A novel lewis acid catalyzed [3 + 3]-annulation strategy for the syntheses of tetrahydro-β-carbolines and tetrahydroisoquinolines

Article abstract of DOI:10.1021/ol4008525

A novel Lewis acid catalyzed [3 + 3]-annulation process for the efficient syntheses of both tetrahydro-β-carbolines and tetrahydroisoquinolines from readily available benzylic alcohols and aziridines was developed, which would be a highly valuable complement to the widely used Pictet-Spengler reaction. A probable mechanism was proposed based on the isolation and characterization of two key intermediates. This strategy enables facile access to important alkaloid frameworks not easily available with other known methods.

Full text of DOI:10.1021/ol4008525

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Novel Lewis Acid Catalyzed
[3 þ 3]-Annulation Strategy for the
Syntheses of Tetrahydro-β-Carbolines
and Tetrahydroisoquinolines
Shaoyin Wang,†,‡ Zhuo Chai,† Shuangliu Zhou,† Shaowu Wang,*,† Xiancui Zhu,† and
Yun Wei†
Laboratory of Functionalized Molecular Solids, Ministry of Education, Anhui Laboratory
of Molecule-Based Materials, Institute of Organic Chemistry, School of Chemistry and
Materials Science, Anhui Normal University, Wuhu, Anhui 241000, and P. R. China, and,
Department of Chemistry, Wannan Medical College, Wuhu, Anhui 241002, P. R. China
swwang@mail.ahnu.edu.cn
Received March 28, 2013
ABSTRACT
A novel Lewis acid catalyzed [3 þ 3]-annulation process for the efficient syntheses of both tetrahydro-β-carbolines and tetrahydroisoquinolines
from readily available benzylic alcohols and aziridines was developed, which would be a highly valuable complement to the widely used
PictetꢀSpengler reaction. A probable mechanism was proposed based on the isolation and characterization of two key intermediates. This
strategy enables facile access to important alkaloid frameworks not easily available with other known methods.
Tetrahydro-β-carbolines and tetrahydroisoquinolines
are highly important alkaloids with numerous valuable
biological activities and pharmaceutical applications.1
As to the construction of these two important structures
(Scheme 1), the century-old one-step PictetꢀSpengler
reaction still stands out as one of the most direct, efficient
methods using amines and aldehydes as starting materials,
especially with the recent remarkable advances in the devel-
opment of various asymmetric catalytic versions.2 For
the syntheses of functionalized tetrahydroisoquinolines,
alternative ways have also been developed, including the
oxidative dehydrogenative coupling of tetrahydroisoquino-
lines with various nucleophiles,3 hydrogenation of 1-sub-
stituted 3,4-dihydroisoquinolines,4 and others.5 Most of
these existing strategies require substrates that already have
€
(2) For selected reviews: (a) Stockkigt, J.; Antonchick, A. P.; Wu, F.;
Waldmann, H. Angew. Chem., Int. Ed. 2011, 50, 8538. (b) You, S.-L.;
Cai, Q.; Zeng, M. Chem. Soc. Rev. 2009, 38, 2190. (c) Lorenz, M.;
VanLinn, M. L.; Cook, J. M. Curr. Org. Synth. 2010, 7, 189. (d)
Chrzanowska, M.; Rozwadowska, M. Chem. Rev. 2004, 104, 3341.
For selected recent examples using this strategy: (e) Ascic, E.; Jensen,
J. L.; Nielsen, T. E. Angew. Chem., Int. Ed. 2011, 50, 5188. (f) Cai, Q.;
Liang, X.-W.; Wang, S.-G.; Zhang, J.-W.; Zhang, X.; You, S.-L. Org.
Lett. 2012, 14, 5022. (g) Muratore, M. E.; Holloway, C. A.; Pilling,
A. W.; Storer, R. I.; Trevitt, G.; Dixon, D. J. J. Am. Chem. Soc. 2009,
131, 10796. (h) Huang, D.; Xu, F.; Lin, X.; Wang, Y. Chem.;Eur. J.
