Synthesis of poly-substituted pyrroles starting from the Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tetlet.2007.04.022

We synthesized poly-substituted pyrrole derivatives 4a-e, 7a-c and 10a-d from the reaction of phenacyl bromide and the aza-Baylis-Hillman adducts 1a-d or their rearranged derivatives 5a-e. The pyrroles were synthesized via the successive N-alkylation, Mic

Full text of DOI:10.1016/j.tetlet.2007.04.022

Tetrahedron Letters 48 (2007) 4119–4122
Synthesis of poly-substituted pyrroles starting from
the Baylis–Hillman adducts
Hyun Seung Lee, Jeong Mi Kim and Jae Nyoung Kim*
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
Received 12 March 2007; revised 30 March 2007; accepted 2 April 2007
Available online 11 April 2007
Abstract—We synthesized poly-substituted pyrrole derivatives 4a–e, 7a–c and 10a–d from the reaction of phenacyl bromide and the
aza-Baylis–Hillman adducts 1a–d or their rearranged derivatives 5a–e. The pyrroles were synthesized via the successive N-alkyl-
ation, Michael addition, elimination of p-toluenesulfinic acid and oxidative aromatization processes.
Ó 2007 Elsevier Ltd. All rights reserved.
A variety of aromatic and heterocyclic compounds have
been synthesized by using suitable chemical transforma-
tions starting from the Baylis–Hillman adducts.1 Pyr-
roles are the basic skeleton of many biologically
important substances and numerous synthetic methods
of pyrroles have been investigated extensively.2,3 How-
ever, the synthesis of pyrrole derivatives from Baylis–
Hillman adducts was not developed much.3 During the
chemical transformations of Baylis–Hillman adducts4
we were interested in the synthesis of poly-substituted
pyrrole derivatives.
Our initial synthetic pathway is depicted in Scheme 1. We
thought that trisubstituted tetrahydropyrrole derivatives
3 could be synthesized from aza-Baylis–Hillman adducts
15 by sequential N-alkylation with phenacyl bromide
(2a) and Michael addition at the conjugated vinyl moi-
ety of the corresponding intermediate.6 Elimination of
O
N
R3
Ts
NH
O
K2CO3 (3 equiv)
DMF, rt, 24 h
Ts
O
+
R2
Br
R3
R1
R1
R2
O
1a: R1 = H, R2 = Me
1b: R1 = Cl, R2 = Me
1c: R1 = Me, R2 = Me
1d: R1 = H, R2 = OEt
2a: R3 = Ph
2b: R3 = 2-naphthyl
(I)
O
N
O
N
DBU (3 equiv)
CH3CN, rt, 24 h
R2
R2
R1
R1
R3
R3
O
Ts
H
O
4a-e (42-61%)
3a-e (63-86%)
Scheme 1.
Keywords: Poly-substituted pyrroles; Baylis–Hillman adducts; Michael addition; DBU.
*
Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389; e-mail: kimjn@chonnam.ac.kr
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.022

4120
H. S. Lee et al. / Tetrahedron Letters 48 (2007) 4119–4122
Table 2. Synthesis of 2,3,4-trisubstituted pyrroles
Table 1. Synthesis of 2,3,5-trisubstituted pyrroles
Entry
1 + 2
3 (%)
4 (%)
Entry
5 + 2
6 (%)
7 (%)
1
2
3
4
5
1a + 2a
1a + 2b
1b + 2a
1c + 2a
1d + 2a
3a (70)
3b (86)
3c (68)
3d (63)
3e (74)
4a (54)
4b (48)
4c (52)
4d (61)
4e (42)
1
2
3
5a + 2a
5a + 2b
5b + 2a
6a (60)
6b (56)
6c (58)
7a (81)
7b (77)
7c (73)
ate yields (42–61%) and the results are summarized in
Table 1.7 Although the mechanism for the dehydrogena-
tive oxidation process is unclear at this stage8 we could
prepare our desired pyrroles very easily in two steps.
p-toluenesulfinic acid from 3 and the following oxidation
would give 2,3,5-trisubstituted pyrroles 4 (Scheme 1).
