Scope and limitations of an efficient four-component reaction for dihydropyridin-2-ones

Article abstract of DOI:10.1021/jo902613j

(Chemical Equation Presentation) A broad range of isonitrile-functionalized 3,4-dihydropyridin-2-ones could be prepared using a fourcomponent reaction between phosphonates, nitriles, aldehydes, and isocyanoacetates. The reaction involves initial formation of a 1-azadiene intermediate which is trapped in situ by an isocyanoacetate to give the desired heterocyclic scaffold through cyclocondensation. The full scope and limitations of this four-component reaction are described. Variation of the nitrile and aldehyde inputs proved to be extensively possible, but variation of the phosphonate input remains limited. Regarding the isocyanoacetate, a-aryl isocyanoacetates give moderate to high yields and result in a complete diastereoselectivity for the 3,4-cis isomer. α-Alkyl isocyanoacetates gave the corresponding dihydropyridin-2-ones in moderate yields, most of them as mixtures of diastereomers. Elevated temperatures during cyclocondensation generally increased the yield and resulted in a change of the diastereomeric ratio in favor of the cis-diastereomer. In addition to isocyanoacetates, a limited number of other α-acidic esters resulted in the formation of dihydropyridin-2-ones, albeit in much lower yield. Computational studies show that the observed difference in yield cannot be simply correlated to specific physical properties (including acidity) of the different α-acidic esters.

Full text of DOI:10.1021/jo902613j

pubs.acs.org/joc
Scope and Limitations of an Efficient Four-Component Reaction for
Dihydropyridin-2-ones
Rachel Scheffelaar,† Monica Paravidino,† Anass Znabet,† Rob F. Schmitz,†
†
§
§
‡
ꢀ
Frans J. J. de Kanter, Martin Lutz, Anthony L. Spek, Celia Fonseca Guerra,
F. Matthias Bickelhaupt,*,‡ Marinus B. Groen,† Eelco Ruijter,*,† and
Romano V. A. Orru*,†
†Department of Chemistry & Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1083,
1081 HV Amsterdam, The Netherlands, ‡Amsterdam Center for Multiscale Modeling (ACMM), Vrije
Universiteit AmsterdamDe Boelelaan 1083, 1081 HV Amsterdam, The Netherlands, and Bijvoet Center for
§
Biomolecular Research, Crystal and Structural Chemistry, Utrecht University, Padualaan 8, 3584 CH,
Utrecht, The Netherlands.
orru@few.vu.nl; e.ruijter@few.vu.nl; fm.bickelhaupt@few.vu.nl
Received December 22, 2009
A broad range of isonitrile-functionalized 3,4-dihydropyridin-2-ones could be prepared using a four-
component reaction between phosphonates, nitriles, aldehydes, and isocyanoacetates. The reaction
involves initial formation of a 1-azadiene intermediate which is trapped in situ by an isocyanoacetate
to give the desired heterocyclic scaffold through cyclocondensation. The full scope and limitations of
this four-component reaction are described. Variation of the nitrile and aldehyde inputs proved to be
extensively possible, but variation of the phosphonate input remains limited. Regarding the
isocyanoacetate, R-aryl isocyanoacetates give moderate to high yields and result in a complete
diastereoselectivity for the 3,4-cis isomer. R-Alkyl isocyanoacetates gave the corresponding dihy-
dropyridin-2-ones in moderate yields, most of them as mixtures of diastereomers. Elevated
temperatures during cyclocondensation generally increased the yield and resulted in a change of
the diastereomeric ratio in favor of the cis-diastereomer. In addition to isocyanoacetates, a limited
number of other R-acidic esters resulted in the formation of dihydropyridin-2-ones, albeit in much
lower yield. Computational studies show that the observed difference in yield cannot be simply
correlated to specific physical properties (including acidity) of the different R-acidic esters.
Introduction
Parallel automated synthesis and combinatorial chemistry
allow the generation of large numbers of compounds. How-
ever, experiences in combinatorial chemistry-based drug
discovery in the past decades have shown that the amount
of relevant hits is not directly proportional to the number
of compounds screened, primarily because of the limited
Organic synthesis has reached a high level of sophistica-
tion. Multistep, sequential synthesis allows access to many
complex and challenging synthetic targets. However, the
present synthetic methodology does not meet the standards
set to future purposes. Certain constraints, including eco-
nomic, societal, and environmental factors, force the syn-
thetic community to conceive novel procedures and synthetic
concepts to optimize efficiency. Ideally, the target molecule is
prepared in one pot from readily available starting materials
in one simple operation. Consequently, multicomponent
reactions (MCRs) receive significant attention since they
are well suited for the rapid construction of various valuable
scaffolds.1
(1) (a) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471–1499.
€
(b) Domling, A. Chem. Rev. 2006, 106, 17–89. (c) Domling, A.; Ugi, I.
Angew. Chem., Int. Ed. 2000, 39, 3168–3210. (d) Zhu, J. P. Eur. J. Org. Chem.
€
€
2003, 7, 1133–1144. (e) Jacobi von Wangelin, A.; Neumann, H.; Gordes, D.;
Klaus, S.; Strubing, D.; Beller, M. Chem.;Eur. J. 2003, 9, 4286–4294.
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(f) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004,
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4957–4980. (g) Ramon, D. J.; Yus, M. Angew. Chem. 2005, 117, 1628–1661.
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DOI: 10.1021/jo902613j
r
Published on Web 02/02/2010
J. Org. Chem. 2010, 75, 1723–1732 1723
2010 American Chemical Society

Scheffelaar et al.
JOCArticle
SCHEME 1. 1-Azadienes as Important Intermediates for Diversity-Oriented Synthesis
structural diversity in these compound collections.2,3 In
recent years, the importance of structural diversity genera-
tion in drug discovery is increasingly recognized. The need
for more molecular diversity is also generally accepted in the
design and development of novel ligand systems for homo-
geneous catalysis.4
SCHEME 2. Proposed Mechanism of the DHP-2-one MCR
Multicomponent chemistry is an ideal tool to generate
both complexity and diversity, especially when a versatile
reaction intermediate is envisaged. Furthermore, when the
product of an MCR has a synthetic handle for another
multicomponent reaction, additional complexity will be
created. Such a strategy fits well in the concept of diversity-
oriented synthesis (DOS).2,5
Recently, we have contributed with several examples in
this area.6,7 The common factor in the reported reactions is
the application of an in situ generated 1-azadiene intermedi-
ate 4 that can be trapped by isocyanates 5 or isothiocyanates
8 to afford functionalized 3,4-dihydropyrimidine-2-ones 6,
triazinane diones 7, 2-aminothiazines 9, and dihydropyrimi-
dine-2-thiones 10 (Scheme 1). 1-Azadiene intermediates 4 are
obtained by reaction of phosphonates 1, nitriles 2, and
aldehydes 3 via a Horner-Wadsworth-Emmons (HWE)
reaction.8 Recently, we reported in a communication an
elaboration of this chemistry by examining isocyanoacetates
11 as the fourth component to gain access to isonitrile-
containing 3,4-dihydropyridin-2-ones 12 (3,4 DHP-2-ones).9
The reaction most likely involves a Michael-type attack of
anion 13 to 1-azadiene 4 followed by lactamization of
intermediate 14 (Scheme 2).
This is the first multicomponent reaction leading to iso-
nitrile-functionalized heterocyclic products. That the isocya-
nide group is not reactive under these conditions is
surprising, since this is a very reactive functional group in
numerous multicomponent reactions.10 A [4 þ 1]-cycloaddi-
tion leading to pyrrole-type structures would be a conceiva-
ble reaction pathway.11 The selective formation of the 3,4-
DHP-2-one scaffold is remarkable, since other reactions
such as 1,2 additions leading to β-lactams12 and either
imidazoline10 or oxazole formation13 could occur.
(2) Spring, D. R. Org. Biomol. Chem. 2003, 1, 3867–3870.
(3) Hann, M. M.; Leach, A. R.; Harper, G. J. Chem. Inf. Comput. Sci.
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therein.
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Schreiber, S. L. Angew. Chem., Int. Ed. 2004, 43, 46–48. (c) Tan, D. S. Nature
Chem. Biol. 2005, 1, 74–84. (d) Spandl, R. J.; Bender, A.; Spring, D. R. Org.
Biomol. Chem. 2008, 6, 1149–1158. (e) Galloway, W. R. J. D.; Bender, A.;
Welch, M.; Spring, D. R. Chem. Commun. 2009, 2446–2462. (f) Nielsen,
T. E.; Schreiber, S. L. Angew. Chem., Int. Ed. 2008, 47, 48–56.
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5474.
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R. V. A. Chem. Commun. 2003, 2594–2595. (b) Vugts, D. J.; Koningstein,
M. M.; Schmitz, R. F.; De Kanter, F. J. J.; Groen, M. B.; Orru, R. V. A.
Chem.;Eur. J. 2006, 12, 7178–7189. (c) Glasnov, T. N.; Vugts, D. J.;
Koningstein, M. M.; Desai, B.; Fabian, W. M. F.; Orru, R. V. A.; Kappe,
C. O. QSAR Comb. Sci. 2006, 25, 509. (d) Groenendaal, B.; Vugts, D. J.;
Schmitz, R. F.; de Kanter, F. J. J.; Ruijter, E.; Groen, M. B.; Orru, R. V. A.
J. Org. Chem. 2008, 73, 719. (e) Groenendaal, B.; Ruijter, E.; de Kanter,
F. J. J.; Lutz, M.; Spek, A. L.; Orru, R. V. A. Org. Biomol. Chem. 2008, 6,
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Schmitz, R. F.; De Kanter, F. J. J.; Lutz, M.; Spek, A. L.; Groen, M. B.; Orru,
R. V. A. Org. Lett. 2006, 8, 5369–5372.
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J. J.; Lutz, M.; Spek, A. L.; Orru, R. V. A. Org. Lett. 2003, 5, 3759–3762.
(b) Bon, R. S.; Van Vliet, B.; Sprenkels, N. E.; Schmitz, R. F.; De Kanter,
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V. A. J. Org. Chem. 2005, 70, 3542–3553. (c) Elders, N.; Schmitz, R. F.; de
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Di Simone, B.; Camerini, R. Synthesis 1994, 8, 805–808. (c) Oare, D. A.;
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SCHEME 3. Isonitrile-Based Follow-up Chemistry on the DHP-2-one Scaffold
SCHEME 4. Schematic Representation of Different Methods
for the Synthesis of 3,4-DHP-2-ones (Substituents Are Removed
for Clarity)
The presence of the isonitrile functionality in the MCR
product allows isocyanide-based multicomponent follow-up
chemistry, further increasing the complexity. Recently, we
have demonstrated this by performing the well-known
Passerini and Ugi MCRs on the DHP-2-one scaffold. For
the Passerini reaction this resulted in a small series of
conformationally constrained depsipeptides of type 15.14
The Ugi reaction gave not the expected product but rather
the unprecedented dihydrooxazolopyridine (DHOP) scaf-
fold 16 (Scheme 3).15 The Ugi reaction can be performed
after alkylation of the DHP-2-one amide, making highly
functionalized conformationally constrained peptide mimics
18 accessible by applying a peptidic alkylating agent
(Scheme 3).16
Besides the possibility for follow-up chemistry, 3,4-DHP-
2-ones are conformationally similar to dihydropyridines,
making them good candidates for the development of cal-
cium channel modulators.17 Moreover, the dihydropyridi-
none skeleton has often been used in natural product
synthesis.18
Several methods for the preparation of 3,4-DHP-2-ones
have been reported in literature. The most commonly used
method is the aza-annulation of enamines and R,β-unsatu-
rated carboxylic acid derivatives (Scheme 4, route I).18-20
Moreover, several 1-azadiene-based syntheses have been
reported, using R-metalated acetate derivatives (Scheme 4,
route II),12a,b,21 or oxazolones22 as reaction partners. These
reactions usually follow a Michael addition/lactamization
sequence (like the proposed mechanism in Scheme 2). DHP-
2-ones have furthermore been synthesized by reacting 1-
azadienes with ketenes giving a formal hetero-Diels-Alder
reaction (Scheme 4, route III).23
(13) (a) Bonne, D.; Dekhane, M.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46,
2485–2488. (b) Elders, N.; Ruijter, E.; De Kanter, F. J. J.; Groen, M. B.;
Orru, R. V. A. Chem.;Eur. J. 2008, 14, 4961–4973.
(14) Paravidino, M.; Scheffelaar, R.; Schmitz, R. F.; De Kanter, F. J. J.;
Groen, M. B.; Ruijter, E.; Orru, R. V. A. J. Org. Chem. 2007, 72, 10239–
10242.
(15) Scheffelaar, R.; Paravidino, M.; Muilwijk, D.; Lutz, M.; Spek, A. L.;
De Kanter, F. J. J.; Orru, R. V. A.; Ruijter, E. Org. Lett. 2009, 11, 125–128.
(16) Scheffelaar, R.; Klein Nijenhuis, R. A.; Paravidino, M.; Lutz, M.;
Spek, A. L.; Ehlers, A. W.; De Kanter, F. J. J.; Groen, M. B.; Orru, R. V. A.;
Ruijter, E. J. Org. Chem. 2009, 74, 660–668.
In addition, an asymmetric N-heterocyclic carbene-cata-
lyzed aza-Diels-Alder synthesis resulting in the forma-
tion of enantioenriched DHP-2-ones has been reported.24
Furthermore, a base-induced rearrangement of ketene-N,
(17) Ochoa, E.; Suarez, M.; Verdecia, Y.; Pita, B.; Martin, N.; Quinteiro,
M.; Seoane, C.; Soto, J. L.; Duque, J.; Pomes, R. Tetrahedron 1998, 54,
12409–12420.
(21) (a) Komatsu, M.; Yamamoto, S.; Ohshiro, Y.; Agawa, T. Tetrahe-
dron Lett. 1981, 22, 3769–3772. (b) Krishnan, K.; Singh, A.; Singh, B.;
Kumar, S. Synth. Commun. 1984, 14, 219–226.
(22) (a) Sain, B.; Sandhu, J. S. J. Heterocycl. Chem. 1986, 23, 1007–1010.
(b) Yadav, L. D. S.; Kapoor, R. Synlett 2008, 2348–2354. (c) Yadav, L. D. S.;
Kapoor, R. Tetrahedron Lett. 2008, 49, 4840–4844. (d) Jiang, J.; Qing, J.;
Gong, L.-Z. Chem.;Eur. J. 2009, 15, 7031–7034.
(18) Stille, J. R.; Barta, N. S. In Studies in Natural Products Chemistry;
Ata-ur-Rahman, Ed.; Elsevier Science: Amsterdam, 1996; Vol. 18, pp
315-389.
(19) (a) Wagman, A. S.; Wang, L.; Nuss, J. M. J. Org. Chem. 2000, 65,
€
9103–9113. (b) Karpov, A. S.; Rominger, F.; Muller, T. J. J. Org. Biomol.
Chem. 2005, 3, 4382–4391. (c) Paulvannan, K.; Chen, T. J. Org. Chem. 2000,
65, 6160–6166. (d) Pilipecz, M. V.; Varga, T. R.; Mucsi, Z.; Scheiber, P.;
Nemes, P. Tetrahedron 2008, 64, 5545–5550.
(23) (a) Brady, W. T.; Shieh, C. H. J. Org. Chem. 1983, 48, 2499–2502.
(b) Elliott, M. C.; Monk, A. E.; Kruiswijk, E.; Hibbs, D. E.; Jenkins, R. L.;
Jones, D. V. Synlett 1999, 1379–1382. (c) Sakamoto, M.; Miyazawa, K.;
Kuwabara, K.; Tomimatsu, Y. Heterocycles 1979, 12, 231–237. (d) Kobayashi,
S.; Semba, T.; Takahashi, T.; Yoshida, S.; Dai, K. Tetrahedron 2009, 65, 920–
933.
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guez, H.; Suarez, M.; Perez, R.; Petit, A.; Loupy, A.
(20) (a) Rodrı
Tetrahedron Lett. 2003, 44, 3709–3712. (b) Verdecia, Y.; Suarez, M.;
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Morales, A.; Rodrıquez, E.; Ochoa, E.; Gonzalez, L.; Martın, N.; Quinteiro,
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M.; Seoane, C.; Soto, J. L. J. Chem. Soc. Perkin Trans. 1 1996, 947–951.
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(c) Svetlik, J. J. Chem. Soc., Perkin Trans. 1 1990, 1315–1318.
(24) He, M.; Struble, J. R.; Bode, J. W. J. Am. Chem. Soc. 2006, 128,
8418–8420.
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SCHEME 5. Mechanism of the Formation of 1-Azadiene 4 Involving a HWE Reaction
O-acetals to DHP-2-ones was published.25 However, the
variation possibilities and the opportunity for isocyanide-
based follow-up chemistry make our novel multicomponent
strategy unique.
The reaction already proved to be quite flexible with
respect to the nitriles and aldehydes used, whereas the
isonitrile input was thus far limited to rather R-acidic iso-
cyanoacetates possessing an aromatic R-substituent.9
Herein we wish to report a full scope study including
the variation of the phosphonate and isocyanoacetate com-
ponents. Also the reactivity of R-acidic isocyanoacetates
compared to other R-acidic esters will be discussed. Further-
more, experimental evidence of the proposed mechanism will
be given.
Aliphatic, aromatic, as well as heteroaromatic nitriles
proved to be good reaction partners. Concerning the carbo-
nyl component, aromatic, heteroaromatic, and R,β-unsatu-
rated aldehydes gave good to excellent yields. Highly
electron-deficient aldehydes such as p-nitrobenzaldehyde
3d were shown to be an exception since no product formation
was observed. Moreover, no aliphatic aldehydes could be
used, since they lead to aldol-type products resulting from
self-condensation (entry 10) and from nucleophilic attack of
the isocyanoacetate to the aldehyde (entry 11).
To investigate the diastereoselectivity of the reaction, also
the commercially available optically pure aldehyde (-)-
myrtenal 3g was used (entry 9) since this input proved to
give an excellent asymmetric induction in the dihydropyr-
imidine MCR (Scheme 6a).7b However, in the present MCR
no asymmetric induction was observed, and a 1:1 mixture of
diastereomers was obtained (Scheme 6b). The absence of
stereoinduction may be caused by the difference in mechan-
ism of the two multicomponent pathways. In the present
reaction, it is proposed that the stereocenters are formed in
the first bond-forming step achieving intermediate 29,
whereas in the dihydropyrimidine case these are formed in
the cyclization step (to obtain 27). More conformational
freedom in the former reaction is therefore probably the
reason for the absence of stereoinduction.
Results and Discussion
The first step in the DHP-2-one synthesis is the generation of
1-azadiene intermediate 4. For this, phosphonate 1 is depro-
tonated by n-BuLi at -78 °C, followed by addition of the
nitrile 2 to afford 21, the starting material for the HWE
reaction (Scheme5). The reaction mixture is gradually warmed
to -5 °C, after which the aldehyde 3 is added. Increasing the
temperature to rt allows the formation of 1-azadiene 4 with
diethylphosphate as the byproduct. As discussed in the Intro-
duction, 4 can be trapped by a fourth component to afford
different heterocyclic scaffolds. Of particular interest for this
work is the use of isocyanoacetates 11 to trap 4, thus affording
3,4 DHP-2-ones of type 12 (Scheme 2).
Various phosphonates 1, nitriles 2, aldehydes 3, and
isocyanoacetates 11 were tested. The isocyanoacetates
(racemic) are readily available in three steps from the corre-
sponding amino acids using a procedure recently described
by our group.10 All phosphonates, nitriles, and aldehydes
used were commercially available.
From our previous study, it had become clear that the
phosphonate component showed limited variation possibi-
lities.7b The best results were obtained using diethyl methyl-
phosphonate 1a, and initial experiments were therefore
performed using this component. The one-pot reaction of
1a and various nitriles, aldehydes, and aromatic isocyano-
acetates is presented in Table 1 (entries 1-13). In all exam-
ples, a complete selectivity for the 3,4-cis-diastereomer was
observed.
Another point of diversity is the R1 substituent that is
derived from the phosphonate component. In a previous
study, we found that besides phosphonate 1a only diethyl
ethylphosphonate 1b is a suitable reaction partner for
1-azadiene formation.7b However, both examples investi-
gated using nitriles 2a and 2c gave only moderate yields
(entries 15 and 16, Table 1).
The majority of the above experiments were performed
using isocyanoacetate 11a, which is an excellent reaction
partner in the 4CR because of the high R-acidity. For the
same reason, 11b (R4 = PCP, entries 12 and 13) also gave
good results. The cyclocondensation reaction was also ac-
complished using the less R-acidic isocyanoacetate 11c (R4 =
H, entry 14). However, this reaction resulted in the forma-
tion of the expected 3,4-DHP-2-one 12n in only 19% yield
(trans:cis = 67:33) along with 18% of 32, derived from the
subsequent conjugate addition of deprotonated 12n to the
1-azadiene 30 still present followed by hydrolysis (Scheme 7).
DHP-2-one 32 was isolated as a single diastereomer.
The results indicate that the cyclocondensation proceeds
less efficient in these cases, probably due to the lower acidity
€
(25) Breuning, M.; Hauser, T. Tetrahedron 2007, 63, 934–940.
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TABLE 1. One-Pot Reaction between Various Phosphonates 1, Nitriles 2, Aldehydes 3, And Isocyanoacetates 11*
*All reactions were carried out using 0.2 M phosphonate, 1.2 equiv of n-BuLi, 1.1 equiv of nitrile, aldehyde, and isocyanoacetate. aIsolated yields.
bIn case no diastereomeric ratio is reported, only the 3,4-cis-diastereomer was observed in the 1H NMR of the crude product. cFor this reaction, the
1-azadiene was added slowly to a solution of the isocyanoacetate. The general order of addition resulted in 19% (trans/cis 67:33) of 12n and 18% of 32.
dThe relative stereochemistry (trans/cis) was determined by NOESY experiments and the 3J between H3 and H4 (12.4 Hz for the trans-12n and 6.7 Hz for
cis-12n). PMP = p-methoxyphenyl, PNP = p-nitrophenyl, PCP = p-chlorophenyl.
of the isocyanoacetate. Formation of 32 was completely
prevented using a reverse addition strategy, resulting in the
formation of 12n in 32% yield as a mixture of diastereomers
(trans:cis = 63:37).
The lower yields of R-alkyl isocyanoacetates in comparison with
the R-aryl isocyanoacetates can be explained, like for isocyanoa-
cetate 11c, by the lower acidity of the R-proton decreasing the
reaction rate and giving rise to the formation of side products.27
Because of the modest yields, an optimization study was
performed using 1a, 2a, 3b, and isocyanoacetate 11g (Table 3).
Performing the cyclocondensation at elevated temperatures
proved successful in increasing the yield. Moreover, the dia-
stereoselectivity increased in favor of the cis-isomer. Concen-
tration of the reaction mixture and the use of a catalytic amount
of AgI did not lead to an increase in yield. AgI is expected to
coordinate to the isonitrile, thereby increasing the R-acidity of
the isocyanoacetate.28 This expected higher reactivity did not
result in improved yield, although a rather high selectivity was
obtained for the cis-diastereomer.
Further variation of the isocyanoacetate component was
investigated by applying isocyanoacetates bearing aliphatic
R4-substituents. Phosphonate 1a, nitrile 2a, and aldehyde 3b
were reacted with several R-alkyl isocyanoacetates leading to
DHP-2-ones 12q-u (Table 2, entries 1-5) in poor to reason-
able yields. In these examples (except for DHP-2-one 12s),
inseparable mixtures of diastereomers were obtained.26
The propensity of varying the nitrile and aldehyde compo-
nents was demonstrated using isocyanoacetate 11h (entries
6-9). Surprisingly, by changing either the nitrile or the alde-
hyde component a higher preference for the cis-diastereomer
was achieved. The use of 1-cyclohexene-1-carboxaldehyde 3f
(entry 8) afforded only the cis-diastereomer. The yields, how-
ever, were all lower compared to DHP-2-one 12u (entry 5).
(27) No clear side products could be isolated, although multiple spots on
thin-layer chromatography were visible.
(28) (a) Grigg, R.; Lansdell, M. I.; Thornton-Pett, M. Tetrahedron 1999,
55, 2025–2044. (b) Soloshonok, V. A.; Kacharov, A. D.; Avilov, D. V.;
Ishikawa, K.; Nagashima, N.; Hayashi, T. J. Org. Chem. 1997, 62, 3470–
3479.
(26) Only in the case of DHP-2-one 12r it was possible to get some pure
fractions of both diastereomers.
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SCHEME 6. (a) Asymmetric Induction Obtained in the Dihydropyrimidine MCR with Optically Pure (-)-Myrtenal. (B) the Absence of
Asymmetric Induction in the DHP-2-one MCR with Optically Pure (-)-Myrtenala
aOnly the 3,4-cis stereoisomers are formed; de 0% refers only to the asymmetric induction of the chiral aldehyde.
TABLE 2. MCR of Phosphonate 1a and Various Nitriles 2 and Aldehydes 3 with R-Alkyl Isocyanoacetates 11 at rt and Reflux
aIsolated yields. Assignment of the cis- and trans-diastereomers will be further discussed in the paragraph about structural analysis. bAfter addition of
the isocyanoacetate, the mixture was heated to reflux and the mixture was stirred at this temperature for 1 night. PMP = p-methoxyphenyl.
SCHEME 7. Follow-up Michael Addition of 12n-30
TABLE 3. Investigated Conditions of the Cyclocondensation Step
Using 1a, 2a, 3b, and 11g
conditionsa
yieldb (%)
dr (cis:trans)
rt
reflux
47
55
46
14
59:41
77:23
59:41
91:9
c
concentrated 2ꢀ
AgOAc (2 mol %)
aThe different conditions depicted are the conditions after addition of
the isocyanoacetate. bIsolated yields. The product is concentrated to
half its volume after 1-azadiene formation.
c
Since the yield and the diastereoselectivity were improved by
using elevated temperatures, all previous reactions were per-
formed utilizing these optimized conditions (Table 2). This
indeed resulted in an improved yield for most of the reactions.
Moreover, the diastereomeric ratio changed in favor of the cis-
diastereomer in the majority of examples that were tested.
The stereoselectivity in this multicomponent reaction
can likely be explained by steric considerations. Since the
stereochemistry is presumably introduced in the first
bond-forming step (Michael-type addition), the diastereo-
meric preference is based on kinetic grounds and the steric
bulk in the transition state of this step becomes important.
There seems to be a trend in steric bulk of the R-substituent of
the isocyanoacetate with the diastereoselectivity obtained.
When combining R-aryl isocyanoacetates with aromatic as
well as R,β-unsaturated aldehydes, a complete selectivity for
the cis-diastereomer is achieved.29 However, isocyanoacetate
(29) The high diastereoselectivity of reactions involving R-aryl isocya-
noacetates may also be the result of π-interaction in the transition state,
apparently favoring in the cis-diastereomer.
1728 J. Org. Chem. Vol. 75, No. 5, 2010

Scheffelaar et al.
JOCArticle
TABLE 4. Proton Affinity Energies (kcal/mol) of Molecules BH in the Gas Phase and THFa
aComputed at (COSMO-)BP86/TZ2P.
11h possessing a benzyl R-substituent did not give this
stereoselectivity (Table 2, entry 5). A possible rationalization
is that the steric bulk of the phenyl group is further away
from the chiral reaction center. The other R-alkyl isocya-
noacetates (11d,e,g) are apparently also less sterically con-
gested, resulting in mixtures of diastereomers (Table 2,
entries 1, 2, and 4). The steric background of the selectivity
is furthermore supported by the fact that reaction of iso-
cyanoacetate 11f (possessing an isopropyl group as the R-
substituent; Table 2, entry 3) resulted in the exclusive for-
mation of the cis-diastereomer. No clear explanation can be
given for the fact that a pronounced preference for the cis-
diastereomer was obtained upon changing R2 (nitrile) from
phenyl to isopropyl or a 2-furyl (Table 2, entries 5-7). The
exclusive formation of the cis-diastereomer when applying
aldehyde 3f (Table 2, entry 8) can be explained by the more
sterically demanding properties of the cyclohexen-1-yl sub-
stituent compared to benzaldehyde.
FIGURE 1. NOE correlations and H4-H5 coupling constants
generally observed for the cis- and trans-diastereomers of DHP-2-
ones 12 possessing aliphatic R4-substituents.
Increasing the temperature during the cyclocondensation
leads to a higher excess of the cis-diastereomer for DHP-2-
ones 12r,t,u,v,y. Epimerization of the C4 center of the DHP-2-
one may account for this observation, leading to the thermo-
dynamic product distribution. Alkaline species in the reaction
mixture, including the 1-azadiene and methoxide, are feasible
initiators. This epimerization does not occur when refluxing
the purified product in THF for one night, which indicates the
necessity of an external base. To prove the tendency of
epimerization under the reaction conditions, a crude reaction
mixture of 12u with a diastereomeric ratio (dr) of 61:39 was
refluxed for an additional night, resulting once more in a
diastereomeric ratio of 76:24. DHP-2-ones 12q and 12w did
not show a difference in dr at rt or reflux conditions, which
indicates that this is already the thermodynamic ratio.
To rationalize if alkaline species like methoxide and the
1-azadiene are indeed able to deprotonate the DHP-2-one at
the C4 position, proton affinity (PA) energies have been
calculated, using the ADF program,30 in the gas phase and in
THF using density functional theory (DFT) at BP86/TZ2P
in combination with the COSMO approach to simulate
solvation. The proton affinity (PA) energy of a molecule
BH is defined as the system’s energy change for the reaction
BHf B- þ Hþ. This means, the smaller the PA energy the
higher the concentration of B-, the higher the acidity of the
compound BH. Therefore, to be a good base, the PA energy
has to be higher than (or at least in the same range as) the PA
energy of the DHP-2-one (proton at the C4 center). Table 4
FIGURE 2. NOE correlations and H3-H4 coupling constants
observed for the cis- and trans-diastereomers of 12n.
shows the PA energy of MeOH, 1-azadieneHþ, and DHP-2-
ones 12u and 12q (cis and trans conformations are
calculated). These results suggest that in the gas phase as
well as in THF, methoxide is sufficiently basic to deproto-
nate the C4 position of the DHP-2-one, while the 1-azadiene
is not.
Structural Analysis. X-ray crystal structure determination
of DHP-2-one 12d unambiguously confirmed the cis-rela-
tionship between the isocyanide group and R3 (phenyl).9
Furthermore, NOESY experiments of all DHP-2-ones pos-
sessing an aromatic R4 substituent confirm the same stereo-
chemical relationship. In these cases, a clear NOE correla-
tion is visible between proton H4 and the ortho protons of
the aromatic R4 group (Figure 1a).
The use of R-alkyl isocyanoacetates in this MCR typically
leads to the formation of inseparable diastereomeric mixtures.
To deduce which peaks are derived from which diastereomer
and thereby determine the diastereomeric ratio, NOESY ex-
periments were also performed for all DHP-2-ones with ali-
phatic R4 substituents. In all examples the major diastereomer
showed a strong NOE correlation between proton H4 and the
R4 substituent, which is indicative for the cis-diastereomer
(30) Te Velde, G.; Bickelhaupt, F. M.; Baerends, E. J.; Fonseca Guerra,
C.; Van Gisbergen, S. J. A.; Snijders, J. G.; Ziegler, T. J. Comput. Chem.
2001, 22, 931–967.
(31) The other diastereomer showed only a weak correlation (or none at
all), which is expected for the trans-diastereomer (Figure 1b).
J. Org. Chem. Vol. 75, No. 5, 2010 1729

Scheffelaar et al.
JOCArticle
SCHEME 8. DHP-2-one 4CR with R-Acidic Esters As Fourth Component
TABLE 5. MCR of Phosphonate 1a, Nitrile 2a, Aldehyde 3b, and R-Acidic Esters 34a-c and Isocyanoacetates 11a and d (as a Comparison)
entry
ester
EWG
R3
R4
DHP-2-one
yield (%) (cis:trans)
1
2
3
4
5
34a
34b
34c
11a
11d
CO2Me
CN
CO2Me
NC
NC
Me
Et
Me
Me
Me
Me
Ph
Ph
Ph
Me
35a
35b
35c
12d
12q
17 (1:1)
7 (cis)
0
98 (cis)
31 (56:44)
(Figure 1a).31 This is supported by the observed difference in 1H
NMR chemical shifts of the H4 protons.
respectively, derived from the COSMO-optimized structures
in THF (DFT: BP86/TZ2P).35
Proton H4 of the minor (trans) diastereomer appeared
significantly more downfield compared to the major one (cis)
(generally for R-alkyl isocyanoacetates: δ(minor) = 4.2-4.4
ppm, δ(major) = 3.7-3.9 ppm).32 This higher chemical shift
in the trans diastereomer might be explained by the orienta-
tion of proton H4 in the deshielding region of the anisotropy
cone of the isocyanide (Figure 1b).
In all examples, there is also a distinct difference in coupling
constants between protons H4 and H5 of both diastereomers.
This coupling is typically around 4.8-6.8 Hz for the major
(cis) diastereomer and 2.8-4.0 Hz for the minor (trans)
diastereomer.33 Indeed, the torsion angle H4-C4-C5-H5
(-40.5(12)°) derived from the molecular structure of the
cis-diastereomer of DHP-2-one 12u (R4 = Bn) in the crystal
(see Figure S1 in the Supporting Information)34 corresponds
with this generally observed H4/H5 coupling constants of the
major cis-diastereomers (4.8-6.8 Hz).35
Application of Other r-Acidic Esters. Since R-isocyano
esters proved to be good reaction partners in the DHP-2-one
MCR, other R-acidic esters (34a-c) were considered as the
fourth, cyclizing component, as well (Scheme 8). By applying
34a-c in a similar procedure as described above, DHP-2-one
scaffolds possessing a different functionality at the C3 posi-
tion are expected. This evidently gives the possibility for
functionalization by different follow-up reactions than the
isocyanide-based reactions reported before.14-16
Although initially a similar R-reactivity of 34a-c com-
pared to 11a and d is expected, the former generates the
corresponding DHP-2-ones in much lower yields (0-17%
compared to 31-98%, respectively, Table 5).
DHP-2-one 35a was obtained in 17% yield (Table 5, entry 1)
together with 28% of ketone 38, which is plausibly formed
by hydrolysis of enamine intermediate 37 (Scheme 9). The
formation of ketone 38 is an important result regarding the
mechanism of the DHP-2-one MCR. It strongly suggests a
stepwise Michael type attack/lactamization pathway instead
of a concerted cycloaddition. Unfortunately, attempts to
facilitate the lactamization by performing the reaction at
elevated temperatures (60 °C) did not lead to better results.
Compound 35a was obtained as a 1:1 diastereomeric mix-
ture, suggesting that during lactamization the amine cannot
discriminate between the two ester functionalities.
DHP-2-one 12n (R4 = H) is also formed as a mixture of
two diastereomers (63:37). The major and minor diastereo-
mers could be assigned by NOESY experiments as well.
There is a clear NOE correlation between proton H3 and
H4 for the minor diastereomer that is absent for the major.
This correlation would be expected for the cis-diastereomer
as indicated in Figure 2a. The major diastereomer shows a
NOE correlation between proton H3 and the ortho protons
of the p-methoxyphenyl substituent, indicative for the trans-
diastereomer (Figure 2b).
The isolation of 35a and 38 (total yield 45%) using malo-
nate 34a indicate that the R-reactivity is not the limiting
Furthermore, there is a notable difference in coupling
constants between protons H3 and H4 (J (minor, cis) =
6.7 Hz; J (major, trans) = 12.4 Hz). These coupling con-
stants are consistent with the dihedral angles of 52° and 177°,
SCHEME 9. Proposed Mechanism for the Formation of DHP-
2-one 35a and Ketone 38
(32) Protons H4 of cis-DHP-2-ones with aromatic R4 substituents (δ =
4.0-4.6 ppm) appear more downfield than those of DHP-2-one with
aliphatic R4 substituents, probably because in the former case these protons
are deshielded by the aromatic R4 substituent.
(33) For cis-DHP-2-ones with aromatic R4 substituents the coupling
constant between protons H4 and H5 is generally between 4.0 and 6.0 Hz.
(34) (a) The cis-diastereomer was selectively crystallized from a solution
containing a 83:17 (cis:trans) mixture of diastereomers; (b) CCDC 751206
contains 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.
(35) This assumption is made based on the standard Karplus Curve; see:
Basic One- and Two-Dimensional NMR Spectroscopy, 3rd revised ed.;
Friebolin, H., Ed.; Wiley-VCH: Weinheim, 1998.
1730 J. Org. Chem. Vol. 75, No. 5, 2010

Scheffelaar et al.
JOCArticle
Conclusion
The new 4CR described here provides access to a broad
range of functionalized DHP-2-ones. Variation of the nitrile
(R2) and aldehyde (R3) inputs proved to be extensively
possible but variation of the phosphonate (R1) input remains
limited. The use of the chiral aldehyde, (-)-myrtenal, did not
result in any stereoinduction. When using aromatic isocya-
noacetates (R4) the DHP-2-ones were obtained in moderate
to high yields with a complete cis-diastereoselectivity. The
use of aliphatic isocyanoacetates (R4 = alkyl) gave the pro-
ducts in moderate to reasonable yields generally as mixtures
of diastereomers. However, elevated temperatures during
the cyclocondensation typically resulted in higher yields and
an improved diastereomeric ratio in favor of the cis-diaster-
eomer. This is most likely the result of epimerization of the
C4 stereocenter leading to the thermodynamically more
stable isomer.
The use of R-acidic esters other than R-isocyano esters
(malonate and R-cyanoacetate) also proved possible,
although these reactions afforded the corresponding DHP-
2-ones in much lower yields. Computational results can not
yet explain the observed difference in reactivity. Future
efforts will focus on developing a deeper understanding of
reaction mechanisms based on experimental and computa-
tional findings as a tool in novel multicomponent reaction
design.
FIGURE 3. Masses observed in the LCMS of the crude reaction
mixture of entry 3, Table 4, and their proposed structures.
factor using this reaction input. Most likely, the increased
steric bulk, resulting from the substitution of a linear isonitrile
(in 11d) for a methyl ester (in 34a), results in a more sluggish
lactamization of 37.
DHP-2-one 35b36 (Table 5, entry 2), was formed in 7%
yield together with various side products, which could not be
identified. Remarkably, DHP-2-one 35c (Table 5, entry 3)
was not formed at all according to LC-MS analysis of the
crude reaction mixture (ESI, 60% MeOH in H2O). Exami-
nation of the masses of all peaks indicate the presence of
enamine 39 (M þ Hþ = 416.1) (Figure 3). Moreover, three
peaks were observed with a mass of 209.0 which may
originate from dimethyl phenylmalonate 34c and 1,3-di-
phenyl-2-propenone 40, formed by hydrolysis of the inter-
mediate 1-azadiene. The formation of enamine 39 provides
additional support for our proposed mechanism.
Experimental Section
The poor results by applying 34b,c compared to isonitrile
equivalents 11a,d may originate from the differences in
acidity and reactivity of the R-acidic esters. To investigate
this in more detail, we calculated the proton affinity energies
(in the gas phase and THF), the orbital energy of the highest
occupied molecular orbital (HOMO) of its carbanion,
and the percentage of the 2pz orbital on the reacting carbon
atom in the HOMO of the carbanion (%2pz).37 Thus, a lower
PA energy is associated with a higher carbanion abundance
General Information. All reactions were carried out under an
inert atmosphere of dry argon. Standard syringe techniques
were applied for transfer of air-sensitive reagents and dry
solvents. Melting points are uncorrected. Infrared (IR) spectra
are measured in KBr, and wavelengths (ν) are reported in cm-1
.
1H and 13C nuclear magnetic resonance (NMR) spectra were
recorded at 250.13 or 400.13 MHz and 62.90 or 100.62 MHz,
respectively, with chemical shifts (δ) reported in ppm down
field from tetramethylsilane. Peak assignment was also done
with the aid of gs-COSY, gs-HMQC, and gs-HMBC measure-
ments. Assignment of relative stereochemistry was achieved
using gs-NOESY measurements. Electron impact (EI) mass
spectrometry was carried out with an electron ionization vol-
tage of 70 eV. MS (ESI) spectra were recorded on a liquid
chromatograph mass spectrometer. Chromatographic purifica-
tion refers to flash chromatography using the indicated solvent
(mixture) and silica gel (40-63 μm, 60 A). Thin layer chroma-
tography was performed using silica plates (silica on aluminum
with fluorescence indicator). Compounds on TLC were visua-
lized by UV-detection. THF was dried and distilled from sodium
benzophenone ketyl prior to use. Benzonitrile was dried with
MgSO4 and then distilled from P2O5 under reduced pressure.
Isobutyronitrile and 2-furaldehyde were both distilled prior to
use. Other commercially available reagents were used as pur-
chased. Experimental details of compounds 12a-n have been
reported elsewhere.9
(active species), whereas a higher HOMO energy (εHOMO
)
and carbanion localization (%2pz) leads to a higher
intrinsic reactivity of the carbanion. Although in previous
studies10b we found a reasonable correlation using similar
calculations, in this case, neither the trends in each of the
parameters PA energy, εHOMO, and %2pz nor combina-
tions thereof led to a consistent correlation with the experi-
mental yields. This strongly suggests that other factors are
decisive for the differences in yield, such as, a more subtle
interplay between electronic and steric factors along the
reaction coordinates and/or the onset of alternative compet-
ing pathways. These issues are to be tackled in future
computational studies focusing on the exploration of the
conceivable network of competing mechanistic pathways
toward DHP-2-ones and their kinetic and thermodynamic
parameters.
General Procedure I for the Synthesis of 3,4-Dihydropyridin-2-
ones. All reactions were carried out at a concentration of 0.2 M
of phosphonate 1, 0.24 M of n-BuLi, 0.22 M of nitrile 2, 0.22 M
of aldehyde 3, and 0.22 M of isocyanoacetate 11 (or malonate/
cyanoacetate 34) in dry THF. A 1.0 mmol portion of the limiting
reaction component, the phosphonate, was used. of n-BuLi (1.2
equiv, 1.6 M solution in hexane) was added at -78 °C to a stirred
solution of phosphonate in THF. After the mixture was stirred
at -78 °C for 1.5 h, the nitrile (1.1 equiv) was added and the
mixture was then stirred at -78 °C for 45 min, at -40 °C for 1 h,
(36) Although the stereochemistry of DHP-2-one 35b was not determined
using NOE experiments, it is expected to have the same cis-diastereoselec-
tivity as the DHP-2-ones prepared with R-aryl isocyanoacetates. The cou-
pling constant between H4 and H5 is 4.4 Hz, which is similar to its isonitrile
variant (4.5 Hz). In addition, the chemical shift value of the H4 proton is
identical (4.34 vs 4.32 ppm).
(37) A table with these values is presented in the Supporting Information.
In addition to the mentioned R-acidic esters, the same parameters are
calculated for 11c and 34a.
J. Org. Chem. Vol. 75, No. 5, 2010 1731

Scheffelaar et al.
JOCArticle
and at -5 °C for 30 min. The aldehyde (1.1 equiv) was added,
and after being stirred at -5 °C for 30 min, the mixture was
allowed to warm to rt and stirred for 1.5 h. Finally, the
isocyanoacetate (or malonate/cyanoacetate) (1.1 equiv) was
added, and the mixture was stirred overnight either at rt or at
reflux. The reaction mixture was concentrated in vacuo (water
bath at rt) and the crude product purified by column chroma-
tography.38
3,4-Dihydropyridin-2-one 12o. According togeneralprocedure
I, reaction between phosphonate 1b, n-BuLi, benzonitrile 2a,
benzaldehyde 3b, and isocyanoacetate 11a, followed by column
chromatography (c-hexane/EtOAc = 9:1f8:2) afforded 12o as a
yellow solid (43 mg, 0.12 mmol, 12%): mp 178-180 °C; 1H NMR
(250 MHz, CDCl3) δ (ppm) 7.69-7.66 (m, 2H), 7.50-7.37 (m,
11H), 7.26-7.18 (m, 3H), 3.97 (s, 1H), 1.67 (s, 3H); 13C NMR (63
MHz, CDCl3) δ 163.8 (C), 161.5 (C), 136.8 (C), 135.3 (C), 134.2
(C), 131.1 (C), 129.7 (CH), 129.3 (3 CH), 129.2 (4 CH), 129.1 (2
CH), 128.8 (CH), 128.4 (2 CH), 125.8 (2 CH), 113.0 (C), 70.4 (C),
56.6 (CH), 18.0 (CH3); IR (KBr) 2141 (w), 1691 (s), 1494 (w),
1447 (w), 1385 (w), 1372 (w), 1280 (w), 1266 (w), 766 (w), 752 (m),
698 (m); HRMS (EI, 70 eV) calcd for C25H20N2O (Mþ) 364.1570,
found 364.1575.
3,4-Dihydropyridin-2-one 12q. According togeneralprocedure
I, reaction between phosphonate 1a, n-BuLi, benzonitrile 2a,
benzaldehyde 3b, and isocyanoacetate 11c, followed by column
chromatography (c-hexane/ EtOAc = 9:1f8:2) afforded 12q at
rt as a yellow solid (88 mg, 0.31 mmol, 31%, cis:trans = 56:44)
and at reflux as a orange solid (118 mg, 0.41 mmol, 41%, cis:trans
= 56:44:. 1H NMR (400 MHz, CDCl3) δ 7.49-7.33 (m, 11H þ
11H), 5.64-5.62 (m, 1H þ 1H), 4.24 (d, J = 4.0 Hz, 1H, minor),
3.79 (d, J = 4.8 Hz, 1H, major), 1.73 (s, 3H, major), 1.46 (s, 3H,
minor);13C NMR (63MHz, CDCl3) δ 167.0 (C, minor), 166.2(C,
major), 160.9 (C, major), 159.7 (C, minor), 137.2 (C), 136.8 (C),
136.4 (C), 135.6 (C), 133.7 (2 C), 129.8 (2 CH), 129.7 (2 CH),
129.3 (4 CH), 129.2 (2 CH), 128.9 (2 CH), 128.8 (2 CH), 128.6 (2
CH), 125.3 (2 CH), 125.2 (2 CH), 105.2 (CH, major), 105.0 (CH,
minor), 63.2 (C, minor), 63.0 (C, major), 50.5 (CH, major), 49.8
(CH, minor), 24.5 (CH3, major), 20.2 ppm (CH3, minor); IR
(KBr) 2148 (w), 2130 (m), 1687 (s), 1655 (m), 759 (m), 700 (m);
HRMS (EI, 70 eV) calcd for C19H16N2O (Mþ) 288.1257, found
288.1254.
(d, J = 3.91 Hz, 1H), 3.77 (s, 3H), 3.43 (s, 3H), 1.61 (s, 3H), 1.27
(s, 3H); 13C NMR (101 MHz, CDCl3) δ 173.3 (C), 171.3 (C),
171.0 (C), 170.8 (C), 139.7 (C), 137.9 (C), 137.3 (C), 137.1 (C),
135.1 (C), 134.8 (C), 129.6 (CH), 129.5 (CH), 129.4 (2 CH), 129.4
(6 CH), 129.1 (2 CH), 128.7 (2 CH), 128.1 (2 CH), 125.6 (2 CH),
125.5 (2 CH), 106.9 (CH), 105.8 (CH), 55.0 (C), 54.6 (C), 53.2
(CH3), 52.4 (CH3), 50.9 (CH), 47.1 (CH), 21.2 (CH3), 17.5
(CH3); HRMS (EI, 70 eV) calcd for C20H19NO3 (Mþ)
1
321.1359, found 321.1371. 38: H NMR (400 MHz, CDCl3) δ
7.93-7.91 (m, 2H), 7.53-7.37 (m, 3H), 7.26-7.15 (m, 5H), 4.19
(X part of ABX, JAX = 3.0 Hz, JBX = 11.0 Hz, 1H), 3.76 (A part
of ABX, JAB = 17.1 Hz, JAX = 11.0 Hz, 1H), 3.76 (s, 3H), 3.65
(s, 3H), 3.57 (B part of ABX, JAB = 17.1 Hz, JBX = 3.0 Hz, 1H),
1.44 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 197.8 (C), 172.1 (C),
171.9 (C), 139.1 (C), 137.1 (C), 133.0 (CH), 129.4 (2 CH), 128.6
(2 CH), 128.3 (2 CH), 128.2 (2 CH), 127.4 (CH), 58.1 (C), 52.6 (2
CH3), 45.7 (CH), 41.2 (CH2), 19.69 (CH3); MS (ESI) 377.1 (M þ
Naþ), 355.1 (M þ Hþ), 209 (C15H13Oþ).
3,4-Dihydropyridin-2-one 35b. According to general proce-
dure I, reaction between phosphonate 1a, n-BuLi, benzonitrile
2a, benzaldehyde 3b, and ethyl phenylcyanoacetate 34b, fol-
lowed by column chromatography (c-hexane f chexane/EtOAc
8:2), afforded at rt 35b as a white foam (23 mg, 0.07 mmol, 7%):
1H NMR (250 MHz, CDCl3) δ 7.69 (br s, 1H), 7.52-7.35
(m, 10H), 7.32-7.18 (m, 5H), 5.76 (dd, J = 1.6, 4.4 Hz, 1H),
4.34 (d, J = 4.4 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 165.2
(C), 137.8 (C), 137.0 (C), 134.4 (C), 134.0 (C), 130.1 (CH), 129.6
(2 CH), 129.3 (3 CH), 129.2 (2 CH), 129.1 (2 CH), 128.8 (CH),
127.58 (2 CH), 125.6 (2 CH), 117.1 (C), 105.9 (CH), 56.5 (C),
50.8 (CH); HRMS (EI, 70 eV) calcd for C24H18N2O (Mþ)
350.1414, found 350.1423.
Acknowledgment. This work was performed with finan-
cial support from the Netherlands Organization for Scientific
Research (NWO, VICI grant). M. C. Smoluch (Vrije Universi-
teit Amsterdam) is kindly acknowledged for HRMS measure-
ments. M.L. and A.L.S. were financially supported by NWO-
CW. F.M.B. and C.F.G. thank the National Research Combi-
nation - Catalysis (NRSC-C) for a postdoctoral fellowship for
C.F.G. and The Netherlands Organization for Scientific Re-
search (NWO-CW and NWO-NCF) for further financial sup-
port.
3,4-Dihydropyridin-2-one 35a. According to general proce-
dure I, reaction between phosphonate 1a, n-BuLi, benzonitrile
2a, benzaldehyde 3b, and dimethyl methylmalonate 34a fol-
lowed by column chromatography (c-hexane f chexane/EtOAc
8:2) afforded at rt 35a as an orange foam (56 mg, 0.17 mmol,
17%, cis:trans = 50:50) and 38 as a white foam (101 mg, 0.28
Supporting Information Available: Detailed experimental
procedures for compounds 12p and 12r-y and X-ray crystal-
lographic data for compound 12u. Copies of 1H NMR and 13
C
1
mmol, 28%). 35a: H NMR (250 MHz, CDCl3) δ 7.97 (br s,
NMR spectra for compounds 12o-y, 35a, 35b, and 38 and
Cartesian coordinates and total energies for compounds 12q (cis
and trans), 12u (cis and trans), 1-azadiene, MeOH, 11a,c,d, and
34a-c. This material is available free of charge via the Internet
at http://pubs.acs.org.
1H þ 1H), 7.51-7.22 (m, 10H þ 10H), 5.67 (dd, J = 1.4, 5.17
Hz, 1H), 5.55 (d, J = 2.2 Hz, 1H), 4.41 (d, J = 5.20 Hz, 1H), 3.88
(38) Major and minor peaks in the 1H NMR and 13C NMR are denoted
where possible.
1732 J. Org. Chem. Vol. 75, No. 5, 2010