Palladium-catalyzed decarboxylative allylation and benzylation of N-alloc and N-Cbz indoles

Article abstract of DOI:10.1021/ol400334u

A set of general methods for the palladium-catalyzed decarboxylative C3-allylation and C3-benzylation of indoles, starting from the corresponding N-alloc and N-Cbz indoles, respectively, is reported. This chemistry provides ready access to a wide range of

Full text of DOI:10.1021/ol400334u

ORGANIC
LETTERS
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Palladium-Catalyzed Decarboxylative
Allylation and Benzylation of N‑Alloc and
N‑Cbz Indoles
Thomas D. Montgomery, Ye Zhu, Natsuko Kagawa, and Viresh H. Rawal*
Department of Chemistry, The University of Chicago, 5735 South Ellis Avenue Chicago,
Illinois 60637, United States
vrawal@uchicago.edu
Received February 4, 2013
ABSTRACT
A set of general methods for the palladium-catalyzed decarboxylative C3-allylation and C3-benzylation of indoles, starting from the corresponding
N-alloc and N-Cbz indoles, respectively, is reported. This chemistry provides ready access to a wide range of functionalized indolenines in good to
excellent yields. A tandem process, wherein the palladium catalyzed allylation chemistry is coupled with a MizorokiÀHeck reaction, offers a
simple route to cinnamylated products.
The selective functionalization of indoles continues to be
the focus of numerous studies, due in no small part to the
prevalence of this fundamental heterocycle in bioactive
natural products and pharmaceutical agents.1,2 The C3
functionalization of 3-substituted indoles, in particular,
presents a significant challenge, as standard alkylation
protocolsnecessitate the use of strong bases and are further
complicated by the formation of a mixture of C1- and
C3-alkylated products.3 To overcome these limitations, a
number of groups have demonstrated the use of palladium
catalysis for the C3-allylation of C3-unsubstituted
indoles.4,5 The allylation of C3-substituted indoles, while
more challenging, as it also generates a quaternary center,
can also be accomplished through transition metal
catalysis.6,7 The scope of this methodology has recently
been extended to the benzylation of C3-substituted
indoles.8 The reported functionalization methods gener-
ally involve the reaction of the two partners, an indole
substrate having a free NH and an allyl or benzyl carbo-
nate, alcohol or acetate (Scheme 1). Given the ready
availability of N-alloc and N-Cbz indoles,9 we considered
the possibility ofusing such simple precursors for the direct
(1) Indole reviews: (a) Saxton, J. E. Indoles; John Wiley and Sons, Inc.:
New York, NY, 1983. (b) Sundberg, R. J. Indoles; Academic Press: London,
UK, 1996. (c) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.;
Blackwell Science: Malden, MA, 2000. (d) Maes, B. U. W.; Gribble, G. W.
Heterocyclic Scaffolds II: Reactions and Applications of Indoles; Springer-
Verlag: Berlin, GE, 2010; Vol. 26.
(2) Indole functionalization: (a) Cacchi, S.; Fabrizi, G. Chem. Rev.
2005, 105, 2873–2920. Update 1: Chem. Rev. 2011, 111, PR215. (b)
Joucla, L.; Djakovitch, L. Adv. Synth. Catal. 2009, 351, 673–714. (c)
Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608–9644.
(d) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev. 2010, 39,
4449–4465.
(3) For examples of alkylation of indolyl anion using alkyl halide: (a)
Hoshino, T. Liebigs Ann. Chem. 1933, 500, 35–42. (b) Nakazaki, M. Bull.
Chem. Soc. Jpn. 1959, 32, 838–840. Reactions between indoles and
o-halomethyl phenol/aniline: (c) Spande, T. F.; Wilchek, M.; Witkop, B.
J. Am. Chem. Soc. 1968, 90, 3256–3258. (d) May, J. A.; Zeidan, R. K.;
Stoltz, B. M. Tetrahedron Lett. 2003, 44, 1203–1205.
(5) (a) Billups, W. E.; Erkes, R. S.; Reed, L. E. Synth. Commun. 1980,
10, 147–154. (b) Bandini, M.; Melloni, A.; Umani-Ronchi, A. Org. Lett.
2004, 6, 3199–3202. (c) Bandini, M.; Melloni, A.; Piccinelli, F.; Sinisi, R.;
Tommasi, S.; Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128, 1424–
1425. (d) Liu, Z.; Liu, L.; Shafiq, Z.; Wu, Y.-C.; Wang, D.; Chen, Y.-J.
Tetrahedron Lett. 2007, 48, 3963–3967. (e) Cheung, H.-L.; Yu, W.-Y.;
Lam, F. L.; Au-Yeung, T. T.-L.; Zhou, Z.; Chan, T. H.; Chan, A. S. C.
Org. Lett. 2007, 9, 4295–4298. (f) Usui, I.; Schmidt, S.; Keller, M.; Breit,
B. Org. Lett. 2008, 10, 1207–1210. (g) Kimura, M.; Tohyama, K.;
Yamaguchi, Y.; Kohono, T. Heterocycles 2010, 80, 787–797. (h) Cao,
Z.; Liu, Y.; Liu, Z.; Feng, X.; Zhuang, M.; Du, H. Org. Lett. 2011, 13,
2164–2167. (i) Hoshi, T.; Sasaki, K.; Sato, S.; Ishii, Y.; Suzuki, T.;
Hagiwara, H. Org. Lett. 2011, 13, 932–935. (j) Yuan, F.-Q.; Gao, L.-X.;
Han, F.-S. Chem. Commun. 2011, 47, 5289–5291.
(4) Reviews on Pd-catalyzed allylation and related processes: (a)
Tsuji, J.; Minami, R. Acc. Chem. Res. 1987, 20, 140–145. (b) Trost,
B. M.; Van Vranken, D. L. Chem. Rev. 1996, 96, 395–422. (c) Trost,
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r
10.1021/ol400334u
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introduction of allyl and benzyl groups on indoles. For
N-alloc indole, for example, treatment with a palladium
catalyst was expected to produce π-allyl palladium and an
indole carboxylate (A), which upon CO2 loss would gen-
erate indoyl-π-allyl palladium (B), the penultimate inter-
mediate in our earlier reported method (Scheme 2).6c We
substituted indoles, including tetrahydrocarbazoles and
β-and γ-tetrahydrocarbolines (Table 1).
Alloc derivatives of indole and tetrahydrocarbazole
were successfully converted to the desired allylated pro-
ducts in high yields under low catalyst loadings (2aÀb).
Electron-donating and -withdrawing groups at the C5
position were tolerated (2cÀd). Both β- and γ-tetrahydro-
carbolines were successfully converted to the allylated
products (2eÀh), albeit under slightly higher catalyst load-
ings (2À5%). For reasons that are unclear, the Boc-
protected carboline, 1f, consistently gave lower yields than
did other carbolines. The alloc derivatives of indole and
2-methyl indole produced a mixture of the respective
mono- and bis-allylated compounds (2iÀ2l). Formation
of the bis-allylated products is noteworthy: it demonstrates
that the decarboxylative allylation does not involve an
intramolecular transfer of the allyl group.12 Finally, more
substituted allylic groups can be incorporated by starting
with the corresponding indole precursor. Thus, the croty-
lated indolesubstrate affordedthe crotylated product (2m)
in 84% yield, completely as the trans-diastereomer.
Scheme 1. Decarboxylative Allylation of Indole
In order to further expand the scope of the allylation
reaction to give the cinnamylated product, we considered
additional pathways to these compounds. One option was
to start with a cinnamyl carbamate precursor (1n), analo-
gous to the crotyl precursor (1m). Indeed, decarboxylative
rearrangement of 1n under the standard conditions gave
the expected cinnamyl product in 80% yield (Scheme 3, I).
However, as the preparation of the required starting
material for the cinnamyl product was neither as trivial
nor asefficient as for the alloc-protected indole derivatives,
we envisioned a tandem sequence in which a decarboxylative
Scheme 2. Catalytic Cycle for Decarboxylative Allylation
(6) (a) Kimura, M.; Futamata, M.; Mukai, R.; Tamaru, Y. J. Am.
Chem. Soc. 2005, 127, 4592–4593. (b) Trost, B. M.; Quancard, J. J. Am.
Chem. Soc. 2006, 128, 6314–6315. (c) Kagawa, N.; Malerich, J. P.;
Rawal, V. H. Org. Lett. 2008, 10, 2381–2384. (d) Xu, Q.-L; Dai, L.-X.;
You, S.-L. Chem. Sci. 2013, 4, 97–102.
(7) Alylation using other transition metals; see, inter alia: (a) Dieter,
J. W.; Li, Z.; Nicholas, K. M. Tetrahedron Lett. 1987, 28, 5415–5418. (b)
Prajapati, D.; Gohain, M.; Gogoi, B. J. Tetrahedron Lett. 2006, 47,
3535–3539. (c) Yadav, J. S.; Reddy, B. V. S.; Aravind, S.; Kumar, G. G.
K. S. N.; Reddy, A. S. Tetrahedron Lett. 2007, 48, 6117–6120. (d)
Zaitsev, A. B.; Gruber, S.; Pregosin, P. S. Chem. Commun. 2007,
4692–4693. (e) Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L. Org. Lett.
2008, 10, 1815–1818. (f) Sundararaju, B.; Achard, M.; Demerseman, B.;
Bruneau, C.; Toupet, L.; Sharma, G. V. M. Angew. Chem., Int. Ed. 2010,
49, 2782–2785.
(8) For the C3-benzylation of indoles, see: Zhu, Y.; Rawal, V. H.
J. Am. Chem. Soc. 2012, 134, 111–114.
describe below the realization of this concept of palla-
dium-catalyzed decarboxylative allylation and benzyla-
tion of indoles.
(9) N-alloc and N-Cbz indoles can be easily accessed by several
methods: (a) Shingarova, I. D.; Sizova, O. S.; Preobrazhenskaya,
M. N. Chem. Hetercycl. Compd. (N.Y.) 1983, 19, 1188–1191. (b)
Weedon, A. C.; Zhang, B. Synthesis 1992, 95–100. (c) Macor, J. E.;
Cuff, A.; Cornelius, L. Terahedron Lett. 1999, 40, 2733–2736. (d)
We began these studies by examining a range of con-
ditions for the decarboxylative allylation of N-alloc 2,3-
dimethylindole (1a).10 Among the palladium sources eval-
uated, Pd2(dba)3•CHCl3 was found to give the best yield.
An investigation of mono- and bidentate ligands revealed
that electron-deficient monodentate phosphines gave
superior results, with trifuryl phosphine11 affording the
highest yields. Optimal conditions involved the use of a 1:1
molar ratio of phosphine to palladium. The reaction
conditions determined by this study proved to be applic-
able to a variety of alloc-protected derivatives of
ꢀ ꢀ
ꢀ
Jacquemard, U.; Beneteau, V.; Lefoix, M.; Routier, S.; Merour, J.-Y.;
Coudert, G. Tetrahedron 2004, 60, 10039–10047.
(10) Please see Supporting Information for a table of some of the
conditions examined.
(11) Andersen, N. G.; Keay, B. A. Chem. Rev. 2001, 101, 997–1030.
(12) In support of this suggestion, we have found that subjection of a
1:1 mixture of 1b and 6-methoxy-1,2,3,4-tetrahydrocarbazole to the
standard decarboxylative allylation conditions produced a 1:1.5 mixture
of 2b:2d.
(13) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971,
44, 581. (b) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320–
2322. For selected reviews, see: (a) de Meijere, A.; Meyer, F. E. Angew.
Chem., Int. Ed. Engl. 1997, 33, 2379–2411. (b) Beletskaya, I. P.;
Cheprakov, A. V. Chem. Rev. 2000, 100, 3009–3066.
B
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of an aryl halide (Scheme 3, II). Since the decarboxylative
allylation takes place at room temperature, this step was
expected to take place prior to the MizorokiÀHeck reac-
tion, which typically requires a higher temperature. In the
event, heating indole 1a, iodobenzene, and K2CO3 in
acetonitrile under the allylation conditions afforded the
cinnamylated product in 98% yield.14,15
Table 1. Substrate Scope for Decarboxylative Allylationa
Scheme 3. Formation of Cinnamyl Producta
a Please see Supporting Information for detailed procedures.
