Highly enantioselective synthesis of tetrahydrocarbolines via iridium-catalyzed intramolecular friedel-crafts type allylic alkylation reactions

Article abstract of DOI:10.1021/ol4027717

A highly enantioselective synthesis of substituted tetrahydrocarbolines via Ir-catalyzed Friedel-Crafts type intramolecular asymmetric allylic alkylation of 2-indolyl allyl carbonates has been developed. This strategy features excellent chemoselectivity a

Full text of DOI:10.1021/ol4027717

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Highly Enantioselective Synthesis
of Tetrahydrocarbolines via Iridium-
Catalyzed Intramolecular FriedelꢀCrafts
Type Allylic Alkylation Reactions
Qing-Long Xu, Chun-Xiang Zhuo, Li-Xin Dai, and Shu-Li You*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
slyou@sioc.ac.cn
Received September 25, 2013
ABSTRACT
A highly enantioselective synthesis of substituted tetrahydrocarbolines via Ir-catalyzed FriedelꢀCrafts type intramolecular asymmetric allylic
alkylation of 2-indolyl allyl carbonates has been developed. This strategy features excellent chemoselectivity and enantioselectivity, mild reaction
conditions, and an easily accessed chiral ligand.
The substituted indole nucleus is a common component
of a vast number of biologically active natural products
and pharmaceuticals.1 Particularly, the tetrahydrocarbo-
line scaffold is among the privileged heterocycles. There-
fore, the functionalization of indole and synthesis of
tetrahydrocarboline derivatives have been an intense sub-
ject in chemical research, and various methods are now
available.2,3 To be noted, the asymmetric FriedelꢀCrafts
reactions including the PictetꢀSpengler reactions have
been the most successful approach for the synthesis of
tetrahydrocarboline derivatives.4 On the other hand, de-
spite the fact that a transition-metal-catalyzed asymmetric
allylic substitution reaction has been widely studied,5,6
only a few examples of FriedelꢀCrafts type asymmetric
allylic alkylation reactions have been reported to date.7
Recently, we reported an efficient synthesis of tetra-
hydrocarbolines by an iridium-catalyzed asymmetric
allylic dearomatization/migration sequence of 3-indolyl
(5) For reviews: (a) Trost, B. M.; Van Vranken, D. L. Chem. Rev.
1996, 96, 396. (b) Trost, B. M.; Crawley, M. L. Chem. Rev. 2003, 103,
2921. (c) Lu, Z.; Ma, S. Angew. Chem., Int. Ed. 2008, 47, 258.
(1) (a) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis,
1st ed.; Wiley-VCH: New York, 1996. (b) Nicolaou, K. C.; Snyder, S. A.
Classics in Total Synthesis II, 1st ed.; Wiley-VCH: Weinheim, 2003.
(2) (a) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, U.K., 1984; Vol. 4, p
313. (b) Vicente, R. Org. Biomol. Chem. 2011, 9, 6469.
(3) (a) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48,
9608. (b) Bartoli, G.; Bencivenni, G.; Dalpozzo, R. Chem. Soc. Rev.
2010, 39, 4449. (c) Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, 215.
(4) For selected recent reviews on FriedelꢀCrafts type reactions of
indole, see: (a) Poulsen, T. B.; Jøgensen, K. A. Chem. Rev. 2008, 108,
2903. (b) You, S.-L.; Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38, 2190.
(c) Marques-Lopez, E.; Diez-Martinez, A.; Merino, P.; Herrera, R. P.
Curr. Org. Chem. 2009, 13, 1585. (d) Zeng, M.; You, S.-L. Synlett 2010,
9, 1289.
(6) Selected examples for transition-metal-catalyzed allylic substitution
reactions with indoles: (a) Bandini, M.; Melloni, A.; Umani-Ronchi, A.
Org. Lett. 2004, 6, 3199. (b) Kimura, M.; Futamata, M.; Mukai, R.;
Tamaru, Y. J. Am. Chem. Soc. 2005, 127, 4592. (c) Kagawa, N.; Malerich,
J. P.; Rawal, V. H. Org. Lett. 2008, 10, 2381. (d) Bandini, M.; Eichholzer,
A. Angew. Chem., Int. Ed. 2009, 48, 9533. (e) Sundararaju, B.; Achard, M.;
Demerseman, B.; Toupet, L.; Sharma, G. V. M.; Bruneau, C. Angew.
