Synthesis of oxygenated 2-methylindolines

Article abstract of DOI:10.1016/j.tetlet.2014.03.095

A palladium-mediated high-yielding synthesis of oxygenated 2-methylindolines 4 from 2-allylnitrobenzene 1 and hydrazine is developed. The one-pot route combines the reduction of 2-allylnitrobenzene 1 and the sequential intramolecular hydroamination. The protocol provides a novel alternative for the synthesis of substituted 2-methylindoline 4.

Full text of DOI:10.1016/j.tetlet.2014.03.095

Tetrahedron Letters 55 (2014) 2876–2878
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of oxygenated 2-methylindolines
⇑
Meng-Yang Chang , Yi-Chia Chen, Chieh-Kai Chan
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
a r t i c l e i n f o
a b s t r a c t
Article history:
A palladium-mediated high-yielding synthesis of oxygenated 2-methylindolines 4 from 2-allylnitroben-
zene 1 and hydrazine is developed. The one-pot route combines the reduction of 2-allylnitrobenzene 1
and the sequential intramolecular hydroamination. The protocol provides a novel alternative for the
synthesis of substituted 2-methylindoline 4.
Received 2 February 2014
Revised 12 March 2014
Accepted 20 March 2014
Available online 28 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
2-Methylindolines
Hydroamination
2-Allylnitrobenzenes
Introduction
Scheme 2.11 The expeditious ring-closure forms a core indoline
structure.
Indoline, with a bicyclic benzannulated ring system, is a key
pharmacophore for a drug candidate.1,2 Among those biologically
active molecules, 2-methylindoline skeleton is known to be widely
used among promising therapeutic agents, such as, indapamide
(diuretic).3 A considerable number of attempts have been made
to synthesize the skeleton. The adopted synthetic routes are
summarized in Scheme 1.4–10 The key transformations include
intramolecular transition metal-mediated hydroamination of
2-allylanilines (e.g., Ir, Zn, Au, Zr, Cu, Pd),4 metal–halogen exchange
(anionic route)5 or free radical ring-cyclization of N-allyl-2-halo-
anilines,6 Lewis acid-mediated hydride reduction or hydrogenation
of indoles.7 Fischer synthesis of ketones with phenylhydrazines is
followed by reductive amination of alkyl aldehydes.8 Lithiation of
indolines is followed by substitution route9 and other
approaches.10
To achieve the best reaction conditions, 1a (R = Me) was se-
lected as the model substrate. One-pot reaction of 4a was treated
with 1a and Pd/C (10%, 50 mg) as the catalyst in boiling a co-sol-
vent of toluene and aqueous hydrazine (80%). The reaction process
was monitored by TLC until the reactant 1a was consumed. By
exchanging different solvents and adjusting the co-solvent ratio
with aqueous N2H4 (80%) and the reaction time, different yields
of 4a were observed (Table 1, entries 1–10). To enhance the yield
of 4a, the amounts of 10% Pd/C were further examined (entries
11–12). But, no obvious improvement was found by the addition
of Pd/C with less (10 mg) or higher (100 mg) loading amounts.
Based on the experiments, we established that the 1:1 volume
5
anionic or
X
6
radical cyclization
R
2
N
P
R
1
R
1
Results and discussion
R
N
P
2
NH
P
In continuation of our investigation on the synthesis of dihydro-
1-benzazepines into the synthetic application of 2-allylnitroben-
zene 1,11 palladium-catalyzed the one-pot route of 2-methylindo-
line 4 with hydrazine, is investigated herein, including (i) nitro
group reduction of 2-allylnitrobenzene 1 and (ii) intramolecular
hydroamination of the corresponding 2-allylaniline 3. 2-Allylnitro-
benzene 1 was prepared in modest yields according to the known
reported methods from 2-methoxy-5-nitrophenol (2), as shown in
7
R
hydrogenation
1
metal-mediated
4
hydroamination
R
1
2
R
2
R
N
P
1
O
R
NH
NH
indolines
NO
2
P-CHO
Fischer synthesis /
reductive amination
2
reduction /
hydroamination
(this work)
8
R -X
2
H
N
P
9
lithiation / substitution
⇑
Corresponding author. Tel.: +886 7 3121101x2220; fax: +886 7 3125339.
E-mail address: mychang@kmu.edu.tw (M.-Y. Chang).