Given the effectiveness of the above sequence, we also
examinedthe possibility of adapting the tandem concept to
our prior work on palladium catalyzed intermolecular
allylation, thereby providing a three-component coupling
route to the cinnamylated products. Under optimized
conditions, the reaction of tetrahydrocarbazole 3, allyl
methyl carbonate, and iodobenzene in the presence of
Pd2(dba)3•CHCl3 (5 mol %) and P(2-furyl)3 (10 mol %)
afforded the desired cinnamylated product in quantitative
yield (Scheme 4).15
Scheme 4. Three-Component Cinnamylation Reaction
The success of the decarboxylative allylation process
encouraged us to apply this strategy to the more challeng-
ing C3-benzylation of C3-substituted indoles. Initial stud-
ies showed the decarboxylative benzylation reaction
to require more forcing conditions than the allylation.
a Reactions performed on 0.5 mmol of substrate at 0.25 M, Pd/
P(2-furyl)3 = 1:1, 4 h. b Reaction performed on 1.0 mmol of substrate at
3.5 M.
(14) An examination of the reaction mixture by NMR during the
course of the reaction showed rapid conversion to an allylated inter-
mediate followed by its gradual transformation to the cinnamylated
product.
(15) See the Supporting Information for a table of conditions for the
optimization of this reaction.
allylation process would be followed by a MizorokiÀHeck
reaction.13 The plan was to use the N-alloc precursor and
carry out the palladium catalyzed allylation in the presence
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as the palladium source. Among the phosphine ligands
screened, the bidentate ligand DPEphos gave the best
yields. Finally, as noted in our earlier work,8 the addition
of boron Lewis acids,16 namely triethylborane, accelerated
the benzylation reaction. The optimized protocol for the
decarboxylative benzylation process was utilized with
several substrates, and the results are summarized in
Scheme 5.
Scheme 5. Substrate Scope of Benzylation Reactiona
The N-Cbz derivatives of 2,3-dimethylindole, tetrahy-
drocarbazole and 6-chloro-tetrahydrocarbazole (4aÀc),
all gave the corresponding C3-benzylated products
(5aÀc) in nearly quantitative yields. The C3-unsubstituted
precursors, N-Cbz-indole (4d) and N-Cbz-2-methyindole
(4f), produced a mixture of the corresponding mono- and
dibenzylated products.
To conclude, we have developed a set of protocols for
the palladium catalyzed decarboxylative C3 allylation and
benzylation of indoles, carbazoles, and carbolines, starting
from the respective N-alloc and N-Cbz protected precur-
sors. This chemistry iswell suited for sequencing with other
transition metal mediated processes, as illustrated through
the decarboxylative allylation/MizorokiÀHeck reaction
tandem sequence.
a Reactions performed on substrate (0.5 mmol), BEt3 (0.55 mmol), in
toluene (0.5 M) at 75 °C.
Optimal reaction conditions called for both higher tem-
peratures (75À80 °C) and longer reaction times.15 Of the
different palladium sources examined, [Pd(C3H5)cod]BF4
and Pd(C3H5)Cp were found to be the most efficient at
catalyzing the reaction. Due to the ease of its preparation
and storage requirements [Pd(C3H5)cod]BF4 was chosen
Acknowledgment. Financial support from the National
Institutes of Health (P50-GM086145) is gratefully ack-
nowledged.
Supporting Information Available. Experimental pro-
cedures, optimization tables, and spectroscopic data for
all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
(16) (a) Tamaru, Y.; Horino, Y.; Araki, M.; Tanaka, S.; Kimura, M.
Tetrahedron Lett. 2000, 41, 5705–5709. (b) Jiang, Y.; Hess, J.; Fox, T.;
Berke, H. J. Am. Chem. Soc. 2010, 132, 18233–18247. Also see reference 6b
for borane use in asymmetric allylation.
The authors declare no competing financial interest.
D
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