2.3 Hz, 1H), 4.88 (s, 2H), 4.03 (q, J¼7.2 Hz, 2H),
3.75 (s, 3H), 3.58 (s, 3H), 1.13 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz,
4.5.1. Ethyl 2-diazo-3-(N-(2,4-dimethoxybenzyl)-N-(phenyl)amino)-
3-oxopropanoate (9a). A solution of N-(2,4-dimethoxybenzyl)ani-
line 7a (550 mg, 2.26 mmol, 1 equiv) in CH2Cl2 (6.30 mL) was
cooled to 0 ꢀC under argon. Distilled Et3N (1.49 mL, 10.60 mmol,
CDCl3)
d
161.9, 161.4 (d, J¼247.0 Hz), 161.3, 160.7, 158.6, 138.9, 131.1,
128.8 (d, J¼8.2 Hz, 2C),117.5,115.7 (d, J¼23.0 Hz, 2C),104.4, 98.5, 61.5,
4.7 equiv) and ethyl 2-diazomalonyl chloride
8
(400 mg,
55.5, 55.3, 49.1, 14.4; 19F NMR (282 MHz, CDCl3)
d
ꢁ114.76; IR (neat,
2.26 mmol, 1 equiv) were successively added dropwise. After 6 h of
stirring at room temperature, a solution of HCl 1 M (2.60 mL) was
added and the mixture was extracted with CH2Cl2 (3ꢂ). The com-
bined CH2Cl2 phases were then dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (heptane/EtOAc, 7/3) to give 9a
(806 mg, 93%) as a yellow solid; mp 57–58 ꢀC. 1H NMR (300 MHz,
cmꢁ1) 3071, 2937, 2122,1713,1624,1505,1385,1261,1207,1105,1027,
833; HRMS (ESþ) m/z [MþNa]þ calcd for C20H20FN3O5Na: 424.1285;
found: 424.1291.
4.5.5. Ethyl 2-diazo-3-(N-(2,4-dimethoxybenzyl)-N-(4-trifluoromethyl-
phenyl)amino)-3-oxopropanoate (9e). Compound 9e was prepared
according to the general procedure (B) reported for 9a starting from N-
CDCl3)
d
7.25 (d, J¼8.3 Hz,1H), 7.21–7.18 (m,1H), 7.11 (br d, J¼7.7 Hz,
(2,4-dimethoxybenzyl)-4-(trifluoromethyl)aniline
7e
(703 mg,
1H), 7.04 (br d, J¼7.7 Hz, 2H), 6.36 (dd, J¼8.3, 2.4 Hz, 2H), 6.28 (d,
J¼2.4 Hz,1H), 4.88 (s, 2H), 3.95 (q, J¼7.1 Hz, 2H), 3.70 (s, 3H), 3.53 (s,
2.26 mmol, 1 equiv), distilled Et3N (1.49 mL, 10.60 mmol, 4.7 equiv),
and ethyl 2-diazomalonyl chloride 8 (400 mg, 2.26 mmol, 1 equiv).
Flash column chromatography on silica gel (heptane/EtOAc, 7/3)
afforded 9e (683 mg, 67%) as a yellow solid; mp 108–109 ꢀC. 1H NMR
3H), 1.06 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 162.3, 161.1,
160.5, 158.5, 143.3, 130.7, 129.1 (2C), 126.9, 126.6 (2C), 117.8, 104.3,
98.5, 61.6, 55.5, 55.3, 49.1, 14.4; IR (neat, cmꢁ1) 3060, 2928, 2124,
1765, 1702, 1642, 1493, 1205, 1102, 697; HRMS (ESþ) m/z [MþNa]þ
calcd for C20H21N3O5Na: 406.1379; found: 406.1382. Anal. Calcd for
C20H21N3O5$0.4AcOEt: C, 61.97; H, 5.83; N, 10.04. Found: C, 61.98;
H, 5.65; N, 9.89.
(300 MHz, CDCl3)
d
7.45 (br d, J¼8.5 Hz, 2H), 7.25 (d, J¼8.4 Hz,1H), 7.18
(br d, J¼8.5 Hz, 2H), 6.36 (dd, J¼8.4, 2.3 Hz, 1H), 6.27 (d, J¼2.3 Hz, 1H),
4.89 (s, 2H), 3.91 (q, J¼7.2 Hz, 2H), 3.69 (s, 3H), 3.51 (s, 3H), 1.01 (t,
J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 161.7, 161.4, 160.6, 158.3,
146.7, 130.6, 128.4 (q, J¼32.4 Hz), 126.5 (2C), 125.9 (q, J¼3.3 Hz, 2C),
123.8 (q, J¼272.8 Hz), 117.1, 104.4, 98.4, 61.6, 55.5, 55.1, 49.2, 14.3; 19F
4.5.2. Ethyl 2-diazo-3-(N-(2,4-dimethoxybenzyl)-N-(4-methoxyphenyl)-
amino)-3-oxopropanoate (9b)36b. Compound 9b was prepared
according to the general procedure (B) reported for 9a starting from
N-(2,4-dimethoxybenzyl)-4-methoxyaniline 7b (618 mg, 2.26 mmol,
1 equiv), distilled Et3N (1.49 mL, 10.60 mmol, 4.7 equiv), and ethyl 2-
diazomalonyl chloride 8 (400 mg, 2.26 mmol, 1 equiv). Flash column
chromatography on silica gel (heptane/EtOAc, 1/1) afforded 9b
NMR (282 MHz, CDCl3)
d
ꢁ62.50; IR (neat, cmꢁ1) 2960, 2126, 1702,
1642,1610,1503,1325,1205,1157,1100, 855; HRMS (ESþ) m/z[MþNa]þ
calcd for C21H20F3N3O5Na: 474.1253; found: 474.1244.
4.5.6. Ethyl 2-diazo-3-(N-(2,4-dimethoxybenzyl)-N-(3,5-dimethoxy-
phenyl)amino)-3-oxopropanoate (9f). Compound 9f was prepared
according to the general procedure (B) reported for 9a starting from
(728 mg, 78%) as a yellow oil. 1H NMR (300 MHz, CDCl3)
d
7.28 (d,
N-(2,4-dimethoxybenzyl)-3,5-dimethoxyaniline
7f
(686 mg,
J¼8.5 Hz,1H), 6.98 (dd, J¼8.8, 3.6 Hz, 2H), 6.76 (dd, J¼8.8, 3.6 Hz, 2H),
6.41 (dd, J¼8.5, 2.4 Hz,1H), 6.33 (d, J¼2.4 Hz,1H), 4.87 (s, 2H), 4.06 (q,
J¼7.2 Hz, 2H), 3.76 (s, 6H), 3.59 (s, 3H),1.15 (t, J¼7.2 Hz, 3H); 13C NMR
2.26 mmol,1 equiv), distilled Et3N (1.49 mL,10.60 mmol, 4.7 equiv),
and ethyl 2-diazomalonyl chloride 8 (400 mg, 2.26 mmol, 1 equiv).
Flash column chromatography on silica gel (heptane/EtOAc, 7/3)

D. Gauthier et al. / Tetrahedron 65 (2009) 8542–8555
8549
afforded 9f (832 mg, 83%) as a yellow solid; mp 52–53 ꢀC. 1H NMR
(300 MHz, CDCl3)
514.0590; found: 514.0563; calcd for C21H2281BrN3O6Na: 516.0569;
found: 516.0547.
d
7.18 (d, J¼8.3 Hz, 1H), 6.34 (dd, J¼8.3, 2.4 Hz,
1H), 6.29 (d, J¼2.4 Hz, 1H), 6.21–6.19 (m, 3H), 4.83 (s, 2H), 4.01 (q,
J¼7.2 Hz, 2H), 3.67 (s, 3H), 3.61 (s, 6H), 3.58 (s, 3H), 1.09 (t, J¼7.2 Hz,
4.5.10. Ethyl 2-diazo-3-(N-(2,4-dimethoxybenzyl)-N-(3-methoxy-
phenyl)amino)-3-oxopropanoate (9j). Compound 9j was prepared
according to the general procedure (B) reported for 9a starting from
N-(2,4-dimethoxybenzyl)-3-methoxyaniline 7j (618 mg, 2.26 mmol,
1 equiv), distilled Et3N (1.49 mL, 10.60 mmol, 4.7 equiv), and ethyl
2-diazomalonyl chloride 8 (400 mg, 2.26 mmol, 1 equiv). Flash
column chromatography on silica gel (heptane/EtOAc, 7/3) afforded
9j (730 mg, 78%) as a yellow solid; mp 97–98 ꢀC. 1H NMR (300 MHz,
3H); 13C NMR (75 MHz, CDCl3)
d 162.3, 160.9 (2C), 160.8, 160.3,
158.3, 144.6, 130.4, 117.8, 104.8 (2C), 104.2, 98.8, 98.3, 61.4, 55.4 (2C),
55.3, 55.2, 48.9, 14.3; IR (neat, cmꢁ1) 2935, 2108, 1726, 1707, 1588,
1286, 1202, 1156, 1100, 1032, 830; HRMS (ESþ) m/z [MþNa]þ calcd
for C22H25N3O7Na: 466.1590; found: 466.1591.
4.5.7. Ethyl 3-(N-(2-bromophenyl)-N-(2,4-dimethoxybenzyl)amino)-
2-diazo-3-oxopropanoate (9g). Compound 9g was prepared accord-
ing to the general procedure (B) reported for 9a starting from
2-bromo-N-(2,4-dimethoxybenzyl)aniline 7g (728 mg, 2.26 mmol,
1 equiv), distilled Et3N (1.49 mL, 10.60 mmol, 4.7 equiv), and ethyl
2-diazomalonyl chloride 8 (400 mg, 2.26 mmol, 1 equiv). Flash col-
umn chromatography on silica gel (heptane/EtOAc, 7/3) afforded 9g
CDCl3)
d
7.27 (d, J¼8.2 Hz, 1H), 7.15 (t, J¼8.2 Hz, 1H), 6.72–6.69 (m,
2H), 6.64 (t, J¼2.4 Hz, 1H), 6.41 (dd, J¼8.2, 2.1 Hz, 1H), 6.34 (d,
J¼2.1 Hz,1H), 4.91 (s, 2H), 4.04 (q, J¼7.0 Hz, 2H), 3.75 (s, 6H), 3.62 (s,
3H), 1.14 (t, J¼7.0 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 162.4, 161.1,
160.5, 160.2, 158.5, 144.3, 130.6, 129.8, 118.9, 117.9, 112.5, 112.4,
104.3, 98.5, 61.5, 53.6 (2C), 53.4, 49.1, 14.4; IR (neat, cmꢁ1) 3059,
2973, 2130, 1688, 1601, 1584, 1488, 1372, 1276, 1193, 1027, 744;
HRMS (ESþ) m/z [MþNa]þ calcd for C21H23N3O6Na: 436.1485;
found: 436.1489.
