DOI: 10.1021/jo902143f Published on Web 12/01/2009 J. Org. Chem.

2010, 75, 1115 11

r
2009 American Chemical Society
pubs.acs.org/joc
Two-Step Synthesis of Aza- and Diazaindoles from Chloroamino-
N-heterocycles Using Ethoxyvinylborolane
Daniel K. Whelligan, Douglas W. Thomson, Dawn Taylor, and Swen Hoelder*
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow
Laboratories, 15 Cotswold Road, Sutton, Surrey SM2 5NG, U.K.
swen.hoelder@icr.ac.uk
Received October 7, 2009
An efficient two-step route to a broad range of aza- and diazaindoles was established, starting from
chloroamino-N-heterocycles, without the need for protecting groups. The method involves an
optimized Suzuki-Miyaura coupling with (2-ethoxyvinyl)borolane followed by acetic acid-cata-
lyzed cyclization.
Introduction
Azaindoles form the core of many biologically active
compounds, such as kinase inhibitors, and are therefore
often employed in drug discovery programs.
1,2
The synthesis
of the azaindole scaffold can prove challenging, and several
of the classical indole formation methods, such as the Fischer
indole synthesis, give poor results or require the use of
protecting groups.
3
We wished to develop a robust method
of synthesizing a variety of aza- and diazaindoles from
readily available, inexpensive starting materials, in particu-
lar, chloroarenes, such as 1 (Scheme 1), which would be
useful for preparing libraries for fragment-based approaches
to drug discovery.
4
We were particularly interested in access
to azaindoles without substitution in the 2-position since this
is often preferred in kinase drug discovery programs.
5
Sev-
eral literature methods start from haloaminopyridines and
install the 5-membered ring through a Pd-catalyzed C-C
coupling reaction (Sonogashira, Stille, Suzuki-Miyaura, or
Heck) and subsequent cyclization. However, few, if any,
such existing methods have been shown to be applicable
to the synthesis of all azaindole regioisomers, especially
5-azaindole.
3,6-9
Furthermore, most of the examples de-
scribed start from the corresponding bromides or iodides
or begin from the halonitroarene.
10,11
We wanted to use
(1) For selected recent examples of kinase inhibitors, see: (a) Dyke, H. J.;
Price, S.; Williams, K. Patent Application WO2008157179, 2008. (b) Graczyk,
P. P.; Dimopoulos, P.; Farthing, C. N.; Bhatia, G. S.; Khan, A. Patent Application
WO2008095943, 2008. (c) Graczyk, P. P.; Dimopoulos, P.; Khan, A.; Bhatia,
G. S.; Farthing, C. N. Patent Application WO2008095944, 2008. (d) Tsai, J.; Lee,
J. T.; Wang, W.; Zhang, J.; Cho, H.; Mamo, S.; Bremer, R.; Gillette, S.; Kong, J.;
Haass, N. K.; Sproesser, K.; Li, L.; Smalley, K. S. M.; Fong, D.; Zhu, Y.-L.;
Marimuthu, A.; Nguyen, H.; Lam, B.; Liu, J.; Cheung, I.; Rice, J.; Suzuki, Y.; Luu,
C.; Settachatgul, C.; Shellooe, R.; Cantwell, J.; Kim, S.-H.; Schlessinger, J.;
Zhang, K. Y. J.; West, B. L.; Powell, B.; Habets, G.; Zhang, C.; Ibrahim, P. N.;
Hirth, P.; Artis, D. R.; Herlyn, M.; Bollag, G. Proc. Natl. Acad. Sci. U.S.A. 2008,
105, 3041. (e) Lefoix, M.; Coudert, G.; Routier, S.; Pfeiffer, B.; Caignard, D.-H.;
Hickman, J.; Pierre, A.; Golsteyn, R. M.; Leonce, S.; Bossard, C.; Merour, J.-Y.
Bioorg. Med. Chem. 2008, 16, 5303. (f ) Echalier, A.; Bettayeb, K.; Ferandin, Y.;
Lozach, O.; Clelment, M.; Valette, A.; Liger, F.; Marquet, B.; Morris, J. C.;
Endicott, J. A.; Joseph, B.; Meijer, L. J. Med. Chem. 2008, 51, 737.
