Palladium-catalyzed synthesis of indoles via ammonia cross-coupling-alkyne cyclization

Article abstract of DOI:10.1039/c1cc11874a

The synthesis of indoles via the metal-catalyzed cross-coupling of ammonia is reported for the first time; the developed protocol also allows for the unprecedented use of methylamine or hydrazine as coupling partners. These Pd/Josiphos-catalyzed reactions proceed under relatively mild conditions for a range of 2-alkynylbromoarenes.

Full text of DOI:10.1039/c1cc11874a

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COMMUNICATION
Palladium-catalyzed synthesis of indoles via ammonia
cross-coupling–alkyne cyclizationw
Pamela G. Alsabeh, Rylan J. Lundgren, Lauren E. Longobardi and Mark Stradiotto*
Received 1st April 2011, Accepted 19th April 2011
DOI: 10.1039/c1cc11874a
The synthesis of indoles via the metal-catalyzed cross-coupling
of ammonia is reported for the first time; the developed protocol
also allows for the unprecedented use of methylamine or hydrazine
as coupling partners. These Pd/Josiphos-catalyzed reactions
maximum of 44% yield after 18 h using 5 mol% Pd and 3
equivalents of KOtBu at 90 1C.9,10
In an effort to develop a more effective catalytic process,
active and commonly employed ligands for Pd-catalyzed
amination reactions were screened (Table 1). While ligands
such as tBu-DavePhos, S-Phos, X-Phos, PtBu3, DiPPF,
Q-Phos, TrippyPhos, IPr, and selected CataCXium ligands
gave poor results, Josiphos (CyPFtBu) provided the desired
indole product in 89% GC yield. Josiphos has been shown by
Hartwig and co-workers to be a highly effective ligand for
amine cross-coupling,4b,11 including ammonia.3a–c
proceed under relatively mild conditions for
2-alkynylbromoarenes.
a range of
The functionalization of ammonia by use of transition-metal
catalysis is emerging as a useful means of streamlining the
synthesis of nitrogen-containing organic molecules.1 Although
the inexpensive and readily available nature of ammonia
makes it an attractive nitrogen source, the use of ammonia
presents considerable difficulties in most metal-catalyzed
reactions, especially in comparison to other classes of substi-
tuted amines. Despite considerable research efforts directed
towards the metal-catalyzed synthesis of indoles and related
heterocycles,2 the direct use of ammonia in such transformations
has, to the best of our knowledge, not been reported. Indeed,
the Pd-catalyzed cross-coupling of ammonia and aryl
(pseudo)halides has only recently been developed,1,3 and such
catalyst systems generally lack the activity and versatility that
can be achieved in the arylation of primary or secondary
amines.4 Given the importance of the indole framework in
molecules of biological relevence,2,5 and inspired by the work
of Ackermann in the field of tandem arylation–hydroamination
involving primary amines or amides,6 we sought to develop a
tandem ammonia cross-coupling/cyclization protocol to
deliver NH-indoles. We report herein the first Pd-catalyzed
synthesis of 2-arylindoles from ammonia and bromophenyl-
acetylenes. Extension of this methodology enables the utiliza-
tion of methylamine as a substrate, while the use of hydrazine
hydrate allows for the preparation of N-aminoindoles.
Using Josiphos as the optimal ligand, variation of the
standard reaction conditions (Table 1) demonstrated the
importance of using KOtBu.10 KOH, Cs2CO3 or NaOtBu failed
to deliver 2a in high yields, but in some cases delivered the
uncyclized aniline; for example, 2-(phenylethynyl)aniline 2a0
could be isolated in 89% yield when using NaOtBu (2 equiv).12
The use of a lower catalyst loading (0.5 mol% [Pd(cinnamyl)Cl]2)
resulted in a lower yield of the desired product (56% yield by
GC), although full conversion of the starting material was
still observed. Aryl chlorides or tosylates were not suitable
substrates. While [Pd(cinnamyl)Cl]2 provided the highest yield
of 2a, other Pd-sources could be employed such as Pd(dba)2 or
Pd[P(o-tolyl)3]2 (73% and 83% GC yield, respectively).
