Catalytic Friedel-Crafts reaction of aminocyclopropanes

Article abstract of DOI:10.1021/ol401616a

A Lewis acid catalyzed Friedel-Crafts reaction between donor-acceptor aminocyclopropanes and indoles and other electron-rich aromatic compounds is reported. Indole alkylation at the C3 position was generally obtained for a broad range of functional groups and substitution patterns. In the case of C3-substituted indoles, C2 alkylation was observed. The reaction gives a rapid access to gamma amino acid derivatives present in numerous bioactive molecules.

Full text of DOI:10.1021/ol401616a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Catalytic FriedelꢀCrafts Reaction
of Aminocyclopropanes
ꢀ ^
Florian de Nanteuil, Joachim Loup, and Jerome Waser*
Laboratory of Catalysis and Organic Synthesis, Institute of Chemical Sciences and
ꢀ ꢀ
Engineering, Ecole Polytechnique Federale de Lausanne, EPFL SB ISIC LCSO,
BCH 4306, 1015 Lausanne, Switzerland
jerome.waser@epfl.ch
Received June 8, 2013
ABSTRACT
A Lewis acid catalyzed FriedelꢀCrafts reaction between donorꢀacceptor aminocyclopropanes and indoles and other electron-rich aromatic
compounds is reported. Indole alkylation at the C3 position was generally obtained for a broad range of functional groups and substitution
patterns. In the case of C3-substituted indoles, C2 alkylation was observed. The reaction gives a rapid access to gamma amino acid derivatives
present in numerous bioactive molecules.
Substituted γ-aminobutyric acid (GABA) derivatives
are found in numerous natural and synthetic neuro-
transmitters,1 in peptidomimetics2 and in the core of a large
number of alkaloid natural products. In particular, elec-
tron-rich aromatic substituents are frequently encountered
in the γ position of GABA derivatives in important classes
of natural products, such as the indole alkaloids vindo-
line (1) and eburnamonine (2) or the Erythrina alkaloid
3-demethoxyerythratidinone (3) (Scheme 1). Consequently,
a fast and general approach to these key building blocks
would be highly desirable.3
In this context, the nucleophilic attack of an electron-
rich aromatic or an amine at the γ position of a carbonyl
group would give an efficient entry into this import-
ant class of GABA derivatives (Scheme 1). In order to
achieve this transformation, the Umpolung of the normal
reactivity at the nucleophilic γ position is required. Acti-
vated donorꢀacceptor (DA) cyclopropanes represent such
Umpolung synthons and have been used in the past as
olefin homologues.4 In previous studies the nucleophilic
attack of an amine onto aromatic DA cyclopropanes has
been reported to access GABA analogues (Scheme 1, (1)).5
If a high diversity in the aromatic substituent is desired,
an alternative approach involving attack of a nucleophilic
aromatic compound onto a nitrogen-substituted synthon
as represented by an aminocyclopropane would be more
efficient (Scheme 1, (2)). Nevertheless, such an approach
has not yet been exploited.
On the other hand, intermolecular FriedelꢀCrafts
reactions between donorꢀacceptor cyclopropanes and
electron-rich aromatic compounds including indoles have
(4) (a) Reissig, H.-U.; Zimmer, R. Chem. Rev. 2003, 103, 1151.
(b) Yu, M.; Pagenkopf, B. L. Tetrahedron 2005, 61, 321. (c) Rubin,
M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117. (d) De
Simone, F.; Waser, J. Synthesis 2009, 2009, 3353. (e) Carson, C. A.; Kerr,
M. A. Chem. Soc. Rev. 2009, 38, 3051. Theoretical study: (f) Schneider,
T. F.; Werz, D. B. Org. Lett. 2011, 13, 1848.
(5) (a) Blanchard, L. A.; Schneider, J. A. J. Org. Chem. 1986, 51,
1372–1374. (b) Lifchits, O.; Charette, A. B. Org. Lett. 2008, 10, 2809.
(c) Lindsay, V. N. G.; Nicolas, C.; Charette, A. B. J. Am. Chem. Soc.
2011, 133, 8972. (d) So, S. S.; Auvil, T. J.; Garza, V. J.; Mattson, A. E.
Org. Lett. 2012, 14, 444. (e) Zhou, Y. Y.; Wang, L. J.; Li, J.; Sun, X. L.;
Tang, Y. J. Am. Chem. Soc. 2012, 134, 9066. (f) Emmett, M. R.; Grover,
H. K.; Kerr, M. A. J. Org. Chem. 2012, 77, 6634.
(1) (a) Johnston, G. A. R. Pharm. Ther. 1996, 69, 173. (b) Chebib, M.;
Johnston, G. A. R. J. Med. Chem. 2000, 43, 1427.