(293 mg, 28%) as a yellow oil. 1H NMR (300 MHz, CDCl3)
d 7.54 (dd,
J¼7.7, 1.8 Hz, 1H), 7.33 (d, J¼8.4 Hz, 1H), 7.11 (dt, J¼7.6, 1.8 Hz, 1H),
7.07 (dt, J¼7.7, 2.0 Hz,1H), 6.92 (dd, J¼7.6, 2.0 Hz,1H), 6.38 (dd, J¼8.4,
2.4 Hz, 1H), 6.25 (d, J¼2.4 Hz, 1H), 5.22 (d, J¼14.3 Hz, 1H), 4.53 (d,
J¼14.3 Hz, 1H), 4.05 (q, J¼7.2 Hz, 2H), 3.74 (s, 3H), 3.44 (s, 3H), 1.13 (t,
4.5.11. Ethyl 3-(N-(3-(tert-butyldiphenylsilyloxy)phenyl)-N-(2,4-di-
methoxybenzyl)amino)-2-diazo-3-oxopropanoate (9k). Compound
9k was prepared according to the general procedure (B) reported for
9a starting from 3-(tert-butyldiphenylsilyloxy)-N-(2,4-dimethoxy-
benzyl)aniline 7k (1.125 g, 2.26 mmol, 1 equiv), distilled Et3N
(1.49 mL, 10.60 mmol, 4.7 equiv), and ethyl 2-diazomalonyl chloride
8 (400 mg, 2.26 mmol, 1 equiv). Flash column chromatography on
silica gel (heptane/EtOAc, 6/4) afforded 9k (1.268 g, 88%) as a yellow
J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 162.3, 161.1, 160.8, 158.9,
140.4, 133.3, 132.4, 131.6, 129.1, 127.6, 124.0, 117.0, 104.2, 98.2, 61.4,
55.5, 55.1, 47.5, 14.5; IR (neat, cmꢁ1) 2936, 2116, 1713, 1612, 1505,
1473, 1385, 1286, 1207, 1099, 750; HRMS (ESþ) m/z [MþNa]þ calcd
for C20H2079BrN3O5Na: 484.0484; found: 484.0480; calcd for
C20H2081BrN3O5Na: 486.0464; found: 484.0467.
4.5.8. Ethyl 3-(N-(2-bromo-4-fluorophenyl)-N-(2,4-dimethoxybenzyl)-
amino)-2-diazo-3-oxopropanoate (9h). Compound 9h wasprepared
according to the general procedure (B) reported for 9a starting from
2-bromo-N-(2,4-dimethoxybenzyl)-4-fluoroaniline 7h (769 mg,
2.26 mmol, 1 equiv), distilled Et3N (1.49 mL, 10.60 mmol, 4.7 equiv),
and ethyl 2-diazomalonyl chloride 8 (400 mg, 2.26 mmol, 1 equiv).
Flash column chromatography on silica gel (heptane/EtOAc, 7/3)
afforded 9h (326 mg, 30%) as a yellow oil. 1H NMR (300 MHz, CDCl3)
oil. 1H NMR (300 MHz, CDCl3)
d 7.57–7.53 (m, 4H), 7.34–7.21 (m, 6H),
7.02 (d, J¼8.8 Hz, 1H), 6.91–6.84 (m, 1H), 6.56–6.53 (m, 1H), 6.50–
6.47 (m, 2H), 6.25–6.20 (m, 2H), 4.68 (s, 2H), 3.95 (q, J¼7.2 Hz, 2H),
3.65 (s, 3H), 3.48 (s, 3H), 1.06 (t, J¼7.2 Hz, 3H), 0.97 (s, 9H); 13C NMR
(75 MHz, CDCl3)
d 162.3, 160.6, 160.3, 158.3, 156.1, 143.8, 135.5 (4C),
132.6 (2C),130.3,130.1 (2C),129.4,128.0 (4C),119.3,118.4,117.8,117.3,
104.1, 98.4, 61.4, 55.4, 55.2, 49.0, 26.6 (3C), 19.5, 14.4; IR (neat, cmꢁ1
)
2937, 2852, 2118,1723, 1587, 1484,1372,1285,1207,1105, 700; HRMS
(ESþ) m/z [MþNa]þ calcd for C36H39N3O6SiNa: 660.2506; found:
660.2505.
d
7.28–7.26 (m, 2H), 6.89–6.82 (m, 2H), 6.38 (dd, J¼8.0, 2.3 Hz, 1H),
6.27 (d, J¼2.3 Hz,1H), 5.18 (d, J¼14.2 Hz, 1H), 4.48 (d, J¼14.2 Hz,1H),
4.05 (q, J¼7.2 Hz, 2H), 3.75 (s, 3H), 3.50 (s, 3H), 1.14 (t, J¼7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3)
d
162.0, 161.5, 161.3 (d, J¼252.5 Hz), 161.0,
4.5.12. Ethyl 2-diazo-3-(N-(2,4-dimethoxybenzyl)-N-(3-fluorophenyl)-
amino)-3-oxopropanoate (9l). Compound 9l was prepared according
to the general procedure (B) reported for 9a starting from N-(2,4-
dimethoxybenzyl)-3-fluoroaniline 7l (591 mg, 2.26 mmol, 1 equiv),
distilled Et3N (1.49 mL, 10.60 mmol, 4.7 equiv), and ethyl 2-diazo-
malonyl chloride 8 (400 mg, 2.26 mmol, 1 equiv). Flash column
chromatography on silica gel (heptane/EtOAc, 7/3) afforded 9l
(816 mg, 90%) as a yellow solid; mp 82–83 ꢀC. 1H NMR (300 MHz,
159.0, 136.7, 132.9 (d, J¼8.8 Hz), 132.6, 124.5 (d, J¼11.0 Hz), 120.2 (d,
J¼25.2 Hz), 116.7, 114.6 (d, J¼22.5 Hz), 104.3, 98.2, 61.5, 55.5, 55.2,
47.7, 14.5; 19F NMR (282 MHz, CDCl3)
d
ꢁ62.86; IR (neat, cmꢁ1) 2937,
2836, 2120, 1713, 1612, 1506, 1486, 1379, 1286, 1207, 1099, 1033;
HRMS (ESþ) m/z [MþNa]þ calcd for C20H1979BrFN3O5Na: 502.0390;
found: 502.0390; calcd for C20H1981BrFN3O5Na: 504.0369; found:
504.0368.
CDCl3)
d
7.27 (d, J¼8.3 Hz, 1H), 7.22–7.16 (m, 1H), 6.91–6.84 (m, 3H),
4.5.9. Ethyl
3-(N-(2-bromo-5-methoxyphenyl)-N-(2,4-dimethoxy-
6.41 (dd, J¼8.3, 2.4 Hz,1H), 6.34 (d, J¼2.4 Hz,1H), 4.92 (s, 2H), 4.01 (q,
benzyl)amino)-2-diazo-3-oxopropanoate (9i). Compound 9i was
prepared according to the general procedure (B) reported for 9a
starting from 2-bromo-N-(2,4-dimethoxybenzyl)-5-methoxyani-
line 7i (796 mg, 2.26 mmol, 1 equiv), distilled Et3N (1.49 mL,
J¼7.2 Hz, 2H), 3.76 (s, 3H), 3.62 (s, 3H), 1.12 (t, J¼7.2 Hz, 3H); 13C NMR
(75 MHz, CDCl3)
d
162.8 (d, J¼247.0 Hz), 161.8, 161.4, 160.6, 158.4,
144.9 (d, J¼10.4 Hz), 130.7, 130.0 (d, J¼9.3 Hz), 122.2 (d, J¼2.7 Hz),
117.5, 113.8 (d, J¼23.1 Hz), 113.6 (d, J¼20.9 Hz), 104.4, 98.5, 61.6, 55.6,
10.60 mmol, 4.7 equiv), and ethyl 2-diazomalonyl chloride
8
55.3, 49.2,12.4; 19F NMR (282 MHz, CDCl3)
d
ꢁ111.81; IR (neat, cmꢁ1
)
(400 mg, 2.26 mmol, 1 equiv). Flash column chromatography on
silica gel (heptane/EtOAc, 7/3) afforded 9i (245 mg, 22%) as a yellow
3062, 2931, 2124, 1698, 1606, 1586, 1503, 1256, 1205, 1102, 1042;
HRMS (ESþ) m/z [MþNa]þ calcd for C20H20FN3O5Na: 424.1285;
found: 424.1272.
oil. 1H NMR (300 MHz, CDCl3)
d
7.40 (d, J¼8.9 Hz, 1H), 7.30 (d,
J¼8.4 Hz, 1H), 6.66 (dd, J¼8.9, 2.9 Hz, 1H), 6.45 (d, J¼2.9 Hz, 1H),
6.39 (dd, J¼8.4, 2.3 Hz, 1H), 6.32 (d, J¼2.3 Hz, 1H), 5.20 (d,
J¼14.2 Hz,1H), 4.44 (d, J¼14.2 Hz,1H), 4.07 (q, J¼7.1 Hz, 2H), 3.71 (s,
3H), 3.55 (s, 3H), 3.47 (s, 3H), 1.12 (t, J¼7.1 Hz, 3H); 13C NMR
4.5.13. Ethyl 2-diazo-3-(N-(2,4-dimethoxybenzyl)-N-(3-trifluoro-
methylphenyl)amino)-3-oxopropanoate (9m). Compound 9m was
prepared according to the general procedure (B) reported for 9a
starting from N-(2,4-dimethoxybenzyl)-3-(trifluoromethyl)aniline
7m (703 mg, 2.26 mmol, 1 equiv), distilled Et3N (1.49 mL,
(75 MHz, CDCl3)
d 162.4, 161.0, 160.9, 159.0 (2C), 141.0, 133.4, 132.5,
117.1, 116.9, 115.7, 114.4, 104.2, 98.3, 61.5, 55.8, 55.6, 55.3, 47.6, 14.5;
IR (neat, cmꢁ1) 2936, 2115, 1764, 1677, 1587, 1506, 1463, 1286, 1207,
1157, 1028; HRMS (ESþ) m/z [MþNa]þ calcd for C21H2279BrN3O6Na:
10.60 mmol, 4.7 equiv), and ethyl 2-diazomalonyl chloride
8
(400 mg, 2.26 mmol, 1 equiv). Flash column chromatography on

8550
D. Gauthier et al. / Tetrahedron 65 (2009) 8542–8555
silica gel (heptane/EtOAc, 7/3) afforded 9m (724 mg, 71%) as a yellow
solid; mp 78–79 ꢀC. 1H NMR (300 MHz, CDCl3)
7.52–7.11 (m, 4H),
Flash column chromatography on silica gel (heptane/EtOAc/Et3N, 6/
d
3.8/0.2) afforded 10c (153 mg, 70%) as a white solid; mp 63–64 ꢀC.
