An experimental and theoretical reinvestigation of the Michael addition of primary and secondary amines to dimethyl acetylenedicarboxylate

Article abstract of DOI:10.1016/j.tetlet.2014.03.013

Theoretical calculations of the Michael addition of diethylamine, pyrrolidine, and benzylamine to DMAD at the DFT (B3LYP/6-31+G^-) level indicate that the reaction follows a stepwise mechanism via a zwitterionic intermediate. The reactions have low activation barriers, 13-15 kcal mol ^-1 and are exothermic, ΔH° = -29 to -44 kcal mol ^-1. The detailed investigation of the reaction of benzylamine with DMAD reveals participation of the reactant-, transition structure-, and the product-complexes and that the 1,3-prototropic shift occurs through the benzylamine molecule. It also predicts formation of dimethyl 2-(N-benzylimino)butane-1,4-dicarboxylate as one of the products, which has been duly isolated and characterized experimentally.

Full text of DOI:10.1016/j.tetlet.2014.03.013

Tetrahedron Letters 55 (2014) 2504–2507
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An experimental and theoretical reinvestigation of the Michael
addition of primary and secondary amines to dimethyl
acetylenedicarboxylate
⇑
Asha Gurjar, Priyadarshni Poonia, Pragya Sinha, Raj K. Bansal
Department of Chemistry, The IIS University, Jaipur 302020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Theoretical calculations of the Michael addition of diethylamine, pyrrolidine, and benzylamine to DMAD
at the DFT (B3LYP/6-31+G⁄) level indicate that the reaction follows a stepwise mechanism via a zwitter-
ionic intermediate. The reactions have low activation barriers, 13–15 kcal molꢀ1 and are exothermic,
Received 25 November 2013
Revised 3 March 2014
Accepted 4 March 2014
Available online 13 March 2014
D
H° = ꢀ29 to ꢀ44 kcal molꢀ1. The detailed investigation of the reaction of benzylamine with DMAD
reveals participation of the reactant-, transition structure-, and the product-complexes and that the
1,3-prototropic shift occurs through the benzylamine molecule. It also predicts formation of dimethyl
2-(N-benzylimino)butane-1,4-dicarboxylate as one of the products, which has been duly isolated and
characterized experimentally.
Keywords:
Michael addition
DMAD
DFT calculations
1,3-Prototropic shift
Ó 2014 Elsevier Ltd. All rights reserved.
a-Imino ester
Introduction
HN Bn
H
MeOC
Bn
CO2Me
HN
H
HN Bn
MeO2C
H
C
O
C
C C
C
C
CO2Me
MeO2C
The Michael reaction though originally implied the base
catalyzed conjugate addition of a nucleophile such as enolate anion
CO2Me
2
1
(Michael donor) to an activated
a,b-unsaturated carbonyl com-
3
pound (Michael acceptor), its connotation and scope broadened
dramatically over the years encompassing a wide range of non-
carbon Michael donors.1 The aza-Michael reaction using amines
and related nitrogen compounds as Michael donors makes a vari-
ety of b-amino carbonyl compounds accessible, which are useful
synthons for the bioactive natural motifs2 and chiral auxiliaries.3
Michael addition of amines to acetylenecarboxylic acid derivatives
has been studied extensively,4–9 and the adducts have been used as
the starting materials for the heterocyclic systems.10,11 Water has
also been used as the solvent for Michael addition of amines to
electron deficient alkenes12 and DMAD.13
The reactions of secondary amines, namely diethylamine and
pyrrolidine with DMAD were reported to give E isomers only,
whereas it was claimed that benzylamine reacted with DMAD to
yield a mixture of E and Z isomers in the ratio of 2.7:1.13 The
proposed mechanism for the conversion of E into Z isomer of the
Mech. 1
H
RHN
H
RHN
H
H2
RHN
C
CO2Me
H
C
C
H
H
C
C
CO2Me
C
CO2Me
H
RHN
4
5
6
RNH2
RNH2
Mech. 2
H
H
N
H
C
H2
C
NH2
H
H
H
C
C
C
Me
C
O
NH
C
C
Me
Me
C
H
O
O
7
8
9
Mech. 3
Scheme 1.
