Versatile and convenient methods for the synthesis of C-2 and C-3 functionalised 5-azaindoles

Article abstract of DOI:10.1055/s-2005-916028

Functionalisation at C-2 and C-3 of N-protected-5-azaindole leads to a variety of very useful new substituted 5-azaindole derivatives in fair to good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-916028

PAPER
3581
Versatile and Convenient Methods for the Synthesis of C-2 and C-3
Functionalised 5-Azaindoles
S
ynthesis of C-
2
and
C
y
-3 Functiona
r
lise
d
5-A
i
zaind
a
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d’Orléans, Rue de Chartres, BP 6759, 45067 Orléans Cedex 2,
France
Fax +33(2)38417281; E-mail: jean-yves.merour@univ-orleans.fr; E-mail: gerard-coudert@univ-orleans.fr
Received 26 April 2005; revised 17 June 2005
Abstract: Functionalisation at C-2 and C-3 of N-protected-5-azain-
dole leads to a variety of very useful new substituted 5-azaindole
derivatives in fair to good yields.
Keywords: 5-azaindole, lithiation, stannylation, 2-substituted-5-
azaindole, 3-substituted-5-azaindole
A considerable number of plant alkaloids or marine or-
ganisms contain indole as the structural core.1 The obvi-
ous importance of bioactive indole derivatives in living
organisms has spurred chemists to design and synthesise
a myriad of indole-containing pharmaceutical agents. The
corresponding azaindolic (pyrrolopyridine) derivatives
are not so well represented, while the 7-azaindole2 frame-
work appears in the variolins family3 (e.g. I) and in tricy-
clic heterocycles isolated from an antartic sponge;3 to the
best of our knowledge, the 4, 5-, and 6-azaindole skele-
Figure 1
tons have not been found so far in nature. Nevertheless,
the evident biological interest, the bioisosteric replace-
tor Xa.11 As well, some patents12 have displayed the po-
tential of azaindoles in medicinal chemistry.
ment of the phenyl by a pyridine moiety, of such deriva-
tives has inspired chemists to synthesise azaindole-
containing compounds.
In the course of a program aimed at designing 5-azaindole
containing biologically active derivatives we were faced,
as others before us,13 with a lack of background informa-
tion concerning the reactivity of this heterocyclic system
and the difficulty to easily prepare such substituted deriv-
atives. Substituted 5-azaindoles were synthesised almost
exclusively from functionalised pyridine precursors. Con-
sequently herein, we wish to describe efficient procedures
for the regioselective functionalisation of C-2 and C-3 of
the 5-azaindole ring system with a view to preparing more
elaborate structures.
For instance fused or non-fused 7-azaindole containing
products are now in continuous development due to the
commercial availability of 7-azaindole. A ligand for
dopamine D4 receptors4 possessing a 7-azaindole frame-
work has been described. In the area of cancer chemother-
apeutics, a 7-aza analogue of the alkaloid olivacine was
prepared in our group.5 In addition, we reported the syn-
thesis of 7-azacarbazoles6 and more recently we described
an original way to synthesise symmetrical and unsymmet-
rical 7-azaindolocarbazoles II7 with potential anti-tumour
activity.
The 5-azaindole unit 1 was prepared from commercially
available 3-picoline N-oxide, according to Dormoy’s
method and was protected as the benzenesulfonyl deriva-
tive in 84% yield using a standard procedure (Scheme 1).
Surprisingly, in the 5-azaindole series, the pioneering
work of Bisagni,8 Dormoy and Heymes9 who reported the
synthesis of 11-aminoazaellipticine derivatives III and
the industrial preparation of pazaellipticine IV, respec-
tively, was not followed by other similar work. The 5-aza-
indole moiety is sometimes introduced as a substituent in
more elaborate structures10 as described for 2-substituted
5-azaindole derivative V, an inhibitor of coagulation fac-
Reactions at C-2 were previously investigated by Bisagni
and Dormoy who first described the formation of the 2-
SYNTHESIS 2005, No. 20, pp 3581–3588
x
x.
x
x
.
2
0
0
5
Advanced online publication: 16.09.2005
DOI: 10.1055/s-2005-916028; Art ID: Z08405SS
Scheme 1
© Georg Thieme Verlag Stuttgart · New York

3582
M. Lefoix et al.
PAPER
lithioderivative of 1-sulfonyl-5-azaindole 2 and its reac- derivative 10 in quantitative yield. 1-Benzenesulfonyl-5-
tion with some electrophiles.8,9 According to them, treat- azaindole 11 was also obtained in 78% yield by the reac-
ment of 2 with a slight excess of LDA (1.2 equiv) in THF tion of the sodium anion of 9 with benzenesulfonyl chlo-
at –20 °C in the presence of TMEDA (1.0 equiv) efficient- ride. Similarly the MOM protecting group was introduced
ly gave the 2-lithioderivative, which was further trapped on 9 using MOMCl and sodium hydride in THF, affording
with a range of electrophiles (2 equiv), leading to the re- 12 in 77% yield (Scheme 3). The use of a strong base
quired 2-substituted derivatives in fair to good yields. (NaH) for the introduction of the MOM and benzenesulfo-
(Scheme 2, Table 1). One clear advantage of using LDA nyl groups might possibly explain the lower yields ob-
instead of BuLi as a base to lithiate 1-sulfonyl-5-azaindole served for compounds 11 and 12.
is that the former is well-tolerated by various functional
groups.
Scheme 2
Table 1 C-2 Functionalisation of 5-Azaindole 2a
Compound Electrophile
E
Time
0.5 h
0.5 h
3 h
Yield (%)
3
4
5
6
7
ClSn(CH3)3
I2
Sn(CH3)3
I
95
62
84
86
79
Scheme 3
DMF
CHO
CH3
Then, we undertook the preparation of the 3-stannyl de-
rivative by reacting compounds 10–12 with hexameth-
ylditin in the presence of a catalytic amount of
dichlorobis(triphenylphosphine)palladium and anhydrous
lithium chloride. The required organostannanes 13–15
were obtained in 90%, 97% and 95% yields, respectively.
It should be mentioned that replacement of the hexameth-
ylditin reagent by the less toxic hexabutylditin was disap-
pointing; the corresponding N-Boc-3-tributylstannyl-5-
azaindole was obtained in only 24% yield (this compound
was previously reported in low yield by halogen–metal
exchange)15 together with the N-Boc-5-azaindole, after
loss of the iodine atom.
ICH3
2 h
Acetophenone
4 h
8
B(OMe)3
B(OH)2
5 h
71
a Reactions were performed using LDA (1.2 equiv) except for com-
pound 8 (1.4 equiv).
