An expedient synthesis of indolo[1,2-a]quinolines via Mn(OAc)3-mediated oxidative free radical cyclization and NaI/O2-assisted dealkoxycarbonylation/ aerobic oxidation cascade

Article abstract of DOI:10.1016/j.tetlet.2010.07.092

An expedient synthetic procedure of indolo[1,2-a]quinolines was developed using a sequential Cu-mediated N-arylation of indole, Mn(OAc) ₃-mediated oxidative free radical cyclization, and NaI/O ₂-assisted concomitant dealkoxycarbonylation/aerobic oxidation. The last step was replaced by a palladium-catalyzed decarboxylation/elimination protocol for the allyl ester derivatives.

Full text of DOI:10.1016/j.tetlet.2010.07.092

Tetrahedron Letters 51 (2010) 5071–5075
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Tetrahedron Letters
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An expedient synthesis of indolo[1,2-a]quinolines via Mn(OAc)3-mediated
oxidative free radical cyclization and NaI/O2-assisted
dealkoxycarbonylation/aerobic oxidation cascade
*
Hyun Seung Lee, Se Hee Kim, Yu Mi Kim, Jae Nyoung Kim
Department of Chemistry and Institute of Basic Science, Chonnam National University, Gwangju 500-757, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
An expedient synthetic procedure of indolo[1,2-a]quinolines was developed using a sequential Cu-med-
iated N-arylation of indole, Mn(OAc)3-mediated oxidative free radical cyclization, and NaI/O2-assisted
concomitant dealkoxycarbonylation/aerobic oxidation. The last step was replaced by a palladium-cata-
lyzed decarboxylation/elimination protocol for the allyl ester derivatives.
Received 7 June 2010
Revised 14 July 2010
Accepted 16 July 2010
Available online 22 July 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Indolo[1,2-a]quinolines
Mn(OAc)3
Dealkoxycarbonylation
Aerobic oxidation
Indole moiety-containing poly-fused heterocyclic compounds
have been found in many biologically important natural prod-
ucts.1,2 For example, numerous indole alkaloids have tetra- to hep-
ta-fused heterocyclic structures, as in mersicarpine, tronocarpine,
strychnine, vincamine, and dippinine.1 N-Fused tetracyclic indo-
lo[1,2-a]quinoline derivatives have also been synthesized in a vari-
ety of methods.2
Very recently, we reported an efficient synthesis of poly-fused
tetracyclic compounds having an indole moiety via the Pd-cata-
lyzed cyclization from the Baylis–Hillman adducts.3 Due to the
potential biological activities of poly-fused indole moiety-contain-
ing compounds including hepatitis C virus (HCV) NS5B polymerase
inhibitory activity,3 we were interested in the synthesis of
indolo[1,2-a]quinoline scaffold. However, the reported synthetic
approaches of indolo[1,2-a]quinoline were somewhat restricted
to a special case and did not provide a general way.2 Thus we wish
to report herein an efficient and practical procedure for the synthe-
sis of indolo[1,2-a]quinoline derivatives.
We reasoned out that indolo[1,2-a]quinoline could be synthe-
sized from indole and methyl 2-iodobenzoate using a sequential
Cu-mediated N-arylation of indole, Mn(OAc)3-mediated oxidative
free radical cyclization,4,5 and NaI/O2-assisted concomitant dealk-
oxycarbonylation/aerobic oxidation,4a,6 as shown in Scheme 1.
The final step could be replaced with a Pd-catalyzed decarboxyl-
ation/elimination protocol for the allyl ester.7
The required starting materials 7a–g were prepared from
methyl 2-iodobenzoate (1) in four steps, as shown in Scheme 2.
The first Cu-catalyzed N-arylation of indoles 2a–c (CuI, K2CO3,
DMF, 120 °C, 2 h) afforded 3a–c in reasonable yields (60–70%).8
Reduction of 3a–c with LiAlH4 (THF, rt, 5 min) to the corresponding
NaI/O2/DMF
COOMe
heating
EWG
EWG
EWG
Cu-mediated
coupling
(R = Me)
COOR
Mn(OAc)3
COOR
I
N
N
N
Pd(OAc)2/PPh3
CH3CN, reflux
(R = allyl)
N
H
indolo[1,2-a]quinoline
Scheme 1.
* Corresponding author. Tel.: +82 62 530 3381; fax: +82 62 530 3389.