2012, 18, 3148. (i) Wanner, M. J.; van der Haas, R. N. S.; de Cuba, K. R.;
van Maarseveen, J. H.; Hiemstra, H. Angew. Chem., Int. Ed. 2007, 46,
7485. (j) Seayad, J.; Seayad, A. M.; List, B. J. Am. Chem. Soc. 2006, 128,
1086. (k) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N.
J. Am. Chem. Soc. 2007, 129, 13404. (l) Taylor, M. S.; Jacobsen, E. N.
J. Am. Chem. Soc. 2004, 126, 10558.
† Anhui Normal University.
‡ Wannan Medical College.
(1) For selected reviews on tetrahydro-β-carbolines: (a) Cao, R.;
Peng, W.; Wang, Z.; Xu, A. Curr. Med. Chem. 2007, 14, 479. (b)
O’Connor, S. E.; Maresh, J. J. Nat. Prod. Rep. 2006, 23, 532. (c) El-
Sayed, M.; Verpoorte, R. Phytochem. Rev. 2007, 6, 277. (d) Chen, F. E.;
Huang, J. Chem. Rev. 2005, 105, 4671. For selected reviews on tetra-
hydroisoquinolines: (e) Bentley, K. W. Nat. Prod. Rep. 2006, 23, 444. (f)
Jack, D.; Williams, R. Chem. Rev. 2002, 102, 1669. (g) Phillipson, J. D.,
Roberts, M. F., Zenk, M. H., Eds. The Chemistry and Biology of
Isoquinoline Alkaloids; Springer: Berlin, 1985.
(3) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (b) Campos, K. R.
Chem. Soc. Rev. 2007, 36, 1069. (c) Jones, K. M.; Karier, P.; Klussmann,
M. ChemCatChem 2012, 4, 51. (d) Zhang, G.; Ma, Y.; Wang, S.; Kong
W.; Wang, R. Chem. Sci. 2013, 4, doi: 10.1039/C3S C50604E.
r
10.1021/ol4008525
XXXX American Chemical Society

the major molecular skeletons of the products or a prior
installation of a relatively labile free amino functionality in
one of the main starting materials. For example, the Pictetꢀ
Spengler reaction, which could be viewed as a [5 þ 1]-
annulation strategy, requires the prepreparation of the not-so-
stable tryptamines. These limitations would inevitably erode
into the product diversity of these methods. Furthermore,
most current methods could only provide the corresponding
products with substitutions at the 1-position, while access
to the 4-substituted products is extremely limited.2a Conse-
quently, a complementary method allowing more diversified
syntheses of these valuable compounds would still be highly
desirable. We presumed a new strategy for this purpose: the
six-membered tetrahydropyridine ring in these two kinds of
alkaloids might be dissected into two three-atom synthons,
which could be assembled by a FriedelꢀCrafts alkylation
and an amine-benzylation process from the corresponding
benzylic alcohols and aziridines (Scheme 1).
Scheme 1. General Direct Strategies for the Syntheses of
Tetrahydro-β-Carbolines and Tetrahydroisoquinolines
Rare-earth metal triflates have been referred to as a type
of environmentally benign efficient Lewis acid catalyst,
because they are usually stable, water-compatible, recover-
able, and reusable while still possessing strong catalytic
activity.6 These advantages have placed them among the
most privileged Lewis acid catalysts in organic synthesis.
