Unusual synthesis of dihydropyrido[2,1-a]isoindolone derivatives by radical cyclization of enamides of Baylis-Hillman adducts

Article abstract of DOI:10.1016/j.tetlet.2007.04.111

During the radical cyclization of enamide derivatives 4 we found unusual formation of dihydropyrido[2,1-a]isoindolone derivatives 5. The enamides were synthesized in four steps from the Baylis-Hillman adducts of ortho-bromobenzaldehydes.

Full text of DOI:10.1016/j.tetlet.2007.04.111

Tetrahedron Letters 48 (2007) 4419–4422
Unusual synthesis of dihydropyrido[2,1-a]isoindolone derivatives
by radical cyclization of enamides of Baylis–Hillman adducts
a
a
b
a,
*
Saravanan Gowrisankar, Seong Jin Kim, Ji-Eun Lee and Jae Nyoung Kim
a
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
Department of Chemistry (BK21) and Central Instrument Facility, Gyeongsang National University, Jinju 660-701, Republic of Korea
b
Received 29 March 2007; accepted 16 April 2007
Available online 27 April 2007
Abstract—During the radical cyclization of enamide derivatives 4 we found unusual formation of dihydropyrido[2,1-a]isoindolone
derivatives 5. The enamides were synthesized in four steps from the Baylis–Hillman adducts of ortho-bromobenzaldehydes.
ꢀ
2007 Elsevier Ltd. All rights reserved.
Recently a variety of chemical transformations using the
Baylis–Hillman adducts have been investigated exten-
sively. Especially the usefulness of the Baylis–Hillman
the Baylis–Hillman adducts have also been examined
by us and other research groups.
2
1
adducts for the synthesis of many heterocyclic com-
pounds is noteworthy. Radical cyclizations involving
Radical cyclizations of enamide derivatives have been
reported for the synthesis of many heterocyclic
1
(
i) Ac O, DMAP, 96%
2
OH
(ii) NaN3, DMSO, 72%
ethyl acrylate
DABCO
COOEt
Br NH2
CHO
(iii) Ph P, aq THF, 88%
3
COOEt
rt, 10 days
Br
Br
9
2%
2
a
1
a
HOOC
O
toluene
reflux, 3 h
COOEt
3
a
N
O
COOEt
N
COOEt
O
2
n
-Bu SnH, AIBN
6
3
H
benzene, reflux
Br
N
1
0b
O
COOEt
H
4
a (41%)
N
H C
3
O
5a (56%)
7
Scheme 1.
Keywords: Dihydropyrido[2,1-a]isoindolone; Radical cyclization; Enamides; Baylis–Hillman adducts.
*
Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389; e-mail: kimjn@chonnam.ac.kr
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.111

4420
S. Gowrisankar et al. / Tetrahedron Letters 48 (2007) 4419–4422
Table 1. Synthesis of dihydropyrido[2,1-a]isoindolone derivatives
Entry Enamide 4 (% yield)
Product 5 (% yield)
COOEt
O
COOEt
Br
Br
N
1
H
N
O
H
H
4
a (41)
5
5
a (56)
COOMe
N
COOMe
O
H
2
3
N
O
4
b (47)
b (56)
F
COOMe
N
F
COOMe
O
Br
N
H
O
H
4
c (39)
5
c (63)
COOEt
COOEt
O
Br
N
H
N
4
5
O
O
Ph
H
4d (53)a
Figure 1. ORTEP drawing of compound 5a.
Ph
COOMe
5d (46)
COOMe
N
3
3a,b
compounds including isoindolobenzazepines,
tetra-
O
3
c
3d
hydroisoquinolines, erythrina alkaloids, and mappi-
cine ketone Nothapodytine B. During the studies
on the chemical transformations of Baylis–Hillman
Br
4e (53)a
N
H
3
e
Ph
H
2
adducts we were interested in the synthesis of eight-
Ph
5e (49)
membered cyclic compounds (vide infra) via the radical
cyclization reaction of enamide derivatives derived from
Baylis–Hillman adducts.
a
We used benzalphthalide (3b) instead of 3a.
The required enamide 4a was synthesized from the
Baylis–Hillman adduct of 2-bromobenzaldehyde 1a
toluene to synthesize enamide 4a in moderate yield
(Scheme 1). With this compound 4a in our hands we
3
a
by following the sequential reactions: (1) acetylation of
examined the cyclization under typical radical cycliza-
0
1
a with Ac O in the presence of DMAP (96%), (2) S 2
tion reaction conditions using n-Bu SnH/AIBN in
2
N
3
4
reaction with NaN in DMSO (72%), (3) Staudinger
benzene. We obtained tricyclic dihydropyrido[2,1-a]
isoindolone compound 5a in 56% yield, unexpectedly.
3
4
,5
reaction with PPh in aq THF to prepare 2a (88%),
3
and (4) the reaction with 2-acetylbenzoic acid (3a) in
We did not observe the other meaningful spots on TLC
COOEt
O
COOEt
O
4
a
N
N
(
II)
(
I)
Ph
N
COOEt
N
COOEt
Ph
5
a
O
O
(
III)
Scheme 2.

S. Gowrisankar et al. / Tetrahedron Letters 48 (2007) 4419–4422
4421
COOEt
O
COOEt
O
same conditions
H
N
Cl
N
4
f (47%)
8 (58%)
Scheme 3.
although many intractable spots were found. In order to
check the possibility for the formation of eight-mem-
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,
6
bered compound 6 or seven-membered compound
3
a,b
7
,
we examined the reaction conditions including
reaction temperature and the amount of n-Bu SnH;
3
2
6, 1481–1490, and further references cited therein.
however, we could not detect nor isolate any new com-
pounds in appreciable amounts.
2
. For the examples of radical cyclization reactions involving
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;
1
The structure of compound 5a was confirmed by IR, H
13
and C NMR, mass, and eventually by its X-ray crys-
4
,7
tallographic structure (Fig. 1). Compound 5a might
be produced via the proposed mechanism in Scheme 2.
The intermediate benzylic radical (III) could be gener-
ated from the initially generated aryl radical (I) by suc-
(
d) Park, D. Y.; Gowrisankar, S.; Kim, J. N. Bull. Korean
Chem. Soc. 2005, 26, 1440–1442; (e) Gowrisankar, S.; Lee,
K. Y.; Kim, J. N. Bull. Korean Chem. Soc. 2006, 27, 929–
932; (f) Gowrisankar, S.; Lee, H. S.; Kim, J. N. Bull. Korean
Chem. Soc. 2006, 27, 2097–2100; (g) Majhi, T. P.; Neogi,
A.; Ghosh, S.; Mukherjee, A. K.; Chattopadhyay, P.
Tetrahedron 2006, 62, 12003–12010; (h) Shanmugam, P.;
Rajasingh, P. Tetrahedron Lett. 2005, 46, 3369–3372; (i)
Shanmugam, P.; Rajasingh, P. Tetrahedron 2004, 60, 9283–
9295; (j) Shanmugam, P.; Rajasingh, P. Synlett 2005, 939–
942.
8
cessive 1,5-hydrogen atom abstraction to form the
intermediate (II) and conversion to benzylic radical
(
III). It is interesting to note that the aryl radical (I)
has allylic protons at 1,5-position thus translocation of
aryl radical to the more stable allyl radical (II) occurred
easily. Radical cyclization of this benzylic radical (III) in
a 6-endo-trig manner and the hydrogen atom abstraction
3
. For the synthesis and radical cyclizations of enamides, see:
from n-Bu SnH furnished 5a.
3
(
a) Cid, M. M.; Dominguez, D.; Castedo, L.; Vazquez-
Lopez, E. M. Tetrahedron 1999, 55, 5599–5610; (b) Rodri-
guez, G.; Cid, M. M.; Saa, C.; Castedo, L.; Dominguez, D.
J. Org. Chem. 1996, 61, 2780–2782; (c) Ishibashi, H.; Kato,
I.; Takeda, Y.; Kogure, M.; Tamura, O. Chem. Commun.
We examined the generality of this reaction by using
enamides 4b–e and we obtained the expected tricyclic
compounds 5b–e in 46–63% yields (Table 1). As shown
in entries 4 and 5 benzylidene derivatives 4d and 4e
showed similar reactivity to produce 5d and 5e, respec-
tively. However, we did not obtain 5a from the reaction
of chloro derivative 4f. Instead we isolated the reduction
compound 8 in 58% yield (Scheme 3).9
2
000, 1527–1528; (d) Guerrero, M. A.; Cruz-Almanza, R.;
Miranda, L. D. Tetrahedron 2003, 59, 4953–4958; (e) Kato,
I.; Higashimoto, M.; Tamura, O.; Ishibashi, H. J. Org.