Compounds 5 and 7 were obtained previously by
Dormoy9 in 52% and 48% yields, respectively; these low-
er yields are probably a result of the use of an excess of
BuLi (1.8 equiv) by the authors. In fact, under such exper-
imental conditions, we observed the formation of 2,3-di-
substituted derivatives as a by-product. Compounds 3 and
8 obtained in satisfactory yield are very useful compounds
in palladium-catalysed cross-coupling reactions by Stille
or Suzuki methodologies; moreover, the 5-azaindole moi-
ety could be introduced by Heck or Sonogashira reactions
on appropriate substrates using the 2-iododerivative 4.
In order to assess the diversity of the reaction, we investi-
gated the halogen–lithium exchange of the 3-iododeriva-
tive 10 with a range of electrophiles, with a view to
obtaining the 3-lithio derivative regioselectively (Scheme
4). Compound 10 was treated with BuLi at –78 °C in THF
for 30 minutes and gave the corresponding 3-lithioderiva-
tive, which was then quenched with various electrophilic
species, affording after work-up the required 3-substituted
azaindoles 16–23 in good yields except for compound 20
(Table 2). Isomerisation of the lithio species to the 2-posi-
tion was never observed, contrary to the indole series.
Alternatively, functionalisation of the C-3 position of the
5-azaindole moiety was carried out. Only two examples,
concerning the preparation of the methyl glyoxal
azaindole14 and the synthesis in low yield of a 3-stannyl
derivative,15 were described. In order to develop a general
method, we first prepared the 3-iodo-N-protected azain-
doles 10–12. Treatment of 5-azaindole 1 with potassium
hydroxide in DMF, followed by addition of iodine, led to
the 3-iodo-5-azaindole 9 in 91% yield (previously report-
ed in 42% yield);15 the latter is more stable compared to
the 3-iodoindole. Protection of 9 with Boc2O, in THF, in
the presence of DMAP as base, gave the Boc-protected
Scheme 4
Synthesis 2005, No. 20, 3581–3588 © Thieme Stuttgart · New York

PAPER
Synthesis of C-2 and C-3 Functionalised 5-Azaindoles
3583
Table 2 C-3 Functionalisation of the 3-Iodo-5-azaindole 10
Compound
Electrophile (equiv)
ClSn(CH3)3 (1.5)
CO2 (excess)
BuLi (equiv)
Time (h)
E
Yield (%)
13
16
17
18
19
20
1.1
1.1
1.1
1.4
1.4
1.4
2
2
2
4
4
5
Sn(CH3)3
COOH
CHO
93
92
70
80
71
47
DMF (3.0)
ICH3 (1.5)
CH3
Allylbromide (1.1)
4-Methoxybenzaldehyde (2.0)
CH2CH=CH2
21
22
Acetophenone (1.3)
1.4
1.4
5
2
72
88
(2.0)
23
Acetone (2.0)
1.4
2
63
performed on a Micromass MS/MS ZAB Spec TOF with an EBE
TOF geometry. Petroleum ether (PE) had a boiling point range 40–
60 °C.
We have prepared, in excellent yield, the carboxylic acid
16 (92% yield) and the aldehyde 17 (70% yield); the stan-
nyl derivative 13 (93% yield) and the boronate ester 22
(88% yield) thus obtained represent attractive intermedi-
ates for the construction of more complex structures pos-
sessing a 5-azaindole subunit. Current work on the Stille
reaction with compound 13 is underway.
1-Benzenesulfonyl-1H-pyrrolo[3,2-c]pyridine (2)
To a suspension of NaH (0.76 g, 19.0 mmol, 60% dispersion in min-
eral oil) in THF (60 mL), under Ar at 0 °C, was added a soln of 5-
azaindole 19 (1.50 g, 12.7 mmol) in THF (15 mL). The reaction mix-
ture was stirred for 30 min at r.t., then cooled to 0 °C and
C6H5SO2Cl (1.78 mL, 14.0 mmol) was added slowly. The mixture
was stirred at r.t. until the starting material had been completely
consumed (TLC). The mixture was poured into H2O (50 mL) and
extracted with EtOAc (3 × 50 mL). The organic layers were washed
with brine (50 mL), dried over MgSO4 and filtered. The solvent was
evaporated in vacuo to give the crude product, which was purified
by flash chromatography (EtOAc) to furnish 2 as a white solid (2.7
g, 84%).
In conclusion we have developed two optimised protocols
allowing easy and efficient substitution of positions 2 or 3
of 5-azaindole. These procedures are quite general and the
observed yields are generally high, which will allow the
design and synthesis of complex 5-azaindole alkaloid an-
alogues. The synthesis of 2,3-disubstituted compounds
from the previously monosubstituted 5-azaindole is in
progress. Elaboration of biologically active products from
stannyl, boronic or iodo derivatives 3, 4, 8, 10, 13 and 22
using palladium-catalysed cross-coupling reactions is also
under investigation.
Mp 124–125 °C; Rf 0.3 (PE–EtOAc, 6:4).
IR (KBr): 1168, 3136 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.74 (d, 1 H, H-3, J3,2 = 3.7 Hz),
7.42–7.61 (m, 4 H, CH, H-2), 7.90–7.93 (m, 3 H, CH, H-6), 8.49 (d,
1 H, H-7, J7,6 = 5.9 Hz), 8.88 (s, 1 H, H-4).
Melting points were determined using a Büchi capillary instrument
and are uncorrected. The IR spectra were recorded on a Perkin-El-
mer FTIR paragon 1000 spectrometer. NMR spectra were recorded
in CDCl3 or DMSO-d6 (at 300 K if not specified) on a Bruker
Avance DPX 250. Chemical shifts are given in ppm relative to TMS
as internal standard. MS were recorded on Perkin-Elmer SCIEX
API 300 using ion spray methodology. TLC were run on pre-coated
silica gel plates (Merck 60F254) and the spots were visualised using
a UV lamp. Flash chromatography was carried out on a column us-
ing flash silica gel 60 Merck (40–63 mm) as the stationary phase. All
reactions requiring anhydrous conditions were conducted in flame-
dried apparatus. HRMS were performed by the Centre Régional de
Mesures Physiques de l’Ouest de Rennes. Electronic impact analy-
ses were performed on a Varian Mat 311 high resolution mass spec-
trometer with double focalisation. Electrospray ionisation were
13C NMR (62.5 MHz, CDCl3): d = 107.6 (CH-3), 108.4 (CH-6),
127.0 (2 × CH), 127.0 (CH-2), 127.1 (Cq), 129.7 (2 × CH), 134.5
(CH), 138.0 (Cq), 139.3 (Cq), 144.3 (CH-7), 144.4 (CH-4).
MS (IS): m/z (%) = 259 (100) [MH]+.
