Direct synthesis of chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines via a catalytic asymmetric intramolecular aza-Friedel-Crafts reaction

Article abstract of DOI:10.1021/ol2018328

The direct asymmetric intramolecular aza-Friedel-Crafts reaction of N-aminoethylpyrroles with aldehydes catalyzed by a chiral phosphoric acid represents the first efficient method for the preparation of medicinally interesting chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines with high yields and high enantioselectivities. This strategy has been shown to be quite general toward various aldehydes and pyrrole derivatives.

Full text of DOI:10.1021/ol2018328

ORGANIC
LETTERS
2011
Vol. 13, No. 17
4490–4493
Direct Synthesis of Chiral 1,2,3,
4-Tetrahydropyrrolo[1,2-a]pyrazines via a
Catalytic Asymmetric Intramolecular
Aza-FriedelꢀCrafts Reaction
Yuwei He,† Maohui Lin,† Zhongmin Li,† Xinting Liang,† Guilong Li,*,† and
Jon C. Antilla*,‡
School of Chemistry and Chemical Engineering, Sun Yat-sen University, 135 Xingang Xi
Lu, Guangzhou, 510275, China, and Department of Chemistry, University of South
Florida, 4202 East Fowler Avenue, CHE 205A, Tampa, Florida 33620, United States
liglong@mail.sysu.edu.cn; jantilla@usf.edu
Received May 27, 2011
ABSTRACT
The direct asymmetric intramolecular aza-FriedelꢀCrafts reaction of N-aminoethylpyrroles with aldehydes catalyzed by a chiral phosphoric acid
represents the first efficient method for the preparation of medicinally interesting chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines with high yields
and high enantioselectivities. This strategy has been shown to be quite general toward various aldehydes and pyrrole derivatives.
The intramolecular aza-FriedelꢀCrafts reaction has
been extensively investigated in the past century.1 While
tremendous progress has been made, the catalytic enantio-
selective intramolecular variant has only been recently
reported. Seminal work by Jacobsen,2 List,3 and others4,5-
describes several types of catalytic asymmetric intramole-
cular aza-FriedelꢀCrafts reactions. One such example is
the PictetꢀSpengler reaction, an invaluable method for the
synthesis of tetrahydro-β-carbolines, from tryptamines or
phenyl ethylamines and carbonyl compounds. Despite
those breakthroughs, the development of novel asym-
metricintramolecularaza-FriedelꢀCraftsreactions, which
tolerate various nucleophilic aryl moieties, would be of
great importance. As part of our continuing efforts in the
development of novel Brønsted acid catalyzed reaction
methodologies,6,7we chose to explore pyrrole derivatives
as competent substrates for asymmetric intramolecular
† Sun Yat-sen University.
‡ University of South Florida.
(1) (a) Pictet, A.; Spengler, T. Ber. Dtsch. Chem. Ges. 1911, 44, 2030.
(b) Tatsui, G. J. Pharm. Soc. Jpn. 1928, 48, 92. For reviews:(c) Cox,
E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797. (b) Royer, J.; Bonin, M.;
Micouin, L. Chem. Rev. 2004, 104, 2311. (d) Bentley, K. W. Nat. Prod.
Rep. 2004, 21, 395.
(2) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126,
10558. (b) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N.
J. Am. Chem. Soc. 2007, 129, 13404. (c) Raheem, I. T.; Thiara, P. S.;
Jacobsen, E. N. Org. Lett. 2008, 10, 1577. (d) Klausen, R. S.; Jacobsen,
E. N. Org. Lett. 2009, 11, 887.
(3) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128,
1086.
(6) (a) Li, G.; Kaplan, M. J.; Wojtas, L.; Antilla, J. C. Org. Lett. 2010,
12, 1960. (b) Li, G.; Antilla, J. C. Org. Lett. 2009, 11, 1075. (c) Li, G.;
Fronczek, F. R.; Antilla, J. C. J. Am. Chem. Soc. 2008, 130, 12216. (d) Li,
G.; Liang, Y.; Antilla, J. C. J. Am. Chem. Soc. 2007, 129, 5830.
