Direct oxidation of 4-methylpyrrole-2-carboxylates with DDQ in the presence of a glycol

Article abstract of DOI:10.3987/COM-12-S(N)126

Oxidation of 4-methylpyrrole-2-carboxylates with DDQ in the presence of a glycol proceeded smoothly on the methyl group at the C4 position regioselectively to afford the corresponding pyrrole-2,4-dicarboxylates directly. Direct oxidation of a methyl group of 2,4,6-trimethylphenol and 3-methyl-9H-carbazole into carboxylates was also demonstrated.

Full text of DOI:10.3987/COM-12-S(N)126

HETEROCYCLES, Vol. 86, No. 2, 2012
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HETEROCYCLES, Vol. 86, No. 2, 2012, pp. 1031 - 1038. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 29th September, 2012, Accepted, 12th November, 2012, Published online, 22nd November, 2012
DOI: 10.3987/COM-12-S(N)126
DIRECT OXIDATION OF 4-METHYLPYRROLE-2-CARBOXYLATES
WITH DDQ IN THE PRESENCE OF A GLYCOL
Kana Takahashi, Ryoji Iwamoto, Ryo Sakata, Takahiro Soeta, Katsuhiko
Inomata, and Yutaka Ukaji*
Division of Material Sciences, Graduate School of Natural Science and
Technology, Kanazawa University, Kakuma, Kanazawa 920-1192, Japan; E-mail:
ukaji@staff.kanazawa-u.ac.jp
Abstract – Oxidation of 4-methylpyrrole-2-carboxylates with DDQ in the
presence of a glycol proceeded smoothly on the methyl group at the C4 position
regioselectively to afford the corresponding pyrrole-2,4-dicarboxylates directly.
Direct oxidation of aꢀ methyl group of 2,4,6-trimethylphenol and
3-methyl-9H-carbazole into carboxylates was also demonstrated.
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is a highly effective oxidant widely used in organic
synthesis and its major functions include dehydrogenation, such as aromatization of hydroaromatic
compounds, introduction of a double bond into carbonyl compounds, and oxidation of alcohols.
Benzylic oxidation with DDQ in the presence of oxygen nucleophiles gives the corresponding
oxygen-functionalized compounds.
reactions have been also reported.1,2
Furthermore, alternative oxidative cyclization and coupling
During our investigation on the syntheses of phytochromobilin (P!B), phycocyanobilin (PCB), biliverdin
(BV) and their analogs including sterically locked derivatives toward elucidation of the structure and
function of phytochromes,3 oxidative functionalization of pyrroles by the use of quinones was explored.
In the case that DDQ was used as an oxidant, the !-position of the alkyl substituent at the C4 position
was regioselectively oxidized in the presence of AcOH to afford 4-(1-acetoxyalkyl)pyrrole derivatives.
In contrast, the corresponding 4-acylpyrroles were produced when MeOH was used instead of AcOH as a
nucleophile (Scheme 1).4
The oxidative transformation of 4-methylpyrrole-2-carboxylates with DDQ
and MeOH was successfully applied to the convergent synthesis of sterically locked 5Za15Ea-BV
Dedicated with respect to Professor Eiichi Negishi on the occasion of his 77th birthday.

