2-aminopyridinium ions activate nitroalkenes through hydrogen bonding

Article abstract of DOI:10.1021/ol071032v

2-Aminopyridinium ions were found to activate nitroalkenes toward conjugate addition of heteroaromatic compounds with low catalyst loadings and the Diels Alder reaction with the periselectivity opposite to that observed with metal Lewis acids, raising the

Full text of DOI:10.1021/ol071032v

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2819-2822
2-Aminopyridinium Ions Activate
Nitroalkenes through Hydrogen Bonding
Norito Takenaka,* Robindro Singh Sarangthem, and Sreehari Kumar Seerla
Department of Chemistry, UniVersity of Miami, 1301 Memorial DriVe,
Coral Gables, Florida 33146-0431
n.takenaka@miami.edu
Received May 3, 2007
ABSTRACT
2-Aminopyridinium ions were found to activate nitroalkenes toward conjugate addition of heteroaromatic compounds with low catalyst loadings
and the Diels Alder reaction with the periselectivity opposite to that observed with metal Lewis acids, raising the possibility that a
2-aminopyridinium core might be a promising catalaphore for the asymmetric catalyst design.
−
Nitroalkanes are important compounds in organic synthesis
due to their propensity to undergo facile R-alkylation
reactions and interconversions to other organic functional
groups.1 The Michael reaction of carbon-centered nucleo-
philes with nitroalkenes represents one of the most direct
approaches to chiral nitroalkanes.1c,d,2 Among such methods,
the Friedel-Crafts alkylation of heteroaromatic compounds
with nitroalkenes3,4 has received relatively little attention,
although it is a powerful carbon-carbon bond forming
reaction that provides the stereochemical motif with a
privileged status in medicinal chemistry.5 Despite recent
advances in this process, identification of new efficient
catalysts, even achiral ones, that lower the LUMO of
nitroalkenes remains an important challenge. It is described
herein that new 7-azaindolium tetrakis[3,5-bis(trifluoro-
methyl)phenyl]borate (TFPB) activated nitroalkenes toward
conjugate addition of heteroaromatic compounds with low
catalyst loadings and also catalyzed the Diels-Alder reaction
of nitroalkenes with the periselectivity opposite to that
observed with metal Lewis acids.
Electrophile activation by small-molecule chiral hydrogen
bond (abbreviated as H-bond) donors has recently emerged
as an important paradigm for enantioselective catalysis.6
Among them, (thio)ureas are becoming a class of privileged
catalaphores7 for designing asymmetric double H-bonding
catalysts. On the other hand, Go¨bel et al. studied acceleration
(1) Selected references: (a) Czekelius, C.; Carreira, E. M. Angew. Chem.,
Int. Ed. 2005, 44, 612-615. (b) Calderari, G.; Seebach, D. HelV. Chim.
Acta 1985, 68, 1592-1604. For reviews, see: (c) Ballini, R.; Bosica, G.;
Fiorini, D.; Palmieri, A.; Petrini, M. Chem. ReV. 2005, 105, 933-971. (d)
Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New York,
2001.
(2) For a review, see: Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J.
Org. Chem. 2002, 1877-1894.
(3) For the Friedel-Crafts alkylation of heteroaromatic compounds with
nitroalkenes catalyzed by substoichiometric amount of achiral catalysts,
see: (a) Gu, Y.; Ogawa, C.; Kobayashi, S. Org. Lett. 2007, 9, 175-178.
(b) Bartoli, G.; Bosco, M.; Giuli, S.; Giuliani, A.; Lucarelli, L.; Marcantoni,
E.; Sambri, L.; Torregiani, E. J. Org. Chem. 2005, 70, 1941-1944. (c)
Murugan, R.; Karthikeyan, M.; Perumal, P. T.; Reddy, B. S. R. Tetrahedron
2005, 61, 12275-12281. (d) Lin, C.; Hsu, J.; Sastry, M. N. V.; Fang, H.;
Tu, Z.; Liu, J.-T.; Ching-Fa, Y. Tetrahedron 2005, 61, 11751-11757. (e)
Gabriella, D.; Herrera, R. P.; Ricci, A. Synlett 2004, 2374-2378. (f) Alam,
M. M.; Varala, R.; Adapa, S. R. Tetrahedron Lett. 2003, 44, 5115-5119.
(g) Komoto, I.; Kobayashi, S. Org. Lett. 2002, 4, 1115-1118. (h)
Harrington, P. E.; Kerr, M. A. Synlett 1996, 1047-1048.
(4) For the Friedel-Crafts alkylation of heteroaromatic compounds with
nitroalkenes catalyzed by substoichiometric amount of chiral catalysts,
see: (a) Fleming, E. M.; McCabe, T.; Connon, S. J. Tetrahedron Lett. 2006,
47, 7037-7042. (b) Lu, S.-F.; Du, D.-M.; Xu, J. Org. Lett. 2006, 8, 2115-
2118. (c) Jia, Y.-X.; Zhu, S.-F.; Yang, Y.; Zhou, Q.-L. J. Org. Chem. 2006,
71, 75-80. (d) Herrera, R. P.; Sgarzani, V.; Bernardi, L.; Ricci, A. Angew.
Chem., Int. Ed. 2005, 44, 6576-6579. (e) Bandini, M.; Garelli, A.; Rovinetti,
M.; Tommasi, S.; Umani-Ronchi, A. Chirality 2005, 17, 522-529. (f)
Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3,
2566-2571.
(5) Paras, N. A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002, 124,
7894-7895 and references cited therein.
10.1021/ol071032v CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/29/2007