HRMS (EI): m/z [M]+· calcd for C13H10N2O2S: 258.04630; found:
258.0464.
Functionalisation of Position 2 of N-Benzenesulfonyl-5-azain-
dole 2; General Procedure A
To a soln of compound 2 (200 mg, 0.77 mmol) and N,N,N¢,N¢-tet-
ramethylethylenediamine (0.12 mL, 0.77 mmol) in THF (5 mL), un-
der Ar at –20 °C, LDA (0.480 mL, 1.54 mmol; 2 M soln, THF–
heptane–ethylbenzene) was added dropwise. The reaction mixture
was stirred for 30 min at –20 °C, followed by the slow addition of
Synthesis 2005, No. 20, 3581–3588 © Thieme Stuttgart · New York

3584
M. Lefoix et al.
PAPER
the electrophile (1.2–2 equiv). The mixture was stirred at –20 °C
until the starting material had been consumed (TLC). The mixture
was poured into H2O (20 mL) and extracted with EtOAc (20 mL).
The organic layers were washed with brine (20 mL), dried over
MgSO4 and filtered. The solvent was evaporated in vacuo to give
the crude product which was purified by flash chromatography.
HRMS (EI): m/z calcd for C14H10N2O3S [M]+·: 286.04121; found:
286.0430.
1-Benzenesulfonyl-2-methyl-1H-pyrrolo[3,2-c]pyridine (6)
The reaction was carried out as described in general procedure A us-
ing CH3I as the electrophile (0.10 mL, 1.5 mmol, 2 equiv). Purifi-
cation by flash chromatography (PE–EtOAc, 6:4) furnished 6 as a
yellow-brown solid (184 mg, 86%).
1-Benzenesulfonyl-2-trimethylstannyl-1H-pyrrolo[3,2-c]pyri-
dine (3)
The reaction was carried out as described in general procedure A us-
ing ClSn(CH3)3 as the electrophile (308 mg, 1.6 mmol, 2 equiv). Pu-
rification by flash chromatography (PE–EtOAc, 8:2) furnished 3 as
a white solid (309 mg, 95%).
Mp 105 °C; Rf 0.2 (PE–EtOAc, 2:8).
IR (KBr): 726, 817, 1093, 1172, 1370, 1449 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.56 (s, 3 H, CH3), 6.38 (s, 1 H,
H-3), 7.40–7.47 (m, 2 H, CH), 7.52–7.59 (m, 1 H, CH), 7.76–7.81
(m, 2 H, CH), 8.02 (d, 1 H, H-6, J6,7 = 5.8 Hz), 8.41 (d, 1 H, H-7,
J6,7 = 5.8 Hz), 8.72 (s, 1 H, H-4).
13C NMR (62.5 MHz, CDCl3): d = 15.4 (CH3), 107.3 (CH-3), 109.2
(CH-6), 125.8 (Cq), 126.4 (2 × CH), 129.5 (2 × CH), 134.3 (CH),
138.4 (Cq), 138.8 (Cq), 141.5 (Cq), 142.8 (CH-4), 143.7 (CH-7).
Mp 125–126 °C; Rf 0.4 (PE–EtOAc, 6:4).
IR (KBr): 1164, 1356 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.47 [s, 9 H, Sn(CH3)3,
JH,117Sn = 55.4, JH,119Sn = 58.0 Hz], 6.91 (s, 1 H, H-3, JH,Sn = 8.1 Hz),
7.41–7.47 (m, 2 H, ArH), 7.52–7.58 (m, 1 H, ArH), 7.68–7.69 (m,
2 H, ArH), 7.73 (d, 1 H, H-6, J6,7 = 6.0 Hz), 8.36 (d, 1 H, H-7,
J6,7 = 6.0 Hz), 8.84 (s, 1 H, H-4).
MS (IS): m/z (%) = 273 (100) [MH]+.
HRMS (EI): m/z calcd for C14H12N2O2S [M]+·: 272.06195; found:
13C NMR (62.5 MHz, CDCl3): d = –6.57 [Sn(CH3)3], 108.5 (CH-6),
118.2 (CH-3), 126.5 (2 × CH), 128.1 (Cq), 129.4 (2 × CH), 134.1
(CH), 138.6 (Cq), 142.6 (Cq), 143.4 (CH-4), 143.5 (CH-7), 145.2
(Cq).
272.0642.
1-Benzenesulfonyl-2-(1-hydroxy-1-phenylethyl)-1H-pyrro-
lo[3,2-c]pyridine (7)9
The reaction was carried out as described in general procedure A us-
ing acetophenone as the electrophile (0.09 mL, 1.5 mmol, 2 equiv).
Purification by flash chromatography (PE–EtOAc, 8:2) furnished 7
as a white solid (229 mg, 79%).
MS (IS): m/z (%) = 259 (100) [MH – Sn(CH3)3]+.
HRMS (EI): m/z calcd for C15H15N2O2S120Sn [M – CH3]+·:
406.98762; found: 406.9896.
Mp 142–143 °C; Rf 0.15 (PE–EtOAc, 3:7).
IR (KBr): 1448, 1597, 2980, 3060, 3518 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.96 (s, 3 H, CH3), 5.38 (br s, 1 H,
OH), 7.02 (s, 1 H, H-3), 7.21–7.28 (m, 9 H, CH), 7.42–7.45 (m, 1
H, CH), 7.94 (d, 1 H, H-6, J6,7 = 5.8 Hz), 8.47 (d, 1 H, H-7, J6,7 = 5.8
Hz), 8.89 (s, 1 H, H-4).
1-Benzenesulfonyl-2-iodo-1H-pyrrolo[3,2-c]pyridine (4)
The reaction was carried out as described in general procedure A us-
ing I2 as the electrophile (393 mg, 1.5 mmol, 2 equiv). Purification
by flash chromatography (EtOAc) furnished 4 as a white solid (184
mg, 62%).
Mp 160–161 °C; Rf 0.35 (PE–EtOAc, 6:4).
13C NMR (62.5 MHz, CDCl3): d = 33.9 (CH3), 73.9 (Cq), 109.5
(CH-3), 109.7 (CH-6), 126.5 (2 × CH), 126.9 (2 × CH), 127.2 (CH),
128.3 (2 × CH), 129.2 (2 × CH), 130.6 (Cq), 134.0 (CH), 137.9
(Cq), 142.4 (Cq), 144.1 (CH-4), 144.7 (CH-7), 146.3 (Cq), 147.6
(Cq).
MS (IS): m/z (%) = 379 (100) [MH]+.
