Microwave-assisted organocatalytic enantioselective intramolecular aza-Michael reaction with α,β-unsaturated ketones

Article abstract of DOI:10.1002/chem.201101292

An organocatalytic enantioselective intramolecular aza-Michael reaction of carbamates bearing conjugated ketones as Michael acceptors is described. By using 9-amino-9-deoxy-epi-hydroquinine as the catalyst and pentafluoropropionic acid as a co-catalyst, a series of piperidines, pyrrolidines, and the corresponding benzo-fused derivatives (indolines, isoindolines, tetrahydroquinolines, and tetrahydroisoquinolines) can be obtained in excellent yields and enantioselectivities. In addition, the use of microwave irradiation at 60 °C improves the efficiency of the process giving rise to the final products with comparable yields and enantiomeric excesses. Some mechanistic insights are also considered.

Full text of DOI:10.1002/chem.201101292

FULL PAPER
DOI: 10.1002/chem.201101292
Microwave-Assisted Organocatalytic Enantioselective Intramolecular aza-
Michael Reaction with a,b-UnACHTUNTRGNEUNGsaturated Ketones
Santos Fustero,*[a, b] Carlos del Pozo,[a] Cristina Mulet,[a] Rubꢀn Lazaro,[a] and
Marꢁa Sꢂnchez-Rosellꢃ*[b]
In memory of Josꢀ Manuel Concellꢁn
Abstract: An organocatalytic enantio-
selective intramolecular aza-Michael
reaction of carbamates bearing conju-
gated ketones as Michael acceptors is
described. By using 9-amino-9-deoxy-
epi-hydroquinine as the catalyst and
pentafluoropropionic acid as a co-cata-
lyst, a series of piperidines, pyrrol-
fused derivatives (indolines, iso
AHCTUNGTRENNGiUN nes, tetrahydroquinolines, and tetrahy-
droisoquinolines) can be obtained in
indol-
excellent yields and enantioselectivi-
ties. In addition, the use of microwave
irradiation at 608C improves the effi-
ciency of the process giving rise to the
final products with comparable yields
and enantiomeric excesses. Some
mechanistic insights are also consid-
ered.
Keywords: aza-Michael reaction ·
cinchona alkaloids · heterocycles ·
microwave chemistry
catalysis
·
organo-
AHCTUNGTRENNUNG
ACHTUNGTRENNUNGidines, and the corresponding benzo-
Introduction
compounds, and their versatility as synthetic intermediates,
make them privileged structures; b-amino acids and b-lac-
tams are classic examples.[3]
The synthesis of enantiomerically pure compounds plays a
pivotal role in medicinal chemistry given that the absolute
configuration of many pharmaceutical ingredients has a cen-
tral importance on their biological activity.[1] During the last
decade, together with classical methods based on the use of
transition metals and enzymes, organocatalysis has become
one of the most exciting and competitive fields in asymmet-
ric catalysis.[2]
The conjugate addition of nitrogen-centered nucleophiles
to a,b-unsaturated compounds, the aza-Michael reaction, is
one of the simplest and most direct strategies to create C N
bonds and access b-amino carbonyl derivatives. Importantly,
the intramolecular version of this reaction allows straightfor-
ward access to nitrogen-containing heterocycles. The ubiqui-
tous presence of such heterocycles in biologically active
Unlike Michael additions with carbon nucleophiles, the
asymmetric aza-Michael reaction has been explored to a
lesser extent, despite being a powerful tool for the synthesis
of chiral b-amino carbonyl compounds.[4] Expanding interest
in organocatalysis prompted several research groups to
study this interesting transformation[5] when faced with the
difficulties arising from the amine nature of most of the or-
ganocatalysts commonly used. The choice of the amine cata-
lyst and the nitrogen nucleophile is crucial to obtain high
levels of enantioselectivity, while avoiding possible competi-
tion between them to react with the Michael acceptor. By
choosing chiral imidazolidinones as catalysts and N-silyloxy-
carbamates as nucleophiles, MacMillan and co-workers suc-
ceeded in the iminium activation of a,b-unsaturated alde-
hydes for a highly enantioselective aza-Michael reaction.[6]
After this work, several examples of organocatalyzed conju-
gate additions of nitrogen nucleophiles to enals appeared in
the literature.[7] However, the participation of enones in the
aminocatalyzed aza-Michael reaction remained elusive until
three years ago when Deng and co-workers reported a
highly enantioselective aza-Michael reaction with a,b-unsa-
turated ketones catalyzed by a 9-aminoquinine derivative.[8,9]
Almost at the same time, Melchiorre and co-workers devel-
oped an enantioselective aziridination of enones proceeding
through a domino iminium–enamine sequence and catalyzed
by a hydroquinine-derived primary amine salt.[7i,10,11] Chiral
primary amines have proved to be efficient activators of
enones in asymmetric, organocatalyzed conjugate additions.
