A novel reaction cascade leading to a spontaneous intramolecular dipolar cycloaddition through simultaneous generation of 1,3-dipole and dipolarophile

Article abstract of DOI:10.1016/j.tetlet.2013.07.009

Ornithine methyl ester reacts with aromatic aldehydes to generate bis-Schiff bases, which depending on the structure of the aromatic aldehyde, further undergo an intramolecular cycloaddition through the transient formation of a reactive 1,3-dipole.

Full text of DOI:10.1016/j.tetlet.2013.07.009

Tetrahedron Letters 54 (2013) 5155–5158
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel reaction cascade leading to a spontaneous intramolecular
dipolar cycloaddition through simultaneous generation of 1,3-dipole
and dipolarophile
a
b
a,b
Nagabushanam Kalyanam a,b, , Keshav R Rapole , Ramanujam Rajendran , Muhammed Majeed
⇑
a Sabinsa Corporation, 20 Lake Drive, East Windsor, NJ 08520, United States
b Sami Labs Limited, Peenya Industrial Area, Bangalore 560058, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Ornithine methyl ester reacts with aromatic aldehydes to generate bis-Schiff bases, which depending on
the structure of the aromatic aldehyde, further undergo an intramolecular cycloaddition through the
transient formation of a reactive 1,3-dipole.
Received 20 June 2013
Accepted 1 July 2013
Available online 8 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Azomethine ylid
1,3-Dipolar addition
Cycloaddition
Dipolarophile
Stereoselective
Bis-Schiff bases of ornithine
Dipolar cycloadditions belong to an important class of reactions
extensively employed in the synthesis of complex molecules.1 The
ability to create multiple stereo centers in a defined way is defi-
nitely a major reason for their utility. Similarly tandem/cascade
synthesis2 creates often in a few steps a complex molecular archi-
tecture in a simple, predictable way. We report herein examples
combining these two concepts to engender bicyclic systems in
appropriately substituted molecules.
OCH
3
H N
O
2
.2HCl
NH
2
(I)
L-Ornithine methylester.dihydrochloride
CHO
Triethylamine
CH2Cl2
L-Ornithine methyl ester hydrochloride (I) reacts at room temp
with 2 equiv of p-chlorobenzaldehyde to form the expected bis-
Schiff base (II-f) as the only product without any apparent racemi-
zation of the bis-Schiff base. On the other hand a bicyclic structure
(IV-a) results (with three stereo centers) as a single diasteromer
(racemic) as the sole isolable product in the case of p-nitrobenzal-
dehyde (Scheme 1). The corresponding bis-Schiff base (II-a) does
not survive under these conditions.
We rationalize the outcome of these reactions as outlined in
Scheme 2. In the case of p-nitrobenzaldehyde, the initially formed
bis-Schiff base, generates a 1,3-dipole in a fast step which further
undergoes a rapid intramolecular cycloaddition with a favorably
positioned imino dipolarophile for cycloaddition. Ostensibly the
p-nitro group enhances the acidity of the alpha-hydrogen
(Scheme 2) and stabilizes the 1,3-dipole formed. The 1,3-dipole
RT
R
R= NO2
R= H, Cl
O
N
OCH
N
O
OCH
H
N
3
3
NO
2
N
Cl
NO
Cl
2
(IIf)
(Racemic)
(IVa)
⇑
Corresponding author. Tel.: +1 732 777 1111; fax: +1 732 777 1443.
E-mail address: Kalyanam@sabinsa.com (N. Kalyanam).
Scheme 1. Reaction of L-ornithine methyl ester dihydrochloride with aromatic
aldehydes.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.009

