Synthesis of 3,4-dihydropyrrolo[2,1-a]isoquinolines based on [3+2] cycloaddition initiated by Rh2(cap)4-catalyzed oxidation

Article abstract of DOI:10.1016/j.tetlet.2013.04.004

Azomethine ylides have been efficiently generated via Rh ₂(cap)₄-catalyzed oxidation of tetrahydroisoquinoline derivatives in the presence of base. The ylides are trapped in situ via [3+2] cycloaddition with dipolarophiles and subjec

Full text of DOI:10.1016/j.tetlet.2013.04.004

Tetrahedron Letters 54 (2013) 3015–3018
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Synthesis of 3,4-dihydropyrrolo[2,1-a]isoquinolines based on [3+2]
cycloaddition initiated by Rh2(cap)4-catalyzed oxidation
Hong-Tu Wang a,b, Chong-Dao Lu a,
⇑
a Xinjiang Technical Institute of Physics & Chemistry, Chinese Academy of Sciences, Urumqi 830011, PR China
b University of Chinese Academy of Sciences, Beijing 100049, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Azomethine ylides have been efficiently generated via Rh2(cap)4-catalyzed oxidation of tetrahydroiso-
quinoline derivatives in the presence of base. The ylides are trapped in situ via [3+2] cycloaddition with
dipolarophiles and subjected to oxidative aromatization facilitated by N-bromosuccinimide to provide
3,4-dihydropyrrolo[2,1-a]isoquinoline derivatives in moderate to excellent yields.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 17 February 2013
Revised 26 March 2013
Accepted 2 April 2013
Available online 8 April 2013
Keywords:
Dirhodium(II)
Catalysis
Oxidation
Cycloaddition
Pyrrolo[2,1-a]isoquinolines
Pyrrolo[2,1-a]isoquinoline, which occurs in lamellarin alka-
loids,1 serves as an important heterocyclic system and has at-
tracted considerable attention in the synthetic organic
community. Various approaches have been developed to synthe-
size this skeleton,2 with transition metal-catalyzed tandem reac-
tions being among the most efficient. For example, using CuBr2
or Ru poly-pyridine complexes3–5 as catalyst in conjunction with
suitable oxidants allowed efficient construction of 3,4-dihydropyr-
rolo[2,1-a]isoquinoline derivatives from tetrahydroisoquinoline
esters via dipolar cycloaddition of azomethine ylides, followed by
oxidative aromatization. In this process, the catalytic oxidation
protocol generated 3,4-dihydroisoquinolinium species, which
served as precursors of the azomethine ylides.6
Pioneering work by Doyle has shown that an extremely effec-
tive way to generate iminium species is catalytic oxidation of ter-
tiary amines using tert-butyl hydroperoxide (TBHP) in the presence
of dirhodium(II) caprolactamate [Rh2(cap)4] catalyst.7–12 Doyle has
further demonstrated that iminium ions generated in situ in this
way can be captured by 2-siloxyfurans via nucleophilic addition.9
Our interest in dirhodium(II) complexes and their applications13
led us to examine whether Doyle’s oxidation protocol could be ex-
tended to a variant of dipolarophilic cycloaddition.
to produce azomethine ylides (B). The ylide intermediate B could
then react with dipolarophiles (2) to give cycloadducts (4), which
could be further oxidized to 3,4-dihydropyrrolo[2,1-a]isoquinoline
derivatives (3). If successful, this approach would extend
Rh2(cap)4/TBHP catalytic oxidation to [3+2] cycloaddition. Here,
we report our preliminary results using this approach.
We optimized reaction conditions using the model reaction of
ethyl 2-(3,4-dihydroisoquinolin-2(1H)-yl) acetate (1a) with N-
phenylmaleimide (2a) (Table 1). Dipolar cycloaddition initiated
by Rh2(cap)4-catalyzed oxidation proceeded quite slowly to give
Rh2(cap)4,
O
O
O
t-BuOOH
N
N
N
OEt
B:
OEt
R
R
A
B
1
H
N
O
base
Rh Rh
Rh2(cap)4
OEt
R
[3+2]
cycloaddition
dipolarophiles (2)
[O]
As shown in Scheme 1, we speculated that Rh2(cap)4-catalyzed
oxidation of tetrahydroisoquinoline derivatives (A) could generate
iminium ions, which could undergo base-facilitated deprotonation
O
O
N
N
oxidative
aromatization
R
R
OEt
OEt
4
3
R'
R'
Scheme 1. Rh2(cap)4-catalyzed oxidation initiates a cascade of iminium formation,
dipolar cycloaddition, and oxidative aromatization.
⇑
Corresponding author. Tel./fax: +86 991 383 8708.
E-mail address: clu@ms.xjb.ac.cn (C.-D. Lu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.004

