Palladium-catalysed tandem alkenyl- and aryl-C-N bond formation: a cascade N-annulation route to 1-functionalised 7-azaindoles

Article abstract of DOI:10.1016/j.tet.2009.08.046

A series of 3-(2-haloalkenyl)-2-pyridyl-halides undergo consecutive palladium-catalysed inter- and intramolecular amination reactions to deliver a series of 1-functionalised 7-azaindoles. Anilines and amines can be readily employed as the N-nucleophile an

Full text of DOI:10.1016/j.tet.2009.08.046

Tetrahedron 65 (2009) 8940–8949
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium-catalysed tandem alkenyl- and aryl-C–N bond formation:
a cascade N-annulation route to 1-functionalised 7-azaindoles
,
Roy C. Hodgkinson a, Jurgen Schulz b, Michael C. Willis a
*
a Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
b Schering Plough Corporation, Newhouse, ML1 5SH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 July 2009
Received in revised form 7 August 2009
Accepted 20 August 2009
Available online 25 August 2009
A series of 3-(2-haloalkenyl)-2-pyridyl-halides undergo consecutive palladium-catalysed inter- and intra-
molecular amination reactions to deliver a series of 1-functionalised 7-azaindoles. Anilines and amines can
be readily employed as the N-nucleophile and incorporation of both electron-donating and electron with-
drawing substituents on the pyridine core is possible.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
We have recently demonstrated that tandem palladium catalysed
amination reactionsdone intermolecular, one intramoleculardcan
Azaindole’s bioisoteric relationship with indoles has resulted in
their evaluation in a host of medicinal chemistry applications.1
Despite their widespread use, the synthesis of these core units is
not always straightforward; the electron-deficient nature of the
pyridine ring, combined with their strong metal-binding ability can
present difficulties in adapting existing indole syntheses to the
required aza-variant.2 Azaindole synthesis is further complicated,
with respect to the parent indole, in that four possible N-isomers
exist (Scheme 1).
be used to access 1-functionalised indoles from acyclic non-nitrogen
containing precursors (1/2, Scheme 2).11,12 Variation of the 1-
substituent was achieved by choice of the N-nucleophile coupling
partner, and includes the successful use of amines, anilines, amides,
sulfonamides and hydrazines. Given the broad utility of azaindoles in
medicinal chemistry, we were interested in developing a related
approach, commencing with pyridine-based substrates, which
would allow access to the corresponding 1-functionalised azain-
doles (3/4, Scheme 2).13 In this account we detail the successful
realisation of this goal with an efficient synthesis of 7-azaindoles.
N
N
R2
R2
N
N
H
N
H
N
H
N
H
N
R3
H2N R4
4-azaindole
5-azaindole
6-azaindole
7-azaindole
R3
R1
R1
Pd cat.
X
X
N
R4
Scheme 1. The four azaindole isomers.
Y
2
1
X = Cl, Br, OTf; Y = Br, Cl
Palladium catalysis has enjoyed considerable success when ap-
plied to heterocycle synthesis;3 azaindoles are no exception and
a number of approaches to these important molecules based on key
palladium- and copper-catalysed bond constructions have been
reported.4,5 The majority of these methods are centred on alkyne-
based approaches,6 but Heck,7 Suzuki8 and Buchwald–Hartwig9
chemistries also feature. A recent report from the Lautens group
demonstrated an elegant tandem process, in which intramolecular
palladium-catalysed amination reactions were combined with in-
termolecular Suzuki couplings to efficiently access all four isomers
of the azaindole core.10
R2
R2
R3
H2N R4
R1
R1
N
N
R3
Pd cat.
N
R4
Y
3
4
Scheme 2. Tandem palladium-catalysed amination routes to 1-functionalised indoles
and azaindoles.
2. Results and discussion
In analogy to the corresponding indole chemistry we planned to
prepare the required (2-haloalkenyl)-pyridylhalide substrates using
simple Wittig chemistry.11b Given the ready availability of a number
* Corresponding author. Tel.: þ44 1865 285126; fax: þ44 1865 285002.
E-mail address: michael.willis@chem.ox.ac.uk (M.C. Willis).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.046

R.C. Hodgkinson et al. / Tetrahedron 65 (2009) 8940–8949
8941
Table 2
of 2-halonicotinaldehydes, we began our investigation by targeting
Initial catalyst evaluationa
the 7-azaindole core. Accordingly, the four substrates 5a–d, fea-
turing all combinations of Br- and Cl-activating groups, were pre-
pared (Table 1).
H2N
Me
Pd(OAc)2, ligand
base
toluene, 110 °C
Table 1
Preparation of 3-(2-haloalkenyl)-2-halopyridine substrates
X
O
N
N
N
Y
[Ph3PCH2X]X
Ar = 4-Me-C6H4-
5
6
Ar
t
KO Bu
H
THF, 0 °C to rt
X
Entry
Substrate (X, Y)
Ligand
Base
Yieldb (%)
N
Y
N
Y
5
1
2
3
4
5a (Br, Br)
5a (Br, Br)
5a (Br, Br)
5a (Br, Br)
5a (Br, Br)
5a (Br, Br)
5b (Cl, Br)
5b (Cl, Br)
5b (Cl, Br)
5c (Br, Cl)
5c (Br, Cl)
5c (Br, Cl)
5d (Cl, Cl)
5d (Cl, Cl)
5d (Cl, Cl)
7
8
9
7
7
7
7
8
9
7
8
9
7
8
9
NaOtBu
NaOtBu
NaOtBu
Cs2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
35
0
0
76
0
61
52
0
80
0
90
<5
0
Entry
Compound
X
Y
E/Z
Yielda (%)
1
2
3
4
5a
5b
5c
5d
Br
Cl
Br
Cl
Br
Br
Cl
Cl
>1:20
1:3
1:13
1:4
80
75
70
70
5
6c
7
8
9
a
Isolated yields.
10
11
12
13
14
15
With the required substrates in hand, we set about evaluating re-
action conditions and the catalyst choice needed to achieve azain-
dole formation (Table 2). We began with the coupling between
dibromo-substrate 5a and p-toluidine to deliver 7-azaindole 6.
Guided by our previous indole chemistry, we selected phosphine
ligands 7, 8 and 9 as the starting point of our investigation.14,15 As
can be seen from the first five entries, the use of biphenyl ligand 7 in
combination with Cs2CO3 as base delivered 76% of azaindole 6 after
6 h reaction in toluene at 110 ꢀC. If the reaction temperature was
reduced to 80 ꢀC, a 16 h reaction provided 61% of the expected
product (entry 6). We next evaluated the same three ligands against
the alternative substrates, 5b–d, featuring the remaining combi-
nations of Br- and Cl-activating substituents. For the vinyl chloride/
aryl bromide substrate, 5b, the use of ligand 9 was optimal, pro-
viding an 80% yield of azaindole 6. For the vinyl bromide/aryl
chloride substrate, 5c, ligand 8 was preferred and delivered azain-
dole 6 in 90% yield. Finally, for the dichloride substrate (5d), ligand 9
was again optimal; however, a 42% yield of azaindole 6 was the
maximum that could be achieved using this substrate.
0
42
a
Conditions: Substrate (1.0 equiv), p-toluidine (2.0 equiv), Pd(OAc)2 (5 mol %), ligand
(12 mol %), base (2.5 equiv), toluene, 110 ꢀC.
b
Isolated yields.
Reaction performed at 80 ꢀC.
c
O
P
MeO
MeO
Et3N
H
Br
Br
Br
DMF, 70 °C, 16 h
60%. E:Z 9:1
N
Br
N
Br
E-5a
Pd(OAc)2, 7
Cs2CO3
Me
NH2
toluene, 110 °C
69%
Ph2P
PCy2
PCy2
OMe
Me
Me
i
i
Pr
Pr
N
O
N
MeO
6
Ar
Ph2P
Scheme 3. Synthesis of azaindole 6 from E-configured substrate 5a. Ar¼4-Me-C6H4.
i
Pr
7
8
9
yields could also be achieved using all combinations of Br- and Cl-
activating groups, we next embarked on exploring the scope of
the N-nucleophile (Table 3). The dibromo-substrate, 5a, was used
throughout. A range of anilines was successfully incorporated,
including those featuring both electron-withdrawing and elec-
tron-donating substituents (entries 1–4). The use of 6-chloropyr-
idin-3-amine as the nucleophile (entry 5) is particularly notable,
given the possibility of oxidative addition to the pyridyl-chloride.
All of the anilines were reacted employing a catalyst system in-
corporating biphenyl ligand 7. However, when pentylamine was
reacted under identical conditions none of the expected azaindole
was obtained (entry 6). A brief survey of alternative ligands
revealed that the use of dppf, 10, allowed the azaindole to be
isolated in 64% yield (entry 7). Reactions incorporating ligands 8
and 9 as well as PCy3 all failed to deliver any product. The dppf
system allowed a range of alkyl amines to be incorporated in good
yields (entries 7–11). The final entry demonstrates that the use of
As shown in Table 1, the alkenyl halide substrates were pro-
duced with varying ratios of E/Z isomers. Although we had pre-
viously established for the related indole substrates that both the
E- and Z-alkene isomers delivered the expected indole product,11b
we needed to confirm this for the pyridine-based substrates.
Accordingly, E-configured dibromo-substrate E-5a was prepared
using Hayes’ modified Hirao reduction procedure (Scheme 3).16
Pleasingly, the E-dibromo-substrate was converted to azaindole 6
using identical conditions to those employed for the Z-substrate. As
with the indole chemistry, the successful use of the E-configured
substrate is attributed to initial coupling at the alkenyl bromide to
generate an enamine intermediate that undergoes isomerisation
under the reaction conditions. This was a synthetically useful ob-
servation as it allowed mixtures of alkene isomers to be used
directly in the azaindole forming reactions, without the need to
isolate the separate geometrical isomers.
t
Having established that both Z- and E-isomers of the dibro-
mide substrates deliver the desired azaindole, and that reasonable
ligand 8 allowed Bu-carbamate to be successfully employed as
the N-coupling partner.