Use of these amines overcomes the difficulties in forming
iminium ions between ketones or sterically demanding ac-
À
[a] Prof. Dr. S. Fustero, Dr. C. del Pozo, C. Mulet, R. Lazaro
Departmento de Quꢀmica Orgꢁnica
Universidad de Valencia
46100 Burjassot (Spain)
Fax : (+34)963-544-939
E-mail: santos.fustero@uv.es
[b] Prof. Dr. S. Fustero, Dr. M. Sꢁnchez-Rosellꢂ
Laboratorio de Molꢃculas Orgꢁnicas
Centro de Investigaciꢂn Principe Felipe
46012 Valencia (Spain)
E-mail: sfustero@cipf.es
msanchezr@cipf.es
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201101292.
Chem. Eur. J. 2011, 17, 14267 – 14272
ꢄ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
14267

ceptors, and commonly used chiral secondary amine cata-
lysts.[12]
Results and Discussion
Despite its synthetic potential, the enantioselective intra-
molecular aza-Michael reaction (IMAMR) still represents a
challenging task in organic synthesis, because only a few ex-
amples have been reported to date. Most of these examples
involve the use of chiral secondary amines that can activate
a,b-unsaturated aldehydes by iminium ion formation to-
wards the intramolecular attack of either carbamates or
amides as nitrogen nucleophiles.[13] In 2007, we described
the first highly enantioselective IMAMR of carbamates
bearing a remote a,b-unsaturated aldehyde in the presence
of a diarylprolinol derivative as the catalyst.[13c] Few other
Michael acceptors, aside from a,b-unsaturated aldehydes,
have been employed. For example, Bandini and Umani-
Ronchi were able to perform an IMAMR of indoles over
a,b-unsaturated esters by using an ammonium salt derived
from a cinchona alkaloid as the catalyst.[14] To the best of
our knowledge, only two examples with a,b-unsaturated ke-
tones have been reported in the literature. Very recently,
You and co-workers reported an enantioselective intramo-
lecular Friedel–Crafts-type aza-Michael addition of indoles
to conjugated ketones catalyzed by a chiral phosphoric
acid.[15] Soon after, Lu and co-workers disclosed an intramo-
lecular conjugate addition of sulfonamides to alkylidene b-
ketoesters in the presence of a bifunctional tertiary-amine/
thiourea catalyst.[16] However, these two examples are not
general, because they concern particular substrates, typically
aromatic ketones as Michael acceptors.
A model reaction on compound 1a was used to optimize
the reaction conditions and catalysts. First, an array of chiral
catalysts, either commercially available or easily prepared in
the laboratory, was investigated for the intramolecular con-
jugate addition of the carbobenzyloxy (Cbz)-protected
amine 1a. Poor enantiomeric excess (ee) values were ach-
ieved in all cases (see the Supporting Information) except
when 9-amino-9-deoxy-epi-hydroquinine (I) and trifluoro-
acetic acid as a co-catalyst were used. In this case, the 2-sub-
stituted piperidine 2a was obtained in 88% yield and
91% ee (Table 1, entry 1). Consequently, the cinchona alka-
loid derivative I was chosen as the catalyst for this transfor-
mation.
