Asymmetric aza-Henry reaction under phase transfer catalysis: An experimental and theoretical study

Article abstract of DOI:10.1021/ja800253z

An efficient catalytic asymmetric aza-Henry reaction under phase transfer conditions is presented. The method is based on the reaction of the respective nitroalkane with α-amido sulfones effected by CsOH·H₂O base in toluene as solvent and in the presence of cinchone-derived ammonium catalysts. This direct aza-Henry reaction presents as interesting features its validity for both nonenolizable and enolizable aldehyde-derived azomethines and the tolerance of nitroalkanes, other than nitromethane, for the production of β-nitroamines. The synthetic value of the methodology described is demonstrated by providing (a) a direct route for the asymmetric synthesis of differently substituted 1,2-diamines and (b) a new asymmetric synthesis of γ-amino α,β-unsaturated esters through a catalytic, highly enantioselective formal addition of functionalized alkenyl groups to azomethines. Finally, a preferred TS that nicely fits the observed enantioselectivity has been identified. Most remarkable, an unusual hydrogen bond pattern for the catalyst-nitrocompound-imine complex is predicted, where the catalyst OH group interacts with the NO₂ group of the nitrocompound.

Full text of DOI:10.1021/ja800253z

Published on Web 05/30/2008
Asymmetric Aza-Henry Reaction Under Phase Transfer
Catalysis: An Experimental and Theoretical Study
Enrique Gomez-Bengoa, Anthony Linden,† Rosa Lo´pez, Idoia Mu´gica-Mendiola,
Mikel Oiarbide, and Claudio Palomo*
Departamento de Qu´ımica Orga´nica I, Facultad de Qu´ımica, UniVersidad del Pa´ıs Vasco, Apdo.
1072, San Sebastia´n, 20080, Spain
Received January 15, 2008; E-mail: claudio.palomo@ehu.es
Abstract: An efficient catalytic asymmetric aza-Henry reaction under phase transfer conditions is presented.
The method is based on the reaction of the respective nitroalkane with R-amido sulfones effected by
CsOH·H2O base in toluene as solvent and in the presence of cinchone-derived ammonium catalysts. This
direct aza-Henry reaction presents as interesting features its validity for both nonenolizable and enolizable
aldehyde-derived azomethines and the tolerance of nitroalkanes, other than nitromethane, for the production
of ꢀ-nitroamines. The synthetic value of the methodology described is demonstrated by providing (a) a
direct route for the asymmetric synthesis of differently substituted 1,2-diamines and (b) a new asymmetric
synthesis of γ-amino R,ꢀ-unsaturated esters through a catalytic, highly enantioselective formal addition of
functionalized alkenyl groups to azomethines. Finally, a preferred TS that nicely fits the observed
enantioselectivity has been identified. Most remarkable, an unusual hydrogen bond pattern for the catalyst-
nitrocompound-imine complex is predicted, where the catalyst OH group interacts with the NO2 group of
the nitrocompound.
Introduction
literature, some general restrictions remain. Nitroalkane partner
is most often restricted to nitromethane or nitroethane, both
Among the existing methods for the synthesis of nitrogen-
containing molecules, the aza-Henry (or nitro-Mannich) reaction
is of prime importance.1 The resulting ꢀ-nitroamines can be
either oxidized, producing R-amino carbonyl compounds,2 or
reduced, affording 1,2-diamines.3 Most significant, by this
reaction, both nitrogen functionalities, the amino and the nitro
groups, are arranged with simultaneous formation of the new
C-C bond while the relative and absolute configurations are
all fixed in a single synthetic operation. To date, however, the
full implementation of this strategy, with high degrees of
stereocontrol and substrate tolerance, is far from being satis-
factorily solved. Important progress has been made in the
catalytic enantioselective aza-Henry reaction of aromatic azome-
thines based on chiral Lewis acid catalysts of ytterbium,4
aluminum,5 copper,6 zinc7 metals, and also organocatalysts.8
Regarding substrate variation in the methods described in
relatively cheap and volatile, which allows their use in large
excess or even as (co)solvent. Longer chain and functionalized
nitroalkanes have been scarcely explored.9 In addition, although
the reactions involving nitromethane do not display syn/anti
isomerism, all other nitroalkanes can produce both diastereo-
mers, an issue poorly solved in the general context of the aza-
Henry and the related Henry reaction.10 On the other hand, the
vast majority of the known methods deal with azomethine
components derived from nonenolizable aldehydes,11 typically
aromatic N-acyl and N-phosphinoyl imines or iminoesters. The
(6) (a) Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.;
Jørgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843–5844. (b)
Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2001, 40, 2992–2995. (c) Knudsen, K. R.;
Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 1362–1364. (d) Handa,
S; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M J. Am. Chem. Soc.
2007, 129, 4900–40091. (e) Zhou, H.; Peng, D.; Qin, B.; Hou, Z.;
Liu, X.; Feng, X. J. Org. Chem. 2007, 72, 10302–10304.
(7) (a) Palomo, C.; Oiarbide, M.; Halder, R.; Laso, A.; Lo´pez, R. Angew.
Chem., Int. Ed. 2006, 45, 117–120. (b) Trost, B. M.; Lupton, D. W
Org. Lett. 2007, 9, 2023–2026.
(8) (a) Nugent, B. M.; Poder, R. A.; Johnston, J. N J. Am. Chem. Soc.
2004, 126, 3418–3419. Bifunctional thioureas: (b) Okino, T.; Naka-
mura, S.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625–627.
(c) Xu, X.; Furukawa, T.; Okino, T.; Miyabe, H.; Takemoto, Y.
Chem.-Eur. J. 2006, 12, 466–476. (d) Yoon, T. P.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2005, 44, 466–468. Alkaloids: (e) Bernardi,
L.; Fini, F.; Herrera, R. P.; Ricci, A.; Sgarzani, V. Tetrahedron 2006,
62, 375–380. N-Sulfinyl ureas: (f) Robak, M. T.; Trincado, M.; Ellman,
J. A. J. Am. Chem. Soc. 2007, 129, 15110–15111.
† X-ray crystal structure analysis. Organich-chemisches Institut der
Universita¨t Zu¨rich, Wintherthurerstrasse 190, CH-8057 Zu¨rich, Switzerland.
(1) For recent racemic versions, see: (a) Bernardi, L.; Bonini, B. F.; Capito`,
E.; Dessole, G.; Comes-Francini, M.; Fochi, M.; Ricci, A. J. Org.
Chem. 2004, 69, 8168–8171. (b) Anderson, J. C.; Blake, A. J.; Howell,
G. P.; Wilson, C. J. Org. Chem. 2005, 70, 549–555. For a highlight
disclosing recent catalytic asymmetric approaches, see: (c) Wester-
mann, B Angew. Chem., Int. Ed. 2003, 42, 151–153.
(2) Reviews on the Nef reaction: (a) Pinnick, H. W. Org. Reac. 1990,
38, 655–792. (b) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017–
1047. For the synthesis of fine chemicals from nitroalkanes, see: (c)
Ballini, R.; Palmieri, A.; Righi, P. Tetrahedron 2007, 63, 12099–
12121.
(3) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998,
37, 2580–2627.
(9) For some examples of addition of long chain or functionalized
nitroalkanes, see refs 5, 6b, d, 7b, 8c, d, and 8f.
(4) Yamada, K.; Harwood, S. J.; Gro¨ger, H.; Shibasaki, M. Angew. Chem.,
Int. Ed. 1999, 38, 3504–3506.
(10) Lecea, B.; Arrieta, A.; Morao, I.; Coss´ıo, F. P. Chem.-Eur. J. 1997,
(5) Yamada, K.; Moll, G.; Shibasaki, M. Synlett 2001, 980–982.
3, 20–28.
9
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2008 American Chemical Society
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A R T I C L E S
Gomez-Bengoa et al.
characteristics.16 In our study, the initial screen of several
cinchone-based quaternary ammonium salts17 for the reaction
of nitromethane with R-amido sulfones, Scheme 1, revealed that
N-Boc derivatives 1 provide the best results in terms of
enantioselectivity. Among the catalysts tested, N-benzylqui-
ninium chloride A was the optimum, a phase transfer catalyst
commercially available at relatively low cost.
Figure 1. Imine precursors and N-phosphinoyl imine employed in this
The exploration of different chiral ammonium salt catalysts
of varying skeletal configuration and functionality led to the
following conclusions: (a) for production of products of R
configuration, catalyst A, derived from quinine, gives rise to
slightly higher selectivities than the cinchonidine-derived coun-
terpart B, whereas production of S products in high selectivity
is conducted by the cinchonine derived salt C; (b) blocking the
free secondary hydroxyl group of the catalysts in the form of
benzyl ether function (catalysts D and E) drastically disrupts
catalytic activity, reaction conversions being typically <10%.
This latter observation was interpreted in terms of the key role
played by hydrogen bonding interaction during substrate activa-
tion. Actually, an intringuing hydrogen-bond network activation
pattern, which will be outlined later, has been computationally
identified to be the responsible of the observed reactivity and
selectivity. In general, for reactions involving nitromethane,
Scheme 1, the corresponding adducts 5 were obtained in isolated
yields in the 70-80% range and, most remarkably, with very
high enantioselectivity, typically 95% ee.
study.
Scheme 1. Aza-Henry Reaction of Nitromethane with Azomethines
Generated from R-Amido Sulfones 1 under PTC
reason is that enolizable aldehyde-derived azomethines tend to
suffer R-deprotonation rather than addition. Apart from these
issues, there is the fact that metal nitronates are quite inert
toward Schiff bases and the aid of a Lewis and/or Brønsted
acid is often required.12 Furthermore, the products of aza-Henry
reaction, ꢀ-nitroamines, are prone to retroaddition.13 In this
work, we present in detail a catalytic asymmetric aza-Henry
reaction under phase transfer catalysis (PTC), valid for both
nonenolizable and enolizable aldehyde-derived azomethines.
Experimental results are complemented with a theoretical
investigation of the reaction mechanism, which uncovered a
rather unusual hydrogen bonding pattern of the TS of the
catalytic reaction with potential implications in a more general
context.
Optimization and Scope. Given the observations noted above
and owing to the lack of methods for the production of R,ꢀ-
disubstituted ꢀ-nitroamines of high enantiomeric purity, we
decided to explore the validity of the approach for various types
of nitroalkanes other than nitromethane. Besides enantioselec-
tivity, control of the relative syn/anti configuration of the newly
generated stereocenters constitutes an additional difficulty. The
initial screening of N-protected R-amido sulfones 1a, 2a, 3a
and phenyl N-phosphinoyl imine 4a,18 employing chiral qua-
ternary ammonium salt A in the presence of CsOH ·H2O, Table
1, revealed the R-amido sulfone 1a to be the most suitable
azomethine precursor for the aza-Henry reaction with nitroet-
hane. Whereas the R-amido sulfones 2a, 3a and imine 4a were
poor imine surrogates in terms of reactivity, diastereoselectivity,
and/or enantioselectivity (Table 1), R-amido sulfone 1a provided
the desired adduct 6a in good chemical yield and, most notably,
with very high diastereo- and enantioselectivity.
It was also found that solvent influences both reactivity and
stereoselectivity (Table 2). For example, the addition of water
to the reaction mixture to mimic a more traditional liquid-liquid
biphasic system (entries 3 and 6) disrupted not only the reactivity
(23 and 30% conversions after 44 h) but, more importantly,
also the diastereo- and enantioselectivity (compare entries 3 and
6 with entries 2 and 5). Solvents of increased polarity such as
CH2Cl2 and THF produced diminished enantiomeric excesses
of the corresponding syn adducts 6a and 6b and had an
Results and Discussion
Background. A recent report14 from this laboratory has
addressed the above issues and found that (Scheme 1) R-amido
sulfones,15 generated from both enolizable and nonenolizable
aldehydes, sodium p-toluensulfinate, and tert-butyl carbamate,
upon reaction with nitromethane in the presence of CsOH·H20
under chiral PTC, provided a good solution to the above
problems. Concurrent with our investigations, Herrera and
Bernardi have also documented an aza-Henry reaction of similar
(11) For recent examples of enantioselective aza-Henry reaction with
aliphatic N-Boc imines, see refs 6d and 8f.
(12) Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K. J. Org.
Chem. 1998, 63, 9932–9934.
(13) (a) Sturgess, M. A.; Yarberry, D. J. Tetrahedron Lett. 1993, 34, 4743–
4746. (b) Anderson, J. C.; Peace, S.; Pih, S. Synlett 2000, 850–852.
(14) Palomo, C.; Oiarbide, M.; Laso, A.; Lo´pez, R. J. Am. Chem. Soc.
2005, 127, 17622–17623.
(16) Fini, F.; Sgarzani, V.; Pettersen, D.; Herrera, R. P.; Bernardi, L.; Ricci,
A. Angew. Chem., Int. Ed. 2005, 44, 7975–7978.
(17) For cinchone-based quaternary ammonium salts catalyzed reactions,
see: (a) Maruoka, K.; Oii, T. Chem. ReV. 2003, 103, 3013–3028. (b)
Oii, T.; Maruoka, K. Acc. Chem. Res. 2004, 37, 526–533. (c) O’Donell,
M. Acc. Chem. Res. 2004, 37, 606–517. (d) Lygo, B.; Andrews, P. I.
Acc. Chem. Res. 2004, 37, 518–525. For a recent review on the
application of phase transfer catalysts, see: (e) Hashimoto, T.; Maruoka,
K. Chem. ReV. 2007, 107, 5656–5682.
(15) For a review on the preparation and reactivity of R-amidosulfones,
see: (a) Petrini, M. Chem. ReV 2005, 105, 3949–3977. For recent
examples involving R-amidosulfones in cinchone catalyzed Mannich
reactions, see: (b) Marianacci, O.; Micheletti, G.; Bernardi, L.; Fini,
F.; Fochi, M.; Pettersen, D.; Sgarzani, V.; Ricci, A. Chem.-Eur. J.
2007, 13, 8338–8351. (c) Lou, S.; Dai, P.; Schauss, S. E. J. Org. Chem.
2007, 72, 9998–10008. (d) Niess, B.; Jørgensen, K. A. Chem. Commun.
2007, 1620–1622. (e) Song, J.; Shih, H.; W; Deng, L Org. Lett. 2007,
9, 603–606.
(18) The corresponding N-phosphinoyl protected R-amido sulfone did not
react under the PTC conditions employed. The enantiomeric purities
were determined by HPLC.
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Aza-Henry Reaction Under Phase Transfer Catalysis
A R T I C L E S
Table 1. Effect of the Imine Protecting Group (PG) on the Yield
and Selectivity of the Aza-Henry Reaction of Nitroethane under
PTCa
(entry 3). Configuration of adducts 6a-g was established by
comparison with published values (see Supporting Information).
In general, the enantiomeric excesses obtained in the aza-
Henry reaction with nitroethane were slightly higher to those
obtained in the reaction with nitromethane (data in parenthesis;
entries 1, 2, and 7). The potential of this catalytic approach was
further demonstrated by the reaction of nitroethane with
enolizable aldehyde-derived R-amido sulfones (1h-l). As a
general trend, the reaction employing alkyl R-amido sulfones
produced adducts 6 in good yields and high enantiomeric excess
of the corresponding syn-adducts (90-96% ee). Good syn
diastereoselectivity was achieved with linear alkyl substituted
R-amido sulfones 1h, 1i, and 1j (entries 8, 9, and 10).
Nevertheless, reactions involving substrates bearing branched
alkyl groups (entries 11, 12) resulted in a considerably attenuated
syn:anti selectivity albeit both the syn and the anti product were
obtained in excellent enantioselectivity.
Due to the essential lack of methods for the production of
R,ꢀ-disubstituted ꢀ-nitroamines, we decided to explore the
validity of the approach for long chain and functionalized
nitroalkanes and provide an entry to polifunctional amino
compounds. As shown in Table 4, nitroalkanes such as
nitropropane, nitropentane, 4-nitropent-1-ene, 2-nitropropane,
1,1-diethoxy-2-nitroethane, 5,5-dimethyl-2-nitromethyl-1,3-di-
oxane, and ethyl-3-nitropropanoate react with both aromatic and
aliphatic-substituted R-amido sulfones to preferentially produce
syn ꢀ-nitroamines. For example, linear nitroalkanes (entries 1-4,
9, and 12) produced adducts 6 in good yields and good syn
diastereoselectivities; ꢀ-branched chain nitroalkanes afforded
less regular diasteromeric ratios ranging from a good 90:10 ratio
(entry 10) to a complete loss of diastereoselection (entry 11).
In general, reactions employing alkyl R-amido sulfones produced
syn adducts in higher enantiomeric excesses (90-99% ee)
compared to those employing aryl R-amido sulfones (80-95%
ee). In contrast, the aza-Henry reaction employing an R-branched
nitroalkane such as 2-nitropropane displayed a poor enantiomeric
excess for adducts 6q and 6t (entries 5 and 8).
compound
product
conversion (%)
syn:antib
ee (%)c
1a
2a
3a
4ad
6a
7a
8a
9a
>95
20
83
92:8
90
67
0
60:40
50:50
80:20
84
78
a Reactions conducted at 1 mmol scale in dry toluene (3 mL) under a
nitrogen atmosphere employing 5 equiv of nitroethane. b Determined by
1H NMR and HPLC. c Determined by HPLC (see Supporting
Information for details). d CsOH·H2O (30 mol %) was employed.
Table 2. Effect of the Solvent in the Aza-Henry Reaction of
Nitroethane with N-Boc Protected R-Amido Sulfones 1a and 1b
under PTCa
entry
R
solvent
T (°C) conversion (%) syn:antid
ee (%)e
1
2
3
Ph
Toluene
-50
-20
>95
>95
23
93:7 94f
89:11 63
50:50 43
Toluene + -20b
H2O(50%)
4
5
6
CH2Cl2
4-Cl-C6H6 Toluene
-50
40
>95
30
68:32 78
88:12 98f
47:53 70 (55 anti)
-40c
Toluene + -40
H2O(10%)
7
8
CH2Cl2
THF
-40
-40
66
40
55:45 90
64:34 83
Chemical Elaboration of Adducts. New Entry to Vinilo-
gous Amino Acids. As outlined in Scheme 2, the ꢀ-nitroamines
obtained in the PTC aza-Henry reaction of R-amido sulfones
with nitroalkanes constitute valuable intermediates for the
synthesis of a variety of enantioenriched compounds such as
R-aminoacids20 and 1,2-diamines. Even though the elaboration
of ꢀ-nitroamines into 1,2-diamines seems trivial, there is a
shortage of methods for the access to enantioenriched dialkyl
1,2-diamines. Thus, the present aza-Henry reaction, that allows
the reaction of enolizable aldehyde-derived azomethines with
nitroalkanes other than nitromethane, provides a new access to
a wide range of 1,2-diamine compounds.
For example, using known procedures, the reduction of the
nitro group in 6k led to the corresponding monoprotected
diamine which was converted into the more stable N-Boc
diprotected diamine 11 (Scheme 3). Also, the simultaneous
reduction of the nitro group and deprotection of the N-Boc in
the syn-6k (99:1 syn:anti, 91% ee) afforded in one step the
hydrochloric salt 12 in high yield. An additional illustrative
example is the transformation of adduct 6x into compound 13,
which is an orthogonally protected form of 3-aminodeoxystatine,
an isosterically modified statine analogue.21 Configuration of
adducts 12 and 13, and therefore of their immediate precursors
a Reactions conducted at 0.5 mmol scale under a nitrogen atmosphere
in the indicated solvent (1.5 mL) employing 5 equiv of nitroethane.
b Reaction carried out at -20 °C to avoid freezing. c Below -40 °C,
R-amido sulfone 1b shows limited solubility. d Determined by 1H NMR
and/or HPLC. e Determined by HPLC. f The assignment of the absolute
and syn/anti configuration of adduct 6a and 6b was made by comparison
with published values (see Supporting Information for details).
important impact in the reactivity and diastereochemical ef-
ficiency of the process (entries 4, 7, and 8).
With these insights into the reaction conditions, we next
explored the aza-Henry reaction of nitroethane using a range
of different N-Boc protected R-amido sulfones, Table 3. Both
aromatic and aliphatic-substituted R-amido sulfones preferen-
tially produced the syn-ꢀ-nitroamines 6 with variable degrees
of diastereoselection19 and high yield of the syn:anti mixture.
Electronically diverse aromatic R-amido sulfones (1a-e, 1g)
displayed excellent enantiomeric excesses (87-98%) for the
syn-diastereomer. An exception is the 3-nitro substituted
R-amido sulfone 1f, which produced the corresponding syn-
adduct 6f with low enantiomeric excess and almost no syn:anti
selectivity. Syn diastereo selection for the rest of aromatic
R-amido sulfones ranged from 73:27 (entry 5) to 95:5 ratios
(19) In control experiments, the d.r. values of the reaction of 1a and 1b
were measured at different degrees of reaction conversion, observing
no dependence of the d.r. value with conversion.
(20) See refs 7a and 8c.
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A R T I C L E S
Gomez-Bengoa et al.
Table 3. Aza-Henry Reaction of Nitroethane with Azomethines Generated from R-Amido Sulfones 1 under PTCa
entry
R-amido sulfone
R
product
yield (%)
syn:antib
ee (%)csyn
1
2
3
4
5
6
7
8
1a
1be
1c
1d
1e
1f
1g
1h
1i
Ph
6a
6b
6c
6d
6e
6f
6g
6h
6i
88 (79)d
70 (79)d
87 (82)d
93
93:7
82:18
95:5
94 (91)d
98 (80)d
90 (91)d
90
4-Cl-C6H4
4-MeO-C6H4
4-Me-C6H4
3-Me-C6H4
3-NO2-C6H4
2-furyl
PhCH2CH2
CH3CH2
(CH3)2CHCH2
(CH3)2CH
cC6H11
92:8
98
73:27
58:42 (75:25)e
81:19
90:10
94:6
97:35
67:33
60:40
87
68 (66)e
80 (72)d
90
40 (77)e
95 (84)d
92
9
90
85
90
65
>90
96
92 (g95 anti)
95 (97 anti)
10
11
12
1j
1k
1l
6j
6k
6l
a Reactions conducted at 0.5 mmol scale in dry toluene (1.5 mL) under a nitrogen atmosphere employing 5 equiv of nitroethane. b Determined by 1H
NMR and/or HPLC. c Determined by HPLC (see Supporting Information for details). d In parenthesis are data for the aza-Henry reaction with
nitromethane. e Reaction conducted at -40 °C.
Table 4. Scope of the Aza-Henry Reaction with Azomethines Generated from R-Amido Sulfones 1 under PTCa
a Reactions conducted at 0.5 mmol scale in dry toluene (1.5 mL) under a nitrogen atmosphere employing 5 equiv of the corresponding nitroalkane.
b Determined by 1H-NMR and/or HPLC. c For syn adduct; determined by HPLC (see Supporting Information for details). d Reaction performed at 5
mmol scale. e Reaction conducted at -40° C.
Scheme 2. Useful Synthetic Transformations of ꢀ-Nitroamines
functionalized nitroamine adducts. In particular, it is known that
nitro groups positioned ꢀ to an electron-withdrawing group can
be eliminated and give alkenes on treatment with base.24
Actually, when adduct 6x (mixture syn:anti 75:25) was treated
with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room tem-
perature, the γ-amino R,ꢀ-unsaturated ester 14x was, to our
delight, cleanly produced in high yield and excellent enanti-
oselectivity (Scheme 4a).25 On the other hand, prior chromato-
graphic separation of anti-6x from the syn/anti mixture and
subsequent treatment with DBU afforded the same compound
6k and 6x, was determined by comparison of chiroptic and
chromatographic data with published values.22,23 For the
remaining syn aza-Henry adducts 6m-w, it was assumed on
the basis of an uniform reaction mechanism.
(21) For references on the topic, see: (a) Babine, R. E.; Bender, S. L. Chem.
ReV. 1997, 97, 1359–1472. (b) Richards, A. D.; Roberts, R.; Dunn,
B. M.; Graves, M. Kay. J. FEBS. Lett. 1989, 247, 113–117. (c) Maly,
D. J.; Huang, L.; Ellman, J. A. ChemBioChem 2002, 3, 16–37.
To expand the synthetic utility of the present method, we
decided to investigate other, little explored, applications of the
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Aza-Henry Reaction Under Phase Transfer Catalysis
A R T I C L E S
to highly enantiopure vinylogous amino acids,26 which are
effective modulators of secondary and tertiary structure in
polypeptide chains,27 constituents of important naturally occur-
ring molecules28 and versatile intermediates of structurally and
biologically relevant compounds.29 It is important to notice that
the overall process, shown in Scheme 5, represents an olefin
umpolung strategy30 carried out in this case, under catalytic
conditions31 and with good overall yield and selectivity.
Scheme 3. Transformation of Aza-Henry Compounds into
1,2-Diamines
Reaction Mechanism
The present aza-Henry reaction proceeds under non homo-
geneous reaction conditions and involves a concatenated
sequence of steps which turn the full understanding of the
reaction mechanism challenging. Despite this complexity, the
combination of some experimental observations with performed
Scheme 4. Base-Promoted Synthesis of γ-Amino R,ꢀ-Unsaturated
Ester 14x
(26) Access to these interesting compounds has traditionally relied on the
olefination of R-amino aldehydes. See, for instance: (a) Gryko, D.;
Chalko, J.; Jurczak, J. Chirality 2003, 15, 514–541. (b) Reetz, M. T
Chem. ReV. 1999, 99, 1121–1162. Also, see: (c) Kotkar, S. P.; Chavan,
V. B.; Sudalai, A. Org. Lett. 2007, 9, 1001–1004.
(27) For recent examples, see: (a) Bang, J. K.; Naka, H.; Teruya, K.;
Aimoto, S.; Konno, H.; Nosaka, K.; Tatsumi, T.; Akaji, K. J. Org.
Chem. 2005, 70, 10596–10599. (b) Grison, C.; Coutrot, P.; Geneve,
S.; Didierjean, C.; Marraud, M. J. Org. Chem. 2005, 70, 10753–10764.
(c) Baldauf, C.; Gu¨nther, R.; Hofmann, H.-J. HelV. Chim. Acta 2003,
86, 2573–2588.
(28) (a) Fusetani, N.; Matsunaga, S.; Matsumoto, H.; Takebayashi, Y. J. Am.
Chem. Soc. 1990, 112, 7053–7054. (b) Coleman, J. E.; Dilip de Silva,
E.; Kong, F.; Andersen, R. J. Tetrahedron 1995, 51, 10653–10662.
(c) Wolin, R. L.; Santilla´n, A, Jr.; Barclay, T.; Tang, L.; Venkatesan,
H.; Wilson, S.; Lee, D. H.; Lovenberg, T. W Bioorg. Med. Chem.
2004, 12, 4493–4509. (d) Swarna, V. M.; Undem, B. J.; Korlipara,
V. L. Bioorg. Med. Chem. 2007, 17, 890–894.
Scheme 5. Formal Catalytic Enantioselective
2-Ethoxycarbonylvinylation of N-Acylimines
(29) Peptide isosters: (a) Thoen, J. C.; Morales-Ramos, A. I.; Lipton, M. A.
Org. Lett. 2002, 4, 4455–4458. (b) Palomo, C.; Oiarbide, M.; Landa,
A.; Esnal., E.; Linden, A. J. Org. Chem. 2001, 66, 4180–4186. (c)
Broady, S. D.; Rexhausen, J. E.; Thomas, E. J. J. Chem. Soc., Perkin
Trans. 1999, 1, 1083–1094. Iminosugars: (d) Hulme, A. N.; Mont-
gomery, C. H Tetrahedron Lett. 2003, 44, 7649–7653. Glutamate
receptors: (e) Oba, M.; Koguchi, S.; Nishiyama, K. Tetrahedron 2002,
58, 9359–9363. (f) Daunan, P.; Saint-Fuscien, C. D.; Acher, F.;
Pre`zeau, L.; Brabet, I.; Pin, J.; Dodd, R. H. Bioorg. Med. Chem. Lett.
2000, 10, 129–133. (g) Dauban, P.; Saint-Fuscien, C. D.; Dodd, R. H.
Tetrahedron 1999, 55, 7589–7600. Amino acids: (h) Hayashi, T.;
Yamamoto, A.; Ito, Y.; Nishioka, E.; Miura, H.; Yanagi, K. J. Am.
Chem. Soc. 1989, 111, 6301–6311. (i) Jumnah, R.; Williams, J. M. J.;
Williams, A. C. Tetrahedron Lett. 1993, 34, 6619–6622. (j) Bower,
J. F.; Jumnah, R.; Williams, A. C.; Williams, J. M. J. J. Chem. Soc.,
Perkin Trans. 1 1997, 1411–1420. (k) Burgess, K.; Liu, L. T.; Pal, B
J. Org. Chem. 1993, 58, 4758–4763. Alkaloids: (l) Magnus, P.; Lacour,
J.; Coldham, I.; Mugragr, B.; Bauta, W. B. Tetrahedron 1995, 51,
11087–11110. (m) Trost, B. M. Angew Chem., Int. Ed. Engl. 1989,
28, 1173–1094. Carbohydrate derivatives: (n) Trost, B. M.; Van
Vranken, D. L. J. Am. Chem. Soc. 1993, 115, 444–458.
14x, from which the configuration of the anti-6x adduct could
be inferred to be (R, R) (Scheme 4b). This assumption would
indicate that the present catalytic aza-Henry reaction proceeds
with almost perfect π-face selectivity over the azomethine
compound.
(30) For reviews on the topic, see: (a) Seebach, D. Angew. Chem., Int. Ed.
Engl. 1969, 8, 639–649. (b) Umpoled Synthons; Hase, T. A., Ed.; John
Wiley: New York, 1987.
Generalization of the base-promoted nitrous acid elimination
process was successful for other nitroamine adducts 14h, i, m
(Scheme 5). Hence, this process represents an unprecedent entry
(31) To the best of our knowledge, base-promoted elimination of nitrous
acid to afford alkenes has only been employed in combination with
racemic transformations: Michael addition to ethyl ꢀ-nitroacrylate: (a)
Patterson, J. W.; McMurry, J. E. Chem. Commun. 1971, 488–489.
Henry and Michael reactions of nitroalkanes: (b) Seebach, D.;
Hoekstra, M. S.; Protschuck, G. Angew. Chem., Int. Ed. 1977, 16,
321–322. (c) Mori, K.; Kitahara, T. Tetrahedron 1984, 40, 2935–2944.
(d) Ballini, R.; Fiorini, D.; Palmieri, A. Tetrahedron. Lett. 2004, 45,
7027–7029. (e) Bakuzis, P.; Bakuzis, M. L. F.; Weingartner, T. F.
Tetrahedron Lett. 1978, 19, 2371–2374. (f) Ballini, R; Bosica, G.
Tetrahedron 1995, 51, 4213–4222. Alkylation of nitroesters: (g)
Seebach, D.; Henning, R.; Mukhopadhyay, T Chem. Ber. 1982, 115,
1705–1720. Diels-Alder reactions: (h) Danishesfsky, S.; Prisbylla,
M. P.; Hiner, S. J. Am. Chem. Soc. 1978, 100, 2918–2920.
(22) Due to some discrepancy in the absolute value of the optical rotation,
relative configuration was confirmed by X-ray crystal structural
analysis of adduct 6x.
(23) For adduct 12, see: (a) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero,
T. Tetrahedron: Asymmetry 1997, 8, 2381–2401. For adduct 13, see:
(b) Arrowsmith, R.; Carter, K.; Dann, J. G.; Davies, D. E.; Harris, J.;
Morton, J. A.; Lister, P.; Robinson, J. A.; Williams, D. J. Chem. Soc.,
Chem. Commun. 1986, 755–757.
(24) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH: New
York, 2001; pp 218-230.
(25) Transformation of 14x into the corresponding knownγ-aminoR,ꢀ-
unsaturated acid 15 allowed the determination of the absolute
configuration (see Supporting Information). The enantiomeric purity
was determined by HPLC.
(32) For related proposals involving catalytic PTC reaction conditions, see:
Mannich reaction: ref 15b; Strecker reaction: Herrera, R. P.; Sgarnazi,
V.; Bernadi, L.; Fini, F.; Pettersen, D.; Ricci, A. J. Org. Chem. 2006,
71, 9869–9872.
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Scheme 6. Enantioselective Aza-Henry Reaction between
Nitromethane and (a) R-Amido Sulfone, under PTC Conditions,
and (b) Preformed N-Acyl Imine
quantum calculations allowed us to propose a general reaction
scheme wherein the role played by the reactants, the added base,
and the catalyst, as well as a plausible stereochemical model
for the transfer of chirality, can be identified as described below.
Experimental Observations. A primary observation was that
the reaction outcome is essentially identical, as shown in Scheme
6, whether we started from the R-amido sulfone 1a or the
corresponding preformed N-acyl imine 16. Accordingly, imine
formation from the respective R-amido sulfones apparently takes
place in an independent event that precedes the aza-Henry
reaction and the evolving sulfinate salts have not influence in
the latter process. On the other hand, NMR monitoring of the
reaction mixture of 1a at different degrees of reaction conversion
revealed no peaks corresponding to the N-acyl imine intermedi-
ate. The absence of appreciable amounts of N-acyl imine
intermediate along the course of the reaction appears to indicate
that base-promoted generation of imine proceeds slower than
the subsequent imine consumption via carbon-carbon coupling
(aza-Henry reaction).
Figure 2. General scheme for the aza-Henry reaction involving R-amido
sulfones under PTC conditions.
A third experimentally supported important conclusion is that
the OH- anions present in the reaction mixture are not by their
own the responsible of imines formation from R-amido sulfone
precursors. Instead, the base-promoted conversion of starting
R-amido sulfones into the N-acyl imines can be ascribed to an
organic base generated in the environment, most likely nitronate
anion, based on the following two observations: (1) treatment
of R-amido sulfone 1a with 1.3 equiv of CsOH in the presence
of ammonium salt A (12 mol%) in toluene as solvent at -50
°C for as long as 44 h did not produce any appreciable reaction,
and starting 1a was recovered unaltered; (2) neither reaction
was observed when 1a was treated with CsOH (1.3 equiv) and
nitroethane in toluene at -50 °C in the absence of catalyst A.
So, both nitroalkane and catalyst A are required for imine
generation. We postulate the general reaction scheme repre-
sented in Figure 2.32 Thus, the initially originated nitronate anion
will be the actual base that promotes elimination of sulfinic acid
from R-amido sulfones to render the intermediate N-acyl imines.
Direct implication of nitronate anion in imine formation is
further sustained by the fact that when more acidic nitroalkanes
such as methyl 2-nitroacetate are involved, the aza-Henry
reaction takes place sluggishly (15% conversion after 44 h).
This slowness could be ascribed to the lower basicity of the
corresponding nitronate anion in this particular case. Steric
effects, which could be invoked as the source of the lower
reactivity of methyl 2-nitroacetate, are ruled out since 2-nitro-
propane, which bears similar steric congestion, but displays
lower acidity, gave the aza-Henry reaction satisfactorily (>95%
conversion after 44 h). In addition, it was observed that the
Figure 3. Kinetic studies on the aza-Henry reaction of 16 with nitromethane
under (a) pseudoconstant concentration of nitromethane and (b) variable
loading of catalyst A.
outcome of the aza-Henry reaction is independent of the excess
amount of CsOH employed, which secures high reproducibility
irrespective of the amount of inorganic salt added.
Kinetic Studies. To obtain further information about the
reaction mechanism, we carried out kinetic studies on the aza-
Henry reaction. The parameters of the reaction between imine
16 and nitromethane catalyzed by A were determined by
1
monitoring the consumption of phenyl N-Boc imine 16 by H
NMR. In the first set of experiments (Figure 3a), the reaction
order in phenyl N-Boc imine 16 was established by using a
large excess of nitromethane (15 equiv) and 12 mol % of
catalyst. Plotting in -ln([16]/[160]) versus time gave a straight
line (R2 ) 0.9906), which indicates first-order dependence in
the imine. The reaction order in catalyst A was established by
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7960 J. AM. CHEM. SOC. VOL. 130, NO. 25, 2008

Aza-Henry Reaction Under Phase Transfer Catalysis
A R T I C L E S
determining the kinetic rate constants (kobs) at various catalyst
concentrations (7, 12, 18, and 25 mol %). Plotting of kobs versus
the catalyst loading gave also a straight line for N-benzylqui-
ninium chloride A (R2 ) 0.9946, Figure 3b), indicating the first-
order dependence in catalyst. Unfortunately, the reaction order
in nitromethane could not be determined using this methodology
due to experimental constraints such as the relatively high
volatility of nitromethane and the low solubility of the reaction
product in the reaction media which difficulted the measurement
of the actual consumption of nitromethane (or actual formation
of coupling product).33 However, for the subsequent quantum
calculations, we assumed that the C-C coupling step in the
aza-Henry reaction is unimolecular with respect to each reactant
(imine and nitrocompound) and catalysts.
Given the above results, the next questions that we addressed
were to establish the role of the free hydroxyl group of catalyst
A for reaction activity and the origin of the high π-facial
selectivity with the present catalytic system. For example, we
have experimentally shown that the free hydroxyl group in the
catalyst A plays a key role in substrate activation because the
corresponding O-benzylated derivatives D and E displayed a
significant lower catalytic activity (typical conversions under
10%) in the reaction with nitromethane. These results suggest
that the catalyst exhibits dual functions and that the free OH
group participates in the activation of one or both substrates by
hydrogen bonding (H-B). The fact that the addition of
nitromethane to N-Boc imine under phase transfer conditions
produced a similar result to that obtained starting from the
corresponding R-amido sulfone, Scheme 6, aimed us to study
computationally the reaction involving already formed imine.
Our first goal was to understand the structure of the possible
hydrogen-bonded reactant complexes and the participation of
the OH during the transition state of the reaction.
Computational Methods. For the initial model studies, all
structures were optimized using the functional B3LYP34 and
the 6-31G* basis sets as implemented in Gaussian 03.35 All
energy minima and transition structures were characterized by
frequency analysis. The energies reported in this work include
zero-point vibrational energy corrections (ZPVE) and are not
scaled. The stationary points were characterized by frequency
calculations to verify that they have the right number of negative
eigenvalues. The intrinsic reaction coordinates (IRC)36 were
followed to verify the energy profiles connecting each TS to
the correct associated local minima. Charge transfers and atomic
charges were calculated within the natural bond orbital (NBO)
analysis.37 For the enantioselectivity studies, a preliminary
search was conducted with the D95V basis set and the most
favored structures were reoptimized at B3LYP/6-31G* level.
Single point calculations were performed at a higher B3LYP/
6-311++G**//B3LYP/6-31G* level to obtain more accurate
energies of the most relevant structures. The single-point
calculations with the self-consistent reaction field (SCRF) based
Figure 4. Representation of computational models 17 and 20, and three
possible ternary complexes, showing distinct hydrogen bond networks.
on the IEF-PCM38 solvation model (toluene ꢀ ) 2.378) were
carried out at B3LYP/6-311++G** level on the previously
optimized structures.
Coordination of the Reactants with the Catalyst. Model
Studies. We set out to study computationally the mode by which
the catalyst and the reacting nitro compound and N-acyl imine
substrates interact (Figures 4 and 5). For optimizing computa-
tional time, the rather large catalyst molecule A was substituted
with the hydroxyethyl trimethyl ammonium cation 17, which
bears the OH and the +NCH groups linked by an ethylene
spacer. This minimal catalyst model comprises the most salient
structural elements of the real catalyst A. On the other hand,
among the reactant nitro compounds, both nitromethane 18 and
its deprotonated form 19 were considered, whereas N-meth-
oxycarbonyl imine 20 was selected as the iminic component
instead of the larger tert-butoxycarbonyl analog. From a
preliminary examination of the structures of these four molecular
entities 17-20, several features can be inferred: (1) catalyst A
and its model 17 show two sites with high H-bonding donor
ability, an O-H and a +N-C-H site;39 (2) Both nitroalkanes
and their conjugate bases (nitronates) bear strongly coordinating
N-O- groups; (3) N-acyl imines can act as Lewis bases through
either the N or the carbonyl O atom; (4) N-acyl imines can exist
in either s-cis (cisoid) or s-trans (transoid) conformations. We
first addressed the conformational issue. Although both s-trans
and s-cis conformations bear similar energies in the isolated
form, the complexation with a multiple hydrogen bond donor
like A or model 17 appears to fit better in the s-trans form,
which has two H-bond acceptor atoms (O, N) pointing toward
the same site (Figure 4); conversely, the O and N atoms of the
s-cis form point in opposite directions and their simultaneous
coordination to a local multiple H-bond donor site seems less
effective. In fact, the calculated energy for the 17:20 complex
is about 3.6 kcal/mol lower for the s-trans conformer (see
Supporting Information for full data). Accordingly, only s-trans
conformations were considered in the subsequent studies. On
the basis of the aforementioned structural features, several
(33) Substrate solubility constraints were found during kinetic studies of a
thiourea-catalyzed Michael reaction to unsaturated imides. See: (a)
Inokuma, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2006, 128,
9413–9419.
(34) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785–789.
(b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652. (c) Kohn, W.;
Becke, A. D.; Parr, R. G. J. Phys. Chem. 1996, 100, 12974–12980.
(35) Frisch, M. J.; Gaussian 03, revision D.03; Gaussian, Inc.: Wallingford,
CT, 2004.
(36) Gonzalez, C.; Schlegel, H. B. J. Phys. Chem. 1990, 94, 5523–5527.
(37) (a) Reed, A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985,
83, 735–746. (b) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem.
ReV. 1988, 88, 899–926.
(38) (a) Cance`s, E.; Mennucci, B.; Tomasi, J. J. Chem. Phys. 1997, 107,
3032–3047. (b) Cossi, M.; Barone, V.; Mennuci, B.; Tomasi, J. Chem.
Phys. Lett. 1998, 286, 253–260. (c) Tomasi, J.; Mennucci, B.; Cance`s,
E. J. Mol. Struct. (Theochem) 1999, 464, 211–226.
(39) Me3N+-CH· · ·OdC hydrogen bonds have been reported to be the
strongest hydrogen bonds of the type C-H· · ·OdC known to
date: Cannizaro, C. E.; Houk, K. N. J. Am. Chem. Soc. 2002, 124,
7163–7169.
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A R T I C L E S
Gomez-Bengoa et al.
Figure 5. Geometries of the hydrogen bonding complexes 17:18, 17:19, and 17:20(N).
Scheme 7. Hydrogen Bonding Complexes between 17 or
Tetramethylammonium Cation (21) and the Different Substrates
Table 5. Charge Distribution and H-B Distances of the Ternary
Complexes, Transition States, and Final Adducts, Computed at
B3LYP/6-31G*
electrostatic charge (e- a
)
total charge (e- b
)
distance (Å)
stationary point O (NO2) N (imine) O (imine)
19
20
OH · · · X N+CH · · · O
c
17:18
17:19
17:20(N)
TSI
TSII
TSIII
FI
-0.38
-0.64
-
-
-
-
-
+0.05
-0.80
-
-
-
+0.06
-
-
-
2.23
2.14
2.04
2.09
2.60
2.36
1.89
1.67
1.81
1.76
1.82
1.81
1.96
1.85
1.69
c
d
c
d
e
c
d
e
-0.55 -0.70
f
-0.53 -0.64 -0.70 -0.48 -0.38
-0.53 -0.66 -0.66 -0.54 -0.30
-0.54 -0.63 -0.73 -0.57 -0.30
-0.40 -0.78 -0.78 -0.04 -0.83
-0.39 -0.81 -0.77 -0.04 -0.80
-0.40 -0.75 -0.81 -0.05 -0.81
g
g
f
g
g
FII
FIII
a Charge of the corresponding atom. b Total charge of the nitronate
fragment (19) or the imine fragment (20) of the structure. c X ) O
(nitro). d X ) N (imine). e X ) O (imine). f Refers to the shortest
N+CH· · ·OdC bond. g Refers to the shortest N+CH· · ·O2N bond.
18-20 bind stronger to the hydroxylated cation 17 than to 21.
Thus, the relative magnitude of ∆G at equilibrium can be taken
as a measure of the relative strength of the hydrogen bond in
each complex. We found that the hydrogen bonding stabilization
energy is maximal for the nitronate 19 (17:19, 10.0 kcal/mol)
and the preferred binding site of imine 20 is the nitrogen atom
(6.8 kcal/mol) vs the oxygen atom (4.4 kcal/mol). From these
data, it can be inferred that type I ternary complex (Figure 4)
is formed preferentially over types II or III prior to reaction.
In addition, deprotonation of nitromethane by the pertinent base
in the presence of the catalyst’s OH is greatly favored as a much
stronger hydrogen bond is formed with nitronate 19 than with
neutral nitromethane 18 (5.0 kcal/mol binding energy differ-
ence). This differential behavior of nitromethane and its nitronate
anion is in agreement with the computed negative charge that
develops on the two oxygens upon deprotonation, which
markedly increases from -0.38e in nitromethane (17:18) to
-0.64e in nitronate (17:19) (Table 5).
The significant differences of the computed H-B distances
are consistent with the above statements (Figure 5). For instance,
the O-H· · ·O2N bond length is larger in 17:18 (1.9 Å) than in
17:19 (1.7 Å), and the N+CH· · ·O2N interactions are also
stronger in nitronate complex 17:19 (1.9 Å, 2.0 Å)41 than in
17:18 (2.7 Å, 2.7 Å). The bonding distances of the correspond-
ing H-B detected in complex 17:20 (N) (Figure 4) are shorter
than those of complex 17:18 but longer than those of 17:19.
These data indicate that imine 17:20 (N) is complexed to the
catalyst stronger than nitromethane does but weaker than
nitronate does.
competitive H-bonding patterns40 can be conceived as repre-
sentations of the complexes formed among the catalyst and the
two components of the reaction, three of which are shown in
Figure 4 as simplified models I, II, and III. Although the
straightforward comparison of the stability of ternary complexes
I-III (Figure 4) would be a plausible starting point of the study,
attempts to do so are met with failure. Several nondesired
interactions arising from the flexibility of model 17 and from
the presence of polar substituents in both reactants and in 17
led to a high conformational ambiguity and many disperse
minima were located, making very difficult the direct evaluation
of their binding affinities (see Supporting Information for details
and structures).
Accordingly, we carried out alternative calculations aimed
at estimating the relative binding energy of the catalyst O-H
to either of the reacting species. As shown in Scheme 7, the
relative binding energies of complexes 17:18, 17:19, 17:20 (N),
and 17:20 (O) were computed by comparison of the preferential
complexation of the different substrates (nitromethane (18),
nitronate anion (19), and imine (20)) to the hydroxylated
tetramethylammonium cation (17) or tetramethylammonium
cation (21). For substrate 20, two distinct complexes were
considered: one with N as the coordinating atom 20 (N) and a
second one with the carbonyl O as the coordinating atom 20
(O). The computed Gibbs energy variations for the four
equilibria were all negative, indicating that the four reactants
Calculations were also carried out introducing the solvent
effects, but the results for the four equilibria depicted in Scheme
(40) For previous theoretical studies dealing with organocatalytic reactions
where the catalyst exhibits two competitive H-bond donor sites, see:
(a) Hamza, A.; Schubert, G.; Soo´s, T.; Papai, I. J. Am. Chem. Soc.
2006, 128, 13151–13160. (b) Hammar, P.; Marcelli, T.; Hiemstra, H.;
Himo, F. AdV. Synth. Catal. 2007, 349, 2537–2548.
(41) This findings are in agreement with the reported data about the strength
of hydrogen bonds of the type Me3N+-CH· · ·OdC, see ref 39.
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Aza-Henry Reaction Under Phase Transfer Catalysis
A R T I C L E S
Figure 6. Energy diagram for the three computed pathways (TSI, TSII, and TSIII) in the aza-Henry reaction. Values correspond to free Gibbs energies and
are given in kcal/mol.
7 were similar to those obtained in the gas phase. The fact that
all computed species have similar electrostatic character may
help to cancel the destabilizing effects of the charges at both
sides of the equilibrium in the gas phase.
carbamate oxygen. On the other hand, charge transfer from the
nitronate to the imine is essentially completed (ca. 0.80e), thus
the carbamate oxygen in adducts bears most of the negative
charge (-0.81e in FIII) and the charge in NO2 oxygen atoms
reduces back to the standards of neutral nitroalkane (-0.40e).
In FI, the OH · · ·O2N bond is much weaker (1.96 Å) than the
OH· · ·Oimine bond in FIII (1.69 Å), which is at its maximum
strength. The energy difference between FI and FIII is very large,
5.7 kcal/mol in favor of FI (5.7 kcal/mol also in toluene).
Nonetheless, this preference may represent a further advantage
for the catalyst turnover and for the completion of the reaction,
because upon protonation of the carbamate, the weak interaction
between neutral NO2 group and catalyst’s OH group would
facilitate the final decomplexation of the adduct or its displace-
ment by a new molecule of incoming nitromethane. Later on,
solvent effects were introduced and computation of the transition
states carried out once again. However, no significant change
was obtained with TSI being the most favorable and TSIII the
less favorable (∆∆Gq ) 2.5 kcal/mol).
Enantioselectivity. The next issue to be addressed was the
origin of the enantioselectivity of the process. For this purpose,
the results from the model study represented in Figure 6, which
involves TS geometries TSI, TSII, and TSIII, were considered
as starting point with two modifications: now the full chiral
catalyst A, instead of the model 17, and N-Boc imine43 16 were
considered as the intervening components. For each sort of
transition states, the search of the most favorable conformations
of the catalyst A was taken, from which four main arrangements
Reaction Transition States. Transition states were computed
for the three different reaction models, I, II, and III as shown
in Figure 6. TSI is the lowest in energy, whereas TSII and TSIII
are 1.6 and 2.5 kcal/mol above in energy, respectively, which
correspond to a reaction rate difference of ca. 15-fold slower
for TSII and ca. 100-fold slower for TSIII. Thus, as happens in
the starting ternary complexes, the most stable TS is that with
the catalyst’s OH group linked to the nitro group, and the imine
component linked through H-bond to the +NCH site of the
catalyst. The prevalence of this H-bond sequence over other
possible sequences is also in agreement with the electronic
charge distribution in the TS. Natural population analysis (Table
5) shows that the formation of the C-C bond is accompanied
by a charge transfer from the nucleophile to the electrophile,
although this transfer is not enough to remarkably weaken the
interaction between the OH and NO2 groups in TS. Monitoring
of net electrostatic charge on the oxygen atoms of the NO2 group
when moving from the initial complex I to TSI and final adduct
FI shows that most of the intial charge (-0.64e) is retained in
TS (-0.53e). With respect to the charge evolution on the N
atom of the imine compound, it goes from -0.55e in the
complexed imine to -0.66e in TSI. In addition, due to the early
character of TSII and TSIII,42 the amount of net charge transfer
is smaller in TSII (0.26e) and TSIII (0.23e) than in TSI (0.32e).
The overall view is that the transition structures and their binding
affinities resemble those of the initial ternary complexes rather
than the final adducts (Figure 6).
(43) Because N-Boc imines show some preference for s-cis/cisoid confor-
mation in the ground state, TS involving N-Boc imines with the OdC-
NdC system in their s-cis conformation were also calculated.
However, the latter lie around 5 kcal/mol higher in energy than the
corresponding s-trans TS, very likely due to the steric interference
between the t-butyl and the catalyst bicyclic skeleton in the TS. See
Supporting Information for more details.
Final Adducts. The most stable complex corresponds to FIII
(Figure 6), which shows the catalyst’s OH bonded to the
(42) Forming bond C-C distances, TSI: 2.18Å; TSII: 2.33Å; TSIII: 2.39Å.
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A R T I C L E S
Gomez-Bengoa et al.
Figure 7. Representation of the transition state geometries corresponding to the attack of nitromethane to the Si face of the imine (according to a TSI type
process). Secondary hydrogen bonds between imine and N+CH hydrogens have been omitted for clarity.
Table 6. Transition State Energies and Relative Contribution Percentages of the TSI Structures at Different Computational Levels
entry
TS
∆∆Eqa
∆∆Gqa
6-311++G** (∆∆Eq)b
PCM (toluene)c
1
2
3
4
5
6
7
8
9
TSIRF-Si
TSIRB-Si
TSILF-Si
TSILB-Si
TSIRF-Re
TSIRB-Re
TSILF-Re
TSILB-Re
ee (%)g
0d (0)e
2.5 (2.6)
2.8 (2.6)
2.9
2.3 (2.2)
5.1
94.9%f
1.4
0.9
0.7
2.1
<0.1
<0.1
<0.1
95.8 (R)g
0d
84.3%f
2.6
6.6
1.5
4.9
0.1
<0.1
<0.1
89.9 (R)g
0d
92.9%f
0.7
3.7
0.7
1.7
0d
91.5%f
3.2
1.7
1.5
0.7
2.1
1.5
2.4
1.7
4.3
5.2
4.5
2.9
1.9
2.9
2.4
4.0
4.5
4.2
2.0
2.4
2.5
2.9
3.1
3.4
3.0
0.1
0.5
0.3
6.2
4.8
<0.1
0.1
0.6
96.1 (R)g
95.8 (R)g
a Energies in kcal/mol computed at B3LYP/D95V level. b Single-point activation energy (∆∆Eq) at B3LYP/6-311++G**//B3LYP/D95V.
c Single-point activation energy at B3LYP/6-311++G** level with the SCRF method based on PCM solvation model (toluene ꢀ ) 2.379). d Energies in
kcal/mol as the relative difference (∆∆Eq or ∆∆Gq) to the lowest one in each column (TSIRF-Si). e In parenthesis, relative energies of the structures
optimized at B3LYP/6-31G*. f Percentage of contribution of each transition state in the reaction according to the Eyring equation and Boltzmann
distribution equation. Each column adds up to 100%. g Enantiomeric excess computed as Σentries(1-4) - Σentries(5-8) in each column.
arose, depending on the back (B) or front (F) orientation of the
quinoline ring and the left (L) or right (R) orientation of the
benzyl group (Figure 7). Additional variation arises from
considering either of the two oxygen atoms of the nitro group
and a Si or Re approach of the imine component, which led to
a total of 16 transition state geometries of the TSI type that
were computed. For the remaining TSII and TSIII type geom-
etries, two additional sets of 8 structures each were considered
in this study. The large number of atoms implied (98) in each
transition state make the extensive conformational search
employing triple-ꢁ basis set prohibitive in terms of computa-
tional cost. The preliminary search was thus conducted with
the shorter D95V basis set, and the most relevant structures
were further optimized at the 6-31G* level.
Among the transition structures of the TSI-type, TSIRF-Si
(entry 1, Table 6) is the lowest-lying in energy at both D95V
and 6-31G* computational levels and is taken as reference (0)
for the energies of the rest of structures in Table 6. Thus, the
RF arrangement of substitutents in the catalyst (benzyl group
to the right and methoxy-quinoline group to the front) is
preferred over the other orientations by at least 1.5 kcal/mol.
According to the Eyring equation and the Boltzmann distribution
equation, TSIRF-Si accounts for 85-95% of the reactivity of
the reaction depending on the computational variable considered
(∆∆Eq or ∆∆Gq) or the introduction of larger basis sets and
solvent effects (Table 6). The preferred Si-face attack is in
accordance with the experimentally encountered formation of
the R-configured product, and the comparison of the relative
energies of all TSI-type structures predicts an enantiomeric
Table 7. Transition State Energies and Relative Contribution
Percentages for the Aza-Henry Reaction through Binding Types II
and III, Computed at the B3LYP/D95V Level
entry
transition state
TSII (OH· · · N ) C)
TSIII (OH· · ·OdC)
1
2
3
4
5
6
7
8
9
TS.RF-Si
TS.RB-Si
TS.LF-Si
TS.LB-Si
TS.RF-Re
TS.RB-Re
TS.LF-Re
TS.LB-Re
ee (%)c
0.1a
43.1%b
0.6
0.2
0.2
55.3
0.2
1.7a
4.8%b
1.8
0.3
2.7
3.4
3.4
0
3.3
2.9
4.2
2.3
3.2
4.6
0
1.3
2.2
4.2
<0.1
82.0
9.2
1.8
0.1
0.4
<0.1
12.0 (S)c
86.1 (S)c
a Energies in kcal/mol as the relative difference (∆∆Eq) to the lowest
one in each column. b Percentage of participation of each transition state
in the reaction according to the Boltzmann equation. Each column adds
up to 100%. c Enantiomeric excess computed as Σentries(1-4)
Σentries(5-8) in each column.
-
excess of 90-96% (entry 9, Table 6), which is in good
agreement with the experiments. Noteworthy, reoptimization of
the most favored structures at B3LYP/6-31G* level of theory
did not alter significantly their geometries and relative energies
(Table 6, entries 1-3, 5, data in parentheses).
Meanwhile, a similar analysis of the transition structures
wherein the catalyst-OH is H-bonded to the imine (TSII and
TSIII, Table 7) leads to completely different results. In both
cases, the TSRF-Re structure, which yields the wrong S
enantiomer, is the lowest in energy and is taken as 0. When the
OH group is H-bonded to the nitrogen atom (TSII), the energy
9
7964 J. AM. CHEM. SOC. VOL. 130, NO. 25, 2008

Aza-Henry Reaction Under Phase Transfer Catalysis
A R T I C L E S
Figure 8. Structures of the two transition states lowest in energy for the
aza-Henry reaction through pathway I calculated at the B3LYP/6-31G* level
of theory.
Figure 9. Structures of the two transition states lowest in energy for the
aza-Henry reaction through pathway II calculated at the B3LYP/D95V level
of theory
difference between TSIIRF-Re (entry 5) and TSIIRF-Si(entry
1) is minimal, and a quasi-racemic product is predicted (S
enantiomer, 12%ee), whereas the computed ee in favor of the
nonexperimental S enantiomer increases to 86% when the H-B
is formed between the OH group and the oxygen atom of the
imine. Thus, only binding mode I can explain the experimental
enantioselectivity, which can be taken as a further proof of the
OH· · ·O2N bonding during transition state.
the model (TSIIRF-Re, Figure 9). This effect would lead to the
wrong S enantiomer or to a quasi-racemic mixture of products
(Table 7).
Conclusions
The origin of the enantioselectivity might result from the
balance of two opposite factors: on the one hand the positive
interaction due to the H-B network between the different basic
sites in the reactants with the OH and N+-CH groups of the
catalyst,44 and on the other hand, the negative effect of the steric
repulsion that arises in such bulky systems (i.e., the t-butyl group
in the carbamate and the catalyst′s bicyclic skeleton). The
lowest-lying transition state (TSIRF-Si, Figure 8) presents five
relatively strong H-B interactions, considering only those
whose bonding distances are shorter than 2.5 Å. The shortest
interaction (A) appears between the OH and one of the oxygens
of the nitro group (1.6 Å). Another three important interactions
appear between the imine-carbamate and diverse CH groups of
the catalyst: B (2.2 Å), C (2.0 Å), and D (2.3 Å). Besides, there
is an intramolecular H-B in the catalyst between the oxygen
and a C-H of the pyridine ring (E, 2.3 Å). The fact that tight
H-B interactions may be formed between the three reacting
components without compromising the steric congestion seems
to be the reason for the preference of that TS. As shown in
TSIRF-Si (Figure 8), when the imine approaches the nitronate
offering the Si face for nucleophilic attack, the tert-butyl group
points away from the catalyst′s bicycle (toward the front of our
view in Figure 8), thus avoiding contact with the catalyst’s
methylenes.
An efficient catalytic asymmetric aza-Henry reaction has been
realized under phase transfer conditions. This direct aza-Henry
reaction holds as interesting features the validity for both
nonenolizable and enolizable aldehyde-derived azomethines and
the tolerance of nitroalkanes, other than nitromethane, for the
production of ꢀ-nitroamines. From a synthetic point of view,
the methodology described implies a direct and efficient route
for the asymmetric synthesis of precursors of differently
susbstituted 1,2-diamines. More interestingly, a new asymmetric
synthesis of γ-amino R,ꢀ-unsaturated esters has been realized
through a catalytic, highly enantioselective formal addition of
ꢀ-acryloyl anion equivalents to azomethines.
Kinetic studies reveal the present reaction to be first order
with respect the N-acyl imine, generated in situ from the
R-amido sulfone, and the catalyst. Computational calculations
at the B3LYP/6-31G* level of theory indicate that the catalyst’s
OH group binds preferentially to the nitro group of the
nucleophile and not the electrophilic N-acyl imine. This is in
accordance with the larger amount of charge that the nitro group
presents along the reaction as compared with the charge
developed by the iminic oxygen and nitrogen atoms. Thus, an
optimal TS can be depicted (TSIRF-Si, Figure 8) that contains
a hydrogen bond network that greatly contributes to the rigidity
and stability of the complex and might be one of the reasons
for the high enantioselectivity of the reaction. The computed
enantiomeric excess of 90-95% favoring the R enantiomer is
in good agreement with experimental observations.
On the other hand, the preferred transition state forming the
S enantiomer (TSIRF-Re) presents a higher energy barrier
(∆∆Gq ≈ 2 kcal/mol). The number of productive H-B between
the carbamate and the N+CH groups is reduced to two (C )
2.3 Å and D ) 2.1 Å), and both are weaker than the
corresponding H–B in TSIRF-Si. The steric factors also play a
negative role in the Re approach, difficulting optimal H-bonding
contact between carbamate and catalyst.
Experimental Section
General Procedure for the Aza-Henry Reaction of Nitro-
alkanes with r-Amido Sulfones under PTC Conditions
Employing Catalyst A. To a suspension of the corresponding
R-amido sulfone 1 (0.5 mmol, 1 equiv) and N-benzylquininium
chloride A (27 mg, 0.06 mmol, 0.12 equiv) in dry toluene (1.5
mL) at -50 °C under a nitrogen atmosphere were successively
added the corresponding nitroalkane (2.5 mmol, 5 equiv) and
CsOH·H2O (109 mg, 0.65 mmol, 1.3 equiv). The mixture was
stirred at the same temperature for 44-54 h, then quenched with
HCl (2 mL, 0.1 N), and extracted with CH2Cl2 (3 × 3 mL). The
organic layer was washed with HCl (1 × 2 mL), dried over MgSO4,
If we consider the other two binding types (TSII and TSIII),
and following a similar reasoning, formation of the wrong S
enantiomer would be predicted. To get the R enantiomer, the
imine must flip over, directing the tert-butyl group toward the
most congested area (TSIIRF-Si, Figure 9), whereas in the Re
face attack, tert-butyl group points to the empty front side of
9
J. AM. CHEM. SOC. VOL. 130, NO. 25, 2008 7965

A R T I C L E S
Gomez-Bengoa et al.
and concentrated under reduced pressure to give the crude product
that was purified by flash column chromatography using mixtures
of ethyl acetate/hexane as the eluent.
pounds, kinetic experiments, Cartesian coordinates of all
computed stationary points, relative and absolute activation
energies for all reactions, and complete ref 35. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. This work was financially supported by the
University of the Basque Country (UPV/EHU) and Ministerio de
Educacio´n y Ciencia (MEC). Thanks are due to SGI/IZO-SGIker
(UPV/EHU) for the generous allocation of computational resources.
I.M.-M. thanks Gobierno Vasco for a predoctoral grant.
JA800253Z
(44) For X-Ray evidence of a H-bond network in a tetrabutyl ammonium
cation, see: Reetz, M. T.; Hu¨ette, S.; Goddard, R. J. Am. Chem. Soc.
1993, 115, 9339–9340.
Supporting Information Available: Experimental details,
analytical data and stereochemical proofs for all new com-
9
7966 J. AM. CHEM. SOC. VOL. 130, NO. 25, 2008