(7) (a) We reported an example of a chiral 1,2,3,4-tetrahydropyrrolo-
[1,2-a]pyrazine derived from an addition to an imine by a pyrrole. See: Li,
G.; Rowland, G. B.; Rowland, E. B.; Antilla, J. C. Org. Lett. 2007, 9, 4065.
(b) While this manuscript was in preparation, Savoia D. et al reported
an auxiliary based method to prepare chiral 1,2,3,4-tetrahedropyrrolo-
[1,2-a]pyrazines. See: Gualandi, A.; Cerisoli, L.; Monari, M.; Savoia, D.
Synthesis 2011, 909.
(4) (a) Wanner, J.; van der Haas, M. R. N. S.; de Cuba, K. R.; van
Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2007, 46, 7485.
(b) Sewgobind, N. V.; Wanner, M. J.; Ingemann, S.; de Gelder, R.; van
Maarseveen, J. H.; Hiemstra, H. J. Org. Chem. 2008, 73, 6405.
(5) Dixon reported an N-acyliminium cyclization cascade; see: (a)
Muratore, M. E.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.; Trevitt,
G.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131, 10796. (b) Holloway,
C. A.; Muratore, M. E.; Storer, R. l.; Dixon, D. J. Org. Lett. 2010, 12,
4720.
r
10.1021/ol2018328
Published on Web 08/11/2011
2011 American Chemical Society

aza-FriedelꢀCrafts reactions. While demonstrative of bio-
logical and medicinal importance, pyrroles are consider-
ably less explored for asymmetric intramolecular aza-
FriedelꢀCrafts reactions.8 A lone example highlighting
pyrroles in an elegant intermolecular N-acyliminium cycli-
zation was reportedby Jacobsen.2c Theirpreviousthiourea
scaffold for transformations of indole derivatives2b was
further optimized for use with 3-pyrrole ethyl hydroxyla-
ctams.
Table 1. Catalyst Screeninga
1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines represent a
class of particularly interesting heterocycles, due to their
potential antiarrhythmic,9 antiamnesic, antihypoxic,10
psychotropic,11 antihypersensitive,12 and aldose reductase
inhibition activities.13 In addition, these compounds have
been reported as potassium channel ligands,14 serotonin
and noradrenaline reuptake inhibitors,15 and cannabinoid
receptor agonists.16 To our knowledge, no example of an
efficient catalytic asymmetric methodology for the pre-
paration of chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyraz-
ines has been reported.7 Herein, we report a catalytic
asymmetric synthesis of chiral 1,2,3,4-tetrahydropyrrolo-
[1,2-a]pyrazines with high enantioselectivities. This strat-
egy features a direct condensation of N-aminoethylpyrrole
and an aldehyde, followed by an intramolecular aza-
FriedelꢀCrafts reaction under very mild reaction condi-
tions (Scheme 1).
a All reactions were run on a 0.1 mmol scale in 1.0 mL of toluene;
yield refers to isolated yield; % ee was determined by Chiral HPLC. See
Supporting Information for details.
developments in organocatalysis. Their tremendous utility
was first reported in 2004 through independent work from
Akiyama18 and Terada.19 In light of this work we believed
that the plan outlined in Scheme 1 could also be catalyzed
by chiral phosphoric acids. We began our investigation
with N-aminoethylpyrrole (1.0 equiv) and benzaldehyde
(1.0 equiv), a 3,30-phenyl substituted BINOL derived
phosphoric acid (PA1a, 5 mol %, Table 1) as the catalyst,
Scheme 1. Proposed Pathway for the Preparation of Chiral
1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines
˚
toluene as the solvent, and 4 A MS as a desiccant. The
reaction was performed under ambient temperature (25 °C).
To our delight, the cyclization proceeded smoothly and
generated the desired 1,2,3,4-tetrahydropyrrolo[1,2-a]-
pyrazine 3a in high yield (86%). A very low enantiomeric
excess (8% ee) was initially observed. Encouraged with
the reactivity, we screened additional BINOL derived
chiral phosphoric acids under similar reaction conditions
(Table 1). Bulky catalyst PA1c provided a moderate yield
but still an extremely poor ee (71% yield and 6% ee). Use
of 9-anthryl substituted catalyst PA1d furnished the pro-
ductinhigh yield but withonlya moderateimprovement in
enantioselectivity (85% yield and 30% ee). Gratifyingly,
the 2,4,6-triisopropylphenyl substituted phosphoric acid
(R)-PA1e20 was found to be a superior catalyst for this
cyclization sequence. The reaction yielded product 3a in
91% yield and 76% ee under mild reaction conditions in
toluene.
Asymmetric transformations catalyzed by chiral phos-
phoric acids17 represent one of the most remarkable
(8) (a) Della Bella, D. Boll. Chim. Farm. 1972, 111, 5. (b) Guzman, A.;
Yuste, F.; Toscano, R. A.; Young, J. M.; Vanhorn, A. R.; Muchowski,
J. M. J. Med. Chem. 1986, 29, 589. (c) Kleemann, A.; Engel, J.; Kutscher,
B.; Reichert, D. Pharmaceutical Substances, 4th ed.; Thieme: New York,
2001. (d) Katritzky, A. R.; Jain, R.; Xu, Y.; Steel, P. J. J. Org. Chem. 2002,
67, 8220.
(9) Likhosherstov, A. M.; Filippova, O. V.; Peresada, V. P.;
Kryzhanovskii, S. A.; Vititnova, M. B.; Kaverina, N. V.; Reznikov,
K. M. Pharm. Chem. J. 2003, 37, 6.
(10) Seredenin, S. B.; Voronina, T. A.; Beshimov, A.; Peresada, V. P.;
Likhosherstov, A. M. RU 2099055, 1997.
(11) Seredenin, S. B.; Voronina, T. A.; Likhosherstov, A. M.; Peresada,
V. P.; Molodavkin, G. M.; Halikas, J. A. US 5378846, 1995, 10 pp.
(12) Peresada, V. P.; Medvedev, O. S.; Likhosherstov, A. M.; Skoldinov,
A. P. Khim.-Farm. Zh. 1987, 21, 1054.
A solvent screen revealed that nonpolar solvents, as well
as polar solvents, allow the transformation to proceed with
good enantioselectivity and yield (Table 2). Toluene pro-
vided a high isolated yield with only moderate ee. Benzene
allowed for an increase in ee to 86%, with slightly dimin-
ished yields of the product (80% yield, entry 2). Similar
(13) Negoro, T.; Murata, M.; Ueda, S.; Fujitani, B.; Ono, Y.;
Kuromiya, A.; Komiya, M.; Suzuki, K.; Matsumoto, J.-i. J. Med. Chem.
1998, 41, 4118.
(14) Merla, B.; Christoph, T.; Oberboersch, S.; Schiene, K.;
Bahrenberg, G.; Frank, R.; Kuehnert, S.; Schroeder, W. WO 2008046582,
2008, 93 pp.
(15) Finkenzeller, K.; Kluge, S. WO 2008000424, 2008.
(16) Gahman, T. C.; Zhao, C.; Lang, H.; Massari, M. E. US
20090062253, 2009, 66 pp.
(17) For recent reviews on chiral phosphoric acid catalysis, see: (a)
Akiyama, T. Chem. Rev. 2007, 107, 5744. (b) You, S.-L.; Cai, Q.; Zeng,
M. Chem. Soc. Rev. 2009, 38, 2190. (c) Kampen, D.; Reisinger, C. M.;
List, B. Top. Curr. Chem. 2010, 291, 395. (d) Terada, M. Synthesis 2010,
1929.
(18) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem.,
Int. Ed. 2004, 43, 1566.
(19) (a) Uraguchi, D.; Sorimachi, K.; Terada, M. J. Am. Chem. Soc.
2004, 126, 11804. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc. 2004,
126, 5356.
(20) Hoffmann, S.; Seayad, A.; List, B. Angew. Chem., Int. Ed. 2005,
44, 7424.
Org. Lett., Vol. 13, No. 17, 2011
4491

Table 2. Optimization of Reaction Conditionsa
Table 3. Scope of Aldehyde Substratesa,b
PA1e
temp
ratio
yield
[%]b
ee
[%]c
entry
solvent
[mol %]
[°C]
1a/2a
1
PhCH3
C6H6
CH2Cl2
CHCl3
Et2O
5
5
25
25
25
25
25
25
25
25
25
25
0
1/1
91
80
88
97
80
82
82
91
86
87
76
86
76
86
86
85
85
81
94
94
86
94
64
88
2
1/1
3
5
1/1
4
5
1/1
5
5
1/1
6
CH3CN
THF
THF
5
1/1
7
5
1/1
8
10
10
10
10
10
1/1
1.5/1
1/1.5
1/1
9
THF
10
11
12
THF
THF
THF
50
1/1
a Unless otherwise noted, all reactions were run on a 0.1 mmol scale
in 1.0 mL of solvent. b Isolated yield. c Ee was determined by Chiral
HPLC; see Supporting Information for details.
results were obtained using ether (entry 5). The cyclization
in dichloromethane and chloroform produced chiral
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine 3a in excellent
yields and high enantioselectivities (88% and 97% yield;
86% and 85% ee, respectively; entries 3 and 4). Addition-
ally, a more polar solvent, acetonitrile, gave a lower yield
and ee (entry 6; 82% yield and 81% ee). THF was found to
be the optimal solvent for the cyclization with respect to
enantioselectivity (ee up to 94%, entry 7). Increasing the
catalyst loading to 10 mol % further improved the yield to
91% without detriment to the enantiomeric excess (entry 8).
It is interesting to note that temperature plays a crucial
role in rendering the cyclization highly enantioselective.
When the reaction was conducted at 0 and 50 °C, a
noticeable drop in enantioselectivity (65% and 88% ee;
entries 9 and 10) was observed. Further optimization of the
substrate ratio showed that when N-aminoethylpyrrole
was used in excess, the ee dropped (86% ee, entry 11). In
the presence of excess benzaldehyde the ee remained
unaffected (94% ee, entry 12). In order to exclude the
possibility of N-aminoethylpyrrole negatively affecting
the enantioselectivity, a small excess of aldehyde was
utilized in most cases for the following studies on the
substrate scope.
a Isolated yield. b Ee was determined by Chiral HPLC; see Support-
ing Information for details. c The absolute configuration was determined
by single X-ray crystal diffraction; see Supporting Information for
details.
(90% and 87% ee’s, respectively; 3e and 3i). Aldehydes
bearing a strong electron-donating group (4-methoxy, 3j) or
a strong electron-withdrawing group (4-nitro, 3k) gave
relatively lower ee values. The decrease in ee can possibly
be attributed to hydrogen-bonding interactions between the
aldehyde substituents and the catalyst, although at this time
the exact reason is unclear. Aliphatic aldehydes underwent
cyclization smoothly to produce the corresponding chiral
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines. Cyclohex-
anecarbaldehyde gave product 3l in 90% yield and 91% ee.
However, other cyclic aliphatic aldehydes bearing smaller
rings, for example, cyclopentanecarbaldehyde and cyclo-
propanecarbaldehyde, gave lower ee’s (3m and 3n). Some
branched aliphatic aldehydes such as isobutyraldehyde
and 3-methylbutanal also provided moderate enantioselec-
tivities (3o and 3p). Linear aliphatic aldehydes showed
poor enantioselectivity under the optimized reaction
conditions.21
In order to further evaluate the generality of this meth-
odology, several derivatives of N-aminoethylpyrrole were
screened. Table 4 reveals that 2-methyl substituted pyrrole
1breactsfasterwithbenzaldehyde thanpyrrole1a, yielding
product 3q in 94% yield, with a slightly lower ee of 87%.
The analogous reaction with 4-chlorobenzaldehyde showed
a similarreduction inee(83%, 3r, Table4). Introductionof
Substituted benzaldehyde derivatives were screened as
substrates in combination with N-aminoethyl pyrrole 1a,
affording chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine
products 3aꢀp in good to excellent yields and ee’s (Table 3).
Halogen substitutions are tolerated at all ring positions on
the aromatic aldehydes (90ꢀ91% ee; 3b, 3c, 3d, 3g). The
sterically hindered R-naphthaldehyde provided the cycli-
zation product in excellent yield and enantioselectivity
(91% yield and 90% ee, 3h). Aromatic aldehydes containing
a 4-methyl substituent, or a much bulkier 4-isopropyl sub-
stituent, proved viable and gave products with high ee’s
(21) For example, butanal and 3-phenylpropanal were utilized as
substrates. However, less than 60% ee was observed by estimation
because baseline separation by chiral HPLC was unattainable. High
isolated yields for both aliphatic aldehydes were obtained (>90%).
4492
Org. Lett., Vol. 13, No. 17, 2011

Table 4. Scope of Pyrrole Substratesa,b
Scheme 2. Intramolecular Aza-FriedelꢀCrafts Reaction and
Amidation Domino To Access a Fused Ring Pyrrole Derivative
system, was formed with excellent yield and ee in the one-pot
reaction (90% ee and 95% yield).
a Isolated yield. b Ee was determined by Chiral HPLC; see Support-
ing Information for details. c Total isolated yield. d Determined by 1H
NMR.
Figure 1. Single crystal X-ray structure of the TFA salt of
product 3c.
a methyl group at C-3 of the pyrrole ring (1c) gave a similar
reactivity and enantioselectivity to those of the monosub-
stituted pyrrole 1b (3s, Table 4). This result suggests that
substitution at C-3 or C-4 of the pyrrole ring might not
affect the enantioselectivity. This hypothesis was con-
firmed after 1-aminoethyl-3-ethylpyrrole (1d) was pre-
pared and screened under the optimized reaction conditions.
In the presence of an achiral Brønsted acid (phenylphos-
phinic acid), racemic 3t was formed with high regioselec-
The absolute configuration of 1,2,3,4-tetrahydropyr-
rolo[1,2-a]pyrazine 3c was unambiguously determined to
be R according to the single crystal X-ray diffraction of its
trifluoroacetic acid (TFA) salt (Figure 1; see Supporting
Information for details).
In conclusion, we have developed the first direct cataly-
tic asymmetric intramolecular aza-FriedelꢀCrafts reac-
tion of N-aminoethylpyrroles catalyzed by chiral pho-
sphoric acids. This one-pot sequence provides an efficient
approach to preparing various medicinally important
chiral 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines in high
yields and high to excellent enantioselectivities under mild
reaction conditions. Further work with respect to exten-
sion and applications of this methodology is ongoing in
our laboratory.
1
tivity (3t/3t0 = 10:1 determined by H NMR). Chiral
catalyst PA1e gave nearly equal amounts of 3t and
3t0 (3t/3t0 = 1.2:1). We presume the poor regioselectivity
can be attributed to the likely increased steric hindrance
that chiral phosphoric acid PA1e introduces in proximity
to the 3-ethyl group of the pyrrole ring. While poor
regioselectivity was observed, excellent enantioselectivities
were obtained for each regioisomer (85ꢀ94% ee, Table 4).
The cyclization of R-naphthaldehyde with pyrrole 1d
produced one regioisomer with excellent ee (92% ee, 3v0,
Table 4) but gave way to the other regioisomer with a
slightly lower enantioselectivity (85% ee, 3v, Table 4).
The present intramolecular aza-FriedelꢀCrafts reaction
provides potential access to polycyclic pyrrole derivatives,
which represent a novel analogue or precursor of pyrrole-
derived alkaloids. As shown in Scheme 2, a tandem
intramolecular amidation sequence occurred in the reaction
between N-aminoethylpyrrole (2a) and methyl 2-formyl-
benzoate (2m). The resulting product 3w, a four-fused-ring
Acknowledgment. The authors acknowledge funds from
the Natural Science Foundation of China (20902113) and
Mr. Matthew J. Kaplan (University of South Florida) for
proofreading the manuscript. G.L. also thanks the ‘Hun-
dred-Talent Program’ at Sun Yat-Sen Univeristy for finan-
cial support.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 17, 2011
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