benzylamine-DMAD adduct has been shown in Scheme
1
(Mechanism 1).13 Huisgen and co-workers on the other hand
postulated a general mechanism for the inter-conversion of (E/Z)
isomers resulting from the Michael addition of amines to the acet-
ylenecarboxylic acid esters.4b The proposed mechanism (Scheme 1,
Mechanism 2) named as addition elimination, involved addition of
⇑
Corresponding author. Tel.: +91 141 265 1030; fax: +91 141 239 5494.
E-mail address: bansal56@gmail.com (R.K. Bansal).
http://dx.doi.org/10.1016/j.tetlet.2014.03.013
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

A. Gurjar et al. / Tetrahedron Letters 55 (2014) 2504–2507
2505
an amine molecule across the carbon–carbon double-bond of the
initially formed product, then rotation about the carbon–carbon
single-bond of the resulting intermediate followed by elimination
of the amine molecule. Dabrowski and Terpinski14 postulated
intermediacy of the b-iminoketone (8) resulting from an intramo-
lecular 1,3-prototropic shift in the cis–trans isomerization of
enaminoketones (Scheme 1, Mechanism 3). Although 8 was not
isolated, its intermediacy could be established on the basis of 1H
NMR experiments.
The mechanism 111 assigning no role to the N–H proton can be
ruled out at the very first glance, as in that event, the products
resulting from the Michael addition of the secondary amines, such
as diethylamine and pyrrolidine, would also be expected to under-
go cis–trans isomerization to form a mixture of two geometrical
isomers. To verify the remaining two mechanisms, we decided to
invoke computational chemistry. Interestingly, our results support,
though partly, mechanisms 2 and 3 both, but at the same time, pre-
dict isolation of the proposed imino intermediate (Mechanism 3),
which has been duly corroborated by our experimental results.
We computed following three reactions at the DFT (B3LYP/
6-31+G⁄) level15 using GAUSSIAN 03 package16 (Scheme 2).
Yoshizawa et al.17 while studying the reaction pathway for the
direct benzene hydroxylation with FeO+ species theoretically,
reported the existence of the reactant-complex and the product-
complex, which alter the energy profile of the reaction. In some
other cases also, involvement of these species has been
established.18–20 In the present case also, we succeeded in locating
the reactant-, the transition structure-, and the product-complexes
between DMAD and benzylamine, which are described later.
All the three reactions have low activation energy barrier (ca.
Figure 1. Optimized geometries of the reactant-complex, RCc, transition structure-
complex, TSc-comp., intermediate-complex, Intc-comp., and product complex,
Prc-comp. at the B3LYP/6-31+G⁄ level along with the bond distance (Å) and the
WBI (in parantheses).
On exploring the PES of the reaction of benzylamine with
DMAD, the reactant-, the transition structure-, and the product-
complexes could be located. The geometries of these complexes
optimized at the B3LYP/6-31+G⁄ level are shown in Figure 1. It
may be noted that RCc does not have an extra molecule of benzyl-
13 kcal molꢀ1 in toluene) and are highly exothermic (
D
H° = ꢀ29
amine, although NBO analysis confirms n ?
p interactions be-
to ꢀ44 kcal molꢀ1). The reaction follows a stepwise ionic mecha-
nism, the first step, which is the rate-determining step, leads to a
zwitterionic intermediate, Inta–c, which subsequently undergoes
1,3-prototropic shift to give the product, Pra–c (Scheme 3).
tween the two reactant molecules. The 1,3-prototropic shift
occurs in the intermediate-complex, Intc-comp. via benzylamine
molecule. It has been shown earlier that the prototropic shifts
occur preferentially through the intermediacy of a solvent or the
reactant molecule,21,22 as the direct transfer is a high energy path.