Having identified a suitable catalyst system for the direct
synthesis of 2-phenylindole (2a) from ammonia using
commercially available stock solutions (0.5 M in 1,4-dioxane),
the scope of the reaction was explored with various 2-bromo-
phenylalkynyl substrates (Table 2), which were generated via
Sonogashira coupling reactions.10
A variety of substituents on the remote arene ring of the
alkyne were tolerated; for instance, heterocycle-containing
examples such as 3-thiophene (2c) and 3-pyridine (2k)
proceeded in good yields (85% and 61%), as did phenylacetylenes
with alkyl, ether, or halogen groups. The reaction appears
relatively insensitive to ortho-substitution of the arene ring at
the 2-position, as compounds 1i, 1j, 1n, and 1o formed the
corresponding 2-arylindoles in moderate to good yields. An
indole featuring an NHBoc-group (2g) could be prepared
without complication from the additional amine functionality
in 63% yield. We observed the tert-butyldimethylsilyl-
protected bromoalkyne substrate 1i to undergo concurrent
deprotection to yield the phenol-containing product 2i,
albeit in slightly reduced yield (49%), while use of a benzyl
We envisioned the synthesis of 2-substituted NH-indoles
could be achieved by the union of the Pd-catalyzed cross-
coupling of ammonia, followed by base-mediated cyclization
of the resultant 2-aminophenylacetylene.7 After screening a
range of conditions, we found mixtures of [Pd(cinnamyl)Cl]2/
Mor-DalPhos3f,8 to yield the desired 2-arylindole 2a in a
Department of Chemistry, Dalhousie University, Halifax,
Nova Scotia, B3H 4J3, Canada. E-mail: mark.stradiotto@dal.ca;
Fax: 1 902 494 1310; Tel: 1 902 494 7190
w Electronic supplementary information (ESI) available: Experimental
procedures and NMR spectral data. See DOI: 10.1039/c1cc11874a
c
6936 Chem. Commun., 2011, 47, 6936–6938
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Table 1 Ligand screen for the Pd-catalyzed synthesis of 2-phenyl-
indole from ammonia and 2-bromophenylacetylenea
Table 2 Scope of the Pd-catalyzed cross-coupling of ammonia or
methylamine with 2-alkynylbromoarenesa
a
0.5 mmol scale, [Pd]/L = 1 : 1, NH3 = 1.5 mmol or MeNH2 =
0.6 mmol, KOtBu = 1.5 mmol, 90 1C in 1,4-dioxane (NH indoles, 3 h
reaction time) or in toluene (NMe indoles, 16–24 h). Yields are of
a
0.1 mmol scale, [Pd]/L = 1 : 1, NH3 = 0.3 mmol, KOtBu = 0.3 mmol,
90 1C in 1,4-dioxane. Conversions of 1a in parentheses and yields of 2a
are based on calibrated GC data using dodecane as an internal
b
isolated products. 5 mol% Pd used. 2g = 3.5 eq. base, 3d = 4.0 eq.
c
d
base. From TBS-protected alcohol substrate. 4.0 eq. Cs2CO3,
e
b
standard. Starting material consumed; product not observed by
c
GC. Isolated yield using 5 mol% Pd after 18 h reaction time.
f
3.0 eq. KOtBu, 48 h. 6.0 eq. KOtBu, 110 1C, 60 h.
protecting group gave the corresponding indole 2j in 53%
yield with the protecting group intact.
Given the success of the Pd/Josiphos system to deliver NH-
indoles from ammonia, we sought to expand the scope of the
reaction to other challenging amine partners. Methylamine13
could be employed to directly prepare N-methylated indoles,
with yields similar to that of ammonia for select substrates
(Table 2, 3a–3f). Notably, dihalogenated indole 3f was
obtained using a two-step one-pot procedure, in which amine
cross-coupling was first achieved by using Cs2CO3 as base
followed by treatment with KOtBu to mediate cyclization to
indole. These results, combined with the comprehensive
studies of Hartwig,3a–c,4b,11 suggest that Pd/Josiphos mixtures
may have broad-ranging scope for tandem cross-coupling/
cyclization reactions to yield N-functionalized indoles.
Brief examination of the reactivity of substrates with substi-
tution on the bromoarene resulted in 4, 5, or 6-substituted
indoles in generally good yields, including an example containing
1,6-dibromo-substitution to yield the mono-cross-coupled
product 2f—a viable precursor for further metal-catalyzed
cross-coupling. While for convenience we employed an inert
atmosphere glovebox for the setup of most catalytic experiments,
use of a glovebox is not necessary. For example, in the reaction
of 1a the catalyst components and base could be weighed out in
air and placed under dinitrogen prior to introduction of the
reactants and solvent to give 2a in 84% yield by GC.