Next, we evaluated the effect of varying the acid co-cata-
lyst, solvent, and temperature in the same model reaction of
1a. As shown in Table 1, reducing the co-catalyst loading
from 40 to 20 mol% was found to be beneficial for both
Table 1. Optimization of the IMAMR conditions (co-catalyst, solvent,
temperature and time) for the synthesis of piperidine 2a by using catalyst
I (9-amino-9-deoxy-epi-hydroquinine).[a]
As part of our efforts to develop a general and highly se-
lective methodology for an IMAMR,[13a,c,17] herein we report
a highly enantioselective IMAMR of carbamates bearing a
remote a,b-unsaturated ketone by using chiral primary
amines as catalysts (Scheme 1). Starting enones were assem-
Co-catalyst
[mol%][b]
Solvent
T
t
Yield
[%][c]
ee
G
[oC]
[h]
[%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17[e]
18[e]
19[e]
20[e]
TFA (40)
TFA (20)
TFA (10)
TFA (20)
TFA (20)
TFA (20)
TFA (20)
TFA (20)
TFA (20)
TFA (20)
NCLP (40)
CSA (20)
BTFMBA (40)
p-NBA (40)
PFP (20)
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
THF
25
25
25
10
4
15
15
15
24
24
15
8
15
15
24
72
24
48
15
15
72
88
91
48
80
71
78
72
88
91
90
48
60
85
76
93
64
91
93
94
60
91
95
91
97
95
97
97
93
84
47
87
69
85
80
96
52
90
95
95
90
25
25
25
25
25
25
25
25
25
25
25
80
60
60
60
Et2O
DCM
toluene
iPrOH
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
THF
DNBS (20)
TFA (20)
TFA (20)
PFP (20)
0.5
1
1
1
Scheme 1. Organocatalytic asymmetric IMAMR.
TFA (20)
[a] Reactions were carried out with 1a (0.07 mmol) and catalyst
I
bled through a cross-metathesis reaction of the correspond-
ing unsaturated N-protected amines with vinyl ketones in
the presence of second-generation Hoveyda–Grubbs catalyst
[Cl2ACHTUNGTRENNUNG(IMes)Ru=CH(o-iPrOC6H4)] (see the Supporting Infor-
mation).
(20 mol%) in the specified solvent (0.1m), time and temperature.
[b] TFA=trifluoroacetic acid, NCLP=N-Cbz-L-phenylalanine, CSA=
(+)-10-camphorsulfonic acid, BTFMBA=3,5-bis(trifluoromethyl)benzoic
acid, p-NBA=4-nitrobenzoic acid, PFP=pentafluoropropionic acid,
DNBS=2,4-dinitrobenzenesulfonic acid. [c] Yields are of isolated com-
pounds after flash chromatography. [d] Determined by HPLC on a chiral
stationary phase (Chiracel OD-H); see Supporting Information for de-
tails. [e] Heating by means of microwave irradiation.
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Chem. Eur. J. 2011, 17, 14267 – 14272

Organocatalytic Enantioselective Intramolecular aza-Michael Reactions
FULL PAPER
Table 2. Substrate scope of the organocatalytic IMAMR. Synthesis of 2-
substituted piperidines and pyrrolidines.[a]
yield and enantioselectivity (Table 1, entry 1 versus 2),
whereas a further decrease to 10 mol% led to a considera-
ble drop in the yield (48%) of the product albeit maintain-
ing a good ee (91%) (Table 1, entry 3). Lowering the tem-
perature resulted in
a slight rise in enantioselectivity
(97% ee at 108C), but a bigger decrease in yield (80%)
(Table 1, entries 4 and 5).[18] Excellent asymmetric induction
was observed when the reaction was carried out in THF, di-
ethyl ether, and also dichloromethane (Table 1, entries 6–8),
whereas the use of toluene and 2-propanol led to a signifi-
cant drop in the ee values (Table 1, entries 9 and 10). In all
these cases yields were lower than that of the reaction per-
formed in chloroform. The co-catalyst required in the reac-
tion was also evaluated.[19] Among different acid additives
screened (Table 1, entries 11–16), pentafluoropropionic acid
(PFP) was the best and afforded the desired product in
93% yield and 96% ee (Table 1, entry 15). The use of a
chiral co-catalyst, such as N-Cbz-l-phenylalanine, had a neg-
ative effect on both the enantioselectivity and the yield of
the reaction (Table 1, entry 11). Finally, we studied the reac-
tion under microwave irradiation.[20] This type of activation
has been described recently in different types of organocata-
lyzed asymmetric reactions with the aim of shortening reac-
tion times and catalyst loadings.[21] We found that microwave
irradiation had a positive effect on the reaction time and re-
tained very good yields and selectivities. When the reaction
was performed in chloroform at 808C, a 90% ee and a 91%
yield were achieved in only 30 min (Table 1, entry 17). Ex-
tending the reaction time to one hour allowed us to obtain
excellent levels of enantioselectivity and excellent yields at
608C in the presence of either TFA or PFP as co-catalysts
(Table 1, entries 18 and 19). However, the reaction in THF
was less efficient both in yield and selectivity relative to the
results obtained at room temperature (Table 1, entry 20
versus 6). To the best of our knowledge this is the first
report of a microwave accelerating effect in a Michael-type
reaction catalyzed by a cinchona alkaloid derivative.