Particularly, their unique high oxophilicity enables the use
of benzylic alcohols as green electrophilic benzylation re-
agents, which usually generates water as the only byproduct.7
Additionally, they have also showed high catalytic activities
in the ring opening of aziridines by many nucleophiles.8
However, the employment of these two processes in a single
system is rare. We report herein the applications of rare-
earth metal triflates as catalysts for a novel Lewis acid
catalyzed [3 þ 3]-annulation reaction, enabling accesses to
both 1- and/or 4-substituted tetrahydro-β-carbolines and
tetrahydroisoquinolines from simple starting materials un-
der mild conditions.
efficient catalyst in catalyzing this reaction among the
catalysts screened. A screen of catalyst loading amounts
revealed that only 2 mol % was needed to complete the
reaction in 2 h in 1,2-DCE (1,2-dichloroethane), giving the
desired product 3a in 74% yield (Table 1, entries 2ꢀ4). It is
worth mentioning that the reaction is tolerant of moisture
and could be performed in commercial solvents under air.
The use of ScCl3 6H2O with weaker Lewis acidicity and
3
other rare-earth metal triflates like those of Y, La, and Yb
were inferior for this reaction (Table 1, entries 6ꢀ10).
Notably, the order of catalytic activity of these catalysts
for this reaction is also in a good accordance with their
Lewis acidity.9 Solvents such as nitromethane and THF
bearing coordinative O-atoms are highly detrimental to
the reaction (Table 1, entries 10ꢀ11). Thus the optimum
reaction conditions for the [3 þ 3]-annulation included 2
mol % of Sc(OTf)3 in 1,2-DCE for 2 h at reflux.
Our initial studies commenced with the reaction of
N-methyl-2-indolylmethanol 1a and aziridine 2a (Table 1).
In the absence of a catalyst, no reaction took place
(Table 1, entry 1). It is found that Sc(OTf)3 was the highly
Table 1. Screen of the Reaction Conditionsa
(4) For recent examples: (a) Berhal, F.; Wu, Z.; Zhang, Z.; Ayad, T.;
Ratovelomanana-Vidal, V. Org. Lett. 2012, 14, 3308. (b) Xie, J.-H.; Yan,
P.-C.; Zhang, Q.-Q.; Yuan, K. X.; Zhou, Q.-L. ACS Catal. 2012, 2, 561.
(c) Chang, M.; Li, W.; Zhang, X. Angew. Chem., Int. Ed. 2011, 50, 10679.
(d) Li, C.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 13208.
entry
cat. (x mol %)
solvent
time
yieldb (%)
(5) (a) Xu, Q.-L.; Dai, L.-X.; You, S.-L. Org. Lett. 2012, 14, 2579. (b)
Richter-Addo, G. B.; Knight, D. A.; Dewey, M. A.; Arit, A. M.; Gladyz,
J. A. J. Am. Chem. Soc. 1993, 115, 11863 and ref 2d.
(6) For reviews: (a) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam,
W. W.-L. Chem. Rev. 2002, 102, 2227. (b) Prakash, G. K. S.; Mathew, T.;
Olah, G. A. Acc. Chem. Res. 2011, 45, 565. (c) Luo, S.; Zhu, L.;
Talukdar, A.; Zhang, G.; Mi, X.; Cheng, J.-P.; Wang, P. G. Mini-Rev.
Org. Chem. 2005, 2, 177.
(7) (a) Noji, M.; Konno, Y.; Ishii, K. J. Org. Chem. 2007, 72, 5161. (b)
Noji, M.; Ohno, T.; Fuji, K.; FuIshii, K. J. Org. Chem. 2003, 68, 9340. (c)
Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S. Synlett 1996,
557. (d) Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S. J. Org.
Chem. 1997, 62, 6997. (e) Sharma, G. V. M; Mahalingam, A. K. J. Org.
Chem. 1999, 64, 8943.
(8) For recent reviews on the ring openings of aziridines: (a)
Stankovic, S.; D’Hooghe, M.; Catak, S.; Eum, H.; Waroquier, M.;
Van Speybroeck, V.; De Kimpe, N.; Ha, H.-J. Chem. Soc. Rev. 2012, 41,
643. (b) Singh, G. S.; D’Hooghe, M.; De Kimpe, N. Chem. Rev. 2007,
107, 2080. (c) Lu, P. Tetrahedron 2010, 66, 2549.
