Chemoselective, accelerated and stereoselective aza-Michael addition of amines to N-phenylmaleimide by using TMEDA based receptors

Article abstract of DOI:10.1016/j.tetasy.2004.10.006

An aza-Michael addition between a maleimide and amines is described in which the presence of simple amine receptors (TMEDA or trans-TMCDA) promote the chemoselectivity of the reaction (respectively, 1,2- and 1,4-addition). Additionally, both receptors are able to accelerate the reaction. Stoichiometries of complexes between receptors and amines were determined by ¹H NMR dilution experiments while enantiomeric excesses were observed on 1,4-adducts by using (1R,2R)-TMCDA.

Full text of DOI:10.1016/j.tetasy.2004.10.006

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 3703–3706
Chemoselective, accelerated and stereoselective
aza-Michael addition of amines to N-phenylmaleimide by using
TMEDA based receptors
Yuefeng Bi, Laetitia Bailly, Francis Marsais, Vincent Levacher,
¨
Cyril Papamicae¨l* and Georges Dupas
´ ´
UMR 6014 IRCOF, CNRS, Universite et INSA de Rouen, BP 08, 76131 Mont-Saint-Aignan Cedex, France
Received 23 August 2004; accepted 4 October 2004
Available online 5 November 2004
Abstract—An aza-Michael addition between a maleimide and amines is described in which the presence of simple amine receptors
(TMEDA or trans-TMCDA) promote the chemoselectivity of the reaction (respectively, 1,2- and 1,4-addition). Additionally, both
receptors are able to accelerate the reaction. Stoichiometries of complexes between receptors and amines were determined by H
1
NMR dilution experiments while enantiomeric excesses were observed on 1,4-adducts by using (1R,2R)-TMCDA.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1.Introduction
Two recent reports of Takemoto et al.4 concerning
the addition reaction of malonates to nitroolefins4a
and nitroalkanes to imines4b by using a relatively
sophisticated thiourea receptor having a 1,2-cyclo-
hexyldiamine moiety, prompted us to describe our
own results. Herein, we report the study of commercially
available TMEDA and trans-N,N,N0,N0-tetramethylcy-
clohexanediamine (trans-TMCDA, Fig. 1) used as new
receptors in the aza-Michael addition reaction of several
primary amines, principally benzylamine derivatives, to
N-phenylmaleimide (Scheme 1).
Chemists working in the biomimetic chemistry field con-
ceive new substances and reactions, which imitate bio-
logical chemistry and expand the scope of chemistry.
Enzymes are not only able to catalyze a wide range of
reactions, but also control their chemo- and/or stereo-
chemical outcomes. Hence, synthetic chemists have
designed a variety of unnatural systems that mimic
enzymes.1
For several years, we have been interested in the synthe-
sis of new flexible receptors2 for amines, acids or both
acids and amines with the view to facilitate the reaction
leading to an amide. During the course of our investiga-
tions concerning synthetic receptors,2b,c we were espe-
cially interested in the synthesis of several 3-
aminosuccinimides by using the enantioselective aza-
Michael addition reaction starting from primary amines
and N-substituted-maleimides. Over the course of our
studies, Philp et al.3 reported the ability of a bis(phos-
phine oxide) host to increase the rate of addition of 4-
fluorobenzylamine to N-phenylmaleimide. This inspired
us to develop new amine receptors, which could be use-
ful tools in the synthesis of 3-aminosuccinimides.
N
N
N
N
TMEDA
Figure 1. Receptors used.
trans-TMCDA
2.Results and discussion
The aza-Michael addition reaction was conducted under
the same conditions as described by Philp et al.3 with
the aim of comparing the efficiency of our receptors.