8942
R.C. Hodgkinson et al. / Tetrahedron 65 (2009) 8940–8949
Table 3
Table 4
Scope of the N-nucleophile coupling partner in combination with dibromide sub-
strate 5aa
Variation of the substrate backbone in the preparation of N-aryl-7-azaindolesa
H2N
Me
Pd(OAc)2, ligand
Cs2CO3
R2
Br
Pd(OAc)2, ligand
H2N
R
R2
Br
toluene, 110 °C, 6 h
Cs2CO3
N
N
Br
R1
R1
N
toluene, 110 °C
Ar = 4-Me-C6H4-
5a
R
N
N
N
Cl
Ar
Entry
1
Nucleophile
Ligand
Yieldb (%)
96
Entry
1
Substrate
E/Z
Ligand
Yieldb (%)
7
7
7
7
H2N
MeO
Br
1:4
8
8
61
20
N
Cl
2
3
4
79
86
91
H2N
OMe
O
2
1:20
Me
H2N
Cl
Me
Br
NMe2
3
4
7
9
11
11
18
41
48
71
N
Cl
H2N
5
6c
Me
Ph
H2N
Cl
5
6
7
7
70
0
7
1:3
1:8
8
60
N
Br
N
Cl
H2N
Me
Me
8
9
8
9
0
O
H2N
7
8
10
10
64
60
OEt
42
H2N
Me
Br
N
Cl
10
11
12
12
36
50
83
9
10
10
73
74
11
H2N
12c
OMe
10
11
H2N
H2N
O
13
14
15
1:>20
1:>20
8
8
7
71
0
Br
N
Cl
10
8
53
68
Cl
Cl
O
12
t
H2N
O Bu
Br
a
N
N
Cl
Conditions: 5a (1.0 equiv), amine (2.0 equiv), Pd(OAc)2 (5 mol %), ligand
(12 mol %), Cs2CO3 (2.2 equiv), toluene, 110 ꢀC, 6 h. Substrate 5a was used as
a >20:1 mixture of Z/E isomers.
b
Isolated yields.
1:>20
95
Br
Br
N
Ph2P
Me
16
17
18
19d
1:2
8
9
12
12
0
0
50
73
PPh2
PPh2
Ph2P
PPh2
O
Fe
Cl
Ph2P
12 (DPEphos)
Br
a
Conditions: substrate (1.0 equiv), toluidine (2.0 equiv), Pd(OAc)2 (5 mol %),
ligand (12 mol %), Cs2CO3 (2.2 equiv), toluene, 110 ꢀC, 6 h.
11 (dppp)
10 (dppf)
b
Isolated yields.
c
Dioxane used as solvent.
We next explored variation of the azaindole backbone; suitable
functionalised aldehydes were either commercially available or
prepared using the Vilsmeier-based chemistry of Rao.17 This
allowed ready access to 2-Cl-nicotinaldehydes. Wittig chemistry
was then used as before to deliver the dihalogenated heterocycle
precursors. p-Toluidine was employed as the standard N-nucleo-
phile throughout (Table 4). Initially, we employed the conditions
developed for the basic alkenyl bromide/pyridyl-chloride sub-
strate, 5c, which used ligand 8 (see Table 2). Using these conditions
the Me-ester substituted backbone delivered the expected N-aryl-
7-azaindole in 61% yield (entry 1). However, application of the
same conditions to the iso-propyl-substituted substrate used in
d
KOtBu used as base.
entry 2 only delivered a 20% yield of the azaindole. For substrates
such as this, in which the original conditions were not optimal,
a brief survey of alternative ligands was undertaken. In the event,
employing dppp (11) as the ligand and using dioxane as solvent
allowed a 70% yield of the desired azaindole to be achieved (see
entries 2–6). The Me,Ph-disubstituted substrate shown in entry 7
was converted to the corresponding azaindole using the original
conditions, however, the next substrate examined, bearing a 2-Et-
ester substituent (azaindole numbering), required optimisation

R.C. Hodgkinson et al. / Tetrahedron 65 (2009) 8940–8949
8943
before an 83% yield was achieved (entries 8–12). Two 2-aryl
substituted substrates were next examined. The first, featuring a 2-
(4-MeO-phenyl)-substituent, performed well under the standard
conditions (entry 13), however, the corresponding substrate in-
corporating a 2-(4-Cl-phenyl)-substituent delivered a complex
mixture of products. The difficulty with this substrate was attrib-
uted to competitive reaction at the arylchloride position. This was
remedied by employing the corresponding 2-bromopyridine sub-
strate; the use of ligand 8 then allowed a 95% yield of the expected
azaindole to be achieved (entries 14 and 15). The final substrate
examined featured a 3-methyl substituent; brief optimisation
allowed a 66% yield 73 of the desired product to be achieved.
Having established reasonable variation of both the N-nucleo-
phile and the substrate backbones in an approach towards 7-
azaindoles, we next began to investigate the synthesis of the
remaining azaindole isomers. It was soon apparent that the stability
of the required dihalogenated precursors was an issue with 4-, 5-
and 6-azaindoles. For 6-azaindoles it was not possible to isolate any
of the substrates corresponding to structures 13 (Scheme 4), with
decomposition being observed upon isolation in every case. In-
troduction of an electron-withdrawing ethyl ester to the alkene
side-chain did confer some stability, and allowed dibromide 14 to be
prepared and used directly in an azaindole forming process
(Scheme 4). Initial experiments established that dibromide 14 un-
derwent coupling with toluidine to deliver the required 6-azaindole
(15) in 88% yield. However, further exploration of this substrate was
limited due to its poor stability and subsequent decomposition.
Unfortunately, preparation and isolation of substrates suitable for
the synthesis of 5-azaindoles were similarly unsuccessful.
It was possible to prepare dibromide 16, required for access to 4-
azaindoles (Scheme 5). Initial experiments employing substrate 16
established that it displayed significantly reduced reactivity relative
to the 7-azaindole system. A similar observation was made by
Lautens,10 and was attributed to potential coordination of the
pyridine nitrogen to palladium. Nevertheless, a 53% yield could be
achieved in the coupling of dibromide 16 with tBu-carbamate.
Lautens was able to remedy the poor reactivity of similar substrates
by preparation of the corresponding N-oxides. However, although
the N-oxide corresponding to pyridine 16 could be prepared, it was
unreactive under a variety of coupling conditions.
3. Conclusion
We have established that a cascade palladium-catalysed inter/
intramolecular amination process can be applied to appropriate
3-(2-haloalkenyl)-2-halopyridine substrates to deliver a series of
N-functionalised 7-azaindoles. Anilines and amines can be readily
employed as the N-nucleophile and incorporation of both electron-
donating and electron-withdrawing substituents on the pyridine
core is possible, delivering the expected azaindoles in good to
excellent yields. Unfortunately, it was not possible to identify a single
effective catalyst for all of the azaindoles produced; however, vari-
ation between a small group of ligands allowed efficient reactions to
be achieved. Preliminary experiments have shown that the general
method is far more limited when applied to 4-, 5- and 6-azaindoles,
with the stability of the dihalogenated precursors being problematic.
4. Experimental section
4.1. General information
H
O
All reactions were performed under an inert atmosphere of ni-
trogen, in oven or flame dried glassware. Palladium catalysts and
ligands were purchased from Aldrich Chemical Company or Strem
Chemical.
N
X
N
Y
Br
13, X, Y = Cl or Br
O
O
NaH, THF
0 to 50 °C
(EtO)2P
4.2. General procedure for Wittig reactions using
[Ph3PCH2X]X; preparation of (Z)-2-bromo-3-(2-
bromovinyl)pyridine (5a, Table 1, entry 1)
OEt
Br
H2N
OEt
Me
Pd(OAc)2, 12
O
Potassium tert-butoxide (1.45 g, 0.13 mol) was added portion-
wise to a stirred solution of (bromomethyl)triphenylphosphonium
bromide (5.63 g, 0.13 mol) in anhydrous THF (100 mL) at ꢁ78 ꢀC
under nitrogen. The resulting mixture was stirred for 1.5 h to give
a bright yellow suspension, which was treated dropwise with 2-
bromonicotinaldehyde (2.00 g, 0.11 mol). This was allowed to
warm to 0 ꢀC and stirred for 5 h. The resulting mixture was purified
by adding silica and evaporating to dryness. Column chromatogra-
phy (diethyl ether) removed the triphenyl phosphine oxide. A second
column chromatography (DCM) yielded the vinyl bromide 5a
(2.26 g, E/Z >1:20, 80%) as a yellow oil. nmax (film)/cmꢁ1 3291, 3073,
2922, 1721, 1682, 1616, 1572, 1550, 1444, 1319, 1252, 1120, 1052, 878;
dH (400 MHz, CDCl3) Z isomer: 6.70 (1H, d, J¼8), 7.17 (1H, d, J¼8),
7.30–7.36(1H, m), 8.10 (1H, dd, J¼4 and2), 8.33 (1H, dd, J¼4 and2); dC
(100 MHz, CDCl3) 111.3,122.3,130.6,138.6,143.1,144.5,149.3; LRMS
(CIþ) 263.9 (79Brꢁ81Brꢁ[MþH]þ,100%), 261.9 (58), 265.9 (53); HRMS
(CIþ): 260.8786 ([M]þ C7H5N79Br2 requires 260.8789).
OEt
Cs2CO3
dioxane, 100 °C
N
Br
N
N
O
Br
Ar
15, 88%
14, 62% (not isolated)
Scheme 4. Synthesis of 6-azaindole 15. Ar¼4-Me-C6H4.
H
[Ph3PCH2Br]Br
N
N
Br
t
O
KO Bu
THF, -78 °C to °C
Br
Br
16, 83%, E:Z >20:1
Pd(OAc)2, 8
Cs2CO3
dioxane, 100 °C
O
t
BuO
NH2
N
4.3. 2-Bromo-3-(2-chlorovinyl)pyridine (5b, Table 1, entry 2)
Prepared using (chloromethyl)triphenylphosphonium chloride
(1.67 g, 0.05 mol) and 2-bromonicotinaldehyde (750 mg,
0.04 mol) at 0 ꢀC for 5 h. The reaction mixture was absorbed onto
silica and separated by column chromatography (DCM) to yield the
vinyl chloride 5b (656 mg, E/Z 1:3, 75%) as a yellow oil. nmax (film)/
N
O
t
17, 53%
BuO
Scheme 5. Synthesis of 4-azaindole 17.