Scheme 1. Synthetic routes of indolines.
http://dx.doi.org/10.1016/j.tetlet.2014.03.095
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

M.-Y. Chang et al. / Tetrahedron Letters 55 (2014) 2876–2878
2877
Table 2
OR
OR
3
MeO
MeO
Synthesis of skeleton 4a
OR
OR
MeO
MeO
Me
R
N
H
NH
2
1
R
1
10% Pd/C, N H
2 4 (aq)
4
4
Me
toluene, reflux, 25 h
N
1
NO
2
H
OR
1
O
OH
MeO
MeO
MeO
4
1
R
R
1
1
Entry
1, R =, R1 =,
4, Yieldb (%)
NO
NO
NO
2
2
2
1
2
3
4
5
6
1a, Methyl, H
1b, Isopropyl, H
1c, n-Butyl, H
1d, Cyclopropyl, H
1e, n-Octyl, H
1f, Methyl, methyl
4a, 84
4b, 80
4c, 81
4d, 76
4e, 83
4f, 70
5a, R = H
5b, R = Me
2
1
1
Scheme 2. Retrosynthesis of oxygenated 2-methylindolines 4.
a
The reactions were run on a 1.0 mmol scale with 1, N2H4 (80% in H2O), Pd/C
ratio of toluene and N2H4(aq) (10 mL) is an optimal combination for
elevating the yields of 4a under boiling conditions for 25 h (entry
4). With the results in hand, one-pot facile preparation of substi-
(10%, 50 mg) in refluxing temperature.
b
The isolated 4 were >95% pure as determined by 1H NMR analysis.
tuted indolines 4 was examined. From our previous reports,11
a
facile three-step route was employed to create skeleton 1, starting
with 2 via (1) O-allylation of 2 with allyl bromide (Table 2, entries
1–5) or trans-crotyl bromide (entry 6), (2) Claisen rearrangement
of O-allyl-1-nitrobenzene and (3) O-alkylation of the resulting 2-
allyl-3-nitrophenol 5a or 5b with alkyl bromides (R = methyl, iso-
propyl, n-butyl, cyclopentyl, n-octyl).
When O-3-substituted 2-allyl-nitrobenzenes 1a–f (Table 2, en-
tries 1–6) were treated under optimal reaction conditions, we ob-
served that indolines 4a–f provided 70–84% yields.12 Changing the
R substituent, a dioxygenated indoline was isolated via the one-pot
reduction/hydroamination protocol. Following the procedure, syn-
thesis of bis-indoline was examined next. As shown in Scheme 3,
four bis-3-O-linked 2-allyl-nitrobenzenes 7a–d with different
lengths of carbon linear chain (propyl, butyl, hexyl and octyl) re-
acted with the one-pot condition to afford a skeleton of bis-indo-
lines 7a–d at 70–78% yields. Adjusting the reaction temperature
to rt, the skeleton of o-allylanilines 8a–d (58–65%) was isolated
in major products along with trace amounts of o-allylanilino-indo-
lines 9a–d (8–14%), as shown in Scheme 4. From the phenomenon,
we found that the reaction temperature could control product
distribution. To deserve to be mentioned, the color of the isolated
skeletons 8 and 9 (pale yellow) was easily converted into a brown-
ish color at room temperature within 1 h under air atmosphere.
This color change shows that quinine derivatives should be formed.
Attempts to construct other oxygenated indoline skeletons are
examined next. Skeleton 10 was subjected to the one-pot reduc-
tion/hydroamination, but 2-allylanilines 11 was isolated as the sole
compound with good yields (80–84%) and no cyclized skeleton 12
was observed (Scheme 5). Increasing the time (25 ? 100 h) in the
reaction of 10a with a one-pot protocol showed no 12a was
yielded. To explore the feasibility, scope, and limitations of this ap-
proach, reaction of 13 or 15 (prepared from ring-closing metathesis
of 4a or cross metathesis of 1a) provided bis-anilines 14 or 16 at
65% or 58% yields (Scheme 6). A skeleton of indoline was still not
found. The structure of 15 was determined by single-crystal
X-ray crystallography.13
According to the above results, we envision that the position of
the methoxy group on a benzene ring is an important substituent
controlling the formation of indoline via the hydroamination
ring-closing process. As shown in Table 2, the C4 electron-donating
methoxy group of skeleton 1 could promote the C1 amino group
(from nitro-reduction) to easily cyclize with the o-allyl group.