Thus, N-phenylmaleimide 1 and amine 2a, both at
50mM in CDCl3, were reacted at 40 and 21ꢁC. The
*
Corresponding author. Tel.: +33 235 522 484; fax: +33 235 522
962; e-mail: cyril.papamicael@insa-rouen.fr
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.10.006

3704
Y. Bi et al. / Tetrahedron: Asymmetry 15 (2004) 3703–3706
R1
R1
R2
with/without
TMEDA
R2
H2N
O
R3
O
NH
R3
or TMCDA
R3
R2
O
O
NH
N
+
+
N
N
H
CDCl3
O
O
R1
2a: R1 = F, R2 = R3 = H
3a: R1 = F, R2 = R3 = H
3b: R1 = R2 = R3 = H
4a: R1 = F, R2 = R3 = H
4b: R1 = R2 = R3 = H
1
2b: R1 = R2 = R3 = H
2c: R1 = CH3, R2 = R3 = H
2d: R1 = OCH3, R2 = R3 = H
2e: R1 = H, R2 = CH3, R3 = H
2f: R1 = R2 = H, R3 = CH3
3c: R1 = CH3, R2 = R3 = H
4c: R1 = CH3, R2 = R3 = H
4d: R1 = OCH3, R2 = R3 = H
3d: R1 = OCH3, R2 = R3 = H
3e: R1 = H, R2 = CH3, R3 = H
3f: R1 = R2 = H, R3 = CH3
4e: R1 = H, R2 = CH3, R3 = H
4f: R1 = R2 = H, R3 = CH3
Scheme 1. Reaction scheme for the aza-Michael addition reaction.
formation of products 3a and 4a was monitored by
using 300MHz H NMR spectroscopy and the concen-
trations determined from these data.
In the literature,6 the presence of a catalytic amount of
triethylamine is known to prompt some other Michael
addition reactions and to play a role in their chemoselec-
tivity. As a result, we decided to carry out a study on the
influence of the amount of TMEDA and trans-TMCDA
in the reaction between 1 and 2a at 40 and 21ꢁC. The
collected data at both temperatures clearly showed that
by changing the amount of TMEDA, or trans-TMCDA
the chemoselectivity of the reaction can be easily con-
trolled. When the reaction is performed at 40 or 21ꢁC
(Fig. 3) with 0.25 equiv. of TMEDA or trans-TMCDA,
the rate for the 1,2-addition reaction leading to 4a is in-
creased, especially with TMEDA. At 40ꢁC, it is note-
worthy that for 0.8equiv of trans-TMCDA, an
inversion in the chemoselectivity of the reaction was
seen whilst no inversion was observed with TMEDA un-
til 2equiv. At 21ꢁC, an inversion occurred at 0.38equiv
with trans-TMCDA and 1.4equiv with TMEDA.
1
The kinetic data at 40ꢁC depicted in Figure 2 show that
almost the same amount of compounds 3a and 4a is
formed and the rate of the reaction is very slow under
these conditions. Thus, we first attempted to add 1equiv
of TMEDA to the reaction and observed an interesting
improvement in the rate of formation concerning the
1,2-addition compound 4a (Fig. 2). This interesting re-
sult led us to find another receptor with a structure
based on TMEDA. Hence, we looked for a receptor that
was either commercially available or with no more than
one step to synthesize. We found that trans-TMCDA
was the best candidate to fit all these conditions.5 We
decided to perform the reaction with trans-TMCDA
under the same conditions as above. Surprisingly, we
observed that, in this case, more of 1,4-addition
compound 3a was obtained than without trans-
TMCDA both at 40ꢁC (Fig. 2) and 21ꢁC. These inter-
esting results motivated us to investigate the control of
chemoselectivity in this aza-Michael addition.
12
1,4-adduct
1,2-adduct
10
8
6
25
4
2
20
15
10
5
1,4-adduct
1,2-adduct
0
0
0.5
1
1.5
2
Equivalent of receptor
Figure 3. Data obtained after 180min of reaction between 4-fluoro-
benzylamine (50mM) and N-phenylmaleimide (50mM) at 21ꢁC (blue)
and 40ꢁC (black) in the presence of TMEDA (dashed lines) or trans-
TMCDA (plain lines) as receptors. Circles represent the concentration
of the 1,2-addition product and triangles the concentration of the 1,4-
addition product.