8944
R.C. Hodgkinson et al. / Tetrahedron 65 (2009) 8940–8949
cmꢁ1 3293, 3069, 1623, 1572, 1551, 1444, 1386, 1179, 1120, 1052, 930,
857; dH (400 MHz, acetone-d6) Z-isomer: 6.72 (1H, d, J¼8), 6.88 (1H,
d), 7.45 (1H, dd, J¼8), 8.13 (1H, dd, J¼6 and 2), 8.33 (1H, dd, J¼6 and
2); E isomer: 7.04 (1H, d, J¼12), 7.08 (1H, d, J¼12), 7.38 (1H, dd, J¼8
and 4), 7.96 (1H, dd, J¼6 and 2), 8.30 (1H, dd, J¼6 and 2); dC
(100 MHz, acetone-d6) 122.4, 123.3, 124.0, 127.7, 132.4, 139.2, 143.3,
149.8; LRMS (ESIþ) 220.0 (35Clꢁ81Brꢁ[MþH]þ, 100%), 218.0 (79),
221.0 (17%); HRMS (ESIþ): 217.9369 ([MþH]þ C7H6N79Br35Cl
requires: 217.9372).
0.02 mol) and dimethyl phosphite (660 mg, 0.6 mL, 0.06 mol) in
DMF (60 mL). The reaction mixture was stirred at 70 ꢀC for 16 h,
then cooled to room temperature, diluted with water (10 mL) and
washed with ethyl acetate (3ꢂ30 mL). The layers were separated
and the organic fractions were washed with brine (3ꢂ30 mL), dried
(MgSO4) and concentrated under reduced pressure. The product was
purified by absorption onto silica and column chromatography
(diethyl ether) to yield the vinyl bromide (236 mg, E/Z 9:1, 60%) as
a yellow oil; dH (400 MHz, CDCl3) E isomer: 6.83 (1H, d, J¼16), 7.24–
7.27 (1H, m), 7.38 (1H, d, J¼16), 7.67 (1H, dd, J¼8 and 1.6), 8.32 (1H,
dd, J¼8 and 1.6).
4.4. 3-(Bromovinyl)-2-chloropyridine (5c, Table 1, entry 3)
Prepared using (bromomethyl)triphenylphosphonium bromide
(4.48 g, 0.13 mol) and 2-chloronicotinaldehyde (2.00 g, 0.11 mol).
The product was purified by column chromatography (DCM) to
yield the vinyl bromide 5c (1.65 g, E/Z 1:13, 70%) as a yellow oil.
nmax (film)/cmꢁ1 3294, 3074, 1619, 1572, 1446, 1392, 1319, 1190,
1068, 943; dH (400 MHz, CDCl3) Z isomer: 6.70 (1H, d, J¼8), 7.21
(1H, d, J¼8), 7.29 (1H, dd, J¼8 and 4), 8.18 (1H, dd, J¼6), 8.36 (1H, d,
J¼6); E isomer: 6.88 (1H, d, J¼14), 7.40 (1H, d, J¼14), 7.59 (1H, dd,
J¼8 and 4), 7.73 (1H, d, J¼6), 8.35 (1H, d, J¼6); dC (100 MHz, CDCl3)
111.4, 121.8, 128.4, 130.0, 138.8, 148.9, 155.4; HRMS (ESIþ): 217.9368
([MþH]þ C7H4N79Br2 requires 217.9372).
4.8. General procedure for the synthesis of 7-azaindoles;
preparation of 1-p-tolyl-7-azaindole, 6
Caesium carbonate (161 mg, 0.84 mmol) was added to an oven
dried flask charged with palladium(II) acetate (4 mg, 0.02 mmol)
and ligand 7 (19 mg, 0.05 mmol) under nitrogen. The sealed tube
was flushed with nitrogen and the reagents suspended in anhy-
drous toluene (1.5 mL). 2-Bromo-3-(2-bromovinyl)pyridine 5a
(100 mg, 0.38 mmol) and p-toluidine (82 mg, 0.76 mmol) were
added and the reaction mixture heated to 110 ꢀC for 6 h in
a sealed tube. After cooling, the reaction mixture was diluted with
DCM (10 mL) and filtered through a Celite pad, washing with DCM
(2ꢂ25 mL). The filtrate was reduced in vacuo. The product was
purfied via column chromatography (DCM) to yield the azaindole 6
(60 mg, 76%) as a yellow oil. nmax (film)/cmꢁ1 2922, 1593, 1520,
1424, 1359, 1323, 1270, 1235, 1147, 893, 817, 796, 773, 720; dH
(400 MHz, CDCl3) 2.43 (3H, s), 6.63 (1H, d, J¼4), 7.13 (1H, dd, J¼5
and 3), 7.34 (2H, d, J¼8), 7.50 (1H, d, J¼4), 7.62–7.64 (2H, m), 7.98
(1H, dd, J¼6 and 2), 8.39 (1H, dd, J¼6 and 2); dC (100 MHz, CDCl3)
21.1, 101.2, 116.2, 121.4, 124.1 (2C), 128.0, 129.0 (2C), 129.9, 135.9,
136.2, 143.5, 147.5; HRMS (ESIþ): 209.1073 ([MþH]þ C14H13N2
requires: 209.1079).
4.5. 2-Chloro-3-(2-chlorovinyl)pyridine (5d, Table 1, entry 4)
Prepared using (chloromethyl)triphenylphosphonium chloride
(2.22 g, 0.06 mol) and 2-chloronicotinaldehyde (750 mg,
0.05 mol) at 0 ꢀC for 5 h. The reaction mixture was absorbed onto
silica and was separated by column chromatography (DCM) to yield
the vinyl chloride 5d (645 mg, E/Z 1:4, 70%) as a yellow oil. nmax
(film)/cmꢁ1 3296, 3071, 1608, 1575, 1556, 1447, 1364, 1341, 1280,
1255,1187,1130, 932, 859; dH (400 MHz, acetone-d6) Z isomer: 6.75
(1H, d, J¼8), 6.94 (1H, d, J¼8), 7.45 (1H, dd, J¼8 and 4), 8.23 (1H, dd,
J¼8 and 4), 8.37 (1H, dd, J¼8 and 4); E isomer: 7.11 (2H, s), 7.45 (1H,
dd, J¼8 and 4), 8.04 (1H, dd, J¼6 and 2), 8.34 (1H, dd, J¼6 and 2); dC
(100 MHz, acetone-d6) 122.5, 123.0, 125.7, 129.3, 139.5, 149.5,
150.3; LRMS (ESþ) 174.0 (35Clꢁ35Clꢁ[MþH]þ, 100%), 176.0 (63);
HRMS (ESIþ): 173.9874 ([MꢁH]þ C7H6N35Cl2 requires 173.9877).
4.9. 1-Phenyl-7-azaindole (Table 3, entry 1)
Prepared using 2-bromo-3-(2-bromovinyl)pyridine (100 mg,
0.38 mmol) and aniline (76 mg, 0.76 mmol). Isolation via column
chromatography (DCM) yielded the azaindole (79 mg, 96%) as
a yellow oil. nmax (film)/cmꢁ1 3047, 2925, 1591, 1516, 1476, 1456,
1423, 1365, 1324, 1270, 1236, 1210, 1147, 893, 797, 753; dH
(400 MHz, CDCl3) 6.61 (1H, d, J¼4), 7.12 (1H, dd, J¼8 and 4), 7.30–
7.34 (1H, m), 7.49–7.53 (3H, m), 7.75 (2H, d, J¼7), 7.95 (1H, d, J¼4),
8.39 (1H, d, J¼7); dC (100 MHz, CDCl3) 101.6, 116.7, 121.5, 124.2,
124.3, 126.3, 127.8, 128.7, 129.0, 129.6, 138.5, 143.6, 147.4; HRMS
(ESIþ): 195.0917 ([M]þ C13H10N2 requires: 195.0922).
4.6. 2-Bromo-3-(2,2-dibromovinyl)pyridine
A solution of carbon tetrabromide (2.14 g, 0.06 mol) in DCM
(25 mL) was added dropwise to a stirred solution of PPh3 (3.40 g,
0.12 mol) in DCM (50 mL) at ꢁ78 ꢀC under nitrogen. The
resulting mixture was stirred for 30 min to give a pale orange
solution, which was then treated dropwise with 2-bromonicoti-
naldehyde (600 mg, 0.03 mol), at ꢁ78 ꢀC. The resulting reaction
mixture was stirred for 2 h and then allowed to warm to room
temperature and stirred for a further 16 h. The reaction mixture
was poured into hexane (100 mL), filtered and concentrated in
vacuo to give a yellow oil. The crude product was purified via ab-
sorbing onto silica and column chromatography (diethyl ether), to
produce the gem-dibromide (580 mg, 53%) as a pale yellow oil. nmax
(film)/cmꢁ1 3023, 1579, 1568, 1552, 1437, 1385, 1273, 1182, 1119,
1054, 945, 873, 804, 732; dH (400 MHz, acetone-d6) 7.54 (1H, dd,
J¼8 and 4), 7.61 (1H, s), 8.03 (1H, dd, J¼8 and 4), 8.41 (1H, dd, J¼8
and 4); dC (100 MHz, acetone-d6) 94.8, 123.5, 134.2, 135.7, 139.4,
141.9, 150.3; LRMS (CIþ) 341.81 (79Br2-81Br-[MþH]þ, 100%), 343.8
(97), 339.8 (34), 345.8 (24); HRMS (CIþ): 339.7983 ([M]þ
C7H479Br3N requires: 339.7972).
4.10. 1-p-Ansidyl-7-azaindole (Table 3, entry 2)
Prepared using 2-bromo-3-(2-bromovinyl)pyridine (100 mg,
0.38 mmol) and p-anisidine (94 mg, 0.76 mmol). Isolation via
column chromatography (DCM) yielded the azaindole (67 mg,
79%) as a yellow oil. nmax (film)/cmꢁ1 2932, 1593, 1519, 1463, 1424,
1358, 1324, 1298, 1272, 1247, 1181, 1147, 1034, 894; dH (400 MHz,
CDCl3) 3.86 (3H, s), 6.60 (1H, d, J¼4), 7.04–7.06 (2H, m), 7.12 (1H, dd,
J¼8 and 4), 7.45 (1H, d, J¼4), 7.60–7.62 (2H, m), 7.97 (1H, dd, J¼6
and 4), 8.36 (1H, dd, J¼6 and 4); dC (100 MHz, CDCl3) 55.6, 100.9,
114.6 (2C), 116.4, 121.2, 125.7 (2C), 128.3, 128.9, 131.5, 143.5, 147.6,
158.1; HRMS (ESIþ): 225.1022 ([MþH]þ C14H13N2O requires:
225.1028).