HRMS (EI): m/z calcd for C21H18N2O3S [M]+: 378.10381; found:
IR (KBr): 1094, 1172, 1366 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.06 (s, 1 H, H-3), 7.49 (dd, 2 H,
ArH, 3J = 7.3, 8.0 Hz), 7.58–7.64 (m, 1 H, ArH), 7.93 (d, 2 H, ArH,
3J = 8.0 Hz), 8.16 (d, 1 H, H-6, J6,7 = 5.7 Hz), 8.45 (d, 1 H, H-7,
J6,7 = 5.7 Hz), 8.77 (s, 1 H, H-4).
13C NMR (62.5 MHz, CDCl3): d = 77.3 (CI), 109.9 (CH-6), 121.6
(CH-3), 127.4 (2 × CH), 128.0 (Cq), 129.5 (2 × CH), 134.7 (CH),
138.0 (Cq), 142.6 (CH-4), 142.7 (Cq), 144.6 (CH-7).
378.1024.
MS (IS): m/z (%) = 385 (100) [MH]+.
HRMS (EI): m/z calcd for C13H9IN2O2S [M]+·: 383.94295; found:
1-Benzenesulfonyl-1H-pyrrolo[3,2-c]pyridine-2-boronic Acid
(8)
383.9419.
The reaction was carried out as described in general procedure A us-
ing B(OMe)3 as the electrophile (0.180 mL, 1.55 mmol, 2 equiv).
The reaction was quenched with H2O (15 mL) and the aqueous layer
was washed with EtOAc (10 mL) to remove impurities. The aque-
ous layer was then acidified to pH 1 with HCl (3 N). After standing,
the product precipitated and was then filtered to afford 8 as an insta-
ble white solid (165 mg, 71%).
1-Benzenesulfonyl-2-formyl-1H-pyrrolo[3,2-c]pyridine (5)15
The reaction was carried out as described in general procedure A us-
ing DMF as the electrophile (0.12 mL, 1.5 mmol, 2 equiv). Purifi-
cation by flash chromatography (PE–EtOAc, 1:1) furnished 5 as a
white solid (185 mg, 84%).
Mp 165 °C; Rf 0.3 (PE–EtOAc, 6:4).
Rf 0.2 (CH2Cl2–MeOH, 9:1).
IR (KBr): 1089, 1175, 1683 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.29 (s, 1 H, H-3), 7.65 (m, 2 H,
CH), 7.75 (m, 1 H, CH), 8.22 (d, 2 H, CH, 3J = 7.8 Hz), 8.55 (d, 1
H, H-6, J6,7 = 6.7 Hz), 8.61 (d, 1 H, H-7, J6,7 = 6.7 Hz), 9.25 (s, 1 H,
H-4).
HRMS (TOF): m/z calcd for C13H12N2O411BS [M]+·: 303.06108;
found: 303.0591.
1H NMR (250 MHz, CDCl3): d = 7.49–7.59 (m, 4 H, CH, H-3), 7.86
(m, 2 H, CH, 3J = 7.3 Hz), 8.13 (d, 1 H, H-6, J6,7 = 5.4 Hz), 8.65 (d,
1 H, H-7, J6,7 = 5.4 Hz), 9.01 (s, 1 H, H-4), 10.49 (s, 1 H, CHO).
13C NMR (62.5 MHz, CDCl3): d = 109.9 (CH-6), 117.0 (CH-3),
123.4 (Cq), 127.0 (2 × CH), 129.9 (2 × CH), 135.1 (CH), 137.8
(Cq), 138.2 (Cq), 142.8 (Cq), 147.2 (CH-7), 147.5 (CH-4), 182.3
(C=O).
3-Iodo-1H-pyrrolo[3,2-c]pyridine (9)15
To a solution of the 5-azaindole 1 (1.50 g, 12.6 mmol) in DMF (6
mL) was added KOH (2.69 g, 48.0 mmol). The reaction mixture
Synthesis 2005, No. 20, 3581–3588 © Thieme Stuttgart · New York

PAPER
Synthesis of C-2 and C-3 Functionalised 5-Azaindoles
3585
was stirred for 10 min at r.t. and then a soln of I2 (3.19 g, 12.6 mmol)
in DMF (6 mL) was added. After 15 min at r.t., the mixture was
poured into a sat. soln of Na2S2O5 (1.29 g) and an aq soln of 28%
NH4OH (13 mL) in H2O (192 mL). The precipitate was filtered and
washed with H2O to afford 9 as a pale yellow solid which was dried
over P2O5 (2.8 g, 91%).
1-Methoxymethyl-3-iodo-1H-pyrrolo[3,2-c]pyridine (12)
To a suspension of NaH (51 mg, 1.28 mmol, 60% dispersion in min-
eral oil) in DMF (5 mL), under Ar at 0 °C, was added a soln of 9
(250 mg, 1.02 mmol) in DMF (15 mL). The reaction mixture was
stirred for 30 min at r.t., then cooled to 0 °C and MOMCl (0.064
mL, 0.85 mmol) was added slowly. The mixture was stirred for 15
min, then poured into H2O (10 mL) and extracted with EtOAc (20
mL). The organic layers were washed with brine (15 mL), dried
over MgSO4 and filtered. The solvent was evaporated in vacuo to
give the crude product, which was purified by flash chromatogra-
phy (EtOAc) to furnish 12 as a white-brown solid (226 mg, 77%).
Mp 178–179 °C (dec.); Rf 0.4 (PE–EtOAc, 6:4).
IR (KBr): 3082, 3421 cm–1.
1H NMR (250 MHz, MeOD): d = 7.43 (dd, 1 H, H-6, J7,6 = 5.8,
J6,4 = 0.9 Hz), 7.49 (s, 1 H, H-2), 8.20 (d, 1 H, H-7, J7,6 = 5.8 Hz),
8.53 (s, 1 H, H-4).
13C NMR (62.5 MHz, MeOD): d = 54.9 (CI), 107.6 (CH-6), 127.5
(Cq), 131.9 (CH-2), 141.1 (Cq), 142.3 (CH-7), 144.2 (CH-4).
MS (IS): m/z (%) = 245 (100) [MH]+.
Mp 78–79 °C; Rf 0.5 (CH2Cl2–MeOH, 9:1).
IR (KBr): 1083, 1119, 3022 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.26 (s, 3 H, OCH3), 5.43 (s, 2 H,
NCH2O), 7.30 (s, 1 H, H-2), 7.33 (d, 1 H, H-6, J6,7 = 6.0 Hz), 8.43
(d, 1 H, H-7, J6,7 = 6.0 Hz), 8.74 (s, 1 H, H-4).
13C NMR (62.5 MHz, CDCl3): d = 56.1 (CI), 56.4 (OCH3), 77.3
(NCH2O), 105.0 (CH-6), 127.4 (Cq), 132.9 (CH-2), 140.6 (Cq),
142.5 (CH-7), 144.7 (CH-4).
1-tert-Butyloxycarbonyl-3-iodo-1H-pyrrolo[3,2-c] pyridine
(10)15
To a soln of 9 (2.35 g, 9.6 mmol) in THF (30 mL) was added Boc2O
(2.52 g, 11.6 mmol) and DMAP (0.12 g, 1.0 mmol). The mixture
was stirred for 16 h at r.t. The solution was poured into H2O (30 mL)
and was extracted with EtOAc (50 mL). The organic layers were
washed with brine (30 mL), dried over MgSO4 and filtered. The sol-
vent was evaporated in vacuo to furnish 10 as a white solid (3.3 g,
100%).
MS (IS): m/z (%) = 289 (100) [MH]+.
Stannylation by a Palladium-Catalysed Reaction; General Pro-
cedure B
To a soln of the appropriate iodo compound (10–12) (1 mmol, 1
equiv) in THF (5 mL), under Ar, was added PdCl2(PPh3)2 (0.05
equiv), (CH3)6Sn2 (1.1 equiv) and anhyd LiCl (6 equiv). The reac-
tion mixture was refluxed for 2 h and then cooled to r.t. The catalyst
was removed by filtration through celite and washed with EtOAc.
The filtrate was washed with H2O (5 mL) and the aqueous layer was
extracted with EtOAc (3 × 10 mL). The organic layers were washed
with brine (10 mL), dried over MgSO4 and filtered. The solvent was
evaporated in vacuo to give the crude product which was purified
by flash chromatography to furnish compounds 13–15.
Mp 127–128 °C; Rf 0.3 (PE–EtOAc, 6:4).
IR (KBr): 1168, 1746, 2982 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.68 [s, 9 H, C(CH3)3], 7.73 (s, 1
H, H-2), 7.95 (dd, 1 H, H-6, J6,7 = 5.7, J6,4 = 0.9 Hz), 8.55 (d, 1 H,
H-7, J6,7 = 5.7 Hz), 8.71 (d, 1 H, H-4, J6,4 = 0.9 Hz).
13C NMR (62.5 MHz, CDCl3): d = 28.2 [C(CH3)3], 62.2 (C-I), 85.7
[C(CH3)3], 109.7 (CH-6), 128.3 (Cq), 131.0 (CH-2), 139.8 (Cq),
144.6 (CH-4), 145.1 (CH-7), 148.2 (t-BuOOC).
MS (IS): m/z (%) = 345 (92) [MH]+, 289 (100) [MH – t-Bu]+, 245
Halogen–Metal Exchange; General Procedure C
(29) [MH – Boc]+.
To a soln of 10 (200 mg, 0.6 mmol) in THF (5 mL), under Ar at
–78 °C, was added BuLi (0.46 mL, 0.64 mmol; 1.4 M, hexanes).
The reaction mixture was stirred for 30 min at –78 °C, followed by
the slow addition of the electrophile (1.1 equiv). The mixture was
stirred at –78 °C until the starting material had been completely
consumed (TLC). The mixture was poured into H2O (5 mL) and ex-
tracted with EtOAc (20 mL). The organic layers were washed with
brine (10 mL), dried over MgSO4 and filtered. The solvent was
evaporated in vacuo to give the crude product which was purified
by column chromatography.
HRMS (EI): m/z calcd for C12H13IN2O2 [M]+·: 344.00218; found:
344.0021.
1-Benzenesulfonyl-3-iodo-1H-pyrrolo[3,2-c]pyridine (11)
To a suspension of NaH (99 mg, 2.46 mmol; 60% dispersion in min-
eral oil) in THF (5 mL) under Ar at 0 °C, was added a soln of 9 (500
mg, 2.05 mmol) in THF (5 mL). The reaction mixture was stirred
for 30 min at r.t., then cooled to 0 °C and ClSn(CH3)3 (0.27 mL,
2.15 mmol) was added slowly. The mixture was stirred at r.t. for 2
h, then poured into H2O (10 mL) and extracted with EtOAc (50
mL). The organic layers were washed with brine (20 mL), dried
over MgSO4 and filtered. The solvent was evaporated in vacuo to
give the crude product. EtOAc (5 mL) was added to the crude prod-
uct, the precipitate formed was collected by filtration and washed
with EtOAc to furnish 11 as a yellow solid (614 mg, 78%).
1-tert-Butyloxycarbonyl-3-trimethylstannyl-1H-pyrrolo[3,2-
c]pyridine (13)
Stannylation was carried out as described in general procedure B.
Purification by flash chromatography (PE–EtOAc, 6:4) furnished
13 as a white solid (343 mg, 90%).
Halogen–metal exchange was carried out as described in general
procedure C using Bu3SnCl as an electrophile (127 mg, 0.6 mmol).
Purification by flash chromatography (PE–EtOAc, 6:4) furnished
13 as a white solid (205 mg, 93%).
Mp 170 °C (dec.); Rf 0.6 (EtOAc).
IR (KBr): 729, 1181, 1371, 1593, 3133 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.27–7.63 (m, 3 H, ArH), 7.70 (s,
1 H, H-2), 7.84 (dd, 1 H, H-6, J6,7 = 5.7, J6,4 = 0.9 Hz), 7.91–7.95
(m, 2 H, ArH), 8.56 (d, 1 H, H-7, J6,7 = 5.7 Hz), 8.70 (d, 1 H, H-4,
J6,4 = 0.9 Hz).
Mp 57–58 °C; Rf 0.3 (PE–EtOAc, 6:4).
IR (KBr): 1740, 2980 cm–1.
1H NMR (250 MHz, CDCl3): d = 0.42 [s, small amount of isotopes,
9 H, Sn(CH3)3, JH,117Sn = 55.0, JH,119Sn = 57.2 Hz], 1.69 [s, 9 H,
C(CH3)3), 7.50 (s, small amount of isotopes, 1 H, H-2, J2,Sn = 9.8
Hz], 7.97 (d, 1 H, H-6, J6,7 = 5.1 Hz), 8.46 (d, 1 H, H-7, J6,7 = 5.1
Hz), 8.83 (s, 1 H, H-4).
13C NMR (62.5 MHz, CDCl3): d = 63.7 (CI), 107.9 (CH-6), 127.1
(2 × CH), 128.4 (Cq), 129.8 (2 × CH), 130.3 (CH-2), 134.8 (CH),
137.5 (Cq), 139.3 (Cq), 145.2 (CH-4), 145.3 (CH-7).
MS (IS): m/z (%) = 385 (100) [MH]+, 244 (59) [MH – SO2Ph]+.