7.24 (d, J¼8.4 Hz, 1H), 6.34 (dd, J¼8.4, 2.3 Hz, 1H), 6.24 (d, J¼2.3 Hz,
1H NMR (300 MHz, CDCl3)
d
7.96 (d, J¼2.0 Hz, 1H), 7.01 (dd, J¼8.6,
1H), 4.87 (s, 2H), 3.99 (q, J¼7.2 Hz, 2H), 3.67 (s, 3H), 3.48 (s, 3H), 1.00
2.0 Hz, 1H), 6.94 (d, J¼8.6 Hz, 1H), 6.45 (d, J¼2.3 Hz, 1H), 6.43 (d,
J¼8.4 Hz, 1H), 6.26 (dd, J¼8.2, 2.3 Hz, 1H), 5.16 (s, 2H), 4.38 (q,
J¼7.0 Hz, 2H), 3.87 (s, 3H), 3.72 (s, 3H), 1.47 (hep, J¼7.6 Hz, 3H), 1.43
(t, J¼7.0 Hz, 3H), 1.06 (d, J¼7.6 Hz, 18H); 13C NMR (75 MHz, CDCl3)
(t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 161.5, 161.4, 160.7, 158.4,
143.7, 132.2 (q, J¼31.3 Hz), 131.3, 130.0, 129.3, 123.8 (q, J¼271.7 Hz),
123.6 (q, J¼3.3 Hz), 123.2 (q, J¼2.7 Hz), 117.1, 104.4, 98.3, 61.4, 55.4,
55.0, 49.0, 14.2; 19F NMR (282 MHz, CDCl3)
d
ꢁ62.7; IR (neat, cmꢁ1
)
d 164.4, 160.5, 157.5, 154.2, 129.7, 127.5 (2C), 126.6, 121.7, 120.8, 116.8,
2960, 2126, 1702, 1640, 1613, 1587, 1337, 1304, 1156, 1091, 1039, 701;
HRMS (ESþ) m/z [MþNa]þ calcd for C21H20F3N3O5Na: 474.1253;
found: 474.1247.
110.6, 104.2, 98.6, 89.4, 59.4, 55.6 (2C), 40.0, 18.1 (6C), 15.0, 14.5 (3C);
IR (neat, cmꢁ1) 2942, 2865, 1693, 1614, 1591, 1537, 1454, 1208, 1145,
1112, 1034, 771; HRMS (ESþ) m/z [MþNa]þ calcd for
C29H4035ClNO5SiNa: 568.2262; found: 568.2273.
4.6. General procedure (C) for the synthesis of the 2-
silyloxyindole-3-carboxylates 10
4.6.4. Ethyl 1-N-(2,4-dimethoxybenzyl)-5-fluoro-2-(triisopropylsilyl-
oxy)-1H-indole-3-carboxylate (10d). Compound 10d was prepared
according to the general procedure (C) reported for 10a starting
from ethyl 2-diazo-3-(N-(2,4-dimethoxybenzyl)-N-(4-fluorophenyl-
amino)-3-oxopropanoate 9d (161 mg, 0.40 mmol, 1 equiv),
4.6.1. Ethyl 1-N-(2,4-dimethoxybenzyl)-2-(triisopropylsilyloxy)-1H-
indole-3-carboxylate (10a). Rh2(NHCOCF3)4 (13 mg, 0.02 mmol,
5 mol %) was added to a solution of ethyl 2-diazo-3-(N-(2,4-dime-
thoxybenzyl)-N-(phenyl)amino)-3-oxopropanoate 9a (153 mg,
0.40 mmol, 1 equiv) in CH2Cl2 (2 mL) held under argon at room
temperature. After stirring for 5 h, the solution was cooled to 0 ꢀC
Rh2(NHCOCF3)4 (13 mg, 0.02 mmol, 5 mol %), distilled Et3N (171
mL,
2.50 mmol, 6.25 equiv), and TIPSOTf (135 L, 0.50 mmol, 1.25 equiv).
m
Flash column chromatography on silica gel (heptane/EtOAc/Et3N, 6/
3.8/0.2) afforded 10d (150 mg, 71%) as a white solid; mp 88–89 ꢀC.
and distilled Et3N (171
lowed by TIPSOTf (135
m
L, 2.50 mmol, 6.25 equiv) was added fol-
mL, 0.50 mmol, 1.25 equiv). The solution was
1H NMR (300 MHz, CDCl3)
d
7.66 (dd, J¼10.3, 2.5 Hz, 1H), 6.92 (dd,
allowed to stir at 0 ꢀC for 15 min before quenching with H2O (2 mL)
and extracted with CH2Cl2 (3ꢂ). The combined CH2Cl2 extracts
were then dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by flash column chromatography on silica
gel (heptane/EtOAc/Et3N, 6/3.8/0.2) to give 10a (160 mg, 78%) as
J¼9.0, 4.5 Hz, 1H), 6.75 (dt, J¼9.0, 2.5 Hz, 1H), 6.45 (d, J¼8.3 Hz, 1H),
6.45 (d, J¼2.3 Hz,1H), 6.25 (dd, J¼8.3, 2.3 Hz,1H), 5.14 (br s, 2H), 4.35
(q, J¼7.2 Hz, 2H), 3.86 (s, 3H), 3.72 (s, 3H), 1.44 (hep, J¼7.6 Hz, 3H),
1.41 (t, J¼7.2 Hz, 3H), 1.05 (d, J¼7.7 Hz, 18H). 13C NMR (75 MHz,
CDCl3)
d
164.8, 160.4, 159.5 (d, J¼235.0 Hz), 157.5, 154.3, 127.7, 127.6,
a white solid; mp 84–85 ꢀC. 1H NMR (300 MHz, CDCl3)
d
8.00 (d,
126.2 (d, J¼10.9 Hz), 116.9, 110.1 (d, J¼9.3 Hz), 109.9 (d, J¼25.8 Hz),
J¼7.9 Hz, 1H), 7.15 (ddd, J¼7.9, 6.2, 2.3 Hz, 1H), 7.08–7.01 (m, 2H),
6.45 (d, J¼8.5 Hz, 1H), 6.44 (d, J¼2.3 Hz, 1H), 6.23 (dd, J¼8.5, 2.3 Hz,
1H), 5.17 (s, 2H), 4.36 (q, J¼7.2 Hz, 2H), 3.87 (s, 3H), 3.72 (s, 3H), 1.44
(hep, J¼7.5 Hz, 3H), 1.42 (t, J¼7.2 Hz, 3H), 1.04 (d, J¼7.5 Hz, 18H); 13C
106.9 (d, J¼25.8 Hz), 104.2, 98.5, 89.8, 59.4, 55.6 (2C), 40.0, 18.1 (6C),
15.0, 14.5 (3C); 19F NMR (282 MHz, CDCl3)
d
ꢁ122.2; IR (neat, cmꢁ1
)
2942, 2865, 1688, 1621, 1591, 1537, 1455, 1209, 1148, 1109, 1034, 780;
HRMS (ESþ) m/z [MþNa]þ calcd for C29H40FNO5SiNa: 552.2558;
found: 552.2564.
NMR (75 MHz, CDCl3) d 165.1, 160.3, 157.5, 153.6, 131.4, 127.6, 125.5,
121.8, 121.3, 120.9, 117.2, 109.5, 104.1, 98.5, 89.3, 59.2, 55.5 (2C), 39.8,
18.1 (6C), 15.0, 14.5 (3C); IR (neat, cmꢁ1) 2941, 2864, 1693, 1614,
1590, 1534, 1454, 1207, 1141, 1106; HRMS (ESþ) m/z [MþNa]þ calcd
for C29H41NO5SiNa: 534.2652; found: 534.2661.
4.6.5. Ethyl 1-N-(2,4-dimethoxybenzyl)-5-(trifluoromethyl)-2-(tri-
isopropylsilyloxy)-1H-indole-3-carboxylate (10e). Compound 10e
was prepared according to the general procedure (C) reported for
10a starting from ethyl 2-diazo-3-(N-(2,4-dimethoxybenzyl)-N-(4-
trifluoromethylphenyl)-amino)-3-oxopropanoate 9e (180 mg,
0.40 mmol, 1 equiv), Rh2(NHCOCF3)4 (13 mg, 0.02 mmol, 5 mol %),
4.6.2. Ethyl 1-N-(2,4-dimethoxybenzyl)-5-methoxy-2-(triisopropylsi-
lyloxy)-1H-indole-3-carboxylate (10b)36b. Compound 10b was pre-
pared according to the general procedure (C) reported for 10a
starting from ethyl 2-diazo-3-(N-(2,4-dimethoxybenzyl)-N-(4-
methoxyphenyl)amino)-3-oxopropanoate 9b (165 mg, 0.40 mmol,
1 equiv), Rh2(NHCOCF3)4 (13 mg, 0.02 mmol, 5 mol %), distilled
distilled Et3N (171 mL, 2.50 mmol, 6.25 equiv), and TIPSOTf (135 mL,
0.50 mmol, 1.25 equiv). Flash column chromatography on silica gel
(heptane/EtOAc/Et3N, 6/3.8/0.2) afforded 10e (167 mg, 72%) as
a yellow solid; mp 124–125 ꢀC. 1H NMR (500 MHz, CDCl3)
d 8.29 (br
Et3N (171
m
L, 2.50 mmol, 6.25 equiv), and TIPSOTf (135
m
L,
s, 1H), 7.29 (dd, J¼8.6, 1.0 Hz, 1H), 7.09 (d, J¼8.6 Hz, 1H), 6.46 (d,
J¼2.4 Hz, 1H), 6.44 (d, J¼8.6 Hz, 1H), 6.26 (dd, J¼8.6, 2.4 Hz, 1H),
5.20 (s, 2H), 4.38 (q, J¼7.0 Hz, 2H), 3.87 (s, 3H), 3.72 (s, 3H), 1.47
(hep, J¼7.6 Hz, 3H), 1.43 (t, J¼7.0 Hz, 3H), 1.05 (d, J¼7.6 Hz, 18H); 13C
0.50 mmol, 1.25 equiv). Flash column chromatography on silica gel
(heptane/EtOAc/Et3N, 6/3.8/0.2) afforded 10b (147 mg, 68%) as
a colorless oil. 1H NMR (300 MHz, CDCl3)
d
7.59 (d, J¼2.5 Hz, 1H),
6.92 (d, J¼8.8 Hz, 1H), 6.68 (dd, J¼8.8, 2.5 Hz, 1H), 6.47 (d, J¼8.4 Hz,
1H), 6.45 (d, J¼2.4 Hz, 1H), 6.24 (dd, J¼8.4, 2.4 Hz, 1H), 5.14 (s, 2H),
4.36 (q, J¼7.1 Hz, 2H), 3.87 (s, 3H), 3.84 (s, 3H), 3.72 (s, 3H), 1.44
(hep, J¼7.6 Hz, 3H), 1.43 (t, J¼7.1 Hz, 3H), 1.05 (d, J¼7.6 Hz, 18H); 13C
NMR (75 MHz, CDCl3) d 164.6, 160.6, 157.6, 154.6, 127.9, 127.5, 125.5
(q, J¼270.3 Hz), 125.1, 124.0 (d, J¼31.8 Hz), 118.5 (d, J¼4.4 Hz), 118.2
(d, J¼3.3 Hz), 116.6, 109.6, 104.3, 98.6, 90.0, 59.6, 55.6 (2C), 40.0, 18.1
(6C), 14.9, 14.6 (3C); 19F NMR (282 MHz, CDCl3)
d
ꢁ60.6; IR (neat,
NMR (75 MHz, CDCl3)
d
165.1, 160.3, 157.5, 155.8, 153.7, 127.6, 126.2,
cmꢁ1) 2943, 2866, 1697, 1618, 1590, 1542, 1454, 1264, 1148, 1111; MS
126.1, 117.2, 110.2, 109.9, 104.4, 104.2, 98.5, 89.5, 59.1, 55.9, 55.6 (2C),
39.9,18.1 (6C),15.0,14.5 (3C); IR (neat, cmꢁ1) 2942, 2864, 1691,1617,
1589, 1531, 1454, 1207, 1143, 1108, 1032, 776; HRMS (ESþ) m/z
[MþNa]þ calcd for C30H43NO6SiNa: 564.2757; found: 564.2723.
