Direct, chemoselective N-teri-prenylation of indoles by C-H functionalization

Full text of DOI:10.1002/anie.200902761

Angewandte
Chemie
DOI: 10.1002/anie.200902761
Synthetic Methods
À
Direct, Chemoselective N-tert-Prenylation of Indoles by C H
Functionalization**
Michael R. Luzung, Chad A. Lewis, and Phil S. Baran*
molecular allylic C H aminations[16] have been accomplished;
however, there have been only a few reports involving the
intermolecular coupling of amines and allylic olefins.[17] The
fundamental mechanistic insights and reaction designs of
Scarborough and Stahl[18] as well as of Wasa and Yu[19] were
À
Prenylated indole alkaloids have long been targets for total
synthesis, since they possess a broad range of medicinal
properties and intriguing architectures.[1] Our interest in this
family began with the stephacidin family of indole alkaloids,[2]
during which the fortuitous finding shown in Scheme 1a was
made. Thus, in 2003, during an attempt to convert N-Boc-
tryptophan methyl ester (1) into the C-2 prenylated trypto-
phan 2 directly using 2-methyl-2-butene by electrophilic
palladation[3] and olefin capture, we instead observed small
amounts (< 10%) of a nonpolar compound which was
identified as N-tert-prenylated indole 3. Whereas many
elegant methods have been invented for accomplishing the
direct prenylation of indoles,[4–7] no methods currently exist
for the direct N-tert-prenylation of indoles (Scheme 1b).[8]
Inspired by our initial findings, we herein delineate a mild,
highly chemoselective, scalable, and one-step route to these
À
biologically relevant motifs by C H functionalization.
The only known route to N-tert-prenylated indoles
requires a four-step sequence, three of which involve non-
strategic redox fluctuations[9] (Scheme 1c): 1) reduction of the
indole to the indoline, 2) propargyl substitution by CuI
catalysis, 3) oxidation back to the indole, and finally 4) Lin-
dlar reduction of the alkyne to the olefin. This chemistry has
been successfully incorporated into a number of total
syntheses.[9]
Building on our initial observations (Scheme 1a), we
envisioned a direct, one-step procedure to synthesize N-tert-
prenylated indoles without the use of prefunctionalized
starting materials and superfluous redox steps—well-known
[10]
À
tenets of C H functionalization logic.
Such a strategy
would be orthogonal to routes that involve nucleophilic
prenylation, which in this case would not be applicable.[11]
À
Specifically, C H activation of indoles is known to occur at C-
2 or C-3, and involves the direct coupling of arenes[12] and
electron-deficient olefins[13] and annulations,[2,9,14] even in the
[15]
À
presence of free N H indoles. Palladium-catalyzed intra-
[*] Dr. M. R. Luzung, Dr. C. A. Lewis, Prof. P. S. Baran
Department of Chemistry, The Scripps Research Institute
10650 North Torrey Pines Road, La Jolla, CA 92037 (USA)
Fax: (+1)858-784-7375
E-mail: pbaran@scripps.edu
[**] We are grateful to Dr. Benjamin Hafensteiner, Dr. Carlos Guerrero,
and Dr. Narendra Ambhaikar for preliminary work, and to Prof. Jin-
Quan Yu for insightful discussions. Financial support for this work
was provided by Bristol-Myers Squibb, the NIH (Grant CA134785
and a postdoctoral fellowship to M.R.L. GM082092-02), and the
Canadian Institutes of Health Research (postdoctoral fellowship to
C.A.L.).
Scheme 1. Inspiration from a failed campaign in the stephacidin total
synthesis (A), currently known direct prenylation modalities (B), and
À
the known route to N-tert-prenylindoles compared to the C H func-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200902761.
tionalization alternative (C). Boc=tert-butoxycarbonyl, DDQ=2,3-
dichloro-5,6-dicyano-p-benzoquinone.
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instrumental in transforming our esoteric observations in
2003 into a useful method for synthesis.
Selected results of extensive optimization with the N-
Phth-tryptophan methyl ester 4 are outlined in Table 1 (see
the Supporting Information for a more comprehensive
Table 1: Optimization of the direct indole N-tert-prenylation.