(2) Sudev, P. G.; Chatterjee, S.; Shamala, N.; Balaram, P. Chem. Rev.
2011, 111, 657.
ꢀ~
(3) Ordonez, M.; Cativiela, C. Tetrahedron: Asymmetry 2007, 18, 3.
r
10.1021/ol401616a
XXXX American Chemical Society

been studied in the past, especially by the groups of Kerr,
Pagenkopf and Ivanova.6 In 2013, Johnson developed
an enantioselective FriedelꢀCrafts reaction between aryl
cyclopropane and silyl-protected indoles using a chiral
Lewis acid catalyst.7 However, only alkyl, aryl or alkoxy
substituents have been used as the donating group on the
cyclopropane.8
(Scheme 2). The reaction worked with unprotected indoles
as well as other electron-rich aromatic compounds and
tolerated a broad range of functional groups. In the case
of C3-substituted indoles, C2-alkylated products could be
obtained, probably via a selective 1,2-shift of the amino
acid side-chain.
Scheme 2. FriedelꢀCrafts with Diester Aminocyclopropane 4a
Scheme 1. Natural Products Containing a GABA-Derived Core
and Key Disconnections
Preliminary screening of Lewis acids and solvents al-
lowed us to identify scandium triflate in nitromethane as
promising conditions for the alkylation of N-protected
indoles with the phthaloyl protected aminocyclopropane
diester 4b at room temperature.10 However, when switch-
ing to unprotected indole (5a), double addition product 7a
was observed as major side product in the reaction mixture
(Scheme 3). Even after extensive optimization of the reac-
tion conditions, it was not possible to achieve full selectiv-
ity toward the desired product 6.
Since 2010, our group has been involved in the study of
the reactivity of aminocyclopropanes.9 The release of ring
strain combined with bond polarization allowed the gen-
eration of reactive a 1,3 zwitterionic synthon, which could
cyclize on indoles or react with enol ethers, aldehydes
and ketones to afford cyclopentyl- and tetrahydrofuryl-
amines. In this latter work, optimization of the electronic
properties of the substituents on the nitrogen resulted in
the discovery that phthalimide-substituted cyclopropane
diesters afford the right balance between reactivity and
stability.9cꢀe Herein, we would like to report the first
successful intermolecular FriedelꢀCrafts reaction of in-
doles with aminocyclopropanesbasedon fine-tuning of the
electron-withdrawing properties of the diester group and
the identification of scandium triflate as the best catalyst
Scheme 3. Fine-Tuning of the Aminocyclopropane Structure
for the FriedelꢀCrafts Alkylation of Indole (5a)d
(6) (a) Harrington, P.; Kerr, M. A. Tetrahedron Lett. 1997, 38, 5949.
(b) Kerr, M. A.; Keddy, R. G. Tetrahedron Lett. 1999, 40, 5671.
(c) England, D. B.; Woo, T. K.; Kerr, M. A. Can. J. Chem. 2002, 80,
992. (d) Grover, H. K.; Lebold, T. P.; Kerr, M. A. Org. Lett. 2011, 13,
220. (e) Emmett, M. R.; Kerr, M. A. Org. Lett. 2011, 13, 4180. (f) Bajtos,
B.; Yu, M.; Zhao, H. D.; Pagenkopf, B. L. J. Am. Chem. Soc. 2007, 129,
9631. (g) Ivanova, O. A.; Budynina, E. M.; Grishin, Y. K.; Trushkov,
I. V.; Verteletskii, P. V. Eur. J. Org. Chem. 2008, 5329. (h) Chagarovskiy,
A. O.; Budynina, E. M.; Ivanova, O. A.; Grishin, Y. K.; Trushkov, I. V.;
Verteletskii, P. V. Tetrahedron 2009, 65, 5385.
a Reaction conditions: cyclopropane (0.034 mmol), 5a (0.051 mmol),
Sc(OTf)3 (3.4 μmol), nitromethane (0.2 mL), rt, 1 h. b Determined by
1H NMR of the crude reaction mixture. c DCM (0.5 mL) was used. d The
bis-indole adduct 7b was not isolated. The NMR ratio was determined
by analogy with 7a.
(7) Wales, S. M.; Walker, M. M.; Johnson, J. S. Org. Lett. 2013, 15,
2558.