(ESþ) m/z 602.3 [MþNaþ], 446.1 [MꢁTIPSþNaþ].
4.6.6. Ethyl 1-N-(2,4-dimethoxybenzyl)-4,6-dimethoxy-2-(triisopro-
pylsilyloxy)-1H-indole-3-carboxylate (10f). Compound 10f was
prepared according to the general procedure (C) reported for 10a
starting from ethyl 2-diazo-3-(N-(2,4-dimethoxybenzyl)-N-
4.6.3. Ethyl 5-chloro-1-N-(2,4-dimethoxybenzyl)-2-(triisopropylsilyl-
oxy)-1H-indole-3-carboxylate (10c). Compound 10c was prepared
according to the general procedure (C) reported for 10a starting
from ethyl 3-(N-(4-chlorophenyl)-N-(2,4-dimethoxybenzyl)amino)-
2-diazo-3-oxopropanoate 9c (167 mg, 0.40 mmol, 1 equiv),
(3,5-dimethoxyphenyl)-amino)-3-oxopropanoate
0.40 mmol, 1 equiv), Rh2(NHCOCF3)4 (13 mg, 0.02 mmol, 5 mol %),
distilled Et3N (171 L, 2.50 mmol, 6.25 equiv), and TIPSOTf (135 L,
9f
(177 mg,
m
m
0.50 mmol, 1.25 equiv). Flash column chromatography on silica gel
Rh2(NHCOCF3)4 (13 mg, 0.02 mmol, 5 mol %), distilled Et3N (171
m
L,
(heptane/EtOAc/Et3N, 6/3.8/0.2) afforded 10f (149 mg, 65%) as
2.50 mmol, 6.25 equiv), and TIPSOTf (135 L, 0.50 mmol,1.25 equiv).
m
a white solid; mp 107–108 ꢀC. 1H NMR (300 MHz, CDCl3)
d 6.51 (d,

D. Gauthier et al. / Tetrahedron 65 (2009) 8542–8555
8551
J¼8.5 Hz, 1H), 6.44 (d, J¼2.3 Hz, 1H), 6.28 (d, J¼2.1 Hz, 1H), 6.25 (dd,
J¼8.5, 2.3 Hz, 1H), 6.22 (d, J¼2.1 Hz, 1H), 5.09 (s, 2H), 4.31 (q,
J¼7.2 Hz, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 3.72 (s, 3H), 3.70 (s, 3H), 1.38
(hep, J¼7.6 Hz, 3H), 1.37 (t, J¼7.2 Hz, 3H), 1.03 (d, J¼7.6 Hz, 18H); 13C
3H), 3.72 (s, 3H), 1.37 (t, J¼7.2 Hz, 3H), 1.33 (hep, J¼7.5 Hz, 3H), 0.99
(d, J¼7.5 Hz, 18H); 13C NMR (75 MHz, CDCl3)
d 165.9, 160.0, 156.6,
152.2, 149.8, 128.6, 126.8, 126.7, 126.3, 119.7, 117.3, 103.9(2C), 98.3,
95.2, 60.5, 55.8, 55.5 (2C), 41.4, 18.0 (6C), 14.7, 14.1 (3C); IR (neat,
cmꢁ1) 2948, 2871, 1697, 1621, 1590, 1546, 1433, 1259, 1208, 1175,
1031; HRMS (ESþ) m/z [MþNa]þ calcd for C30H4279BrNO6SiNa:
642.1862; found: 642.1873; calcd for C30H4281BrNO6SiNa: 644.1842;
found: 644.1858.
NMR (75 MHz, CDCl3) d 165.9, 160.3, 157.4, 156.7, 153.8, 150.5, 133.0,
129.7, 127.9, 117.3, 104.2, 98.4, 93.8, 89.7, 86.8, 59.8, 55.8, 55.7, 55.6,
55.3, 39.9, 18.1 (6C), 14.9, 14.3 (3C); IR (neat, cmꢁ1) 2940, 2863,
1675, 1616, 1582, 1533, 1502, 1452, 1207, 1156, 1117, 1034; HRMS
(ESþ) m/z [MþH]þ calcd for C31H46NO7Si: 572.3044; found:
572.3041.
4.6.10. Ethyl 1-N-(2,4-dimethoxybenzyl)-6-methoxy-2-(triisopro-
pylsilyloxy)-1H-indole-3-carboxylate (10j) and ethyl 1-N-(2,4-dime-
thoxybenzyl)-4-methoxy-2-(triisopropylsilyloxy)-1H-indole-3-car-
boxylate (10j0). Compounds 10j and 10j0 were prepared according
to the general procedure (C) reported for 10a starting from ethyl 2-
diazo-3-(N-(2,4-dimethoxybenzyl)-N-(3-methoxyphenyl)-amino)-
3-oxopropanoate 9j (166 mg, 0.40 mmol, 1 equiv), Rh2(NHCOCF3)4
4.6.7. Ethyl 7-bromo-1-N-(2,4-dimethoxybenzyl)-2-(triisopropylsilyl-
oxy)-1H-indole-3-carboxylate (10g). Compound 10g was prepared
according to the general procedure (C) reported for 10a starting
from
amino)-2-diazo-3-oxopropanoate 9g (185 mg, 0.40 mmol, 1 equiv),
Rh2(NHCOCF3)4 (13 mg, 0.02 mmol, 5 mol %), distilled Et3N (171 L,
2.50 mmol, 6.25 equiv), and TIPSOTf (135 L, 0.50 mmol,1.25 equiv).
ethyl
3-(N-(2-bromophenyl)-N-(2,4-dimethoxybenzyl)-
m
(13 mg, 0.02 mmol, 5 mol %), distilled Et3N (171
mL, 2.50 mmol,
m
6.25 equiv), and TIPSOTf (135 L, 0.50 mmol, 1.25 equiv). Flash
m
Flash column chromatography on silica gel (heptane/EtOAc/Et3N, 6/
column chromatography on silica gel (CH2Cl2/Et2O/heptane/Et3N,
4.9/3/2/0.1) afforded an inseparable mixture of regioisomers 10j/
10j0 (73:27, respectively, 206 mg, 95%) as a colorless oil. Compound
3.8/0.2) afforded 10g (201 mg, 85%) as a yellow foam. 1H NMR
(300 MHz, CDCl3)
d
8.09 (dd, J¼7.9, 0.9 Hz, 1H), 7.28 (dd, J¼7.9,
0.9 Hz, 1H), 7.04 (t, J¼7.9 Hz, 1H), 6.49 (d, J¼2.4 Hz, 1H), 6.27 (dd,
J¼8.2, 2.4 Hz, 1H), 6.23 (d, J¼8.2 Hz, 1H), 5.65 (br s, 2H), 4.41 (q,
J¼7.0 Hz, 2H), 3.90 (s, 3H), 3.76 (s, 3H), 1.47 (hep, J¼7.6 Hz, 3H), 1.46
(t, J¼7.0 Hz, 3H), 1.04 (d, J¼7.6 Hz, 18H); 13C NMR (75 MHz, CDCl3)
10j: 1H NMR (300 MHz, CDCl3)
d
7.90 (d, J¼8.7 Hz, 1H), 6.81 (dd,
J¼8.7, 2.3 Hz, 1H), 6.62 (d, J¼2.3 Hz, 1H), 6.55 (d, J¼8.4 Hz, 1H), 6.47
(d, J¼2.4 Hz, 1H), 6.27 (dd, J¼8.4, 2.4 Hz, 1H), 5.15 (br s, 2H), 4.36 (q,
J¼7.1 Hz, 2H), 3.88 (br s, 3H), 3.74 (br s, 3H), 3.72 (br s, 3H), 1.54–
1.43 (m, 3H), 1.43 (t, J¼7.1 Hz, 3H), 1.07 (d, J¼7.5 Hz, 18H); 13C NMR
d
164.5, 160.0, 156.7, 154.5, 128.5, 128.2, 126.9, 126.4, 122.6, 120.1,
119.4,103.9,103.4, 98.3, 89.6, 59.5, 55.4 (2C), 41.6,18.0 (6C),14.9,14.6
(3C); IR (neat, cmꢁ1) 2942, 2864, 1693, 1614, 1590, 1546, 1441, 1108,
1034; HRMS (ESþ) m/z [MþNa]þ calcd for C29H4079BrNO5SiNa:
612.1757; found: 612.1743; calcd for C29H4081BrNO5SiNa: 614.1736;
found: 614.1743.