Entry
Catalyst
(loading, mol%)
Oxidant
Solvent
Yield
[%][a]
1
2
3
4
5
6
7
8
Pd(OAc)2 (25)
[PdCl2(CH3CN)2] (25)
Pd(OAc)2 (25)
Pd(TFA)2 (30)
Pd(TFA)2 (30)
Pd(OAc)2 (40)
Pd(OAc)2 (40)
Pd(OAc)2 (40)
O2, pyridine
CuSO4
Cu(OAc)2, air
BQ, Ph3P
BQ, tBuOOH
Cu(OAc)2
AgOTf
THF
THF
THF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
NR
5
10
37
NR
31
22
70
Scheme 2. Scalable, one-step routes to previously employed N-tert-
prenylindole intermediates.
Cu(OAc)2, AgOTf
[a] Yield of isolated pure compound. The conditions giving the highest
yield are highlighted in bold. Phth=phthalimide, TFA=trifluoroacetate,
BQ=p-benzoquinone, Tf=trifluoromethanesulfonyl, NR=no reaction.
3-carboxylate (10) and leads to 11 in a single step in 83% yield
(gram scale).
As delineated in Scheme 3, this mild reaction exhibits
broad functional-group tolerance. For example, tryptophan
derivatives with various protecting groups can be prenylated
(Scheme 3, 13a–i). Peptides containing tryptophan also
undergo prenylation (13a, 13h), including a tripeptide
(13b). The presence of amides, particularly at the tryptophan
nitrogen atom (13d, 13h), reduces the reactivity, possibly
because of ligation of the amides onto electrophilic PdII.
However, a sterically hindered amide substrate does lead to
an increased yield (13e) compared to other amide substrates.
A tryptamine derivative (13j) is also prenylated, albeit in
lower yield, but starting material can be recovered. Free
alcohol, acid, and protected phenol substrates are well-
tolerated under the reaction conditions (13i, 13k, and 13m
respectively). Halogenated substrates (13 f, 13g), including
those incorporated in the indole ring (13l) work well, and are
not oxidatively cleaved under these conditions.
To gain insight into the mechanism of this transformation,
we studied the interactions that Pd may have with both the
indole and the olefin. We initially believed that the indole was
being palladated at C-2, thus providing proximal delivery of
the prenyl group to the nitrogen atom.[3,13] When a methyl
group occupied the C-2 position, there was less than 5%
conversion to the desired product (Scheme 4a). However,
when deuterium was placed on C-2 (16), we found that the
deuterium was fully incorporated in product 17. We also
found that [1,1,1-D3]3-methyl-2-butene reacted at the same
rate as its protio isomer with PdII, consistent with the
listing). The work of Scarborough and Stahl pointed us to
the use of CH3CN as a solvent, while the research from Wasa
and Yu inspired the use of Cu(OAc)2 and AgOTf in concert.
Ultimately, we found that 40 mol% of a Pd source (either
40 mol% Pd(OAc)2 or 20 mol% [Pd2(dba)3]·CHCl3) with
30 equivalents of 2-methyl-2-butene in the presence of Cu-
(OAc)2 and an AgI source (AgOTf or AgTFA) as the
cooxidants in CH3CN was optimal for this transformation.
With these conditions in hand, the synthetic utility could
be immediately demonstrated by applying it to known
intermediates in total synthesis (Scheme 2). For example,
compound 3, an intermediate in the okaramine N synthesis[9c]
that required the aforementioned four-step sequence (50%
overall yield), could be obtained in 66% yield on a gram scale
and in a single step, with no other regioisomers observed
under these conditions. Similarly, N-Cbz-tryptophan methyl
ester (6) was converted into 7, an intermediate towards the
synthesis of the rufomycins,[9b] in 61% yield (gram scale) as
compared to 60% over 4 steps. Indole 3-carboxaldehyde (8)
was prenylated to give 9, an intermediate in a cyclomarin
synthesis,[9d] on a gram scale and in 68% yield versus 70% for
the 4-step sequence from indoline. The use of methyl
acrylate[18] and 3-NO2-pyridine[12b,14] (possibly as stabilizing
ligands for Pd0) was needed when an electron-withdrawing
group was present at C-3. The natural product 11, isolated
from Aporpium caryae,[20] has been previously synthesized
starting from indoline[9a] and indole[9e] in 60% yield over
5 steps and 34% over 7 steps, respectively. The current
approach starts from commercially available methylindole
À
mechanistic studies by Bercaw and co-workers of allylic C
À
H activation (the C H activation step is not rate determin-
ing).[21]
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Scheme 3. Scope of N-tert-prenylation. [a] Reaction conditions: Meth-
od A: Pd(OAc)2 (10 mol%ꢀ4), AgTFA (2 equiv), Cu(OAc)2 (2 equiv),
CH3CN (0.1m), 358C, air, 24 h. Method B: [Pd2(dba)3]·CHCl3
(5 mol%ꢀ4), AgTFA (2 equiv), Cu(OAc)2 (2 equiv), CH3CN (0.1m),
358C, air, 24 h. Method C: Pd(OAc)2 (40 mol%), 3-NO2-pyridine
(40 mol%), methyl acrylate (1 equiv), AgOTf (2.5 equiv), Cu(OAc)2
(2.5 equiv), CH3CN (0.08m), 408C, Ar. [b] Yield of isolated product.
