Polarity-reversible conjugate addition tuned by remote electronic effects

Article abstract of DOI:10.1021/ol902551m

(Figure presented) A new concept, polarity-reversible conjugate addition, has been described, based on the findings that the polarity of a classical Michael acceptor can be reversed through remote electronic effects. In addition, the remote electronic eff

Full text of DOI:10.1021/ol902551m

ORGANIC
LETTERS
2010
Vol. 12, No. 2
244-247
Polarity-Reversible Conjugate Addition
Tuned by Remote Electronic Effects
Yifei Li, Xianxiu Xu,* Jing Tan, Peiqiu Liao, Jingping Zhang, and Qun Liu*
Department of Chemistry, Northeast Normal UniVersity, Changchun 130024, China
xuxx677@nenu.edu.cn; liuqun@nenu.edu.cn
Received November 3, 2009
ABSTRACT
A new concept, polarity-reversible conjugate addition, has been described, based on the findings that the polarity of a classical Michael
acceptor can be reversed through remote electronic effects. In addition, the remote electronic effects are tunable, and both five- and six-
membered nitrogen rings can be constructed starting from acyclic precursors having the same enone structure unit simply by varying a
remote substituent in the molecules.
The conjugate addition (or Michael addition) of nucleophilic
species to alkenes substituted with electron-withdrawing
Scheme 1. Regiodivergent Reactions of 1
groups (such as carbonyl, nitro, or sulfonyl) to give 1,4-
addition products is one of the most fundamental reactions
in organic chemistry.1,2 Through our research in this area3
we found that biologically active tetramic acid derivatives 4
can be synthesized via an unusual intramolecular aza-anti-
Michael addition of N-aryl-cinnamoylacetamides 1 bearing
a ꢀ-electron-deficient aromatic/heteroaromatic group under
basic conditions (addition of amide anion to the enone R-C-
atom, Scheme 1, 1 to 4).4 However, in one case where the
enone moiety of N-aryl-cinnamoylacetamide 1 has a ꢀ-elec-
tron-rich 4-methoxyphenyl group, the intramolecular aza-
(1) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon: Oxford, 1992. (b) Jung, M. E. ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Semmelhack, M. F., Eds.; Pergamon: Oxford,
1991; Vol. 4, pp 1-67.
(2) For recent reviews, see: (a) Enders, D.; Saint-Dizier, A.; Lannou,
M.-I.; Lenzen, A. Eur. J. Org. Chem. 2006, 29–49 (phospha-Michael
addition). (b) Nising, C. F.; Brase, S. Chem. Soc. ReV. 2008, 37, 1218–
1228 (oxa-Michael addition). (c) Sun, X.-L.; Tang, Y. Acc. Chem. Res.
2008, 41, 937–948 (ylide-initiated Michael addition-cyclization reactions).
(d) Enders, D.; Luttgen, K.; Narine, A. A. Synthesis 2007, 959–980
(asymmetric sulfa-Michael addition).
Michael adduct 2b was produced in 20% yield (Scheme 1).4
The significant difference in the orientation of the conjugate
addition reactions, which has not been defined in the
literature,1,2,4-6 prompted us to initiate studies on the
structural dependence of the cyclization process. In this
communication we describe a new concept, polarity-revers-
(3) For selected examples, see: (a) Tan, J.; Xu, X.; Zhang, L.; Li, Y.;
Liu, Q. Angew. Chem., Int. Ed. 2009, 48, 2868–2872. (b) Dong, D.; Bi,
X.; Liu, Q.; Cong, F. Chem. Commun. 2005, 3580–3582. (c) Bi, X.; Dong,
D.; Liu, Q.; Pan, W.; Zhao, L.; Li, B. J. Am. Chem. Soc. 2005, 127, 4578–
4579.
(4) Bi, X.; Zhang, J.; Liu, Q.; Tan, J.; Li, B. AdV. Synth. Catal. 2007,
349, 2301–2306.
(5) For a review of anti-Michael addition, see: Lewandowska, E.
Tetrahedron 2007, 63, 2107–2122
.
10.1021/ol902551m  2010 American Chemical Society
Published on Web 12/17/2009