Chem. 2003, 68, 7983–7989; (f) Zhou, A.; Njogu, M. N.;
Pittman, C. U., Jr. Tetrahedron 2006, 62, 4093–4102.
. Typical procedure for the synthesis of 5a and the spectro-
scopic data of 4a and 5a–e are as follows: A stirred mixture
4
In summary, we disclosed the synthesis of dihydro-
pyrido[2,1-a]isoindolone derivatives from the radical
cyclization reaction of enamide derivatives, which were
synthesized in 4 steps from the Baylis–Hillman adducts
of ortho-bromobenzaldehydes.
3
of 4a (165 mg, 0.4 mmol), n-Bu SnH (175 mg, 0.6 mmol),
AIBN (13 mg, 0.08 mmol) in benzene (5 mL) was heated to
reflux for 3 h. After usual aqueous workup procedure and
column chromatographic purification process (hexanes/
EtOAc, 6:4), we obtained 5a as a white solid, 75 mg (56%).
Compound 4a: 41%; colorless oil; IR (KBr) 2981, 1718,
ꢀ1
1
1
248 cm
;
H NMR (500 MHz, CDCl ) d 1.20 (t,
3
Acknowledgments
J = 7.5 Hz, 3H), 4.21 (q, J = 7.5 Hz, 2H), 4.62 (d,
J = 2.5 Hz, 1H), 4.83 (d, J = 1.5 Hz, 2H), 5.07 (d, J =
2
7
7
1
1
1
4
.5 Hz, 1H), 7.05–7.09 (m, 1H), 7.21–7.24 (m, 1H), 7.27–
This work was supported by the Korea Research Foun-
dation Grant funded by the Korean Government
.30 (m, 1H), 7.40–7.44 (m, 1H), 7.48–7.56 (m, 3H), 7.71–
1
3
3
.74 (m, 1H), 7.86 (s, 1H); C NMR (125 MHz, CDCl ) d
(
MOEHRD, KRF-2006-311-C00384). Spectroscopic
4.00, 36.95, 61.24, 90.17, 119.51, 122.95, 123.24, 127.05,
28.89, 129.16, 129.41, 129.86, 130.43, 131.78, 132.54,
data was obtained from the Korea Basic Science Insti-
tute, Gwangju branch.
34.84, 136.12, 140.81, 141.11, 166.13, 166.78; LCMS m/z
+
11 (M ). Anal. Calcd for C21
3
H18BrNO : C, 61.18; H, 4.40;
N, 3.40. Found: C, 61.32; H, 4.51; N, 3.97. Compound 5a:
56%; white solid, mp 195–198 ꢁC; IR (KBr) 2925, 1714,
References and notes
ꢀ
1 1
1
626, 1261 cm ; H NMR (500 MHz, CDCl ) d 1.04 (t,
3
1
. For the review articles on Baylis–Hillman reaction, see: (a)
Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev.
J = 7.0 Hz, 3H), 1.57–1.65 (m, 1H), 2.81–2.86 (m, 1H),
3.94–4.00 (m, 1H), 4.02–4.08 (m, 2H), 4.75 (dd, J = 12.5
and 2.5 Hz, 1H), 7.16–7.28 (m, 5H), 7.46 (d, J = 7.5 Hz,
2
003, 103, 811–891; (b) Ciganek, E. In Organic Reactions;

4
422
S. Gowrisankar et al. / Tetrahedron Letters 48 (2007) 4419–4422
H), 7.52 (t, J = 7.5 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.94
1
5. For the synthesis of similar pyridoisoindole derivatives, see:
(a) Marion, F.; Courillon, C.; Malacria, M. Org. Lett. 2003,
5, 5095–5097; (b) Ha, D.-C.; Yun, C.-S.; Yu, E. Tetrahe-
dron Lett. 1996, 37, 2577–2580; (c) Othman, M.; Pigeon, P.;
Decroix, B. Tetrahedron 1998, 54, 8737–8744; (d) Mange-
ney, P.; Pays, C. Tetrahedron Lett. 2003, 44, 5719–5722; (e)
Pays, C.; Mangeney, P. Tetrahedron Lett. 2001, 42, 589–
592; (f) Zhang, W.; Zheng, A.; Liu, Z.; Yang, L.; Liu, Z.
Tetrahedron Lett. 2005, 46, 5691–5694; (g) Zhang, W.;
Pugh, G. Tetrahedron 2003, 59, 3009–3018; (h) Varlamov,
A. V.; Zubkov, F. I.; Boltukhina, E. V.; Sidorenko, N. V.;
Borisov, R. S. Tetrahedron Lett. 2003, 44, 3641–3643.