4.7. (E)-2-Bromo-3-(2-bromovinyl)pyridine, E-5a
4.11. 1-(4-Chlorophenyl)-7-azaindole (Table 3, entry 3)
Triethylamine (8.15 g, 11.10 mL, 0.08 mmol) was added to
solution of 2-bromo-3-(2,2-bromovinyl)pyridine (500 mg,
Prepared using 2-bromo-3-(2-bromovinyl)pyridine (100 mg,
0.38 mmol) and 4-chloroaniline (97 mg, 0.76 mmol). Isolation
a

R.C. Hodgkinson et al. / Tetrahedron 65 (2009) 8940–8949
8945
via column chromatography (DCM) yielded the azaindole (75 mg,
4.16. 1-Benzyl-7-azaindole (Table 3, entry 9)19
86%) as a yellow solid; mp 165–168 ꢀC. nmax (film)/cmꢁ1 2922,
1592, 1521, 1495, 1420, 1359, 1325, 1278, 1266,1236, 1147, 1095, 893,
821; dH (400 MHz, CDCl3) 6.64 (1H, d, J¼4), 7.15 (1H, dd, J¼8 and 5),
7.48–7.51 (3H, m), 7.72–7.75 (2H, m), 7.97 (1H, dd, J¼8 and 2), 8.36
(1H, dd, J¼8 and 2); dC (100 MHz, CDCl3) 102.1, 116.9, 121.6, 125.0
(2C), 127.4, 129.2, 129.5 (2C), 131.7, 137.0, 143.7, 147.4. Anal. Calcd for
C13H9N2Cl: C: 68.33; H, 3.90; N, 12.29. Found: C, 68.37; H, 3.97; N,
12.36.
Prepared using 2-bromo-3-(2-bromovinyl)pyridine (100 mg,
0.38 mmol), dppf 10 (28 mg, 0.05 mmol) and benzylamine
(81 mg, 83
mL, 0.76 mmol). Isolation via column chromatography
(DCM) yielded the azaindole (58 mg, 73%) as a tan oil. nmax (film)/
cmꢁ1 3120, 3060, 2916, 1961, 1873, 1716, 1658, 1592, 1492, 1434,
1349, 1314, 1253, 1183, 1120, 1075, 1031, 965, 890; dH (400 MHz,
CDCl3) 5.55 (2H, s), 6.51 (1H, d, J¼4), 7.09 (1H, dd, J¼8 and 5), 7.22–
7.34 (5H, m), 7.49 (1H, d, J¼4), 7.97 (1H, dd, J¼6 and 2), 8.30 (1H, dd,
J¼6 and 2); dC (100 MHz, CDCl3) 47.7,100.0,116.1,120.8,127.8,127.9
(2C), 128.8, 128.8, 128.9 (2C), 139.2, 143.1, 148.2.
4.12. 1-(4-(N,N-Dimethyl)methyl)phenyl-7-azaindole
(Table 3, entry 4)
Prepared using 2-bromo-3-(2-bromovinyl)pyridine (100 mg,
0.38 mmol) and 4-(dimethylaminomethyl)aniline (114 mg, 0.76
mmol). Isolation via column chromatography (DCM) yielded the
azaindole (87 mg, 91%) as a yellow oil. nmax (film)/cmꢁ1 2934, 2815,
2772, 1593, 1427, 1423, 1361, 1323, 1269, 1147, 1111, 1018, 893, 838; dH
(400 MHz, CDCl3) 2.28 (6H, s), 3.48 (2H, s), 6.62 (1H, d, J¼4), 7.13 (1H,
dd, J¼8 and 4), 7.46 (2H, d, J¼6), 7.51 (1H, d, J¼4), 7.71 (2H, d, J¼6), 7.96
(1H, d, J¼4), 8.36 (1H, d, J¼4); dC (100 MHz, CDCl3) 45.5 (2C), 63.9,
101.9, 116.6, 121.6, 121.6, 123.7, 127.9, 129.0, 129.2, 129.9, 137.1, 137.4,
143.6, 147.5; HRMS (ESIþ): 252.1495 ([MþH]þ C16H18N3 requires:
252.1511).
4.17. 1-(2-Phenoxyethyl)-7-azaindole (Table 3, entry 10)
Prepared using 2-bromo-3-(2-bromovinyl)pyridine (100 mg,
0.38 mmol), dppf 10 (28 mg, 0.05 mmol) and 2-phenoxyethan-
amine (104 mg, 99
mL, 0.76 mmol). Isolation via column chroma-
tography (DCM) yielded the azaindole (67 mg, 74%) as a tan oil. nmax
(film)/cmꢁ1 3053, 2933, 2874,1927,1851,1721,1597,1496,1427,1347,
1318, 1244, 1207, 1172, 1107, 1080, 1062, 962, 906; dH (400 MHz,
CDCl3) 4.34 (2H, t, J¼6), 4.72 (2H, t, J¼6), 6.47 (1H, d, J¼4), 6.86–6.90
(2H, m), 6.92–6.97(1H, m), 7.09(1H, dd, J¼8and4), 7.24–7.29(2H, m),
7.42 (1H, dd, J¼4), 7.93 (1H, dd, J¼6 and 4), 8.34 (1H, dd, J¼6 and 4); dC
(100 MHz, CDCl3) 44.0, 66.9, 99.6, 114.5 (2C), 115.8, 120.8, 121.1,
128.9, 129.2, 129.5 (2C), 142.7, 147.3, 158.4; LRMS (ESþ) 239.1
([MþH]þ, 100%), 240.1 (10); HRMS (ESIþ): 239.1179 ([MþH]þ
C15H15N2O requires: 239.1184).
4.13. 1-(6-Chloropyridin-3-yl)-7-azaindole (Table 3, entry 5)
Prepared using 2-bromo-3-(2-bromovinyl)pyridine (100 mg,
0.38 mmol) and 5-amino-2-chloropyridine (98 mg, 0.76 mmol).
Isolation via column chromatography (DCM) yielded the azaindole
(61 mg, 70%) as a yellow solid; mp 169–172 ꢀC. nmax (film)/cmꢁ1
3029, 2922, 2857, 1596, 1571, 1517, 1490, 1457, 1416, 1399, 1312,
1246, 1179, 1091, 1013, 961; dH (400 MHz, CDCl3) 6.70 (1H, d, J¼4),
7.18 (1H, dd, J¼8 and 5), 7.47 (1H, s), 7.49–7.51 (1H, m), 7.98 (1H, dd,
J¼8 and 2), 8.32–8.38 (2H, m), 8.77 (1H, d, J¼3); dC (100 MHz,
CDCl3) 103.3, 117.5, 121.7, 124.5, 126.4, 129.5, 133.6, 134.3, 143.7,
143.9, 147.4. 148.0; HRMS (ESIþ): 230.0479 ([MþH]þ C12H935ClN3
requires: 230.0485).
4.18. 1-(4-Phenylbutyl)-7-azaindole (Table 3, entry 11)
Prepared using 2-bromo-3-(2-bromovinyl)pyridine (100 mg,
0.38 mmol), dppf 10 (28 mg, 0.05 mmol) and 4-phenylbutyl-1-
amine (113 mg, 120
mL, 0.76 mmol). Isolation via column chro-
matography (DCM) yielded the azaindole (50 mg, 53%) as a tan oil.
nmax (film)/cmꢁ1 3052, 3025, 2935, 2858, 1593, 1569, 1509, 1453,
1426, 1402, 1346, 1307, 1205, 1087, 1030, 894; dH (400 MHz, CDCl3)
1.63–1.75 (2H, m), 1.89–1.94 (2H, m), 2.65 (2H, t, J¼8), 4.33 (2H, t,
J¼8), 6.45 (1H, d, J¼4), 7.06 (1H, dd, J¼8 and 5), 7.11–7.12 (4H, m),
7.23–7.29 (2H, m), 7.91 (1H, dd, J¼6 and 1), 8.33 (1H, dd, J¼6 and 1);
dC (CDCl3) 100 MHz 28.7, 30.0, 35.5, 44.4, 99.3, 115.5, 120.6, 125.8
(2C),127.9,128.3 (2C),128.4 (2C),128.7,142.1,142.7; LRMS (FIþ) 250.1
(Mþ, 100%), 251.2 (10); HRMS (FIþ): 250.1470 ([M]þ C17H18N2 re-
quires: 250.1470).
4.14. 1-Pentyl-7-azaindole (Table 3, entry 7)18
Prepared using 2-bromo-3-(2-bromovinyl)pyridine (100 mg,
0.38), dppf 10 (28 mg, 0.05 mmol) and pentylamine (66 mg, 88 mL,
0.76 mmol). Isolation via column chromatography (DCM) yielded
the azaindole (46 mg, 64%) as a tan oil. nmax (film)/cmꢁ1 2957, 2930,
2860, 1594, 1569, 1509, 1426, 1306, 1205, 1096, 894, 796, 773, 717; dH
(500 MHz, CDCl3) 0.85–0.92 (3H, m), 1.25–1.40 (4H, m), 1.80–1.95
(2H, m), 4.30 (2H, t, J¼7), 6.46 (1H, d, J¼3), 7.05 (1H, dd, J¼8 and 4),
7.23 (1H, d, J¼3), 7.92 (1H, dd, J¼6 and 2), 8.33 (1H, dd, J¼6 and 2); dC
(125 MHz, CDCl3) 14.0, 22.4, 28.1, 29.1, 44.5, 99.1, 115.5, 120.5, 127.7,
128.0, 142.6, 147.3.
4.19. tert-Butyl-7-azaindole-1-carboxylate
(Table 3, entry 12)20
Prepared using 2-bromo-3-(2-bromovinyl)pyridine (100 mg,
0.38 mmol), X-Phos 8 (24 mg, 0.05 mmol) and tert-butyl carba-
mate (87 mg, 0.76) in anhydrous dioxane (1.5 mL). Isolation via
column chromatography (10%/20% EtOAc/Petrol) yielded the
azaindole (52 mg, 63%) as a yellow oil. nmax (film)/cmꢁ1 2981, 1730,
1530, 1411, 1321, 1256, 1158, 1114, 1089, 773; dH (400 MHz, CDCl3)
1.68 (9H, s), 6.51 (1H, d, J¼4), 7.20 (1H, dd, J¼8 and 6), 7.65 (1H, d,
J¼4), 7.89 (1H, dd, J¼8 and 2), 8.52 (1H, dd, J¼6 and 2); dC
(125 MHz, CDCl3) 28.3 (3C), 84.1, 104.5, 118.6, 123.0, 126.6, 129.2,
145.2, 148.0, 148.4.