(75 MHz, CDCl3) d 165.0, 160.3, 157.4, 155.8, 153.0, 132.1, 127.7,
121.6, 119.1, 117.3, 109.8, 104.2, 98.4, 94.6, 88.9, 59.1, 55.7, 55.4
(2C), 39.6, 18.1 (6C), 14.9, 14.5 (3C). Compound 10j0: 1H NMR
(300 MHz, CDCl3)
d
6.99 (t, J¼8.0 Hz, 1H), 6.70 (d, J¼8.0 Hz, 1H),
6.62 (d, J¼8.0 Hz, 1H), 6.46–6.45 (m, 2H), 6.25–6.22 (m, 1H), 5.17
(br s, 2H), 4.35 (q, J¼7.1 Hz, 2H), 3.88 (br s, 3H), 3.75 (br s, 3H),
3.73 (br s, 3H), 1.44–1.41 (m, 3H), 1.30–1.27 (m, 3H), 1.09–1.05
4.6.8. Ethyl 7-bromo-1-N-(2,4-dimethoxybenzyl)-5-fluoro-2-(triiso-
propylsilyloxy)-1H-indole-3-carboxylate (10h). Compound 10h was
prepared according to the general procedure (C) reported for 10a
starting from ethyl 3-(N-(2-bromo-4-fluorophenyl)-N-(2,4-dime-
thoxybenzyl)amino)-2-diazo-3-oxopropanoate 9h (192 mg, 0.40 mmol,
1 equiv), Rh2(NHCOCF3)4 (13 mg, 0.02 mmol, 5 mol %), distilled
(m, 18H); 13C NMR (75 MHz, CDCl3)
d 165.7, 160.2, 157.3, 150.8,
132.8, 130.2, 127.5, 121.9, 117.3, 114.5, 104.0, 103.4, 103.1, 98.3,
89.5, 59.8, 55.6 (3C), 40.0, 18.1 (6C), 14.4, 14.2 (3C); HRMS (ESþ)
m/z [MþNa]þ calcd for C30H43NO6SiNa: 564.2757; found:
564.2784.
Et3N (171 mL, 2.50 mmol, 6.25 equiv), and TIPSOTf (135 mL,
0.50 mmol, 1.25 equiv). Flash column chromatography on silica gel
4.6.11. Ethyl 6-(tert-butyldiphenylsilyloxy)-1-N-(2,4-dimethoxy-
benzyl)-2-(triisopropylsilyloxy)-1H-indole-3-carboxylate (10k) and
ethyl 4-(tert-butyldiphenylsilyloxy)-1-N-(2,4-dimethoxybenzyl)-2-(tri-
isopropylsilyloxy)-1H-indole-3-carboxylate (10k0). Compounds 10k
and 10k0 were prepared according to the general procedure (C)
reported for 10a starting from ethyl 3-(N-(3-(tert-butyldiphe-
nylsilyloxy)phenyl)-N-(2,4-dimethoxybenzyl)amino)-2-diazo-3-
oxopropanoate 9k (255 mg, 0.40 mmol, 1 equiv), Rh2(NHCOCF3)4
(heptane/EtOAc/Et3N, 6/3.8/0.2) afforded 10h (97 mg, 40%) as
a yellow solid; mp 117–118 ꢀC. 1H NMR (300 MHz, CDCl3)
d 7.73 (dd,
J¼9.7, 2.5 Hz, 1H), 7.00 (dd, J¼8.9, 2.5 Hz, 1H), 6.44 (d, J¼2.2 Hz, 1H),
6.23 (dd, J¼8.4, 2.2 Hz, 1H), 6.15 (d, J¼8.4 Hz, 1H), 5.55 (br s, 2H),
4.35 (q, J¼7.1 Hz, 2H), 3.84 (s, 3H), 3.72 (s, 3H), 1.42 (hep, J¼7.7 Hz,
3H), 1.41 (t, J¼7.1 Hz, 3H), 1.00 (d, J¼7.7 Hz, 18H); 13C NMR (75 MHz,
CDCl3)
d
164.2, 160.1, 158.3 (d, J¼238.8 Hz), 156.7, 155.4, 128.8 (d,
J¼11.0 Hz), 126.3, 124.9, 119.1, 114.6 (d, J¼28.0 Hz), 106.2 (d,
J¼24.7 Hz), 103.9, 102.8 (d, J¼11.5 Hz), 98.4, 90.2 (d, J¼3.8 Hz), 59.6,
55.5 (2C), 41.6, 18.0 (6C), 14.9, 14.6 (3C); 19F NMR (282 MHz, CDCl3)
(13 mg, 0.02 mmol, 5 mol%), distilled Et3N (171
mL, 2.50 mmol,
6.25 equiv), and TIPSOTf (135 L, 0.50 mmol, 1.25 equiv). Flash
m
column chromatography on silica gel (CH2Cl2/Et2O/heptane/Et3N,
4.9/3/2/0.1) afforded an inseparable mixture of regioisomers 10k/
10k0 (90:10, respectively, 285 mg, 93%) as a yellow solid. Compound
d
: ꢁ121.2; IR (neat, cmꢁ1) 2941, 2864, 1693, 1614, 1590, 1537, 1454,
1207, 1141, 1107, 1034; MS (ESþ) m/z 474 [MꢁTIPSþNa, 79Br]þ, 476
[MꢁTIPSþNa, 81Br].
10k: 1H NMR (300 MHz, CDCl3)
d
7.69 (d, J¼8.8 Hz, 1H), 7.66–7.65
(m, 4H), 7.37–7.32 (m, 2H), 7.29–7.24 (m, 4H), 6.67 (dd, J¼8.8,
2.1 Hz, 1H), 6.47 (d, J¼2.1 Hz, 1H), 6.39–6.36 (m, 2H), 6.18 (dd, J¼8.2,
1.8 Hz, 1H), 4.93 (s, 2H), 4.30 (q, J¼7.0 Hz, 2H), 3.76 (s, 3H), 3.75 (s,
3H), 1.44 (hep, J¼7.4 Hz, 3H), 1.37 (t, J¼7.0 Hz, 3H), 1.05 (br s, 9H),
4.6.9. Ethyl 7-bromo-1-N-(2,4-dimethoxybenzyl)-4-methoxy-2-(tri-
isopropylsilyloxy)-1H-indole-3-carboxylate (10i). Compound 10i was
prepared according to the general procedure (C) reported for 10a
starting from ethyl 3-(N-(2-bromo-5-methoxyphenyl)-N-(2,4-
dimethoxybenzyl)-amino)-2-diazo-3-oxopropanoate 9i (197 mg,
0.40 mmol, 1 equiv), Rh2(NHCOCF3)4 (13 mg, 0.02 mmol, 5 mol %),
1.03 (d, J¼7.4 Hz, 18H); 13C NMR (75 MHz, CDCl3)
d 166.7, 160.1,
155.3, 151.2, 144.0, 134.8 (4C), 133.2 (2C), 131.5, 129.5 (2C), 127.9
(5C), 120.8, 117.7, 118.2, 112.3, 104.4, 101.6, 97.7, 93.2, 59.5, 55.5, 55.3,
39.7, 26.9 (3C), 18.2, 18.1 (6C), 14.9, 13.6 (3C). Compound 10k0: 1H
distilled Et3N (171 mL, 2.50 mmol, 6.25 equiv), and TIPSOTf (135 mL,
0.50 mmol, 1.25 equiv). Flash column chromatography on silica gel
NMR (300 MHz, CDCl3) d 7.66–7.65 (m, 4H), 7.37–7.32 (m, 2H), 7.29–
(heptane/EtOAc/Et3N, 6/3.8/0.2) afforded 10i (166 mg, 67%) as
7.24 (m, 4H), 7.01 (t, J¼7.8 Hz, 1H), 6.72 (d, J¼7.8 Hz, 1H), 6.62 (d,
J¼7.8 Hz, 1H), 6.46–6.41 (m, 2H), 6.38–6.32 (m, 1H), 4.90 (s, 2H),
4.30 (q, J¼7.0 Hz, 2H), 3.74 (s, 3H), 3.71 (s, 3H), 1.42 (hep, J¼7.1 Hz,
3H), 1.36 (t, J¼6.9 Hz, 3H), 1.03 (d, J¼7.1 Hz, 18H), 1.02 (br s, 9H); 13C
a white solid; mp 114–115 ꢀC. 1H NMR (300 MHz, CDCl3)
d 7.12 (d,
J¼8.5 Hz, 1H), 6.45 (d, J¼8.6 Hz, 1H), 6.43 (d, J¼1.9 Hz, 1H), 6.21–6.20
(m, 2H), 5.56 (br s, 2H), 4.31 (q, J¼7.2 Hz, 2H), 3.85 (s, 3H), 3.83 (s,

8552
D. Gauthier et al. / Tetrahedron 65 (2009) 8542–8555
NMR (75 MHz, CDCl3)
d
166.5, 161.9, 155.1, 143.9, 141.3 (2C), 135.4
116.8, 113.2, 104.2, 98.6, 91.3, 60.6, 55.5 (2C), 40.0, 18.1 (6C), 14.5
(4C), 132.8 (2C), 132.5, 130.3 (2C), 128.4, 127.8 (4C), 124.0, 120.6,
113.8, 104.9, 99.2, 98.1, 93.2, 59.5, 55.3, 55.1, 37.8, 26.9 (3C), 17.9, 17.7
(6C), 14.9, 13.6 (3C); HRMS (ESþ) m/z [MþNa]þ calcd for
C45H59NO6Si2Na: 788.3779; found: 788.3754.
(4C); 19F NMR (282 MHz, CDCl3)
d
ꢁ61.6; HRMS (ESþ) m/z
[MþNa]þ calcd for C30H40F3NO5SiNa: 580.2706; found: 580.2734.
4.7. N,N-Diethyl 3-oxobutanamide (11)
4.6.12. Ethyl 1-N-(2,4-dimethoxybenzyl)-6-fluoro-2-(triisopropylsi-
lyloxy)-1H-indole-3-carboxylate (10l) and ethyl 1-N-(2,4-dime-
thoxybenzyl)-4-fluoro-2-(triisopropylsilyloxy)-1H-indole-3-carb-
oxylate (10l0). Compounds 10l and 10l0 were prepared according
to the general procedure (C) reported for 10a starting from ethyl
2-diazo-3-(N-(2,4-dimethoxybenzyl)-N-(3-fluorophenyl)-amino)-
3-oxopropanoate 9l (161 mg, 0.40 mmol, 1 equiv), Rh2(NHCOCF3)4
To a solution of diketene (2.30 mL, 30 mmol, 2 equiv) in toluene
(16.50 mL) held at 0 ꢀC was added a solution of diethylamine
(1.60 mL, 15 mmol, 1 equiv) and distilled Et3N (2.50 mL, 18 mmol,
1.2 equiv) in MeOH (7.5 mL). After completion of the addition, the
mixture was stirred at 0 ꢀC for 2 h. The solution was then concen-
trated in vacuo to afford a crude oil, which was purified by flash
column chromatography on silica gel (heptane/EtOAc, 7/3) to give
(13 mg, 0.02 mmol, 5 mol %), distilled Et3N (171
m
L, 2.50 mmol,
11 (2.24 g, 95%) as a yellow oil. 1H NMR (300 MHz, CDCl3)
2H), 3.29 (q, J¼7.2 Hz, 2H), 3.10 (q, J¼7.2 Hz, 2H), 2.18 (s, 3H), 1.05
d 3.40 (s,
6.25 equiv), and TIPSOTf (135 L, 0.50 mmol, 1.25 equiv). Flash
m
column chromatography on silica gel (CH2Cl2/Et2O/heptane/Et3N,
4.9/3/2/0.1) afforded an inseparable mixture of regioisomers 10l/
10l0 (73:27, respectively, 197 mg, 93%) as a white solid. Compound
(m, 6H); 13C NMR (75 MHz, CDCl3)
d 202.9, 166.8, 50.0, 42.7, 40.2,
30.2, 14.2, 13.0; IR (neat, cmꢁ1) 2974, 2934, 1720, 1633, 1590, 1360,
1272, 1153, 1086, 1047, 773; HRMS (ESþ) m/z [MþNa]þ calcd for
C8H15NO2Na: 180.1000; found: 180.0998.
