Intramolecular aza-anti-Michael addition of an amide anion to enones: A regiospecific approach to tetramic acid derivatives

Article abstract of DOI:10.1002/adsc.200600542

A novel intramolecular aza-anti-Michael addition was disclosed in the one-pot reactions between 3-oxobutanamides and aryl (heteroaryl) aldehydes under basic conditions, in which amide anions regiospecifically attacked the ct-carbon of an enone fragment, p

Full text of DOI:10.1002/adsc.200600542

FULL PAPERS
DOI: 10.1002/adsc.200600542
Intramolecular Aza-Anti-Michael Addition of an Amide Anion to
Enones: A Regiospecific Approach to Tetramic Acid Derivatives
Xihe Bi,a Jingping Zhang,a,* Qun Liu,a,* Jing Tan,a and Bing Lia
a
Department of Chemistry, Northeast Normal University, Changchun, 130024, Peopleꢀs Republic of China
Fax : (+86)-431-8568-4937; e-mail: zhangjp162@nenu.edu.cn
Received: October 19, 2006; Revised: June 4, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: A novel intramolecular aza-anti-Michael the results of experiments and theoretical calcula-
addition was disclosed in the one-pot reactions be- tions, which is ascribed to (1) the conjugated and
tween 3-oxobutanamides and aryl (heteroaryl) alde- rigid molecular skeleton, and (2) proximity effects of
hydes under basic conditions, in which amide anions the nucleophilic site and the enone a-carbon.
regiospecifically attacked the a-carbon of an enone
fragment, providing a new route to biologically im-
portant tetramicacid derivatives. An explanation for
Keywords: amide anion; anti-Michael addition;
the unexpected regioselectivity is proposed based on enones; tetramicacids
Introduction
During the course of our study of a-oxoketene S,S-
acetal chemistry,[7] we reported an intramolecular
In recent years, some reactions known as the anti-Mi- oxo-anti-Michael reaction, in which the carboxyl acid
chael addition have been reported, in which the oxygen could regioselectively attack the a-carbon of
carbon-carbon and carbon-heteroatom bonds were the b-(2-/4-pyridyl)-substituted enone fragment under
formed regioselectively at the a-position of activated acidic conditions, allowing the formation of tetronic
olefins.[1a] So far, some intelligent approaches for redi- acids.[8] However, in that case the anti-Michael addi-
recting the regioselectivity of addition of a nucleo- tion occurred only in b-(2-/4-pyridyl)-substituted
phile from the classical b-addition mode to an a-addi- enone substrates; at the same time, the presence of a
tion have been developed. They include: 1) transition protonic acid appears indispensable, because the cor-
metal-catalyzed hydrocarbonation of an activated ole- responding sodium carboxylate of 4-pyridyl-substitut-
fin;[1b] 2) addition of alkyllithium or -magnesium re- ed enones failed in the cyclization reaction, which
agents to cinnamic acids, its esters, or primary or sec- proved that the 2-/4-pyridinium induced the anti-Mi-
ondary amides, through a free radical mechanism;[2] chael addition due to a strong ÀC effect (negative
3) using a much stronger electron-withdrawing b-sub- conjugation effect). Indeed, our latest theoretical cal-
stituent, such as 2-/4-pyridinium and b,b-bis(trifluoro- culation on the intermediate (i) showed that the 4-pyr-
methyl) groups, to induce an umpolung of the carbon/ idinium group led to an umpolung of the C/C double
carbon double bond of the a,b-unsaturated carbonyl bond of the enone (Figure 1); therefore, this reaction
system;[3] 4) directing an intramolecular oxo-anti-Mi- should belong to the third type of anti-Michael addi-
chael addition using azide activation at the a-position tions described above.
of o-hydroxychalcones.[4] Different from the Morita–
Baylis–Hillman[5] and a-formylation reactions[6] in
which the a-C of activated olefins is nucleophilic, in
an anti-Michael reaction the a-C of activated olefins
acts as an electrophilic center. This change should
bring new syntheticapplications, for example, the ring
size by an intramolecular anti-Michael addition would
contain one carbon atom less than the normal Mi-
chael addition, and thus adds a new reaction to the
repertoire of currently known processes.
Figure 1. NBO charge distribution on the C/C double bond
of pyridinium (i).
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Table 1. The one-pot reactions of compounds 1 with aldehy-
Herein, we report a new intramolecular anti-Mi-
chael reaction in which an amide anion exclusively at-
tacks the a-carbon of enones under basic conditions,
providing a regiospecific synthesis of biologically im-
portant tetramicaicd (pyrrolidine-2,4-dione) deriva-
tives. Importantly, the b-substituent in the enone frag-
ment has a lower effect on the aza-anti-Michael addi-
tion than on the pyridinium-induced anti-Michael ad-
dition.[8] As part of these studies, we also explored the
reason for the unexpected regioselectivity.
des.[a]
Entry
1
R
Ar
2
Yields [%][b]
1
1a Ph
4-Pyridyl
2b 78
2
1a Ph
3-Pyridyl
2c 92
3
4
5
6
7
8
9
10
11
1a Ph
1a Ph
1a Ph
1a Ph
3-NO2C6H4
2-NO2C6H4
4-NO2C6H4
2-ClC6H4
2-Pyridyl
2d 86
2e 0[c]
Results and Discussion
2f
0[c]
2g 80
2h 89
Initially, upon treatment of 2-(1,3-dithiolan-2-yli-
dene)-3-oxo-N-phenylbutanamide 1a with pyridine-2-
carboxyaldehyde in the presence of NaOEt in ethanol
at 708C for 1.5 h, tetramicacid derivative 2a was ob-
tained in 85% yield as the sole product, whose struc-
ture was confirmed by NMR spectral analysis of the
corresponding 4-hydroxy derivative 3a after reduction
with NaBH4 [Eq. (1)]. Other base systems (NaOH/
1b 4-ClC6H4
1c
4-MeC6H4 2-Pyridyl
2i
2j
83
52
1d Bn
1e Et
1a Ph
2-Pyridyl
2-Pyridyl
2,6-Cl2C6H3 2l
2k 66
82
[a]
0.5 equivalent of NaOEt was used in all reactions.
Isolated yields.
No desired product was isolated.
[b]
[c]
more, variation of R in 1 from aryl to alkyl groups
(1b–1e) was also tolerated although slightly lower
yields were observed in the cases of 1d and 1e (en-
tries 7–10). The results exhibit the scope of the one-
pot cyclization reactions with respect to a range of
substrates. Thus, we present here a new and facile
one-pot method for the synthesis of tetramicacids, a
key structural unit in numerous biologically active
[9]
natural and syntheticcompounds.
Moreover, the in-
troduction of a characteristic 1,3-dithiolan-2-ylidene
group to the 3-position of tetramicaicds is useful,
EtOH, KOH/EtOH, NaOEt/DMF and NaH/DMSO) since it has the potential to be converted into other
were tested, but NaOEt/EtOH was the most efficient functional groups such as thioesters,[10] 1,3-dithiolan-2-
[12]
and was selected for the following investigations. yl,[7f,g,11] enamines[7f,g,8] and aromaticrings
through
From the results listed in Table 1, it can be seen that ring opening, reduction, substitution and cycloaroma-
both pyridine-4-carboxyaldehyde and pyridine-3-car- tization reactions, respectively. Therefore, products 2
boxyaldehyde smoothly reacted with 1a, affording tet- could act as a valuable synthetic scaffold in the prepa-
ramicacids 2b and 2c in 78% and 92% yields, respec- ration of natural and syntheticocmpounds with im-
tively (entries 1 and 2).
portant biological and pharmacological activities.
Subsequently, a stepwise experiment was designed
The structure of 2c was unambiguously determined
by X-ray diffraction analysis (Figure 2). In addition to starting from compound 4 to determine what factors
pyridinecarboxyaldehydes, 3-nitrobenzaldehyde also are responsible for the ring closure in the above one-
participated in the one-pot reaction with 1a, leading pot reactions (Scheme 1). Acids 5 were first prepared
to tetramicacid 2d in 86% yield (entry 3). However, by a Claisen–Schmidt condensation reaction between
2- and 4-nitrobenzaldehyde both failed in this cycliza- 4 and aldehydes,[13] followed by conversion to the re-
tion process under identical and a variety of other sultant enone 6 by using a classical method. Subse-
conditions (for example, at reflux temperature or with quently, the cyclization of 6 was performed in the
t-BuOK as the base), and led to unidentified mixtures presence of NaOEt in ethanol, as expected leading to
(entries 4 and 5). Notably, the one-pot reaction also tetramicacids 2c, 2e and 2f in high yields, respective-
occurred with 2-Cl- and 2,6-di-Cl-substituted benzal- ly. From these results, it can be concluded that the in-
dehydes to give tetramicaicds 2g and 2l in 80 and tramolecular aza-anti-Michael addition of amide
82% yields, respectively (entries 6 and 11). Further- anion to the enone fragment of 3-oxo-pent-4-enam-
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Regiospecific Approach to Tetramic Acid Derivatives
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Figure 2. ORTEP drawing of molecule 2c. Crystallographicdata for the structure 2c have been deposited with the Cam-
bridge Crystallographic Data Centre as supplementary publication no. CCDC-299148. Copies of the data can be obtained
free of charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax.: (internat.) +44-1223/336-033; e-
mail: deposit@ccdc.cam.ac.uk].
ring closure of 6, that is, 5-exo-trig and 6-endo-trig, re-
spectively. It is known that the electron-withdrawing
ability of pyridyl and substituted phenyl is far weaker
than that of carbonyl group,[15] so the 6-endo-trig path-
way for the ring closure of 6 appears a much more
reasonable choice,[16] however, no such products, i.e.,
Michael adducts, could be obtained in the cases
where an enone substrate (or intermediate) 6 has an
electron-withdrawing b-aryl group.[17] Therefore, we
tried to elucidate the reason for the unexpected regio-
selectivity, and also to explore the scope and limita-
tions of the one-pot reaction described above.
To examine the effect of conjugation between
acetyl and carbamoyl units in amides 6, compounds
7a–7c, containing instead an sp3 carbon atom at the 2-
position, were prepared by reacting 3-oxo-N-phenyl-
butanamide with 1,4-dibromobutane, 1,2-dibromo-
ethane and iodomethane in the presence of K2CO3 in
Scheme 1. Reagents and Conditions: (i) ArCHO, NaOH,
C2H5OH, r.t. 6–9 h; (ii) HCl aqueous; (iii) SOCl2, anhydrous
CH2Cl2, reflux, 2 h; (iv) PhNH2, CH2Cl2, reflux, 1.5 h; (v)
NaOEt/C2H5OH, 708C, 1–2 h.
ides 6 is the ring-closure step. Further, successful DMF
at
ambient
temperature,
respectively
preparation of 2e and 2f by this stepwise method sug- (Scheme 2). Then, the reactions of 7 with selected ar-
gests that the one-pot cyclizations of 1 with 2- and 4- omatic aldehydes were carried out in the presence of
nitrobenzaldehydes (Table 1, entries 4 and 5) failed in NaOEt in ethanol. From these results listed in
the Claisen–Schmidt condensation step. These results Table 2, it can be seen that a new group of tetramic
indicate that the one-pot reaction shown in Table 1 in- acids 8 was successfully synthesized in good yields
volves sequential Claisen–Schmidt condensation and from the one-pot reactions between 7 and the corre-
intramolecular aza-anti-Michael addition to yield tet- sponding pyridinecarboxyaldehydes (entries 1–3 and
ramicacids of type 2.
6). The five-membered structure of products 8 was
According to Baldwinꢀs guidelines on ring closure confirmed by NMR spectral analysis of the corre-
reactions,[14] there exist two allowed pathways in the sponding 4-hydroxy derivatives 3. When reaction of
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Scheme 2.
Table 2. The reactions of compounds 7 with aldehydes.
Figure 3. Comparison of the NBO charge distribution on a-
and b-carbon of the enone fragment.
tron-withdrawing ability of the carbonyl group than
that of an aryl (heteroaryl) group. Upon removing the
proton, a nearly equal NBO charge density is found
on the two a- and b-C for the anion forms 6aÀ and
9aÀ, respectively. This feature is in agreement with
the anti-Michael additions. The umpolung on the C/C
double bond of anion 6aÀ might be due to the elec-
tron-donating effect of both amide anion and two al-
kylthio groups to the carbonyl of the enone system
through their respective conjugated chains.[20] Besides,
a remarkable decrease of negative charge density was
observed at the a-carbon of unconjugated species 9aÀ,
Entry
7
Ar
8/9
Yields [%][a]
1
2
7a
7a
7b
7a
7a
7c
4-Pyridyl
2-Pyridyl
4-Pyridyl
2-Pyridyl
3-NO2C6H4
2-Pyridyl
8a
8b
8c
8b/9a
9b
85
76
89
3
4[b]
5
48%/43%
94
61
6
8d
[a]
Isolated yields based on 7.
Quenching the reaction at midway.
[b]
7a was quenched in the middle of the reaction with which suggests the steroelectronic effect between the
pyridine-2-carboxyaldehyde, 8b and intermediate 9a N-nucleophile with the carbonyl as well as the alpha
were isolated in 48% and 43% yields, respectively carbon of the enone system may exist.[4b] At the same
(entry 4), which indicated the formation of 3-spiro- time, the proximity effects[21] may also play a crucial
tetramicaicds
8 subjected to the same ring-closure role in the observed regioselectivity, namely the
mechanism as tetramic acids 2. By contrast, reaction amide anion attacks the enone C/C double bond from
of 3-nitrobenzaldehyde with 7a only afforded 94% of the closer direction to a-C rather than b-C, hence the
9b under identical conditions (entry 5). These results attack will be preferential to a-C, corresponding to
indicate that the conjugation between the nucleophilic the anti-Michael addition. Furthermore, the p orbital
site and the electrophilic site appears not to be essen- on the N atom of the HOMO is in the same phase as
tial for the anti-Michael addition of amides 6, but that of the a-C atom of the LUMO for the conforma-
may have an accessory role because a much wider tion of optimized anion 6aÀ (9aÀ), favoring anti-Mi-
range of b-substituents was tolerated in the cycliza- chael addition. Additionally, the thermodynamic sta-
tion of substrates 6 than that in amides 9. Also, the bility of the products of alpha and beta addition were
rigid skeleton of the species 6 should be considered as calculated and compared. We found that the total
another beneficial factor since it can provide a con- energy of optimized 2a (8b) is lower than that of cor-
straint on the system[18] that forces the reaction to responding Michael product by 9.977 (11.445) kcal
proceed with the observed regiochemistry, i.e., anti- molÀ1; therefore, the alpha addition product 2a (8b) is
Michael addition.
also energetically stable.
To rationalize the preference for the anti-Michael
addition described above, we performed ab initio
(HF/6-31G*) calculations on 6a (9a) and its anion 6aÀ Conclusions
(9aÀ), respectively.[19] The NBO charge densities on a-
and b-C in 6a (9a) and anion 6aÀ (9aÀ) are schemati- We have disclosed a novel intramolecular aza-anti-
cally shown in Figure 3, from which it can be seen Michael addition of an amide anion to a,b-unsturated
that a-C possesses more negative charge than b-C enones. As the key ring-closure step, a new route to
both in 6a and 9a owing to the much stronger elec- biologically important tetramic acid derivatives has
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Cho, S. C. Shim, Y. Yamamoto, Chem. Commun. 2002,
852–853.
been developed through the one-pot reactions be-
tween 3-oxobutanamides and aryl (heteroaryl) alde-
hydes under basicconditions. The reason for the ob-
served regioselectivity in the ring-closure step was
also explored through experiments and theoretical
calculations, and mainly ascribed to (1) the conjugat-
ed and rigid molecular skeleton and (2) proximity ef-
fects of the nucleophilic site and the enone a-carbon.
Our findings help define the structural prerequisites
for an anti-Michael addition to an a,b-unsaturated
enone system. Studies to further extend the intramo-
lecular anti-Michael addition to other molecular sys-
tems are underway in our laboratory.
[2] a) G. W. Klumpp, A. J. C. Mierop, J. J. Vrielink, A.
Brugman, M. Schakel, J. Am. Chem. Soc. 1985, 107,
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E. MuÇoz, Tetrahedron 2001, 57, 1067–1074.
[3] a) G. S. Ponticello, M. B. Freedman, C. N. Habecker, M.
Katharine Holloway, J. S. Amato, R. S. Conn, J. J. Bald-
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C. O. Della Vꢂdova, A. Haas, M. Winter, J. Fluor.
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[4] a) E. Patonay-Pꢂli, G. Litkei, T. Patonay, Synthesis
1990, 511–514. If no azide group is present at the a-po-
sition of enones, an exclusive intramolecular Michael
addition will occur instead of the anti-Michael addition,
please see: b) C. D. Johnson, Acc. Chem. Res. 1993, 26,
480.
Experimental Section
Typical Procedures for the Syntheses of Tetramic
Acids 2 via One-Pot Reaction (with 2a as an
Example)
[5] D. Basavaiah, A. J. Rao, T. Satyanarayana, Chem. Rev.
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To a solution of 2-(1,3-dithiolan-2-ylidene)-3-oxo-N-phenyl-
butanamide 1a (0.56 g, 2.0 mmol) and pyridine-2-carboxyal-
dehyde (0.24 mL, 2.5 mmol) in ethanol (6 mL) was added
NaOEt (0.08 g, 1.0 mmol) in one portion at 08C. The reac-
tion mixture was then heated to 708C and stirred for 1.5 h.
After completion of the reaction as indicated by TLC, the
reaction mixture was cooled to room temperature, quenched
with saturated aqueous NH4Cl (25 mL), and vigorously
stirred for another 15 min to allow the formation of a pre-
cipitate. Collection of the precipitate by filtration at reduced
pressure followed by drying under vacuum afforded the
product 2a as a yellowish solid; yield: 0.62 g (85%); mp
157–1588C; 1H NMR (DMSO-d6, 500 MHz): d=3.13 (dd,
J=6.5, 15.0 Hz, 1H), 3.20 (dd, J=4.0, 15.0 Hz, 1H), 3.53–
3.63 (m, 4H), 5.14 (dd, J=4.0, 6.5 Hz, 1H), 6.81 (d, J=
8.0 Hz, 1H), 7.09–7.13 (m, 2H), 7.29–7.32 (m, 2H), 7.43 (d,
J=7.5 Hz, 2H), 7.47–7.50 (m, 1H), 8.35 (d, J=4.0 Hz, 1H);
13C NMR (DMSO-d6, 125 MHz): d=191.7 (C), 177.0 (C),
165.5 (C), 156.6 (C), 149.2 (CH), 137.3 (CH), 136.4 (C),
128.9 (CH), 125.0 (CH), 124.3 (CH), 123.2 (CH), 122.0 (C),
113.0 (CH), 63.5 (CH), 38.1 (CH2), 37.8 (CH2), 37.4 (CH2);
IR (KBr): n=1658, 1594, 1517, 1489, 1436, 1372, 1274, 1205,
1149, 838, 775, 753, 610 cmÀ1; ES-MS: m/z=369.3 [(M+
1)]+; anal. calcd. for C19H16N2O2S2: C 61.93, H 4.38, N 7.60;
found: C 62.30, H 4.61, N 7.72.
[8] X. Bi, Q. Liu, S. Sun, J. Liu, W. Pan, L. Zhao, D. Dong,
Synlett 2005, 49–54.
[9] For reviews, see: a) A. Gossauer, Prog. Chem. Org.
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Rev. 1995, 95, 1981–2001. For selected recent examples,
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Munro, J. Nat. Prod. 2006, 69, 151–153; d) A. R. Rat-
nayake, R. A. Davis, M. K. Harper, C. A. Veltri, C. D.
Andjelic, L. R. Barrows, C. M. Ireland, J. Nat. Prod.
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Chai, K. J. Duffy, Org. Lett. 2005, 7, 5521–5524; f) P.
Huang, T.-J. Wu, Y.-P. Ruan, Org. Lett. 2003, 5, 4341–
4344.
[10] S. K. Nair, R. Samuel, C. V. Asokan, Synthesis 2001,
573–576.
[11] J. M. Mellor, S. R. Schofield, S. R. Korn, Tetrahedron
1997, 53, 17151–17162.
[12] a) P. J. Kocienski, A. Pontiroli, Q. Liu, J. Chem. Soc.,
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Acknowledgements
Financial supports of this research by the NNSFC (20672019)
and analysis and testing foundation of Northeast Normal
University are gratefully acknowledged.
[13] M. Wang, X. Xu, Q. Liu, L. Xiong, B. Yang, L. Gao,
Synth. Commun. 2002, 32, 3437–3443.
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Scheme 1, from which an aza-Michael adduct 6m-i was
separated and confirmed by subsequent reduction and
elimination reactions.
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