When the position of the C4 methoxy group was moved to a C3 po-
sition, the indoline ring was not formed (for 10d). The plausible
reason should be C4-substituent forces the o-allyl moiety closer
to the C1 amino group via the required aminopalladation proce-
dure. The resulting phenomenon with the accelerated cyclization
is similar to Thorpe-Ingold effect.14 On the other hand, the o-allyl
group was a key arm in the formation of an indoline skeleton, as
shown in Scheme 5. For the o-cinnamyl side chain (for 10a–c),
the C1 amino group was not cyclized with the olefinic motif of
the styryl group since it possessed the steric hindrance which im-
peded its coordination to palladium center. The similar results
have been found for the ineffective cyclization of skeleton 13 and
Table 1
Synthesis of compound 4aa
OMe
OMe
MeO
MeO
Pd/C, N H
2
4 (aq)
Me
reflux
N
H
NO
2
4a
1a
Entry
Solvent (mL), N2H4 (mL), time (h)
4a, Yieldb (%)
1
2
3
4
5
6
7
8
9
Toluene (10), 1, 10
Toluene (10), 5, 10
Toluene (10), 5, 25
Toluene (5), 5, 25
Toluene (5), 5, 50
Toluene (1), 10, 25
DME (5), 5, 25
1,4-Dioxane (5), 5, 25
THF (10), 5, 25
EtOH (5), 5, 25
42
70
74
84
78
70
66
60
44
56
65c
76d
MeO
O
O
OMe
10% Pd/C, N H
MeO
4 (aq)
O
O
OMe
(
)
( )
n
n
10
11
12
2
Toluene (5), 5, 25
Toluene (5), 5, 25
toluene, reflux, 25 h
N
H
N
H
O N
2
NO
2
n = 1, 2, 4, 6
Me Me
a
The reactions were run on a 1.0 mmol scale with 1a, N2H4 (80% in H2O), Pd/C
(10%, 50 mg) in refluxing temperature.
6a, n = 1; 6b, n = 2
6c, n = 4; 6d, n = 6
7a (72%); 7b (70%)
7c (75%); 7d (78%)
b
The isolated 4a were >95% pure as determined by 1H NMR analysis.
c
Pd/C (10%, 10 mg) was added.
d
Pd/C (10%, 100 mg) was added.
Scheme 3. Synthesis of skeleton 7.

2878
M.-Y. Chang et al. / Tetrahedron Letters 55 (2014) 2876–2878
MeO
MeO
O
O
OMe
Supplementary data
(
)
n
Supplementary data (scanned photocopies of NMR spectral
data) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2014.03.095.
H N
2
NH
2
MeO
O
O
OMe
10% Pd/C, N H
8a (65%); 8b (61%)
8c (58%); 8d (64%)
(
)
n
2
4 (aq)
References and notes
toluene, rt, 25 h
O
O
OMe
O N
NO
2
2
(
)
n
1. (a) Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg, J. A. Chem. Rev. 1997,
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6a, n = 1; 6b, n = 2
6c, n = 4; 6c, n = 6
N
H
NH
2
Me
9a (8%); 9b (11%)
9c (10%); 9d (14%)
3. (a) Bermudez, J.; Dabbs, S.; Joiner, K. A.; King, F. D. J. Med. Chem. 1929, 1990, 33;
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Adachi, S.; Koike, K.; Takayanagi, I. Pharmacology 1996, 53, 250.
Scheme 4. Synthesis of skeletons 8 and 9.
4. For Ir, see: (a) Liu, W. B.; He, H.; Dai, L.-X.; You, S.-L. Synthesis 2009, 2076; For
Zn, see: (b) Yadav, J. S.; Reddy, B. V. S.; Rasheed, M. A.; Kuman, H. M. S. Synlett
2000, 487; For Au, see (c) Zhang, J.; Yang, C.-G.; He, C. J. Am. Chem. Soc. 2006,
128, 1798; For Zr, see: (d) Leitch, D. C.; Payne, P. R.; Dunbar, C. R.; Schafer, L. L. J.
Am. Chem. Soc. 2009, 131, 18246; For Cu, see: (e) Turnpenny, B. W.; Hyman, K.
L.; Chemler, S. R. Organometallics 2012, 31, 7819; (f) Liwosz, T. W.; Chemler, S.
R. J. Am. Chem. Soc. 2012, 134, 2020; (g) Zabawa, T. P.; Kasi, D.; Chemler, S. R. J.
Am. Chem. Soc. 2005, 127, 11250; (h) Sherman, E. S.; Chemler, S. R.; Tan, T. B.;
Gerlits, O. Org. Lett. 2004, 6, 1573; (i) Lin, J.-S.; Xiong, Y.-P.; Ma, C.-L.; Zhao, L.-J.;
Tan, B.; Liu, X.-Y. Chem. Eur. J. 2014, 20, 1332; For Pd, see: (j) Schultz, D. M.;
Wolfe, J. P. Org. Lett. 2010, 12, 1028; (k) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc.
2004, 126, 13906; (l) Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc.
2005, 127, 7690; (m) Michael, F. E.; Cochran, B. M. J. Am. Chem. Soc. 2006, 128,
4246.
5. (a) Ketcha, D. M.; Lieurance, B. A. Tetrahedron Lett. 1989, 30, 6833; (b) Lanzilotti,
A. E.; Littell, R.; Fanshawe, W. J.; McKenzie, T. C.; Lovell, F. M. J. Org. Chem. 1979,
44, 4809; (c) Coulton, S.; Gilchrist, T. L.; Graham, K. Tetrahedron 1997, 53, 791;
(d) Kuwano, R.; Kaneda, K.; Ito, T.; Sato, K.; Kurokawa, T.; Ito, Y. Org. Lett. 2004,
6, 2213; (e) Chandrasekhar, S.; Basu, D.; Reddy, C. R. Synthesis 2007, 1509.
6. (a) Bailey, W. F.; Carson, M. W. Tetrahedron Lett. 1997, 38, 1329; (b) Bailey, W.
F.; Luderer, M. R.; Mealy, M. J. Tetrahedron Lett. 2003, 44, 5303; (c) Zhang, D.;
Liebeskind, L. S. J. Org. Chem. 1996, 61, 2594; (d) Nakao, J.; Inoue, R.; Shinokubo,
H.; Oshima, K. J. Org. Chem. 1910, 1997, 62; (e) Uchiyama, M.; Kameda, M.;
Mishima, O.; Yokoyama, N.; Koike, M.; Kondo, Y.; Sakamoto, T. J. Am. Chem. Soc.
1998, 120, 4934.
MeO
RO
MeO
RO
MeO
RO
N
H
NO
NH
2
2
Ph
Ph
Ph
10a, R = Me
10b, R = n-Bu
10c, R = c-C H
11a (84%)
11b (80%)
11c (81%)
12a-c (not observed)
10% Pd/C, N H
2
4 (aq)
5
9
toluene, reflux
25 h
MeO
MeO
MeO
Me
N
H
NO
NH
2
2
Me
Me
11d (76%)
Me
10d
12d (not observed)
Scheme 5. Synthesis of skeleton 11.
O
O
MeO
O
MeO
O
OMe
OMe
7. (a) Li, C.; Chen, J.; Fu, G.; Liu, D.; Liu, Y.; Zhang, W. Tetrahedron 2013, 69, 6839;
(b) Kurono, N.; Honda, E.; Komatsu, F.; Orito, K.; Tokuda, M. Tetrahedron 2004,
60, 1791; (c) Murphy, J. A.; Rasheed, F.; Gastaldi, S.; Ravishanker, T.; Lewis, N. J.
Chem. Soc., Perkin Trans. 1 1997, 1549; (d) Leroi, C.; Bertin, D.; Dufils, P.-E.;
Gigmes, D.; Marque, S.; Tordo, P.; Couturier, J.-L.; Uerret, O.; Ciufolini, M. A. Org.
Lett. 2003, 5, 4943; (e) Pitts, M. R.; Harrison, J. R.; Moody, C. J. J. Chem. Soc.,
Perkin Trans. 1 2001, 955.
NO
NH
2
2
O N
H N
2
2
13
14 (65%)
10% Pd/C, N H
2
4 (aq)
NO
NH
2
2
toluene, reflux
25 h
OMe
MeO
MeO
OMe
OMe
8. Liu, K. G.; Lo, J. R.; Robichaud, A. J. Tetrahedron 2010, 66, 573.
OMe
OMe
9. Gross, K. M. B.; Jun, Y. M.; Beak, P. J. Org. Chem. 1997, 62, 7679.
10. (a) Kang, K. H.; Kim, Y.; Im, C.; Park, Y. S. Tetrahedron 2013, 69, 2542; (b) Correa,
A.; Tellitu, I.; Dominguez, E.; SanMartin, R. J. Org. Chem. 2006, 71, 8316; (c)
Gleave, D. M.; Brickner, S. J. J. Org. Chem. 1996, 61, 6470; (d) Gleave, D. M.;
Brickner, S. J.; Manninen, P. R.; Allwine, D. A.; Lovasz, K. D.; Rohrer, D. C.;
Tucker, J. A.; Zurenko, G. E.; Ford, C. W. Bioorg. Med. Chem. Lett. 1998, 8, 1231;
(e) Nicolaou, K. C.; Roecker, A. J.; Pfefferkorn, J. A.; Cao, G.-Q. J. Am. Chem. Soc.
2000, 122, 2966; (f) Yin, Y.; Zhao, G. Heterocycles 2006, 68, 23; (g) Dion, I.;
Vicent-Rocan, J.-F.; Zhang, L.; Cebrowski, P. H.; Lebrun, M.-E.; Pfeiffer, J. Y.;
Bedard, A.-C.; Beauchemin, A. M. J. Org. Chem. 2013, 78, 12735.
O N
2
OMe
H N
2
15
16 (58%)
Scheme 6. Synthesis of compounds 14 and 16.
15. To affect the hydroamination process, C4-substituent and less
hindrance were needed.
11. Chang, M.-Y.; Chan, C.-K.; Lin, S.-Y. Heterocycles 2013, 87, 1519.
12. A representative synthetic procedure of skeleton 4 is as follows: Pd/C (10%, 50 mg)
was added to a stirred solution of skeleton 1 (1.0 mmol) in toluene (5 mL) at rt.
The reaction mixture was stirred at rt for 10 min. N2H4 (80% in H2O, 5 mL) was
added to the reaction mixture at rt. The reaction mixture was refluxed for 25 h,
cooled to rt, and the solvent was concentrated. The residue was diluted with
water (10 mL) and the mixture was extracted with CH2Cl2 (3 Â 20 mL). The
combined organic layers were washed with brine, dried, filtered and
evaporated to afford crude product. Purification on silica gel (hexanes/
EtOAc = 4/1 ꢀ 2/1) afforded skeleton 4. For 4a, yield = 84% (162 mg); brown
oil; HRMS (ESI, M++1) calcd for C11H16NO2 194.1181, found 194.1188; 1H NMR
(400 MHz, CDCl3): d 6.60 (d, J = 8.0 Hz, 1H), 6.30 (d, J = 8.0 Hz, 1H), 4.02–3.95
(m, 1H), 3.86 (s, 3H), 3.78 (s, 3H), 3.33 (br s, 1H), 3.22 (dd, J = 8.4, 15.6 Hz, 1H),
2.67 (dd, J = 7.6, 15.6 Hz, 1H), 1.29 (d, J = 6.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d 146.47, 145.86, 145.77, 121.65, 112.44, 103.95, 60.00, 56.94, 55.82,
35.63, 22.10.
Conclusion
In summary, we have successfully presented a one-pot syn-
thetic methodology for oxygenated indolines 4 and 7, which in-
volves the tandem reduction of nitrobenzenes 1 and 6 with 10%
palladium on the activated carbon, 80% aqueous solution of hydra-
zine and hydroamination of the resulting 2-allyl anilines. Further
investigation regarding one-pot cascade synthesis of functional-
ized heterocycles will be conducted and published in due course.
Acknowledgments
13. CCDC 979311 (15) contains the supplementary crystallographic data for this
paper. This data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: +44 1223 336033; E-mail: deposit@ccdc.cam.ac.uk).
14. (a) Levine, M. N.; Raines, R. T. Chem. Sci. 2012, 3, 2412; (b) Beesley, R. M.;
Ingold, C. K.; Thorpe, J. F. J. Chem. Soc., Trans. 1915, 107, 1080.
The authors would like to thank the National Science Council of
the Republic of China for its financial support (NSC 102-2113-M-
037-005-MY2).