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HETEROCYCLES, Vol. 86, No. 2, 2012
derivative.5,6
Herein we describe
a
regioselective direct oxidation of t-butyl
4-methylpyrrole-2-carboxylates with DDQ in the presence of a glycol as a nucleophile to afford the
corresponding 2,4-dicarboxylates.
OAc
Nu
R1
R2
R2
DDQ
AcOH
Nu
base
t
t
R1
R2
CO2 Bu
CO2 Bu
(R1= H)
N
H
N
H
O
t
CO2 Bu
R1
R2
N
H
DDQ
MeOH
5Za15Ea-BV
derivative
t
R1= H
R2 = CH2CH2CO2Allyl
CO2 Bu
N
H
Scheme 1
First, oxidation of t-butyl 3-[2-(allyloxycarbonyl)ethyl]-4-methyl-1H-pyrrole-2-carboxylate (1A), which
is a useful synthon for the B- and C-ring components of bilin chromophores,3 was examined by the use of
4.0 equiv of DDQ in the presence of 15 equiv of ethylene glycol (2a) in CH2Cl2 in order to trap the
oxidation product as an acetal form. To our surprise, a desired 1,3-dioxolane 6Aa was not obtained but
the corresponding 2-hydroxyethyl ester 3Aa was obtained in 50% yield (Table 1, Entry 1). The
2-hydroxyethyl ester 3Aa might be produced as follows: Oxidation of 1A with DDQ occurred at the C4
position to afford an intermediate 5Aa via nucleophilic attack of the glycol 2a to an intermediary
azafulvene 4A.4 The second oxidation of 5Aa with DDQ furnished 6Aa, which was subjected to the
third oxidation, followed by hydrolysis resulting in the formation of 3Aa as shown in Scheme 2ꢀsince the
acetal 6Aa might be more easily oxidized by DDQ than 5Aa. Then propylene glycol (2b) instead of
ethylene glycol (2a) was used as a nucleophile for the present oxidation. The corresponding
3-hydroxypropyl ester 3Ab was obtained in slightly enhanced chemical yield (Entry 2). The oxidation
in the presence of 1,4-butanediol (2d) instead of ethylene glycol (2a) also proceeded to give the
corresponding ester 3Ad, but in lower yield along with the formation of aldehyde 8A (Entry 11). The
oxygen atom of the resulting ester carbonyl might be originated from
AllylO2C
H2O. When the oxidation was carried out in the presence of 1 equiv
CO2Allyl
of H2O, the chemical yield was improved as expected (Entry 3).
O
When the amount of H2O was increased, the chemical yield was
decreased (Entries 4 and 5) and the aldehyde 8A was obtained (Entry
5). In the present oxidation, the production of a small amount of a
dimeric compound 9 was often observed.7 In order to suppress the
tBuO2C
N
H
t
CO2 Bu
N
H
9

HETEROCYCLES, Vol. 86, No. 2, 2012
1033
Table 1. Oxidation of 4-methylpyrrole-2-carboxylate 1A with DDQ in the presence of a glycol
CO2Allyl
CO2Allyl
HO X
O
DDQ (l equiv)
2 (m equiv)
H2O (n equiv)
O
HO X OH
t
t
CO2 Bu
CO2 Bu
CH2Cl2, rt, time
N
H
N
H
1A
3A
Time
/h
Yield of 3A
/%
Entry
HO–X–OH
2
l
m
n
3A
1
2
HO–CH2CH2–OH
a
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.5
4.0
4.0
4.0
15
15
15
15
15
15
15
15
30
15
15
0
0
21
15
19
22
20
16
20
15
18
15
15
Aa
Ab
50
52
65
63
55a
71
70
68
70
67
15d
HO–CH2CH2CH2–OH
b
3
1
4
5
5
10
1
6b
7c
8b
9b
10b
11
1
1
1
HO–CH2C(Me)2CH2–OH
HO–CH2CH2CH2CH2–OH
c
1
Ac
Ad
d
0
aAldehyde 8A was also obtained in 12% yield. bA solution of pyrrole 1A and H2O in
CH2Cl2 was slowly added to a mixture of DDQ and glycol 2 in CH2Cl2 in a period of 3 h.
cA solution of pyrrole 1A and H2O in CH2Cl2 was slowly added to a mixture of DDQ and
glycol 2 in CH2Cl2 in a period of 6 h. dAldehyde 8A was also obtained in 47% yield.
OH
O X
R2
X
X
HO
HO
HO
H
H
O
H
O
O
O
X
X
HO
2
R2
R2
X
R2
HO
O
DDQ
DDQ
DDQ
1
E
E
E
E
N
H
N
N
N
H
H
4
5
6
7
H2O
O
H2O
t
(E = CO2 Bu)
HO X
O
R2
O
R2
H
E
E
N
H
N
H
8
3
Scheme 2