6. For the synthesis of eight-membered ring compounds via
radical cyclizations, see: (a) Bremner, J. B.; Sengpracha, W.
Tetrahedron 2005, 61, 941–953; (b) Lee, E.; Yoon, C. H.;
Lee, T. H.; Kim, S. Y.; Ha, T. J.; Sung, Y.-S.; Park, S.-H.;
Lee, S. J. Am. Chem. Soc. 1998, 120, 7469–7478; (c) Lang,
S.; Corr, M.; Muir, N.; Khan, T. A.; Schonebeck, F.;
Murphy, J. A.; Payne, A. H.; Williams, A. C. Tetrahedron
Lett. 2005, 46, 4027–4030; (d) Kaim, L. E.; Grimaud, L.;
Miranda, L. D.; Vieu, E. Tetrahedron Lett. 2006, 47, 8259–
8261.
1
3
(
d, J = 7.5 Hz, 1H), 8.35 (s, 1H); C NMR (125 MHz,
CDCl ) d 13.90, 38.11, 41.12, 57.12, 60.04, 115.50, 122.23,
3
1
1
24.57, 126.42, 126.73, 128.50, 128.94, 131.17, 131.80,
33.07, 144.10, 144.22, 165.45, 166.21; LCMS m/z 333
+
(
M ). Anal. Calcd for C21
H19NO
3
: C, 75.66; H, 5.74; N,
4.20. Found: C, 75.45; H, 5.87; N, 4.03.
Compound 5b: 56%; white solid, mp 189–191 ꢁC; IR (KBr)
ꢀ
1
1
2
1
4
7
1
5
1
1
925, 1714, 1261 cm ; H NMR (300 MHz, CDCl ) d
3
.62–1.64 (m, 1H), 2.80–2.84 (m, 1H), 3.57 (s, 3H), 4.02–
.08 (m, 1H), 4.73–4.78 (m, 1H), 7.16–7.31(m, 5H), 7.45–
.65 (m, 3H), 7.94 (d, J = 7.5 Hz, 1H), 8.36 (d, J = 1.5 Hz,
H); C NMR (75 MHz, CDCl ) d 38.20, 41.11, 51.31,
3
7.12, 115.17, 122.28, 124.67, 126.55, 126.73, 128.61,
13
29.02, 131.23, 132.10, 133.15, 143.98, 144.26, 165.49,
66.61; LCMS m/z 319 (M ). Anal. Calcd for
+
20 3
C H17NO : C, 75.22; H, 5.37; N, 4.39. Found: C, 75.09;
H, 5.56; N, 4.36.
Compound 5c: 63%; white solid, mp 193–195 ꢁC; IR (KBr)
ꢀ
1
1
2
1
4
6
7
950, 1712, 1275 cm ; H NMR (300 MHz, CDCl ) d
3
.52–1.64 (m, 1H), 2.80–2.88 (m, 1H), 3.59 (s, 3H), 4.02–
.11 (m, 1H), 4.72–4.77 (m, 1H), 6.86–6.88 (m, 2H), 6.94–
.97 (m, 1H), 7.20–7.27 (m, 1H), 7.46–7.55 (m, 2H), 7.61–
7. Crystal data of compound 5a: solvent of crystal growth
1
3
.66 (m, 1H), 7.93 (d, J = 7.5 Hz, 1H), 8.37 (s, 1H);
C
(hexanes/CH Cl , 95:5); empirical formula C21H19NO ,
2 2 3
3
NMR (75 MHz, CDCl ) d 37.93, 40.79, 51.32, 56.90,
Fw = 333.37, crystal dimensions 0.60 · 0.20 · 0.02 mm ,
3
˚
1
1
1
1
13.28, 113.53, 113.56, 113.82, 114.31, 122.28, 122.33,
22.37, 124.66, 129.06, 129.98, 130.08, 131.09, 132.46,
33.21, 144.07, 146.59, 146.68, 161.27, 164.53, 165.39,
66.38. Anal. Calcd for C H FNO : C, 71.21; H, 4.78;
monoclinic, space group P2(1)/c, a = 17.9110(19) A, b =
˚
˚
6.3191(7) A, c = 15.3166(17) A, a = 90ꢁ, b = 94.424(2)ꢁ,
˚
3
3
c = 90ꢁ, V = 1728.4(3) A , Z = 4, Dcalcd = 1.281 mg/m .