4.15. 1-Octyl-7-azaindole (Table 3, entry 8)
Prepared using 2-bromo-3-(2-bromovinyl)pyridine (100 mg,
0.38 mmol), dppf 10 (28 mg, 0.05 mmol) and octylamine (98 mg,
126
mL, 0.76 mmol). Isolation via column chromatography (DCM)
yielded the azaindole (53 mg, 60%)as a tan oil. nmax (film)/cmꢁ13424,
3051, 2925, 2855, 1593, 1509, 1464, 1426, 1403, 1307, 1205, 1111, 958,
894; dH (400 MHz, acetone-d6) 0.81–0.93 (3H, m), 1.23–1.35 (10H,
m),1.82–1.92 (2H, m), 4.32 (2H, t, J¼7), 6.45 (1H, d, J¼3), 7.05 (1H, dd,
J¼8 and 4), 7.46 (1H, d, J¼3), 7.93 (1H, dd, J¼6 and 2), 8.26 (1H, dd, J¼6
and 2); dC (100 MHz, CDCl3) 14.1, 22.6, 26.9, 29.2 (2C), 30.4, 31.2, 44.6,
99.1, 115.4, 120.6, 127.9, 128.7, 142.6, 147.4; LRMS (FIþ) 230.2 (Mþ,
100%), 231.2 (14); HRMS (FIþ): 230.1781 ([M]þ C15H22N2 requires:
230.1783).
4.20. (Z)-Methyl-5-(2-bromovinyl)-6-chloropicolinate
(Table 4, entry 1 substrate)
Prepared using (bromomethyl)triphenylphosphonium bromide
(1.31 g, 0.03 mol) and methyl-6-chloro-5-formylpicolinate17 (500
mg, 0.03 mol). The product was purified by flash chromatography
(DCM) to yield the vinyl bromide (138 mg, E/Z 1:4, 20%) as an oil. nmax

8946
R.C. Hodgkinson et al. / Tetrahedron 65 (2009) 8940–8949
(film)/cmꢁ1 3075, 2957, 2925,1744,1727,1555,1445,1358,1317,1222,
1138,1067, 819; dH (500 MHz, CDCl3) Z-isomer: 4.00 (3H, s), 6.81 (1H,
d, J¼10), 7.26 (1H, d, J¼10), 8.10 (1H, d, J¼5), 8.35 (1H, d, J¼5); E-iso-
mer:3.99(3H, s), 7.04(1H, d,J¼15), 7.45 (1H, d, J¼15), 7.87(1H, d, J¼8),
7.97 (1H, d, J¼8); dC (125 MHz, CDCl3) 53.2, 113.2, 123.4, 127.9, 133.6,
135.7, 143.0, 146.9, 164.3; LRMS (ESþ) 278.0 (35Clꢁ81Brꢁ[MþH]þ,
100%), 276.0 (81), 280.0 (19); HRMS (ESIþ): 275.9413 ([MꢁH]þ
C9H879Br35ClNO2 requires: 275.9421).
(79), 294.0 (25); HRMS (CIþ): 289.9588 ([M]þ C10H979Br35ClNO2
requires: 289.9583).
4.24. 2-Chloro-3-(2,2-dibromovinyl)pyridine
A solution of carbon tetrabromide (4.71 g, 0.14 mol) in DCM
(50 mL) was added dropwise to a stirred solution of PPh3 (7.45 g,
0.28) in DCM (100 mL) at ꢁ78 ꢀC under nitrogen. The resulting
mixture was stirred for 30 min to give a pale orange solution, which
was then treated dropwise with 2-chloronicotinaldehyde (1.00 g,
0.07 mol), at ꢁ78 ꢀC. The resulting reaction mixture was stirred for
2 h and then allowed to warm to room temperature and stirred for
a further 16 h. The reaction mixture was poured into hexane
(200 mL), filtered and concentrated in vacuo. The crude product
was purified via absorbing onto silica and column chromatography
(diethyl ether), to produce the gem-dibromide (158 g, 75%) as
a white solid; mp 57–59 ꢀC. nmax (film)/cmꢁ1 3026, 2201,1599,1571,
1391, 1187, 1131, 1071, 978, 945; dH (400 MHz, acetone-d6) 7.51 (1H,
dd, J¼8 and 4), 7.67 (1H, s), 8.10 (1H, dd, J¼8 and 4), 8.43 (1H, dd, J¼8
and 4); dC (125 MHz, acetone-d6) 95.2, 123.8, 131.9 134.4, 140.1,
149.9, 150.0; LRMS (FIþ) 296.8 (35Clꢁ81Br2ꢁMþ, 100%), 298.8 (69),
294.8 (44); HRMS (FIþ): 294.8409 ([M]þ C7H479Br235ClN requires:
294.8399).
4.21. (Z)-3-(2-Bromo)-2-chloro–5-iso-propylpyridine (Table 4,
entry 2 substrate)
Prepared using (bromomethyl)triphenylphosphonium bromide
(2.85 g, 0.07 mol) and 2-chloro-5-iso-propyl nicotinaldehyde17
(1.00 g, 0.05 mol). The product was purified by flash chroma-
tography (DCM) to yield the vinyl bromide (0.92 g, E/Z ꢃ1:20, 65%)
as a tan oil. nmax (film)/cmꢁ1 3299, 3076, 3028, 2964, 2929, 2872,
1619, 1607, 1585, 1553, 1463, 1423, 1398, 1366, 1338, 1317, 1280,
1224, 1177, 1163, 1149, 1086, 1020, 924, 909, 864, 833; dH
(400 MHz) 1.28 (3H, s), 1.30 (3H, s), 2.88–3.03 (1H, m), 6.68 (1H, d,
J¼8), 7.21 (1H, d, J¼8), 8.07 (1H,d, J¼4), 8.21 (1H, d, J¼4); dC
(100 MHz, CDCl3) 23.6 (2C), 31.1, 111.0, 123.9, 128.6, 129.3, 137.0,
140.2, 142.4; LRMS (CIþ) 261.0 (35Clꢁ81Brꢁ[MþH]þ, 100%), 260.0
(80), 264.0 (20); HRMS (CIþ): 258.9771 ([M]þ C10H11N35Cl79Br re-
quires: 258.9763).
4.25. (Z)-3-(2-Bromo-2-(4-methoxyphenyl)vinyl)-2-
chloropyridine (Table 4, entry 13 substrate)
4.22. (Z)-3-(2-Bromovinyl)-2-chloro-5-methyl-6-
phenylpyridine (Table 4, entry 7 substrate)
p-Methoxyphenylboronic acid (86 mg, 0.6 mmol) was added
to a flask charged with Pd(OAc)2 (2 mg, 0.01 mmol) and P(2-fur)3
(19 mg, 0.08 mmol). The flask was flushed with argon and the
reagents suspended in degassed dioxane (2.0 mL). To this sus-
pension a degassed 1 M solution of NaHCO3 (1.0 mL) and 2-
chloro-3-(2,2-dibromovinyl)pyridine (150 mg, 0.5 mmol) were
added and the reaction mixture heated to 70 ꢀC for 4 h. After
cooling to room temperature the reaction mixture was partitioned
with water (10 mL), extracted with DCM (3ꢂ20 mL) and the or-
ganic fractions dried (MgSO4), filtered and concentrated in vacuo.
The crude material was purified by column chromatography (DCM)
to yield the pyridine (131 mg, 81%) as an off-white solid; mp 112–
114 ꢀC. nmax (film)/cmꢁ1 3039, 3004, 2931, 1723, 1651, 16.03, 1571,
1551, 1461, 1415, 1385, 1304, 1273, 1228, 1117, 1030, 943; dH
(400 MHz, CDCl3) 3.88 (3H, s), 7.04 (2H, d, J¼8), 7.25 (1H, s), 7.54
(1H, dd, J¼8 and 4), 7.74 (2H, d, J¼8), 8.11 (1H, dd, J¼8 and 4), 8.36
(1H, dd, J¼8 and 4); dC (125 MHz, acetone-d6) 55.4, 114.3, 123.2,
126.2, 128.6, 128.7, 129.6, 132.0, 133.6, 135.4, 139.9, 143.2, 149.5,
161.4; LRMS (FIþ) 325.0 (35Clꢁ81BrꢁMþ, 100%), 323.0 (78), 327.0
(28); HRMS (FIþ): 322.9712 ([M]þ C14H1179Br35ClNO requires:
322.9713). Anal. Calcd for C14H11N: C, 52.87; H, 3.31; N, 4.26. Found:
C, 52.92; H, 3.37; N, 4.26.
Prepared using (bromomethyl)triphenylphosphonium bromide
(567 mg, 0.01 mol) and 2-chloro-5-methyl-6-phenylnicotinal-
dehyde17 (250 mg, 0.01 mol). The product was purified by flash
chromatography (DCM) to yield the vinyl bromide (1.05 g, E/Z 1:3,
95%) as a tan oil. nmax (film)/cmꢁ1 3060, 2960, 2926,1614,1577,1535,
1494, 1444, 1386, 1316, 1263, 1194, 1144, 1002, 937; dH (500 MHz,
MeOH-d4) Z-isomer: 2.33 (3H, s), 6.85 (1H, d, J¼10), 7.24 (1H, d,
J¼10), 7.42–7.48 (5H, m), 8.12 (1H, s); E-isomer: 2.28 (3H, s), 7.22 (1H,
d, J¼15), 7.36 (1H, d, J¼15), 7.42–7.48 (5H, m), 7.86 (1H, s); dC
(125 MHz, MeOH-d4) 19.7,112.6,112.9,124.4,129.4 (2C),129.9,130.1,
131.4, 139.5, 140.0, 142.9, 147.8, 160.3; LRMS (FIþ) 309.0
(
35Clꢁ81BrꢁMþ, 100%), 307.0 (76), 311.0 (23); HRMS (FIþ): 306.9769,
([M]þ C14H1179Br35ClN requires: 306.9763).
