Construction of spiro -tetrahydroquinolines via intramolecular dearomatization of quinolines: Free of a preinstalled activation group

Article abstract of DOI:10.1021/ol4002416

A highly efficient synthesis of spiro-tetrahydroquinolines (up to 99% yield) has been realized via cascade hydrogenative dearomatization of quinoline and intramolecular aza-Friedel-Crafts alkylation reaction.

Full text of DOI:10.1021/ol4002416

ORGANIC
LETTERS
2013
Vol. 15, No. 7
1488–1491
Construction of Spiro-
tetrahydroquinolines via Intramolecular
Dearomatization of Quinolines: Free
of a Preinstalled Activation Group
Shou-Guo Wang, Wei Zhang, 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 January 28, 2013
ABSTRACT
A highly efficient synthesis of spiro-tetrahydroquinolines (up to 99% yield) has been realized via cascade hydrogenative dearomatization of
quinoline and intramolecular aza-FriedelÀCrafts alkylation reaction.
Dearomatization reactions have shown great potential
in the synthesis of complicated targets from relatively
simple planar molecules, especially due to their unique
efficiency in building spiro quaternary carbon centers.1
In contrast to the abundant dearomatization protocols
of electron-rich aromatic rings, the dearomatization
of electron-deficient nitrogen-containing aromatic rings
(pyridines, quinolines, isoquinolines, etc.) generally re-
quires activation by N-acylation or alkylation. Although
this strategy has received broad interest and witnessed full
development for constructing spiro nitrogen-containing
heterocycles, the removal of the protecting group on
nitrogen is needed in a late stage and can be difficult in
many cases.2 Consequently, synthesis of spiro nitrogen-
containing heterocycles via dearomatization reactions
without preinstallation of activation groups will be highly
desirable. As another efficient dearomatization tactic,
asymmetric hydrogenation of (hetero)arenes catalyzed by
transition-metal complexes or organocatalysts has been
successfully explored,3,7 providing efficient stereoselective
construction of various nitrogen-containing skeletons.
(1) For recent reviews of dearomatization reactions, see: (a) Roche,
S. P.; Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50, 4068. (b) Zhuo,
C.-X.; Zhang, W.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 12662.
(2) (a) Takamura, M.; Funabashi, K.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2000, 122, 6327. (b) Takamura, M.; Funabashi, K.;
Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2001, 123, 6801. (c)
Funabashi, K.; Ratni, H.; Kanai, M.; Shibasaki, M. J. Am. Chem.
Soc. 2001, 123, 10784. (d) Ichikawa, E.; Suzuki, M.; Yabu, K.; Albert,
M.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 11808. (e)
Taylor, M. S.; Tokunaga, N.; Jacobsen, E. N. Angew. Chem., Int. Ed.
2005, 44, 6700. (f) Frisch, K.; Landa, A.; Saaby, S.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 6058. (g) Yamaoka, Y.; Miyabe, H.;
Takemoto, Y. J. Am. Chem. Soc. 2007, 129, 6686. (h) Taylor, A. M.;
Schreiber, S. L. Org. Lett. 2006, 8, 143. (i) Sun, Z.; Yu, S.; Ding, Z.; Ma,
D. J. Am. Chem. Soc. 2007, 129, 9300. (j) Black, D. A.; Beveridge, R. E.;
(3) For recent reviews on asymmetric hydrogenation of aromatic
compounds, see: (a) Dyson, P. J. Dalton Trans. 2003, 2964. (b) Glorius,
F. Org. Biomol. Chem. 2005, 3, 4171. (c) Zhou, Y.-G. Acc. Chem. Res.
2007, 40, 1357. (d) Wang, D.-S.; Chen, Q.-A.; Lu, S.-M.; Zhou, Y.-G.
Chem. Rev. 2012, 112, 2557. (e) Yu, Z.; Jin, W.; Jiang, Q. Angew. Chem.,
Int. Ed. 2012, 51, 6060. (f) Shi, F.; Gong, L.-Z. Angew. Chem., Int. Ed.