10l: 1H NMR (300 MHz, CDCl3)
d
7.91 (dd, J¼9.4, 2.3 Hz, 1H), 6.91–
6.84 (m, 1H), 6.75 (dd, J¼8.8, 5.6 Hz, 1H), 6.49 (d, J¼8.4 Hz, 1H),
6.46–6.44 (m, 1H), 6.26 (dd, J¼8.4, 2.4 Hz, 1H), 5.12 (s, 2H), 4.35 (q,
J¼7.1 Hz, 2H), 3.87 (s, 3H), 3.73 (s, 3H), 1.49–1.38 (m, 3H), 1.41 (t,
J¼7.1 Hz, 3H), 1.06–1.03 (m, 18H); 13C NMR (75 MHz, CDCl3)
4.8. N,N-Diethyl 2-diazo-3-oxobutanamide 12
To
a solution of N,N-diethyl-3-oxobutanamide 11 (2.03 g,
d
164.8, 160.5, 159.5 (d, J¼236.6 Hz), 157.6, 153.8, 131.5 (d,
12.91 mmol) in acetonitrile (17 mL) was added Et3N (5.43 mL,
14.20 mmol, 1.1 equiv) at 0 ꢀC. p-Acetamidobenzenesulfonyl azide
(3.41 g,14.20 mmol,1.1 equiv) was then introduced by portions. The
mixture was warmed to room temperature and stirred for 20 h. The
solution was concentrated in vacuo and the residue was triturated
with a mixture of Et2O/petroleum ether (1:1, 35 mL). After removal
of the sulfonamide by-product by filtration, the filtrate was con-
centrated in vacuo and the resulting residue was purified by flash
columnchromatographyon silica gel (Et2O/EP,1/1) togive 12 (2.21 g,
J¼12.1 Hz), 127.7, 121.8 (d, J¼8.8 Hz), 121.5 (d, J¼1.1 Hz), 116.7,
109.5 (d, J¼23.1 Hz), 104.3, 98.6, 96.7 (d, J¼26.9 Hz), 89.8, 59.4,
55.6 (2C), 39.9, 18.2 (6C), 15.0, 14.6 (3C); 19F NMR (282 MHz,
CDCl3)
d
ꢁ121.5. Compound 10l0: 1H NMR (300 MHz, CDCl3)
d 7.25
(m, 1H), 7.07 (d, J¼8.6 Hz, 1H), 6.52 (dd, J¼9.0, 6.9 Hz, 1H), 6.52 (d,
J¼8.2 Hz, 1H), 6.46–6.44 (m, 1H), 6.30 (dd, J¼8.2, 2.1 Hz, 1H), 5.10
(s, 2H), 4.31 (q, J¼7.0 Hz, 2H), 3.76 (s, 3H), 3.72 (s, 3H), 1.70–1.33
(m, 3H), 1.37 (t, J¼7.0 Hz, 3H), 1.04–0.86 (m, 18H); 13C NMR
(75 MHz, CDCl3)
d
164.1, 161.7, 158.3, 152.7 (d, J¼220.1 Hz), 148.5,
94%) as a yellow oil. 1H NMR (300 MHz, CDCl3)
d
3.28 (q, J¼7.1 Hz,
135.5, 128.5, 124.6 (2C, J¼18.7 Hz), 117.1, 107.6 (d, J¼21.1 Hz), 104.1,
4H), 2.22 (s, 3H), 1.09 (t, J¼7.1 Hz, 6H). 13C NMR (75 MHz, CDCl3)
102.1, 98.2, 87.8, 61.4, 55.3 (2C), 39.2, 18.2 (6C), 14.8, 14.4 (3C); 19F
d
190.1, 160.4, 41.9 (2C), 27.3, 13.2 (2C); IR (neat, cmꢁ1) 2974, 2872,
NMR (282 MHz, CDCl3)
for C29H40FNO5SiNa: 552.2558; found: 552.2563.
d
ꢁ119.0; HRMS (ESþ) m/z [MþNa]þ calcd
2095, 1621, 1421, 1285, 1257, 1057, 633; MS (ESþ) m/z 206 [MþNa]þ.
4.9. N,N-Diethyl 2-diazoacetamide 13
4.6.13. Ethyl
1-N-(2,4-dimethoxybenzyl)-6-(trifluoromethyl)-2-
(triisopropylsilyloxy)-1H-indole-3-carboxylate (10m) and ethyl
1-N-(2,4-dimethoxybenzyl)-4-(trifluoromethyl)-2-(triisopropylsi-
lyloxy)-1H-indole-3-carboxylate (10m0). Compounds 10m and
10m0 were prepared according to the general procedure (C)
reported for 10a starting from ethyl 2-diazo-3-(N-(2,4-dime-
thoxybenzyl)-N-(3-trifluoromethyl-phenyl)amino)-3-oxopropa-
noate 9m (181 mg, 0.40 mmol, 1 equiv), Rh2(NHCOCF3)4 (13 mg,
To
a
solution of N,N-diethyl-2-diazo-3-oxobutanamide 12
L) held at 0 ꢀC was added
(200 mg, 1.10 mmol) in MeOH (350
m
MeONa (0.060 g, 1.11 mmol, 1.01 equiv) by portions. After comple-
tion of the addition, the mixture was stirred at 0 ꢀC for an additional
hour. The reaction solution was then poured into ice water
(2.50 mL), and the resulting mixture was extracted with Et2O. The
aqueous phase was saturated with NaCl and extracted with Et2O.
The combined Et2O extracts were washed with H2O, dried over
Na2SO4, and filtered. The solution was then concentrated in vacuo
0.02 mmol, 5 mol %), distilled Et3N (171
mL, 2.50 mmol, 6.25
equiv), and TIPSOTf (135 L, 0.50 mmol, 1.25 equiv). Flash column
m
chromatography on silica gel (CH2Cl2/Et2O/heptane/Et3N, 4.9/3/
2/0.1) afforded an inseparable mixture of regioisomers 10m/10m0
(64:36, respectively, 160 mg, 69%) as a yellow solid. Compound
to afford a
crude oil, which was distilled (bp 120–125 ꢀC;
2ꢂ10ꢁ1 mbar) to yield 13 (0.152 mg, 98%) as a yellow oil. 1H NMR
(300 MHz, CDCl3)
d
4.91 (s, 1H), 3.19 (br s, 4H), 1.06 (t, J¼7.2 Hz, 6H);
10m: 1H NMR (300 MHz, CDCl3)
d
8.06 (d, J¼8.7 Hz, 1H), 7.39–
13C NMR (75 MHz, CDCl3)
d 165.8, 46.4, 41.4(2C), 13.9 (2C); IR (neat,
7.36 (m, 1H), 7.36 (br s, 1H), 6.53 (d, J¼8.5 Hz, 1H), 6.46 (br s, 1H),
6.27 (dd, J¼8.5, 2.4 Hz, 1H), 5.20 (s, 2H), 4.37 (q, J¼7.2 Hz, 2H),
3.89 (s, 3H), 3.73 (s, 3H), 1.47 (hep, J¼7.7 Hz, 3H), 1.42 (t, J¼7.2 Hz,
cmꢁ1) 3065, 2974, 2933, 2095, 1599, 1429, 1354, 1257, 1134, 724;
HRMS (ESþ) m/z [MþNa]þ calcd for C6H11N3ONa: 164.0800; found:
164.0804.
3H), 1.07–1.02 (m, 18H); 13C NMR (75 MHz, CDCl3)
d 164.7, 160.6,
157.5, 154.9, 130.5, 128.5, 127.9, 123.2 (q, J¼31.8 Hz), 118.6 (q,
J¼3.2 Hz), 118.4 (q, J¼256.2 Hz), 113.1 (2C), 106.8 (q, J¼3.2 Hz),
104.4, 98.6, 90.0, 59.5, 55.6 (2C), 39.7, 18.1 (6C), 14.9, 14.2 (3C); 19F
4.10. 2-Diazo-3-(diethylamino)-3-oxopropanoyl chloride 14
To a solution of triphosgene (0.850 g, 2.86 mmol, 0.40 equiv) in
toluene (3.80 mL) held at 0 ꢀC was added pyridine (180
mL,
NMR (282 MHz, CDCl3)
(300 MHz, CDCl3)
d
ꢁ60.5. Compound 10m0: 1H NMR
d
7.44 (d, J¼7.9 Hz, 1H), 7.20 (d, J¼7.9 Hz, 1H),
2.2 mmol, 0.30 equiv). A white precipitate was formed and to the
mixture was then slowly added 2-diazo-N,N-diethylacetamide 13
(1 g, 7.08 mmol). The reaction mixture was warmed to room tem-
perature and stirred for 6 h. After filtration through a pad of Celite,
the filtrate was concentrated in vacuo and purified by flash column
chromatography on silica gel (Et2O/petroleum ether, 6/4) to give 14
7.07 (t, J¼7.9 Hz, 1H), 6.46–6.43 (m, 2H), 6.27–6.24 (m, 1H), 5.19
(br s, 2H), 4.30 (q, J¼7.2 Hz, 2H), 3.88 (br s, 3H), 3.73 (br s, 3H),
1.46–1.37 (m, 3H), 1.34 (t, J¼7.2 Hz, 3H), 1.07–1.02 (m, 18H); 13C
NMR (75 MHz, CDCl3) d 165.8, 160.5, 157.4, 151.9, 132.5, 131.5 (m),
127.6 (2C), 123.5 (q, J¼261.3 Hz), 123.3 (q, J¼33.2 Hz), 120.3 (m),

D. Gauthier et al. / Tetrahedron 65 (2009) 8542–8555
8553
(0.674 g, 46%) as a yellow oil. 1H NMR (300 MHz, CDCl3)
d
3.35 (q,
(2C), 26.6 (3C), 19.6, 12.7 (2C); IR (neat, cmꢁ1) 2931, 2091, 1614,
1587, 1484, 1427, 1377, 1277, 1207, 1106, 1036, 700; HRMS (ESþ) m/z
[MþNa]þ calcd for C38H44N4O5SiNa: 687.2979; found: 687.2991.