Fmoc=9-fluorenylmethyloxy carbonyl, dba=dibenzylideneacetone,
Ts =p-toluenesulfonyl.
Scheme 4. Mechanistic probe experiments (A), and postulated mecha-
nism (B).
Claisen rearrangement.[22] A Wacker-type mechanism (21),
not involving C H activation, may also be operative.[16a,b] The
À
Pd0 species then undergoes oxidation with AgI and CuII to
close the cycle. To rule out initial allylic oxidation of the olefin
to prenyl acetate a control experiment was performed using
prenyl acetate in place of 2-methyl-2-butene (following
Method A). The reaction did not provide the desired product,
but rather produced 22 (Scheme 5) in approximate 10% yield
(tentative assignment).
Based on these results, we have proposed the following
À
mechanism (Scheme 4b). First, C H activation of the olefin
with PdII gives intermediate 18. The palladated olefin reacts
with indole in two possible modes. The first involves direct
coordination of the indole nitrogen atom to the Pd center to
give 19. Alternatively, palladation of the indole at C-3 takes
place to give 20, which rearranges to the product by a metallo-
The use of cis-butene substituted for 2-methyl-2-butene
did afford desired products in respectable yield (23, 24). This
method is clearly not without limitations. For example,
terminal olefins provided only enamine products. Lowering
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Acetonitrile (CH3CN) was added, followed by the addition of 2-
methyl-2-butene (30 equiv) and methyl acrylate (1 equiv). The
mixture was heated to 408C and allowed to stir for 24 h. The solvent
was then evaporated and the mixture was loaded directly onto silica
gel for purification.
Method D: Similar to Method A, but using cis-butene.
Received: May 23, 2009
Revised: July 22, 2009
Published online: August 22, 2009
À
Keywords: C H functionalization · indoles · prenylation ·
synthetic methods
.
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Scheme 5. Informative products using prenyl acetate or cis-2-butene as
the olefin source.
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II
À
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Experimental Section
Method A: Indole (1 g, 1 equiv), Cu(OAc)2 (2 equiv), and AgTFA
(2 equiv) were added to a flame-dried flask or vial charged with a stir
bar. Acetonitrile (CH3CN) was added followed by the addition of
Pd(OAc)2 (10 mol%) and 2-methyl-2-butene (30 equiv). The mixture
was heated to 358C, followed by 3 sequential additions of Pd(OAc)2
(10 mol% after each hour). The mixture was allowed to stir for 24 h in
total. The solvent was then evaporated and the mixture was loaded
directly onto silica gel for purification.
À
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Method B: Similar to method A, but using [Pd2(dba)3]·CHCl3
(5 mol% ꢀ 4).
Method C: Indole (1 g, 1 equiv), Pd(OAc)2 (40 mol%), Cu-
(OAc)2 (2.5 equiv), AgOTf (2.5 equiv), and 3-NO2-pyridine
(40 mol%) were added to a flame-dried flask charged with a stir
bar. The flask was evacuated and backfilled with argon (3 times).
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[23] That four-step sequence generally involves the following
reagents (Ref. [9c]): NaBH3CN (1000 mol%, a toxic expensive
reagent that releases HCN), CuCl (10 mol%), 2-acetoxy-2-
methyl-3-butyne (110 mol%), DDQ (105 mol%), and Pd
(10 mol%). It also requires four separate purifications (silica
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À
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À
[16] a) For the first Pd-catalyzed allylic C H amination, an insightful
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