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HETEROCYCLES, Vol. 86, No. 2, 2012
production of the dimer, the pyrrole 1A and H2O were added to the mixture of glycol 2b and DDQ in a
period of 3 h to obtain the ester 3Ab in enhanced 71% yield (Entry 6).8 Slow addition of 1A and H2O in
a longer period did not improve the yield any more (Entry 7). Furthermore, increase of the amount of
DDQ or glycol was not so effective (Entries 8 and 9). The use of 2,2-dimethyl-1,3-propanediol (2c) as a
glycol realized a similar result (Entry 10).
Next, the oxidation of other pyrroles with DDQ in the presence of a glycol was examined as listed in
Table 2, together with the results of oxidation of 1A.
The reaction of t-butyl
3-ethyl-4-methyl-1H-pyrrole-2-carboxylate (1B) afforded esters 3Bb and 3Bc in 58% and 59% yields by
the use of propylene glycol (2b) and 2,2-dimethyl-1,3-propanediol (2c), respectively (Entries 3 and 4).
3,4-Dimethyl-1H-pyrrole-2-carboxylate (1C) was oxidized regioselectively at the C4 methyl group
(Entries 5 and 6). In this case, chemical yield was enhanced up to 71% by the use of
2,2-dimethyl-1,3-propanediol (2c) as a glycol. In the case of 3-phenyl-substituted pyrrole 1D in the
presence of 1b, the reaction proceeded rather slowly to give the corresponding aldehyde 8D as a major
product, but the yield of an ester 3Db was poor (Entry 7). In the oxidation using the glycol 2c at 40 °C,
reaction was still sluggish to give the ester 3Dc in 27 % yield along with the aldehyde 8D (6%) and an
acetal 6Dc (13%) (Entry 8).
In order to reveal the reaction mechanism of the present oxidation, the 1,3-dioxolane 6Aa (Scheme 2) was
treated with DDQ in the presence of ethylene glycol (2a): The oxidized ester 3Aa was obtained in 63%
yield accompanied with aldehyde 8A (7%) (Eq. 1).9 This fact supported that the ester was produced via
oxidation of the intermediary acetal 6Aa. Although the oxidation of the 3-phenyl substituted acetal 6Dc
with DDQ was also examined at 40 °C, the reaction was sluggish and the yield of ester 3Dc was low (Eq.
2). The exact reason for the poor reactivity of the phenyl-substituted acetal 6Dc toward DDQ oxidation
is not yet clear, however, steric hindrance of phenyl group, which prevents the attack of DDQ to 6Dc,
might be a possible reason.
It is well known that DDQ oxidation of methyl group on aromatic ring in the presence of MeOH and/or
H2O gives the corresponding aldehydes.1,2h,10 Thus, the present DDQ oxidation using a glycol as a
nucleophile was applied to such substrates. 2,4,6-Trimethylphenol (mesitol) (10)2h was converted to an
ester 11 in 77% yield regioselectively in the presence of glycol 2c (Eq. 3). Carbazole compounds are
intriguing because of containing pyrrole skeleton.10c-e 3-Methyl-9H-carbazole (12) was subjected to the
present DDQ oxidation to afford the corresponding ester 13 in 66% yield (Eq. 4).

HETEROCYCLES, Vol. 86, No. 2, 2012
1035
Table 2. Oxidation of 4-methylpyrrole-2-carboxylates 1 with DDQ in the presence of a glycol
HO X
O
DDQ (4.0 equiv)
HO X OH 2 (15 equiv)
H2O (1.0 equiv)
R
O
R
t
t
CO2 Bu
CO2 Bu
CH2Cl2, rt, time
N
H
N
H
1
3
Time
/h
Yield of 3
Entry
R
1
HO–X–OH
2
3
/%
71
67
58
59
58
71
8c
1a CH2CH2CO2Allyl A
HO–CH2CH2CH2–OH
HO–CH2C(Me)2CH2–OH
HO–CH2CH2CH2–OH
HO–CH2C(Me)2CH2–OH
HO–CH2CH2CH2–OH
HO–CH2C(Me)2CH2–OH
HO–CH2CH2CH2–OH
HO–CH2C(Me)2CH2–OH
b
c
16
15
14
14
14
14
15
88e
Ab
Ac
Bb
Bc
Cb
Cc
Db
Dc
2a
3a
4a
5a
6a
7b
8d
Et
Me
Ph
B
C
D
b
c
b
c
b
c
27f
aA solution of pyrrole 1 and H2O in CH2Cl2 was slowly added to a mixture of DDQ and
glycol 2 in CH2Cl2 in a period of 3 h. bA solution of pyrrole 1 in CH2Cl2 was added
(without addition of H2O) all at once to a mixture of DDQ and glycol 2 in CH2Cl2.
cAldehyde 8D was also obtained in 43% yield. dA solution of pyrrole 1 in CH2Cl2 was
slowly added (without addition of H2O) to a mixture of DDQ and glycol 2 in CH2Cl2 in a
period of 3 h. eReaction was carried out at rt for 20 h and at 40 °C for 68 h. fAldehyde
8D and acetal 6Dc were also obtained in 6% and 13% yields, respectively.
CO2Allyl
HO
CO2Allyl
O
O
DDQ (2.0 equiv)
HO CH2CH2 OH
H2O (1.0 equiv)
O
(2a) (15 equiv)
O
(1)
8A
t
t
CH2Cl2, rt, 17 h
CO2 Bu
CO2 Bu
N
H
N
H
7%
6Aa
3Aa 63%
HO
O
O
O
DDQ (2.0 equiv)
HO CH2C(Me)2CH2 OH
Ph
Ph
O
(2c) (15 equiv)
(2)
t
t
CH2Cl2, 40 °C, 4 d
CO2 Bu
CO2 Bu
N
H
N
H
6Dc
3Dc 25%

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HETEROCYCLES, Vol. 86, No. 2, 2012
DDQ (4.0 equiv)
HO CH2C(Me)2CH2 OH
H2O (1.0 equiv)
O
(2c) (15 equiv)
HO
O
(3)
OH
10
CH2Cl2, rt, 1 h
OH
11 77%
(slow addition, 3 h)
O
O
HO
DDQ (4.0 equiv)
HO CH2C(Me)2CH2 OH
H2O (1.0 equiv)
(2c) (15 equiv)
(4)
CH2Cl2, rt, 20 h
N
H
N
H
12
(slow addition, 3 h)
13 66%
As described above, the regioselective oxidation of t-butyl 4-methyl-1H-pyrrole-2-carboxylate was
achieved with DDQ in the presence of a glycol to give the corresponding pyrrole-2,4-dicarboxylates.11
This method could be also applied to the DDQ oxidation of methyl groups attached to aromatic rings into
the corresponding esters. The direct oxidation of methylarenes to the carboxylic acids and its
derivatives is very important, since such carbonyl derivatives are versatile building blocks in the synthesis
of pharmaceutical chemicals. A variety of oxometal oxidants have been employed for such oxidative
processes.12 The present reaction would provide an efficient method for metal-free oxidation to produce
useful carboxylic acid derivatives.
ACKNOWLEDGEMENTS
The present work was financially supported in part by the Mitani Foundation for Research and
Development and a Grant-in-Aid for Scientific Research (B) from Japan Society for the Promotion of
Science (JSPS).
REFERENCES AND NOTES
1. D. Walker and J. D. Hiebert, Chem. Rev., 1967, 67, 153; A. B. Turner, 'Synthetic Reagents,' Vol. 3,
ed. by J. S. Pizey, Halstead-Wiley, New York, 1977, 193; D. R. Buckle and I. L. Pinto,
'Comprehensive Organic Synthesis,' Vol. 7, ed. by B. M. Trost and I. Fleming, Pergamon Press, New
York, 1991, pp. 135–139.
2. Examples of oxidation reaction using DDQ. Aromatization: a) P. P. Fu and R. G. Harvey Chem.
Rev., 1978, 78, 317; b) U. Kämpfen and A. Eschenmoser, Tetrahedron Lett., 1985, 26, 5899.
Benzylic oxidation: c) H. Lee and R. G. Harvey, J. Org. Chem., 1983, 48, 749; d) T. Ishiguro, H.
Mizuguchi, K. Tomioka, and K. Koga, Chem. Pharm. Bull., 1985, 33, 609; e) E. J. Corey and Y. B.