E-mail address: kimjn@chonnam.ac.kr (J.N. Kim).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.092

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H. S. Lee et al. / Tetrahedron Letters 51 (2010) 5071–5075
COOMe
R3
(i) LiAlH4 (2.0 equiv), THF
R1
2a-c (1.0 equiv)
rt, 5 min, R3 = OH (4a-c)
COOMe
I
R2
CuI (10 mol%)
N
N
+
R1
(ii) PBr3 (1.0 equiv), Et2O
R1
K2CO3 (2.0 equiv)
DMF, 120 ºC, 2 h
N
H
rt, 1 h, R3 = Br (5a-c)
1
2a: R1 = R2 = H
3a: 70%
3b: 60%
3c: 64%
5a: 78%
5b: 65%
5c: 61%
4a: 94% R2
4b: 92%
R2
2b: R1 = Me, R2 = H
2c: R1 = H, R2 = OMe
4c: 88%
EWG1
EWG2
EWG1
EWG2
6a-e (1.5 equiv)
N
5a-c
+
K2CO3 (2.0 equiv)
CH3CN, rt, 12 h
R1
6a-e
7a: 70% (from 5a + 6a)
7b: 87% (from 5b + 6a)
7c: 74% (from 5c + 6a)
7d: 83% (from 5a + 6b)
7e: 72% (from 5a + 6c)
7f: 54% (from 5a + 6d)
7g: 94% (from 5a + 6e)
6a: EWG1 = COOMe, EWG2 = COOMe
6b: EWG1 = COOMe, EWG2 = COOallyl
6c: EWG1 = COMe, EWG2 = COOMe
6d: EWG1 = COMe, EWG2 = COOallyl
6e: EWG1 = COPh, EWG2 = COOEt
R2
7a-g
Scheme 2.
alcohols 4a–c (88–94%) and the following bromination with PBr3
(Et2O, rt, 1 h) gave the bromides 5a–c (61–78%). The reactions of
5a–c and active methylene compounds 6a–e (K2CO3, CH3CN, rt,
12 h) produced the starting materials 7a–g in moderate-to-good
yields (54–94%).9 Dimethyl malonate (6a), allyl methyl malonate
(6b), methyl acetoacetate (6c), allyl acetoacetate (6d), and ethyl
benzoylacetate (6e) were used as the representative active methy-
lene compounds. During the synthesis of 7, a bis-alkylation prod-
Table 1
Synthesis of indolo[1,2-a]quinolines 9a–c, 9e, and 9g
Entry
Substrate 7
Product 8a (%)
COOMe
COOMe
Product 9b (%)
COOMe
N
N
N
N
1
7a
9a (70)
8a (75)
COOMe
COOMe
COOMe
N
N
Me
2
3
7b
7c
Me
9b (64)
8b (77)
COOMe
COOMe
COOMe
9c (68)
OMe
8c (78)
OMe
COMe
COOMe
COMe
Me
COMe
N
N
N
N
4
5
7e
7e
8e (77)
9e (21)
9ec (46)
10e (52)
9ac (14)
8e
COPh
COOEt
COPh
COOEt
N
N
6
7g
8g (76)d
9g (45)c
9g' (17)c
a
b
c
Conditions: compound 7, Mn(OAc)3 (3.0 equiv), MeOH, reflux, 3 h (for 8a–c) and 1 h (for 8e and 8g).
Conditions: compound 8, NaI (3.0 equiv), O2 balloon, DMF, 120 °C, 2 h.
Conditions: compound 9, NaI (3.0 equiv), O2 balloon, DMF, H2O (3.0 equiv), 120 °C, 4 h.
EtOH was used as a solvent.
d

H. S. Lee et al. / Tetrahedron Letters 51 (2010) 5071–5075
5073
Table 2
Pd-catalyzed synthesis of indolo[1,2-a]quinolines 9a and 9e
Entry
Substrate 7
Product 8a (%)
Conditions
Products (%)
COOMe
COOMe
COOMe
COOallyl
Pd(OAc)2 (10 mol %)
N
N
N
1
7d
PPh3 (4 mol %)
9a (73)
CH3CN, reflux, 15 min
11d (17)
10d (0)
8d (80)
2
3
8d
8d
Pd(OAc)2 (5 mol %)
PPh3 (40 mol %)
toluene, reflux, 20 min
Pd(OAc)2 (5 mol %)
PPh3 (10 mol %)
9a (0)
9a (0)
10d (85)
10d (0)
11d (5)
11d (85)
Et3N (2.0 equiv)
HCOOH (1.7 equiv)
CH3CN, reflux, 10 min
COMe
COMe
COMe
COOallyl
Pd(OAc)2 (10 mol %)
PPh3 (4 mol %)
N
N
N
4
7f
9e (78)
CH3CN, reflux, 15 min
11f (13)
10f (0)
8f (74)
5
6
8f
8f
Pd(OAc)2 (5 mol %)
PPh3 (40 mol %)
toluene, reflux, 20 min
Pd(OAc)2 (5 mol %)
PPh3 (10 mol %)
9e (0)
9e (0)
10f (83)
10f (0)
11d (8)
11d (84)
Et3N (2.0 equiv)
HCOOH (1.7 equiv)
CH3CN, reflux, 10 min
a
Conditions: compound 7, Mn(OAc)3 (3.0 equiv), MeOH, reflux, 3 h (for 8d) and 1 h (for 8f).