of the Diels-Alder reaction by amidinium ions (including
2-benzylaminopyridinium TFPB8c 2, Table 1) and subse-
quently developed enantiopure amidinium catalysts.8,9
In this context, we are intrigued in particular by the unique
structural feature of 2-aminopyridinium ions (Figure 1). This
its ability as a H-bonding catalyst.8c To our delight, it turned
out to efficiently catalyze the conjugate addition of N-
methylindole to â-nitrostyrene3e (Table 1, entry 1). With
respect to the mode of catalysis, we hypothesized that if 2
activates â-nitrostyrene via specific acid catalysis6a more
acidic 2-benzylpyridinium TFPB10 3 should be a better
catalyst than 2.11,12 However, under all three conditions
investigated, the catalyst 2 clearly showed reactivity higher
than that of 3 (entries 1-3). It is difficult to explain the
superior reactivity of the 2-benzylaminopyridinium ion to
the 2-benzylpyridinium ion by the difference in their acidities.
Therefore, these results imply the cooperative double H-
bonding ability of 2-benzylaminopyridinium TFPB on the
analogy of (thio)ureas and bisphenols.13
The level of catalyst loadings was next investigated (Table
2). The reaction became sluggish when less than 0.1 mol %
of 2 was employed (entries 1 and 2). However, 7-azaindolium
TFPB 1, which was originally synthesized in connection with
the Diels-Alder reaction (vide infra), promoted the reaction
well with catalyst loadings as low as 0.05 mol % (entry 4).
Figure 1. General structures of 2-aminopyridinium, amidinium
ions, and (thio)urea; R* denotes that the skeleton is chiral.
is that its double H-bonding part is embedded in its skeleton
where chirality can be introduced, and thus the relative
conformational ambiguity between the center of reactivity
and the chiral element could be minimized in principle. As
such, the 2-aminopyridinium core appears to be a potentially
attractive catalaphore compared to amidinium and (thio)-
urea catalysts in which catalaphores and chiraphores7 are
connected via a rotary single bond.
Table 2. 7-Azaindolium Ion Catalyzed Friedel-Crafts
Reactions
Table 1. Model Reaction with Different H-Bond Donors
cat
(mol %)
temp
(°C)
time
(h)
yield w/2
yield w/3
entry
(%)
(%)
1
2
3
1
1
10
0
-20
-50
24
24
72
99
56
51
75
22
trace
We set out to study 2-benzylaminopyridinium TFPB 2
since there is not much information in the literature regarding
(6) For reviews, see: (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 2006, 45, 1520-1543. (b) Connon, S. J. Chem.sEur. J. 2006, 12,
5418-5427. (c) Akiyama, T.; Itoh, J.; Fuchibe, K. AdV. Synth. Catal. 2006,
348, 999-1010. (d) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299-
4306. (e) Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L. Angew. Chem.,
Int. Ed. 2005, 44, 1758-1763. (f) Pihko, P. M. Angew. Chem., Int. Ed.
2004, 43, 2062-2064. (g) Schreiner, P. R. Chem. Soc. ReV. 2003, 32, 289-
296.
(7) For discussion of terms “catalaphore” and “chiraphore”, see: Mulzer,
J. Basic Principles of Asymmetric Synthesis. In ComprehensiVe Asymmetric
Catalysis; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-
Verlag: Berlin, Heidelberg, 2004; Vol. 1, Chapter 3.
(8) (a) Tsogoeva, S. B.; Du¨rner, G.; Bolte, M.; Go¨bel, M. W. Eur. J.
Org. Chem. 2003, 1661-1664. (b) Schuster, T.; Bauch, M.; Du¨rner, G.;
Go¨bel, M. W. Org. Lett. 2000, 2, 179-181. (c) Schuster, T.; Kurz, M.;
Go¨bel, M. W. J. Org. Chem. 2000, 65, 1697-1701.
a Unless otherwise noted, Ar-H (1.5 mmol) and nitroalkenes (1.0 mmol)
were used for all entries. b Yields without catalysts. c Equimolar amounts
(1.0 mmol) of N-methylindole and â-nitrostyrene were reacted for 48 h.
d Nondistilled PhMe was used. e The reaction was run for 2 h. f N-
Methylpyrrole (4 equiv) was used. g The reaction was run at 0 °C for 1 h.
2820
Org. Lett., Vol. 9, No. 15, 2007