J¼7.1 Hz, 4H), 1.20 (t, J¼7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d
157.6, 154.9, 42.1 (2C), 13.1 (2C); IR (neat, cmꢁ1) 2974, 2937, 2136,
1731, 1632, 1425, 1274, 1247, 1212, 727; HRMS (MALDIþ) m/z
[MþH]þ calcd for C7H1135ClN3O2: 204.0534; found: 204.0527.
4.11.4. N3,N3-Diethyl-N1-(2,4-dimethoxybenzyl)-N1-(3-fluorophenyl)-
2-diazomalonamide (15l). Compound 15l was prepared according to
the general procedure (D) reported for 15a starting from N-(2,4-
dimethoxybenzyl)-3-fluoroaniline 7l (123 mg, 0.47 mmol, 1 equiv),
distilled Et3N (0.31 mL, 2.20 mmol, 4.7 equiv), and 2-diazo-3-(dieth-
ylamino)-3-oxopropanoyl chloride 14 (96 mg, 0.47 mmol, 1 equiv).
Flash column chromatography on silica gel (heptane/AcOEt, 7/3)
afforded 15l (199 mg, 99%) as a yellow solid; mp 108–109 ꢀC. 1H NMR
4.11. General procedure (D) for the synthesis of the diazo
malonamides 15
4.11.1. N3,N3-Diethyl-N1-(2,4-dimethoxybenzyl)-N1-phenyl-2-diazo-
malonamide (15a). To a solution of N-(2,4-dimethoxybenzyl)ani-
line 7a (114 mg, 0.47 mmol, 1 equiv) in CH2Cl2 (1.40 mL) held at
0 ꢀC under argon were successively added dropwise distilled Et3N
(0.31 mL, 2.20 mmol, 4.7 equiv) and 2-diazo-3-(diethylamino)-3-
oxopropanoyl chloride 14 (96 mg, 0.47 mmol, 1 equiv). After
warming to room temperature and stirring for 6 h, a solution of
1 M HCl (0.60 mL) was added and the mixture was extracted with
CH2Cl2. The combined CH2Cl2 extracts were then dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was pu-
rified by flash column chromatography on silica gel (Et2O/petro-
leum ether, 6/4) to give 15a (176 mg, 91%) as a yellow solid; mp
(300 MHz, CDCl3)
d
7.39 (d, J¼8.4 Hz, 1H), 7.18 (br q, J¼8.0 Hz, 1H),
6.88–6.79 (m, 3H), 6.43 (dd, J¼8.4, 2.3 Hz, 1H), 6.32 (d, J¼2.3 Hz, 1H),
4.90 (s, 2H), 3.74 (s, 3H), 3.56 (s, 3H), 3.10 (q, J¼7.1 Hz, 4H), 0.93 (t,
J¼7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3)
163.5,162.7 (d, J¼247.6 Hz),
d
160.7, 160.5, 158.3, 144.4 (d, J¼9.9 Hz), 130.7, 129.8 (d, J¼9.3 Hz), 122.8
(d, J¼2.7 Hz), 117.6, 114.3 (d, J¼23.0 Hz), 113.7 (d, J¼20.9 Hz), 104.4,
98.4, 55.5, 55.2, 48.8, 41.4 (2C), 12.7 (2C); 19F NMR (282 MHz, CDCl3)
d
ꢁ111.9; IR (neat, cmꢁ1) 2935, 2091, 1720, 1604, 1587, 1505, 1421,
1376, 1262, 1207, 1155, 1034; HRMS (ESþ) m/z [MþNa]þ calcd for
122–123 ꢀC. 1H NMR (300 MHz, CDCl3)
d
7.43 (d, J¼8.5 Hz, 1H),
C22H25FN4O4Na: 451.1758; found: 451.1740.
7.29–7.15 (m, 3H), 7.11–7.08 (m, 2H), 6.47 (dd, J¼8.5, 2.3 Hz, 1H),
6.34 (d, J¼2.3 Hz, 1H), 4.95 (s, 2H), 3.78 (s, 3H), 3.57 (s, 3H), 3.13 (q,
J¼7.2 Hz, 4H), 0.97 (t, J¼7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3)
4.11.5. N3,N3-Diethyl-N1-(2,4-dimethoxybenzyl)-N1-(3-tri-
fluoromethylphenyl)-2-diazomalonamide (15m). Compound 15m
was prepared according to the general procedure (D) reported for
15a starting from N-(2,4-dimethoxybenzyl)-3-(trifluoromethyl)-
aniline 7m (146 mg, 0.47 mmol, 1 equiv), distilled Et3N (0.31 mL,
2.20 mmol, 4.7 equiv), and 2-diazo-3-(diethylamino)-3-oxopropa-
noyl chloride 14 (96 mg, 0.47 mmol, 1 equiv). Flash column chro-
matography on silica gel (Et2O) afforded 15m (218 mg, 97%) as
d
163.5, 161.2, 160.4, 158.4, 142.7, 130.7, 128.9 (2C), 127.3 (2C), 127.1,
118.0, 104.3, 98.3, 55.5, 55.2, 48.7, 41.5 (2C), 12.9 (2C); IR (neat,
cmꢁ1) 2934, 2087, 1619, 1591, 1421, 1377, 1276, 1207, 1155, 1034,
697; HRMS (ESþ) m/z [MþNa]þ calcd for C22H26N4O4Na: 433.1852;
found: 433.1812.
4.11.2. N3,N3-Diethyl-N1-(2,4-dimethoxybenzyl)-N1-(3-methoxy-
phenyl)-2-diazomalonamide (15j). Compound 15j was prepared
according to the general procedure (D) reported for 15a starting
from N-(2,4-dimethoxybenzyl)-3-methoxyaniline 7j (128 mg,
0.47 mmol, 1 equiv), distilled Et3N (0.31 mL, 2.20 mmol, 4.7 equiv),
and 2-diazo-3-(diethylamino)-3-oxopropanoyl chloride 14
(96 mg, 0.47 mmol, 1 equiv). Flash column chromatography on
silica gel (Et2O) afforded 15j (197 mg, 95%) as a yellow solid; mp
a yellow solid; mp 63–64 ꢀC. 1H NMR (500 MHz, CDCl3)
d 7.42 (d,
J¼8.2 Hz,1H), 7.38–7.24 (m, 4H), 6.42 (dd, J¼8.2, 2.1 Hz,1H), 6.27 (d,
J¼2.1 Hz,1H), 4.91 (s, 2H), 3.72 (s, 3H), 3.48 (s, 3H), 3.01 (q, J¼7.0 Hz,
4H), 0.84 (m, 6H); 13C NMR (75 MHz, CDCl3)
d 163.9, 160.6, 160.4,
158.3, 143.5, 131.3, 131.0, 130.6 (d, J¼32.9 Hz), 129.5, 124.0 (d,
J¼3.8 Hz), 123.8 (d, J¼272.8 Hz), 123.4 (d, J¼3.3 Hz), 117.4, 104.4,
98.2, 55.5, 55.0, 48.9, 41.3 (2C),12.6 (2C); 19F NMR (282 MHz, CDCl3)
d
ꢁ62.4; IR (neat, cmꢁ1) 2931, 2091, 1614, 1587, 1484, 1427, 1377,
97–98 ꢀC. 1H NMR (500 MHz, CDCl3)
d
7.35 (d, J¼8.2 Hz, 1H), 7.12 (t,
1277, 1207, 1106, 1036, 700; HRMS (ESþ) m/z [MþNa]þ calcd for
J¼8.1 Hz, 1H), 6.68 (dd, J¼8.1, 2.1 Hz, 1H), 6.66 (dd, J¼8.1, 2.1 Hz,
1H), 6.60 (t, J¼2.1 Hz, 1H), 6.42 (dd, J¼8.1, 2.1 Hz, 1H), 6.32 (d,
J¼2.1 Hz,1H), 4.90 (s, 2H), 3.74 (s, 3H), 3.68 (s, 3H), 3.57 (s, 3H), 3.13
C23H25F3N4O4Na: 501.1726; found: 501.1711.
(q, J¼7.1 Hz, 4H), 0.96 (m, 6H); 13C NMR (75 MHz, CDCl3)
d
163.6,
4.12. General procedure (E) for the synthesis of the 2-
silyloxyindole-3-carboxamides 16
161.2, 160.4, 160.1, 158.4, 143.8, 130.6, 129.6, 119.5, 118.1,113.1, 112.4,
104.3, 98.4, 55.5 (2C), 55.3, 48.7, 41.5 (2C), 12.9 (2C); IR (neat, cmꢁ1
)
3054, 2933, 2098, 1618, 1587, 1422, 1375, 1282, 1206, 1032, 732;
HRMS (ESþ) m/z [MþNa]þ calcd for C23H28N4O5Na: 463.1957;
found: 463.1969.