Some limitations to the current method were established
during substrate scope studies. Heterocyclic substrates with
the heteroatom ortho to the bromo or alkyne group gave low
yields. The reaction appears limited to aryl-substituted alkyne
groups, as replacement at this position (R0, Table 2) with
silyl (TMS), alkyl (propyl or hexyl) or alkenyl groups resulted
in degradation of the starting material without significant
product formation.
We recently reported the first example of Pd-catalyzed
hydrazine cross-coupling to generate aryl hydrazines8a and
were pleased to find that hydrazine hydrate could be employed
to generate NH2-substituted aminoindoles from 2-bromophenyl-
alkynes (Table 3).14,15 Under the standard conditions using
5 mol% Pd, the N-aminoindole 4a was formed in 56% yield,
along with the indazole product 4a0 (31%) after 1 h. Attempts
to bias the product ratio by altering the base, solvent, or
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 6936–6938 6937

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Table 3 Pd-catalyzed cross-coupling of hydrazine with 2-alkynyl-
bromoarenesa
2009, 131, 11049; (c) Q. Shen and J. F. Hartwig, J. Am. Chem. Soc.,
2006, 128, 10028; (d) D. S. Surry and S. L. Buchwald, J. Am. Chem.
Soc., 2007, 129, 10354; (e) T. Schulz, C. Torborg, S. Enthaler,
B. Schaffner, A. Dumrath, A. Spannenberg, H. Neumann,
A. Borner and M. Beller, Chem.–Eur. J., 2009, 15, 4528;
(f) R. J. Lundgren, B. D. Peters, P. G. Alsabeh and
M. Stradiotto, Angew. Chem., Int. Ed., 2010, 49, 4071.
4 For selected reviews see: (a) D. S. Surry and S. L. Buchwald,
Chem. Sci., 2011, 2, 27; (b) J. F. Hartwig, Organotransition
Metal Chemistry, University Science Books, Sausalito, 2010,
p. 907; (c) J. F. Hartwig, Acc. Chem. Res., 2008, 41, 1534.
5 For selected examples see: (a) F.-R. Alexandre, A. Amador, S. Bot,
C. Caillet, T. Convard, J. Jakubik, C. Musiu, B. Poddesu,
L. Vargiu, M. Liuzzi, A. Roland, M. Seifer, D. Standring,
R. Storer and C. B. Dousson, J. Med. Chem., 2011, 54, 392;
(b) K.-H. Lim, O. Hiraku, K. Komiyama, T. Koyano,
M. Hayashi and T.-S. Kam, J. Nat. Prod., 2007, 70, 1302.
6 Selected reports: (a) L. Ackermann, R. Sandmann and
M. V. Kondrashov, Synlett, 2009, 1219; (b) L. Ackermann,
R. Sandmann, M. Schinkel and M. V. Kondrashov, Tetrahedron,
2009, 65, 8930; (c) L. T. Kaspar and L. Ackermann, Tetrahedron,
2005, 61, 11311; (d) L. Ackermann, Org. Lett., 2005, 7, 439;
(e) L. Ackermann, S. Barfußer and H. K. Potukuchia, Adv. Synth.
Catal., 2009, 351, 1064.
a
0.5 mmol scale, [Pd]/L = 1 : 1, N2H4ꢀH2O = 1.0 mmol, KOtBu =
1.25 mmol, 90 1C in 1,4-dioxane; isolated yield of 4 (40 in parentheses).
b 1H NMR yield of 4 (40) relative to 1,3,5-trimethoxybenzene.
7 (a) A. L. Rodriguez, C. Koradin, W. Dohle and P. Knochel,
Angew. Chem., Int. Ed., 2000, 39, 2488; (b) C. Koradin,
W. Dohle, A. L. Rodriguez, B. Schmid and P. Knochel,
Tetrahedron, 2003, 59, 1571; (c) A. H. Stoll and P. Knochel, Org.
Lett., 2008, 10, 113; (d) R. Sanz, V. Guilarte and M. P. Castroviejo,
Synlett, 2008, 3006.
8 (a) R. J. Lundgren and M. Stradiotto, Angew. Chem., Int. Ed.,
2010, 49, 8686; (b) K. D. Hesp, R. J. Lundgren and M. Stradiotto,
J. Am. Chem. Soc., 2011, 133, 5194.
including additives (CuCl2 or Ag2CO3) were not successful.