This result is reproducible at 10 mmol scale. The high
catalyst activity of 1 might be attributable to its favorable
geometry for double H-bonding and increased acidity.14 The
following is also worthy of mention: Only 0.5 mol % of 1
was enough to complete the reaction with equimolar amounts
of substrates (entry 5). 1 tolerated nondistilled toluene
presumably because it is a nonhygroscopic, bench-stable salt
(entry 6). Furthermore, the 2-position of the indole nucleus
may also be accessed with the present method since the
dihydroindole15 reacted well (entry 12). Overall, the reaction
was effectively catalyzed with 0.5 mol % of 7-azaindolium
TFPB, which represents the lowest catalyst/substrate ratio
for the Friedel-Crafts alkylation reaction with nitroalkenes.
The Diels-Alder (DA) reaction of nitroalkenes has proven
highly useful in organic synthesis; however, the catalysis of
this process remains quite elusive.1d The reaction of cyclo-
pentadiene and nitroalkenes provides the DA products under
thermal conditions. In contrast, Denmark et al. reported that
the same reaction undergoes the inverse-electron-demand
hetero-Diels-Alder (HDA) reaction in the presence of Lewis
acid catalysts, such as SnCl4.16 They rationally pointed out
that unsymmetrical coordination of the Lewis acid with one
of the oxygen atoms of the nitro group serves to localize
double-bond character (OdN), resulting in a reversal of
periselectivity. The study of this reaction in the presence of
H-bonding catalysts has not been reported to our knowledge,
thus it was conducted (Table 3).17
Table 3. Nitroalkene Diels-Alder Reactions Catalyzed by
Double H-Bond Donors
temp time yield (4) endo:exo yield (5)
entrya cat
1
R
(°C)
(h)
(%)
(4)
(%)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
Me
rt
rt
rt
rt
6
6
6
6
-10
-10
-10
-10
8
8
8
9
44
42
49
13
46
49
54
7
7:1
25:1
25:1
22:1
9:1
30:1
30:1
25:1
25:1
0
11
0
trace
0
10
0
trace
0
2
0
2
3
4
2
6
1
8
5
72
72
72
72
36
36
36
36
6
7
8
2
6
1
9
10
11
12
2
6
1
30
24
37
>30:1
>30:1
>30:1
trace
2-Benzylaminopyridinium ion 2 provided the desired DA
product 4 in 44% yield with a high endo/exo ratio and the
product 5 in 11%, which resulted presumably from sequential
HDA and [3 + 2] reactions (entry 2).18 On the basis of
Denmark’s study, we hypothesized that the charge on oxygen
is evenly dispersed within the O-N-O bonding array in
the nitroalkene complexed with a symmetrical double H-bond
donor, and thus it may not electronically participate as a
a CP (1.0 mmol) and nitroalkenes (0.5 mmol) were used for all entries.
diene. Therefore, symmetric thiourea6 6 was tested and found
to provide neither HDA products nor 5 (entries 3, 7, and
11). Hence, we synthesized the 7-azaindolium catalyst 1 with
the expectation that both of its N-H bonds are somewhat
similar in nature due to enhanced electronic communication
between two nitrogen atoms.19 It gave higher periselectivity
than the 2-benzylaminopyridinium ion did (entries 4, 8, and
12). This is an interesting observation, although a definitive
answer regarding the periselectivity is still to be firmly
established. Since metal Lewis acids do not promote the
formation of DA products, even these achiral H-bonding
catalysts are very useful tools to obtain them with high endo-
selectivity. It should be mentioned that the yield of an endo-
isomer (R ) Ph) of the H-bonding catalyzed reaction is
comparable to that of the corresponding thermal reaction.20
The experimental observation about competing DA and
HDA reactions21 and shifts in product ratios by different
catalysts could be understood from the expected electronic
structure of the nitro group complexed with a catalyst and
the single malleable bis-pericyclic transition state (TS) model
(9) For recent examples of highly enantioselective reactions catalyzed
by amidinium and guanidinium ions, see: (a) Singh, A.; Yoder, R. A.; Shen,
B.; Johnston, J. N. J. Am. Chem. Soc. 2007, 129, 3466-3467. (b) Terada,
M.; Nakano, M.; Ube, H. J. Am. Chem. Soc. 2006, 128, 16044-16045. (c)
Shen, J.; Nguyen, T. T.; Goh, Y.-P.; Ye, W.; Fu, X.; Xu, J.; Tan, C.-H. J.
Am. Chem. Soc. 2006, 128, 13692-13693. (d) Terada, M.; Ube, H.;
Yaguchi, Y. J. Am. Chem. Soc. 2006, 128, 1454-1455. (e) Nugent, B. M.;
Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418-3419.
(f) Corey, E. J.; Grogan, M. J. Org. Lett. 1999, 1, 157-160.
(10) 2-Benzylpyridine was chosen instead of pyridine to guarantee
sufficient solubility of the corresponding salt.
(11) The pKa of 2-benzylpyridinium ion is 5.1 (H2O). See: (a) Linnell,
R. H. J. Org. Chem. 1960, 25, 290-291. The pKa of 2-aminopyridinium
ion is 6.9 (H2O). See: (b) Angyal, S. J.; Angyal, C. L. J. Chem. Soc. 1952,
1461-1466.
(12) A 1:1 mixture of 3 and 2-benzylaminopyridine in DMSO-d6
completely and cleanly shifted to a mixture of 2-benzylpyridine and 2 by
1H NMR in the transprotonation experiment, indicating the distinct acidity
difference between 2 and 3.
(13) Kelly, T. R.; Meghani, P.; Ekkundi, V. S. Tetrahedron Lett. 1990,
31, 3381-3384.
(14) The pKa of 7-azaindolium ion is 4.6 (H2O). See: Adler, T. K.;
Albert, A. J. Chem. Soc. 1960, 1794-1797.
(15) (a) Evans, D. A.; Fandrick, K. R. Org. Lett. 2006, 8, 2249-2252.
(b) C¸ avdar, H.; Sarac¸oglu, N. Tetrahedron, 2005, 61, 2401-2405.
(16) Denmark, S. E.; Kesler, B. S.; Moon, Y.-C. J. Org. Chem. 1992,
57, 4912-4924.
(19) Me´rour, J.-Y.; Joseph, B. Curr. Org. Chem. 2001, 5, 471-506 and
references cited therein.
(20) (a) Node, M.; Nishide, K.; Imazato, H.; Kurosaki, R.; Inoue, T.;
Ikariya, T. Chem. Commun. 1996, 2559-2560. (b) Bourguignon, J.; Nard,
G. L.; Queguiner, G. Can. J. Chem. 1985, 63, 2354-2361. (c) Parham, W.
E.; Hunter, W. T.; Hanson, R. J. Am. Chem. Soc. 1951, 73, 5068-5070.
(21) DA and HDA products are potentially related to each other by a
[3,3] sigmatropic rearrangement; however, control experiments (R ) Ph)
indicated that, under the conditions of the reaction, no product intercon-
version was occurring. See Supporting Information.
(17) The intramolecular Diels-Alder reaction of nitroalkene was cata-
lyzed by silica gel. See: Jubert, C.; Knochel, P. J. Org. Chem. 1992, 57,
5431-5438.
(18) CP and the corresponding syn-nitronate prepared according to ref
16 provided 5 (R ) Ph) in the presence of 2. See Supporting Information.
Org. Lett., Vol. 9, No. 15, 2007
2821