4.12.1. N,N-Diethyl-1-N-(2,4-dimethoxybenzyl)-2-(triisopropylsilyl-
oxy)-1H-indole-3-carboxamide (16a). To a solution of compound
15a (164 mg, 0.40 mmol, 1 equiv) in CH2Cl2 (2 mL) held at room
temperature under argon was added Rh2(NHCOCF3)4 (13 mg,
0.02 mmol, 5 mol %). After 5 h of stirring under argon, the solution
4.11.3. N1-(3-(tert-Butyldiphenylsilyloxy)phenyl)-N3,N3-diethyl-N1-
(2,4-dimethoxybenzyl)-2-diazomalonamide (15k). Compound 15k
was prepared according to the general procedure (D) reported for
15a starting from 3-(tert-butyldiphenylsilyloxy)-N-(2,4-dimethoxy-
benzyl)aniline 7k (234 mg, 0.47 mmol, 1 equiv), distilled Et3N
(0.31 mL, 2.20 mmol, 4.7 equiv), and 2-diazo-3-(diethylamino)-3-
oxopropanoyl chloride 14 (96 mg, 0.47 mmol, 1 equiv). Flash column
chromatography on silica gel (heptane/AcOEt, 7/3) afforded 15k
was cooled to 0 ꢀC. Distilled Et3N (171
and TIPSOTf (135 L, 0.50 mmol, 1.25 equiv) were then successively
mL, 2.50 mmol, 6.25 equiv)
m
added. The solution was allowed to stir at 0 ꢀC for 15 min before
quenching with H2O (2 mL) and extracted with CH2Cl2. The com-
bined CH2Cl2 extracts were then dried over Na2SO4, filtered, and
concentrated in vacuo. The residue was purified by flash column
chromatography on silica gel (CH2Cl2/Et2O/Et3N, 9/7/0.1) to give
16a (181 mg, 84%) as a light yellow oil. 1H NMR (300 MHz, CDCl3)
(303 mg, 97%) as a yellow oil. 1H NMR (500 MHz, CDCl3)
d 7.62 (d,
J¼7.3 Hz, 4H), 7.40 (t, J¼7.3 Hz, 2H), 7.32 (t, J¼7.3 Hz, 4H), 7.13 (d,
J¼8.3 Hz, 1H), 6.94 (t, J¼8.0 Hz, 1H), 6.59–6.55 (m, 2H), 6.54–6.53
(m, 1H), 6.33 (dd, J¼8.3, 2.3 Hz, 1H), 6.30 (d, J¼2.3 Hz, 1H), 4.75 (s,
2H), 3.75 (s, 3H), 3.53 (s, 3H), 3.08 (q, J¼7.1 Hz, 4H),1.05 (s, 9H), 0.98
d
7.36–7.33 (m, 1H), 7.08–7.00 (m, 3H), 6.45 (d, J¼2.4 Hz, 1H), 6.44
(d, J¼8.3 Hz, 1H), 6.23 (dd, J¼8.3, 2.4 Hz, 1H), 5.16 (s, 2H), 3.86 (s,
3H), 3.72 (s, 3H), 3.51 (q, J¼6.7 Hz, 4H), 1.36 (hep, J¼7.7 Hz, 3H), 1.16
(t, J¼6.7 Hz, 6H), 1.03 (d, J¼7.7 Hz, 18H); 13C NMR (75 MHz, CDCl3)
(t, J¼7.1 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d
162.8, 161.7, 160.3,
d 166.7, 160.2, 157.5, 146.8, 131.0, 127.6, 125.6, 120.5, 120.4, 118.5,
158.4, 156.3, 143.5, 135.6 (4C), 132.6 (2C), 130.5, 130.3 (2C), 129.6,
128.0 (4C), 119.8, 118.6, 118.4, 118.0, 104.2, 98.4, 55.5, 55.3, 48.7, 41.7
118.0, 109.4, 104.1, 98.4, 93.3, 55.5 (2C), 41.0 (2C), 39.8, 18.1 (6C),14.1
(2C), 13.6 (3C); IR (neat, cmꢁ1) 3420, 2937, 2862, 1712, 1613, 1463,

8554
D. Gauthier et al. / Tetrahedron 65 (2009) 8542–8555
1361, 1207, 1126, 1035, 881, 674; HRMS (ESþ) m/z [MþH]þ calcd for
Rh2(NHCOCF3)4 (13 mg, 0.02 mmol, 5 mol %), distilled Et3N (171
mL,
C31H47N2O4Si: 539.3305; found: 539.3298.
2.50 mmol, 6.25 equiv), and TIPSOTf (135 L, 0.50 mmol,1.25 equiv).
m
Flash column chromatography on silica gel (CH2Cl2/Et2O/Et3N, 5.9/
4.12.2. N,N-Diethyl-1-N-(2,4-dimethoxybenzyl)-6-methoxy-2-(triiso-
propylsilyloxy)-1H-indole-3-carboxamide (16j). Compound 16j was
prepared according to the general procedure (E) reported for 16a
starting from diazo 15j (176 mg, 0.40 mmol, 1 equiv),
4/0.1) afforded 16m (102 mg, 42%) as a light yellow oil. 1H NMR
(300 MHz, CDCl3)
d
7.40–7.37 (m, 2H), 7.27 (dd, J¼7.8, 1.4 Hz, 1H),
6.50 (d, J¼8.5 Hz, 1H), 6.46 (d, J¼2.3 Hz, 1H), 6.26 (dd, J¼8.5, 2.3 Hz,
1H), 5.19 (s, 2H), 3.88 (s, 3H), 3.73 (s, 3H), 3.48 (q, J¼7.1 Hz, 4H), 1.37
(hep, J¼7.5 Hz, 3H), 1.15 (t, J¼7.1 Hz, 6H), 1.04 (d, J¼7.5 Hz, 18H); 13C
Rh2(NHCOCF3)4 (13 mg, 0.02 mmol, 5 mol %), distilled Et3N (171
mL,
2.50 mmol, 6.25 equiv), and TIPSOTf (135 L, 0.50 mmol,
m
NMR (75 MHz, CDCl3) d 166.0, 160.6, 157.6, 148.5, 130.0, 128.1, 127.9,
1.25 equiv). Flash column chromatography on silica gel (CH2Cl2/
Et2O/Et3N, 5.9/4/0.1) afforded 16j (200 mg, 88%) as a light yellow oil.
124.1 (q, J¼251.3 Hz), 122.4 (q, J¼31.8 Hz), 118.4, 117.35, 117.33 (q,
J¼3.0 Hz), 106.9 (d, J¼4.4 Hz), 104.4, 98.5, 94.0, 55.6, 55.5, 48.9, 41.3
(2C), 18.1 (6C), 14.1 (2C), 13.7 (2C), 12.5 (3C); 19F NMR (282 MHz,
1H NMR (300 MHz, CDCl3)
d
7.27 (d, J¼8.5 Hz, 1H), 6.75 (dd, J¼8.5,
2.3 Hz, 1H), 6.64 (d, J¼2.3 Hz, 1H), 6.53 (d, J¼8.5 Hz, 1H), 6.49 (d,
J¼2.4 Hz, 1H), 6.29 (dd, J¼8.5, 2.4 Hz, 1H), 5.15 (s, 2H), 3.90 (s, 3H),
3.76 (s, 6H), 3.53 (q, J¼7.0 Hz, 4H), 1.38 (hep, J¼7.5 Hz, 3H), 1.19 (t,
J¼7.0 Hz, 6H), 1.07 (d, J¼7.5 Hz, 18H); 13C NMR (75 MHz, CDCl3)
CDCl3)
d
ꢁ60.3; IR (neat, cmꢁ1) 3424, 2940, 2864, 1614, 1557, 1462,
1301, 1208, 1158, 1112, 881; HRMS (ESþ) m/z [MþNa]þ calcd for
C32H45F3N2O4Si Na: 629.2998; found: 629.3019.
d
166.8, 160.2, 157.5, 155.4, 145.8, 131.7, 127.8, 119.6, 119.1, 117.9,
Acknowledgements
109.0, 104.2, 98.3, 94.4, 92.8, 55.8, 55.5, 55.4, 41.5(2C), 39.7, 18.2
(6C), 14.1 (2C), 13.6 (3C); IR (neat, cmꢁ1) 3424, 2938, 2863, 1713,
1614, 1455, 1377, 1260, 1207, 1035, 809; HRMS (ESþ) m/z [MþNa]þ
calcd for C32H48N2O5SiNa: 591.3230; found: 591.3249.
We thank the Institut de Chimie des Substances Naturelles for
a fellowship (D.G.).
References and notes
4.12.3. N,N-Diethyl-6-(tert-butyldiphenylsilyloxy)-1-N-(2,4-dime-
thoxybenzyl)-2-(triisopropylsilyloxy)-1H-indole-3-carboxamide
(16k). Compound 16k was prepared according to the general
procedure (E) reported for 16a starting from diazo 15k (266 mg,
0.40 mmol, 1 equiv), Rh2(NHCOCF3)4 (13 mg, 0.02 mmol, 5 mol %),
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´
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91%) as a light yellow oil. 1H NMR (300 MHz, CDCl3)
d 7.62 (dd,
J¼7.9, 1.1 Hz, 4H), 7.35–7.22 (m, 6H), 7.01 (d, J¼8.5 Hz, 1H), 6.54 (dd,
J¼8.5, 2.1 Hz, 1H), 6.42 (d, J¼2.1 Hz, 1H), 6.37 (d, J¼2.3 Hz, 1H), 6.32
(d, J¼8.5 Hz, 1H), 6.15 (dd, J¼8.5, 2.3 Hz, 1H), 4.88 (s, 2H), 3.74 (s,
3H), 3.73 (s, 3H), 3.45 (q, J¼7.0 Hz, 4H), 1.32–1.22 (m, 3H), 1.13–1.07
(m, 6H), 1.03 (br s, 9H), 0.99 (d, J¼7.5 Hz, 18H); 13C NMR (75 MHz,
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129.8 (2C), 127.7 (5C), 119.8, 118.7, 117.9, 113.7, 104.0, 100.6, 98.3,
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14.0 (2C), 13.6 (3C), 12.5; IR (neat, cmꢁ1) 3379, 2932, 2863, 1619,
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[MþNa]þ calcd for C47H64N2O5Si2Na: 815.4252; found: 815.4264.
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`
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mL,
2.50 mmol, 6.25 equiv), and TIPSOTf (135 L, 0.50 mmol,1.25 equiv).
m
Flash column chromatography on silica gel (CH2Cl2/Et2O/heptane/
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Et3N, 4.9/3/2/0.1) afforded 16l (160 mg, 72%) as a light yellow oil. 1H
NMR (300 MHz, CDCl3)
d 7.35–7.24 (m, 1H), 6.82–6.76 (m, 1H), 6.74
(dd, J¼9.4, 2.4 Hz, 1H), 6.47 (d, J¼8.4 Hz, 1H), 6.45 (d, J¼2.4 Hz, 1H),
6.25 (dd, J¼8.4, 2.4 Hz,1H), 5.10 (s, 2H), 3.86 (s, 3H), 3.73 (s, 3H), 3.45
(q, J¼7.3 Hz, 4H), 1.32 (hep, J¼7.7 Hz, 3H), 1.15 (m, 6H), 1.03 (d,
J¼7.7 Hz, 18H); 13C NMR (75 MHz, CDCl3)
d 166.5, 160.4, 159.3 (d,
J¼250.1 Hz), 155.6 (2C), 135.5 (d, J¼9.7 Hz), 127.2, 121.7, 119.1 (d,
J¼9.3 Hz), 117.3, 108.4 (d, J¼24.2 Hz), 104.2, 98.5 (2C), 96.5 (d,
J¼26.3 Hz), 55.6 (2C), 41.1 (2C), 40.0, 18.1 (6C), 15.0 (2C), 14.6 (3C);
19F NMR (282 MHz, CDCl3)
d
ꢁ122.4; HRMS (ESþ) m/z [MþNa]þ
calcd for C31H45FN2O4SiNa: 556.3133; found: 556.3139.
4.12.5. N,N-Diethyl-1-N-(2,4-dimethoxybenzyl)-6-(trifluoromethyl)-
2-(triisopropylsilyloxy)-1H-indole-3-carboxamide (16m). Compound
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