HETEROCYCLES, Vol. 86, No. 2, 2012
1037
Xiang, Tetrahedron Lett., 1987, 28, 5403. Oxidation of alcohol: f) H.-D. Becker, A. Björk, and E.
Adler, J. Org. Chem., 1980, 45, 1596; g) L. Wang, J. Li, H. Yang, Y. Lv, and S. Gao, J. Org. Chem.,
2012, 77, 790. Oxidative coupling and cyclization reaction: h) H.-D. Becker, J. Org. Chem., 1965,
30, 982; i) Y. Zhang and C.-J. Li, J. Am. Chem. Soc., 2006, 128, 4242; j) L. Liu and P. E. Floreancig,
Org. Lett., 2010, 12, 4686.
3. H. Khawn, L.-Y. Chen, H. Kinoshita, and K. Inomata, Chem. Lett., 2008, 37, 198; K. Inomata, Bull.
Chem. Soc. Jpn., 2008, 81, 25; L.-Y. Chen, H. Kinoshita, and K. Inomata, Chem. Lett., 2009, 38,
602; K. Inomata, H. Khawn, L.-Y. Chen, H. Kinoshita, B. Zienicke, I. Molina, and T. Lamparter,
Biochemistry, 2009, 48, 2817; K. Nishiyama, A. Kamiya, M. A. S. Hammam, H. Kinoshita, S.
Fujinami, Y. Ukaji, and K. Inomata, Bull. Chem. Soc. Jpn., 2010, 83, 1309; R. Yang, K. Nishiyama,
A. Kamiya, Y. Ukaji, K. Inomata, and T. Lamparter, Plant Cell, 2012, 24, 1936 and references cited
therein.
4. R. Iwamoto, Y. Ukaji, and K. Inomata, Chem. Lett., 2010, 39, 176.
5. L.-Y. Chen, R. Iwamoto, Y. Ukaji, and K. Inomata, Chem. Lett., 2011, 40, 632.
6. Related oxidation reaction using o-chloranil: R. Sakata, R. Iwamoto, S. Fujinami, Y. Ukaji, and K.
Inomata, Heterocycles, 2011, 82, 1157.
7. The dimeric compound 9 might be formed by Friedel-Crafts-type reaction of the azafulvene 4A with
unreacted 1A followed by further oxidation with DDQ as shown in Scheme 3.
AllylO2C
AllylO2C
CO2Allyl
CO2Allyl
DDQ DDQ
tBuO2C
tBuO2C
9
N
H
N
H
1A
t
t
CO2 Bu
CO2 Bu
N
H
N
4A
Scheme 3
8. Slow addition procedure was also effective even in the case of ethylene glycol (2a) and
1,4-butanediol (2d) to give the corresponding esters 3Aa and 3Ad in 57% and 62% yields
accompanied with the aldehyde 8A in 7% and 17% yields, respectively.
9. It was reported that 1,3-dioxolanes and 1,3-dioxanes with an aromatic group at C2 position,
especially with an electron-donating p-methoxyphenyl group, were oxidized by DDQ into the
corresponding carboxylates and their equivalents, for example: a) J.-I. Iwamura, N. Iwamoto, and N.
Hirao, Nippon Kagaku Kaishi, 1977, 1009; b) K. Nakayama and J. D. Rainier, Tetrahedron, 1990,
46, 4165; c) B. Wünsch and S. Nerdinger, Eur. J. Org. Chem., 1999, 503; d) H. Tanabe, X. He, P.
Kothandaraman, and M. Yamane, Synlett, 2010, 1190.