2012, 51, 11423. For related examples, see: (g) Wang, W.-B.; Lu, S.-M.;
Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem. Soc. 2003, 125,
10536. (h) Chen, Q.-A.; Wang, D.-S.; Zhou, Y.-G.; Duan, Y.; Fan, H.-J.;
Yang, Y.; Zhang, Z. J. Am. Chem. Soc. 2011, 133, 6126. (i) Chen, Q.-A.;
Chen, M.-W.; Yu, C.-B.; Shi, L.; Wang, D.-S.; Yang, Y.; Zhou, Y.-G.
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Arndsten, B. A. J. Org. Chem. 2008, 73, 1906. (k) Fernandez-Ibanez, M.
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r
10.1021/ol4002416
Published on Web 03/07/2013
2013 American Chemical Society

However, a hydrogenation reaction featuring CÀH bond
formation could not be utilized for constructing spiro
compounds with quaternary carbon centers. As part of
our ongoing research on dearomatization reactions,4
we recently envisaged that partial hydrogenation of quino-
line followed by cyclization with a tethered nucleophile
would provide a straightforward synthesis of spiro-
tetrahydroquinoline derivatives (Scheme 1). It is note-
worthy that spiro-tetrahydroquinoline represents an im-
portant structural motif in pharmaceuticals and therefore
its synthesis has attracted intense attention.5,6 Here, we
report an efficient synthesis of spiro-tetrahydroquinolines
via cascade hydrogenative dearomatization of quinoline
and aza-FriedelÀCrafts alkylation reaction (indole as the
nucleophile).8
Table 1. Screening of Brønsted Acid Catalysts
2a
time
(h)
yield
(%)b
entrya
cat.
(equiv)
1
2
3
3a
3a
1
1
1
8
70
75
72
16
16
Scheme 1. Proposed Synthesis of Spiro-tetrahydroquinolines
from Quinolines
L-camphorsulfonic
acid
4
5
6
7
TFA
1
1
1
1
16
16
24
24
68
TsOH•H2O
3,5-(NO2)2C6H3COOH
63
53
3-NO2C6H4COOH
<10
a Reactions were performed with 1a (0.1 mmol), Hantzsch ester 2a,
and 20 mol % catalyst in 1 mL of toluene. b Isolated yield.
We began our study by choosing compound 1a as a
model substrate, which was subjected to Hantzsch ester 2a
in the presence of a catalytic amount of acids.9 To ourgreat
delight, most of the tested acids could catalyze the trans-
formation smoothly. As shown in Table 1, with 1 equiv of
Hantzsch ester 2a and 20 mol % of racemic phosphoric
acid 3a, the desired product 4a was obtained in 70% yield
in 8 h (entry 1). Prolonging the reaction time could slightly
increase the yield of 4a (entry 2, Table 1). Several acidic
catalysts such as L-camphorsulfonic acid, trifluoroacetic
acid (TFA), toluenesulfonyl acid (TsOH), and 3,5-(NO2)2-
C6H3COOH all could be employed to give the product
(53À72% yields, entries 3À6, Table 1). 3-NO2C6H4COOH
proved to be inefficient to catalyze this reaction likely due
to its relatively weak acidity (entry 7, Table 1).
(4) (a) Wu, Q.-F.; He, H.; Liu, W.-B.; You, S.-L. J. Am. Chem. Soc.
2010, 132, 11418. (b) Wu, Q.-F.; Liu, W.-B.; Zhuo, C.-X.; Rong, Z.-Q.;
Ye, K.-Y.; You, S.-L. Angew. Chem., Int. Ed. 2011, 50, 4455. (c) Zhuo,
C.-X.; Liu, W.-B.; Wu, Q.-F.; You, S.-L. Chem. Sci. 2012, 3, 205. (d) Wu,
Q.-F.; Zheng, C.; You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 1680.
(e) Cai, Q.; Zheng, C.; Zhang, J.-W.; You, S.-L. Angew. Chem., Int. Ed.
2011, 50, 8665. (f) Cai, Q.; You, S.-L. Org. Lett. 2012, 14, 3040.
