Nucleophilic properties of a nonstabilized azomethine ylide derived from sarcosine and cyclohexanone. A novel domino reaction leading to substituted 4-aryl-2-pyrrolidones

Article abstract of DOI:10.1016/j.tetlet.2012.05.008

A nonstabilized asymmetric azomethine ylide derived from sarcosine and cyclohexanone reacts with 3-substituted coumarins and ethyl benzylidene malonate to give 4-aryl-2-pyrrolidones in moderate yields, and the adducts of classical 1,3-dipolar cycloadditions as the minor products. The main reaction proceeds via a domino process, starting with 1,4-nucleophilic addition to the conjugated double bond, and represents the first example of the nucleophilic properties of a nonstabilized azomethine ylide.

Full text of DOI:10.1016/j.tetlet.2012.05.008

Tetrahedron Letters 53 (2012) 3568–3572
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Tetrahedron Letters
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Nucleophilic properties of a nonstabilized azomethine ylide derived from
sarcosine and cyclohexanone. A novel domino reaction leading to substituted
4-aryl-2-pyrrolidones
Vladimir S. Moshkin a, , Vyacheslav Ya. Sosnovskikh a, Gerd-Volker Röschenthaler b
⇑
a Department of Chemistry, Ural Federal University, pr. Lenina 51, 620083 Ekaterinburg, Russia
b School of Engineering and Science, Jacobs University Bremen, 28759 Bremen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
A nonstabilized asymmetric azomethine ylide derived from sarcosine and cyclohexanone reacts with 3-
substituted coumarins and ethyl benzylidene malonate to give 4-aryl-2-pyrrolidones in moderate yields,
and the adducts of classical 1,3-dipolar cycloadditions as the minor products. The main reaction proceeds
via a domino process, starting with 1,4-nucleophilic addition to the conjugated double bond, and repre-
sents the first example of the nucleophilic properties of a nonstabilized azomethine ylide.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 7 February 2012
Revised 5 April 2012
Accepted 2 May 2012
Available online 11 May 2012
Keywords:
Nonstabilized asymmetric azomethine ylide
Domino reaction
4-Aryl-2-pyrrolidones
1,4-Nucleophilic addition
3-Substituted coumarins
[3+2] Cycloaddition
R2
NH
There are three main types of decarboxylative reactions of
-amino acids with carbonyl compounds, which proceed via the
R1
O
a
formation of intermediate nonstabilized azomethine ylides, and
then depending on the reaction conditions, lead to different prod-
ucts. The first type is the Strecker amino acid degradation resulting
in amino acetal formation, which hydrolyzes to give an aldehyde
containing one carbon atom less than the starting amino acid.1
However, in this case the intermediacy of a nonstabilized azome-
thine ylide is rare, and the process has no wide synthetic applica-
tion.1b,d,e The second type are the [3+2] cycloadditions, which have
been investigated extensively by Rizzi, Grigg, Tsuge, and others
(Scheme 1).2 The third type are 1,5- and 1,7-electrocyclizations
of conjugated azomethine ylides.3
The 1,3-dipolar cycloaddition and electrocyclization reactions
are carried out in an inert aprotic medium with the removal of
water; the azomethine ylide either reacts with the dipolarophile
or cyclizes intramolecularly, due to its inability to take part in ionic
interactions. In contrast, Strecker amino acid degradation assisted
by carbonyl compounds is performed in an alcoholic or aqueous
medium, resulting in hydrolysis of the intermediate azomethine
ylide with formation of an aldehyde. In 1979, Cohen reported on
the reaction of proline with o-hydroxyacetophenones (a process
similar to Strecker decarboxylation).4 The azomethine ylide
intermediate was able to deactivate its negative charge by
+
CO2H
R3
- H2O - CO2
R2
N
R2
N
R1
R1
R3
R3
R4
X=O,
CH(EWG)
X
H+
R2
N
R2
N
R1
H
H
R1
R4
R3
R3
Nu
X
+
R2
N
R2
N
R1
R3
R1
X
Nu R3
R4
Rizzi,
Grigg,Tsuge
Strecker,
Cohen, Seidel
⇑
Corresponding author. Fax: +7 343 261 59 78.
E-mail address: mvslc@mail.ru (V.S. Moshkin).
Scheme 1. Decarboxylative reactions of
a
-amino acids with carbonyl compounds.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.05.008

V. S. Moshkin et al. / Tetrahedron Letters 53 (2012) 3568–3572
3569
Me
In the course of our work on the reactions of nonstabilized
azomethine ylides with 3-substituted coumarin,7 we attempted
the reaction with the asymmetric nonstabilized azomethine ylide
derived from cyclohexanone and sarcosine. Surprisingly, only one
reaction of this ylide was known previously2f in which N-(p-
tolyl)maleimide gave the normal product of 1,3-dipolar cycloaddi-
tion in high yield (Scheme 2). Unexpectedly, we found that diethyl
O
N
O
MeNHCH2CO2H
O
N
Ph
N
Ph
O
O
(91%)
ref. 2f
coumarin-3-phosphonate
1 (1 equiv) reacted with sarcosine
(3 equiv) and cyclohexanone (1 equiv) in boiling toluene for 48 h
to form pyrrolidone 2 as the main product (47%) and a second
product of the classical [3+2] cycloaddition, 3 (20%).8,9 Compounds
2 and 3 were isolated by column chromatography on silica gel and
identified on the basis of 1H, 31P, and 13C NMR, MS, IR and elemen-
tal analyses, as well as 2D 1H–13C HMQC, HMBC, and 1H–1H NOESY
experiments. When this reaction was carried out in the presence of
(i-Pr)2NEt (DIPEA) (0.5 equiv) for 36 h followed by acidification
with HCl (5 equiv), pyrrolidone 2 was isolated by simple filtration
in 39% yield. In this case, the cycloaddition product 3 was obtained
in a yield of 14% from the aqueous layer by neutralization with
NaHCO3 and subsequent flash chromatography on silica gel
(Scheme 2).
Such an atypical property of this nonstabilized azomethine
ylide is clearly associated with its structure as well as that of the
activated alkene. The more nucleophilic center of the intermediate
ylide A (Scheme 3) located on the terminal carbon atom, and favor-
able electronic orientation of the interacting molecules in the tran-
sition state of the reaction is associated with unfavorable steric
interactions between the axial hydrogens and functional group of
PO(OEt)2
CO2H
NH
O
+
+
O
O
Me
1
Me
Me
N
N
OH
O
PO(OEt)2
+
PO(OEt)2
(47%)
O
O
2
3 (20%)
Scheme 2. Reactions of azomethine ylide derived from cyclohexanone and
sarcosine.
protonation and demonstrated electrophilic properties relative to
the internal nucleophile (phenolate anion). Only in the last 5 years
has this chemistry achieved momentum.5 In particular, Seidel ex-
panded the reaction scope to various C-nucleophilic compounds
and increased significantly the synthetic utility of azomethine
ylides in non-pericyclic reactions.6 It would be logical to assume
the existence of nucleophilic properties in nonstabilized azome-
thine ylides, however, to the best of our knowledge, examples of
such reactions have not been published to date.
the coumarin. Additionally, ylide A contains hydrogens at the
a-
position which are able to eliminate with concomitant deactivation
of the cationic center and loss of the dipolar properties of the azo-
methine ylide. The combination of these factors prevents forma-
tion of the 1,3-dipolar cycloaddition product with structure 4.
O
O
N
CO2H
O
+
NH
- H2O
Me
Me
- CO2
base
Me
H2C
H
Me
N
Me
N
Me
CH2
N
N
H
H
A
PO(OEt)2
O
PO(OEt)2
O
PO(OEt)2
O
O
PO(OEt)2
O
O
3
4
O
O
1
(without base)
~H+
base
Me
NH
Me
N
H
Me
Me
N
N
OH
OH
H
O
PO(OEt)2 ~H+
CO2H
PO(OEt)2
O
2H2O
PO(OEt)2
- C6H10
O
- H2O
PO(OEt)2
O
O
O
2
B
C
D
Side process:
H
Me
Me
Me
HN
Me
CH2
H2O
- C6H10
N
N
Me
O
A
Scheme 3. A plausible reaction route.

3570
V. S. Moshkin et al. / Tetrahedron Letters 53 (2012) 3568–3572
Instead, 1,4-nucleophilic addition to the activated double bond of
the coumarin took place.
aromatic protons of the phenolic fragment (Fig. 1). Due to the dif-
ferent spatial environments, the ethoxy hydrogens were not equiv-
alent and they had different chemical shifts and spin–spin
couplings according to the 1H NMR spectrum, as has been previ-
ously described for related structures.11 An interesting feature of
the structure of compound 2 is the presence of free phenolic hy-
droxy and phosphonate groups, which could in principle form a
cyclic phosphate, however under these conditions this does not oc-
cur. A 1H–13C HMQC experiment was performed to assign the sig-
nals of the 13C NMR spectrum and to provide additional
confirmation of the location of the protons. The regiochemistry
was confirmed by the 1H–13C HMBC experiment. Evidence for the
trans arrangement of the two substituents in pyrrolidone 2 was ob-
tained from the 1H–1H NOESY data, which showed clearly visible
differences between the intensities of the benzylic proton cross-
peaks with three vicinal neighbors.
To study the steric requirements and the scope of the process
we carried out reactions of cyclohexanone and sarcosine with ben-
zylidene malonate 5, 3-ethoxycarbonylcoumarin (6), and 3-ben-
zoylcoumarin (7) (Scheme 4). Substituted 4-aryl-2-pyrrolidones
were obtained in all reactions, but each case had its own peculiar-
ities. The reactions of diethyl benzylidene malonate (5) and 3-eth-
oxycarbonylcoumarin (6) were accompanied by nucleophilic
attack of dimethylamine on the carbonyl groups and led to the
pyrrolidones 8 and 9, respectively. Dimethylamine evolves as a re-
sult of a side process (Scheme 3) and is an active nucleophile to-
ward the carbonyls of the starting materials and intermediates. It
should be noted that in the case of the phosphonate 1, we did
not detect even a trace of phosphoramide in view of the much low-
er susceptibility of the phosphonate group to nucleophilic attack
by secondary amines. 3-Benzoylcoumarin (7) gave pyrrolidone 10
in equilibrium with its cyclic tautomer 100 (ratio 85:15).12
Due to the presence of water in the medium, enamine C under-
went hydrolysis with regeneration of cyclohexanone. Next, the
amino group of intermediate D attacks the carboxylic group and
cyclization finishes the domino-process to give trans-substituted
pyrrolidone 2. This reaction represents a new approach to the syn-
thesis of a 2-pyrrolidone ring, and 4-aryl-2-pyrrolidones are partic-
ularly interesting due to their biological activity. For example,
commercial drugs such as phenotropil, cebaracetam, rolipram,
and lidanserin contain this moiety.10
It should be noted that after boiling for 24 h the ratio of pyrrol-
idone 2 to pyrrolidine 3 was 2.4:1, and after 48 h was 2.7:1 (Ta-
ble 1). It can be assumed that the formation of pyrrolidone 2 was
catalyzed by the presence of a base which had formed by 1,3-dipo-
lar cycloaddition and an intramolecular [1,4]-H shift in the azome-
thine ylide A (Scheme 3, side process). A threefold increase in the
concentration of the reagents improved slightly the yield of the de-
sired product and the rate of reaction increased (entry 3). Addition
of 0.5 equiv of DIPEA resulted in a further increase in the reaction
rate and the quantity of pyrrolidone 2 (entry 4). Based on these
data, we concluded that the preliminary intermolecular deproto-
nation of ylide A or deactivation of the ionic centers after reaction
with the coumarin is more likely than intramolecular 1,6- or 1,8-
migration of the proton in intermediate B.
The experiment with the addition of 0.5 equiv of cyclohexanone
led to the same ratio of products as with 1.0 equiv, but the reaction
rate decreased, according to amount of starting coumarin (entries 4
and 6). Heating of sarcosine and diethyl coumarin-3-phosphonate
without cyclohexanone led to no reaction, and therefore confirmed
its participation in the formation of product 2. Thus, it can be
assumed that cyclohexanone is the catalyst for this domino
reaction.
Along with the pyrrolidones 8–10, the adducts of 1,3-dipolar
cycloaddition 11–13 were obtained in each reaction in 7–17%
yields. Products 8–10 were isolated by column chromatography.
The 1H NMR spectrum of compound 2 contained characteristic
signals due to four protons of the pyrrolidone ring and shielded
Table 1
31P NMR spectroscopic analysis of the reaction products
Entry
Conditions
Solvent
Time (h)
Product ratio by 31P NMR
2
3
1
1
2
3
4
5
6
7
8
9
1 equiv C6H10
1 equiv C6H10
Conc. increased threefold
0.5 equiv (i-Pr)2NEt, 1 equiv C6H10
0.5 equiv (i-Pr)2NEt, 1 equiv C6H10
0.5 equiv (i-Pr)2NEt, 0.5 equiv C6H10
without C6H10
1 equiv C6H10
1 equiv C6H10O, 80 °C
1 equiv C6H10O, 120 °C
O
O
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
s-BuOH
DMSO
DMSO
24
48
24
24
36
24
24
24
3
2.4
2.7
2.8
3.1
3.1
3.0
0
1
1
1
1
1
1
0
0
0
3.6
1.1
1.8
1.2
0.6
1.6
1
O
O
O
O
O
0
0
1
1
10
3
Complex mixture of products
Cross-peaks present in
the 2D NOESY 1H-1H spectrum
1H NMR (400 MHz, CDCl3)
3.47 (ddd, J = 9.5, 5.7, 2.3 Hz)
H
H
H
O
H
H
3.73 (t, J = 9.3 Hz)
N
H
2.86 (d, J = 1.5 Hz)
Me
N
H
H
H
H
OH
Ar protons
6.77-7.11 ppm
O
PO(OEt)2
3.39 (dd, J = 21.9, 6.8 Hz)
H
H
OH
PO(OEt)2
3.90-4.00 (m)
Figure 1. Spectral data of pyrrolidone 2.
red - strong NOE,
blue - weak NOE interactions
8.76 (br s)

V. S. Moshkin et al. / Tetrahedron Letters 53 (2012) 3568–3572
3571
Me
N
Me
N
CO2Et
CO2Et
O
Ph
MeNHCH2CO2H
+
CO2Et
C6H10O
Me
N
CO2Et
O
5
Me
8
(37%)
11
(16%)
Me
N
Me
N
OH
CO2Et
O
MeNHCH2CO2H
C6H10
+
Me
O
CO2Et
O
O
O
N
O
O
Me
6
9
12
(17%)
(30%)
Me
N
Me
N
Me
N
OH
COPh
O
O
O
MeNHCH2CO2H
C6H10
+
+
COPh
O
O
OH
Ph
O
Ph
O
O
O
7
13 (7%)
10 (49%)
10'
Scheme 4. Another examples of nucleophilic properties of the nonstabilized azomethine ylide.
Their 1H NMR spectra resembled closely the spectrum of pyrroli-
done 2 and contained characteristic signals for the four protons
of the 2-pyrrolidone ring. Additionally, 13C, 1H–13C HMQC and
1H–1H NOESY NMR spectra were recorded for compounds 8–13.
Reactions of diethyl coumarin-3-phosphonate 1 and cyclohexa-
none with proline or glycine led to mixtures of more than five
products, according to 31P NMR spectroscopy. In the case of pro-
line, this may be explained by the formation of additional diaste-
reomers during the 1,3-dipolar cycloaddition and the presence of
3. (a) Anaç, O.; Güngör, F. Sß. Tetrahedron 2010, 66, 5931–5953; (b) Pinho e Melo, T.
M. V. D. Eur. J. Org. Chem. 2006, 2873–2888.
4. Cohen, N.; Blount, J. F.; Lopresti, R. J.; Trullinger, D. P. J. Org. Chem. 1979, 44,
4005–4007.
5. (a) Zheng, L.; Yang, F.; Dang, Q.; Bai, X. Org. Lett. 2008, 10, 889–892; (b) Mao, H.;
Wang, S.; Yu, R.; Lv, H.; Xu, R.; Pan, Y. J. Org. Chem. 2011, 76, 1167–1169; (c)
Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008, 130, 416–417; (d)
Deb, I.; Coiro, D. J.; Seidel, D. Chem. Commun. 2011, 47, 6473–6475.
6. (a) Zhang, C.; Seidel, D. J. Am. Chem. Soc. 2010, 132, 1798–1799; (b) Das, D.;
Richers, M. T.; Ma, L.; Seidel, D. Org. Lett. 2011, 13, 6584–6587; (c) Zhang, C.;
Das, D.; Seidel, D. Chem. Sci. 2011, 2, 233–236.
7. Moshkin, V. S.; Sosnovskikh, V. Ya.; Slepukhin, P. A.; Röschenthaler, G.-V.
Mendeleev Commun. 2012, 22, 29–31.
protons at the a-position of the pyrroline ring; in the case of gly-
8. General procedure:
A mixture of the corresponding coumarin or diethyl
cine—a less stable N-protonated intermediate ylide. We conclude
that further efforts should be directed to develop a more effective
catalyst for this new reaction to increase the yield of the desired
pyrrolidones and the scope of the amino acids.
Thus, we have reported a novel domino reaction consisting of
two successive attacks of the methylaminomethyl anion species
from sarcosine (via its C- and N-centers) to an activated alkene
to give substituted pyrrolidones. The nucleophilic properties of
nonstabilized azomethine ylides have been described for the first
time, and continued studies are in progress.
benzylidene malonate (1.0 mmol), cyclohexanone (0.10 g, 1.0 mmol), finely
ground sarcosine (0.27 g, 3.0 mmol) and DIPEA (0.06 g, 0.5 mmol) was refluxed
in dry toluene (3.3 mL) with magnetic stirring and removal of the water formed
by means of a Dean–Stark trap. Refluxing was continued for 24–48 h. The
resulting mixture was cooled to room temperature and filtered. The solution
was evaporated in vacuo to give a viscous mixture of crude products, which
were isolated by column chromatography on silica gel.
9. Diethyl [(3R⁄,4S⁄)-4-(2-hydroxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]phospho-
nate (2): This compound was prepared from coumarin 1 according to the
general procedure (48 h), except DIPEA was not employed. White crystals, yield
47%, mp 129–133 °C; IR: 3158, 1686, 1459, 1219, 1052, 1022, 774 cm–1 1H
;
NMR (400 MHz, CDCl3) d 1.20 (t, 3H, Me, J = 7.1 Hz), 1.28 (t, 3H, Me, J = 7.1 Hz),
2.86 (d, 3H, NMe, J = 1.5 Hz), 3.39 (dd, 1H, H-3, J = 21.9, 6.8 Hz), 3.47 (ddd, 1H,
5-CHH, J = 9.5, 5.7, 2.3 Hz), 3.73 (t, 1H, 5-CHH, J = 9.3 Hz), 3.90–4.00 (m, 1H, H-
4), 3.99–4.11 (m, 2H, OCH2), 4.19 (quin, 2H, OCH2, J = 7.1 Hz), 6.77 (t, 1H, H-50,
J = 7.5 Hz), 6.96 (dd, 1H, H-30, J = 8.0, 1.1 Hz), 7.04–7.11 (m, 2H, H-60, H-40), 8.76
(br s, 1H, OH); 13C NMR (101 MHz, CDCl3) d 16.3 (d, OCH2Me, J = 6.2 Hz), 16.4
(d, OCH2Me, J = 6.1 Hz), 30.0 (NMe), 35.3 (C4), 46.9 (d, C3, J = 143.5 Hz), 54.4 (d,
C5, J = 7.1 Hz), 62.8 (d, OCH2, J = 6.8 Hz), 63.5 (d, OCH2, J = 6.5 Hz), 116.6 (C30),
119.7 (C50), 127.5 (d, C10, J = 5.7 Hz), 128.6 (C60), 128.7 (C40), 155.2 (C20), 169.5
(d, C2, J = 3.0 Hz); 31P NMR (162 MHz, CDCl3) d 25.54 (PO(OEt)2). Anal. Calcd for
Acknowledgment
This work was supported financially by the DFG RO 362/50/1.
References and notes
C
15H22NO5Pꢀ0.5H2O: C, 53.57; H, 6.89; N, 4.16. Found: C, 53.52; H, 6.97; N, 4.20.
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2. (a) Rizzi, G. P. J. Org. Chem. 1970, 35, 2069–2072; (b) Grigg, R.; Thianpatanagul,
S. J. Chem. Soc., Chem. Commun. 1984, 180–181; (c) Grigg, R.; Aly, M. F.;
Sridharan, V.; Thianpatanagul, S. J. Chem. Soc., Chem. Commun. 1984, 182–183;
(d) Grigg, R.; Idle, J.; McMeekin, P.; Vipond, D. J. Chem. Soc., Chem. Commun.
1987, 49–51; (e) Grigg, R.; Idle, J.; McMeekin, P.; Surendrakumar, S.; Vipond, D.
J. Chem. Soc., Perkin Trans. 1 1988, 2703–2713; (f) Tsuge, O.; Kanemasa, S.; Ohe,
M.; Takenaka, S. Bull. Chem. Soc. Jpn. 1987, 60, 4079–4089; (g) Tsuge, O.;
Kanemasa, S. Adv. Heterocycl. Chem. 1989, 45, 231–344; (h) Pandey, G.;
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12. (3S⁄,4S⁄)-3-Benzoyl-4-(2-hydroxyphenyl)-1-methylpyrrolidin-2-one and 4-hydroxy
-2-methyl-4-phenyl-1,3a,4,9b-tetrahydrochromeno[3,4-c]pyrrol-3(2H)-one (10):
Pale-brown crystals, yield 49%, mp 82–87 °C; IR: 3159, 2927, 1660, 1455, 1259,
754, 686 cmꢁ1 1H NMR (400 MHz, CDCl3) (10, 85%) d 2.94 (s, 3H, NMe), 3.63 (dd,
;
1H, CHH, J = 9.7, 6.6 Hz), 3.82 (dd, 1H, CHH, J = 9.7, 8.9 Hz), 4.30 (dt, 1H, H-4,
J = 8.9, 6.9 Hz), 4.70 (d, 1H, H-3, J = 7.2 Hz), 6.85 (td, 1H, H-50, J = 7.4, 1.1 Hz), 6.87
(dd, 1H, H-30, J = 8.0, 1.1 Hz), 7.11 (ddd, 1H, H-40, J = 8.0, 7.4, 1.6 Hz), 7.14 (dd, 1H,
H-60, J = 7.4, 1.6 Hz), 7.41 (tt, 2H, H-300, H-500, J = 7.7, 1.6 Hz), 7.54 (ddt, 1H, H-400,
J = 8.0, 6.9, 1.3 Hz), 8.04 (dd, 2H, H-200, H-600, J = 8.5, 1.3 Hz); (100, 15%) d 2.84 (s,
3H, NMe), 3.37 (d, 1H, CHH, J = 9.7 Hz), 3.48 (br d, 2H, H-3a, H-9b, J = 3 Hz), 3.84–
3.89 (m, 1H, CHH), 6.92 (td, 1H, H-8, J = 7.5, 1.2 Hz), 7.03 (dd, 1H, H-6, J = 8.1,

3572
V. S. Moshkin et al. / Tetrahedron Letters 53 (2012) 3568–3572
1.2 Hz), 7.04 (dd, 1H, H-9, J = 7.7, 1.6 Hz), 7.17–7.22 (m, 1H), 7.26–7.30 (m, 3H),
(C2), 197.1 (COPh); (100, 15%) d 30.0 (NMe), 33.7, 46.8, 56.4 (C1), 98.8 (C4), 118.1
(C6), 122.0 (C8), 126.2, 127.7, 128.3, 128.8, 128.9, 173.7 (C3). Anal. Calcd for
7.46–7.50 (m, 2H); 13C NMR (101 MHz, CDCl3) (10, 85%) d 30.2 (Me), 36.8 (C4),
53.7 (C5), 57.7 (C3), 116.8 (C30), 120.5 (C50), 127.3 (C10), 128.6 (C300, C500), 128.8
(C60), 129.0 (C4’), 129.9 (C200, C600), 133.8 (C400), 136.3 (C100), 154.7 (C20), 170.5
C
18H17NO3ꢀ0.75H2O: C, 70.00; H, 6.04; N, 4.54. Found: C, 70.35; H, 5.69; N, 4.38.