Preparation of 3-substituted-2-pyridin-2-ylindoles: regioselectivity of Larock's indole annulation with 2-alkynylpyridines

Article abstract of DOI:10.1016/j.tetlet.2007.11.040

A regioselective Larock approach to 3-substituted-2-pyridin-2-ylindoles from 2-alkynylpyridines and 2-iodoanilines is described herein. The unexpectedly high regioselectivity can be rationalized by a combination of steric, coordinative and electronic effects.

Full text of DOI:10.1016/j.tetlet.2007.11.040

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 363–366
Preparation of 3-substituted-2-pyridin-2-ylindoles:
regioselectivity of Larock’s indole annulation
with 2-alkynylpyridines
Frank Roschangar,a,* Jianxiu Liu,a Emilie Estanove,a Marine Dufour,a
a
a
a
a
a
´
Sonia Rodrıguez, Vittorio Farina, Eugene Hickey, Azad Hossain, Paul-James Jones,
Heewon Lee,a Bruce Z. Lu,a Richard Varsolona,a Jurgen Schro¨der,b Pierre Beaulieu,c
¨
James Gillardc and Chris H. Senanayakea
aChemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA
bBoehringer Ingelheim Pharma GmbH & Co. KG, A Verfahrensentwicklung, Binger Straße 173, 55216 Ingelheim am Rhein, Germany
cBoehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Que´bec, Canada H7S2G5
Received 10 October 2007; revised 5 November 2007; accepted 6 November 2007
Available online 13 November 2007
Abstract—A regioselective Larock approach to 3-substituted-2-pyridin-2-ylindoles from 2-alkynylpyridines and 2-iodoanilines is
described herein. The unexpectedly high regioselectivity can be rationalized by a combination of steric, coordinative and electronic
effects.
ꢀ 2007 Elsevier Ltd. All rights reserved.
R2
The assembly of functionalized indoles, which are pres-
ent in scores of natural products and pharmaceutical
compounds,1 has captured the attention of synthetic
chemists, and is reflected by a large number of review
articles.2 Our interest in these compounds derived from
the need to develop a short and cost-efficient route to
3-substituted-2-pyridin-2-ylindoles which have been
identified as key synthetic intermediates in an ongoing
program.
X
Z
Y
R2
Z
R3
N
I
R1
H
Pd(0)
3
+
R3
NH2
R1
X
Y
Δ
Y
X
R3
Z
2
1
R2
N
R1
The regioselective construction of 2,3-disubstituted
indoles remains challenging although lately several
elegant approaches have been developed,3 including
the palladium-catalyzed reaction of o-haloanilines with
internal alkynes,4 which is known as the Larock indole
annulation and appeared most appropriate for our
purposes (Scheme 1).5
H
4
Scheme 1. Larock indole annulation with ethynylpyridines.
vinyl-Pd intermediate, and finally reductive elimination
of Pd(0).4 The annulation has been described as regio-
selective with unsymmetrical alkynes generally attaching
the aniline nitrogen moiety to the sterically more con-
gested carbon atom of the alkyne, so that alkyne inser-
tion occurs in a way to minimize steric strain in the
vicinity of the developing carbon–carbon bond, which
is shorter than the carbon–palladium bond.4
Mechanistically, this reaction involves oxidative addi-
tion of Pd(0) to the aryl halide, usually the iodide, to
Pd(0), syn-insertion of the alkyne into the Ar–Pd bond,
nitrogen displacement of the halide at Pd in the resulting
*
Early laboratory experiments demonstrated that the
ratio of regioisomeric indole products was significantly
Corresponding author. Tel.: +1 203 791 5905; fax: +1 203 837
5905; e-mail: frank.roschangar@boehringer-ingelheim.com
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.040

364
F. Roschangar et al. / Tetrahedron Letters 49 (2008) 363–366
Table 1. Composition of product mixtures for the reaction 1+2!3+4a versus steric parameters and pyridyl pKa
11
Entry
Alkyne 2
pKa
Molar ratio of 3:4b
Yield 3+4c (%)
A-value (ArR3)/A-value (R2)12
1
2.77
94:6
94
2.97/1.67
N
a
2
3
4
5
3.99
4.98
n/a
68:32
72:28
67:33
87:13
93
76
86
88
3.06/1.67
2.99/1.67
3.26/1.67
3.19/1.67
N
b
N c
d
3.49
N
N
Me
e
6
7
0.93
2.67
80:20
97:3
84
91
2.93/1.67
2.97/1.54
OMe
g
f
N
8
2.57
31:69
78
2.97/4.69
N
h
MeO
9
1.76
2.29
41:59
57:43
56
63
2.97/3.24
2.97/3.26
N
i
10
N
j
a All reactions were carried out on 1.5–3.0 mmol scale using 1.0 equiv 3-amino-4-iodobenzoic acid methyl ester 1a, 1.5 equiv alkyne, 0.05 equiv
Pd(OAc)2, 0.075 equiv dppf, and 5.0 equiv KOAc in 50 vol NMP at 140 ꢁC, and monitored by HPLC.13
b Determined by 1H NMR integration.
c Isolated yield after column chromatography.
higher for 2-cyclopentylethynylpyridine (2a; Table 1,
entry 1) than for cyclopentylethynylbenzene (2d, entry
4) and could therefore not be rationalized by steric dif-
ferences between the acetylenic substituents. This
intriguing observation, coupled with the absence of
published studies describing the use of alkynylpyridines
in Larock’s indole annulation, prompted us to initiate a
systematic investigation probing the influence of
steric and electronic factors on the regioselectivity
of the Larock indole annulation with selected
alkynylpyridines.
1), optimized with respect to reaction rate, conversion,
ratio of regioisomeric indoles 3 and 4 (with 3 being
desired), and suppression of impurities derived from
multiple alkyne insertion7 and aniline dimerization.8 It
should be noted that while the palladium source and
nature of the ligand affected the reaction rate consider-
ably, they did not influence the regioselectivity. There-
fore, all reactions were carried out using 1.5–3.0 mmol
of aniline, 1.5 equiv of alkyne, 0.05 equiv of Pd(OAc)2,
0.075 equiv of dppf and 5.0 equiv of KOAc in 50 mL
of NMP per gram of aniline at 140 ꢁC.
We arrived at a suitable set of reaction conditions for
the Larock reaction of a selected 2-iodoaniline 16 and
a 2-alkynylpyridine (2, X = N, Y = Z = CH; Scheme
With these reactions conditions in hand, we embarked
on the study of steric and electronic influences of
alkynylpyridines on the regioselectivity of Larock’s

F. Roschangar et al. / Tetrahedron Letters 49 (2008) 363–366
365
indole annulation. Thus, 3-amino-4-iodobenzoic acid
L
I
L
R
methyl ester (1a; R1 = CO2Me)9 was reacted with disub-
stituted acetylenes 2a–j, and the ratio and yield of the
regioisomeric products 3 and 4 were determined (Table
1).10 To qualitatively assess the influence of steric bulk
of the acetylenic substituents, the A-values of these
groups were determined by computational studies.12
N
Pd
I
NH2
NH2
5
L
R
I
L
6
Pd
Entries 1–4 provide results in accordance with Larock’s
observation in that the sterically bulkier acetylenic sub-
stituent favors its placement at C-2 of the resulting
indole.4 However, while acetylenes 2a–d carry substitu-
ents with similar respective A-values, 2-cyclopentylethy-
nylpyridine (2a) provided a significantly higher ratio of
regioisomeric indoles 3 and 4 (94:6) compared to 2b–d
(ca. 69:31). It became apparent that the pyridin-2-yl
moiety played an important role in this unexpected
enhancement of regioselectivity favoring pyridin-2-yl-
indoles 3. This was further supported by entries 9 and
10, in which a ca. 50:50 ratio of indoles 3 and 4 would
have been anticipated based on the A-values of the
acetylenic substituents. These entries also suggest a role
for mesomeric effects which needs to be studied further.
However, the fact that sterics are still a significant com-
ponent with respect to regioselectivity in the Larock ind-
olization was supported by entry 8, as the large steric
bulk of the tert-butyl group overrode the electronic
effect of the pyridin-2-yl group favoring production of
3-pyridin-2-ylindole 4h by 69 to 31. In general, however,
introduction of the pyridin-2-yl substituent significantly
favored 2-pyridin-2-ylindoles 3 over 3-pyridin-2-yl-
indoles 4. It became apparent that we were dealing with
a complex overlap of steric and electronic effects.
PdL2
NH2
N
R
L
R
N
L
N
N
Pd
H
L
N
H
HI
7
Scheme 2. Proposed mechanism of Larock’s indolization with 2-
alkynylpyridines.
ring (6!7). This coordination effect appears insignifi-
cant for pyridin-3-yl and pyridin-4-yl moieties.
In summary, while steric effects are an important factor
in governing the regiochemical outcome of Larock’s
indole annulation with 2-alkynylpyridines, the influence
of the pyridin-2-yl nitrogen was also found to be signi-
ficant and did correlate to some extent with its pKa.
The relative steric bulk and strong r-donicity of the
pyridin-2-yl moiety act in synergy to provide high regio-
selectivity favoring 2-pyridin-2-ylindoles 3 over 3-pyr-
idin-2-ylindoles 4 observed in this study. This could
render the Larock annulation to 2-pyridin-2-ylindoles
an attractive synthetic protocol.
Clearly, only 2-alkynylpyridines exhibit a behavior that
deviates from a sterically-driven reaction. Their effect
may be due to electronic effects (mesomeric or inductive)
or to coordination of Pd by the pyridin-2-yl nitrogen
lone pair at some point of the catalytic cycle. To probe
the latter possibility, we examined the relationship of the
pyridinyl pKa of the alkynes with the observed regio-
selectivity. The calculated pKa values11 are shown in
Table 1. Without the possibility of p-backbonding from
the Pd to the pyridinyl moiety, a good correlation
between r-donicity and pKa can be assumed.14 In gen-
eral, higher basicity at nitrogen, that is, increasing
r-donicity of the pyridinyl nitrogen towards palla-
dium,15 furnished enhanced regioselectivity in favor of
2-pyridin-2-yl indoles 3 (see entries 5 vs 6 and 10 vs 9).
But this trend does not hold through the series (entry
1 vs 5), indicating that steric effects must play a role in
the annulation with 2-cyclopentylethynyl-6-methylpyri-
dine (2e), because the 2,6-disubstituted pyridines may
have more difficulty in coordinating the Pd center. Since
the pKa effect goes against it, this particular steric effect
must be considerable.
Experimental
Representative procedure for the Larock’s indole annula-
tion: To a 100 mL three-necked flask equipped with a
magnetic stirrer, internal thermocouple, condenser and
argon inlet, was added, at room temperature, the disub-
situted alkyne (3.61 mmol), palladium(II) acetate
(20.7 mg, 0.090 mmol), 1,10-bis(diphenylphosphino)-
ferrocene (75.8 mg, 0.135 mmol), potassium acetate
(887 mg, 9.03 mmol), the 2-haloaniline (1.81 mmol),
followed by anhydrous NMP (25 mL). The resulting
dark mixture was heated at 140 ꢁC until completion of
reaction was determined by HPLC. Typically, the reac-
tions completed within 1 h. The mixture was cooled to
room temperature, filtered through a pad of Celiteꢂ
which was rinsed with EtOAc (ca. 150 mL). Water
(100 mL) was added and the two layers were separated.
The aqueous phase was washed with EtOAc (1 ·
100 mL). The organic layers were combined, washed
with water, dried (MgSO4) and concentrated to give
generally a brown oil, which was purified by flash
column chromatography (silica gel, 70–230 mesh,
In an attempt to rationalize the role of the pyridin-2-yl
substituent, the mechanism shown in Scheme 2 is postu-
lated.4 The pyridine moiety, which is known to act as a
ligand for palladium, favors syn-insertion of the arylpal-
ladium complex in a way to maintain coordination of
palladium to the pyridyl nitrogen via a four-member
˚
60 A) using hexane–EtOAc (10:1 to remove excess
acetylene, then 5:1).

366
F. Roschangar et al. / Tetrahedron Letters 49 (2008) 363–366
internal alkynes (a) Shen, M.; Li, G.; Lu, B. Z.; Hossain,
Acknowledgments
A.; Roschangar, F.; Farina, V.; Senanayake, C. H. Org.
Lett. 2004, 6, 4129; (b) Li, G.; Liu, J.; Lu, Z.-H.;
Roschangar, F.; Senanayake, C. H.; Shen, M. U.S. Patent
Application US 2,005,209,465, 2005.
We thank Dr. Ruomei Li, Soraia Ahmadyar, Joseph
Russell and Natasha Reddinger for technical support.
7. (a) Pfeffer, M. Recl. Trav. Chim. Pays-Bas 1990, 109, 567;
(b) Ryabov, A. D. Synthesis 1985, 3, 233.
Supplementary data
8. Dimerization of anilines 1 can occur via double Buch-
wald–Hartwig amination (a) Guram, A. S.; Rennels, R.
A.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1995, 34,
1348; (b) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995,
36, 3609.
Experimental procedures and characterizations for com-
pounds 3a–j, 4a–f and 4h–j are available. Supplementary
data associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2007.11.040.
9. When 2-iodo-5-methoxyaniline (1b; R1 = OMe) and 2-
iodophenylamine (1c; R1 = H) were annulated with
2-cyclopentylethynylpyridine (2a), the molar ratio of
isomeric indoles 3 and 4 declined from 94:6, obtained
with aniline 1a, to 72:28 and 89:11, respectively. The
reduced regioselectivity observed with anilines 1b and 1c
versus 1a may be the result of weaker coordination
between the more electron-rich palladium and the pyridyl
nitrogen of postulated complex 6 (Scheme 2).
References and notes
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8.02).
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(axial) ꢀ DHf (equatorial), where DHf (axial) is the calcu-
lated heat of formation of the substituent in the axial
position of a cyclohexane ring and DHf (equatorial) is the
calculated heat of formation of the substituent in the
equatorial position of a cyclohexane ring. To ensure that
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equatorial position on
a cyclohexyl ring. The DHf
(formation) values were calculated using MOPAC6
(AM1, geometry optimization, in Cerius2 v.4.9, Accelrys
Inc., San Diego, CA, 2003).
13. Agilent 1100 HPLC system. Column: Agilent Zorbax
Eclipse XDB-C8, 4.6 · 150 mm, 5 lm; P/N 935967-906.
Mobile phase: A = water w/0.1% v/v trifluoroacetic acid
(TFA), B = acetonitrile w/0.1% v/v TFA. Gradient Pro-
file: 30–95% B over 14 min. UV detection @ 248 nm.
1.0 mL/min flow rate with injection volume of 5 lL.
14. It was demonstrated that the basicity, or the pKa, of
phosphines is related primarily to their r-donicity, which
is the ability of a ligand to donate r-electrons to a
transition metal, and to a lesser degree to the size of the
ligand, and it was concluded that pKa values are reason-
able measures of the r-donicity for those ligands that are
pure r-donor ligands and not p-acceptors Rahman, M. d.
M.; Liu, H.-Y.; Eriks, K.; Prock, A.; Giering, W. P.
Organometallics 1989, 8, 1.
4. (a) Larock, R. C.; Yum, E. K.; Refvik, M. D. J. Org.
Chem. 1998, 63, 7652; (b) Larock, R. C.; Yum, E. K.
J. Am. Chem. Soc. 1991, 113, 6689.
5. Larock’s methodology has recently been employed by
other research groups for the synthesis of 2,3-disubstituted
indoles (a) Chae, J.; Konno, T.; Ishihara, T.; Yamanaka,
H. Chem. Lett. 2004, 33, 314; (b) Konno, T.; Chae, J.;
Ishihara, T.; Yamanaka, H. J. Org. Chem. 2004, 69, 8258;
(c) Charrier, N.; Demont, E.; Dunsdon, R.; Maile, G.;
Naylor, A.; O’Brien, A.; Redshaw, S.; Theobald, P.;
Vesey, D.; Walter, D. Synthesis 2006, 3467.
15. Palladium–olefin complexes with pyridine r-donor ligands
have been isolated and characterized. For example, see
Kluwer, A. M.; Elsevier, C. J.; Buhl, M.; Lutz, M.; Spek,
¨
A. L. Angew. Chem., Int. Ed. 2003, 42, 3501.
6. Our group also developed a catalyst/ligand system that
allowed for Larock indolization of 2-chloroanilines with