0
0
100
200
Time (Min)
300
400
500
Figure 2. Kinetic data obtained for reaction between 4-fluorobenzyl-
amine (50mM) and N-phenylmaleimide (50mM) at 40ꢁC in the
absence of receptor (open symbols) and in the presence of TMEDA
(filled symbols, long dashed lines for 1equiv and small dashed lines for
0.25equiv) or 1equiv of trans-TMCDA (filled symbols, plain lines).
Circles represent the concentration of the 1,2-addition product and
triangles the concentration of the 1,4-addition product.
These unexpected results are particularly interesting
when compared to the bis(phophine oxide) host de-
scribed by Philp and co-workers3 who observed almost
identical kinetic data and no changes in the chemoselec-
tivity when the reaction was performed in the presence
of 1 or 0.2equiv of receptor. In our case, by using

Y. Bi et al. / Tetrahedron: Asymmetry 15 (2004) 3703–3706
3705
Table 1. Concentrations (mM) of 3a–d and 4a–d, determined by 1H NMR, obtained via Scheme 1 at 21ꢁC starting from 1 (50mM) and 2a–d
(50mM) after 24h
Entry
Additive (equiv)
3a
7.0
4a
9.2
3b
8.7
4b
9.9
3c
4c
3d
4d
1
2
3
—
TMEDA (0.25)
trans-TMCDA (2)
12.9
13.8
30.1
12.9
24.3
3.0
15.2
15.4
37.5
17.1
25.2
3.0
4.8
18.2
21.3
1.6
9.3
25.4
22.0
2.5
0.25equiv of TMEDA at 40ꢁC (Figs. 2 and 3) or 21ꢁC,
we were able to favour predominantly the formation of
the 1,2-addition compound 4a while by using trans-
TMCDA with more than 0.8equiv at 40ꢁC or 0.38equiv
at 21ꢁC the 1,4-addition compound 3a was obtained as
the major product. To compare our results with those
described by Philp,3 we used 4-fluorobenzylamine 1
and obtained similar rate accelerations with the advan-
tage of controlling the chemoselectivity of the reaction.
We were interested in also knowing whether the results
we obtained were a specificity of 1 due to the presence
of the fluoro group. We decided to conduct the same ki-
netic study with several other benzylamine derivatives
with 0.25equiv of TMEDA and 2equiv of trans-
TMCDA at 21ꢁC to favour, respectively, 1,2- and 1,4-
addition. Data collected after 24h of reaction are pre-
sented in Table 1. The present results showed that, as
we expected, the change in the chemoselectivity of the
reaction for benzylamine derivatives 2b–d is the same
as the one observed with 4-fluorobenzylamine 2a when
TMEDA is replaced by trans-TMCDA. Then, even
though TMEDA and trans-TMCDA have a very close
structure, we observed a different behaviour during the
course of the reaction.
plot analysis between trans-TMCDA and amines 3a–d
or phenethylamine. However in this case, we observed
that complexes (Fig. 5) were not 1:1 as expected but
probably 1:4 (host/guest). At the moment, we do not
have any explanation for this observation, but this find-
ing could be a direction to follow to account for the dif-
ferent chemoselectivity between TMEDA and trans-
TMCDA.
0.0008
0.0007
0.0006
0.0005
0.0004
0.0003
0.0002
0.0001
0
0
0.2
0.4
0.6
0.8
1
X
Figure 5. Job plot of trans-TMCDA (host) with 4-fluorobenzylamine
(guest). The sum of host and guest concentrations was constant
(C0 = 0.0130molLꢀ1, guest concentration = xC0) and the chemical
shift of the NH2 protons was monitored.
We then decided to establish the stoichiometry of the
complexes formed between amines (guests) and TME-
D A ortrans-TMCDA (hosts). A Job-plot7 analysis of
NMR spectroscopy titration experiments in CDCl3
showed that TMEDA binds one amine 3a (Fig. 4).