1
no catalyst
Sc(OTf)3 (10)
Sc(OTf)3 (5)
Sc(OTf)3 (2)
Sc(OTf)3 (1)
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
CHCl3
12 h
0.5 h
1 h
0
2
74
74
74
56
36
55
46
62
46
0
3
4
2 h
5
5 h
6
ScCl3 6H2O (10)
4 h
3
7
Y(OTf)3 (10)
La(OTf)3 (10)
Yb(OTf)3 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (10)
Sc(OTf)3 (10)
4 h
8
12 h
1 h
9
10
11
12
0.5 h
0.2 h
0.5 h
CH3NO2
THF
15
a Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), catalyst
(x mmol), solvent (3 mL). b Yield of the isolated pure product.
B
Org. Lett., Vol. XX, No. XX, XXXX

Next, a series of 2-indolyl methanols 1and aziridines 2were
examined in the reactions to give 4-aryl-1,2,3,4-tetrahydro-
β-carbolines under the optimized reaction conditions (Table 2).
For aziridines derived from different substituted styrenes,
substrates with electron-withdrawing substituents on the
benzene ring generally gave better yields of the products than
those with electron-donating ones (entries 1ꢀ7). A substitu-
ent at the ο-position is detrimental to the yield of the product,
probably due to steric reasons (entry 5). The presence of an
aryl group, which might facilitate the opening of the aziridine
ring, is crucial for the reaction, and aziridines derived from
aliphatic alkenes failed to react in the present conditions. As
to different 2-indolylmethanols 1, functional groups such as a
terminal alkene or alkyne in the substituent R1 were well
tolerated in the reaction, which allows for further elaboration
of the structure (entries 9ꢀ10). However, when electron-
withdrawing groups such as halogens are present at the
5-position of the indolyl ring, somewhat diminished yields
were obtained (entries 11ꢀ14). Substrates 1f and 1g with sub-
stituents at the 7- and 8-positions of the indole ring, respec-
tively, also participated in the reaction to give the desired
products (entries 15ꢀ16). The structures of the products 3a
and 3k were additionally confirmed by X-ray crystallographic
analyses.10
alcohols, providing 4-aryl tetrahydroisoquinolines (Table 3).
Generally, compared to 2-indolyl methanols, these benzylic
alcohols are less reactive and a larger catalyst loading
(5 mol %) and a longer reaction time (15 h) were required.
The reactivityof aziridines issimilar:electron-withdrawing
substituents (R3) on the benzene ring were more favorable
to the annulation than electron-donating ones (entries 2ꢀ6).
The use of 4-tert-butylphenylsulfonyl group gave a signifi-
cantly improved yield (entry 7), while changing the protecting
group of the N-atom of the aziridines to a more electron-
deficient 4-nitrophenylsulfonyl group was deleterious to the
reaction (entry 8). Notably, substrate 4b with an acid-
sensitive acetal functionality was well-tolerated in the
reaction to furnish the desired products in comparable
yields (entries 9ꢀ11).
Table 3. Scope Study for the Syntheses of
4-Aryl-1,2,3,4-tetrahydroquinolines 5a
entry
4
2 (R3/ R4)
5
yieldb (%)
1
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
H/4-CH3C6H4 (2a)
F/4-CH3C6H4 (2b)
Cl/4-CH3C6H4 (2c)
Br/4-CH3C6H4 (2d)
CH3/4-CH3C6H4 (2f)
tBu/4-CH3C6H4 (2g)
H/4-tBuC6H4 (2h)
H/4-O2NC6H4 (2i)
H/4-CH3C6H4 (2a)
Cl/4-CH3C6H4 (2c)
CH3/4-CH3C6H4 (2f)
5a
5b
5c
5d
5e
5f
70
72
74
74
69
66
76
55
68
73
67
2
Table 2. Scope Study for the Syntheses of
4-Aryl-1,2,3,4-tetrahydro-β-carbolines 3a
3
4
5
6
7
5g
5h
5i
8
9
10
11
5j
entry
R/R1
R2
Ph (2a)
3
yieldb(%)
5k
1
H/CH3 (1a)
H/CH3 (1a)
H/CH3 (1a)
H/CH3 (1a)
H/CH3 (1a)
H/CH3 (1a)
H/CH3 (1a)
H/CH3 (1a)
H/allyl (1b)
3a (X-ray)
74
77
75
72
46
55
57
72
70
68
47
55
68
62
72
46
a Reaction conditions: 1(0.6 mmol), 2(0.5 mmol), Sc(OTf)3 (0.025 mmol),
2
4-FC6H4 (2b)
4-ClC6H4 (2c)
3b
3c
1,2-DCE (3.0 mL), 15 h. b Yield of the isolated pure product.