We then turned our attention to the further adjustment
of the structure of the aminocyclopropane. A series of
aminocyclopropanes 4cꢀf with different nitrogen protect-
ing groups were examined in the alkylation reaction. The
use of electron-poor bromo and dichloro derivatives 4c
and 4dofphthalimide aswell asa smaller maleimide 4eor a
(8) There is a single example of aminocyclopropanes opening by
trimethoxybenzene: Gharpure, S. J.; Vijayasree, U.; Reddy, S. R. B. Org.
Biomol. Chem. 2012, 10, 1735. During their recent work on the Friedelꢀ
Crafts alkylation of indoles,7 Johnson and co-workers studied the use of
phthalimido-cyclopropanes, but no reactivity was observed under their
conditions.
(9) (a) De Simone, F.; Gertsch, J.; Waser, J. Angew. Chem., Int. Ed.
2010, 49, 5767. (b) De Simone, F.; Saget, T.; Benfatti, F.; Almeida, S.;
Waser, J. Chem.;Eur. J. 2011, 17, 14527. (c) de Nanteuil, F.; Waser, J.
Angew. Chem., Int. Ed. 2011, 50, 12075. (d) Benfatti, F.; de Nanteuil, F.;
Waser, J. Org. Lett. 2012, 14, 386. (e) Benfatti, F.; de Nanteuil, F.;
Waser, J. Chem.;Eur. J. 2012, 18, 4844.
(10) See Supporting Information for a complete list of tested reaction
conditions and Lewis acids.
B
Org. Lett., Vol. XX, No. XX, XXXX

largernaphthylimide 4fonthe cyclopropanedid not havea
favorable impact on the selectivity. In contrast, modifica-
tion of the acceptor diester group (cyclopropanes 4g
and 4a) had a strong influence on the reaction outcome.
The best selectivity was obtained using the more electron-
withdrawing trifluoro ethanol derivative 4a, which af-
forded only the desired product. Finally, replacing the
toxic nitromethane by diethyl ether was possible without
loss of selectivity.
Table 1. FriedelꢀCrafts Reaction with Aminocyclopropane 4ag
With this simple protocol for the addition of indole to
aminocyclopropanes in hand, we investigated the scope of
the reaction (Table 1). As showed during optimization,
unprotected indole (5a) was a suitable partner for the
reaction and the product 6aa could be isolated in 85%
yield on a 0.2 mmol scale and in 87% yield on a 2.8 mmol
scale, showing that scaling up was straightforward for this
transformation (entry 1). Electron-donating (methoxy)
and -withdrawing (chloro, bromo and nitro) substituents
on the benzene ring were well tolerated (entries 2ꢀ6). The
compatibility with halogens or a boronic ester is particu-
larly interesting, as the obtained products are easily further
functionalized via cross-coupling reactions. Next, the use
of N-alkyl substituted indoles was investigated (entries
7ꢀ9). N-Methyl indole (5g) afforded the alkylation pro-
duct 6ag in 94% yield on a 0.2 mmol scale and in 83% yield
on a 2.4 mmol scale (entry 7). A protected alcohol on the
N-alkyl chain (entry 8) as well as an ester group on the
benzene ring (entry 9) were well tolerated. Alkylation of
indolessubstitutedatthe position C2by analkyl, anarylor
a moresensitive alkynyl11 functionalitywas alsopossiblein
52ꢀ97% yield (entries 10ꢀ12). When C3-substituted in-
doles were examined as substrates, selective C2-alkylation
was observed (entries 13ꢀ15). This product is probably
formed by C3-alkylation, followed by 1,2-alkyl shift.6c,12
This result is interesting, as in most reactions of C3-sub-
stituted indoles with cyclopropanes, a [3 þ 2] annulation
occurs preferentially over 1,2-shift.6b,13 The observed out-
come could be due to the ability of the nitrogen substituent
to stabilize a partial positive charge during the alkyl shift.
The C2 alkylation was not limited to skatole (entry 13),
but the reaction was slower for other substrates, and
heating to 60 °C was required to obtain full conversion
in the case of 3-alkynyl indole 5n14 (entry 14) and protected
tryptophol 5o (entry 15). For the latter, protection of the
oxygen was required to prevent side reactions.