1038
HETEROCYCLES, Vol. 86, No. 2, 2012
10. Recent examples of DDQ oxidation of methyl groups attached to aromatic rings to the corresponding
aldehydes: a) J. H. P. Utley and G. G. Rozenberg, Tetrahedron, 2002, 58, 5251; b) S. Nandi, K.
Panda, J. R. Suresh, H. Ila, and H. Junjappa, Tetrahedron, 2004, 60, 3663; c) R. Forke, M. P. Krahl,
F. Däbritz, A. Jäger, and H.-J. Knölker, Synlett, 2008, 1870; d) M. Schmidt and H.-J. Knölker,
Synlett, 2009, 2421; e) R. Bautista, P. Bernal, L. E. Montiel, F. Delgado, and J. Tamariz, Synthesis,
2011, 929.
11. A representative procedure for the oxidation of 1A (Table 1, Entry 6): To a solution of DDQ (454
mg, 2.0 mmol) and 1,3-propanediol (571 mg, 7.5 mmol) in CH2Cl2 (9 mL) was slowly added a
solution of 1A (147 mg, 0.5 mmol) and H2O (9 mg, 0.5 mmol) in CH2Cl2 (6 mL) in a period of 3 h at
rt under a nitrogen atmosphere. After stirring for another 16 h at rt, the reaction mixture was
quenched by the addition of an aqueous solution containing ascorbic acid (0.7%), citric acid (1.3%),
and sodium hydroxide (0.9%). The mixture was extracted with ether and the combined extracts
were washed with brine, and dried over Na2SO4. The solvent was evaporated and the residue was
separated by TLC on SiO2, which was pretreated with hexane/Et3N (100/1, v/v), (hexane/AcOEt =
2/1, v/v) to afford 3Ab (136 mg, 71%) as an oil. 3Ab: IR (neat) 3308, 2976, 1734, 1716, 1697,
1557, 1541, 1507, 1457, 1417, 1369, 1288, 1141, 1050, 943, 840, 786, 757 cm!1. 1H NMR (400
MHz, CDCl3) ! 1.58 (s, 9H), 1.93–1.99 (m, 2H), 2.54 (br, 1H), 2.60 (t, 2H, J = 8.3 Hz), 3.40 (t, 2H,
J = 8.3 Hz), 3.71–3.79 (m, 2H), 4.40 (t, 2H, J = 6.0 Hz), 4.59 (d, 2H, J = 6.0 Hz), 5.22 (d, 1H, J =
10.6 Hz), 5.30 (d, 1H, J = 17.0 Hz), 5.86–5.97 (m, 1H), 7.48 (d, 1H, J = 3.6 Hz), 9.87 (br, 1H). 13C
NMR (100 MHz, CDCl3) ! 20.9, 28.2, 31.8, 35.2, 59.0, 60.6, 64.9, 82.0, 115.7, 118.0, 122.1, 127.2,
130.5, 132.1, 161.0, 164.7, 172.8. HRMS (FAB+) (M+ + H), found: m/z 382.1864. Calcd for
C19H28NO7: 382.1866.
12. R. A. Sheldon and J. K. Kochi, 'Metal-Catalyzed Oxidations of Organic Compounds,' Academic
Press, New York, 1981, Chap. 10; A. H. Haines, 'Methods for the Oxidation of Organic
Compounds,' Academic Press, London, 1985, Chap. 2.5.