4.23. (Z)-Ethyl-2-bromo-3-(2-chloropyridin-3-yl)acrylate
(Table 4, entry 9 substrate)
A solution of sodium hydride (60% dispersion in mineral oil,
236 mg, 0.08 mol) in THF (30 mL) was added to ethyl-2-bromo-
2-(diethoxyphosphoryl)acetate21 (4.24 g, 0.14 mol) at room
temperature. The solution was stirred for 1 h and then 2-chloro-
nicotinaldehyde (1.00 g, 0.07 mol) was added at room tempera-
ture then the reaction mixture was heated to 50 ꢀC for 12 h. The
reaction mixture was cooled to room temperature and water
(20 mL) was added and extracted with DCM (3ꢂ50 mL). The layers
were separated and the organic portions dried over MgSO4, filtered
and concentrated in vacuo. The crude material was purified by
column chromatography (DCM) to yield the acrylate (1.26 g, 62%)
as a white solid; mp 36–38 ꢀC; nmax (film)/cmꢁ1 2982, 2937, 1726,
1616, 1574, 1557, 1447, 1369, 1219, 1154, 1029, 838; dH (400 MHz,
acetone-d6) Z-isomer: 1.38 (3H, t, J¼7), 4.38 (2H, q, J¼8), 7.56 (1H,
dd, J¼8), 8.28 (1H, s), 8.29 (1H, dd, J¼8 and 4), 8.48 (1H, dd, J¼8 and
4); E-isomer: 1.08 (3H, t, J¼7 and 2, Me), 4.14 (2H, q, J¼7 and 4), 7.45
(1H, dd, J¼8), 7.64 (1H, s), 7.84 (1H, d, J¼6), 8.42 (1H, d, J¼6); dC
(100 MHz, acetone-d6) 13.9, 63.3, 119.0, 123.1, 130.2, 136.9, 139.8,
150.7, 162.2; LRMS (CIþ) 292.0 (35Clꢁ81Brꢁ[MþH]þ, 100%), 290.0
4.26. (Z)-3-(2-Bromo-2-(4-chlorophenyl))-2-chloropyridine
(Table 4, entry 14 substrate)
p-Chlorophenylboronic acid (289 mg,1.85 mmol) was added to
a flask charged with Pd(OAc)2 (6.7 mg, 0.03 mmol) and P(2-fur)3
(55 mg, 0.24 mmol). The flask was flushed with argon and the
reagents suspended in degassed dioxane (5.0 mL). To this suspen-
sion a degassed 1 M solution of NaHCO3 (3.0 mL) and 2-chloro-3-
(2,2-dibromovinyl)pyridine (500 mg, 1.68 mmol) were added and
the reaction mixture heated to 70 ꢀC for 4 h. After cooling to room
temperature the reaction mixture was partitioned with water
(10 mL), extracted with DCM (3ꢂ20 mL) and the organic fractions
dried (MgSO4), filtered and concentrated in vacuo. The crude mate-
rial was purified by column chromatography (DCM) to yield the
pyridine (473 mg, 86%) as a white solid; mp 61–63 ꢀC. nmax (film)/
cmꢁ1 3047, 1612, 1590, 1574, 1556, 1487, 1447, 1301, 1264, 1225, 1180,

R.C. Hodgkinson et al. / Tetrahedron 65 (2009) 8940–8949
8947
1126, 1093, 1070, 1012, 977; dH (400 MHz, acetone-d6) 7.46 (1H, s),
4.30. 5-iso-Propyl-1-p-tolyl-7-azaindole (Table 4, entry 6)
7.51–7.55 (3H, m), 7.79–7.83 (2H, m), 8.20 (1H, ddd, J¼8, 2 and 1),
8.43 (1H, dd, J¼5 and 2); dC (100 MHz, acetone-d6) 123.0, 127.0,
129.0,129.1,129.5,129.9,132.5,133.6,135.4,138.5,140.1,148.6,149.6;
LRMS (FIþ) 328.9 (35Cl2ꢁ81BrꢁMþ, 100%), 326.9 (63), 330.9 (47);
HRMS (FIþ): 326.9216 ([M]þ C13H879Br35Cl2N requires: 326.9217).
Prepared using (Z)-3-(2-bromovinyl)-2-chloro5-iso-propylpyr-
idine (100 mg, 0.38 mmol), dppp 11 (21 mg, 0.05 mmol) and p-
toluidine (46 mg, 0.43 mmol). Isolation via column chromatogra-
phy (DCM) yielded the azaindole (49 mg, 71%) as a yellow oil. nmax
(film)/cmꢁ1 3104, 3036, 3009, 2959, 2868, 1603, 1583, 1567, 1481,
1407, 1384, 1362, 1262, 1209, 1179, 1121, 1068, 1020, 965, 921; dH
(500 MHz, CDCl3) 1.34 (3H, s),1.35 (3H, s), 2.42 (3H, s), 3.07 (1H, spt,
J¼8), 6.57 (1H, d, J¼3), 7.32 (2H, d, J¼10), 7.46 (1H, d, J¼3), 7.61–7.63
(2H, m), 7.82 (1H, d, J¼2), 8.27 (1H, d, J¼2); dC (125 MHz, CDCl3) 21.0,
24.5, 31.9,100.9,121.3,123.8 (2C),126.1,128.0,129.9 (2C),135.9,136.1,
136.7, 143.2, 146.5, 153.5; LRMS (CIþ) 251.1 ([MþH]þ, 100%), 252.2
(16); HRMS (ESþ): 251.1550 ([MþH]þ C17H19N2 requires: 251.1548).
4.27. (Z)-2-Bromo-3-(2-bromo-2-(4-chlorophenyl))pyridine
(Table 4, entry 15 substrate)
p-Chlorophenylboronic acid (200 mg, 1.29 mmol) was added
to a flask charged with Pd(OAc)2 (4.7 mg, 0.02 mmol) and P(2-
fur)3 (38 mg, 0.17 mmol). The flask was flushed with argon and
the reagents suspended in degassed dioxane (3.5 mL). To this
suspension a degassed 1 M solution of NaHCO3 (2.0 mL) and 2-
bromo-3-(2,2-dibromovinyl)pyridine (400 mg, 1.17 mmol) were
added and the reaction mixture heated to 70 ꢀC for 4 h. After
cooling to room temperature the reaction mixture was partitioned
with water (10 mL), extracted with DCM (3ꢂ20 mL) and the or-
ganic fractions dried (MgSO4), filtered and concentrated in vacuo.
The crude material was purified by column chromatography (DCM)
to yield the pyridine (327 mg, 85%) as a white solid; mp 76–78 ꢀC.
nmax (film)/cmꢁ1 3052, 1630, 1590, 1566, 1522, 1486, 1445, 1397,
1385, 1264, 1226, 1175, 1118, 1092, 1052, 1013, 979, 947, 905; dH
(400 MHz, acetone-d6) 7.41 (1H, s), 7.53–7.57 (3H, m), 7.81–7.83
(2H, m), 8.11–8.13 (1H, m), 8.40 (1H, d, J¼4); dC (100 MHz, acetone-
d6) 123.3, 127.3, 128.8, 129.2 (2C), 129.8 (2C), 135.0, 135.4, 138.5,
139.8, 143.0, 149.9; LRMS (FIþ) 372.9 (35Clꢁ81Br2ꢁMþ, 100%), 374.9
(78), 370.9 (50); HRMS (FIþ): 370.8708 ([M]þ C13H879Br235ClN re-
quires: 370.8712). Anal. Calcd for C13H8Br2ClN: C, 41.81; H, 2.16; N,
3.75. Found: C, 41.91; H, 2.09; N, 3.65.
4.31. 5-Methyl-6-phenyl-1-p-tolyl-7-azaindole
(Table 4, entry 7)
Prepared using (Z)-3-(2-bromovinyl)-2-chloro-5-methyl-6-phenyl-
pyridine (100 mg, 0.32 mmol), X-Phos 8 (19 mg, 0.04 mmol) and
p-toluidine (69 mg, 0.64 mmol). Isolation via column chroma-
tography (DCM) yielded the azaindole (60 mg, 60%) as a yellow
solid; mp 90–92 ꢀ.; nmax (film)/cmꢁ1 3105, 3082, 3034, 2953, 2924,
2855,1722,1609,1583,1555,1466,1439,1381,1360,1289,1175,1122,
1072, 1020, 995, 935; dH (500 MHz, acetone-d6) 2.38 (3H, s), 2.46
(3H, s), 6.66 (1H, d, J¼4), 7.31 (2H, d, J¼10), 7.39–7.49 (1H, m), 7.49–
7.46 (2H, m), 7.62–7.64 (2H, m), 7.79 (1H, d, J¼4), 7.84–7.87 (2H, m),
7.94 (1H, s); dC (125 MHz, acetone-d6) 20.6, 21.0, 101.7, 121.7 (2C),
123.8 (2C), 124.3, 128.2, 128.7 (2C), 129.1 (2C), 130.3 (2C), 130.4 (2C),
131.7, 136.0, 137.5, 142.8, 147.1, 153.5; LRMS (CIþ) 298.1 (Mþ, 100%),
299.2 (86); HRMS (CIþ): 298.1479 ([M]þ C21H18N2 requires:
298.1470).
4.28. 2-Bromo-3-(1-chloroprop-1-en-2-yl)pyridine
(Table 4, entry 16 substrate)
4.32. Ethyl 1-p-tolyl-7-azaindole-2-carboxylate
(Table 4, entry 12)
Prepared using (chloromethyl)triphenylphosphonium chloride
(6.25 g, 0.18 mol) and 1-(2-bromopyridin-3-yl)ethanone22
(1.00 g, 5.02 mmol). The product was purified by flash chroma-
tography (DCM) to yield the vinyl chloride (2.58 g, E/Z 2:1, 74%) as
colourless crystalline solid; mp 69–71 ꢀC. nmax (film)/cmꢁ1 3067,
2973, 2913, 2849,1679,1634,1574,1551,1443,1387,1324,1255,1232,
1193, 1105, 1013, 987, 840; dH (500 MHz, MeOH-d4) Z-isomer: 2.15
(3H, d, J¼2), 6.28 (1H, q, J¼4 and 2), 7.43 (1H, dd, J¼8 and 4), 7.67 (1H,
dd, J¼6 and 2), 8.31 (1H, dd, J¼6 and 2); E-isomer: 2.10 (3H, d, J¼2),
6.39 (1H, q, J¼4 and 2), 7.47 (1H, dd, J¼8 and 4), 7.64 (1H, dd, J¼6 and
2), 8.32 (1H, dd, J¼6 and 2); dC (125 MHz, MeOH-d4) 21.0, 116.9,
123.7, 137.5, 138.4, 139.3, 139.8, 141.0, 149.2; LRMS (CIþ) 233.9
Prepared using (Z)-ethyl-2-bromo-3-(2-chloropyridin-3-yl)
acrylate (100 mg, 0.34 mmol), DPE-Phos (22 mg, 0.04 mmol)
and p-toluidine (73 mg, 0.68 mmol) in anhydrous dioxane
(1.5 mL). Isolation via column chromatography (DCM) yielded the
azaindole (79 mg, 83%) as a off-white solid; mp 93–95 ꢀC. nmax
(film)/cmꢁ1 3041, 2981, 2925, 1722, 1594, 1567, 1475, 1427, 1377,
1319, 1250, 1206, 1185, 1114, 1041, 1025, 983; dH (400 MHz, CDCl3)
1.26 (3H, t, J¼8), 2.45 (3H, s), 4.26 (2H, q, J¼8), 7.17 (1H, dd, J¼4),
7.26–7.29 (2H), 7.33–7.36 (2H, m), 7.39 (1H, s), 8.06 (1H, dd, J¼6 and
2), 8.47 (1H, dd, J¼6 and 2); dC (125 MHz, CDCl3) 14.1, 21.3, 60.8,
109.0, 117.5, 118.7, 127.9 (2C), 129.4, 129.6 (2C), 130.8, 134.6, 138.1,
147.5, 150.5, 161.0; LRMS (CIþ) 281.1 ([MþH]þ, 100%), 252.1 (21);
HRMS (CIþ): 281.1291 ([MþH]þ C17H17N2O2 requires: 281.1290).
(
35Clꢁ81Brꢁ[MþH]þ, 100%), 231.9 (85), 235.9 (21); HRMS (CIþ):
230.9458, ([M]þ C8H779Br35ClN requires:230.9450). Anal. Calcd for
C8H7BrClN: C, 41.33; H, 3.03; N, 6.02. Found: C, 41.40; H, 2.90; N, 5.99.
4.33. 2-(4-Methoxyphenyl)-1-p-tolyl-7-azaindole
4.29. Methyl 1-p-tolyl-7-azaindole-6-carboxylate
(Table 4, entry 13)
(Table 4, entry 1)
Prepared using (Z)-3-(2-bromo-2-(4-methoxy phenyl)vinyl)-2-
Prepared using (Z)-methyl-5-(2-bromovinyl)-6-chloropicolinate
(100 mg, 0.36 mmol), X-Phos 8 (19 mg, 0.04) and p-toluidine
(77 mg, 0.72 mmol). Isolation via column chromatography (DCM)
yielded the azaindole (47 mg, 61%) as a yellow oil. nmax (film)/cmꢁ1
3036, 2950, 2922, 1716, 1612, 1590, 1425, 1374, 1310, 1288, 1242,
1192, 1121, 1021, 1002, 958, 913; dH (400 MHz, CDCl3) 2.43 (3H, s),
3.99 (3H, s), 6.70 (1H, d, J¼4), 7.34 (2H, d, J¼8), 7.72 (1H, d, J¼4), 7.71
(2H, d, J¼8), 8.03 (1H, d, J¼8), 8.07 (1H, d, J¼8); dC (100 MHz, CDCl3)
21.1, 52.6, 101.6, 118.1, 123.5, 124.4, 128.5, 128.6, 130.0, 131.5, 132.1,
135.6, 136.3, 141.3, 146.6, 166.8; LRMS (CIþ) 267.1 ([MþH]þ, 100%),
268.1 (14); HRMS (CIþ): 267.1142 ([MþH]þ C16H15N2O2 requires:
267.1134).
chloropyridine (70 mg, 0.22 mmol), X-Phos
8
(14 mg,
0.03 mmol) and p-toluidine (46 mg, 0.43 mmol). Isolation via
column chromatography (DCM) yielded the azaindole (49 mg,
71%) as a yellow solid; Mp 117–119 ꢀC. nmax (film)/cmꢁ1 3039, 2957,
2835, 1610, 1592, 1568, 1514, 1499, 1440, 1370, 1315, 1299, 1249,
1110, 1030, 918; dH (400 MHz, acetone-d6) 2.38 (3H, s), 3.79 (3H, s),
6.72 (1H, s), 6.86–6.90 (2H, m), 7.15 (1H, dd, J¼8 and 4), 7.19–7.30
(6H, m), 7.99 (1H, dd, J¼6 and 4), 8.19 (1H, dd, J¼6 and 4); dC
(100 MHz, acetone-d6) 20.7, 55.1, 100.7, 114.2 (2C), 117.4, 121.3,
125.0, 128.2, 128.8 (2C), 129.6 (2C), 130.6 (2C), 135.3, 137.1, 141.5,
143.2, 150.2, 158.0; LRMS (ESþ) 315.2 ([MþH]þ, 100%), 316.2 (17);
HRMS (ESIþ): 315.1485 ([MþH]þ C21H19N2O requires: 315.1497).

8948
R.C. Hodgkinson et al. / Tetrahedron 65 (2009) 8940–8949
4.34. 2-(4-Chlorophenyl)-1-p-tolyl-7-azaindole
4.38. (E)-3-Bromo-2-(2-bromovinyl)pyridine, 16
(Table 4, entry 15)
Prepared using (bromomethyl)triphenylphosphonium bromide
(5.63 g, 0.13 mol) and 3-bromo-2-formyl pyridine (2.00 g,
0.11 mol). Theproduct was purifiedby flashchromatography (DCM)
to yield the vinyl bromide as a single isomer (2.36 g, 83%) as a yellow
oil. nmax (film)/cmꢁ1 3081, 3048, 1602, 1566, 1435, 1414, 1224, 1198,
1122, 1067, 1046, 1016, 934; dH (400 MHz, CDCl3) 7.08 (1H, dd, J¼8
and 4), 7.57 (1H, d, J¼16), 7.61 (1H, d, J¼16), 7.48 (1H, dd, J¼6 and 2),
8.47 (1H, dd, J¼6 and 2); dC (100 MHz, CDCl3) 116.6, 119.6, 123.8,
133.8, 140.8, 148.1, 152.0; LRMS (FIþ) 262.9 (79Brꢁ81BrꢁMþ, 100%),
260.9 (49), 264.9 (46); HRMS (FIþ): 260.8784 ([M]þ C7H5N79Br2 re-
quires 260.8789).
Prepared using (Z)-3-(2-bromo-2-(4-chlorophenyl)vinyl)-2-
chloropyridine (100 mg, 0.30 mmol), S-Phos
7
(16 mg,
0.04 mmol) and p-toluidine (64 mg, 0.60 mmol). Isolation via
column chromatography (DCM) yielded the azaindole (91 mg, 95%)
as a yellow oil. nmax (film)/cmꢁ1 3029, 2922, 2857, 1596, 1517, 1490,
1457, 1416, 1399, 1337, 1312, 1246, 1179, 1091, 1013, 961, 908; dH
(500 MHz, acetone-d6) 2.30 (3H, s), 6.82 (1H, dd, J¼10 and 5), 7.13
(2H, d, J¼10), 7.49–7.51 (2H, m), 7.66–7.70 (4H, m), 7.79 (1H, dd, J¼7
and 2), 7.83 (1H, br s), 8.20 (1H, dd, J¼7 and 2); dC (125 MHz, ace-
tone-d6) 20.8, 86.0, 96.1, 104.9, 114.8, 121.0, 121.2, 122.4, 129.7 (2C),
129.8 (2C), 132.2, 134.0, 134.3, 135.2, 139.0, 141.2, 148.6, 156.6; LRMS
(ESþ) 319.1 ([MþH]þ, 100%), 320.1 (10); HRMS (FIþ): 319.0990
([MꢁH]þ C20H1635ClN2 requires: 319.1002).
4.39. tert-Butyl-4-azaindole-1-carboxylate, 17
Prepared using 3-bromo-2-(2-bromovinyl)pyridine 16 (100 mg,
0.38 mmol), DPE-Phos 12 (27 mg, 0.05 mmol) and tert-butyl
carbamate (87 mg, 0.76) in anhydrous dioxane (1.5 mL). Isolation
via column chromatography (DCM) yielded the 4-azaindole 17
(44 mg, 53%) as a yellow oil. nmax (film)/cmꢁ1 2979, 1736, 1597,
1567, 1530, 1477, 1410, 1370, 1352, 1317, 1253, 1156, 1129, 1076, 1021,
850, 782, 737; dH (500 MHz, CDCl3) 1.71 (9H, s), 6.82 (1H, d, J¼4),
7.26 (1H, dd, J¼4 and 5), 7.86 (1H, d, J¼4), 8.41 (1H, d, J¼6) 8.53 (1H,
d, J¼6); dC (125 MHz, CDCl3) 28.2 (3C), 85.3, 108.9, 119.1, 122.4,
129.1, 129.3, 146.3, 146.5, 170.9; LRMS (ESþ) 219.1 ([MþH]þ, 100%),
220.1 (10); HRMS (ESIþ): 219.1124 ([MþH]þ C12H15N2O2 requires:
219.1134).
4.35. 1-p-Tolyl-3-methyl-7-azaindole (Table 4, entry 19)
Prepared using 1-(2-bromopyridin-3-yl)ethanone (100 mg,
0.43), DPE-Phos 12 (16 mg, 0.03 mmol), potassium tert-butoxide
(107 mg, 0.95 mmol) and p-toluidine (92 mg, 0.86 mmol).
Isolation via column chromatography (DCM) yielded the azaindole
(70 mg, 73%) as a yellow oil. nmax (film)/cmꢁ1 2918, 1602, 1548,
1429, 1361, 1335, 1285, 1268, 1232, 1260, 1125, 1070, 1037, 818; dH
(400 MHz, acetone-d6) 2.37 (3H, d, J¼1), 2.39 (3H, s), 7.16 (1H, dd,
J¼8 and 4), 7.32–7.34 (2H, m), 7.58 (1H, s), 7.79–7.83 (2H, m), 8.00
(1H, dd, J¼6 and 2), 8.31 (1H, dd, J¼6 and 2); dC (100 MHz, ac-
etone-d6) 9.2, 20.4, 111.0, 116.4 (2C), 122.6, 123.2 (2C), 125.5, 127.3,
129.9, 135.2, 136.9, 143.4, 148.0; LRMS (ESþ) 223.2 ([MþH]þ,
100%), 224.1 (11); HRMS (ESIþ): 223.1230 ([MþH]þ C15H15N2 re-
quires: 223.1235).