Chem., Int. Ed. 2010, 49, 2782. (f) Trost, B. M.; Osipov, M.; Dong, G.
J. Am. Chem. Soc. 2010, 132, 15800. (g) Wu, Q.-F.; He, H.; Liu, W.-B.;
You, S.-L. J. Am. Chem. Soc. 2010, 132, 11418. (h) Bandini, M.; Bottoni,
A.; Chiarucci, M.; Cera, G.; Miscione, G. P. J. Am. Chem. Soc. 2012, 134,
20690. (i) Wu, Q.-F.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2012,
51, 1680. (j) Liu, Y.; Du, H. Org. Lett. 2013, 15, 740. (k) Montgomery,
T. D.; Zhu, Y.; Kagawa, N.; Rawal, V. H. Org. Lett. 2013, 15, 1140. (l)
Zhang, X.; Yang, Z.-P.; Liu, C.; You, S.-L. Chem. Sci. 2013, 4, 3239.
r
10.1021/ol4027717
XXXX American Chemical Society

allyl carbonates (Scheme 1, path a).8 The reaction pro-
ceeded via a dearomatized spiro-indolenine intermediate,
featuring the switch of the substituent from the C3 to the
C2 position of the indole. Given the high reactivity of
the C3 position of indole, we envisaged, by utilizing the
2-indoyl allyl carbonate 1 as the substrate, the chiral
tetrahydrocarboline framework could also be easily ac-
cessed via the iridium-catalyzed intramolecular Friedelꢀ
Crafts type allylic alkylation reaction (Scheme 1, path b).
The two approaches utilized different starting materials
but led to identical products. Herein, we describe such a
highly enantioselective synthesis of substituted tetrahydro-
carbolines via Ir-catalyzed FriedelꢀCrafts type intramolecu-
lar asymmetric allylic alkylation of 2-indolyl allyl carbonates.
phosphoramidite ligand L1 (Table 1).9,10 To our great
delight, with either Cs2CO3 or K3PO4 as the base, the
reaction proceeded withexcellent chemoselectivity in favor
of the alkylation product, delivering the tetrahydrocarbo-
line 2a in excellent yields and enantioselectivity (82ꢀ86%
yields, 85% ee, entries 1ꢀ2, Table 1). Notably, the reaction
also occurred smoothly in 74% yield and 85% ee in the
absence of an additional base (entry 3, Table 1).
Table 1. Optimization of Reaction Conditionsa
Scheme 1. Different Approaches for the Synthesis of Chiral
Tetrahydrocarboline Frameworks
To begin the study, indoyl allyl carbonate 1a was taken
as the model substrate for optimizing the reaction condi-
tions. First, different bases were tested in the reaction with
an iridium-catalytic system derived from [Ir(cod)Cl]2 and
(7) Selected examples: (a) Bandini, M.; Melloni, A.; Piccinelli, F.;
Sinisi, R.; Tommasi, S.; Umani-Ronchi, A. J. Am. Chem. Soc. 2006, 128,
1424. (b) Cheung, H. Y.; Yu, W.-Y.; Lam, F. L.; Au-Yeung, T. T.-L.;
Zhou, Z.; Chan, T. H.; Chan, A. S. C. Org. Lett. 2007, 9, 4295. (c) Liu,
W.-B.; He, H.; Dai, L.-X.; You, S.-L. Org. Lett. 2008, 10, 1815. (d)
Hoshi, T.; Sasaki, K.; Sato, S.; Ishii, Y.; Suzuki, T.; Hagiwara, H. Org.
Lett. 2011, 13, 932. (e) Cao, Z.; Liu, Y.; Liu, Z.; Feng, X.; Zhuang, M.;
Du, H. Org. Lett. 2011, 13, 2164. (f) Suzuki, Y.; Nemoto, T.; Kakugawa,
K.; Hamajima, A.; Hamada, Y. Org. Lett. 2012, 14, 2350. (g) Xu, Q.-L.;
Dai, L.-X.; You, S.-L. Org. Lett. 2012, 14, 2579. (h) Schafroth, M. A.;
Sarlah, D.; Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc. 2012, 134,
20276. (i) Xu, Q.-L.; Dai, L.-X.; You, S.-L. Chem. Sci. 2013, 4, 97. (j)
Mino, T.; Ishikawa, M.; Nishikawa, K.; Wakui, K.; Sakamoto, M.