3
4
4-BrC6H4 (2d) 3d
2-BrC6H4 (2e) 3e
5
Then, we turned to the utilization of secondary diaryl-
methanols for the reaction, which provided 1,4-disubstituted
tetrahydroquinolines in a single step (Table 4). Although the
product yields obtained with these more sterically demand-
ing diarylmethanols were appreciably lower, the exclusive
diastereoselectivity was very remarkable: only the 1,4-cis
diastereomer was observed. Interestingly, contrary to the
above findings from the use of primary benzylic alcohols,
aziridines with electron-donating groups on the benzene
ring were more favored here (Table 4, entries 1ꢀ4). When
the diarylmethanol has two different aryl groups, not un-
expectedly, only the more electron-rich one participated in
the annulation process (Table 4, entry 5).
6
4-CH3C6H4 (2f) 3f
4-tBuC6H4 (2g) 3g
(2h)c
7
8c
9
3h
Ph (2a)
3i
10
11
12
13
14
15
16
H/propargyl (1c) Ph (2a)
3j
5-F/CH3 (1d)
5-Cl/CH3 (1e)
5-Cl/CH3 (1e)
5-Cl/CH3 (1e)
6-Cl/CH3 (1f)
Ph (2a)
Ph (2a)
3k (X-ray)
3l
4-BrC6H4 (2d) 3m
4-CH3C6H4 (2f) 3n
Ph (2a)
3o
3p
7-CH3/CH3 (1g) Ph (2a)
a Reaction conditions: 1(0.6 mmol), 2(0.5 mmol), Sc(OTf)3 (0.01 mmol),
1,2-DCE (3.0 mL). b Yield of the isolated product. c N-(4-tert-Butylphenyl-
sulfonyl)-2-phenylaziridine 2h was used.
To gain some insight into the mechanism of this cascade
sequence, some controlled experiments were conducted
(Scheme 2). Terminating the reaction of 4a and aziridine
Subsequently, after some experimentation, the reaction
was successfully extended to electron-rich primary benzylic
(10) CCDC 924751 (3a), 924752 (3k), 924753 (5l), 924754 (5p), and
930713 (7) contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data _request/cif.
(9) (a) Waller, F. J.; Barrett, A. G. M.; Braddock, D. C.; McKinnell,
R. M.; Ramprasad, D. J. Chem. Soc., Perkin Trans. 1 1999, 867. (b)
Tsuruta, H.; Yamaguchi, K.; Imamoto, T. Chem. Commun. 1999, 1703.