Acknowledgements
This work was supported by the EPSRC and Schering Plough.
References and notes
4.36. (Z)-Ethyl-2-bromo-3-(3-bromopyridin-4-yl)acrylate, 14
1. For recent examples of medicinal applications of azaindoles, see: (a) Schirok, H.;
Kast, R.; Figueroa-Pørez, S.; Bennabi, S.; Gnoth, M. J.; Feurer, A.; Heckroth, H.;
Thutewohl, M.; Paulsen, H.; Knorr, A.; Hu¨ tter, J.; Lobell, M.; Mu¨ nter, M.; Geiß, V.;
Ehmke, H.; Lang, D.; Radtke, M.; Mittendorf, J.; Stasch, J.-P. J. ChemMedChem
2008, 3, 1893; (b) Xia, M.; Hou, C.; DeMong, D.; Pollack, S.; Pan, M.; Singer, M.;
Matheis, M.; Murray, W.; Cavender, D.; Wachter, M. Bioorg. Med. Chem. Lett.
2008, 18, 6468; (c) Leblanc, Y.; Roy, P.; Dufresne, C.; Lachance, N.; Wang, Z.;
O’Neill, G.; Greig, G.; Denis, D.; Mathieu, M.-C.; Slipetz, D.; Sawyer, N.; Tsou, N.
Bioorg. Med. Chem. Lett. 2009, 19, 2125; (d) Lu, R. J.; Tucker, J. A.; Pickens, J.;
Ma, Y.-A.; Zinevitch, T.; Kirichenko, O.; Konoplev, V.; Kuznetsova, S.; Svir-
idov, S.; Brahmachary, E.; Khasanov, A.; Mikel, C.; Yang, Y.; Liu, C.; Wang,
J.; Freel, S.; Fisher, S.; Sullivan, A.; Zhou, J.; Stanfield-Oakley, S.; Baker, B.;
Sailstad, J.; Greenberg, M.; Bolognesi, D.; Bray, B.; Koszalka, B.; Jeffs, P.;
Jeffries, C.; Chucholowski, A.; Sexton, C. J. Med. Chem. 2009, 52, 4481;
(e) Porter, J.; Lumb, S.; Franklin, R. J.; Gascon-Simorte, J. M.; Calmiano, M.;
Le Riche, K.; Lallemand, B.; Keyaerts, J.; Edwards, H.; Maloney, A.; Delgado,
J.; King, L.; Foley, A.; Lecomte, F.; Reuberson, J.; Meier, C.; Batchelor, M.
Bioorg. Med. Chem. Lett. 2009, 19, 2780.
A solution of sodium hydride (60% dispersion in mineral oil,
259 mg, 0.07 mol) in THF (30 mL) was added to ethyl 2-bromo-
2-(diethoxyphosphoryl)acetate (3.27 g, 0.11 mol) at room tem-
perature. This solution was stirred for 1 h at room temperature,
and then 3-bromonicotinaldehdye (1.00 g, 0.05 mol) was added
and the reaction mixture heated to 50 ꢀC and stirred for 12 h. The
reaction mixture was cooled to room temperature, water (20 mL)
was added, extracted with DCM (3ꢂ50 mL), dried over MgSO4 and
concentrated in vacuo. Crude material was purified by column
chromatography (DCM) to produce the ester (1.26 g, 62%) as
a white solid. The compound was used immediately, due to de-
composition. Characterisation not possible.
2. For reviews on azaindole synthesis, see: (a) Popowycz, F.; Me´rour, J.-Y.; Joseph,
B. Tetrahedron 2007, 63, 8689; (b) Popowycz, F.; Routier, S.; Joseph, B.; Me´rour,
J.-Y. Tetrahedron 2007, 63, 1031.
4.37. Ethyl 1-p-tolyl-6-azaindole-2-carboxylate, 15
3. (a) Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395; (b) Li, J. J.; Gribble, G.
W. Palladium in Heterocyclic Chemistry, 2nd ed.; Pergamon: Oxford, 2007;
(c) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127.
4. Song, J. J.; Reeves, J. T.; Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake. Chem. Soc. Rev.
2007, 36, 1120.
5. Selected examples of recent, alternative, syntheses of azaindoles: (a) Ma, Y.;
Breslin, S.; Keresztes, I.; Lobkovsky, E.; Collum, D. B. J. Org. Chem. 2008, 73, 9610;
(b) Jeanty, M.; Suzenet, F.; Guillaumet, G. J. Org. Chem. 2008, 73, 7390; (c) Wipf,
P.; Maciejewski, J. P. Org. Lett. 2008, 10, 4383; (d) Schirok, H. J. Org. Chem. 2006,
71, 5538; (e) Zheng, X.; Kerr, M. A. Org. Lett. 2006, 8, 3777.
6. Selected recent examples: (a) Ackermann, L.; Barfu¨ßerPotukuchi, H. Adv. Synth.
Catal. 2009, 351, 1064; (b) Suzuki, Y.; Ohta, Y.; Oishi, S.; Fujii, N.; Ohno, H. J. Org.
Chem. 2009, 74, 4246; (c) Koolman, H.; Heinrich, T.; Bo¨ttcher, H.; Rautenberg,
W.; Reggelin, M. Biorg. Med. Chem. Lett. 2009, 19, 1879; (d) Layek, M.; Gajare, V.;
Kalita, D.; Islam, A.; Mukkanti, K.; Pal, M. Tetrahedron 2009, 65, 4814; Also see
Ref. 4.
Prepared using (Z)-ethyl-2-bromo-3-(2-chloropyridin-4-yl)
acrylate 14 (100 mg, 0.30 mmol), DPE-Phos 12 (11 mg,
0.02 mmol) and p-toluidine (64 mg, 0.60 mmol) in anhydrous
dioxane (1.5 mL). Isolation via column chromatography (DCM)
yielded the azaindole (84 mg, 88%) as a yellow oil. nmax (film)/cmꢁ1
2982, 1726, 1557, 1515, 1441, 1403, 1334, 1262, 1220, 1185, 1117, 1025,
833; dH (400 MHz, acetone-d6) 1.20 (3H, t, J¼6), 2.47 (3H, s), 4.22
(2H, q, J¼8), 7.33–7.35 (2H, m), 7.39–7.41 (2H, m), 7.42 (1H, s), 7.69
(1H, d, J¼8), 8.30 (1H, d, J¼8), 8.49 (1H, s); dC (125 MHz, CDCl3) 13.8,
20.8, 61.1,109.6,116.3,127.9 (2C),130.1 (2C),130.8,132.1,132.5,135.5,
135.8, 138.8140.1, 160.6; LRMS (ESþ) 281.1 ([MþH]þ, 100%), 282.2
(17); HRMS (ESIþ): 281.1287 ([MþH]þ C17H17N2O2 requires:
281.1290).
7. For example: (a) Xu, Z.; Hu, W.; Zhang, F.; Li, Q.; Lu¨ , Z.; Zhang, L.; Jia, Y. Synthesis
2008, 3981; (b) Lachance, N.; April, M.; Joly, M.-A. Synthesis 2005, 2571.

R.C. Hodgkinson et al. / Tetrahedron 65 (2009) 8940–8949
8949
8. For example: Kumar, V.; Dority, J. A.; Bacon, E. R.; Singh, B.; Lesher, G. Y. J. Org.
Chem. 1992, 57, 6995.
9. For example: Martin, R.; Rivero, M. R.; Buchwald, S. L. Angew. Chem., Int. Ed.
2006, 45, 7079.
14. Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.
15. Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.;
Goubitz, K.; Fraanje, J. Organometallics 1995, 14, 3081.
16. Abbas, S.; Hayes, C. J.; Worden, S. Tetrahedron Lett. 2000, 41, 3215.
17. Gangadasu, B.; Narender, P.; Kumar, S. B.; Ravinder, M.; Rao, B. A.; Ramesh, C.;
Raju, B. C.; Rao, R. J. Tetrahedron 2006, 62, 8398.
18. Aoki, K.; Obata, Y.; Yamazaki, Y.; Mori, Y.; Hirokawa, H.; Koseki, J.-I.; Hattori, T.;
Niitsu, K.;Takeda, S.;Aburada, M.;Miyamoto, K.-I. Chem. Pharm. Bull. 2007, 55, 255.
19. Mahadevan, I.; Rasmussen, M. Tetrahedron 1993, 49, 7337.
20. Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippin, L. A.; Repke, D. B.; Souchet,
M. Synthesis 1991, 10, 871.
21. McKenna, C. E.; Khawli, L. A. J. Org. Chem. 1986, 51, 5467.
22. Romero, D. L.; Morge, R. A.; Biles, C.; Berrios-Pena, N.; May, P. D.; Palmer, J. R.;
Johnson, P. D.; Smith, H. W.; Busso, M.; Tan, C.-K.; Voorman, R. L.; Reusser, F.;
Althaus, I. W.; Downey, K. M.; So, A. G.; Resnick, L.; Tarpley, W. G.; Aristoff, P. A.
J. Med. Chem. 1994, 37, 999.
10. Fang, Y.-Q.; Yuen, J.; Lautens, M. J. Org. Chem. 2007, 72, 5152.
11. (a) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem., Int. Ed. 2005, 44,
403; (b) Willis, M. C.; Brace, G. N.; Findlay, T. J. K.; Holmes, I. P. Adv. Synth.
Catal. 2006, 348, 851; (c) Fletcher, A. J.; Bax, M. N.; Willis, M. C. Chem.
Commun. 2007, 4764; (d) Hodgkinson, R. C.; Schulz, J.; Willis, M. C. Org. Bi-
omol. Chem. 2009, 7, 432.
12. For application of the same substrate class to benzofuran and quinolone syn-
thesis, see: (a) Tadd, A. C.; Fielding, M. R.; Willis, M. C. Tetrahedron Lett. 2007, 48,
7578; (b) Tadd, A. C.; Fielding, M. R.; Willis, M. C. Org. Lett. 2009, 11, 583.
13. Our initial report (Ref. 11a) on indole synthesis included a single example in
which
a pyridyl bromide/alkenyl triflate substrate was converted into
a 7-azaindole.