5156
N. Kalyanam et al. / Tetrahedron Letters 54 (2013) 5155–5158
The acidity of this alpha
hydrogen is modulated
by aryl group (Ar)
Ar
NH2
N
H
2 eq. ArCHO
2 eq. Et3 N
OMe
H2N
OMe
N
Ar
.2 HCl
CH2Cl2 at RT
II- Bis Schiff Base
O
O
I
COOMe
O
H
-------
H
N
Ar
Ar
N+
OMe
N
N
Ar
Ar
IV- Bicyclic Heterocycle
III. Proposed reactive conformation
Scheme 2. Bicyclic heterocycle formation through an intramolecular 1,3-dipolar addition.
Table 1
Influence of Ar in ArCHO on the dipolar cycloaddition I þ 2Ar-CHOꢁ! Bis-Schiff Base ðIIÞ þ Bicyclic Hetrocycle ðIVÞ
Sl.no.
Ar in ArCHO
IIa,b
IVa
Sl.no.
Ar in ArCHO
IIa,b
IVa
a
b
c
d
e
4-Nitrophenyl–
2-Nitrophenyl–
3-Nitrophenyl–
4-Pyridyl–
0
0
92
0
90
100
100c
8
f
4-Chlorophenyl
2,3 Dichlorophenyl–
3,4 Dichlorophenyl–
2,6 Dichlorophenyl–
Phenyl–
100d
85
100
100e
100
0
15
0
0
0
g
h
i
100
2-Chlorophenyl–
10c
j
a
b
c
The relative ratios of II and IV are estimated from the NMR integrations of the crude product.
NMRs of all the bis-Schiff bases reported herein indicate a single isomer only; anti-geometry at both imino groups.
Specific rotations were measured to be essentially zero for both these products {[ 0° for IV-b and [ 0.8 for IV-e, 2% in CHCl3}.
a]
a]
D
D
d
e
For II-f, [
a
]
ꢁ100.6°.
D
For II-i, [
a
]
29.4°.
D
assumes a distortionless conformation stabilized and held in
position in a reactive conformation by the intramolecular H-bond-
ing as shown.3 Further the endo-type transition state and aryl-aryl
stacking interactions may further favor this transition state. Race-
mization occurs on formation of the 1,3-dipole and the bicyclic
heterocycle is isolated as a racemic product (all bicyclic heterocy-
cles reported in this Letter are isolated as racemic compounds).
This is an interesting case of an intramolecular dipolar cycload-
dition4 wherein the partners of the cycloaddition, namely, the 1,3-
dipole and the dipolarophile are both generated in the same flask
simultaneously and in situ undergo further cycloaddition. The imi-
no group is also an uncommon dipolarophile.
In the other case (see Scheme 1) involving p-chlorobenzalde-
hyde, the p-chloro substituent does not enhance the acidity of
the alpha-hydrogen enough to lead to the 1,3-dipole leaving the
bis-Schiff base as the end product. The inertia toward dipole for-
mation is further indicated by the preservation of enantiomeric
purity of the bis-Schiff base evidenced by unchanged optical rota-
tion of this bis-Schiff base (IIf) on prolonged continuous stirring
under the reaction conditions (see Table 1). Once the 1,3-dipolar
structure forms, reversion back to the starting Schiff base or pro-
gress toward the product, namely IV, will result in racemization.
The mechanism derives impressive support from the observa-
alpha-hydrogen, (see Scheme 2) whereas the reaction halts at
bis-Schiff base stage for m-nitrobenzaldehyde (Scheme 3). This is
expected since the o-nitro substituent will increase the acidity of
the alpha-hydrogen greatly whereas m-nitro does not exercise
the same influence on the acidity.
The structures of the bicyclic heterocycles are derived from
NMR and supported by the X-ray structure6 for IV-b. The X-ray
structure of IV-b (Fig. 1) shows some interesting features. The nitro
groups are forced away from the carboxymethyl group presumably
by dipole–dipole repulsions. The cis orientation of the two o-nitro-
phenyl rings is confirmed by the torsion angle (in degrees) about
the C(2)–C(3) bond: C(8)–C(2)–C(3)–C(17) = 38.1° (Fig. 1). The ni-
tro substituent on each of the phenyl rings is not coplanar with
the respective phenyl ring and is rotated approximately 45° out
of plane of the phenyl rings. Even though the X-ray structure
was obtained for only one analog, namely IV-b, from the similarity
of the NMR spectra in particular the near identity of the coupling
constants (JH2-H3 ꢀ6.6 Hz), it is concluded that the stereochemistry
of all bicyclic compounds IV is the same.
We probed the reaction further by influencing the acidity of the
alpha-hydrogen (see Scheme 2). Using pyridine-4-carboxaldehyde,
the bicylclic product (IVd) is the sole one formed. It is well known
that the pyridine structure stabilizes carbanionic character at
attached carbons at C-2 and C-4 positions.7,8
tion that o-nitrobenzaldehyde reacts with L-Ornithine methyl ester
hydrochloride (I) under the reaction conditions readily to form
exclusively the bicyclic structure (1,3-dipole formation) facilitated
by the o-nitro substitutent through enhanced acidity5 of the
Next we examined a series of chloro substituted benzaldehydes
to modulate the acidity of the alpha-hydrogen inductively. Ortho-
chlorine substituent induces some propensity toward bicyclic

N. Kalyanam et al. / Tetrahedron Letters 54 (2013) 5155–5158
5157
OCH
6 positions of the phenyl group are both occupied by a chlorine
atom (van der walls radius ꢀ1.8 Å), such a coplanar structure is
rendered very unfavorable.
3
H N
O
2
In summary, a novel intramolecular 1,3-dipolar cycloaddition
(wherein both the 1,3-dipole and the dipolarophile are both con-
temporaneously generated) occurring at rt under mild conditions
has been demonstrated with structural influences on the mecha-
nism of cycloaddition.9 The recently reported10 asymmetric varia-
tions of 1,3-dipolar cycloaddition, especially using chiral catalysis,
provide further impetus to explore this reaction along such lines.
Chiral forms of the bi-proline structures of IV offer interesting pos-
sibilities in iminium ion chemistry.
.2HCl
NH
2
(I)
L-Ornithine methylester.dihydrochloride
Triethylamine
CH2Cl2
RT
CHO
CHO
NO2
NO2
Acknowledgement
O
N
OCH
O
OCH
H
N
3
The authors acknowledge the expert help of Dr. Douglas M. Ho
for the crystal structure measurements done at the Dept of Chem-
istry, Princeton University under the Industrial Associate Program.
3
O N
2
N
NO
2
N
Supplementary data
O N
2
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
07.009. These data include MOL files and InChiKeys of the most
important compounds described in this article.
(Racemic)
(IVb)
Sole product
O N
(IIc)
2
Major product, ~92%
(see table)
Scheme 3. Bicyclic heterocycle formation through intramolecular 1,3-dipoar
addition.
References and notes
1. For recent reviews on dipolar additions, (a) Coldham, I.; Hufton, R. Chem. Rev.
2005, 105, 2765; (b) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247.
2. For reviews on cascade reactions, Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G.
Angew. Chem. Int. Ed. 2006, 45, 7134; Bunce, R. A. Tetrahedron 1995, 51, 13103.
3. For a discussion on the factors affecting the geometry of 1,3-dipolar systems
relating to azomethine ylids, see Grigg, R. Chem. Soc. Rev. 1987, 16, 89; Also see,
Drew, M. G. B.; Harwood, L. M.; Price, D. W.; Choi, M.-S.; Park, G. Tetrahedron
Lett. 2000, 41, 5077; Viseux, E. M. E.; Parsons, P. J.; Pavey, J. B. J.; Carter, C. M.;
Pinto, I. Synlett 2003, 1856; Ess, D. H.; Jones, G. O.; Houk, K. N. Adv. Synth. Catal.
2006, 348, 2337.
4. For an example of asymmetric cascade involving azomethine ylids, Grigg, R.
Tetrahedron: Asymmetry 1995, 6, 2475.
5. o-Nitrotoluene forms benzylic carbanion which undergoes further reactions.
(a) Mundla, S. R. Tetrahedron Lett. 2000, 41, 6319; (b) Suzuki, H.; Gyoutoku, H.;
Yokee, H.; Shinba, M.; Sato, Y.; Mukaramai, Y. Synlett 2000, 8, 1196.
6. Crystal data for IV-b: a = 11.6597(4) Å, b = 7.5080(2) Å, c = 22.9561 (6) Å,
a = 90°
b = 100.664(2)°
c
= 90° V = 1974.89(10) Å3, Z = 4, and space group P21/c (No.
14). Crystallographic data (excluding structure factors) for IV-b have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 714913. Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (fax: +44
(0)1223 336033 or email: deposit@ccdc.cam.ac.uk).
7.
c-Picolines undergo aldol condensation with aldehydes, see (a) Efange, S. M. N.;
Michelson, R. H.; Remmel, R. P.; Boudreau, R. J.; Dutta, A. K.; Freshler, A. J. Med.
Chem. 1990, 33, 3133; (b) DeBernardis, J. F.; Gifford, P.; Rizk, M.; Ertel, R.;
Abraham, D. J.; Siuda, J. F J. Med. Chem. 1988, 31, 117.
8. Use of pyridoxal in the place of pyridine-4-carboxaldehyde gave a complex
mixture of products.
9. Experimental: Following is the procedure for IV-b, but is representative for all
Figure 1. X-ray structure of IV-b.
the other bicyclic heterocycles (IV-a, IV-d, IV-e, and IV-g). In
a RB flask
equipped with a magnetic stirrer, -ornithine methyl ester dihydrochloride (I,
L
5.0 g, 22.9 mmol) and 2-Nitrobenzaldehyde (7.5 g, 49.7 mmol) were taken in
methylene chloride (70 ml). The suspension was stirred at 0 °C and after
15 min, triethylamine (4.6 g, 46 mmol) in 10 ml of methylene chloride was
added slowly. The reaction mixture was allowed to warm to rt and stirred
overnight. The reaction mixture was diluted with methylene chloride, washed
with water, dried over Na2SO4, and the solvent was evaporated to give the
crude product (the relative ratios of bis-Schiff bases to cyclized heterocycle
were deduced from the NMR spectra at this stage). The crude product IV was
purified by column chromatography on silica gel using hexane-ethyl acetate as
eluent. Isolated yield: 5.6 g (60%); mp 126–128 °C; C20H20N4O6 Calcd C, 58.24,
H, 4.89, N, 13.58; Found: C, 58.00; H, 4.75; N, 13.54; 1H NMR (CDCl3, 500 MHz)
1.98 (1H, m); 2.10 (2H, m); 2.38 (1H, m); 3.13 (1H, m); 3.23 (1H, br s); 3.46 (1H,
m); 3.89 (3H, s); 5.32, and 5.34 (2H, ABq, J = 6.60 Hz); 6.91 (1H,dd, J = 1.47,
8.06 Hz); 7.18 (1H,dt, J = 1.47, 7.33 Hz); 7.23–7.28 (2H,m); 7.49–7.53 (2H,m);
7.72–7.80 (2H,m); 13C NMR (125 MHz) 174.91, 149.45, 148.53, 134.60, 132.33,
131.80, 131.66, 130.66, 128.78, 128.27, 127.74, 124.54, 123.81, 89.31, 69.53,
58.78, 56.02, 52.80, 37.48, 25.01;
heterocycle formation. Distant halogen substitution on the aryl
ring of the reaction partner aromatic aldehyde (at meta and para
positions) results in exclusive bis-Schiff base formation not eager
to react further (see Table 1).
Interestingly when 2,6-dichlorobenzaldehyde was used, no
bicylclic product resulted. Only the bis-Schiff base (IIi) was formed
as a nice solid. Prolonged stirring under the reaction conditions
resulted in neither the formation of the corresponding bicyclic
heterocycle nor the racemization of the bis-Schiff base (IIi) thus
showing its resistance to form the 1,3-dipole. In this case, the
1,3-dipole stabilization (and for the requisite acidity of the alpha-
hydrogen as a precedent) would compel coplanarity of the 2,6-
dichlorophenyl group with the 1,3-dipole plane. When the 2 and