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H.-T. Wang, C.-D. Lu / Tetrahedron Letters 54 (2013) 3015–3018
Table 1
hexahydropyrrolo[2,1-a]isoquinoline 3a in 5% yield and dihydro-
Optimizing the reaction of 1a with 2aa
pyrrolo[2,1-a]isoquinoline 4a in 50% yield after 60 h (entry 1).
Incorporating N-bromosuccinimide (NBS) oxidation4 by adding
NBS (2.0 equiv) to the reaction mixture after complete consump-
tion of substrate 2a gave 3a as the only product in 57% yield (entry
2). Adding typical inorganic or organic bases (50 mol %) consider-
ably shortened the reaction time from 60 to 3–5 h with compara-
ble yields (entries 3–5). Moreover, catalyst loading could be
reduced to 0.5 mol % without a notable decrease in yield (entry
6).14 To our delight, 3a was isolated in excellent yield (97%) when
2a was added slowly over 2 h using a syringe pump (entry 7).15
Reactions did not occur in the absence of Rh2(cap)4 or TBHP.
We examined the substrate scope of the cascade transformation
using the optimized reaction conditions and various dipolarophiles
2 reported in Ref. 4 (Table 2).16 Various N-substituted maleimides
2a–2e reacted smoothly with 1a to give the corresponding prod-
ucts 3a–3e in moderate to excellent yields (entries 1–5). When
Entry
Catalyst loading
(mol %)
Base
(50 mol %)
Time
(h)
Yieldb (%)
(3a/4a)
1
1
1
1
1
1
0.5
0.5
None
None
60
60
5
3
3
5/50
57/0
51/0
63/0
49/0
62/0
97/0
2c
3c
4c
5c
6c
7d
NaHCO3
K2CO3
i-Pr2NEt
K2CO3
K2CO3
3.5
4
a
Reaction conditions: 1a (0.36 mmol), 2a (0.30 mmol), Rh2(cap)4, t-BuOOH
(5.5 M in decane, 2.0 equiv), and CH3CN (3.0 mL) at room temperature.
Isolated yield after silica gel chromatography.
N-Bromosuccinimide (2.0 equiv) was added to the reaction mixture at the
indicated times, and stirring was continued for 1 h.
b
c
d
2a was dissolved in CH3CN (1.0 mL) and added slowly to the reaction mixture
over 2 h using a syringe pump.
Table 2
Reaction of tetrahydroisoquinolines with dipolarophilesa
Entry
Dihydroisoquinoline
Dipolarophile
Product
Yieldb (%)
97 (94)
O
CO2Et
O
N
N
N
O
OEt
1a
O
1
N
O
2a
3a
O
N
O
CO2Et
O
N
N
N
OEt
OMe
O
1a
N
O
2
3
95 (81)
2b
2c
OMe
3b
3c
O
N
O
CO2Et
O
N
NO2
OEt
O
1a
N
O
97 (68)
NO2
O
CO2Et
O
N
N
N
N
O
Me
OEt
O
1a
1a
4
5
76 (94)
69 (76)
N
O
2d
Me
3d
CO2Et
O
O
N
O
N
OEt
O
N
O
2e
3e
NO2
CO2Et
O
N
N
N
N
OEt
1a
1a
1a
2f
6
7
8
57 (64)
48 (62)
46 (53)
NO2
3f
NO2
CO2Et
O
N
OEt
Me
Me
Br
2g
NO2
3g
NO2
CO2Et
O
N
OEt
Br
2h
NO2
3h