structure of the nitro group coordinated with unsymmetrical
H-bond donor 2 is expected to be between the two cases
shown in Scheme 1, leading to the TS in which orbital
interactions at both A and B are important.
Scheme 1. TS Models for Competing DA and HDA
Reactions
In summary, 2-aminopyridinium ions were identified as
efficient LUMO-lowering catalysts for nitroalkenes. These
catalysts promoted conjugate addition of heteroaromatic
compounds to nitroalkenes with low catalyst loadings.
Furthermore, they were also found to promote the Diels-
Alder reaction of nitroalkenes with high diastereoselectivity.
They can therefore be expected to complement ongoing
(thio)urea systems and thus to be attractive catalaphores for
the designs of new asymmetric catalysts, which are currently
underway and will be reported in due course.
recently reported by Houk et al.22 (Scheme 1). The nitro-
alkene complexed with a symmetrical double H-bond donor
would undergo the TS in which orbital interaction is less at
A than at B due to the evenly dispersed charge within the
nitro group, leading mainly to the DA product. On the other
hand, unsymmetrical coordination of SnCl4 would localize
double-bond character and thus increase orbital interaction
at A in the TS,23 resulting in the HDA product. The electronic
Acknowledgment. We thank the University of Miami
for financial support.
Supporting Information Available: Preparation of cata-
lysts, experimental details, and characterization of products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL071032V
(23) Coordination of SnCl4 to â-nitrostyrene causes a significant decrease
in the LUMO coefficient of the carbon adjacent to the nitro group by
calculations. See ref 22.
(22) C¸ elebi-O¨ lc¸u¨m, N.; Ess, D. H.; Aviyente, V.; Houk, K. N. J. Am.
Chem. Soc. 2007, 129, 4528-4529.
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Org. Lett., Vol. 9, No. 15, 2007