In the present case, 1,3-prototropic shift of the N–H proton to the
carbanionic center C3 of the intermediate, Intc-comp. appears to
be very fast, as all attempts to locate the transition structure for
the transfer of the N–H proton to the benzylamine molecule in
the intermediate-complex led directly to the product-complex,
Prc-comp. by transfer of the N–H proton via benzylamine
molecule.
To look into the reason for the formation of the cis-product only,
we did Frontier Molecular Orbital (FMO) and Natural Bond Orbital
(NBO) analyses of the intermediate, Inta (R1 = R2 = Et). It is found
that the HOMO, which is a
p orbital, encompasses C2C3C4 moiety,
thus restricting the rotation about the C2C3 bond. It is supported
by the Wiberg Bond Indexes (WBI) of the C2C3 and C3C4 bonds,
which are found to be 1.801 and 1.151, respectively. Furthermore,
the delocalization of the C2C3 double bond onto the C4@O
carbonyl group in the final product Pra (as suggested in mech. 1)
is ruled out by the fact that the WBIs of the C2C3 and C3C4 bonds
are 1.829 and 0.975, respectively.
On scanning the PES of the reaction of benzylamine with DMAD
further, it is found that the initially formed product-complex,
0
Prc-comp. changes to Intc -comp. by intramolecular transfer of the
second N–H proton to the benzylamine molecule; the intervening
transition structure, however, could not be located. In the resulting
intermediate, the extra proton of the C6H5CH2N+H3 moiety is
subsequently transferred to C3 leading to the formation of the final
CO2Me
C
R1R2NH
0
product-complex, Prc -comp., namely dimethyl 2-(N-benzylimi-
TSa-c
Int.a-c
Pra-c
Prc'
C
no)butane-1,4-dicarboxylate complexed with a benzylamine mole-
CO2Me
0
cule (Scheme 4). The HOMO of Intc -comp. is shown in Figure 2. It
10
11
a
10
b
c
may be noted that the HOMO is a p orbital centered on C3, which
R1/R2
(CH2)4
Et/Et
Bn/H
has the anionic charge and encompasses
r N–H orbital. This
Scheme 2.
H
CO2Me
CO2Me
H
CO2Me
CO2Me
BnNH2.
Bn
BnNH3
Bn N
TSc'_comp.
H
N
Prc_comp.
Intc'_comp.
4
CO2Me
CO2Me
CO2Me
H
C
3
H
H
CO2Me
H
TSa-c
1,3-Proto. shift
C
C
CO2Me
10 + 11
H
C
BnNH2.
R1R2
N
H
2 CO2Me
2 N
R1R
BnN CO2Me
1
BnN CO2Me
Inta-c
Prc'_comp.
Pra-c
Prc'
Scheme 3.
Scheme 4.

2506
A. Gurjar et al. / Tetrahedron Letters 55 (2014) 2504–2507
0
Figure 2. The highest occupied molecular orbital (HOMO) of Intc -comp.
Figure 4. Energy profile diagram with and without complex formation.
0
feature of the HOMO explains the speedy transfer of the N–H
complex formation. Furthermore, once the product Prc is formed,
0
0
proton to C3. An attempt to change Prc -comp. into its trans-isomer
in contrast to the N–H proton in Prc, CH proton in Prc is no more
by rotation about the C2C3 bond failed due to steric hindrance
sufficiently activated to be taken up by the benzylamine molecule,
0
0
caused by the benzylamine molecule. On optimizing Prc , its
which makes the conversion of Prc back into Prc untenable in spite
interaction energy with a benzylamine molecule is found to be
of an energy barrier of 20.86 kcal molꢀ1 only.
2.73 kcal molꢀ1
.