Tetrahedron: Asymmetry 2013, 24, 499. (k) Du, L.; Cao, P.; Xing, J.;
Lou, Y.; Jiang, L.; Li, L.; Liao, J. Angew. Chem., Int. Ed. 2013, 52, 4207.
(8) Zhuo, C.-X.; Wu, Q.-F; Zhao, Q.; Xu, Q.-L.; You, S.-L. J. Am.
Chem. Soc. 2013, 135, 8169.
temp
t
conv
yield
ee
b
entry
L
solvent (°C) (h) (%)b 2a/2a0
(%)c (%)d
1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L9
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
50
50
50
50
50
50
50
50
50
50
50
50
rt
3
3
5
2
21
2
2
2
2
2
2
2
>95
>95
85
50/1
20/1
82
86
74
58
ꢀ
85
85
85
ꢀ
2e
3f
>50/1
3.5/1
4
>95
57
5
50/1
ꢀ
6
>95
>95
>95
>95
>95
>95
>95
>50/1
>50/1
>50/1
>50/1
>50/1
>50/1
>50/1
>50/1
>50/1
>50/1
>50/1
>50/1
81
79
90
64
85
80
88
81
84
76
74
80
90
84
81
ꢀ83
80
92
85
96
96
98
99
>99
7
8
9
10
11
12
13
14e
15e
16e
17e
(9) For reviews: (a) Miyabe, H.; Takemoto, Y. Synlett 2005, 1641. (b)
Takeuchi, R.; Kezuka, S. Synthesis 2006, 3349. (c) Helmchen, G.;
L10 THF
L9
L9
L9
L9
L9
THF
2.5 >95
2.5 >95
2.5 >95
€
Dahnz, A.; Dubon, P.; Schelwies, M.; Weihofen, R. Chem. Commun.
THF
rt
2007, 675. (d) Helmchen, G. In Iridium Complexes in Organic Synthesis;
Oro, L. A., Claver, C., Eds.; Wiley-VCH: Weinheim, Germany, 2009; p 211.
(e) Hartwig, J. F.; Stanley, L. M. Acc. Chem. Res. 2010, 43, 1461. (f)
Hartwig, J. F.; Pouy, M. J. Top. Organomet. Chem. 2011, 34, 169. (g) Liu,
W.-B.; Xia, J.-B.; You, S.-L. Top. Organomet. Chem. 2012, 38, 155. (h)
Tosatti, P.; Nelson, A.; Marsden, S. P. Org. Biomol. Chem. 2012, 10,
3147.
toluene
Et2O
rt
rt
2
2
>95
>95
CH2Cl2
rt
a Reaction conditions: 2 mol % of [Ir(cod)Cl]2, 4 mol % of L,
0.2 mmol of 1a, and 100 mol % of Cs2CO3 in solvent (2 mL), unless noted
otherwise. b Determined by 1H NMR of the crude reaction mixture.
c Isolated yield of 2a. d Determined by HPLC analysis. e 100 mol % of
K3PO4 was used. f No base was used in the reaction.
(10) Selected recent examples: (a) Stanley, L. M.; Bai, C.; Ueda, M.;
€
Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 8918. (b) Gartner, M.;
Mader, S.; Seehafer, K.; Helmchen, G. J. Am. Chem. Soc. 2011, 133,
~
ꢀ
2072. (c) Teichert, J. F.; Fananas-Mastral, M.; Feringa, B. L. Angew.
Chem., Int. Ed. 2011, 50, 688. (d) Gao, N.; Zheng, S.; Yang, W.; Zhao, X.
Org. Lett. 2011, 13, 1514. (e) Tosatti, P.; Campbell, A. J.; House, D.;
Nelson, A.; Marsden, S. P. J. Org. Chem. 2011, 76, 5495. (f) Chen, W.;
Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 15249. (g) Roggen, M.;
Carreira, E. M. Angew. Chem., Int. Ed. 2012, 51, 8652. (h) Schafroth,
M. A.; Sarlah, D.; Krautwald, S.; Carreira, E. M. J. Am. Chem. Soc.
2012, 134, 20276. (i) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. J. Am.
Chem. Soc. 2013, 135, 994. (j) Chen, W.; Hartwig, J. F. J. Am. Chem. Soc.
2013, 135, 2068. (k) Liu, W.-B.; Reeves, C. M.; Virgil, S. C.; Stoltz, B. M.
J. Am. Chem. Soc. 2013, 135, 10626.
With Cs2CO3 as the base, different ligands were then ex-
amined. The results are summarized in Table 1. All ligands
led to the complete conversion affording the desired prod-
uct 2a, except for L3 with only 57% conversion (entries
4ꢀ12, Table 1). The reaction with ligand L9 gave the best
enantioselectivity (entry 11, Table 1).11 Interestingly, when
B
Org. Lett., Vol. XX, No. XX, XXXX

follows: 1a in DCM (0.1 M), 2 mol % of [Ir(cod)Cl]2,
4 mol % of L9, 1.0 equiv of K3PO4 at rt. Under these
reaction conditions, product 2a was obtained in 80% yield
and >99% ee (entry 17, Table 1).
Scheme 2. Reaction Substrate Scopea
Under the optimized reaction conditions, the substrate
scope of the reaction was explored. The results are sum-
marized in Scheme 2. As to substituents on the nitrogen
linkage, Bn, Me, and allyl groups could be well tolerated
delivering alkylated products (2aꢀ2c) in excellent enan-
tioselectivity (98ꢀ 99%ee). The reactions of 5-substituted
>
indole substrates generated the products (2dꢀ2h) in good
yields(70ꢀ77%) and excellent enantioselectivity (98ꢀ 99%
>
ee). Substrates bearing either an electron-donating group
(MeO) or an electron-withdrawing group (Cl) at the
6-position of indole could be employed in the reaction,
and the products were obtained in good yields with excel-
lent enantioselectivity (2iꢀ2j, 75ꢀ76% yields, 98ꢀ 99% ee).
>
To further confirm the absolute configuration of
the product, an X-ray crystallographic analysis of a deriv-
ative of the enantiopure compound 2j disclosed the
absolute configuration as (R) (see the Supporting Informa-
tion for details), which is consistent with the previous
study.8
In summary, we have developed an efficient iridium-
catalyzed FriedelꢀCrafts type intramolecular asymmetric
allylic alkylation reaction of 2-indolyl allyl carbonates,
affording tetrahydrocarboline derivatives in moderate to
good yields as well as excellent chemoselectivity and
enantioselectivity. The products obtained in this study
from 2-indolyl allyl carbonates are identical with those
from the 3-indolyl allyl carbonates with higher enantio-
selectivity. The reaction features mild reaction conditions,
excellent chemo- and enantioselectivity, and the utilization
of an easily accessed ligand.
a Reaction conditions: 2 mol % of [Ir(cod)Cl]2, 4 mol % of (Ra)-L9,
0.2 mmol of 1, and 100 mol % of K3PO4 in DCM (2 mL) at rt. 2/20 ratios
were determined by 1H NMR analysis of the crude reaction mixture. Ee
value of 2 was determined by HPLC analysis.
the reaction was run at room temperature, the enantios-
electivity of the product was increased to 96% ee (entry 13,
Table 1). With K3PO4 as the base, the yield can be fur-
ther improved to 84% with 96% ee (entry 14, Table 1). In
addition, several additional solvents (toluene, Et2O,
and CH2Cl2) were tested, and all led to the formation
of the desired product 2a in excellent enantioselectivity
Acknowledgment. We thank the National Basic Re-
search Program of China (973 Program 2010CB833300)
and the National Natural Science Foundation of China
(21025209, 20923005, 20932008, 21121062) for generous
financial support.
Supporting Information Available. Experimental pro-
cedures and analysis data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(98ꢀ 99% ee, entries 15ꢀ17, Table 1). After the optimi-
>
zation study, the optimized conditions were obtained as
(11) (a) Liu, W.-B.; He, H.; Dai, L.-X.; You, S.-L. Synthesis 2009,
2076. (b) Liu, W.-B.; Zheng, C.; Zhuo, C.-X.; Dai, L.-X.; You, S.-L.
J. Am. Chem. Soc. 2012, 134, 4812.
The authors declare no competing financial interest.
Org. Lett., Vol. XX, No. XX, XXXX
C