n
1
PG
R
T
t
2
Yield
[%][b]
ee
[oC]
[h]
[%][c]
1
2
3
4
5
1
1
1
1
0
1
1
1
1
0
1b
1c
1d
1e
1 f
1b
1c
1d
1e
1 f
Boc
Cbz
Cbz
Cbz
Cbz
Boc
Cbz
Cbz
Cbz
Cbz
Me
nPr
nPn
Ph
Me
Me
nPr
nPn
Ph
25
25
25
25
25
60
60
60
60
60
15
2b
2c
2d
2e
2 f
2b
2c
2d
2e
2 f
92
95
92
58
80
97
94
89
75
85
93
98
98
93
82
90
96
97
84
79
15
15
240
24
1
6[d]
7[d]
8[d]
9[d]
10[d]
1
1
4
1
Me
[a] Reactions were carried out with 1 (0.15 mmol), catalyst I (20 mol%)
and pentafluoropropionic acid (PFP) (20 mol%) in chloroform (0.1m).
[b] Yields are of isolated compounds after flash chromatography. [c] De-
termined by HPLC on a chiral stationary phase (Chiracel OD-H); see
the Supporting Information for details. [d] Heating by means of micro-
wave irradiation.
tion was performed at 608C under microwave irradiation,
comparable results of yield and enantioselectivity were ach-
ieved. (Table 2, entries 6–10).
The absolute configuration of the newly created stereo-
center was determined to be R by comparing the optical ro-
tation values of compounds 2a–2d and 2 f with those report-
ed in the literature (see the Supporting Information).[22]
Identical stereochemical outcomes were assumed for all
other substrates. It is worth noting that piperidines 2a and
2b are direct precursors of the alkaloid pelletierine[22a–d,23]
requiring only removal of the nitrogen protecting group.