The results were exactly the same when this experiment
was conducted with other amines 3b–d and phenethyl-
amine. The association constants Ka were then deter-
mined assuming a 1:1 complexation process. Ka values
of 400, 420, 470, 475 and 208Mꢀ1 were obtained for
2a–d and phenethylamine, respectively. The stoichiome-
try of complexation was also investigated using a Job-
The cyclohexane-1,2-diamine structural framework is
often used as a ligand in asymmetric synthesis.8 Encour-
aged by the above successful acceleration with trans-
TMCDA in the formation of compounds 3a–f, we
turned our attention to the 1,4-enantioselective addition
of amines to N-phenylmaleimide with (1R,2R)-
TMCDA.5 To study the enantioselectivity, we tested
several different experimental conditions by changing
Table 2. Enantioselective addition of amines 2a,c,e and 2f to male-
imide 1 with (1R,2R)-TMCDA after 24h reaction at 21ꢁC
Entry (1R,2R)-TMCDA Product % Eea,b % Eea,c % Eea,d
(equiv)
0.0006
0.0005
0.0004
0.0003
0.0002
0.0001
0
1
2
3
4
0.5
2
3a
3c
3e
3f
16
14
14
15e
9
7
9
2
2
4
6e
2
3e
1
a EeÕs were measured by HPLC analysis using the chiral column,
Daicel OD column for 3a and 3c9a and Daicel OJ column for 3e and
3f.9b
b Reaction run in CHCl3.
c Reaction run in toluene.
0
0.2
0.4
0.6
0.8
1
d Reaction run in THF.
X
e The (S)-absolute configuration was assigned by comparison with the
retention time measured by HPLC analysis9b with (S)-enantiopure
analytical samples of 3f prepared by reacting the 2-methylbenzalde-
hyde with (S)-3-amino-N-phenylsuccinimide10 in EtOH followed by
NaBH4.
Figure 4. Job plot of TMEDA (host) with 4-fluorobenzylamine
(guest). The sum of host and guest concentrations was constant
(C0 = 0.0130molLꢀ1, guest concentration = xC0) and the chemical
shift of the NH2 protons was monitored.

3706
Y. Bi et al. / Tetrahedron: Asymmetry 15 (2004) 3703–3706
`
2. (a) Charpentier, P.; Briere, J.-F.; Dupas, G.; Queguiner,
G.; Bourguignon, J. Tetrahedron 1996, 52, 10441–10454;
´
the amount of trans-TMCDA from 0.5 to 2equiv,
amines, solvents and temperature (21 and 40ꢁC). The
main results at 21ꢁC are shown in Table 2, and although
the enantiomeric excesses we obtained are modest, they
are still significant.
`
(b) Briere, J.-F.; Charpentier, P.; Dupas, G.; Queguiner,
G.; Bourguignon, J. Tetrahedron 1997, 53, 2075–2086; (c)
´
`
´
Briere, J.-F.; Dupas, G.; Queguiner, G.; Bourguignon, J.
Tetrahedron 2000, 56, 8679–8688; (d) Moore, G.; Leva-
cher, V.; Bourguignon, J.; Dupas, G. Tetrahedron Lett.
2001, 42, 261–263; (e) Moore, G.; Papamicae¨l, C.;
Levacher, V.; Bourguignon, J.; Dupas, G. Tetrahedron
2004, 60, 4197–4204.
The highest enantioselectivity was observed when the
reaction was conducted in CHCl3 with amines 2a,c,e
and 2f. However, concerning amines 2b and 2d, we were
unable to determine the enantiomeric excesses for 3b
and 3d, while with phenethylamine or tert-butylamine,
no excesses were observed.
3. Ashton, P. R.; Calcagno, P.; Spencer, N.; Harris, K. D.
M.; Philp, D. Org. Lett. 2000, 2, 1365–1368.