(2) For recent examples of nonkinase inhibitors, see: (a) Stoit, A.; Coolen,
H. K. A. C.; Van Der Neut, M. A. W.; Kruse, C. G. Patent Application WO
2008003736, 2008. (b) Lu, R.-J.; Tucker, J. A.; Zinevitch, T.; Kirichenko, O.;
Konoplev, V.; Kuznetsova, S.; Sviridov, S.; Pickens, J.; Tandel, S.; Brahmachary,
E.; Yang, Y.; Wang, J.; Freel, S.; Fisher, S.; Sullivan, A.; Zhou, J.; Stanfield-
Oakley, S.; Greenberg, M.; Bolognesi, D.; Bray, B.; Koszalka, B.; Jeffs, P.;
Khasanov, A.; Ma, Y.-A.; Jeffries, C.; Liu, C.; Proskurina, T.; Zhu, T.;
Chucholowski, A.; Li, R.; Sexton, C. J. Med. Chem. 2007, 50, 6535.
(3) For reviews on azaindoles, see: (a) Popowycz, F.; Routier, S.; Joseph,
B.; Merour, J.-Y. Tetrahedron 2007, 63, 1031. (b) Popowycz, F.; Merour,
J.-Y.; Joseph, B. Tetrahedron 2007, 63, 8689. (c) Song, J. J.; Reeves, J. T.;
Gallou, F.; Tan, Z.; Yee, N. K.; Senanayake, C. H. Chem. Soc. Rev. 2007, 36,
1120. (d) Merour, J.-Y.; Joseph, B. Curr. Org. Chem. 2001, 5, 471. (e) Le
Hyaric, M.; Vieira de Almeida, M.; Nora de Souza, M. V. Quim. Nova 2002,
25, 1165.
(4) Hajduk, P. J.; Greer, J. Nature Rev. Drug Discov. 2007, 6, 211.
(5) Numerous examples exist in the literature. In this one, substituents in
the 2-position decrease the activity of the azaindole inhibitor: Tang, J.;
Hamajima, T.; Nakano, M.; Sato, H.; Dickerson, S. H.; Lackey, K. E.
Bioorg. Med. Chem. Lett. 2008, 18, 4610.
(6) Xu, Z.; Hu, W.; Zhang, F.; Li, Q.; L u, Z.; Zhang, L.; Jia, Y. Synthesis
2008, 24, 3981.
(7) (a) Majumdar, K. C.; Mondal, S. Tetrahedron Lett. 2007, 48, 6951. (b)
Majumdar, K. C.; Samanta, S.; Chattopadhyay, B. Tetrahedron Lett. 2008,
49, 7213.
(8) Jeanty, M.; Suzenet, F.; Guillaumet, G. J. Org. Chem. 2008, 73, 7390.
(9) Schirock, H. J. Org. Chem. 2006, 71, 5538.
(10) Sun, L.-P.; Wang, J.-X. Synth. Commun. 2007, 37, 2187.
(11) Jensen, T.; Pedersen, H.; Bang-Andersen, B.; Madsen, R.; Jrgensen,
M. Angew. Chem., Int. Ed. 2008, 47, 888.
12 J. Org. Chem. Vol. 75, No. 1, 2010
JOCFeatured Article
Whelligan et al.
chloroarenes as they are often cheaper and more readily
commercially available thanbromo- or iodoarenes, although
they are generally known to be more difficult coupling
partners in Pd-catalyzed cross-coupling reactions.
12
Of all
the chloroaminopyridines available, 4-amino-3-chloropyri-
dine 1 (Scheme 1) was considered the most difficult regio-
isomer to couple in Pd-catalyzed reactions for two reasons:
(i) the chlorine atom on the ring is meta to the pyridine
nitrogen atom and thus is less activated and (ii) the position
of the amino group para to the pyridine nitrogen makes
the whole molecule rather basic (pK
a
=7.2) and strongly
coordinating.
13,14
To the best of our knowledge, use of this
unprotected substrate in a Pd-catalyzed coupling reaction
has never been reported.
Results and Discussion
Our initial attempts at this transformation included Sono-
gashira coupling of trimethylsilylacetylene (it was presumed
the TMS group could be removed from the 2-position at a
later stage) followed by base-mediated cyclization, described
by McLaughlin,
15
but this left the starting material 1 intact.
Also tested was the use of an ethoxyvinyltin reagent in a Stille
coupling (prior to acid-mediated cyclization)
16
but, with
substrate 1, this proceeded in only 7% LC yield. The low
yield and the toxic nature of the tin reagent prompted us to
use the respective borolane, a catechol version of which
has been described for the synthesis of 7-azaindoles from
2-amino-3-iodopyridine.
17,18
Borolane 5 is commercially available
19
or can be synthe-
sized in one step (Scheme 2) by Cp
2
ZrHCl-catalyzed hydro-
boration
20
of ethoxyethyne 4. Borolane 5 could be obtained
in 92% yield through use of an optimized purification
procedure involving filtration through a pad of neutral
alumina topped with a layer of Celite and elution with DCM.
Withthis reagent inhand, optimizationstudies onits Suzuki-
Miyaura coupling with 4-amino-3-chloropyridine 1 were carried
out (Table 1). Commonly used Suzuki-Miyaura conditions
failed (entry 1) or gave up to 5% product when forced at high
temperature under microwave conditions (entry 2). Buchwald
et al. have shown the use of a catalyst generated in situ from
2-dicyclohexylphosphino-2
0
,6
0
-dimethoxybiphenyl (SPhos) and
Pd(OAc)
2
to be particularly good for Suzuki-Miyaura-type
cross-couplings with aryl chlorides.
21
Unfortunately, with sub-
strate 1 in refluxing THF no product was formed (entry 3).
However, repetition at higher temperature in dioxane (entry 4)
did provide a very small amount of the product. The addition of
extra Pd(OAc)
2
/SPhos and/or borolane 5 did not push the
reaction any further. Reaction at an even higher temperature
using a sealed tube under microwave conditions gave the same
result (entry 5). Furthermore, neither increasing the catalyst
loadingto20mol %nor usingPd(dba)
2
as asource of Pd(0) gave
any significant increase in yield.
Alternative regioisomers 3-chloro-2-aminopyridine and
2-chloro-3-aminopyridine and the more reactive 4-amino-
3-bromopyridine also did not couple with borolane 5 beyond
3% yield under these conditions.
To eliminate the possibility that ethoxyvinylborolane 5
cannot couple or decomposes under these conditions, it was
tested in a reaction with 4-chloroaniline 7, previously shown
to couple efficiently with a range of borolanes.
21
This reac-
tion was successful, giving 52% product (entry 1, Table 2).
Conversely, 2,4-difluorophenylboronic acid reacted mini-
mally with 4-amino-3-chloropyridine 1. Since 2,4-difluoro-
phenylboronic acid has been shown to readily undergo
Suzuki-Miyaura couplings, it was thought that the amino-
pyridine compounds (starting material, an intermediate or
the small amount of product produced) were poisoning
the catalyst by complexing palladium.
13
This has been
noted previously in similar systems by Lautens
22
and was
SCHEME 1. Desired Synthetic Conversion
SCHEME 2. Synthesis of Ethoxyvinylborolane 5
TABLE 1. Development of Coupling Conditions
entry base solvent catalyst
temp
/C
yield
a
(%)
1 Na
2
CO
3
DME/H
2
O
(9:1)
Pd(PPh
3
)
4
85 0
2 Na
2
CO
3
DME/H
2
O
(7:3)
PdCl
2
(dppf)
b
140
c
<5
3 K
3
PO
4
THF Pd(OAc)
2
/SPhos 66 0
4 K
3
PO
4
dioxane Pd(OAc)
2
/SPhos 101 <5
5 K
3
PO
4
dioxane Pd(OAc)
2
/SPhos 130
c
<5
6 K
3
PO
4
or Cs
2
CO
3
dioxane Various - see text 101 0
7 K
3
PO
4
dioxane Pd(OAc)
2
/D-t-BPF
b
101 <5
8 K
3
PO
4
MeCN Pd(OAc)
2
/SPhos 81 34
d
9 K
3
PO
4
MeCN/H
2
O
(3:2)
Pd(OAc)
2
/SPhos 75 31
a
After stirring overnight (unless stated otherwise), LC yield refer-
enced to anthracene internal standard.
b
3 mol % of ligand.
c
Microwave
for 10 min (entry 2) or 1 h (entry 5).
d
After 72 h.
(12) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(13) Itoh, T.; Mase, T. Tetrahedron Lett. 2005, 46, 3573.
(14) Rasala, D. Bull. Soc. Chim. Fr. 1992, 5, 509.
(15) McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8, 3307.
(16) (a) Sakamoto, T.; Satoh, C.; Kondo, Y.; Yamanaka, H. Heterocycles
1992, 34, 2379 and references cited therein. (b) Cheung, M.; Harris, P. A.; Lackey,
K. E. Tetrahedron Lett. 2001, 42, 999. (c) Hong, J.; Gray, N. S.; Schultz, P. Patent
Application WO2005/107760, 2005. (d) Moriarty, K. J.; Koblish, H. K.; Garrabrant,
T.; Maisuria, J.; Khalil, E.; Ali, F.; Petrounia, I. P.; Crysler, C. S.; Maroney, A. C.;
Johnson, D. L.; Galemmo, R. A., Jr. Bioorg. Med. Chem. Lett. 2006, 16, 5778.
(e) Choi, H.-S.; Wang, Z.; Richmond, W.; He, X.; Yang, K.; Jiang, T.; Sim, T.;
Karanewsky, D.; Gu, X-j.; Zhou, V.; Liu, Y.; Ohmori, O.; Caldwell, J.; Gray, N.; He,
Y. Bioorg. Med. Chem. Lett. 2006, 16, 2173.
(17) Satoh, M.; Miyaura, N.; Suzuki, A. Synthesis 1987, 373.
(18) Kumar, V.; Dority, J. A.; Bacon, E. R.; Singh, B.; Lesher, G. Y.
J. Org. Chem. 1992, 57, 6995.
(19) (Z-isomer): Apollo Scientific Ltd. (http://www.apolloscientific.co.
uk) and Synthonix Corporation (http://www.synthonix.com).
(20) Hoffmann, R. W.; Kr uger, J.; Br uckner, D. New. J. Chem. 2001, 25,
102.
(21) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685.
(22) Fang, Y.-Q.; Yuen, J.; Lautens, M. J. Org. Chem. 2007, 72, 5152.
J. Org. Chem. Vol. 75, No. 1, 2010 13
Whelligan et al.
JOCFeatured Article
supported by further experiments shown in Table 2: addition
of 1 equiv of 4-amino-3-chloropyridine 1 to the normally
successful reaction with chloroaniline 7 effectively halted the
reaction (entry 2). Furthermore, only 6 mol % of 1 reduced
the yield from 52% to 35%. The similarly basic ethoxyviny-
laminopyridine product 6 also inhibited the reaction, though
to a slightly lesser degree (entries 3 and 4).
We hypothesized that an alternative ligand might prevent
complexationof palladiumbythe aminopyridines soascreening
of several ligands was performed. However, under the same
conditions, Pd(PPh
3
)
4
, PdCl
2
(dppf), Pd(OAc)
2
/(adamantyl)
2
-
BuP,
23
Pd(OAc)
2
/XPhos
24
and Pd(OAc)
2
/2-(dimethylamino)-
2
0
-dicyclohexylphosphinobiphenyl
25
in combination with either
K
3
PO
4
or Cs
2
CO
3
as base (entry 6, Table 1) gave no detectable
product by LC. Itohhas shownthat, under the same conditions,
bis(di-tert-butylphosphino)ferrocene (D-t-BPF) is a particu-
larly good ligand for the Suzuki-Miyaura coupling of NH
2
-
substituted heterocycles.
13
Again, with our substrate, only a
trace amount of product was formed (entry 7, Table 1). Further
research with SPhos showed that the use of toluene at reflux
resulted in no reaction but DMA at 120 C promoted a fast
reaction which stopped at 10% product after 30 min. A
significant improvement was achieved with MeCN which gave
a yield of 34% but only after 72 h at reflux (entry 8, Table 1).
Finally, use of a 3:2 mixture of MeCN/H
2
O, as used by
Buchwald et al., gave 31% yield overnight (entry 9, Table 1).
26
Further optimization, shown in Table 3, revealed that
K
3
PO
4
was the most effective base of those tested (entries
1-4), a ligand to Pd ratio (P:Pd) of 2.5:1 was best (entries
4-6) and the use of 2.0 equiv of borolane 5 was optimum
(entries 7-9). SPhos/Pd(OAc)
2
is still the catalyst of choice
in this solvent mixture as tests with Pd(PPh
3
)
4
, PdCl
2
(dppf ),
and Pd(OAc)
2
/D-t-BPF gave no product or 5%(LCyield)
with the latter.
Upon finding successful coupling conditions (entry 8, Ta-
ble 3, hereafter named method A), the scope of the reaction
was assessed with a range of substrates (Table 4) including all
pyridine regioisomers. All substrates reacted in good to high
yields except for 2,4-dichloro-5-aminopyrimidine (entry 10)
and 2-chloroaniline (entry 12) which produced a range of
unidentified decomposition products. Of the pyridines, the
4-amino-3-halopyridines gave the lowest yields (entries 2 and
5) which is attributed to their strong Lewis basicity and the
unreactive position of the halide, as described above.
The Suzuki-Miyaura products 10 were all successfully
cyclized to the desired azaindoles 11 in good to excellent
yields using acetic acid.
It was thought that the change in solvent systemto include
water might allowthe reaction to work because of the in situ
generation of KOH. Accordingly, NaOH was the base used
by Suzuki to couple ethoxyvinylboranes with iodoanilines.
17
We tested this hypothesis in three experiments on substrate 1
(entry 2, Table 4) by using KOH in MeCN (method B),
dioxane (method C), and the MeCN/H
2
O mixture (method
D). The reaction proceeded to an extent in all solvents, but
MeCN gave the highest yield thus far with substrate 1. The
yield could be further increased to 69% by doubling the
amount of catalyst. Interestingly, use of KOHin the MeCN/
H
2
O mixture gave a low yield of product. One possible
explanation for these results is a requirement for a constantly
small concentration of KOH which might arise through
partial solubility (in MeCN or dioxane) or by existing in
equilibrium with K
3
PO
4
and water.
Interestingly, use of KOH in MeCN (method B) with the
more sensitive substrates 4-chloro-3-aminopyridine (entry 3),
3-bromo-4-aminopyridine (entry 5), and dichloroaminopyri-
midine (entry 10) gave considerably lower yields, the latter
giving a complex mixture of products. On the other hand, the
yield of product formed fromchloroaniline using these condi-
tions was quantitative (method B, entry 12), a dramatic
increase from that using the original conditions of method A.
Although the 3-position of azaindoles can be substituted
readily by well-known halogenation and cross-coupling,
27
it
was still of interest to see if this substitution could be
achieved using 1-substituted borolanes. Thus, n-butyl-sub-
stituted borolane 13 was synthesized as shown in Scheme 3.
28
TABLE 2. Catalyst Poisoning Tests
entry additive mol % yield
a
(%)
1 none 52
2 1 100 trace (96% SM)
3 1 6 35
4 6 100 9 (52% SM)
5 6 6 44
a
Yield of isolated product.
TABLE 3. Optimization of the Coupling Conditions
entry base borolane 5 (equiv) ratio P:Pd yield
a
(%)
1 K
3
PO
4
1.2 2.5 31
2 Na
2
CO
3
1.2 2.5 24
3 K
2
CO
3
1.2 2.5 26
4 Cs
2
CO
3
1.2 2.5 31
5 K
3
PO
4
1.2 2.0 24
6 K
3
PO
4
1.2 3.0 28
7 K
3
PO
4
1.5 2.5 40
8 K
3
PO
4
2.0 2.5 45 (44)
9 K
3
PO
4
2.5 2.5 39
a
After stirring overnight, LC yield referenced to anthracene internal
standard. Yield of isolated product in parentheses.
(23) Pews-Davtyan, A.; Tillack, A.; Ortinau, S.; Rolfs, A.; Beller, M. Org.
Biomol. Chem. 2008, 6, 992.
(24) Billingsley, K.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 3358.
(25) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722.
(26) Billingsley, K. L.; Anderson, K. W.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 3484.
(27) (a) Gallou, F.; Reeves, J. T.; Tan, Z.; Song, J. J.; Yee, N. K.;
Harcken, C.; Liu, P.; Thomson, D.; Senanayake, C. H. Synlett 2007, 2,
211. (b) Sakamoto, T.; Kondo, Y.; Sato, S.; Yamanaka, H. J. Chem. Soc.,
Perkin Trans. 1 1996, 5, 459. (c) Kelly, T. A.; McNeil, D. W.; Rose, J. M.;
David, E.; Shih, C.-K.; Grob, P. M. J. Med. Chem. 1997, 40, 2430.
(28) Acetylene 12 was synthesized according to Pons, J.-M.; Kocieski, P.
Tetrahedron Lett. 1989, 30, 1833, but DMPUwas substituted for highly toxic
HMPA.
14 J. Org. Chem. Vol. 75, No. 1, 2010
JOCFeatured Article
Whelligan et al.
Unfortunately, using method B, this compound did not
couple at all with 4-amino-3-chloropyridine 1, leaving only
starting material. To check that borolane 13 was indeed
active, it was coupled with the simpler and more reactive
iodoaniline 14. This reaction went in 74% yield (and the
product was readily cyclized to the 3-substituted indole 16).
These results might indicate that the 1-substituted borolane,
though functional, requires more reactive iodo-Pd-Ar inter-
mediates to overcome its own steric hindrance-mediated lack
of reactivity.
Conclusion
A two-step procedure has been established that yields an
unprecedented range of aza- and diazaindole isomers from
chloro- or bromoamino-N-heterocycles, including all pyri-
dine regioisomers, without the need of protecting groups.
The first step, a Suzuki-Miyaura coupling with an etho-
xyvinylborolane, has been fully investigated to find the
optimum conditions which involve using 3 mol % of
SPhos/Pd(OAc)
2
(2.5:1) as catalyst in refluxing MeCN/
H
2
O (3:2) with K
3
PO
4
as base or, when more forcing
conditions are required, in refluxing MeCN with KOH as
base. The second step, acetic acid-catalyzed cyclization to
form the azaindole, takes place readily to afford the azain-
doles in high yields. As intended, this route does not intro-
duce a substituent in the 2-position.
Experimental Section
(E)-2-(2-Ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lane (5). Ethoxyethyne (40% w/w solution in hexane, 6.25 mL,
35.7 mmol) was dissolved in DCM(60 mL) under N
2
and cooled to
0 C. To this was added 4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(5.69 mL, 39.2 mmol) followed by the catalyst bis(cyclopenta-
dienyl)zirconium(IV) chloride hydride (0.55 g, 2.1 mmol). The
reaction mixture was warmed to rt and stirred overnight. It was
thenfilteredthrougha padof neutral alumina toppedwitha layer of
Celite and eluted with DCM. Fractions containing product (TLC)
were combined, evaporated, and dried in vacuo to give the title
compoundas a pale orange oil (6.5 g, 92%): R
f
=0.32 (hexane/Et
2
O
9:1);
1
H NMR (500 MHz, CDCl
3
) 7.03 (1H, d, J=14.5 Hz), 4.42
(1H, d, J=14.5Hz), 3.83(2H, q, J=7.2 Hz), 1.28 (3H, t, J=7.2Hz),
1.25 (12H, s);
13
C NMR (125 MHz, CDCl
3
) 163.0, 86.9 (very
broad), 82.6, 64.3, 24.6, 14.4.
General Procedure for the Suzuki-Miyaura Coupling Reac-
tion (Table 4). The appropriate starting aminoheterocycle
(0.23-0.78 mmol), base (2 equiv, for type see Table 4), and
2-(2-ethoxyvinyl)pinacolatoborolane (2 equiv) were added to a
carousel tube and put under nitrogenusing the vacuum/nitrogen
line. The solvent (volume to make a 0.1 Msolution of substrate,
for type see Table 4) was added, and the solution was briefly
degassed by applying vacuum until boiling occurred and then
flushed with nitrogen (3). Palladium(II) acetate (3 mol %) and
SPhos (7.5 mol %) were added, and the mixture was further
degassed as described above. This mixture was then heated at
reflux overnight after which time the reaction was worked up by
TABLE 4. Coupling of Various Substrates Followed by Cyclization
a
Solvent volume to make a 0.1 M solution of substrate.
b
Method A:
K
3
PO
4
, MeCN/H
2
O(3:2). Method B: KOH, MeCN. Method C: KOH,
dioxane. MethodD: KOH, MeCN/H
2
O(3:2)
c
Yield of isolated product.
d
6 mol % of Pd(OAc)
2
, 15 mol % of SPhos.