Synthesis 2005, No. 20, 3581–3588 © Thieme Stuttgart · New York

3586
M. Lefoix et al.
PAPER
13C NMR (62.5 MHz, CDCl3): d = –9.0 [Sn(CH3)3], 28.2 [C(CH3)3],
84.7 [C(CH3)3], 110.2 (CH-6), 114.3 (CSn), 132.3 (CH-2), 132.9
(Cq), 140.9 (Cq), 143.9 (CH-4), 144.8 (CH-7), 149.2 (t-BuOOC).
HRMS (EI): m/z calcd for C8H6N2O2 [M – Boc]+·: 162.04293;
found: 162.0421.
1-tert-Butyloxycarbonyl-3-formylpyrrolo[3,2-c]pyridine (17)
Halogen–metal exchange was carried out as described in general
procedure C with DMF as the electrophile (0.13 mL, 1.7 mmol, 2.9
equiv). Purification by flash chromatography (PE–EtOAc, 4:6) fur-
nished 17 as a white solid (100 mg, 70%).
MS (IS): m/z (%) = 382 (37) [MH]+, 322 (100) [MH – t-Bu]+, 282
(60) [MH – Boc]+.
HRMS (IS): m/z calcd for C15H22N2NaO2120Sn [M + Na]+:
405.0601; found: 405.0598.
Mp 152–153 °C; Rf 0.3 (PE–EtOAc, 6:4).
IR (KBr): 1673, 1743, 2837–2978 cm–1.
1-Benzenesulfonyl-3-trimethylstannyl-1H-pyrrolo [3,2-c]pyri-
dine (14)
Stannylation was carried out as described in general procedure B.
Purification by flash chromatography (PE–EtOAc, 6:4) furnished
14 as a white solid (410 mg, 97%).
1H NMR (250 MHz, CDCl3): d = 1.74 [s, 9 H, C(CH3)3], 7.99 (d, 1
H, H-6, J6,7 = 5.8 Hz), 8.26 (s, 1 H, H-2), 8.58 (d, 1 H, H-7, J6,7 = 5.8
Hz), 9.52 (s, 1 H, H-4), 10.10 (s, 1 H, CHO).
Mp 142–143 °C; Rf 0.3 (PE–EtOAc, 6:4).
IR (KBr): 1187, 1375 cm–1.
13C NMR (62.5 MHz, CDCl3): d = 28.0 [C(CH3)3], 86.9 [C(CH3)3],
110.0 (CH-6), 120.9 (Cq), 122.5 (Cq), 136.4 (CH-2), 140.3 (CH-3),
145.0 (CH-4), 145.8 (CH-7), 148.1 (t-BuOOC), 185.0 (CHO).
1H NMR (250 MHz, CDCl3): d = 0.41 [s, 9 H, Sn(CH3)3,
JH,117Sn = 55.2, JH,119Sn = 57.5 Hz], 7.43 (s, small amount of iso-
topes, 1 H, H-2), 7.46–7.63 (m, 3 H, ArH), 7.86 (dd, 1 H, H-6,
J6,7 = 5.6, J6,4 = 0.9 Hz), 7.91–7.94 (m, 2 H, ArH), 8.46 (d, 1 H, H-
7, J6,7 = 5.6 Hz), 8.80 (s, 1 H, H-4).
13C NMR (62.5 MHz, CDCl3): d = –8.8 [Sn(CH3)3], 108.4 (CH-6),
116.1 (CSn), 127.0 (2 × CH), 129.6 (2 × CH, Cq), 131.8 (CH-2),
134.4 (CH), 138.2 (Cq), 140.5 (Cq), 143.9 (CH-7), 145.2 (CH-4).
MS (HN): m/z (%) = 247 (71) [MH]+, 191 (100) [MH – t-Bu]+, 147
(91) [MH – Boc]+.
HRMS (EI): m/z calcd for C13H14N2O3 [M – Boc]+·: 246.10044;
found: 246.1014.
1-tert-Butyloxycarbonyl-3-methylpyrrolo[3,2-c]pyridine (18)
Halogen–metal exchange was carried out as described in general
procedure C using CH3I as the electrophile (0.07 mL, 1.2 mmol).
Purification by flash chromatography (PE–EtOAc, 4:6) furnished
18 as a white solid (108 mg, 80%).
MS (HN): m/z (%) = 423 (100) [MH]+.
HRMS (EI): m/z calcd for C15H15N2O2S120Sn [M – ·CH3]+:
406.98762; found: 406.9851.
Mp > 250 °C; Rf 0.2 (PE–EtOAc, 6:4).
1-Methoxymethyl-3-trimethylstannyl-1H-pyrrolo[3,2-c]pyri-
dine (15)
Stannylation was carried out as described in general procedure B;
after extraction 15 was obtained as an unstable crude product (310
mg, 95%).
IR (KBr): 1673, 1743, 2837–2978 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.67 [s, 9 H, C(CH3)3], 2.32 (s, 3
H, CH3), 7.34 (s, 1 H, H-2), 7.93 (d, 1 H, H-6, J6,7 = 5.5 Hz), 8.47
(d, 1 H, H-7, J6,7 = 5.5 Hz), 8.82 (s, 1 H, H-4).
13C NMR (62.5 MHz, CDCl3): d = 9.5 (CH3), 28.2 [C(CH3)3], 84.4
[C(CH3)3], 109.9 (CH-6), 115.5 (Cq), 123.5 (CH-2), 127.6 (Cq),
139.9 (Cq), 142.1 (CH-4), 144.2 (CH-7), 149.2 (t-BuOOC).
Rf 0.3 (PE–EtOAc, 6:4).
1H NMR (250 MHz, CDCl3): d = 0.40 [s, 9 H, Sn(CH3)3,
JH,117Sn = 27.5, JH,119Sn = 28.3 Hz], 3.27 (s, 3 H, CH3O), 5.45 (s, 2 H,
NCH2O), 7.43 (s, 1 H, H-2, JH2,Sn = 8.6), 7.40 (d, 1 H, H-6,
JH6,H7 = 5.5 Hz), 8.31 (d, 1 H, H-7, JH6,H7 = 5.5 Hz), 8.83 (s, 1 H, H-
4).
MS (IS): m/z (%) = 233 (59) [MH]+, 177 (100) [MH – t-Bu]+, 133
(61) [MH – Boc]+.
HRMS (EI): m/z calcd for C13H16N2O2 [M]+·: 232.12118; found:
232.1221.
HRMS (EI): m/z calcd for C12H18N2O120Sn [M]+·: 326.04411;
found: 326.0461.
1-tert-Butyloxycarbonyl-3-(prop-2-enyl)pyrrolo[3,2-c]pyridine
(19)
Halogen–metal exchange was carried out as described in general
procedure C using allyl bromide as the electrophile (0.10 mL, 1.2
mmol). Purification by flash chromatography (PE–EtOAc, 4:6) fur-
nished 19 as a brown oil (106 mg, 71%).