The reaction of 1a–d and phenacyl bromide (2a) or 2-
bromo-20-acetonaphthone (2b) under the influence of
K2CO3 in DMF gave the corresponding diastereomeric
mixtures of tetrahydropyrroles 3a–e in moderate yields
(63–86%) via the intermediate (I). Actually we observed
the formation of several isomers of 3 having similar Rf
values on TLC. We separated them together by using
a short path silica column and used them together in
the next elimination reaction. The elimination of p-tolu-
enesulfinic acid was examined with DBU in CH3CN.
However, to our surprise, we obtained 2,3,5-trisubsti-
tuted pyrroles 4 directly under the conditions in moder-
Encouraged by the results we examined the reaction of
rearranged tosylamide derivatives 5a and 5b, which
could be easily synthesized from the corresponding Bay-
lis–Hillman acetates and tosylamide in an SN20 manner.5
The reactions of 5a and 5b showed the same reactivity as
those of 1a–d and we synthesized 2,3,4-trisubstituted
pyrroles 7a–c in good yields (73–81%) under the same
conditions. The results are summarized in Scheme 2
and in Table 2.
However, the reactions of 5c–e were somewhat different
from those of the cases of Schemes 1 and 2. The reac-
K2CO3 (3 equiv)
DMF, rt, 24 h
EWG
EWG
O
Ph
+
Br
R3
R3
N
NHTs
Ts
(II)
O
2a, b
5a: EWG = COOMe
5b: EWG = COOEt
Ph
Ph
DBU (3 equiv)
CH3CN, rt, 24 h
EWG
EWG
O
O
N
R3
N
R3
H
Ts
7a-c (73-81%)
6a-c (56-60%)
Scheme 2.
O
O
K2CO3 (3 equiv)
DMF, rt, 8-20 h
O
+
Br
R3
R3
R1
N
Ts
R1
NHTs
O
5c: R1= H
5d: R1 = Cl
5e: R1 = Me
2a, b
(III)
aldol
R1
R1
DBU (3 equiv)
CH3CN, rt, 24 h
OH
O
O
O
O
O
(i) retro-aldol to (III)
(ii) Michael to 9
N
Ts
R3
R1
N
N
R3
R3
H
Ts
9a-d
8a-d (50-86%)
syn/anti = 39-66%/11-20%
10a-d (51-71%)
Scheme 3.

H. S. Lee et al. / Tetrahedron Letters 48 (2007) 4119–4122
Table 3. Synthesis of 2,3,4-trisubstituted pyrroles
4121
Chen, Q.; Wang, T.; Zhang, Y.; Wang, Q.; Ma, J. Synth.
Commun. 2002, 32, 1051–1058; (h) Nicolaou, I.; Demopo-
ulos, V. J. J. Med. Chem. 2003, 46, 417–426; (i) Gupton, J.
T.; Banner, E. J.; Scharf, A. B.; Norwood, B. K.; Kanters,
R. P. F.; Dominey, R. N.; Hempel, J. E.; Kharlamova, A.;
Bluhn-Chertudi, I.; Hickenboth, C. R.; Little, B. A.; Sartin,
M. D.; Coppock, M. B.; Krumpe, K. E.; Burnham, B. S.;
Holt, H.; Du, K. X.; Keertikar, K. M.; Diebes, A.;
Ghassemi, S.; Sikorski, J. A. Tetrahedron 2006, 62, 8243–
8255; (j) Cadamuro, S.; Degani, I.; Dughera, S.; Fochi, R.;
Gatti, A.; Piscopo, L. J. Chem. Soc., Perkin Trans. 1 1993,
273–283; (k) Cohnen, E.; Dewald, R. Synthesis 1987, 566–
568; (l) Misra, N. C.; Panda, K.; Ila, H.; Junjappa, H. J.
Org. Chem. 2007, 72, 1246–1251.