SCHEME 3. Synthesis and Reaction of Bu-Substituted
Borolane 13
J. Org. Chem. Vol. 75, No. 1, 2010 15
Whelligan et al.
JOCFeatured Article
the addition of water (8-27 mL) and extraction with DCM(3
8-27 mL). The combined organic layers were dried over
MgSO
4
, filtered, concentrated, and purified as stated in the
Supporting Information.
(E)-3-(2-Ethoxyvinyl)pyridin-4-amine (6). The crude material
was purified by silica column chromatography (1 M NH
3
in
MeOH solution) in DCM 0-10%to give the title compound as
a cream solid: mp=75-77 C; R
f
=0.27 (DCM/1 M NH
3
in
MeOH solution 9:1); IR (NaCl) 3482, 3405, 3054, 2985, 1656,
1641, 1617 cm
-1
;
1
HNMR(500 MHz, CDCl
3
) 8.15 (1H, s), 8.10
(1H, d, J=5.5 Hz), 6.76 (1H, d, J=12.7 Hz), 6.51 (1H, d, J=5.5
Hz), 5.62 (1H, d, J=12.7 Hz), 4.17 (2H, br s), 3.93 (2H, q, J=7.0
Hz), 1.36 (3H, t, J=7.0 Hz);
13
CNMR(125 MHz, CDCl
3
) 150.1,
149.9, 148.1, 147.9, 117.7, 109.3, 97.7, 66.4, 14.8; MS (ESI) m/z
165 ([M H]

, 100); HRMS (ESI) found [M H]

165.1024,
C
9
H
12
N
2
O requires [M H]

165.1022.
General Procedure for the Cyclization Reaction (Table 4). The
appropriate starting ethoxyvinyl compound 10 was dissolved in
acetic acid to make a 0.1 M solution under N
2
. This was heated
at reflux for 4 h. The solvent was then evaporated and residual
AcOH removed by azeotropic evaporation with toluene. The
crude material was purified as stated below.
1H-Pyrrolo[3,2-c]pyridine (2) (Table 4, Entry 2). The crude
material was purified by silica column chromatography MeOH
in DCM 0-15% to give the title compound as a cream solid:
mp =104-105 C (lit.
1
mp 110-111 C); R
f
=0.17 (DCM/
MeOH9:1); IR(NaCl) 3472, 3018, 1615, 1578 cm
-1
;
1
HNMR
(500 MHz, CDCl
3
) 9.86 (1H, br s), 8.98 (1H, d, J=0.8 Hz),
8.30(1H, d, J=5.8 Hz), 7.37 (1H, d, J=5.8 Hz), 7.32 (1H, d, J=
3.2 Hz), 6.68 (1H, dd, J=3.2, 0.8 Hz);
13
C NMR (125 MHz,
CDCl
3
) 143.1, 140.0, 139.9, 125.9, 125.0, 116.8, 112.8; MS (ESI)
m/z 119 ([M H]

, 100); HRMS (ESI) found [M H]

119.0610, C
7
H
6
N
2
requires [M H]

119.0604.
1
H NMR data
agrees with that given in the literature.
16a
Acknowledgment. We acknowledge NHS funding to
the NIHR Biomedical Research Centre and funding from
Cancer Research UK program Grant No. C309/A8274. We
also thank Dr. Amin Mirza, Mr. Meirion Richards, and
Dr. Maggie Liu for their help with LC, NMR, and mass
spectrometry.
Supporting Information Available: General experimental
conditions, procedures for the optimization reactions, all com-
pound characterization data not included in the main text, and
copies of the NMR spectra of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.