Likewise, starting from compounds 2c and 2d, several mem-
bers of the tetraponerine[22e,f,24] family could be synthesized
in a straightforward manner. Additionally, the reduction of
the Cbz group in 2 f would lead to the skeleton of the pyr-
Once reaction conditions had been optimized, we extend-
ed this methodology to other carbamates bearing a remote
a,b-unsaturated ketone. For the optimized conditions we
choose catalyst I in the presence of PFP as co-catalyst. Re-
actions were carried out in chloroform both at room temper-
ature and under microwave irradiation at 608C. The results
are summarized in Table 2. We found that the nitrogen pro-
tecting group (tert-butoxycarbonyl (Boc) or Cbz) had no in-
fluence on the selectivity or the yield of the final product
2a/2b (Table 1, entry 15 versus Table 2, entry 1). The pro-
cess was highly efficient for both propyl- and pentyl-substi-
tuted ketones 1c and 1d, and afforded products 2c and 2d,
respectively, in 98% ee and excellent yields (Table 2, en-
tries 2 and 3). When the starting substrate was an aromatic
ketone (1e, R=Ph), longer reaction times were needed to
obtain an acceptable yield, although the enantioselectivity
was very good (93% ee) (Table 2, entry 4). The formation of
a five-membered ring was less efficient in terms of yield and
selectivity; the corresponding pyrrolidine 2 f was obtained in
80% yield and 82% ee (Table 2, entry 5). When this reac-
AHCTUNGTRENNUNG
ganocatalytic conjugate additions of nitrogen nucleophiles
to a,b-unsaturated carbonyl compounds involves activation
of the Michael acceptor by the catalyst through the forma-
tion of an iminium ion, thereby facilitating the intramolecu-
lar addition of the nucleophile to the b-carbon. We propose
a possible mechanism that accounts for the R stereochemi-
cal assignment mentioned above. First, the primary amine
catalyst would react with the enone 1a to form an iminium
intermediate under the acid conditions. Indeed, no reaction
took place in the absence of acid.[19] Simultaneously, the qui-
nuclidine nitrogen would be protonated and a hydrogen-
bond interaction would be established with the carbamate
carbonyl oxygen. In this conformation, the attack of the ni-
trogen nucleophile would take place onto the Re face of the
less sterically constrained (E)-iminium transition state A to
furnish the aza-Michael product (R)-2a after hydrolysis
(Scheme 2).[26]
Chem. Eur. J. 2011, 17, 14267 – 14272
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14269

S. Fustero, M. Sꢁnchez-Rosellꢂ et al.
intramolecular conjugate addi-
tion of carbamates to a,b-unsa-
turated ketones as Michael ac-
ceptors. We were able to obtain
2-substituted
piperidines,
pyrrolidines, and several benzo-
AHCTUNGTRENNUNG
fused nitrogen heterocycles
with excellent yields and enan-
tioselectivities. Interestingly, the
cyclization step under micro-
wave irradiation led to compa-
rable results in terms of yield
and ee to those obtained at
room temperature. This is, as
far as we know, the first report
Scheme 2. Plausible mechanistic pathway and transition state of the intramolecular aza-Michael reaction.
The extension of this protocol to the synthesis of several
benzo-fused heterocycles was examined next. The optimal
conditions for the IMAMR were applied to conveniently
functionalized aniline and benzylamine substrates 3 to
obtain enantiomerically enriched indolines, isoindolines, tet-
rahydroquinolines, and tetrahydroisoquinolines. The pyrrol-
of a microwave accelerating effect in a Michael-type reac-
tion catalyzed by a cinchona alkaloid derivative.
Table 3. Substrate scope of the organocatalytic IMAMR. Synthesis of
benzo-fused heterocycles.[a]
ACHTUNGTRENNUNGidine benzo-fused products 4a and 4b were obtained in ex-
cellent yields and ee values either at room temperature or
under microwave heating at 608C (Table 3, entries 1 and 2).
Even better results were achieved in the preparation of two
tetrahydroisoquinolines 4d and 4e (Table 3, entries 4 and 5).
The synthesis of the tetrahydroquinoline derivative 4c pro-
ceeded with lower enantioselectivity (88 and 86% ee at
room temperature and 608C, respectively; Table 3, entry 3).
However, this ee value, as well as the yield of the aza-Mi-
chael product, improved when two methoxy groups were at-
tached to the benzene ring (Table 3, entry 6). This is proba-
bly due to the enhanced nitrogen nucleophilicity making the
conjugate addition faster, thus avoiding alternative reaction
pathways promoted by protons liberated during the process
(Brønsted acid catalysis). This nonselective process would
compete with iminium activation by the organocatalyst and
decrease the enantioselectivity of the overall reaction. This
effect was proved by comparing the results achieved in the
synthesis of indolines 4g and 4h, with an electron-donating
and an electron-withdrawing group, respectively. Although
4g was obtained in good yield and enantioselectivity
(Table 3, entry 7), the aza-Michael addition on compound
3h bearing a trifluoromethyl moiety was less efficient
(Table 3, entry 8). Both at room temperature and under mi-
crowave heating, these reactions proceeded in lower yield,
and significantly diminished ee, possibly due to electronic
issues related to the nitrogen nucleophilicity, as indicated
above.
4
Yield
ee
Yield
ee
[%][b,d]
[%][c,d] [%][b,e]
[%][c,e]
1
2
4a 90
93
93
83
91
91
92
4b 96
3
4
4c 80
4d 97
88
97
93
95
86
97
5
4e 94
98
91
96
6
7
4 f 95
4g 85
91
92
92
81
87
90
8
4h 71
68
68
63
Conclusion
[a] Reactions were carried out with 0.15 mmol of starting substrate,
20 mol% of catalyst I and pentafluoropropionic acid (PFP) (20 mol%) in
chloroform (0.1m). [b] All yields are of isolated compounds after flash
chromatography. [c] Enantiomeric excesses were determined by HPLC
on a chiral stationary phase (Chiracel OD-H); see the Supporting Infor-
mation for details. [d] At room temperature for 20 h. [e] Microwave irra-
diation at 608C for 1 h.
In conclusion, a general protocol for a highly enantioselec-
tive organocatalytic IMAMR has been developed. The com-
bination of 9-amino-9-deoxy-epi-hydroquinine and penta-
fluoropropionic acid is an efficient catalytic system for the
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Chem. Eur. J. 2011, 17, 14267 – 14272

Organocatalytic Enantioselective Intramolecular aza-Michael Reactions
FULL PAPER
t
major =19.4 min,
t
minor =15.8 min; [a]2D5 =+82.5 (c=1.0 in CHCl3);
Experimental Section
1H NMR (300 MHz, CDCl3): d=2.10 (s, 3H), 2.61–2.73 (m, 2H), 3.00–
3.04 (m, 1H), 3.45 (dd, J=16.6, 9.6 Hz, 1H), 4.83–4.89 (m, 1H), 5.29 (s,
2H), 6.94–6.99 (m, 1H), 7.12–7.17 (m, 2H), 7.33–7.41 (m, 5H), 7.70–
7.81 ppm (m, 1H); 13C NMR (75.5 MHz, CDCl3): d=30.4 (CH3), 34.5
(CH2), 48.2 (CH2), 55.6 (CH) 67.3 (CH2), 115.4 (CH), 123.1 (CH), 125.1
(CH), 127.6 (CH), 128.1 (CH), 128.3 (CH), 128.6 (CH), 129.7 (C), 136.1
(C), 136.7 (C), 161.0 (C), 206.7 ppm (C); IR (film): n˜ =3489, 2884, 1707,
1600, 1482, 1402, 1128, 751 cmÀ1; HRMS (EI): m/z calcd for C19H19NO3:
309.1365 [M+]; found: 309.1369.
General procedure for the preparation of N-protected amines 1 and 3:
The corresponding conjugated ketone (3.0 equiv) and Hoveyda–Grubbs
second-generation catalyst (5 mol%) were added to a solution of N-pro-
tected amine (1.0 equiv) in CH2Cl2 (0.1m) under nitrogen atmosphere.
The resulting solution was stirred for 12 h at room temperature before
the solvent was removed and the crude mixture purified by flash chroma-
tography with hexanes and ethyl acetate as eluents.
(E)-8-Benzyloxycarbonylamino-3-octen-2-one (1a): By means of the gen-
eral procedure described above, 1a (212 mg) was obtained from methyl
vinyl ketone and N-benzyloxycarbonyl-5-hexenamine as a pale yellow oil
in 90% yield after flash chromatography with hexanes/ethyl acetate 3:1
as eluent. 1H NMR (300 MHz, CDCl3): d=1.48–1.53 (m, 4H), 2.15–2.26
(m, 2H), 2.21 (s, 3H), 3.15–3.21 (m, 2H), 4.94 (brs, 1H), 5.07 (s, 2H),
6.04 (d, J=16.2 Hz, 1H), 6.70–6.80 (m, 1H), 7.28–7.35 ppm (m, 5H);
13C NMR (75.5 MHz, CDCl3): d=25.0 (CH2), 26.8 (CH3), 29.4 (CH2),
31.9 (CH2), 40.6 (CH2), 66.5 (CH2), 128.0 (CH), 128.2 (CH), 128.4 (CH),
131.4 (CH) 136.5 (C), 147.6 (CH), 156.3 (C), 198.6 ppm (C); HRMS (EI):
m/z calcd for C16H21NO3: 275.1521 [M+]; found: 275.1519.
Acknowledgements
This work was supported by the Ministerio de Ciencia e Innovaciꢂn of
Spain (CTQ2010–19774-C02) and Generalitat Valenciana (GV/PROME-
TEO/2010/061). M.S.-R. thanks the same institution for a Juan de la
Cierva contract.
(E)-5-(2-Benzyloxycarbonylamino)phenyl-3-penten-2-one (3a): By means
of the general procedure described above, 3a (210 mg) was obtained
from methyl vinyl ketone and N-benzyloxycarbonyl-2-allylaniline as a
pale brown solid in 91% yield after flash chromatography with hexanes/
ethyl acetate 3:1 as eluent. M.p. 47–498C; 1H NMR (300 MHz, CDCl3):
d=2.07 (s, 3H), 3.40 (d, J=6.3 Hz, 2H), 5.07 (s, 2H), 5.88 (dt, J=15.9,
1.4 Hz, 1H), 6.55 (brs, 1H), 6.71–6.81 (m, 1H), 7.03 (d, J=4.1 Hz, 2H),
7.15–7.28 (m, 6H), 7.56 ppm (d, J=7.7 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3): d=27.0 (CH3), 34.4 (CH2), 67.0 (CH2), 125.4 (CH), 127.8 (CH),
127.9 (CH), 128.1 (CH), 128.2 (CH), 128.4 (CH), 130.1 (CH), 131.9
(CH), 135.4 (C), 135.9 (C), 136.5 (C), 144.6 (CH), 154.0 (C), 198.0 ppm
(C); HRMS (EI): m/z calcd for C19H19NO3: 309.1365 [M+]; found:
309.1363.
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General procedure for the organocatalytic IMAMR reaction at room
temperature (A) and under microwave irradiation (B): Preparation of 2-
substituted nitrogen heterocycles 2 and 4. A) In a 10 mL round bottomed
flask, a,b-unsaturated ketones (1 or 3) (1.0 equiv) were dissolved in
chloroform (0.1m). A mixture of catalyst I (20 mol%) and pentafluoro-
propionic acid (PFP) (20 mol%, added from a freshly prepared stock so-
lution in chloroform) was added and the resulting solution was stirred at
room temperature. After 12–96 h, the crude reaction mixture was subject-
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and ethyl acetate as eluents to afford the corresponding heterocycles 2
and 4. The enantiomeric ratios were determined by means of HPLC anal-
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form (0.1m) in a microwave vial and then catalyst I (20 mol%) and PFP
(20 mol%, added from a freshly prepared stock solution in CHCl3) were
added successively. The vial was sealed and the corresponding solution
was heated under microwave irradiation at 608C for 1–4 h. After this
time, the crude reaction mixture was purified by means of flash chroma-
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ACHTUNGTRENNUNG(2R)-N-Benzyloxycarbonyl-2-(2-oxopropyl)piperidine (2a): By means of
the general procedure described above, 2a (38 mg) was obtained as a col-
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spectroscopic data are in agreement with those previously reported in the
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rate=1.0 mLminÀ1, tmajor =14.1 min, tminor =14.8 min; [a]2D5 =+11.6 (c=1.0
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ACHTUNGTRENNUNG(2R)-N-Benzyloxycarbonyl-2-(2-oxopropyl)indoline (4a): By means of
the general procedure described above, 4a (42 mg) was obtained as color-
less oil from 3a in 90% yield and 93% ee at room temperature [83%
yield (38 mg) and 91% ee at 608C under microwave irradiation]. The ee
values were determined by means of HPLC analysis by using a Chiracel
OD-H column (hexane:isopropanol 95:5). Flow rate=1.0 mLminÀ1
,
Chem. Eur. J. 2011, 17, 14267 – 14272
ꢄ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
14271

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Received: April 28, 2011
Revised: August 14, 2011
Published online: November 14, 2011
14272
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Chem. Eur. J. 2011, 17, 14267 – 14272