(5) (a) Hamann, L. G.; Higuchi, R. I.; Zhi, L.; Edwards, J. P.; Wang,
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Chem. 1998, 41, 623. (b) Ramesh, E.; Manian, R. D. R. S.; Raghunathan,
R.; Sainath, S.; Raghunathan, M. Bioorg. Med. Chem. 2009, 17, 660.
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tetrahydro-quinoline compounds. United States Patent No. US6350759B1.
(6) (a) Denmark, S. E.; Venkatraman, S. J. Org. Chem. 2006, 71,
1668. (b) Fotie, J.; Wangun, H. V. K.; Fronczek, F. R.; Massawe, N.;
Bhattarai, B. T.; Rhodus, J. L.; Singleton, T. A.; Bohle, D. S. J. Org.
Chem. 2012, 77, 2784. (c) Tverdokhlebov, A. V.; Gorulya, A. P.;
Tolmachev, A. A.; Kostyuk, A. N.; Chernega, A. N.; Rusanov, E. B.
Tetrahedron 2006, 62, 9146. (d) Zubkov, F. I.; Nikitina, E. V.; Kouznetsov,
V. V.; Duarte, L. D. A. Eur. J. Org. Chem. 2004, 5064.
(7) For reviews on transfer hydrogenation reactions with Hantzsch
esters, see: (a) You, S.-L. Chem.;Asian J. 2007, 2, 820. (b) Ouellet, S. G.;
Walji, A. M.; MacMillan, D. W. C. Acc. Chem. Res. 2007, 40, 1327.
(c) Connon, S. J. Org. Biomol. Chem. 2007, 5, 3407. (d) Wang, C.; Wu,
X.; Xiao, J. Chem.;Asian J. 2008, 3, 1750. (e) Rueping, M.; Sugiono, E.;
Schoepke, F. R. Synlett 2010, 852. (f) Rueping, M.; Dufour, J.;
Schoepke, F. R. Green Chem. 2011, 13, 1084. (g) Zheng, C.; You, S.-L.
Chem. Soc. Rev. 2012, 41, 2498. For selected examples, see: (h) Rueping,
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1, 473. (k) Rueping, M.; Stoeckel, M.; Sugiono, E.; Theissmann, T.
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With 20 mol % of 3a as the catalyst, various solvents
were then screened to further optimize the reaction condi-
tions. The results are summarized in Table 2. Among these
tested solvents, CH2Cl2 and CHCl3 were the optimal ones
(93% yield, entries 3 and 7, Table 2). The reactions in
toluene, ClCH2CH2Cl, CH3CN, and EtOAc afforded
(8) For reviews on FriedelÀCrafts reaction, see: (a) Wang, Y.; Ding,
K.-L. Chin. J. Org. Chem. 2001, 21, 763. (b) Bandini, M.; Melloni, A.;
Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004, 43, 550. (c) Bandini, M.;
Melloni, A.; Tommasi, S.; Umani-Ronchi, A. Synlett 2005, 1199. (d)
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(h) Zeng, M.; You, S.-L. Synlett 2010, 1289. (i) Terrasson, V.; de
Figueiredo, R. M.; Campagne, J. M. Eur. J. Org. Chem. 2010, 2635.
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Org. Lett., Vol. 15, No. 7, 2013
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relatively lower yields (entries 1, 4, 6, and 8, Table 2). Et2O,
CCl4, and n-hexane are poor solvents of choice for this
reaction (entries 2, 5, and 9, Table 2). Furthermore, the
loadings of catalyst 3a as well as Hantzsch ester 2a were
then examined. With 5 mol % of catalyst 3a in CH2Cl2, the
reaction could also proceed smoothly but with a prolonged
reaction time (entries 7 and 10, Table 2). Notably, with
5 mol % of 3a, the reaction could proceed to completion
with 1.2 equiv of 2a (entries 11 and 12, Table 2). To our
delight, a 90% yield of 4a could be obtained even with
1 mol % of 3a in 48 h (entry 13, Table 2).