4. (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem.
Soc. 2003, 125, 12672–12673; (b) Okino, T.; Nakamura,
S.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625–
627.
5. We prepared trans-TMCDA and (1R,2R)-TMCDA start-
ing from commercially available trans-diaminocyclohex-
ane and (1R,2R)-diaminocyclohexane, respectively, by
using a procedure closed to that described by Chooi, S.
Y. M.; Tan, M. K.; Pak-Hing, L.; Mok, K. F. Inorg.
Chem. 1994, 33, 3096–3103.
6. For example, see (a) Kamimura, A.; Murakami, N.;
Yokota, K.; Shirai, M.; Okamoto, H. Tetrahedron Lett.
2002, 43, 7521–7523; (b) Kamimura, A.; Murakami, N.;
Kawahara, F.; Yokota, K.; Omata, Y.; Matsuura, K.;
Oishi, Y.; Morita, R.; Mitsudera, H.; Suzukawa, H.;
Kakehi, A.; Shirai, M.; Okamoto, H. Tetrahedron 2003,
59, 9537–9546.
7. Job, A. Ann. Chim. (10th series) 1928, 9, 113–203.
8. For example, see: (a) Arena, C. G.; Casilli, V.; Faraone, F.
Tetrahedron: Asymmetry 2003, 14, 2127–2131; (b) Calter,
M. A.; Orr, R. K. Tetrahedron Lett. 2003, 44, 5699–5701;
(c) Kizirian, J.-C.; Caille, J.-C.; Alexakis, A. Tetrahedron
Lett. 2003, 44, 8893–8895; (d) Cabello, N.; Kizirian, J.-C.;
Alexakis, A. Tetrahedron Lett. 2004, 45, 4639–4642.
9. General HPLC conditions: Spectra System P1000xR and
AS3000 monitoring with a photo diod array; Wavelength
used: 230nm. (a) Daicel OD column (250 · 4.6mm,
10lL); 3a, 1mLminꢀ1, i-PrOH/heptane: 10:90 to 25:75
over 60min; retention time = 45 and 48min. 3c, i-PrOH/
heptane: 12:88; retention time = 42 and 47min; (b) Daicel
OJ column (250 · 4.6mm, 10lL); 3e, 1mLminꢀ1, i-PrOH/
heptane: 28:72; retention time = 48 and 70min. 3f, i-
PrOH/heptane: 28:72; retention time = 50min (3S config-
uration) and 65min.
3.Conclusion
In conclusion, TMEDA and trans-TMCDA are capable
of accelerating the nucleophilic addition of an amine to
a maleimide. The chemoselectivity of the reaction was
also efficiently controlled either by the presence of TME-
DA as a receptor of amines to promote the 1,2-addition
reaction or by trans-TMCDA to favour the 1,4-addition
reaction. The stoichiometry of complexation with
amines showed the formation of two different complexes
with TMEDA or trans-TMCDA. Finally, by using
(1R,2R)-TMCDA, we obtained a low but interesting
enantioselectivity in the formation of 3-aminosuccin-
imides. These preliminary results are very promising
and the study of other Michael addition reactions is cur-
rently in progress in our laboratory.
Acknowledgements
This work was supported in part by the French Embassy
´
in China and in part by ÔRegion Haute-NormandieÕ.
References
1. (a) Hartley, J. H.; James, T. D.; Ward, C. J. J. Chem. Soc.,
Perkin Trans. 1 2000, 3155–3184; (b) Rowlands, G. J.
Tetrahedron 2001, 57, 1865–1882; (c) Jarvo, E. R.; Miller,
S. J. Tetrahedron 2002, 58, 2481–2495; (d) Schreiner, P. R.
Chem. Soc. Rev. 2003, 32, 289–296.
10. Witiak, D. T.; Muhi-Eldeen, Z.; Mahishi, N.; Sethi, O. P.;
Gerald, M. C. J. Med. Chem. 1971, 14, 24–30.