Org. Lett., Vol. XX, No. XX, XXXX
C

Table 4. Scope Study for the Syntheses of
1,4-Diaryl-1,2,3,4-Tetrahydroquinolines 5a
Scheme 3. A Mechanistic Proposal for the [3 þ 3]-Annulation
entry
R1
R2
Ph (2a)
product
yieldb (%)
1
2
3
4
5
H (4c)
H (4c)
H (4c)
H (4c)
Cl (4d)
5l (X-ray)
5m
43
38
45
46
39
4-ClC6H4 (2c)
4-CH3C6H4 (2f)
4-tBuC6H4 (2g)
Ph (2a)
5n
5o
5p (X-ray)
a Reaction conditions: 4 (0.6 mmol), 2 (0.5 mmol), Sc(OTf)3 (0.025
proposed, as illustrated by the formation of 5a in Scheme 3. It
is assumed that the reaction was initiated by a nucleophilic
ring-opening reaction of the aziridine by the benzylic alcohol
to give the intermediate 6.11 In the presence of the rare-earth
metal catalysts, 6 would then undergo an intramolecular
amination of the benzylic ether to give 7, which would
undergo an intramolecular FriedelꢀCrafts-type alkylation
to furnish the final product with one molecule of H2O as the
only byproduct. Two points of this process are noteworthy.
First, probably due to the rapid racemization of the aziridine
in the presence of a Lewis acid,12 the use of enantiomerically
enriched aziridine (S)-2a (>99% ee) led to racemic 6, which
was also transformed into racemic 5a in the same yield
under these reaction conditions. Second, the occurrence of
the intramolecular amination of the benzylic ether step from
6 to 7 is highly dependent on the electron nature of the
benzene ring, and electron-rich substituents are necessary:
using the simple electron-neutral benzyl alcohol only pro-
vided the ring-opening product 8 in high yield.13
mmol), 1,2-DCE (3.0 mL), 24 h. b Yield of the isolated pure product.
Scheme 2. Controlled Experiments for Mechanistic Study of the
[3 þ 3]-Annulation
In summary, a novel Lewis acid catalyzed [3 þ 3]-annula-
tion strategy was developed for the construction of tetrahy-
dro-β-carbolines and tetrahydroisoquinolines. This efficient
practical method features readily available starting materials,
a wide substrate scope, environmental benignity, easy opera-
tion, and mild reaction conditions. Such a new strategy
provides an excellent complement to other methods such as
the PictetꢀSpengler reaction using a [5 þ 1]-annulation
strategy. Efforts toward the development of an enantioselec-
tive version of the [3 þ 3] annulation are underway.
2a at an early stage (3 h) gave compound 6 as the major
product, which could be transformedintothe final product
5a in fairly good yield under the same reaction conditions
after 15 h. In this process, another intermediate 7 (X-ray)
could be isolated (plus 5a) when the reaction was inter-
cepted at 6 h, and the isolated 7 underwent a fast conver-
sion (4 h) to 5a in good yield under the reaction conditions.
Based on these experimental findings and previous related
reports, a probable mechanism for the [3 þ 3]-annulation was
Acknowledgment. This work was supported by the Na-
tional Natural Science Foundation of China (20832001,
21072004, 21202001), the National Basic Research Program
of China (2012CB821600), Natural Science Foundation of
Anhui Province (1308085QB25, 1308085MB17), and grants
from the Ministry of Education (20103424110001).
(11) An alternate initiation step involving an intermolecular Friedelꢀ
Crafts-type reaction between the electron-rich aromatic ring of the benzylic
alcohol and the aziridine could not be ruled out at present, though no
corresponding product was isolated from the reaction system. A control
experiment with the O-methylated analog of 4a also gave 5a in 52% yield
after 5 h.
(12) For relevant studies on the ring openings of aziridines by
benzylic alcohols: (a) Ghorai, M. K.; Shukla, D.; Bhattach- aryya, A.
J. Org. Chem. 2012, 77, 3740. (b) Ghorai, M. K.; Das, K.; Shukla, D.
J. Org. Chem. 2007, 72, 5859 and ref 7b.
Supporting Information Available. Spectral and X-ray
data and experimental procedures; CIF files for compounds
1
3a, 3k, 5l, 5p, and 7; H and 13C NMR copies of all new
compounds; and HPLC traces. This material is available free
of charge via the Internet at http://pubs.acs.org.
(13) The use of several other benzylic alcohols such as 4-bromobenzyl
alcohol, 4-methoxybenzyl alcohol, and naphthalen-2-ylmethanol all led
to similar results.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX