Mild and Practical Indole C2 Allylation by Allylboration of in situ Generated 3-Chloroindolenines

Article abstract of DOI:10.1002/ejoc.201801745

C2 allylation of indole derivatives is a challenging but important transformation given the biological relevance of the products. Herein we report a selective C2 allylation strategy that proceeds via allylboration of in situ-generated 3-chloroindolenines. The reaction is mild, practical, and compatible with a wide range of C3-substituted indoles. As allylboronates are readily accessible from commercial precursors, various substituted allyl moieties can be introduced using the same protocol. To showcase the utility of this method we applied it to the synthesis of the natural product, tryprostatin B.

Full text of DOI:10.1002/ejoc.201801745

A Journal of
Accepted Article
Title: Mild and Practical Indole C2 Allylation by Allylboration of in situ-
Generated 3-Chloroindolenines
Authors: Jordy M. Saya, Ellen D. H. van Wordragen, Romano V. A.
Orru, and Eelco Ruijter
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801745
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801745
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10.1002/ejoc.201801745
European Journal of Organic Chemistry
COMMUNICATION
Mild and Practical Indole C2 Allylation by Allylboration of in situ-
Generated 3-Chloroindolenines
Jordy M. Saya, Ellen D. H. van Wordragen, Romano V. A. Orru and Eelco Ruijter*[a]
Abstract: C2 allylation of indole derivatives is a challenging but
important transformation given the biological relevance of the
products. Herein we report a selective C2 allylation strategy that
proceeds via allylboration of in situ-generated 3-chloroindolenines.
The reaction is mild, practical, and compatible with a wide range of
C3-substituted indoles. As allylboronates are readily accessible from
commercial precursors, various substituted allyl moieties can be
introduced using the same protocol. To showcase the utility of this
method we applied it to the synthesis of the natural product,
tryprostatin B.
has shifted focus to selective functionalization of readily
available indoles.[4] While functionalization at the C3 and N1
positions is typically straightforward owing to their nucleophilic
properties (in the latter case after deprotonation), and
substituents at the benzenoid ring are mostly introduced during
construction of the indole core, selective functionalization of the
C2 position is more challenging. Radicals have been reported to
react preferentially at the indole C2 position.[5] Recently, Bach et
al. reported a convenient C–H activation strategy that allows
alkylation and arylation at the indole C2 position.[6]
During our studies on the reactivity of indole-functionalized
isocyanides,[7] we became interested in the C2 allylation of
indoles en route to natural product scaffolds. The importance of
this transformation is underlined by the numerous examples in
the literature.[8] Most strategies involve either directed lithiation
(either by lithium-halogen exchange or by deprotonation) of the
C2 position or C–H activation by a directing group (Scheme 1).
Introduction
Indoles have been an important target in organic synthesis ever
since Baeyer reported the first synthesis of the parent
heterocycle in 1866.[1] In these early days of organic chemistry,
many classical methods (e.g. the Fischer, Bischler, Reissert,
and Madelung indole syntheses), were developed, several of
which are still widely used today.[2] The interest in this ‘privileged
scaffold’ originates in part from the numerous naturally occurring
bioactive indole alkaloids (Figure 1).[3]
Figure 1. Selected naturally occurring indole alkaloids bearing an allyl moiety
Unfortunately, the state of the art in indole synthesis does not
always allow construction of the indole ring system with the
desired substitution pattern. Consequently, research in this area
[a]
J. M. Saya, E. D. H van Wordragen, Prof. Dr. Romano V. A. Orru,
Dr. E. Ruijter
Department of Chemistry & Pharmaceutical Sciences
Amsterdam Institute for Molecules, Medicines & Systems
Vrije Universiteit Amsterdam
Scheme 1. C2 allylation strategies of indoles. (a) lithiation of the C2 position
via either lithium-halogen exchange or deprotonation. (b) transition metal
catalyzed C–H activation by use of a directing group. (c) two step chloronation
of indoles followed by a allylation / rearomatization sequence.
De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands
E-mail: e.ruijter@vu.nl
http://www.syborch.com/
Although these strategies have great potential, they generally
require a directing group at N1 which needs to be removed
afterwards. In our pursuit of a more general and practical
procedure for this selective conversion, we came across a
method developed by Danishefsky et al. involving nucleophilic
Supporting information for this article is given via a link at the end of
the document
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10.1002/ejoc.201801745
European Journal of Organic Chemistry
COMMUNICATION
additions on in situ-generated 3-chloroindolenines.[9] After
addition of a nucleophile to the imine, rearomatization by
elimination of HCl gives back the indole. In our opinion, this
method represents the most convenient strategy for the direct
C2-allylation of indoles to date. However, the authors did not
show the generality of the reaction with respect to allylating
reagents and C3-substituted indoles. Moreover, the addition of
nucleophiles (mostly toxic organotin reagents) required
activation by BF3·Et2O, thus limiting the functional group
tolerance. In this communication we present a milder and more
general procedure for allylboration of 3-chloroindolenines.
conditions. We therefore limited our selection to 3-substituted
indoles (Scheme 2). As hypothesized, the mild reaction
conditions tolerated a variety of functional groups. For example,
the reactions of ester-functionalized substrates 5b and 5c
afforded the corresponding allylation products 7ba and 7ca in
very good yield. In contrast, reaction of methyl indole-3-
carboxylate (5d) gave product 7da in lower efficiency. This can
be rationalized by the instability of the 3-chloroindolenine
intermediate, which is destabilized by the electron-withdrawing
properties of the ester. On the other hand, cyclohexyl- and
phenyl-substituted products 7ea and 7fa were obtained in good
yield. We were pleased to see that also N-Boc-tryptamine and
Boc-Trp-OMe (5g and 5h) were well accepted. Finally, we
successfully achieved double allylation with bis(indolyl)methane
(5i) which was converted to bisallyl species 7ia in high yield
(83%). Monoallylation of 5i was also possible, however, this
gave a statistical mixture of starting material, monoallylation and
bisallylation products.
Results and Discussion
In search of a mild and readily available nucleophilic allylation
reagent, we arrived at allylboronic acid pinacol ester (allylBpin,
8a). AllylBpin and related reagents effectively react with
aldehydes and imines, and several convenient ways to
synthesize substituted allylBpin derivatives from allylic alcohols
and halides, 1,3-dienes, and allenes have been reported.[10]
Reaction of 3-methylindole (5a) with NCS as the electrophilic
chlorine reagent in the presence of triethylamine at 0 °C
selectively generated 3-chloroindolenine 6a in situ. After
subsequent addition of 8a and stirring this crude mixture for 1 h,
we conveniently obtained 2-allylindole 7aa in 44% yield (Table 1,
entry 1). We then showed that no reaction occurs in the absence
of either Et3N or NCS (entries 2 and 3).[11] Optimization of
reagent stoichiometry (entries 4-7) allowed us to identify
conditions affording 7aa in 75% isolated yield. Finally, we found
that our initial choice for CH2Cl2 as the solvent was ideal for this
reaction.
Table 1: Optimization of reaction conditions.
Entry
Solvent
Et3N
(equiv)
NCS
(equiv)
8a
(equiv)
Yield
(%)[a]
Scheme 2. Scope of indoles 5. Reaction conditions: Indole 5 (1 mmol), Et3N
(1.5 mmol), NCS (1.3 mmol) in CH2Cl2 (4 mL, 0.25 M) at 0 °C; then 8a (1.5
mmol) at rt. [a] reagent stoichiometry adapted to bisindole 5i.
43
0
0
72
73
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
1.5
0.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.1
1.3
0.0
1.3
1.3
1.3
1.3
1.3
1.3
1.5
1.5
1.5
1.1
1.3
1.5
1.5
1.5
1.5
Encouraged by the high functional group tolerance of our
method in comparison to other literature precedents for this
transformation, in particular by the compatibility of Boc-Trp-OMe
(to give 7ha), we wondered whether we could even use an N-
protected amino acid. This would be highly interesting for
peptide chemistry, as the resulting C2-allylated tryptohan could
be readily incorporated in a peptide sequence by standard solid-
phase peptide synthesis. To our delight, reaction of Fmoc-Trp-
OH (5j) afforded 7ja in 76% yield (Scheme 3).
75[b]
0[c]
15%
12%
Toluene
MeCN
a) Yield determined by 1H NMR analysis with 2,5-dimethylfuran as internal
standard. b) Isolated yield on 1.0 mmol scale. c) The 3-chloroindolenine
intermediate was not formed.
With the optimized conditions in hand, we started to
evaluate the scope with regard to indoles 5. We initially checked
if unsubstituted indole would provide the desired allylated
species. Unfortunately, the 3-chloroindolenine intermediate
rapidly rearomatized to form 3-chloroindole. Reaction of 1,3-
dimethylindole only led to decomposition under the reaction
Scheme 3. C2 allylation of Fmoc-Trp-OH (5j).
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10.1002/ejoc.201801745
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COMMUNICATION
Allylboronates are generally readily accessible from simple
starting materials in one or two reaction steps. In addition, some
simple allylboronates are commercially available. Moreover, they
are non-toxic and easy to handle (i.e., air and temperature
stable). We sought to exploit these advantages by evaluating the
compatibility of a set of readily available allylboronates with our
reaction manifold (Scheme 4). Reaction of 5a with commercially
available trans-crotylboronic acid pinacol ester (8b) cleanly
afforded reverse crotylation product 7ab in 69% yield, nicely
comparable to 7aa. Encouraged by this result, we then tested
prenylBpin (8c), however, only traces of reverse prenylation
product 7ac were obtained.[12] Possibly, the sterically
encumbered γ-position is not sufficiently nucleophilic to attack
the in situ-generated 3-chloroindolenine under these conditions.
In contrast, C2 prenylation using 8d proved highly compatible
with our method, as we could obtain product 7ad in 83% yield.
Unlike all other 2-allylindoles, 7ad needed to be handled with
care, as the product readily decomposed during chromatography
if the silica gel was not pretreated with base.[13] Next, we could
even demonstrate the possibility to introduce a propargyl
substituent at the C2 position by using commercially available
allenylBpin (8e).[14] This significantly broadens the scope for
post-modification as alkynes are versatile reagents in robust
chemistry (e.g. azide-alkyne cycloaddition, Sonagashira
coupling, Favorskii reaction, A3 coupling). We then successfully
performed the allylation with 1,2-diboryl reagent 8f which was
conveniently prepared by diborylation of phenylallene. (β-
Boryl)cinnamyl indole 7af is again interesting for post-
modifcation as vinylboronates are suitable reactants for Suzuki
cross-coupling, Petasis reaction, or oxidation to the
corresponding ketone.
in rather modest yield. Finally, cross metathesis of 7aa and ethyl
acrylate in the presence of Grubbs’ 2nd generation catalyst gave
11 in 42% yield as a 3:1 E:Z mixture.
Scheme 5. Chemical transformations of 7aa.
Having established the scope of this C2 allylation procedure of
indoles, we wanted to demonstrate its utility in the synthesis of a
natural product. We envisioned that we could efficiently access
tryprostatin B (4) via this synthetic strategy. Danishefsky et al.
already showed that their method could be applied to a five-step
synthesis of this natural product starting from N-phthalamide
protected 12 (Scheme 6).[9] Our initial plan was to simply
prenylate brevianamide F (16) to obtain 4 in a single step.
Unfortunately, this route proved unsuccessful, not even
producing
a
trace of 4. We hypothesized that the
diketopiperazine was not stable under the reaction conditions,
resulting in a mixture of unidentified products. However, since
we had shown that Boc-Trp-OMe was well tolerated in the
allylation reaction, we anticipated that Boc-Pro-Trp-OMe (14)
would be a suitable substrate for prenylation with boronate 8d.
To our delight, dipeptide 14 was smoothly converted to
prenylated product 15 in 62% yield without loss of optical purity.
Then, Boc deprotection by treatment with TMSI followed by
base-mediated cyclization (NH3/MeOH) as previously described
by Danishefsky completed the total synthesis of tryprostatin B.
Scheme 4. Scope with regard to allylic boronates 8. Reaction conditions:
Indole 5a (1 mmol), Et3N (1.5 mmol), NCS (1.3 mmol) in CH2Cl2 (4 mL, 0.25
M) at 0 °C; then 8a (1.5 mmol) at rt. [a] 2.5 equiv of 8d was added. [b] reaction
was performed on 0.2 mmol scale.
To demonstrate the versatility of the 2-allyl moiety we performed
some follow-up transformations with 7aa (Scheme 5). As
expected, catalytic hydrogenation of the alkene readily furnished
9 in 82% yield. Hydroboration with 9-BBN followed by H2O2
oxidation afforded anti-Markovnikov hydration product 10, albeit
Scheme 6. Total synthesis of tryprostatin B by Danishefsky and our method.
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European Journal of Organic Chemistry
COMMUNICATION
[7]
[8]
a) J. M. Saya, B. Oppelaar, R. C. Cioc, G. van der Heijden, C. M. L.