Entry
5 + 2
Time (h)
8 (%, syn/anti)a
10 (%)
1
2
3
4
5c + 2a
5c + 2b
5d + 2a
5e + 2a
8
8
10
20
8a (86, 66/20)
8b (73, 56/17)
8c (79, 59/20)
8d (50, 39/11)b
10a (71)
10b (51)
10c (67)
10d (67)
a Isolated yields of syn and anti isomers.
b The yield of 8d was relatively low due to low reactivity of 5e.
tions of 5c–e and 2 under the same conditions (K2CO3/
DMF) produced 8a–d as the major products as separa-
ble syn/anti mixtures.9 The formation of 8 can be
explained by an intramolecular aldol reaction of
intermediate (III). However, when we subjected 8 under
the conditions of DBU in CH3CN we could obtain
2,3,4-trisubstituted pyrroles 10a–d in moderate yields
(51–71%), fortunately. Compounds 8a–d could be con-
verted to intermediate (III) by the retro-aldol pathway
and intermediate (III) was slowly transformed to 9a–d
via the Michael addition pathway. The last step for
the formation of 10 from 9 could be explained as in
Schemes 1 and 2. The results are summarized in Scheme
3 and in Table 3.
3. For the examples on the synthesis of pyrroles from Baylis–
Hillman adducts, see: (a) Declerck, V.; Ribiere, P.; Marti-
nez, J.; Lamaty, F. J. Org. Chem. 2004, 69, 8372–8381; (b)
Shi, M.; Xu, Y.-M. Eur. J. Org. Chem. 2002, 696–701; (c)
Roy, A. K.; Pathak, R.; Yadav, G. P.; Maulik, P. R.; Batra,
S. Synthesis 2006, 1021–1027.
4. For our recent papers on chemical transformations involv-
ing the Baylis–Hillman adducts, see: (a) Gowrisankar, S.;
Lee, K. Y.; Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2006,
47, 5785–5788; (b) Gowrisankar, S.; Lee, K. Y.; Kim, J. N.
Tetrahedron 2006, 62, 4052–4058; (c) Gowrisankar, S.; Lee,
K. Y.; Kim, J. N. Tetrahedron Lett. 2005, 46, 4859–4863;
(d) Lee, K. Y.; Gowrisankar, S.; Lee, Y. J.; Kim, J. N.
Tetrahedron 2006, 62, 8798–8804; (e) Park, D. Y.; Gowri-
sankar, S.; Kim, J. N. Tetrahedron Lett. 2006, 47, 6641–
6645; (f) Park, D. Y.; Kim, S. J.; Kim, T. H.; Kim, J. N.
Tetrahedron Lett. 2006, 47, 6315–6319; (g) Gowrisankar, S.;
Kim, S. J.; Kim, J. N. Tetrahedron Lett. 2007, 48, 289–292;
(h) Park, D. Y.; Lee, K. Y.; Kim, J. N. Tetrahedron Lett.
2007, 48, 1633–1636; (i) Kim, S. J.; Lee, H. S.; Kim, J. N.
Tetrahedron Lett. 2007, 48, 1069–1072, and further refer-
ences cited therein.
In summary, we developed an expeditious synthetic
method of poly-substituted pyrrole derivatives from
the reaction of phenacyl bromide and the aza-Baylis–
Hillman adducts or their rearranged derivatives via
successive N-alkylation, Michael addition, elimination
of p-toluenesulfinic acid and oxidative aromatization
processes. The studies on DBU-mediated interesting
oxidation process are underway.
5. For the synthesis of aza-Baylis–Hillman adducts and the
rearranged compounds, see: (a) Park, D. Y.; Lee, M. J.;
Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2005, 46, 8799–
8803; (b) Lee, M. J.; Kim, S. C.; Kim, J. N. Bull. Korean
Chem. Soc. 2006, 27, 439–442; (c) Kim, J. N.; Lee, H. J.;
Lee, K. Y.; Gong, J. H. Synlett 2002, 173–175; (d) Balan,
D.; Adolfsson, H. J. Org. Chem. 2001, 66, 6498–6501; (e)
Balan, D.; Adolfsson, H. J. Org. Chem. 2002, 67, 2329–
2334; (f) Balan, D.; Adolfsson, H. Tetrahedron Lett. 2004,
45, 3089–3092.
6. For the synthesis of indole derivatives by using the similar
approach, N-alkylation with phenacyl bromide and the
following Michael type reaction, please see: Caron, S.;
Vazquez, E.; Stevens, R. W.; Nakao, K.; Koike, H.;
Murata, Y. J. Org. Chem. 2003, 68, 4104–4107.