uct was formed in small amounts (ca. 5%), and the yield of 7 was
low in some cases even though 6 was used in excess amounts
(1.5 equiv).
quenching of the in situ-generated enolate with water could in-
crease the yield of 9e by suppressing the formation of 10e. As
shown in entry 5, the yield of 9e was increased to 46% in the pres-
ence of 3.0 equiv of water.12 The formation of a methylated prod-
uct 10e was controlled completely as expected; however,
deacetylation13/oxidation product 9a was produced in 14% yield
(entry 5). The reaction of benzoyl derivative 8g produced 9g
(45%) similarly in the presence of water (entry 6) along with
debenzoylation/oxidation compound 9g0 (17%).12
A Pd(0)-catalyzed decarboxylation/elimination protocol was
used for the allyl esters 8d and 8f, and the results are summarized
in Table 2. The decarboxylation/elimination reaction was carried
out in CH3CN with low loading of PPh3 (Pd/PPh3 = 5:2) as re-
ported.7 Indolo[1,2-a]quinolines 9a and 9e were prepared in good
yields (73–78%) along with low yields (13–17%) of protonation
products 11d and 11f (entries 1 and 4).14 Besides the Pd(0)-cata-
lyzed decarboxylation/elimination, decarboxylative allylation15
Mn(OAc)3-assisted cyclizations of 7a–g were carried out in
MeOH,4,5 and the dihydroindolo[1,2-a]quinoline derivatives 8a–g
were prepared in good yields (74–80%), as shown in Table 1 (see
also Table 2).10 With these compounds 8a–g in our hands, we
examined the synthesis of indolo[1,2-a]quinolines 9a–g. Conver-
sions of 8a–c to 9a–c were carried out under the conditions of
NaI/O2 (balloon) in DMF at 120 °C for 2 h (entries 1–3 in Table 1)
in good yields (64–70%) according to the reported method.4a,11
The reaction of 8e, however, provided low yield of 9e (21%, entry
4) along with a methylation product 10e in 52% yield. Compound
10e must be formed by the reaction of iodomethane and an enolate
(I), which was liberated during NaI-mediated decarboxylation
stage (vide infra, Scheme 3). Thus we modified the reaction condi-
tions in order to increase the yield of 9e. We thought that a rapid
COMe
methyl acrylate
(4.0 equiv)
COOMe
N
NaI (3.0 equiv)
10e (13%)
+
8e
+
11f (3%)
without O2
DMF, 120 ºC, 2 h
12 (44%)
COOMe
Me
O
Me
- MeI
- CO2
O
O
Me
I
NaI
8e
O
N
N
(I)
Scheme 3.

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H. S. Lee et al. / Tetrahedron Letters 51 (2010) 5071–5075
Me
COMe
NaI (3.0 equiv)
O
11f (17%)
+
10f (60%)
8f
+
N
without O2
DMF, 120 ºC, 4 h
I
N
(I)
13 (12%)
Scheme 4.
and decarboxylative protonation15 were also carried out with 8d
and 8f. Decarboxylative allylation was performed with high load-
ing of PPh3 (Pd/PPh3 = 1:8) in toluene (entries 2 and 5), and allyl
derivatives 10d and 10f were obtained in good yields (83–85%)
along with small amounts of protonation products (5–8%). Decarb-
oxylative protonation was carried out in the presence of Et3N/
HCOOH in CH3CN (entries 3 and 6). The reaction was very fast
and compounds 11d and 11f were obtained in good yields (84–
85%).
As noted above, a methyl derivative 10e was formed as the ma-
jor product (52%) in the reaction of 8e under the typical NaI/O2
conditions in DMF (entry 4 in Table 1). Based on the results, we
examined the feasibility of Michael reaction with methyl acrylate,
as shown in Scheme 3. The reaction of 8e and methyl acrylate
(4.0 equiv) under N2 atmosphere in the presence of NaI in DMF
afforded 12 in a reasonable yield (44%). Compound 12 was formed,
most likely, by the Michael addition of the in situ-generated eno-
late (I) to methyl acrylate.2b Small amounts of a methyl derivative
10e and a protonation product 11f were also formed.
Similarly the synthesis of allyl derivative 10f was examined in
the absence of oxygen, as shown in Scheme 4. Compound 10f
was obtained in moderate yield (60%) along with a protonation
product 11f (17%). Interestingly, allyl derivative 13 was isolated
in 12% yield via the allylation of enolate (I) at the C-3 position of
the indole moiety and the following 1,3-H shift.
In summary, an expedient synthetic pathway of indolo[1,2-
a]quinolines was developed using a sequential Cu-mediated N-ary-
lation of indole, Mn(OAc)3-mediated oxidative cyclization, and NaI/
O2-assisted concomitant dealkoxycarbonylation/aerobic oxidation
process.
Yamashita, M.; Horiguchi, H.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009,
74, 7481–7488.
3. For our previous synthesis of indole-containing poly-fused heterocycles, see:
(a) Lee, H. S.; Kim, S. H.; Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2008, 49, 1773–
1776; (b) Lee, H. S.; Kim, S. H.; Gowrisankar, S.; Kim, J. N. Tetrahedron 2008, 64,
7183–7190. and further references cited therein.
4. For the Mn(OAc)3-mediated cyclizations between aromatics and active
methylene compounds, see: (a) Im, Y. J.; Lee, K. Y.; Kim, T. H.; Kim, J. N.
Tetrahedron Lett. 2002, 43, 4675–4678; (b) Citterio, A.; Fancelli, D.; Finzi, C.;
Pesce, L. J. Org. Chem. 1989, 54, 2713–2718.
5. For the Mn(OAc)3-mediated cyclizations between indoles and active methylene
compounds, see: (a) Tsai, A.-I.; Lin, C.-H.; Chuang, C.-P. Heterocycles 2005, 65,
2381–2394; (b) Wang, S.-F.; Chuang, C.-P. Heterocycles 1997, 45, 347–359.
6. Santi, R.; Bergamini, F.; Citterio, A.; Sebastiano, R.; Nicolini, M. J. Org. Chem.
1992, 57, 4250–4255. For the similar synthetic applications of NaI/O2-mediated
concomitant dealkoxycarbonylation/aerobic oxidation process, see Ref. 4a..
7. For the Pd-catalyzed decarboxylation/elimination, see: (a) Shimizu, I.; Tsuji, J. J.
Am. Chem. Soc. 1982, 104, 5844–5846; (b) Kataoka, H.; Yamada, T.; Goto, K.;
Tsuji, J. Tetrahedron 1987, 43, 4107–4112; (c) Tsuji, J.; Nisar, M.; Minami, I.
Chem. Lett. 1987, 23–24; (d) Tsuji, J.; Nisar, M.; Minami, I. Tetrahedron Lett.
1986, 27, 2483–2486; (e) Tsuji, J.; Minami, I. Acc. Chem. Res. 1987, 20, 140–145;
(f) Kim, K. H.; Kim, E. S.; Kim, J. N. Tetrahedron Lett. 2009, 50, 5322–5325.
8. For the Cu or Pd-catalyzed N-arylation of indole and related heterocycles, see:
(a) Crawford, L. A.; McNab, H.; Mount, A. R.; Wharton, S. I. J. Org. Chem. 2008, 73,
6642–6646; (b) Crawford, L. A.; Clemence, N. C.; McNab, H.; Tyas, R. G. Org.
Biomol. Chem. 2008, 6, 2334–2339; (c) Zhu, L.; Guo, P.; Li, G.; Lan, J.; Xie, R.; You,
J. J. Org. Chem. 2007, 72, 8535–8538; (d) Mino, T.; Harada, Y.; Shindo, H.;
Sakamoto, M.; Fujita, T. Synlett 2008, 614–620; (e) Old, D. W.; Harris, M. C.;
Buchwald, S. L. Org. Lett. 2000, 2, 1403–1406.
9. Typical procedure for the preparation of 7a: preparation of compound 3a was
carried out according to the reported method,8a,b and its reduction to 4a
(LiAlH4, THF, 0 °C to rt, 5 min) and the following bromination (PBr3, Et2O, rt,
1 h) to 5a were performed according to the general method. A mixture of 5a
(572 mg, 2.0 mmol), dimethyl malonate (6a, 490 mg, 3.0 mmol), and K2CO3
(555 mg, 4.0 mmol) in CH3CN (5 mL) was stirred at room temperature for 12 h.
After the usual aqueous workup and column chromatographic purification
process (hexanes/CH2Cl2/Et2O, 20:20:1) compound 7a was obtained as
a
colorless oil, 472 mg (70%). Other compounds were prepared similarly and the
selected spectroscopic data of 7a and 7d are as follows.
Compound 7a: 70%; colorless oil; IR (film) 1737, 1497, 1461 cmꢀ1 1H NMR
;
(CDCl3, 300 MHz) d 3.00–3.18 (m, 2H), 3.23–3.28 (m, 1H), 3.47 (s, 3H), 3.53 (s,
3H), 6.68 (d, J = 3.0 Hz, 1H), 6.99–7.38 (m, 8H), 7.65–7.69 (m, 1H); 13C NMR
(CDCl3, 75 MHz) d 30.57, 51.62, 52.29, 103.06, 110.19, 119.99, 120.82, 122.23,
128.07, 128.24, 128.46, 128.61, 128.85, 130.65, 135.41, 137.15, 138.22, 168.65;
ESIMS m/z 360 (M++Na). Anal. Calcd for C20H19NO4: C, 71.20; H, 5.68; N, 4.15.
Found: C, 71.57; H, 5.44; N, 4.07.
Acknowledgments
This research was supported by the Basic Science Research Pro-
gram through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Technology
(2010-0015675). Spectroscopic data were obtained from the Korea
Basic Science Institute, Gwangju branch.
Compound 7d: 83%; colorless oil; IR (film) 1736, 1497, 1461, 1235 cmꢀ1 1H
;
NMR (CDCl3, 300 MHz, 60 °C) d 3.10 (br s, 2H), 3.27 (t, J = 7.8 Hz, 1H), 3.53 (s,
3H), 4.42 (d, J = 4.8 Hz, 2H), 5.09–5.17 (m, 2H), 5.64–5.77 (m, 1H), 6.67 (d,
J = 3.3 Hz, 1H), 6.68–7.01 (m, 1H), 7.09–7.17 (m, 3H), 7.26–7.39 (m, 4H), 7.63–
7.68 (m, 1H); 13C NMR (CDCl3, 75 MHz) d 30.76, 51.78, 52.41, 65.86, 103.18,
110.32, 118.38, 120.09, 120.92, 122.34, 128.18, 128.36, 128.55, 128.71, 128.97,
130.88, 131.32, 135.51, 137.24, 138.37, 168.04, 168.75; ESIMS m/z 364 (M++1).
Anal. Calcd for C22H21NO4: C, 72.71; H, 5.82; N, 3.85. Found: C, 72.67; H, 5.58;
N, 3.97. The 1H NMR spectrum of 7d showed somewhat complex and broad
peaks presumably due to slow rotation around the single bond between
benzene and indole. Thus the 1H NMR spectrum was taken at 60 °C, and
appreciable coalescence of peaks were observed. The 13C NMR spectrum of 7d
was taken at room temperature. For the line broadening and complex nature of
peaks of similar compounds, see: Hwang, S. J.; Cho, S. H.; Chang, S. J. Am. Chem.
Soc. 2008, 130, 16158–16159.
References and notes
1. For the synthesis and biological activities of indole-containing poly-fused
compounds, see: (a) Du, D.; Li, L.; Wang, Z. J. Org. Chem. 2009, 74, 4379–4382;
(b) Magolan, J.; Carson, C. A.; Kerr, M. A. Org. Lett. 2008, 10, 1437–1440; (c)
Magolan, J.; Kerr, M. A. Org. Lett. 2006, 8, 4561–4564; (d) Grigg, R.;
Somasunderam, A.; Sridharan, V.; Keep, A. Synlett 2009, 97–99; (e) Khdour,
O.; Ouyang, A.; Skibo, E. B. J. Org. Chem. 2006, 71, 5855–5863; (f) Dorbec, M.;
Florent, J.-C.; Monneret, C.; Rager, M.-N.; Fosse, C.; Bertounesque, E. Eur. J. Org.
Chem. 2008, 1723–1731; (g) Franck, R. W.; Bernady, K. F. J. Org. Chem. 1968, 33,
3050–3055; (h) Tucker, J. W.; Narayanam, J. M. R.; Krabbe, S. W.; Stephenson, C.
R. J. Org. Lett. 2010, 12, 368–371.
2. For the synthesis of indolo[1,2-a]quinolines and related compounds, see: (a)
Takaya, J.; Udagawa, S.; Kusama, H.; Iwasawa, N. Angew. Chem., Int. Ed. 2008, 47,
4906–4909; (b) Chai, D. I.; Lautens, M. J. Org. Chem. 2009, 74, 3054–3061; (c)
Hulcoop, D. G.; Lautens, M. Org. Lett. 2007, 9, 1761–1764; (d) Xie, C.; Zhang, Y.;
Huang, Z.; Xu, P. J. Org. Chem. 2007, 72, 5431–5434; (e) Baik, C.; Kim, D.; Kang,
M.-S.; Song, K.; Kang, S. O.; Ko, J. Tetrahedron 2009, 65, 5302–5307; (f) Murarka,
S.; Zhang, C.; Konieczynska, M. D.; Seidel, D. Org. Lett. 2009, 11, 129–132; (g)
Cai, Q.; Li, Z.; Wei, J.; Fu, L.; Ha, C.; Pei, D.; Ding, K. Org. Lett. 2010, 12, 1500–
1503; (h) Schultz, D. M.; Wolfe, J. P. Org. Lett. 2010, 12, 1028–1031; (i)
10. Typical procedure for the synthesis of 8a: A mixture of 7a (337 mg, 1.0 mmol)
and Mn(OAc)3 (696 mg, 3.0 mmol) in MeOH (4 mL) was heated to reflux for 3 h.
After cooling to rt, the reaction mixture was filtered through a Celite pad. After
dilution with CH2Cl2 and the usual aqueous workup, the product 8a was
obtained by column chromatographic separation process (hexanes/EtOAc, 4:1)
as a colorless oil, 251 mg (75%). Other compounds were synthesized similarly
and the selected spectroscopic data of 8a and 8d are as follows.
Compound 8a: 75%; white solid, mp 123–125 °C; IR (KBr) 1740, 1495,
1456 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 3.52 (s, 2H), 3.74 (s, 6H), 6.62 (s,
;
1H), 7.12 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.27–7.43 (m, 3H), 7.65 (d,
J = 7.5 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3,
75 MHz) d 34.95, 53.31, 56.53, 102.43, 111.59, 117.14, 121.18, 121.41, 123.14,

H. S. Lee et al. / Tetrahedron Letters 51 (2010) 5071–5075
5075
124.03, 124.95, 128.29, 129.05, 129.35, 133.42, 134.32, 136.28, 168.94; ESIMS
m/z 358 (M++Na). Anal. Calcd for C20H17NO4: C, 71.63; H, 5.11; N, 4.18. Found:
C, 71.83; H, 5.45; N, 4.01.
Compound 13: 12%; colorless oil; IR (film) 1715, 1494, 1458 cmꢀ1
;
1H NMR
(CDCl3, 300 MHz) d 1.90 (s, 3H), 3.07 (dd, J = 15.0 and 5.7 Hz, 1H), 3.36 (dd,
J = 15.0 and 2.4 Hz, 1H), 3.48–3.66 (m, 2H), 4.10 (dd, J = 5.7 and 2.4 Hz, 1H),
5.05–5.17 (m, 2H), 5.95–6.08 (m, 1H), 7.09 (t, J = 7.5 Hz, 1H), 7.18–7.39 (m, 4H),
7.65 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 7.5 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H); 13C NMR
(CDCl3, 75 MHz) d 28.64, 29.07, 30.09, 45.86, 111.39, 111.49, 115.62, 117.20,
119.41, 120.71, 122.84, 123.78, 126.79, 127.85, 129.55, 129.62, 131.87, 134.07,
135.95, 136.60, 206.96; ESIMS m/z 302 (M++1). Anal. Calcd for C21H19NO: C,
83.69; H, 6.35; N, 4.65. Found: C, 83.53; H, 6.67; N, 4.46.
Compound 8d: 80%; colorless oil; IR (film) 1741, 1495, 1456, 1227 cmꢀ1 1H
;
NMR (CDCl3, 300 MHz) d 3.52 (s, 2H), 3.73 (s, 3H), 4.54–4.68 (m, 2H), 5.13–5.21
(m, 2H), 5.67–5.80 (m, 1H), 6.64 (s, 1H), 7.10 (t, J = 7.8 Hz, 1H), 7.18 (t,
J = 7.8 Hz, 1H), 7.26–7.40 (m, 3H), 7.64 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 7.8 Hz,
1H), 7.95 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 34.94, 53.20, 56.57,
66.60, 102.43, 111.54, 117.11, 118.74, 121.11, 121.38, 123.08, 123.95, 124.91,
128.24, 129.04, 129.34, 131.00, 133.38, 134.29, 136.32, 168.08, 168.81; ESIMS
m/z 362 (M++1). Anal. Calcd for C22H19NO4: C, 73.12; H, 5.30; N, 3.88. Found: C,
73.17; H, 5.48; N, 3.63.
12. During the evaluation process one of the reviewers suggested to insert the
plausible mechanisms for the formation of 9e and 9g0. The mechanism for the
formation of 9e from 8e could be thought as follows: NaI-assisted formation of
(I) as proposed in Scheme 3, protonation of (I) to form the dihydro analog of 9e
(11f in Table 2), and the following aerobic oxidation to 9e. Actually, the
dihydro derivative of 9e (11f) was observed during the reaction progress;
however, the dihydro analog of 9e was air-oxidized to 9e completely after 4 h,
as summarized in entry 5 (Table 1). The mechanism for the formation of 9g0
could be proposed as follows: water-mediated debenzoylation13 of 8g to the
corresponding dihydro analog of 9g0 and the following aerobic oxidation to 9g0.
13. (a) Chamakh, A.; Amri, H. Tetrahedron Lett. 1998, 39, 375–378; (b) Im, Y. J.; Lee,
C. G.; Kim, H. R.; Kim, J. N. Tetrahedron Lett. 2003, 44, 2987–2990. and further
examples were mentioned in Ref. 1b.
14. Typical procedure for the synthesis of 9a (Pd method: entry 1 in Table 2): A
mixture of 8d (181 mg, 0.5 mmol), Pd(OAc)2 (11 mg, 10 mol %), and PPh3 (5 mg,
4 mol %) in CH3CN (1.5 mL) was heated to reflux for 15 min. After the usual
aqueous workup and column chromatographic purification process (hexanes/
EtOAc, 4:1) compound 9a was obtained as a colorless oil, 100 mg (73%) along
with 11d (24 mg, 17%). Other entries in Table 2 were performed similarly, and
the selected spectroscopic data of 9e and 10d are as follows.
11. Typical procedure for the synthesis of 9a (NaI/O2 method: entry 1 in Table 1): A
mixture of 8a (168 mg, 0.5 mmol) and NaI (225 mg, 1.5 mmol) in DMF (2 mL)
was heated to 120 °C for 2 h under O2 atmosphere (O2 balloon). After the usual
aqueous workup and column chromatographic purification process (hexanes/
EtOAc, 4:1) compound 9a was obtained as a reddish solid, 96 mg (70%). Other
compounds were synthesized similarly and the selected spectroscopic data of
9a, 9c, 10e, 12, and 13 are as follows.
Compound 9a: 70%; reddish solid, mp 120–122 °C; IR (KBr) 1719, 1446,
1231, 1213 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 4.03 (s, 3H), 7.31–7.48 (m, 3H),
;
7.62 (s, 1H), 7.67–7.76 (m, 2H), 7.90–7.94 (m, 1H), 8.04 (s, 1H), 8.45 (d,
J = 8.1 Hz, 1H), 8.58 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 52.59, 99.77,
114.45, 115.67, 121.14, 122.05, 122.50, 122.57, 122.75, 123.31, 130.80, 130.86,
131.04, 131.62, 133.01, 133.04, 138.34, 165.82; ESIMS m/z 276 (M++1). Anal.
Calcd for C18H13NO2: C, 78.53; H, 4.76; N, 5.09. Found: C, 78.84; H, 4.95; N,
4.92.
Compound 9c: 68%; reddish solid, mp 101–103 °C; IR (KBr) 1720, 1452,
1214 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 3.94 (s, 3H), 4.03 (s, 3H), 7.08 (dd,
;
J = 9.0 and 2.4 Hz, 1H), 7.30–7.36 (m, 2H), 7.55 (s, 1H), 7.66–7.77 (m, 2H), 8.04
(s, 1H), 8.34 (d, J = 9.0 Hz, 1H), 8.52 (d, J = 8.4 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
d 52.25, 55.61, 99.11, 102.18, 112.71, 114.99, 115.06, 120.56, 122.24, 122.79,
127.92, 130.26, 130.77, 131.33, 131.63, 133.42, 137.83, 155.45, 165.57; ESIMS
m/z 306 (M++1). Anal. Calcd for C19H15NO3: C, 74.74; H, 4.95; N, 4.59. Found: C,
74.59; H, 5.01; N, 4.38.
Compound 9e: 78%; reddish solid, mp 145–147 °C; IR (KBr) 1673, 1445,
1217 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 2.65 (s, 3H), 7.25 (t, J = 7.5 Hz, 1H),
;
7.34–7.43 (m, 2H), 7.58–7.71 (m, 4H), 7.85–7.90 (m, 1H), 8.31–8.35 (m, 1H),
8.43 (d, J = 9.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 27.29, 100.41, 114.05,
115.25, 121.82, 122.11, 122.14, 122.31, 122.82, 127.59, 130.59, 130.63, 130.84,
131.48, 131.88, 132.28, 137.89, 196.39; ESIMS m/z 260 (M++1). Anal. Calcd for
Compound 10e: 52%; white solid, mp 83–85 °C; IR (KBr) 1711, 1494, 1458,
C
18H13NO: C, 83.37; H, 5.05; N, 5.40. Found: C, 83.52; H, 5.09; N, 5.17.
Compound 10d: 85%; white solid, mp 96–98 °C; IR (KBr) 1734, 1495,
1458 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 2.59 (dd, J = 14.1 and 7.2 Hz, 1H),
1352 cmꢀ1 1H NMR (CDCl3, 300 MHz) d 1.63 (s, 3H), 1.90 (s, 3H), 2.75 (d,
;
J = 14.7 Hz, 1H), 3.35 (d, J = 14.7 Hz, 1H), 6.62 (s, 1H), 7.09 (t, J = 8.1 Hz, 1H),
7.17–7.38 (m, 4H), 7.66 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.97 (d,
J = 8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 23.09, 27.09, 37.40, 49.70, 100.62,
111.52, 117.12, 120.95, 121.04, 122.72, 124.01, 127.69, 127.70, 129.50, 129.54,
134.41, 136.10, 140.84, 209.30; ESIMS m/z 276 (M++1). Anal. Calcd for
;
2.89 (dd, J = 14.1 and 7.2 Hz, 1H), 2.93 (d, J = 15.0 Hz, 1H), 3.30 (d, J = 15.0 Hz,
1H), 3.60 (s, 3H), 5.06–5.16 (m, 2H), 5.75–5.88 (m, 1H), 6.63 (s, 1H), 7.07–7.38
(m, 5H), 7.63 (d, J = 7.2 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H);
13C NMR (CDCl3, 75 MHz) d 34.61, 40.63, 48.07, 52.38, 100.92, 111.58, 116.96,
119.31, 120.94, 121.05, 122.59, 123.80, 126.85, 127.64, 129.42, 129.52, 132.71,
134.19, 136.18, 138.35, 172.89; ESIMS m/z 340 (M++Na). Anal. Calcd for
C
19H17NO: C, 82.88; H, 6.22; N, 5.09. Found: C, 82.72; H, 6.47; N, 5.02.
Compound 12: 44%; colorless oil; IR (film) 1736, 1710, 1495, 1458 cmꢀ1
;
1H
NMR (CDCl3, 300 MHz) d 1.97 (s, 3H), 2.29–2.61 (m, 4H), 2.72 (d, J = 14.4 Hz,
1H), 3.37 (d, J = 14.4 Hz, 1H), 3.66 (s, 3H), 6.64 (s, 1H), 7.11 (t, J = 7.5 Hz, 1H),
7.19–7.38 (m, 4H), 7.67 (d, J = 7.5 Hz, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.98 (d,
J = 8.1 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 27.11, 29.02, 29.65, 33.86, 51.79,
53.01, 101.41, 111.68, 117.02, 121.09, 121.18, 122.91, 124.13, 127.05, 127.78,
129.47, 129.78, 134.38, 135.80, 138.54, 173.31, 207.97; ESIMS m/z 370
(M++Na). Anal. Calcd for C22H21NO3: C, 76.06; H, 6.09; N, 4.03. Found: C,
76.41; H, 6.37; N, 3.87.
C21H19NO2: C, 79.47; H, 6.03; N, 4.41. Found: C, 79.70; H, 6.13; N, 4.37.
15. For the Pd-catalyzed decarboxylative allylation and protonation, see: (a) Kim,
S. H.; Kim, E. S.; Kim, T. H.; Kim, J. N. Tetrahedron Lett. 2009, 50, 6256–6260; (b)
Gowrisankar, S.; Kim, K. H.; Kim, S. H.; Kim, J. N. Tetrahedron Lett. 2008, 49,
6241–6244; (c) Kim, J. M.; Kim, S. H.; Lee, H. S.; Kim, J. N. Tetrahedron Lett.
2009, 50, 1734–1737; (d) Gowrisankar, S.; Kim, E. S.; Kim, J. N. Bull. Korean
Chem. Soc. 2009, 30, 33–34; (e) Kim, S. H.; Lee, H. S.; Kim, S. H.; Kim, J. N.
Tetrahedron Lett. 2009, 50, 3038–3041.