Vande Velde, R. V. A. Orru, E. Ruijter, Chem. Commun. 2016, 52,
12482–12485. b) J. M. Saya, T. R. Roose, J. J. Peek, B. Weijers, T. J.
S. de Waal, C. M. L. Vande Velde, R. V. A. Orru, E. Ruijter, Angew.
Chem. Int. Ed. 2018, 47, 15232-15236; Angew. Chem. 2018, 130,
15452-15456.
Conclusions
In conclusion, we report a mild and practical C2 allylation
strategy of 3-substituted indoles via allylboration of in situ-
generated 3-chloroindolenines. The reaction is compatible with a
range of functionalized indoles, providing the products in a short
amount of time. We also demonstrated the compatibility with
various allylic boronates, thus further expanding the range of
accessible products. To show the potential of this method we
synthesized tryprostatin B in a very efficient three step sequence
starting from dipeptide 13. We believe that this method is the
most efficient C2 allylation of 3-substituted indoles in terms of
scope and practical use, which can be employed as either an
early or a late stage modification strategy to generate valuable
building blocks.
For allylation reactions that proceed via C2 lithiation see: a) Y. Kondo,
T. Sakamoto, J. Chem. Soc. Perkin Trans. 1 1996, 2331–2332; b) S.
Zhao, T. Gan, P. Yu, J. M. Cook, Tetrahedron Lett. 1998, 39, 7009–
7012; c) M. Abarbri, J. Thibonnet, L. Bérillon, F. Dehmel, M. Rottländer,
P. Knochel, J. Org. Chem. 2000, 65, 4618–4634; d) S. H. Wunderlich,
P. Knochel, Angew. Chem. Int. Ed. 2007, 46, 7685–7688; Angew.
Chem. 2007, 119, 7829-7832. For examples of transition metal
catalyzed C–H activation see: e) A. García-Rubia, R. G. Arrayas, J. C.
Carretero, Angew. Chem. Int. Ed. 2009, 48, 6511–6515; Angew. Chem.
2009, 121, 6633-6637; f) M. Kim, J. Park, S. Sharma, S. Han, S. H.
Han, J. H. Kwak, Y. H. Jung, I. S. Kim, Org. Biomol. Chem. 2013, 11,
7427–7434; g) D. G. Yu, T. Gensch, F. De Azambuja, S. Vásquez-
Céspedes, F. Glorius, J. Am. Chem. Soc. 2014, 136, 17722–17725; h)
S. Sharma, Y. Shin, N. K. Mishra, J. Park, S. Han, T. Jeong, Y. Oh, Y.
Lee, M. Choi, I. S. Kim, Tetrahedron 2015, 71, 2435–2441; i) M.
Moselage, N. Sauermann, J. Koeller, W. Liu, D. Gelman, L. Ackermann,
Synlett 2015, 26, 1596–1600; j) Y. Suzuki, B. Sun, K. Sakata, T.
Yoshino, S. Matsunaga, M. Kanai, Angew. Chem. Int. Ed. 2015, 54,
9944–9947; Angew. Chem. 2015, 127, 10082-10085; k) W. Liu, S. C.
Richter, Y. Zhang, L. Ackermann, Angew. Chem. Int. Ed. 2016, 55,
7747–7750; Angew. Chem. 2016, 128, 7878-7881; l) J. Y. Lee, H. Ha,
S. Bae, I. Han, J. M. Joo, Adv. Synth. Catal. 2016, 358, 3458–3470; m)
G. S. Kumar, M. Kapur, Org. Lett. 2016, 18, 1112–1115; n) J. Xia, L.
Kong, X. Zhou, G. Zheng, X. Li, Org. Lett. 2017, 19, 5972–5975; o) M.
R. Sk, S. S. Bera, M. S. Maji, Org. Lett. 2018, 20, 134–137; p) X. Wu, H.
Ji, Org. Lett. 2018, 20, 2224–2227.
Experimental Section
To a solution of an indole 5 (1.0 equiv) in CH2Cl2 (0.25 M) was added
triethylamine (1.5 equiv) and N-chlorosuccinimide (1.3 equiv) at 0 °C.
After stirring for 15 minutes at this temperature allylboronate 8 (1.5 equiv)
was added, followed by stirring for an additional hour at room
temperature. The reaction was quenched by the addition of aq. NaOH
solution (0.125 M) and stirred for an additional two hours. Then, the
reaction mixture was extracted with EtOAc (3 x), washed with brine, dried
over Na2SO4, and concentrated in vacuo. The crude product was purified
by silica gel column chromatography.
[9]
J. M. Schkeryantz, J. C. G. Woo, P. Siliphaivanh, K. M. Depew, S. J.
Danishefsky, J. Am. Chem. Soc. 1999, 121, 11964–11975.
Acknowledgments
[10] For an overview of the synthesis and reactivity of allylic boronates, see:
C. Diner, K. J. Szabó, J. Am. Chem. Soc. 2017, 139, 2–14.
We thank Jurriën Collet and Daniel Preschel for HRMS
measurements and Elwin Janssen for practical and NMR
support (all Vrije Universiteit Amsterdam). This work was
financially supported by the Netherlands Organisation for
Scientific Research (NWO).
[11] Reactions in the absence of NCS did not lead to reductive C2 allylation
as previously reported (under different conditions) by Batey and Szabó:
a) F. Nowrouzi, R. A. Batey, Angew. Chem. Int. Ed. 2013, 52, 892–895;
Angew. Chem. 2013, 125, 926-929; b) R. Alam, A. Das, G. Huang, L.
Eriksson, F. Himo, K. J. Szabó, Chem. Sci. 2014, 5, 2732–2738.
[12] In contrast, reductive reverse prenylation of indoles with allylboronic
acid derivatives was previously reported: R. Alam, C. Diner, S. Jonker,
L. Eriksson, K. J. Szabó, Angew. Chem. Int. Ed. 2016, 55, 14417–
14421; Angew. Chem. 2016, 125, 14629–14633.
Keywords: indoles • allylation • boron reagents • heterocycles •
tryptophan
[13] Danishefsky et al. also noted the acid lability of 2-prenylated indoles
(see ref [9]).
[1]
[2]
[3]
a) A. Baeyer, Justus Liebigs Ann. Chem. 1866, 140, 295–313; b) A.
Baeyer, A. Emmerling, Ber. Dtsch. Chem. Ges. 1869, 2, 679–682.
for a comprehensive review on indole synthesis see: D. F. Taber, P. K.
Tirunahari, Tetrahedron 2011, 67, 7195–7210.
[14] A single example of reductive propargylation of indole was recently
reported by Szabó: J. Zhao, S. J. T. Jonker, D. N. Meyer, G. Schulz, C.
D. Tran, L. Eriksson, K. J. Szabó, Chem. Sci. 2018, 9, 3305–3312.
a) M. Ishikura, K. Yamada, T. Abe, Nat. Prod. Rep. 2010, 27, 1630–
1680; b) M. Ishikura, T. Abe, T. Choshi, S. Hibino, Nat. Prod. Rep. 2013,
30, 694–752; c) M. Ishikura, T. Abe, T. Choshi, S. Hibino, Nat. Prod.
Rep. 2015, 32, 1389–1471.
[4]
[5]
For an overview, see: M. Bandini, A. Eichholzer, Angew. Chem. Int. Ed.
2009, 48, 9608; Angew. Chem. 2009, 121, 9786.
See, for example: a) L. Furst, B. S. Matsuura, J. M. R. Narayanam, J.
W. Tucker, C. R. J. Stephenson, Org. Lett. 2010, 12, 3104–3107. b) .M.
M. Nebe, D. Loeper, F. Fürmeyer, T. Opatz, Eur. J. Org. Chem. 2018,
2471–2476.
[6]
a) L. Jiao, T. Bach, J. Am. Chem. Soc 2011, 133, 12990–12993; b) L.
Jiao, E. Herdtweck, T. Bach, J. Am. Chem. Soc. 2012, 134, 14563–
14572; c) H. K. Potukuchi, T. Bach, J. Org. Chem. 2013, 78, 12263-
12267; d) M. Wegmann, M. Henkel, T. Bach, Org. Biomol. Chem. 2018,
16, 5376–5385.
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European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Indoles
Jordy M. Saya, Ellen D.H. van
Wordragen, Romano V. A. Orru and
Eelco Ruijter*
Page No. – Page No.
ALL(yl) IN(dole)!: Allylboration of in situ generated 3-chloroindolenines allows the
mild and operationally simple C2 allylation of 3-subsituted indoles. The reaction has
a broad functional group tolerance and is compatible with various substituted
allylboronates. The utility of this method is demonstrated by the total synthesis of
tryprostatin B.
Mild and Practical Indole C2 Allylation
by Allylboration of in situ-Generated
3-Chloroindolenines
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