˚
F
000
= 704, MoKa (k = 0.71073 A), R = 0.0747, wR =
1 2
2
0
16
3
N, 4.15. Found: C, 71.13; H, 4.97; N, 4.38.
0.1718 (I > 2r(I)). We omitted hydrogen atoms for clarity
(Fig. 1). The X-ray data has been deposited in CCDC with
number 634382.
Compound 5d: 46%; white solid, mp 200–202 ꢁC; IR (KBr)
ꢀ1 1
2
909, 1714, 1263 cm ; H NMR (300 MHz, CDCl ) d 1.04
3
(
1
5
t, J = 6.9 Hz, 3H), 3.94–4.16 (m, 3H), 4.62 (dd, J = 2.4 Hz,
H), 5.24 (d, J = 3.6 Hz, 1H), 6.62 (s, 2H), 6.81–6.82 (m,
8. For the examples of intramolecular hydrogen transfer of
radical intermediates, see: (a) Dort, P. C. V.; Fuchs, P. L. J.
Org. Chem. 1997, 62, 7142–7147; (b) Curran, D. P.; Yang,
F.; Cheong, J.-H. J. Am. Chem. Soc. 2002, 124, 14993–
15000; (c) Zeng, L.; Kaoudi, T.; Schiesser, C. H. Tetrahe-
dron Lett. 2006, 47, 7911–7914; (d) Rancourt, J.; Gorys, V.;
Jolicoeur, E. Tetrahedron Lett. 1998, 39, 5339–5342; (e)
Amrein, S.; Bossart, M.; Vasella, T.; Studer, A. J. Org.
Chem. 2000, 65, 4218–4288; (f) Qian, X.; Cui, J.; Zhang, R.
Chem. Commun. 2001, 2656–2657; (g) Karady, S.; Cum-
mins, J. M.; Dannenberg, J. J.; del Rio, E.; Dormer, P. G.;
Marcune, B. F.; Reamer, R. A.; Sordo, T. L. Org. Lett.
2003, 5, 1175–1178; (h) Renaud, P.; Beaufils, F.; Feray, L.;
Schenk, K. Angew. Chem. 2003, 115, 4362–4365; (i) Clive,
D. L. J.; Yang, W.; MacDonald, A. C.; Wang, Z.; Cantin,
M. J. Org. Chem. 2001, 66, 1966–1983.
H), 6.96–6.98 (m, 3H), 7.18–7.45 (m, 3H), 7.74 (d,
1
3
J = 7.8 Hz, 1H), 8.47 (d, J = 2.1 Hz, 1H); C NMR
75 MHz, CDCl ) d 13.90, 45.63, 48.32, 60.25, 60.78,
15.21, 122.58, 124.28, 125.84, 126.71, 127.50, 127.77,
(
3
1
1
1
28.51, 131.41, 132.14, 132.78, 135.40, 140.71, 143.19,
66.97, 166.68 (two aromatic carbons were overlapped);
+
LCMS m/z 409 (M ).
Compound 5e: 49%; white solid, mp 211–213 ꢁC; IR (KBr)
2
ꢀ1 1
950, 1714, 1397 cm ; H NMR (300 MHz, CDCl ) d 3.60
3
(
s, 3H), 3.95 (dd, J = 3.9 Hz, 1H), 4.62 (dd, J = 2.3 Hz, 1H),
.25 (d, J = 3.9 Hz, 1H), 6.61 (s, 2H), 6.80–6.81 (m, 5H),
5
6
1
4
1
1
.93–7.00 (m, 3H), 7.26–7.46 (m, 3H), 7.74 (d, J = 7.8 Hz,
1
3
H), 8.48 (d, J = 2.4 Hz, 1H); C NMR (75 MHz, CDCl ) d
3
5.52, 48.36, 51.44, 60.72, 114.75, 122.59, 124.29, 125.89,
26.72, 127.54, 127.70, 127.76, 128.53, 131.36, 132.45,
32.82, 135.44, 140.52, 143.20, 165.98, 167.04 (one aromatic
9. The formation of compound 8 from 4f clearly stated that the
corresponding aryl radical must be generated in the reaction.
However, we could not explain the different reactivity of two
aryl radicals generated from 4a and 4f at this stage.
carbon was overlapped). Anal. Calcd for C H NO : C,
7
2
6
21
3
8.97; H, 5.35; N, 3.54. Found: C, 78.65; H, 5.37; N, 3.39.