1-(tert-Butyloxycarbonyl)pyrrolo[3,2-c]pyridine-3-carboxylic
Acid (16)
Halogen–metal exchange was carried out as described in general
procedure C with some modifications. CO2 (the electrophile) was
dried over H2SO4 and was bubbled though the reaction mixture for
1 h at –78 °C. The solution was then stirred for a further 2 h. The
reaction was quenched by the addition of H2O (2 mL) and the sol-
vent was removed by evaporation. The residue was dried in high
vacuum over P2O5 to give 16 as a white solid (140 mg, 92%).
Rf 0.3 (PE–EtOAc, 6:4).
IR (KBr): 1146, 1732, 2976 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.56 [s, 9 H, C(CH3)3], 3.50 (dd,
2 H, Hc, 3J = 1.2, 2J = 6.7 Hz), 5.13–5.24 (m, 2 H, Ha, Ha¢), 5.96–
6.09 (m, 1 H, Hb), 7.37 (s, 1 H, H-2), 7.95 (d, 1 H, H-6, J6,7 = 5.6
Hz), 8.47 (d, 1 H, H-7, J6,7 = 5.6 Hz), 8.85 (s, 1 H, H-4).
Mp > 250 °C; Rf 0.2 (CH2Cl2–MeOH, 9:1).
IR (KBr): 1627, 1743, 2969, 2751, 3600 cm–1.
13C NMR (62.5 MHz, CDCl3): d = 28.2 [C(CH3)3], 29.4 (CH2), 84.7
[C(CH3)3], 110.1 (CH-6), 116.9 (CH-a), 118.4 (Cq), 123.6 (CH-2),
135.3 (CH-b), 140.2 (Cq), 142.6 (CH-4), 144.3 (CH-7), 149.3 (t-
BuOOC).
1H NMR (250 MHz, CDCl3): d = 1.62 [s, 9 H, C(CH3)3], 7.89 (m, 2
H, H-2, H-6), 8.37 (d, 1 H, H-7, J6,7 = 6.0 Hz), 9.49 (s, 1 H, H-4).
13C NMR (62.5 MHz, CDCl3): d = 27.6 [C(CH3)3], 84.7 [C(CH3)3],
109.3 (CH-6), 121.4 (Cq), 125.7 (Cq), 128.7 (CH-2), 139.2 (CH-3),
143.3 (CH-7), 145.4 (CH-4), 148.8 (t-BuOOC), 166.2 (COOH).
MS (HN): m/z (%) = 259 (75) [MH]+, 203 (85) [MH – t-Bu]+, 159
(100) [MH – Boc]+.
MS (IS): m/z (%) = 263 (100) [MH]+, 207 [MH – t-Bu]+ (54), 163
HRMS (EI): m/z calcd for C15H18N2O2 [M]+·: 258.13683; found:
258.1380.
[MH – Boc]+ (43).
Synthesis 2005, No. 20, 3581–3588 © Thieme Stuttgart · New York

PAPER
Synthesis of C-2 and C-3 Functionalised 5-Azaindoles
3587
1-tert-Butyloxycarbonyl-3-[hydroxyl-(4-methoxyphenyl)meth-
yl]pyrrolo[3,2-c]pyridine (20)
Halogen–metal exchange was carried out as described in general
procedure C using 4-methoxybenzaldehyde as the electrophile
(0.14 mL, 1.2 mmol). Purification by flash chromatography (PE–
EtOAc, 1:1) furnished 20 as a yellow oil (97 mg, 47%).
1-tert-Butyloxycarbonyl-3-(1-hydroxy-1-methylethyl)pyrro-
lo[3,2-c]pyridine (23)
Halogen–metal exchange was carried out as described in general
procedure C using distilled acetone as the electrophile (0.09 mL, 1.2
mmol). Purification by flash chromatography (PE–EtOAc, 1:1) fur-
nished 23 as a yellow oil (101 mg, 63%).
Rf 0.1 (PE–EtOAc, 6:4).
Rf 0.3 (PE–EtOAc, 4:6).
IR (KBr): 1740, 2836–2980 cm–1.
IR (KBr): 1671, 2964, 3150–3528 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.56 [s, 9 H, C(CH3)3], 3.64 (s, 3
H, OCH3), 5.94 [s, 1 H, CH(OH)], 6.75 (d, 2 H, CH, 3J = 8.5 Hz),
7.30 (d, 2 H, CH, 3J = 8.5 Hz), 7.48 (s, 1 H, H-2), 7.83 (d, 1 H, H-
6, J6,7 = 5.7 Hz), 8.19 (d, 1 H, H-7, J6,7 = 5.7 Hz), 8.59 (s, 1 H, H-4).
13C NMR (62.5 MHz, CDCl3): d = 28.2 [C(CH3)3], 55.3 (OCH3),
69.6 [CH(OH)], 84.9 [C(CH3)3], 110.2 (CH-6), 114.1 (2 × CH),
123.8 (CH-2), 124.1 (Cq), 125.2 (Cq), 128.1 (2 × CH), 135.0 (Cq),
140.4 (Cq), 143.0 (CH-7), 143.7 (CH-4), 149.3 (t-BuOOC), 159.4
(Cq).
1H NMR (250 MHz, CDCl3): d = 1.67 [s, 9 H, C(CH3)3], 1.71 (s, 6
H, 2 × CH3), 7.47 (s, 1 H, H-2), 7.94 (d, 1 H, H-6, J6,7 = 5.7 Hz),
8.37 (d, 1 H, H-7, J6,7 = 5.7 Hz), 9.10 (s, 1 H, H-4).
13C NMR (62.5 MHz, CDCl3): d = 28.3 [C(CH3)3], 31.0 (2 × CH3),
69.8 (Cq), 84.9 [C(CH3)3], 110.2 (CH-6), 121.6 (CH-2), 124.9 (Cq),
128.7 (Cq), 140.6 (Cq), 143.8 (CH-7), 144.2 (CH-4), 149.3 (t-
BuOOC).
MS (IS): m/z (%) = 258 (100) [M – H2O]+.
HRMS (EI): m/z calcd for C15H20N2O3 [M]+·: 276.14739; found:
MS (IS): m/z (%) = 355 (100) [MH]+, 299 (96) [MH – t-Bu]+.
276.1461.
1-tert-Butyloxycarbonyl-3-(1-hydroxy-1-phenylethyl)pyrro-
lo[3,2-c]pyridine (21)
Halogen–metal exchange was carried out as described in general
procedure C using acetophenone as the electrophile (0.12 mL, 0.9
mmol). Purification by flash chromatography (PE–EtOAc, 4:6) fur-
nished 21 as a yellow oil (148 mg, 72%).
References
(1) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004,
104, 3079. (b) Knölker, H.-J.; Reddy, K. R. Chem. Rev.
2002, 102, 4303.
(2) (a) Le Hyaric, M.; Viera de Almeida, M.; Norade Souza, M.
V. Quim. Nova 2002, 25, 1165. (b) Mérour, J.-Y.; Joseph,
B. Curr. Org. Chem. 2000, 5, 471. (c) L’Heureux, A.;
Thibault, C.; Ruel, R. Tetrahedron Lett. 2004, 45, 2317.
(d) Lane, B. S.; Sames, D. Org. Lett. 2004, 6, 2897.
(3) (a) Mendiola, J.; Baeza, A.; Alvarez-Builla, J. J. J. Org.
Chem. 2004, 69, 4974. (b) Molina, P.; Fresnada, P. M.;
Delgado, S. J. Org. Chem. 2003, 68, 489. (c) Ahaidar, A.;
Fernández, D.; Danelón, G.; Cuevas, C.; Manzanares, I.;
Albericio, F.; Joule, J. A.; Álvarez, M. J. Org. Chem. 2003,
68, 10020. (d) Anderson, R. J.; Morris, J. C. Tetrahedron
Lett. 2001, 42, 8697. (e) Fernández, D.; Ahaidar, A.;
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Albericio, F.; Joule, J. A.; Álvarez, M. Monatsh. Chem.
2004, 135, 614.
Rf 0.1 (PE–EtOAc, 4:6).
IR (KBr): 1743, 2751–3587 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.68 [s, 9 H, C(CH3)3], 2.00 (s, 3
H, CH3), 3.36 (br s, 1 H, OH), 6.75 (d, 2 H, CH, 3J = 8.5 Hz), 7.23–
7.33 (m, 1 H, CH), 7.50 (d, 2 H, CH, 3J = 8.5 Hz), 7.58 (s, 1 H, H-
2), 7.88 (d, 1 H, H-6, J6,7 = 5.6 Hz), 8.28 (d, 1 H, H-7, J6,7 = 5.6 Hz),
8.58 (s, 1 H, H-4).
13C NMR (62.5 MHz, CDCl3): d = 28.2 [C(CH3)3], 31.0 (CH3)],
72.9 (Cq), 85.0 [C(CH3)3], 110.0 (CH-6), 123.0 (CH-2), 125.4 (2 ×
CH), 125.9 (Cq), 127.3 (CH), 127.9 (Cq), 128.4 (2 × CH), 140.5
(Cq), 143.7 (CH-7), 144.4 (CH-4), 146.4 (Cq), 149.3 (t-BuOOC).
MS (IS): m/z (%) = 339 (100) [MH]+, 283 (51) [MH – t-Bu]+.
HRMS (EI): m/z calcd for C20H22N2O3 [M]+·: 338.16304; found:
(4) (a) Curtis, N. R.; Kulagowski, J. J.; Leeson, P. D.; Ridgill,
M. P.; Emms, F.; Freedman, S. B.; Patel, S.; Patel, S. Bioorg.
Med. Chem. Lett. 1999, 9, 585. (b) Oh, S.-J.; Lee, K. C.;
Lee, S.-Y.; Ryu, E. K.; Saji, H.; Choe, Y. S.; Chi, D. Y.;
Kim, S. E.; Lee, J.; Kim, B.-T. Bioorg. Med. Chem. 2004,
12, 5505.
338.1604.
1-tert-Butyloxycarbonyl-3-(4,4,5,5-tetramethyl[1,3,2]dioxa-
borolan-2-yl)pyrrolo[3,2-c]pyridine (22)
Halogen–metal exchange was carried out as described in general
procedure C using 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxa-
borolane as the electrophile (0.24 mL, 1.3 mmol). The crude prod-
uct is unstable on silica gel and was dried under a high vacuum to
give 22 as a pale pink solid (182 mg, 88%).
(5) Desarbre, E.; Coudret, S.; Meheust, C.; Mérour, J.-Y.
Tetrahedron 1997, 53, 3637.
(6) Joseph, B.; Da Costa, H.; Mérour, J.-Y.; Léonce, S.
Tetrahedron 2000, 56, 3189.
(7) Routier, S.; Ayerbe, N.; Mérour, J.-Y.; Coudert, G.; Bailly,
C.; Pierré, A.; Pfeiffer, B.; Caignard, D.-H.; Renard, P.
Tetrahedron 2002, 58, 6621.
(8) (a) Praly-Deprez, I.; Rivalle, C.; Belehradek, J.; Huel, C.;
Bisagni, E. J. Chem. Soc., Perkin Trans. 1 1991, 3173.
(b) Bisagni, E.; Chi Hung, N.; Lhoste, J. M. Tetrahedron
1983, 39, 1777.
(9) Dormoy, J.-R.; Heymes, A. Tetrahedron 1993, 49, 2885.
(10) (a) Eldrup, A. B.; Prhavc, M.; Brooks, J.; Bhat, B.; Prakash,
T. P.; Song, Q.; Bera, S.; Bhat, N.; Dande, P.; Cook, P. D.;
Bennett, C. F.; Carroll, S. S.; Ball, R. G.; Bosserman, M.;
Burlein, C.; Colwell, L. F.; Fay, J. F.; Flores, O. A.; Getty,
K.; LaFemina, R. L.; Leone, J.; MacCoss, M.; McMasters,
D. R.; Tomassini, J. E.; Von Langen, D.; Wolanski, B.;
Olsen, D. B. J. Med. Chem. 2004, 47, 5284. (b)McCort,G.;
Hoornaert, C.; Aletru, M.; Denys, C.; Duclos, O.; Cadilhac,
Mp 95 °C; Rf 0–0.2 (PE–EtOAc, 1:1).
IR (KBr): 1748, 2931–2989 cm–1.
1H NMR (250 MHz, CDCl3): d = 1.38 (s, 12 H, 4 × CH3), 1.67 [s, 9
H, C(CH3)3], 7.99 (m, 2 H, H-2, H-6), 8.47 (d, 1 H, H-7, J7,6 = 5.4
Hz), 9.22 (s, 1 H, H-4).
13C NMR (62.5 MHz, CDCl3): d = 25.0 (4 × CH3), 28.2 [C(CH3)3],
83.9 (Cq-pinacol), 85.1 [C(CH3)3], 109.9 (CH-6), 129.8 (Cq), 135.7
(CH-2), 140.7 (Cq), 144.1 (CH-7), 145.6 (CH-4), 148.9 (t-BuOOC).
MS (IS): m/z (%) = 345 (100) [MH]+.
HRMS (EI): m/z calcd for C18H25N2O411B [M]+·: 344.19074; found:
344.1919.
Synthesis 2005, No. 20, 3581–3588 © Thieme Stuttgart · New York

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