These theoretical results predicting the formation of a new
product, namely dimethyl 2-(N-benzylimino)butane-1,4-dicarbox-
0
0
The optimized geometries of Intc _comp., TSc _comp., and
Prc _comp. at the B3LYP/6-31+G level are shown in Figure 3 and
⁄
0
ylate, which incorporates
a
-imino ester23 as well as the b-imino
the reaction profile diagrams along with the relative energies are
given in Figure 4. It may be noted from Figure 4 that formation
of the reactant-, and the transition structure-complexes alters
the reaction profile energetics remarkably: the relative activation
energy barrier for the attack of benzylamine on DMAD is reduced
from 13.86 to 5.50 kcal molꢀ1 only. The intermediate and the tran-
sition structure for the transfer of the N–H proton in Prc to C3
could not be located on the PES of the reaction occurring without
complex formation. However, the proton transfer is facilitated via
ester functionalities, besides the normal aza-Michael adduct, moti-
vated us to investigate the reaction of these amines with DMAD
experimentally (Scheme 5) (experimental details, note 24).
The products 12a,b are colorless syrupy mass, readily soluble in
chloroform. They have been characterized on the basis of IR and 1H
and 13C NMR studies (note 25). The reaction of benzylamine with
DMAD yields a mixture of two products, which could be separated
by column chromatography on silica gel (eluent/EtOAc/pet.ether
(60–80 °C); 2: 98% v/v) (note 26). The 1H NMR spectra of these
two products 12c and 12c0 between d 3 and 6 ppm are reproduced
in Figure 5. It is noteworthy that in the case of 12c, methylene
protons of the benzyl group give a doublet at d 4.33 (3JHH = 5.7 Hz)
due to coupling with the NH proton. The singlet of the vinylic pro-
ton, @C3AH overlaps with the singlet of the OCH3 at d 4.63. The NH
proton gives a broad signal at d 5.67. However, the methylene
protons of the benzyl group in 12c0 give a singlet at d 3.34 showing
CO2Me
CO2Me
H
CO2Me
CO2Me
H
H
Toluene
0oC
+
10a-c
11
R1R2
N
BnN
12c'
12a-c
Scheme 5.
0
0
0
Figure 3. Optimized geometries of Intc _comp., TSc _comp., Prc _comp. optimized
at the B3LYP/6-31+G⁄ level.
Figure 5. The H NMR spectra of 12c and 12c0 between d 3 and 6 ppm.
1

A. Gurjar et al. / Tetrahedron Letters 55 (2014) 2504–2507
9. Sun, J.; Xia, E.; Wu, Q.; Yan, C. ACS Comb. Sci. 2011, 13, 421.
2507
the absence of the NH proton. The doublets at d 3.50 and d 5.06
resulting from the geminal coupling (2JHH = 14.7 Hz) confirm the
presence of two protons, HA, HB at C3, which are diastereotopic.
The diastereotopic nature of these protons was confirmed by com-
putational calculations, when total energies of the two products
resulting from their successive replacement by the test group Cl
10. (a) Yavari, I.; Souri, S. Synlett 2007, 2969; (b) Yavari, I.; Souri, S. Synlett 2008,
1208.
11. Hadijebi, M.; Hashtroudi, M. S.; Bijanzadeh, H. R.; Balalaie, S. Helv. Chim. Acta
2011, 94, 382.
12. Ranu, B. C.; Dey, S. S.; Hajra, A. ARKIVOC 2002, 7, 76.
13. Ziyaei-Halimehjani, A.; Saidi, M. R. Tetrahedron Lett. 2008, 49, 1244.
14. Dabrowski, J.; Terpinski, J. Tetrahedron Lett. 1965, 6, 1363.
15. (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648; (b) Lee, C.; Yang, W.; Parr, R. G.
Phys. Rev. B. 1988, 37, 785; (c) Geometry optimizations were performed at
B3LYP/6-31+G⁄ level. Stationary points were analyzed by frequency
calculations at the same level to confirm their character as local minima or
transition states. IRC calculations were performed in order to validate the
connection of each transition state with the respective reactants and the
product. Solvent effect was computed by carrying out the single point energy
calculations of the gas phase optimized geometries using polarized continuum
model (PCM).
determined at the B3LYP/6-31+G⁄ level differed by 2.64 kcal molꢀ1
Thus we succeeded for the first time in isolating the -imino ester
.