A
brief survey of additional substrates proved other
N-aminoindoles could be formed in moderate yields
(36–65%). Given the difficulties associated with the use of
hydrazine as a nitrogen-source in cross-coupling reactions,
we view this transformation as representing a significant
contribution towards the establishment of direct routes to
hydrazine-containing heterocycles.
9 The low yields of 2a were the result of hydrodehalogenation as well
as conversion to other unidentified products. In the course of this
study we found that the presence of the alkyne functionality slowed
catalytic turnover and promoted the reduction of the haloarene
In summary, we have developed a straightforward method
for the synthesis of 2-arylindoles directly from ammonia
through a tandem cross-coupling/alkyne amination sequence.
Additionally, the challenging amine partners methylamine and
hydrazine have been shown to form indole structures using the
same catalyst system. We believe that this protocol represents
an important contribution towards the development of a more
direct and benign synthesis of the ubiquitous indole substructure,
and continued improvements to the described reaction should
engender the process as a viable alternative to more traditional
syntheses of NH-, NMe- and N-aminoindoles.
substrate10
.
10 See the ESIw for additional details.
11 (a) E. Avaro and J. F. Hartwig, J. Am. Chem. Soc., 2009, 131,
7858; (b) Q. Shen and J. F. Hartwig, Org. Lett., 2008, 10, 4109;
(c) M. A. Fernandez-Rodrıguez, Q. Shen and J. F. Hartwig,
Chem.–Eur. J., 2006, 12, 7782; (d) Q. Shen, S. Shekhar,
J. P. Stambuli and J. F. Hartwig, Angew. Chem., Int. Ed., 2005,
44, 1371.
12 Beller and co-workers3e have reported the cross-coupling of a
2-alkynyl substrate to yield the corresponding aniline in modest
yield.
13 For some examples of the use of methylamine in Buchwald–
Hartwig amination, see: (a) B. P. Fors and S. L. Buchwald,
J. Am. Chem. Soc., 2010, 132, 15914; (b) R. J. Lundgren,
A. Sappong-Kumankumah and M. Stradiotto, Chem.–Eur. J.,
2010, 16, 1983; (c) B. P. Fors, D. A. Watson, M. R. Biscoe and
S. L. Buchwald, J. Am. Chem. Soc., 2008, 130, 13552.
14 Disubstituted hydrazines have been employed in tandem
cross-coupling/cyclization reactions to yield either indazoles or
N-aminoindoles, although the substitution pattern of the
hydrazine substrates precludes the formation of indole/indazole
mixtures, see: (a) N. Halland, M. Nazare, O. R’kyek, J. Alonso,
M. Urmann and A. Lindenschmidt, Angew. Chem., Int. Ed., 2009,
48, 6879; (b) N. Halland, M. Nazare, J. Alonso, O. R’kyek and
A. Lindenschmidt, Chem. Commun., 2011, 47, 1042.
Acknowledgment is made to the NSERC of Canada, and
Dalhousie University for their support of this work. Solvias is
acknowledged for the gift of the Josiphos ligand.
Notes and references
1 For recent reviews see: (a) J. L. Klinkenberg and J. F. Hartwig,
Angew. Chem., Int. Ed., 2011, 50, 86; (b) Y. Aubin, C. Fischmeister,
C. M. Thomas and J.-L. Renaud, Chem. Soc. Rev., 2010, 39, 4130;
(c) J. I. van der Vlugt, Chem. Soc. Rev., 2010, 39, 2302.
2 (a) J. E. R. Sadig and M. C. Willis, Synthesis, 2011, 1;
(b) G. R. Humphrey and J. T. Kuethe, Chem. Rev., 2006, 106,
2875; (c) S. Cacchi and G. Fabrizi, Chem. Rev., 2005, 105,
2873.
15 For a report concerning Cu-catalyzed cross-coupling/cyclization of
substituted hydrazines to yield either pyrroles or pyrazoles see:
R. Martın, M. Rodrıguez Rivero and S. L. Buchwald, Angew.
Chem., Int. Ed., 2006, 45, 7079.
3 (a) J. L. Klinkenberg and J. F. Hartwig, J. Am. Chem. Soc., 2010,
132, 11830; (b) G. D. Vo and J. F. Hartwig, J. Am. Chem. Soc.,
c
6938 Chem. Commun., 2011, 47, 6936–6938
This journal is The Royal Society of Chemistry 2011