ible conjugate addition, based on the fact that the polarity
of a classical Michael acceptor can be reversed and either
intramolecular aza-Michael-adducts 2 (six-membered nitro-
gen rings) or intramolecular aza-anti-Michael adducts 4 (five-
membered nitrogen rings) can be constructed, preferentially,
through remote electronic effects.
Table 1. Intramolecular aza-Michael Addition of
N-Aryl-alkenoyl-acetamides 1a
To understand the reason why the cyclization reactions
have different regioselectivity (Scheme 1), the present study
aimed first to examine the ꢀ-substituent dependence of the
reactions of N-aryl-alkenoylacetamides 1. After optimization
of the reaction conditions, the intramolecular aza-Michael
adduct, piperidine-2,4-dione 2a, was obtained in 61% yield
by treatment of N-(4-methylphenyl)-cinnamoylacetamide 1a
(1.0 mmol) with NaOH (1.0 equiv) in EtOH (5.0 mL) at 70
°C for 1.0 h (Table 1, entry 1).7 Under identical conditions,
a series of selected experiments was performed, and the
results are summarized in Table 1. It was proven that N-(4-
methylphenyl)-alkenoylacetamides 1a-1h with phenyl (entry
1), an electron-rich aromatic (entries 2-4) and hetero
aromatic group (entries 5 and 6), alkyl (entry 7), or less
electron-deficient aromatic group (entry 8) at the ꢀ-position
of the enone moiety can afford the corresponding intramo-
lecular aza-Michael adducts 2a-2h in good to high yields,
respectively. In addition, intramolecular aza-Michael adducts
2i-2k were also obtained from the corresponding arylamides
1i-1k bearing an electron-deficient N-(p-chlorophenyl)
group (entries 9 and 10) or N-phenyl (entry 11).
entry
1
R
Ar
time (h)
2
yieldb (%)
1
2
3
4
5
6
7
8
1a Ph
1b 4-MeOPh
1c 3,4-O2CH2Ph 4-MePh
4-MePh
4-MePh
1.0
1.0
1.5
1.0
2.0
1.5
0.5
3.8
1.5
2.5
1.0
1.5
2a
2b
2c
2d
2e
2f
2g
2h
2i
61
71
74
65
82
96
80
71
60
75
72
83
1d 4-MePh
1e 2-thienyl
1f 2-furyl
1g t-Bu
1h 4-BrPh
1i 4-ClPh
1j 2-furyl
1k Ph
4-MePh
4-MePh
4-MePh
4-MePh
4-MePh
4-ClPh
4-ClPh
Ph
9
10
11
12
2j
2k
2l
1l 4-ClPh
2,6-Me2Ph
The above results suggest that N-aryl-alkenoylacetamides
1 bearing alkyl, phenyl, electron-rich, or less electron-
deficient aryl groups at the ꢀ-position of the enone moiety
favor intramolecular aza-Michael addition (Table 1). In
contrast, as demonstrated by previous experiments,4 sub-
strates 1 bearing a more electron-deficient aromatic substitu-
ent at the ꢀ-position of the enone moiety prefer intramolec-
ular aza-anti-Michael addition (also see Scheme 1). Clearly,
these results, which show changes in the orientation of
conjugate addition reactions, cannot be compared with the
a Conditions: 1 (1.0 mmol), NaOH (1.0 equiv), in EtOH (5 mL), 70 °C.
b Yield of isolated products.
results in the literature,1,2,5 regardless of Michael1,2 or anti-
Michael addition.5
To gain a better insight into the difference in the
regioselectivity, the intramolecular conjugate addition
reactions of cinnamoylacetamides 3 having an N-alkyl
instead of an N-aryl group on the amide nitrogen were
performed to examine the electronic effects beyond the
enone moiety. To our surprise, instead of the intramo-
lecular aza-Michael adduct like 2a (Table 1, entry 1), the
intramolecular aza-anti-Michael adduct, tetramic acid
derivative 4a, was obtained in 78% yield by treatment of
N-benzyl amide 3a (1.0 mmol) with NaH (1.0 equiv) in
DMSO (5.0 mL) at room temperature for 0.5 h (Table 2,
entry 1)! Further experiments showed that not only
alkylamides 3b and 3c bearing ꢀ-electron-deficient aro-
matic group (Table 2, entries 2 and 3) but also the
alkylamides 3d and 3e (Table 2, entries 4 and 5) bearing
ꢀ-electron-rich aromatic group can react very smoothly
to give the corresponding anti-Michael adducts 4b-4e in
high yields.8
(6) (a) Li, Y.; Liang, F.; Bi, X.; Liu, Q. J. Org. Chem. 2006, 71, 8006–
8010. (b) Bi, X.; Liu, Q.; Sun, S.; Liu, J.; Pan, W.; Zhao, L.; Dong, D.
Synlett 2005, 49–54. (c) Cheng, X.; Liang, F.; Shi, F.; Zhang, L.; Liu, Q.
Org. Lett. 2009, 11, 93–96. (d) Liu, J.; Wang, M.; Han, F.; Liu, Y.; Liu, Q.
J. Org. Chem. 2009, 74, 5090–5092.
(7) The reaction of N-aryl amide 1a (Ar ) Ph, 1.0 mmol) with NaH
(1.0 equiv) in DMSO (5.0 mL) at room temperature for 40 min gave a
mixture of 2a and 9a in 38% and 35% yields, respectively. It was found
that 9a was formed in a diastereospecific manner on the basis of its 1H and
13C NMR spectra. Similarly, a mixture of 2d and 9d was obtained in 30%
and 22% yields, respectively, from 1d (Ar ) p-MePh) under identical
conditions for 40 min. The configurations of 9a and 9d were further
confirmed on the basis of the X-ray diffraction analysis of 9d (CCDC
751596). These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For comparison, under the same conditions as in Table 2,
the alkylamides 5a and 5b led to the formation of intramo-
(8) The configurations of 4a-4e were further confirmed on the basis of
the X-ray diffraction analysis of 4b. CCDC 739101 (4b) and CCDC 739100
(6b) contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Org. Lett., Vol. 12, No. 2, 2010
245

aim of evaluating proximity effects.9 Under the conditions
as described in Table 1, the intramolecular aza-Michael
adducts 8a-8c were obtained in good yields, respectively
(Scheme 3), which indicates the reactions of 7a-7c subjected
Table 2. Intramolecular aza-anti-Michael Addition of
N-Alkyl-cinnamoylacetamides 3a
Scheme 3. Intramolecular aza-Michael Addition of
N-(4-Methylphenyl)-cinnamoylacetamides 7a-7c
entry
3
Ar
Ph
4-BrPh
2-ClPh
2-furyl
2-furyl
4-ClPh
alkyl
time (h)
4
yieldb (%)
1
2
3
4
5
6
3a
3b
3c
3d
3e
3f
Bn
Bn
Bn
Bn
n-Pr
t-Bu
0.5
0.5
0.5
0.5
0.5
1.0
4a
4b
4c
4d
4e
4f
78
76
73
86
89
60
to the same mechanism as 1a-1l. Therefore, it is impossible
to predict a substantial impact of the proximity effect on the
intramolecular conjugate addition reactions because both five-
(Scheme 1)4 and six-membered rings (Table 1 and Scheme
3) can be formed preferentially depending on the nature of
the ꢀ-substituent on the enone moiety.
a Conditions: 3 (1.0 mmol), NaH (1.0 equiv), in DMSO (5 mL), room
temperature. b Yield of isolated products.
lecular aza-Michael adducts 6a and 6b in 67% and 70%
yields, respectively (Scheme 2), whereas in the presence of
Furthermore, the steric effects of the remote N-aryl/alkyl
groups were considered. Under the conditions as described
in Table 1, the cyclization of arylamide 1l having a sterically
hindered N-aryl group (2,6-dimethylphenyl) led to the
corresponding aza-Michael adduct 2l in 83% yield (Table
1, entry 12). In a comparison, the anti-Michael adduct 4f
was obtained in 60% yield (Table 2, entry 6) when the
reaction of alkylamide 3f bearing a bulky N-tert-butyl group
was carried out under the conditions as described in Table
2. These results suggest that the remote steric effect from
either the N-alkyl or N-aryl group is less significant.
Therefore, the nature of the substituent on the remote amide
nitrogen atom seems to play a key role in determining the
regioselective induction observed.
Scheme 2. Intramolecular aza-Michael Addition of
N-Alkyl-cinnamoylacetamides 5a and 5b
Finally, the influence of kinetic and thermodynamic factors
on the reaction was investigated by performing the reaction
at different temperatures. Treatment of N-aryl-cinnamoylac-
etamide 1b under the same conditions as in Table 1 but at
room temperature for 24 h led to the recovery of 1b in 93%
yield. No product 2b could be detected. On the other hand,
performing the reaction of N-alkyl-cinnamoylacetamide 3a
under the same conditions as in Table 2 but at 70 °C for
1.0 h led to the anti-Michael adduct 4a in 53% yield. The
corresponding intramolecular Michael adduct was not de-
tected. In addition, compound 4a was recovered in 89% yield
under the conditions of Table 2 after reaction at 70 °C for
24 h. As a result, all of the results (including the results in
Scheme 1 and ref 7) do not give any information concerning
relatively weak base, for example, under the reaction
conditions as described in Table 1, no reaction product was
detected and the starting materials were recovered unchanged,
presumably as a result of the decreased acidity of the amino
group in alkylamides 5 compared with that of the amino
group in arylamides 1. The structure of 6a and 6b was further
confirmed by the X-ray diffraction analysis of 6b.8 These
results, similar to that obtained with arylamides 1b (Table
1, entry 2), show the role of the strong electron-donating
ꢀ-methoxyphenyl group in the regioselectivity of the reac-
tions (see also Scheme 1).
To understand the source of the unusual divergence in the
regioselectivity of the above processes, several selected
experiments were conducted to evaluate the influence of
steric, kinetic, and thermodynamic effects on the reaction.
First, the reaction of selected N-(4-methylphenyl)-cin-
namoylacetamides 7a-7c bearing a tetra-substituted carbon
atom between two carbonyl groups were examined with the
(9) For a general discussion of the importance of the proximity effects
in intramolecular reactions, see: (a) Menger, F. M. Acc. Chem. Res. 1985,
18, 128–134. (b) Menger, F. M. Acc. Chem. Res. 1993, 26, 206–212. (c)
Jung, M. E.; Piizzi, G. Chem. ReV. 2005, 105, 1735–1766.
246
Org. Lett., Vol. 12, No. 2, 2010

kinetic and thermodynamic control on reaction products of
the tunable conjugate addition.10
ability to tune the polarity-reversal of the enone moiety than
the less electron-donating arylamide anion Ia (Table 1). As
a result, the tiny change in a remote substituent can even
lead to a pronounced polarity return, for example, the
formation of five-membered nitrogen rings 4a, 4b, 4d, 4f
versus six-membered nitrogen rings 2a, 2h, 2f, 2i. Moreover,
this research is helpful in understanding the nature of the
electronic effects in similar systems6a,b and provides a basis
for more detailed investigation.
In summary, we have described a new concept, polarity-
reversible conjugate addition and showed how the regiose-
lectivity of a conjugate addition can be reversed with a simple
and subtle change in a remote substituent. This concept
provides new insights into the conjugate addition chemistry.
Further studies and applications of this concept are in
progress.
Taken together, the previous4 and present results, including
the impact of the nature of ꢀ-substituents of the enone
moiety, a carbon atom between two carbonyl groups, the
electronic and steric effects of the N-aryl/alkyl groups, and
kinetic and thermodynamic factors as well, suggest that the
polarity-reversible intramolecular conjugate addition of N-
aryl/alkyl-alkenoylacetamides can be tuned by a remote
substituent and can be viewed as remote electronic effects
in nature.4,11 Therefore, it is understandable that the ability
to reverse the polarity of the classical conjugate addition of
the enone unit mainly depends on the electron-donating
nature of the remote amide anion, as indicated by the
calculation results.4
Collectively, our findings allow us to conclude that (1)
the regioselectivity of an intramolecular Michael addition
reaction can be tuned by the remote electronic effects, and
(2) the degree of the polarity reversal of a Michael acceptor
depends on the electron-donating ability of the remote
substituent. As expected, the more electron-donating (higher
electron density) alkylamide anion Ib (Table 2) has a stronger
Acknowledgment. Financial support of this research
provided by the NNSFC (20872015), the Science Foundation
for Young Teachers of NENU (20090404), and the Young
Scientific Research Foundation of Jilin Province (20090149)
is gratefully acknowledged.
Supporting Information Available: Experimental details
and spectra data for all new compounds and crystal structure
data for 4b, 6b and 9d in CIF format. This material is
available free of charge via the Internet at http://pubs.acs.org.
(10) Johnson, C. D. Acc. Chem. Res. 1993, 26, 476–482.
(11) For selected examples of catalyst-controlled regiodivergent synthesis
of cyclic compounds, see: (a) Xiao, Y.; Zhang, J. Chem. Commun. 2009,
3594–3596. (b) Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am. Chem.
Soc. 2005, 127, 10500–10051. (c) Alcaide, B.; Almendros, P.; del Campo,
T. M. Angew. Chem., Int. Ed. 2007, 46, 6684–6687. (d) Xiong, T.; Zhang,
Q.; Zhang, Z.; Liu, Q. J. Org. Chem. 2007, 72, 8005–8009
.
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