a
intermediate earlier postulated as the transient species in the
cis–trans isomerization of the Michael adducts with the acetylene-
carboxylic acid derivatives. As revealed by the computational cal-
culation, 12c0 forms a complex with benzylamine, which could be
removed only after repeated column chromatography. The isola-
tion of this product has another significance, that it incorporates
16. Frisch, M. J. et al. GAUSSIAN 03, revision B. 05; Gaussian: Wallingford, CT, 2003.
17. Yoshizawa, K.; Shiota, Y.; Yamabe, T. J. Am. Chem. Soc. 1999, 121, 147.
18. Yoshizawa, K.; Shiota, Y.; Yumura, T.; Yamabe, T. J. Phys. Chem. B 2000, 104,
734.
dual functionalities, namely
important synthons.
a- and b-imino esters, which are
19. Mascal, M.; Armstrong, A.; Bartbeger, M. D. J. Am. Chem. Soc. 2002, 124, 6274.
20. Bento, A. P.; Solà, M.; Bickelhaupt, F. M. J. Comput. Chem. 2005, 26, 1497.
21. (a) Noda, M.; Hirota, N.; Sumitani, M.; Yoshihara, K. J. Phys. Chem. 1985, 89,
399; (b) Adamo, C.; Cossi, M.; Barone, V. J. Comput. Chem. 1997, 18, 1993; (c)
Patni, M.; Gupta, R.; Gupta, N.; Bansal, R. K. Int. J. Chem. 2012, 1, 495; (d) Patni,
M.; Gupta, R.; Kotikalapudi, R.; Kumara Swamy, K. C.; Bansal, R. K. Tetrahedron
Lett. 2013, 54, 2321.
Acknowledgments
Financial support from the U.G.C., New Delhi in the form of a
Junior Research Fellowship to A.G. is gratefully acknowledged.
22. Alkorta, I.; Elguero, J. J. Chem. Soc., Perkin Trans. 2 1998, 2497.
23. Taggi, A. E.; Hafez, A. M.; Lectka, T. Acc. Chem. Res. 2003, 36, 10–19.
24. DMAD (1.6 mmol, 231.2 mg, 0.2 mL) was dissolved in toluene (10 mL) and the
solution was cooled to 0 °C. To it was added a solution of the amine (1.6 mmol)
in toluene (5 mL) dropwise by maintaining the temperature at 0 °C, whereby
an intense yellow color developed. The reaction was complete in 2–3 h.
(monitored by TLC (solvent/EtOAc/pet.ether (60–80°), 60:40 v/v %). The crude
product was purified by column chromatography over silica gel (eluent/EtOAc/
pet.ether (60–80°) 2:98 v/v %). The column chromatography of the crude
product obtained from the reaction of benzylamine with DMAD afforded two
products, 12c and 12c0. All the compounds gave satisfactory C,H,N analysis.
Supplementary data
Supplementary data (total energies of all the species in the gas
phase and in toluene (Table S1), and Cartesian coordinates of the
optimized B3LYP/6-31+G⁄ level (Table S2)) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2014.03.013.
25. Physical and spectral data 12a: colorless syrupy mass; yield 66%; IR (Nuj.
m
cmꢀ1): 1744 (s, C@O str.), 1694 (s, C@O str.); 1H NMR (300 MHz, CDCl3, d ppm, J
Hz): 1.18 (t, 3JHH = 7.2, 6H, CH3), 3.19 (q, 3JHH = 7.2, 4H, CH2), 3.60 (s, 3H, OCH3),
3.90 (s, 3H, OCH3), 4.58 (s, 1H, @CAH); 13C NMR (75.47 MHz, CDCl3, d ppm):
12.68 (CH3), 44.94 (ACH2), 50.45 (AOCH3), 52.67 (AOCH3), 83.22 (NAC), 154.45
(@CAH), 166.06 (AC@O), 168.21 (AC@O). Compound 12b: colorless syrupy
References and notes
1. (a) Jung, M. E. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: Oxford, 1991; Vol. 4, pp 1–67; (b) Perlmutter, P. Conjugate Addition
Reactions in Organic Synthesis In Tetrahedron Organic Chemistry Series;
Pergamon: Oxford, 1992; Vol. 9, p 114; (c) Shibasaki, M.; Sasai, H.; Arai, T.