Scheme 2. Substrate Scope for Dearomatization of Quinolines
Table 2. Screening of Solvents, Loadings of Catalyst, and
Hantzsch Ester
3a
2a
time
(h)
yield
(%)b
entrya
solvent
toluene
(mol %)
(equiv)
1
20
20
20
20
20
20
20
20
20
5
1
16
16
16
16
16
16
16
16
16
48
16
16
48
75
29
93
81
38
69
93
84
NR
92
98
98
90
2
Et2O
1
3
CHCl3
1
4
ClCH2CH2Cl
CCl4
1
5
1
6
CH3CN
CH2Cl2
EtOAc
1
7
1
8
1
9
n-hexane
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
1
Scheme 3. Epimerization of 4a under Acidic Conditions
10
11
12
13c
1
5
1.5
1.2
1.2
5
1
a Reactions were performed with 1a (0.1 mmol), Hantzsch ester 2a,
and catalyst 3a in 1 mL of solvent. b Isolated yield. c The reaction was
carried out on a 0.3 mmol scale.
Under the optimal reaction conditions (5 mol % of 3a as
catalyst, 1.2 equiv of Hantzsch ester 2a, CH2Cl2, rt), the
substrate scope was then explored to test the generality of
the reaction. The results are shown in Scheme 2. In general,
all the tested substrates were transformed to their corre-
sponding dearomatization products 4 in satisfactory yields
(84À99%). Notably, 10% of double hydrogenation by-
products were isolated for two substrates bearing electron-
withdrawing groups on the indole core (4f, 4g, Scheme 2).
Substrates with electron-withdrawing substituents on the
pyridine moiety were converted to the products completely
in excellent yields (4h and 4i, Scheme 2). The substrate
bearing the 7-OMe group also gave the product in 84%
yield (4j, Scheme 2). It should be noted that various
protecting groups (Ms, Ns, or Ac) of the N-linker could
be tolerated, and the dearomatization products were all
obtained in good to excellent yields (4k, 4l, and 4m,
Scheme 2).
The enantioselective dearomatization reaction of quino-
lines was then examined. Unfortunately, due to the epi-
merization of 4a under acidic conditions, the initial
attempt to develop an enantioselective reaction failed
(eq 1, Scheme 3).8 Inspired by the enantioselective hydro-
genation of 4-substituted quinolines reported by Rueping
and co-workers,7m we envisaged that the substrate with the
4-substituent on the quinoline moiety might be suitable
for stereoselective control of this dearomatization trans-
formation, given thatthe generatedchiral centerduring the
hydrogenation reaction might induce a diastereoselective
1490
Org. Lett., Vol. 15, No. 7, 2013

Scheme 4. Stereoselective Synthesis of Spiro-tetrahydroquino-
lines
Figure 1. X-ray crystal structure of Spiro-tetrahydroquinoline 4n.
aza-FriedelÀCrafts alkylation reaction. Indeed, the reac-
tion of 1n led to the formation of product 4n in moderate
levels of yield, diastereoselectivity, and enantioselectivity
when chiral phosphoric acid (S)-3b was used (eq 2,
Scheme 4). Utilization ofHantzsch ester 2bprovided better
diastereoselectivity for 4n than 2a (eq 2, Scheme 4). Inter-
estingly, the diastereoselectivity of4n could be significantly
enhanced after treatment with 10 mol % of chiral phos-
phoric acid (S)-3b without affecting the enantiomeric
purity (from 4.7:1 to 13.5:1 dr, eq 3, Scheme 4). Finally,
the absolute configuration of 4n was assigned by X-ray crys-
tallographic analysis of an enantiopure sample (Figure 1).10
In conclusion, an efficient synthesis of spiro-tetrahydro-
quinolines has been realized via a cascade hydrogenative
dearomatization of quinoline and an aza-FriedelÀCrafts
alkylation reaction. This methodology features readily
available starting materials, operational simplicity, excel-
lent yields, and dearomatization of quinolines without
preinstallation of an activation group. Further develop-
ment of highly enantioselective reactions is currently un-
derway in our laboratory.
Acknowledgment. We thank the National Basic Re-
search Program of China (973 Program 2009CB825300)
and National Natural Science Foundation of China
(21025209, 21102160, 21121062) for financial support.
Supporting Information Available. Experimental pro-
cedures and characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) CCDC 917093 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 7, 2013
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