Acknowledgments
This work was supported by the Korea Research Foun-
dation Grant funded by the Korean Government
(MOEHRD, KRF-2006-311-C00384). Spectroscopic
data were obtained from the Korea Basic Science Insti-
tute, Gwangju branch.
References and notes
7. Typical procedure for the synthesis of compound 4a and some
selected spectroscopic data of 4a, 7a, 8a-syn, 8a-anti and 10a
are as follows: A solution of 1a (329 mg, 1.0 mmol), K2CO3
(415 mg, 3.0 mmol) and 2a (300 mg, 1.5 mmol) in DMF
(2 mL) was stirred at room temperature for 24 h. After the
usual aqueous workup and column chromatographic puri-
fication process (hexanes/CH2Cl2/ether, 4:1:1) we obtained
compound 3a (313 mg, 70%) as a yellow solid (Rf value of
the major diastereoisomer on TLC is 0.25 in hexanes/
ether = 1:3). Compound 3a (224 mg, 0.5 mmol) was dis-
solved in CH3CN (2 mL) and DBU (228 mg, 1.5 mmol) was
added and stirred at room temperature for 24 h. After the
usual aqueous workup and column chromatographic puri-
fication process (hexanes/CH2Cl2/ether, 2:1:1) we obtained
compound 4a (79 mg, 54%) as a white solid.
1. For the review articles on Baylis–Hillman reaction, see: (a)
Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
2003, 103, 811–891; (b) Ciganek, E. In Organic Reactions;
Paquette, L. A., Ed.; John Wiley & Sons: New York, 1997;
Vol. 51, pp 201–350; (c) Basavaiah, D.; Rao, P. D.; Hyma,
R. S. Tetrahedron 1996, 52, 8001–8062; (d) Kim, J. N.; Lee,
K. Y. Curr. Org. Chem. 2002, 6, 627–645; (e) Lee, K. Y.;
Gowrisankar, S.; Kim, J. N. Bull. Korean Chem. Soc. 2005,
26, 1481–1490, and further references cited therein.
2. For the synthesis of poly-substituted pyrroles and their
biological activities, see: (a) Bellina, F.; Rossi, R. Tetrahe-
dron 2006, 62, 7213–7256; (b) Knight, D. W.; Sharland, C.
M. Synlett 2004, 119–121; (c) Singh, V.; Kanojiya, S.;
Batra, S. Tetrahedron 2006, 62, 10100–10110; (d) Knight,
D. W.; Sharland, C. M. Synlett 2003, 2258–2260; (e)
Magnus, N. A.; Staszak, M. A.; Udodong, U. E.; Wepsiec,
J. P. Org. Proc. Res. Dev. 2006, 10, 899–904; (f) Zen, S.;
Harada, K. Chem. Pharm. Bull. 1982, 30, 366–369; (g)
Compound 4a: 54%; white solid, 178–180 °C; IR (film)
3259, 1674, 1616, 1468, 1257 cmꢀ1 1H NMR (CDCl3,
;
300 MHz) d 2.34 (s, 3H), 7.33 (d, J = 2.7 Hz, 1H), 7.46–7.55

4122
H. S. Lee et al. / Tetrahedron Letters 48 (2007) 4119–4122
(m, 5H), 7.60–7.65 (m, 3H), 7.89 (d, J = 7.2 Hz, 2H), 10.11
80.69, 123.83, 127.47, 127.80, 128.56, 128.70 (2C), 128.89,
129.55, 133.79, 135.51 (2C), 136.59, 140.59, 143.65, 197.20;
LCMS m/z 447 (M+).
(br s, 1H); 13C NMR (CDCl3, 75 MHz) d 29.01, 121.12,
123.96, 128.54, 128.56, 128.97, 129.28, 129.68, 129.81,
130.89, 132.47, 137.43, 141.72, 184.94, 193.96; LCMS m/z
289 (M+). Anal. Calcd for C19H15NO2: C, 78.87; H, 5.23;
N, 4.84. Found: C, 78.65; H, 5.37; N, 4.79.