H.-T. Wang, C.-D. Lu / Tetrahedron Letters 54 (2013) 3015–3018
3017
Table 2 (continued)
Entry
Dihydroisoquinoline
Dipolarophile
Product
Yieldb (%)
CO2Et
CO2Et
O
2i
N
N
N
N
OEt
1a
1a
1a
9
53 (52)
73 (65)
CO2Et
CO2Et
3i
MeO2C
CO2Me
O
2j
N
OEt
CO2Me
CO2Me
10
3j
O
O
CO2Et
O
N
OEt
O
11
45 (51)
91 (89)
O
O
O
2k
3k
MeO
O
N
O
CO2Et
O
N
N
O
MeO
OEt
1b
12
N
O
2a
MeO
OMe
3l
a
Reaction conditions: 1a (0.36 mmol), Rh2(cap)4 (1.1 mg, 0.5 mol %), t-BuOOH (0.60 mmol, 5.5 M in decane, 2.0 equiv), and K2CO3 (0.15 mmol, 50 mol %) were dissolved in
CH3CN (2.0 mL) at room temperature, and then 2a (0.3 mmol) in CH3CN (1.0 mL) was added slowly over 2 h using a syringe pump. When 2a had been completely consumed,
N-bromosuccinimide (2.0 equiv) was added to the reaction mixture, and stirring was continued for 1 h.
b
Isolated yield; yields reported in Ref. 4 are given in parentheses.
Ploypradith, P.; Mahidol, C.; Sahakitpichan, P.; Wongbundit, S.; Ruchirawat, S.
Angew. Chem., Int. Ed. 2004, 43, 866; (f) Cironi, P.; Manzanares, I.; Albericio, F.;
Alvarez, M. Org. Lett. 2003, 5, 2959; (g) Handy, S. T.; Zhang, Y. N.; Bregman, H. J.
nitroolefins 2f–2h were used as starting materials, the correspond-
ing products 3f–3h were obtained in 46–57% yields (entries 6–8).
The unsymmetrical dipolarophile 2i gave the regioisomer 3i exclu-
sively (entry 9), while the reaction of symmetrical alkyne 2j with
tetrahydroisoquinoline 1a yielded the desired adduct 3j in 73%
yield (entry 10). Maleic anhydrides 2k showed low reactivity in
the tandem reaction, giving 3,4-dihydropyrrolo[2,1-a]isoquinoline
product 3k in 45% yield (entry 11). The dihydroisoquinoline ester
derivative 1b reacted smoothly with 2a to give 3l in 91% yield (en-
try 12). The yields obtained using the protocol described here were
comparable to those reported in Ref. 4 (Table 2, yields in parenthe-
ses), indicating that 3,4-dihydropyrrolo[2,1-a]isoquinolines can be
synthesized effectively via [3+2] cycloaddition initiated by
Rh2(cap)4-catalyzed oxidation. This approach can therefore be con-
sidered a proper alternative to the photocatalytic oxidation process
based on Ru poly-pyridine complexes reported in Ref. 4.
In summary, we have developed an efficient cascade involving
Rh2(cap)4-catalyzed oxidation, [3+2] cycloaddition, and oxidative
aromatization, and we have used it to construct a variety of 3,4-
dihydropyrrolo[2,1-a]isoquinoline derivatives. This approach uses
Doyle’s oxidative protocol to generate azomethine ylides and trap
them in situ via dipolarophilic cycloaddition.
Org. Chem. 2004, 69, 2362; (h) Ploypradith, P.; Kagan, R. K.; Ruchirawat, S. J. Org.
Chem. 2005, 70, 5119; (i) Hamasaki, A.; Zimpleman, J. M.; Hwang, I.; Boger, D. L.
J. Am. Chem. Soc. 2005, 127, 10767; (j) Ploypradith, P.; Petchmance, T.;
Sahakitpichan, P.; Litvinas, N. D.; Ruchirawat, S. J. Org. Chem. 2006, 71, 9440;
(k) Su, S.; Porco, A. J., Jr. J. Am. Chem. Soc. 2007, 129, 7744; (l) Gupton, J. T.;
Banner, E. J.; Sartin, M. D.; Coppock, M. B.; Hempel, J. E.; Kharlamova, A.; Fisher,
D. C.; Giglio, B. C.; Smith, K. L.; Keough, M. J.; Smith, T. M.; Kanters, R. P. F.;
Dominey, R. N.; Sikorski, J. A. Tetrahedron 2008, 64, 5246; (m) Ohta, T.; Fukuda,
T.; Ishibashi, F.; Iwao, M. J. Org. Chem. 2009, 74, 8143; (n) Verma, A. K.;
Kesharwani, T.; Singh, J.; Tandon, V.; Larock, R. C. Angew. Chem., Int. Ed. 2009,
48, 1138; (o) Li, Q.; Jiang, J.; Fan, A.; Cui, Y.; Jia, Y. Org. Lett. 2011, 13, 312; (p)
Ackermann, L.; Wang, L.; Lygin, A. V. Chem. Sci. 2012, 3, 177.
3. For catalytic oxidation using CuBr2, see: Yu, C.; Zhang, Y.; Zhang, S.; Li, H.;
Wang, W. Chem. Commun. 2011, 1036.
4. For catalytic oxidation using Ru poly-pyridine complexes, see: Zou, Y.-Q.; Lu, L.-
Q.; Fu, L.; Chang, N.-J.; Rong, J.; Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed.