Angew. Chem., Int. Ed. 1997, 36, 1236; (d) Gellman, S. Acc. Chem. Res. 1998, 31,
173.
2. (a) Nicolaou, K. C.; Dai, V.-M.; Guy, R. K. Angew. Chem., Int. Ed. Engl. 1994, 33, 15;
(b) Frackenpohl, J.; Arridson, P. I.; Screiber, J. V.; Seebach, D. Chem. Biol. Chem.
2001, 2, 445; (c) Liu, M.; Sibi, M. P. Tetrahedron 2002, 58, 7991; (d) Cardillo, G.;
Tomasini, C. Chem. Soc. Rev. 1996, 25, 117.
3. (a) Eliel, E. L.; He, X.-C. J. Org. Chem. 1990, 55, 2114; (b) Hayashi, Y.; Rode, J. J.;
Corey, E. J. J. Am. Chem. Soc. 1996, 118, 5502; (c) Genov, M.; Dimitrov, V.;
Ivanova, V. Tetrahedron: Asymmetry 1997, 8, 3703.
4. (a) Huisgen, R.; Herbig, K.; Siegl, A.; Huber, H. Chem. Ber. 1966, 99, 2526; (b)
Herbig, K.; Huisgen, R.; Huber, H. Chem. Ber. 1966, 99, 2546.
mass; yield 62%; IR (Nuj.
m
cmꢀ1): 1732 (s, C@O str.), 1680 (s, C@O str.); 1H
NMR (300 MHz, CDCl3, d ppm): 1.96–2.06 (unresolved t, 4H, AH2CACH2A),
3.08–3.38 (unresolved t, 4H, AH2CANACH2A), 3.78 (s, 3H, OCH3), 3.83 (s, 3H,
OCH3), 3.97 (s, 1H, @CAH); 13C NMR (75.47 MHz, CDCl3,
d ppm): 25.58
(AH2CACH2A), 48.12 (AH2CANACH2A), 50.53 (OCH3), 52.76 (OCH3), 83.53
(@CAN), 152.35 (@CAH), 166.10 (AC@O), 168.19 (AC@O).
26. Total yield of crude 12c+12c0: 79%; Physical and spectral data: compound 12c:
yellow solid; mp116–118 °C; IR (KBr m
cmꢀ1) 3450 (w, NAH str.), 1626 (s, C@O
str.), 1730 (s, C@O str.); 1H NMR (300 MHz, CDCl3, d ppm, J Hz): 4.33 (d,
3JHH = 5.7, 2H, CH2), 4.63 (s, 4H, OCH3 & @CHA), 4.88 (s, 3H, OCH3), 5.67 (b, 1H,
NAH), 7.28–7.40 (unresolved m, 5H, C6H5); 13C NMR (75.47 MHz, CDCl3, d
ppm) :29.71, 41.16, 48.47, 85.56, 127.61, 127.74, 128.32, 128.59, 129.04,
166.32, 167.29; Compound 12c0: white solid; mp 190–192 °C; 1H NMR
5. Kandell, K. A.; Vernon, J. M. J. Chem. Soc., Perkin Trans. 1 1987, 2023.
6. Fan, M.; Li, G.; Liang, Y. Tetrahedron 2006, 62, 6782.
7. Schwan, A. L.; Warkentin, J. Can. J. Chem. 1988, 66, 1686.
2
(300 MHz, CDCl3, d ppm, J Hz): 3.34 (s, 2H, CH2AN), 3.50 (d, JHH = 14.7, 1H,
2
HA), 4.04 (s, 3H, OCH3), 4.79 (s, 3H, OCH3), 5.06 (d, JHH = 14.7, 1H, HB), 7.05–
8. Vedejs, E.; Gingras, M. J. Am. Chem. Soc. 1994, 116, 579.
7.32 (unresolved m, 5H, C6H5).