Compound 10a: 71%; white solid, 228–230 °C; IR (film)
3213, 1658, 1620, 1377, 1281 cmꢀ1 1H NMR (CDCl3,
;
300 MHz) d 2.16 (s, 3H), 6.98–7.11 (m, 7H), 7.17–7.34 (m,
3H), 7.72 (d, J = 3.6 Hz, 1H), 10.02 (br s, 1H); 13C NMR
(CDCl3, 75 MHz) d 29.44, 126.84, 127.66, 127.71 (2C),
128.21, 128.95, 130.17, 131.20, 131.59, 132.19, 133.70,
137.31, 188.35, 194.54; LCMS m/z 289 (M+). Anal. Calcd
for C19H15NO2: C, 78.87; H, 5.23; N, 4.84. Found: C,
78.75; H, 5.11; N, 4.92.
Compound 7a: 81%; white solid, 204–206 °C; IR (film)
3319, 1703, 1622, 1389, 1281 cmꢀ1 1H NMR (CDCl3,
;
300 MHz) d 3.70 (s, 3H), 6.98–7.09 (m, 7H), 7.17–7.35 (m,
3H), 7.74 (d, J = 3.3 Hz, 1H), 10.23 (br s, 1H); 13C NMR
(CDCl3, 75 MHz) d 51.09, 116.32, 126.99, 127.11, 127.38,
128.78, 128.86, 129.72, 131.06, 131.34, 132.87, 133.36,
137.01, 164.14, 187.97; LCMS m/z 305 (M+). Anal. Calcd
for C19H15NO3: C, 74.74; H, 4.95; N, 4.59. Found: C,
74.81; H, 5.01; N, 4.57.
8. The studies on DBU-mediated interesting dehydrogenative
oxidation process are actively underway in our laboratory.
Some interesting base-promoted oxidations or base-
induced disproportionations were reported, see: (a) Pal,
M.; Swamy, N. K.; Hameed, P. S.; Padakanti, S.;
Yeleswarapu, K. R. Tetrahedron 2004, 60, 3987–3997; (b)
Chung, K. H.; Moon, B. C.; Lim, C. H.; Kim, J. P.; Lee, J.
H.; Chi, D. Y. Bull. Korean Chem. Soc. 2006, 27, 1203–
1205; (c) Basavaiah, D.; Sharada, D. S.; Veerendhar, A.
Tetrahedron Lett. 2006, 47, 5771–5774; An example of
simultaneous thermal elimination of sulfinic acid and
oxidation reaction was also reported, see: (d) Boger, D.
L.; Corbett, W. L. J. Org. Chem. 1993, 58, 2068–2074.
9. We separated the syn and anti isomers in all cases;7
however, we did not find any differences in their reactivity
for the next reaction. The spectroscopic interpretation and
the stereochemistry assignment by NOE experiment will be
published in due course.
Compound 8a-syn: 66%; white solid, 98–100 °C; IR (film)
3487, 1691, 1342, 1159, 1095 cmꢀ1 1H NMR (CDCl3,
;
300 MHz) d 1.58 (s, 3H), 2.12 (s, 1H), 2.38 (s, 3H), 4.57 (d,
J = 2.4 Hz, 2H), 5.39 (s, 1H), 6.53 (s, 1H), 7.19–7.63 (m,
12H), 7.92 (d, J = 7.8 Hz, 2H); 13C NMR (CDCl3,
75 MHz) d 21.52, 28.71, 49.53, 67.85, 80.45, 122.58,
127.21, 127.59, 128.56, 128.61, 128.68, 128.73, 129.61,
133.73, 135.63, 135.72, 136.85, 142.34, 143.70, 198.60;
LCMS m/z 447 (M+).
Compound 8a-anti: 20%; white solid, 158–160 °C; IR (film)
3475, 1687, 1338, 1157, 1095 cmꢀ1 1H NMR (CDCl3,
;
300 MHz) d 1.31 (s, 3H), 2.37 (s, 3H), 2.54 (s, 1H), 4.54 (d,
J = 14.4 Hz, 1H), 4.65 (d, J = 14.4 Hz, 1H), 5.53 (s, 1H),
6.49 (s, 1H), 7.18–7.70 (m, 12H), 7.98 (d, J = 7.5 Hz, 2H);
13C NMR (CDCl3, 75 MHz) d 21.49, 21.94, 50.10, 70.81,