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N. Kalyanam et al. / Tetrahedron Letters 54 (2013) 5155–5158
Bis-Schiff bases: The following procedure for II-f,i,j is exemplary. Schiff bases
IIg, h were not isolated in a state of purity. In a clean dry flask containing
methylene chloride (600 ml), p-chlorobenzaldehyde (77.0 g, 548 mmol) was
C:61.39, H:5.15, N:7.16; Found: C:61.16, H:4.98, N:7.26; 1H NMR (CDCl3,
500 MHz) 1.63–1.76 (2H, m); 1.99 (1H, m), 2.09 (1H,m); 3.63 (2H, t,
J = 6.84 Hz); 3.75 (3H, s); 4.04 (1H, dd, J = 4.88, 8.79 Hz); 7.37 (2H, d,
J = 7.81 Hz); 7.39 (2H, d, J = 7.81 Hz); 7.64 (2H, d, J = 7.81 Hz); 7.71 (2H, d,
J = 7.81 Hz); 8.22 (1H, s); 8.25 (1H, s). The bis-Schiff bases were not stable
toward chromatography on silica gel. The NMR of all the bis-Schiff bases
disclosed in this letter showed a single isomer only (syn–anti isomers about the
two imine bonds; presumably only anti–anti isomer exists both in solid and
solution states).
added followed by
L-ornithine methyl ester dihydrochloride(I) (60.0 g,
274 mmol). The flask was cooled to 0–5 °C and triethyl amine (63.0 g,
617 mmol) was added over a period of 3–4 h keeping the temp below 10 °C.
At the end of the addition, the reaction was allowed to warm upto rt and
stirring was continued for 15 h. The precipitated TEAꢂHCl was filtered and the
organic layer was washed with water and dried over sodium sulfate. Methylene
chloride was removed under vacuum and hexane (500 ml) was added to the
resulting thick liquid to induce crystallization. The product was filtered and
dried under vacuum. Yield 80.0 g (75%). mp: 92–94 °C; C20H20Cl2N2O2 Calcd
10. Stanley, L. M.; Sibi, M. Chem. Rev. 2008, 108, 2887; Pellissier, H. Tetrahedron
2007, 63, 3235; Guo, C.; Song, J.; Gong, L.-Z. Org. Lett. 2013, 15, 2676.