2011, 50, 7171. and Ref. 5.
5. Rueping, M.; Leonori, D.; Poisson, T. Chem. Commun. 2011, 9615.
6. Huisgen, R.; Grashey, R.; Steingruber, E. Tetrahedron Lett. 1963, 4, 1441.
7. For Rh2(cap)4-catalyzed allylic oxidation, see: (a) Catino, A. J.; Forslund, R. E.;
Doyle, M. P. J. Am. Chem. Soc. 2004, 126, 13622; (b) Choi, H.; Doyle, M. P. Org.
Lett. 2007, 9, 5349; (c) McLaughlin, E. C.; Choi, H.; Wang, K.; Chiou, G.; Doyle, M.
P. J. Org. Chem. 2009, 74, 730.
8. For Rh2(cap)4-catalyzed benzylic oxidation, see: Catino, A. J.; Nichols, J. M.;
Choi, H.; Gottipamula, S.; Doyle, M. P. Org. Lett. 2005, 7, 5167.
9. For Rh2(cap)4-catalyzed oxidation of tertiary amines to initiate the Mannich
reaction, see: Catino, A. J.; Nichols, J. M.; Nettles, B. J.; Doyle, M. P. J. Am. Chem.
Soc. 2006, 128, 5648.
Acknowledgments
10. For Rh2(cap)4-catalyzed oxidation of secondary amines, see: Choi, H.; Doyle, M.
P. Chem. Commun. 2007, 745.
This work was supported by the National Natural Science Foun-
dation of China (21172251) and the Chinese Academy of Sciences.
11. For Rh2(cap)4-catalyzed propargylic oxidation, see: McLaughlin, E. C.; Doyle, M.
P. J. Org. Chem. 2008, 73, 4317.
12. For Rh2(cap)4-catalyzed oxidation of phenol and aniline, see: Ratnikov, M. O.;
Farkas, L. E.; McLaughlin, E. C.; Chiou, G.; Choi, H.; El-Khalafy, S. H.; Doyle, M. P.
J. Org. Chem. 2011, 76, 2585.
13. (a) Tusun, X.; Lu, C.-D. Synlett 2012, 1801; (b) Wusiman, A.; Tusun, X.; Lu, C.-D.
Eur. J. Org. Chem. 2012, 3088.
14. Further reductions in catalyst loading decreased yields and prolonged reaction
times. For example, performing the reaction with 0.1 mol % catalyst loading
afforded 3a in 37% yield after 24 h.
References and notes
1. For recent reviews on lamellarins and related alkaloids, including their
synthesis, see: (a) Fan, H.; Peng, J.; Hamann, M. T.; Hu, J.-F. Chem. Rev. 2008,
108, 264; (b) Pla, D.; Albericio, F.; Alvarez, M. Anti-Cancer Agents Med. Chem.
2008, 8, 746; (c) Pla, D.; Albericio, F.; Alvarez, M. Med. Chem. Commun. 2011, 2,
689; (d) Fukuda, T.; Ishibashi, F.; Iwao, M. Heterocycles 2011, 83, 491.
2. For representative examples, see: (a) Heim, A.; Terpin, A.; Steglich, W. Angew.
Chem., Int. Ed. 1997, 36, 155; (b) Banwell, M.; Flynn, B.; Hockless, D. Chem.
Commun. 1997, 2259; (c) Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.;
Jin, Q. J. Am. Chem. Soc. 1999, 121, 54; (d) Ridley, C. P.; Reddy, M. V. R.; Rocha, G.;
Bushman, F. D.; Faulkner, D. J. Bioorg. Med. Chem. 2002, 10, 3285; (e)
15. The reasons for the improvement resulted from slow introduction of substrate
2a on the reaction are unclear.
16. General
experimental
procedure:
Rh2(cap)4Á2CH3CN
(0.0015 mmol),
tetrahydroisoquinoline
1
(0.36 mmol), and K2CO3 (0.15 mmol) in CH3CN
(2.0 mL) were mixed and kept under stirring while t-BuOOH (5.5 M in
decane, 0.60 mmol) was added in one portion at room temperature. Then N-

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H.-T. Wang, C.-D. Lu / Tetrahedron Letters 54 (2013) 3015–3018
phenylmaleimide 2 (0.30 mmol) in CH3CN (1.0 mL) was added dropwise over
filtered. The filtrate was concentrated and the residue purified by flash column
chromatography on silica gel using petroleum ether-dichloromethane-ethyl
acetate as the eluent, giving the desired product 3. The structures of the
cycloadducts 3a–l were identified by comparison with the 1H NMR spectra in
Ref. 4 and confirmed by mass spectra.
2 h using a syringe pump. The reaction was stirred until substrate 2 was
completely consumed (ca. 3 h), and then N-bromosuccinimide (0.60 mmol)
was added and stirring continued for 1 h. Saturated NaHSO3 (5 mL) was added
to quench the reaction. The crude mixture was extracted with CH2Cl2 (10 mL
Â3), and the combined organic phases were dried over sodium sulfate and