Finally, we wondered if this protocol could be extended
to other classes of electron-rich aromatic compounds
(11) Obtained in one step by the alkynylation of N-methyl indole (5g)
using a method developed in our group: Tolnai, G. L.; Ganss, S.; Brand,
J. P.; Waser, J. Org. Lett. 2013, 15, 112.
(12) Alternative mechanisms involving direct addition on the C2
position or reversible C3-addition in competition with irreversible C2
addition cannot be completely excluded, but appeared less probable: the
former because of the higher electron-density at the C3 position, and the
latter as it would require the formation of an highly reactive carboca-
tionic intermediate or a strained cyclopropane.
a E = CO2CH2CF3. Reaction conditions: 4a (0.20 mmol), indole
(0.22 mmol), Sc(OTf)3 (0.01 mmol), Et2O (1.2 mL), rt. b Isolated yields.
c On a 1.5 g scale. d Isolated after transesterification (see Supporting
Information for more details). e On a 1.3 g scale. f Reaction in Et2O at
35 °C. g Reaction in toluene at 60 °C.
(13) Xiong, H.; Xu, H.; Liao, S.; Xie, Z.; Tang, Y. J. Am. Chem. Soc.
2013, 135, 7851.
(14) Obtained in one step by the alkynylation of indole (5a) using a
method developed in our group: Brand, J. P.; Charpentier, J.; Waser, J.
Angew. Chem., Int. Ed. 2009, 48, 9346.
(Figure 1). Although furans and thiophenes were unreac-
tive under these conditions, pyrrole reacted efficiently to
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 4. Synthetic Transformations of the Alkylation
Products
Figure 1. Products of the alkylation of electron-rich aromatic
compounds. Reaction conditions: 4a (0.20 mmol), aromatic
compound (0.22 mmol), Sc(OTf)3 (0.01 mmol), Et2O (1.2 mL),
rt. (a) Isolated yield. (b) Ratio of isolated material. (c) Deter-
mined by 1H NMR.
give a 2:1 C2/C3 mixture of regioisomers 8a and 8b in 91%
yield.15 Protection of the nitrogen of pyrrole with a triiso-
propylsilyl group allowed to switch the selectivity and to
isolate the C3-alkylated product 9b with good selectivity.
Anisole could also be used, leading to a mixture of para/
ortho-alkylation products 10a and 10b. In the case of
phenol, product 11b resulting from O-alkylation was the
major product. These preliminary results highlight the
broad potential of donorꢀacceptor substituted aminocy-
clopropanes for the FriedelꢀCrafts alkylation of electron-
rich aromatic compounds.
In order to show that the products are useful synthetic
precursors, deprotection of the phthalimide was conducted
using diaminoethane in isopropanol after transesteri-
fication of the difluoroethanol malonate (Scheme 4, (1)).
During this process, the free amine cyclized on the malonic
ester giving lactam 12a and 12b as a 1:1 ratio of equilibrat-
ing diastereoisomers. An efficient access to substituted γ
lactams is interesting, as they represent an important
class of bioactive natural products and synthetic drugs.
Modified Krapcho conditions16 allowed us to obtain the
monoester derivative 13 in quantitative yield (Scheme 4,
(2)). When these conditions were applied to C2 adduct
6am, tricyclic product 14, which corresponds to the core
skeleton of natural products such as eburnamonine (2),
was isolated in 73% yield (Scheme 4, (3)).
In conclusion, we have shown that phthaloyl protected
diester aminocyclopropanes are powerful homo-olefin
equivalents in FriedelꢀCrafts alkylation reactions and
readily react with electron-rich aromatic compounds to
afford GABA analogues. C2-alkylation was observed for
C3-substitued indoles, which is probably the result of
C3-alkylation followed by selective shift of the amino-
substituted alkyl chain. Finally, the synthetic potential of
the products was highlighted by the easy removal of the
phthaloyl protecting group, as well as Krapcho decarboxyla-
tion. Future works will focus on the development of en-
antioselective methods, as well as the application of this
transformation in the synthesis of bioactive natural products.
Supporting Information Available. Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank the EPFL and SNF (Grant
200021_129874) for funding and F. Hoffmann-La Roche,
Ltd., for an unrestricted research grant. Eloisa Serrano and
Nicolas Gaeng (both EPFL) are acknowledged for the
synthesis of starting materials.
(15) These results are in accordance with the lower nucleophilicity of
furans and thiophenes as quantified by Mayr’s reactivity scale: Mayr,
H.; Ofial, A. R. J. Phys. Org. Chem. 2008, 21, 584.
(16) Kaburagi, Y.; Tokuyama, H.; Fukuyama, T. J. Am. Chem. Soc.
2004, 126, 10246.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX