Novel photosensitized cyclization reactions of ethyl 3-amino-3-phenyl-2- propenoate derivatives to highly substituted pyrroles

Article abstract of DOI:10.3987/COM-13-12755

Irradiation of nitrogen-saturated acetonitrile solutions containing ethyl 3-amino-3-phenyl-2-propenoate derivatives with the (Z)-configuration [(Z)- 1] and 10-methylacridinium perchlorate (MAP) at wavelengths longer than 340 nm afforded the corresponding pyrrole derivatives in good to high yields without exhibiting a profound effect related to the substituents. An analysis of the Stern-Volmer plots for the fluorescence quenching of MAP by (Z)-1 showed that this sensitizer fluorescence is efficiently quenched, and hence electron transfer is confirmed to be involved in the primary process of the MAPsensitized cyclization reactions of 1.

Full text of DOI:10.3987/COM-13-12755

HETEROCYCLES, Vol. 87, No. 8, 2013
1691
HETEROCYCLES, Vol. 87, No. 8, 2013, pp. 1691 - 1698. © 2013 The Japan Institute of Heterocyclic Chemistry
Received, 4th June, 2013, Accepted, 25th June, 2013, Published online, 4th July, 2013
DOI: 10.3987/COM-13-12755
NOVEL PHOTOSENSITIZED CYCLIZATION REACTIONS OF ETHYL
3-AMINO-3-PHENYL-2-PROPENOATE DERIVATIVES TO HIGHLY
SUBSTITUTED PYRROLES
Yohsuke Ishida, Yuhki Yoshida, Tetsutaro Igarashi, and Tadamitsu
Sakurai*
Department of Material and Life Chemistry, Faculty of Engineering, Kanagawa
University, Kanagawa-ku, Yokohama 221-8686, Japan
Abstract – Irradiation of nitrogen-saturated acetonitrile solutions containing
ethyl 3-amino-3-phenyl-2-propenoate derivatives with the (Z)-configuration [(Z)-
1] and 10-methylacridinium perchlorate (MAP) at wavelengths longer than 340
nm afforded the corresponding pyrrole derivatives in good to high yields without
exhibiting a profound effect related to the substituents. An analysis of the
Stern–Volmer plots for the fluorescence quenching of MAP by (Z)-1 showed
that this sensitizer fluorescence is efficiently quenched, and hence electron
transfer is confirmed to be involved in the primary process of the MAP-
sensitized cyclization reactions of 1.
Recently, photoinduced electron transfer (PET)-initiated cyclization reactions have received considerable
attentions because of their wide range of synthetic applications.1 In addition, a systematic study of these
PET reactions proceeding through exciplexes or radical ions has provided new and interesting
mechanistic information about organic photochemistry. In the course of our study of the PET reactions
of N-acyl-!-dehydroarylalaninamides and N-acyl-!-dehydroarylalanine alkyl esters (!-dehydroamino
acid derivatives), we found that these derivatives readily undergo one-electron reduction in the presence
of a tertiary aliphatic amine to enable the highly selective construction of 3,4-dihydroquinolinone and 4,5-
dihydrooxazole ring systems, respectively, through the corresponding reactive radical ion pair
intermediates.2,3 The finding that PET reactions of these !-dehydroamino acid derivatives efficiently
construct pharmaceutically useful heterocyclic rings allows us to confidently expect that "-dehydroamino
acid derivatives also undergo PET reactions to enable the construction of such heterocyclic rings.
However, a careful literature survey revealed that no study on the photochemical reactions of "-
dehydroamino acid derivatives has been reported. Thus, the development of the PET reactions of these
amino acid derivatives as an extension of the PET-initiated cyclization reactions of substituted !-

1692
HETEROCYCLES, Vol. 87, No. 8, 2013
dehydroamino acids would be significant. Because a simple and efficient method for the synthesis of N-
unsubstituted and N-alkyl substituted ethyl 3-amino-3-aryl-2-propenoates ("-dehydroarylalanine ethyl
ester derivatives) has been established,4 we conducted a preliminary study regarding the reactivity and
product distribution of several "-dehydroarylalanine ethyl ester derivatives 1a–g activated by 10-
methylacridinium perchlorate (MAP) as a photosensitizer (Chart 1). In this communication, we present
results demonstrating that selective excitation of MAP enables the progress of efficient electron transfer
from the ground-state 1 to the singlet-excited-state MAP in order to result in a novel cyclization to
substituted pyrroles.
O
OEt
O
OEt
(Z)-1b (R1 = OMe, R2 = H
(Z)-1c (R1 = Me, R2 = H
(Z)-1d (R1 = R2 = H
(Z)-1e (R1 = Cl, R2 = H
(Z)-1f (R1 = CN, R2 = H
(Z)-1g (R1 = OMe, R2 = Bu
)
H
N
H2N
)
R2
)
)
MeO
OMe
)
R1
(Z)-1a
)
Chart 1
The starting "-dehydroarylalanine ethyl ester derivatives 1a–g with the (Z)-configuration were prepared
in 30–45% overall yields by reactions between ethyl acetoacetate and substituted benzoyl chlorides,
followed by a heat treatment of the resultant ethyl aroyl acetates in ethanol that contained a five-fold
molar excess of acetic acid and ammonia (1a–f) or acetic acid and butylamine (1g).5 To examine the
distribution and composition of the products generated from the photosensitized reaction of 1, a nitrogen-
saturated acetonitrile solution (100 mL) that contained (Z)-1a (5.0 # 10–3 mol dm–3) and MAP (1.0 # 10–2
mol dm–3) was irradiated at wavelengths longer than 340 nm for 24 h at room temperature (light source:
500-W high-pressure Hg lamp). Because MAP exhibits fairly low solubility in ethyl acetate, repeated
extraction of the photoproducts with this solvent from the reaction mixture (concentrated to dryness in
vacuo) and subsequent preparative thin-layer chromatography using silica gel (eluent: EtOAc–hexane)
enabled us to isolate 2,5-bis(3,5-dimethoxyphenyl)-3,4-bis(ethoxycarbonyl)-pyrrole (2a) in 46% yield,
along with a small amount of 1a.6 1H NMR spectral analysis of this mixture showed that it contained
small amounts of byproducts in addition to 1a, 2a, and MAP, which strongly suggests the occurrence of a
side reaction, although no attempt was made to isolate these byproducts (Scheme 1). In addition, we
were able to revaluate the yield (1H NMR yield) of 2a and the conversion of 1a to be 60% and 96%,
respectively, on the basis of the internal standard method using 1,3,5-trimethoxybenzene. The structure
of the pyrrole derivative 2a was confirmed by the following three experimental results: (1) proton signals
for the two ethoxycarbonyl groups and for the two 3,5-dimethoxyphenyl groups gave the same chemical

HETEROCYCLES, Vol. 87, No. 8, 2013
1693
shift values, respectively; (2) the calculated molecular weight for 2a ([M + Na]+ 506.19) was consistent
with its observed value ([M + Na]+ 505.99); and (3) a large difference NOE (35% in CDCl3) was
observed between the NH proton in the pyrrole ring and the proton at the 2-position on the benzene ring.
O
O
EtO
OEt
MeO
OMe
h!
(Z)-1a
N
H
MAP/MeCN
MeO
OMe
2a
Scheme 1
Next, we focused on the effects of the substituent on the photoreactivity (conversion) of the starting "-
dehydroarylalanine ethyl ester 1 as well as on the 1H NMR yield of the pyrrole product 2; the results are
summarized in Table 1. Although the pyrrole yield tended to increase with an increase in the electron-
withdrawing ability of the substituent introduced onto the benzene ring, the photoreactivity indicated no
correlation with this electron-withdrawing ability. In addition, the replacement of the amino hydrogen
in 1b by the butyl group (1g) slightly enhanced the conversion of 1 without affecting the yield of 2.
The contribution of a side reaction that affords byproducts likely complicates the relationship between
the reactant conversion and the 1H NMR yield of the pyrrole product.
Table 1. Effects of the substituent on the conversion of (Z)-1 and the
1H NMR yield of pyrrole derivative 2, obtained by the 24 h irradiation
of a nitrogen-saturated acetonitrile solution of 1 (5.0
containing MAP (1.0
10–2 mol dm–3) at room temperature
x
10–3 mol dm–3)
x
1H NMR yield of
2
(%)
Conversion of (Z)-1 (%)
(Z)-1
1a
1b
1c
1d
1e
1f
96
96
60
60
66
66
74
96
60
94
94
88
96
1g
100

1694
HETEROCYCLES, Vol. 87, No. 8, 2013
The observations that MAP exhibits its first UV absorption band at a much longer wavelength compared
to that of 1 and undergoes no decomposition during irradiation confirm that MAP functions as a
photosensitizer with the ability to accept an electron from the "-dehydroamino acid ester 1. To explore
the relationship between the photoreactivity of ester 1 and the efficiency of electron transfer (ET) from 1
to the excited-state MAP, we estimated quenching constants (KSV’s) through the fluorescence quenching
of MAP by 1a–g in argon-saturated acetonitrile at room temperature. As shown in Figure 1, the
fluorescence of MAP ([MAP] = 1.0 # 10–4 mol dm–3 and excitation wavelength = 366 nm) was
quenched by 1a according to the Stern–Volmer equation: I0/I = 1 + KSV[1a], where I and I0 are the
fluorescence intensities of MAP with and without 1a, respectively. Because similar results were
obtained for the other "-dehydroamino acid esters, the KSV values were determined from the slopes of
the linear Stern–Volmer plots: KSV (dm3 mol–1) = 7.0 # 102 (1a), 8.9 # 102 (1b), 7.0 # 102 (1c), 7.8 # 102
(1d), 7.7 # 102 (1e), 3.2 # 103 (1f), and 7.8 # 102 (1g). Clearly, the ET fluorescence quenching of MAP
occurs with a high efficiency irrespective of the electronic properties of the substituents introduced;
however, the magnitude of KSV, which is a measure of ET efficiency, does not correlate with the
observed photoreactivity of 1 (Table 1). Because prolonged irradiation is required to complete the
examined photoreactions, this finding suggests that at least two regeneration processes of the starting
dehydroamino acid ester reactants occur prior to the appearance of the pyrrole products. Interestingly,
the presence of the electron-withdrawing cyano group in 1 enhanced the efficiency of ET from this
amino acid ester to MAP by a factor of approximately 4–5. The strong ability of the cyano group to
accept an electron may assist ET to the sensitizer in the singlet-excited state.
3.5
3.0
2.5
2.0
1.5
1.0
0
0.5
1.0
1.5
2.0
2.5
3.0
[
1a] (10–3 mol dm–3)
Figure 1. Stern–Volmer plot for the fluorescence quenching of MAP by 1a in acetonitrile.

HETEROCYCLES, Vol. 87, No. 8, 2013
1695
h!
MAP
MAP
*
O
O
R2 NH
Ar
OEt
OEt
R2 NH
Ar
OEt
MAP
MAP
*
ET
R2 = H, Bu
1
O
R2 NH
Ar
MAP
OEt
MAP
O
1
back ET
O
O
R2 NH
Ar
H+
R2
N
OEt
R2
N
OEt
H+ dissociation
Ar
Ar
IA
IB
I
H+
H
MAP
MAP
H2
back ET
coupling
coupling
H
H
1
IA
R2
N
Ar
Ar
N R2
IB
H
H
coupling
cyclization
EtO
OEt
O
O
II
R2
N
R2
N
H
N
Ar
Ar
Ar
R2
Ar
H2N R2
H
EtO
OEt
EtO
OEt
O
O
O
O
2
Scheme 2
On the basis of the previously discussed results of the ET fluorescence quenching, we propose a
mechanism that explains the formation of the pyrrole derivatives 2a–g (Scheme 2). As shown in
Scheme 2, in competition with the regeneration of "-dehydroamino acid ester 1 by back ET from the
MAP anion radical to the 1 cation radical, this strongly acidic cation radical formed in the primary
process of the photosensitized reaction is dissociated into a proton and the imino radical I, in which the
nitrogen-centered radical IA and the carbon-centered radical IB resonate with each other. The
coupling reaction of the former imino radical with a hydrogen atom, which is produced by back ET from
the MAP anion radical to the proton, regenerates the amino acid ester 1 to result in a decrease in the

1696
HETEROCYCLES, Vol. 87, No. 8, 2013
sensitized reaction efficiency along with the back ET reaction that regenerates 1 and MAP. In addition,
the coupling reaction of the latter imino radical that occurs in competition with the regeneration of 1
yields the dimerized intermediate II. The cyclization of this intermediate and the subsequent release of
amine from the 2-pyrroline ring furnish the highly substituted pyrrole derivative 2. No attempt was
made to detect the liberated amine.
Although numerous thermal routes to pyrrole derivatives are known,7 the number of photochemical routes
to these derivatives is limited.8 The procedure for the preparation of the variously substituted (Z)-!-
dehydroarylalanine ethyl ester derivatives (Z)-1a–g is simple and readily applicable to their related
compounds. Although prolonged irradiation is required to complete the PET reactions of 1 in the
presence of MAP, the pyrrole photoproducts 2 that undergo only a small extent of secondary
decomposition can be obtained in good to high yields by the brief post-treatment of the irradiated reaction
mixtures. Therefore, the MAP-sensitized cyclization reaction of 1 provides a novel photochemical
method for constructing the pyrrole ring, which is the structural unit of naturally occurring chlorophylls,
porphyrins, and bilirubins.
REFERENCES AND NOTES
1. a) 'Synthetic Organic Photochemistry,' ed. by W. M. Horspool, Plenum, New York, 1984; b) K.
Mizuno, N. Ichinose, and Y. Yoshimi, J. Photochem. Photobiol., C, 2000, 1, 167; c) 'Handbook of
Photochemistry and Photobiology,' Vol. 2, ed. by H. S. Nalwa, American Scientific Publishers,
California, 2003; d) 'Synthetic Organic Photochemistry,' ed. by A. G. Griesbeck and J. Mattay, Marcel
Dekker, New York, 2005; e) A. G. Griesbeck, N. Hoffmann, and K. Warzecha, Acc. Chem. Res.,
2007, 40, 128; f) M. Kitamura and K. Narasaka, Bull. Chem. Soc. Jpn., 2008, 81, 539; g) D. W. Cho,
U. C. Yoon, and P. S. Mariano, Acc. Chem. Res., 2011, 44, 204.
2. a) K. Maekawa, T. Igarashi, K. Kubo, and T. Sakurai, Tetrahedron, 2001, 57, 5515; b) T. Motohashi,
K. Maekawa, K. Kubo, T. Igarashi, and T. Sakurai, Heterocycles, 2002, 57, 269; c) K. Maekawa, H.
Kajiwara, Y. Iseya, T. Igarashi, and T. Sakurai, Heterocycles, 2003, 60, 637; d) K. Maekawa, A.
Shinozuka, M. Naito, T. Igarashi, and T. Sakurai, Tetrahedron, 2004, 60, 10293; e) K. Maekawa, K.
Fujita, K. Iizuka, T. Igarashi, and T. Sakurai, Heterocycles, 2005, 65, 117.
3. a) K. Maekawa, T. Sasaki, K. Kubo, T. Igarashi, and T. Sakurai, Tetrahedron Lett., 2004, 45, 3663; b)
K. Maekawa, N. Hishikawa, K. Kubo, T. Igarashi, and T. Sakurai, Tetrahedron, 2007, 63, 11267; c)
Y. Sato, A. Yoshida, T. Igarashi, and T. Sakurai, Heterocycles, 2010, 81, 997.
4. a) J. M. Straley and A. C. Adams, Org. Synth., Coll. Vol. 4, 415; b) T. Sano, Y. Horiguchi, J. Toda,
K. Imafuku, and Y. Tsuda, Chem. Pharm. Bull., 1984, 32, 497.
1
5. Data for (Z)-1a: oily liquid; H NMR (500 MHz, CDCl3) ! = 1.30 (3H, t, J = 7.5 Hz), 3.81 (6H, s),
4.18 (2H, q, J = 7.5 Hz), 4.95 (1H, s), 6.52 (1H, d, J = 2.5 Hz), 6.67 (2H, d, J = 2.5 Hz), 7.25 (1H, br

HETEROCYCLES, Vol. 87, No. 8, 2013
1697
13
s), 8.09 (1H, br s); C NMR (125 MHz, CDCl3) ! = 14.6, 55.5 (2C), 58.9, 84.6, 102.1, 104.2 (2C),
139.8, 160.4, 161.0 (2C), 170.3.
Data for (Z)-1g: oily liquid; 1H NMR (500 MHz, CDCl3) ! = 0.85 (3H, t, J = 6.5 Hz), 1.28 (3H, t, J =
7.0 Hz), 1.30 (2H, tq, J = 6.5, 6.5 Hz), 1.46 (2H, tt, J = 6.5, 6.5 Hz), 3.08 (2H, dt, J = 6.5, 6.5 Hz),
3.84 (3H, s), 4.14 (2H, q, J = 7.0 Hz), 4.57 (1H, s), 6.90 (2H, d, J = 8.5 Hz), 7.29 (2H, d, J = 8.5 Hz),
13
8.53 (1H, t, J = 6.5 Hz); C NMR (125 MHz, CDCl3) ! = 13.7, 14.6, 19.8, 33.0, 44.3, 55.2, 58.5,
84.5, 113.6 (2C), 128.6, 129.2 (2C), 160.2, 165.0, 170.5.
6. Data for 2a: 46% isolated yield; oily liquid; 1H NMR (500 MHz, CDCl3) ! = 1.26 (6H, t, J = 7.5 Hz),
3.78 (12H, s), 4.25 (4H, q, J = 7.5 Hz), 6.45 (2H, d, J = 2.5 Hz), 6.71 (4H, d, J = 2.5 Hz), 8.76 (1H,
br s); 13C NMR (125 MHz, CDCl3) ! = 14.1 (2C), 55.4 (4C), 60.7 (2C), 100.7 (2C), 106.3 (4C),
114.6 (2C), 132.5 (2C), 133.7 (2C), 160.7 (4C), 165.2 (2C). MALDI TOF-MS m/z calcd for
C26H29NNaO8 [M + Na]+: 506.19. Found: 505.99.
Data for 2b: 41% isolated yield; oily liquid; 1H NMR (500 MHz, CDCl3) ! = 1.25 (6H, t, J = 7.0 Hz),
3.81 (6H, s), 4.22 (4H, q, J = 7.0 Hz), 6.90 (4H, d, J = 9.0 Hz), 7.47 (4H, d, J = 9.0 Hz), 8.61 (1H, br
13
s); C NMR (125 MHz, CDCl3) ! = 14.1 (2C), 55.3 (2C), 60.6 (2C), 113.5 (2C), 113.8 (4C), 123.3
(2C), 129.5 (4C), 134.1 (2C), 159.7 (2C), 165.4 (2C). MALDI TOF-MS m/z calcd for C24H25NNaO6
[M + Na]+: 446.17. Found: 445.84.
Data for 2c: 43% isolated yield; oily liquid; 1H NMR (500 MHz, CDCl3) ! = 1.25 (6H, t, J = 7.0 Hz),
2.37 (6H, s), 4.23 (4H, q, J = 7.0 Hz), 7.20 (4H, d, J = 9.0 Hz), 7.43 (4H, d, J = 9.0 Hz), 8.51 (1H, br
13
s); C NMR (125 MHz, CDCl3) ! = 14.1 (2C), 21.3 (2C), 60.6 (2C), 114.0 (2C), 128.0 (6C), 129.2
(4C), 134.2 (2C), 138.5 (2C), 165.3 (2C). MALDI TOF-MS m/z calcd for C24H25NNaO4 [M + Na]+:
414.18. Found: 414.41.
Data for 2d: 37% isolated yield; oily liquid; 1H NMR (500 MHz, CDCl3) ! = 1.26 (6H, t, J = 7.5 Hz),
4.24 (4H, q, J = 7.5 Hz), 7.35–7.38 (2H, m), 7.39–7.44 (4H, m), 7.55–7.56 (4H, m), 8.57 (1H, br s);
13C NMR (125 MHz, CDCl3) ! = 14.0 (2C), 60.7 (2C), 114.5 (2C), 128.1 (4C), 128.5 (4C), 130.9
(2C), 134.2 (2C), 165.2 (2C). MALDI TOF-MS m/z calcd for C22H21NNaO4 [M + Na]+: 386.15.
Found: 385.93.
Data for 2e: 49% isolated yield; oily liquid; 1H NMR (500 MHz, CDCl3) ! = 1.27 (6H, t, J = 7.0 Hz),
4.26 (4H, q, J = 7.0 Hz), 7.39 (4H, d, J = 9.0 Hz), 7.50 (4H, d, J = 9.0 Hz), 8.69 (1H, br s); 13C NMR
(125 MHz, CDCl3) ! = 13.7 (2C), 60.4 (2C), 114.5 (2C), 128.1 (4C), 129.2 (2C), 129.5 (6C), 133.9
(2C), 164.9 (2C). MALDI TOF-MS m/z calcd for C22H19Cl2NNaO4 [M + Na]+: 454.07. Found:
454.36.
Data for 2f: 70% isolated yield; oily liquid; 1H NMR (500 MHz, CDCl3) ! = 1.26 (6H, t, J = 7.0 Hz),
4.23 (4H, q, J = 7.0 Hz), 7.59 (4H, d, J = 9.0 Hz), 7.66 (4H, d, J = 9.0 Hz), 9.92 (1H, br s); 13C NMR
(125 MHz, CDCl3) ! = 13.9 (2C), 61.3 (2C), 111.6 (2C), 116.2 (2C), 128.7 (4C), 132.0 (6C), 133.0

1698
HETEROCYCLES, Vol. 87, No. 8, 2013
(2C), 134.8 (2C), 164.7 (2C). MALDI TOF-MS m/z calcd for C24H19N3NaO4 [M + Na]+: 436.14.
Found: 435.88.
Data for 2g: 40% isolated yield; oily liquid; 1H NMR (500 MHz, CDCl3) ! = 0.55 (3H, t, J = 6.5 Hz),
0.87 (2H, tq, J = 6.5, 6.5 Hz), 1.14 (6H, t, J = 7.0 Hz), 1.15 (2H, tt, J = 6.5, 6.5 Hz), 3.67 (2H, t, J =
6.5 Hz), 3.87 (6H, s), 4.13 (4H, q, J = 7.0 Hz), 6.97 (4H, d, J = 9.0 Hz), 7.34 (4H, d, J = 9.0 Hz); 13C
NMR (125 MHz, CDCl3) ! = 13.3, 14.0 (2C), 19.4, 32.4, 44.5, 55.3 (2C), 60.2 (2C), 113.6 (4C),
114.2 (2C), 123.4 (2C), 131.9 (4C), 136.1 (2C), 159.7 (2C), 165.1 (2C). MALDI TOF-MS m/z calcd
for C28H33NNaO6 [M + Na]+: 502.23. Found: 502.56.
7. a) A. R. Katritzky and A. F. Pozharskii, 'Handbook of Heterocyclic Chemistry,' 2nd ed., Pergamon,
Oxford, 2000, pp. 529–544; b) M. A. Sukari and J. M. Vernon, Tetrahedron, 1983, 39, 793; c) L. F.
Lee and R. K. Howe, J. Org. Chem., 1984, 49, 4780; d) P.-F. Zhang and Z.-C. Chen, Synth.
Commun., 2001, 31, 1619; e) A.-I. Tsai and C.-P. Chuang, Tetrahedron, 2006, 62, 2235; f) I. Yavari
and E. Kowsari, Synlett, 2008, 897; g) B. Das, N. Bhunia, and M. Lingaiah, Synthesis, 2011, 3471; h)
A. L. Cardoso, R. M. D. Nunes, L. G. Arnaut, and T. M. V. D. Pinho e Melo, Synthesis, 2011, 3516;
i) H. Batchu and S. Batra, Eur. J. Org. Chem., 2012, 2935; j) B. V. S. Reddy, M. R. Reddy, Y. G.
Rao, J. S. Yadav, and B. Sridhar, Org. Lett., 2013, 15, 464; k) N. Bhunia and B. Das, Synthesis,
2013, 45, 1045.
8. a) A. G. Schultz and C.-K. Sha, J. Org. Chem., 1980, 45, 2040; b) R. S. Givens, D. J. Choo, S. N.
Merchant, R. P. Stitt, and B. Matuszewski, Tetrahedron Lett., 1982, 23, 1327; c) K. Oda, M. Sakai,
K. Ohno, and M. Machida, Heterocycles, 1999, 50, 277.