Highly stereoselective 7-endo-trig /ring contraction cascade to construct pyrrolo[1,2- a ]quinoline derivatives

Article abstract of DOI:10.1021/ol100220c

With the cooperation of Cram's phenonium ion, a novel cascade reaction was illustrated to construct pyrrolo[1,2-a]quinolines as a sole diastereoisomer in good to excellent yields. Preliminary mechanistic studies revealed that the γ-lactam ring and electron-rich arene are important driving forces for ring contraction.

Full text of DOI:10.1021/ol100220c

ORGANIC
LETTERS
2010
Vol. 12, No. 8
1696-1699
Highly Stereoselective 7-Endo-Trig/Ring
Contraction Cascade To Construct
Pyrrolo[1,2-a]quinoline Derivatives
Xinyu Li, Cheng Li, Wenjing Zhang,† Xiang Lu, Shiqing Han,† and Ran Hong*
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of
Organic Chemistry, CAS, 345 Lingling Road, Shanghai 200032, China
rhong@mail.sioc.ac.cn
Received January 28, 2010
ABSTRACT
With the cooperation of Cram’s phenonium ion, a novel cascade reaction was illustrated to construct pyrrolo[1,2-a]quinolines as a sole
diastereoisomer in good to excellent yields. Preliminary mechanistic studies revealed that the γ-lactam ring and electron-rich arene are important
driving forces for ring contraction.
Substituted hydroquinolines are widely embedded in numer-
ous natural products and medicinal compounds. These
Scheme 1
.
Construction of Pyrroloquinoline via Phenonium Ion
and Represented Natural Products
hetereocycles have been an interesting topic in synthetic
chemistry. A plethora of methods have been dedicated to
construct functionalized hydroquinolines.1 During our en-
deavor in total synthesis of tetrapetalones, a cationic cy-
clization of the N-acyliminium ion with terminal alkene
indicated a π-bridged interaction which may be crucial for
the stereochemistry outcome of the corresponding substituted
benzazepines.2 We envisaged that the potential phenonium
ion intermediate can be formed if the carbocation at C-ꢀ is
not tertiary. In this way, a ring-contraction would thus be
promoted to give pyrroloqinolines (Scheme 1). As high-
lighted in the represented complex natural products, isos-
† College of Biotechnology and Pharmacy, Nanjing University of
Technology, 5 Xinmofan Road, Nanjing 210009, China.
(1) (a) For a recent review on the synthesis of hydroquinolines, see:
Kouznetsov, V. V. Tetrahedron 2009, 65, 2721–2750, and references therein.
(b) Pigeon, P.; Othman, M.; Netchitailo, P.; Decroix, B. J. Heterocycl. Chem.
1999, 36, 691–695. (c) Santos, L. S.; Pilli, R. A. Synthesis 2002, 87–93.
(d) Zhang, W.; Huang, L.; Wang, J. Synthesis 2006, 2053–2063. (e) Wan,
C.; Tunge, J. A. J. Am. Chem. Soc. 2008, 130, 8118–8119. (f) Liu, H.;
Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. J. Am. Chem. Soc. 2009,
131, 4598–4599. (g) Zhou, Y.; Qian, L.; Zhang, W. Synlett 2009, 843–
847.
chizogamine and haplophytine, the resulting hydroquinoline
or pyrroloquinoline skeleton renders this 7-endo-trig/ring
contraction cascades approach rather intriguing.3,4
With these considerations in mind, the model cation
precursor 1-aryl-γ-hydroxylactam (2a) was prepared in two
steps from readily available 2-allylaniline.5 As shown in
Table 1, although hydroxyamide 2a can be successfully
(2) Li, C.; Li, X.; Hong, R. Org. Lett. 2009, 11, 4036–4039.
10.1021/ol100220c  2010 American Chemical Society
Published on Web 03/19/2010

Table 1. Screen of Lewis Acids for N-Acyliminium Ion Cyclizationa
entry
acid
TFA
HCOOH
SnCl4
TiCl4
solvent
CH2Cl2
HCOOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
CHCl3
c-hexane
X
time (h)
convn (%)
3/4b
yieldc (%)
1
2
3
4
5
6
7
8
OCOCF3
OCHO
Cl
12
24
1
>98
10e
>98
>98
20
3aa only
n.d.f
89:11
84:16
n.d.
77:23
83:17
89:11
g
65d
n.d.
85
89
n.d.
60
75
85
n.d.
n.d.
80
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
1
ZnCl2
AlCl3
24
24
24
1
24
24
24
79
FeCl3
SnCl4
SnCl4
SnCl4
SnCl4
>98
>98
30e
30e
95
9
10
g
11h
CH2Cl2
84:16
a Reaction conditions: 2a (0.25 mmol), TFA (0.5 mL), CH2Cl2 (5 mL), rt; 2a (0.25 mmol), Lewis acid (1.5 equiv), CH2Cl2 (5 mL), rt. b Ratios were
determined by H NMR (300 MHz) of unpurified mixtures. c The combined yields of isolated 3 and 4. d The combined isolated yield of ester and alcohol,
1
see ref 7. e The conversion was determined based on recovered starting material. f Not determined. g Unidentified products were observed. h A catalytic
amount of SnCl4 (10 mol %) and TMSCl (2 equiv) was used.
consumed within 12 h in the presence of TFA (entry 1),6 it
was found that the instability of the corresponding product
to silica gel and complex results after treatment with base
retarded further characterization.7 Substrate 2a was almost
fully recovered when weaker Bro¨nsted acids such as HCOOH
were used (entry 2). An excellent diastereoselectivity and
overall isolated yield was achieved when SnCl4 was used as
the promoter for the cyclization (entry 3). The stereochem-
istry of the corresponding pyrroloquinonline 3a and pyr-
rolobenzazepine 4a were determined by 2D NOE experi-
ments and unambiguously confirmed with X-ray diffraction
(Figure 1).8 Several oxophilic Lewis acids were screened
was found when 1,2-dichloroethane was used as a solvent
(entry 8), whereas CHCl3 and cyclohexane dramatically
retarded the reaction rate and resulted in complex product
mixtures (entries 9 and 10). In the presence of TMSCl, a
catalytic amount of SnCl4 was still able to promote this novel
rearrangement to give products in slightly decreased selectiv-
ity and isolated yield (entry 11).
The substrate scope was then examined for the generality
of the arene with substituents at the meta-, para-, or ortho-
(3) Several approaches to synthesize lactones via the phenonium ion
intermediate were reported, however, application of phenonium ion in
synthetic chemistry is rather unexplored. See: (a) Nagumo, S.; Furukawa,
T.; Ono, M.; Akita, H. Tetrahedron Lett. 1997, 38, 2849–2852. (b) Nagumo,
S.; Ishii, Y.; Kakimoto, Y.; Kawahara, N. Tetrahedron Lett. 2002, 43, 5333–
5337. (c) Nagumo, S.; Ono, M.; Kakimoto, Y.; Furukawa, T.; Hisano, T.;
Mizukami, M.; Kawahara, N.; Akita, H. J. Org. Chem. 2002, 67, 6618–
6622. (d) Boye, A. C.; Meyer, D.; Ingison, C. K.; French, A. N.; Wirth, T.
Org. Lett. 2003, 5, 2157–2159. (e) Ehara, T.; Tanikawa, S.; Ono, M.; Akita,
H. Chem. Pharm. Bull. 2007, 55, 1361–1364. (f) Protti, S.; Fagnoni, M.;
Albini, A. J. Am. Chem. Soc. 2006, 128, 10670–10671.
(4) For methods to construct 4-substituted pyrrolo[1,2-a]quinolines, see:
(a) Speckamp, W. N.; De Boer, J. J. J. Recl. TraV. Chim. Pays-Bas 1983,
102, 410–414. (b) Pearson, W. H.; Fang, W.-k. J. Org. Chem. 2000, 65,
7158–7174. (c) Murarka, S.; Zhang, C.; Konieczynska, M. D.; Seidel, D.
Org. Lett. 2009, 11, 129–132, and references therein.
(5) See the Supporting Information for details.
(6) For a comprehensive review dedicated to the N-acyliminium ion
cyclization, see: Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.; Turchi, I. J.;
Maryanoff, C. A. Chem. ReV. 2004, 104, 1431–1628.
(7) Based on the 1H NMR and 19F NMR spectrum of the unpurified
mixtures, 3aa (X ) OTFA) was observed as the major product. The relative
configuration was deduced from the hydrolyzed product (X ) OH).
(8) For the convenience of discussion, the nomenclature of cyclized
products 3 and 4 is based on the core structures such as the quinoline ring
and 1-benzazepine ring, respectively.
(9) A free N-acyliminium ion intermediate should result in identical rate
and product distribution; however, experimental results in Table 1 may imply
a tight ion pair with the counterion or a complex with the Lewis acid used.
This scenario was widely recognized in the Friedel-Crafts reaction; see:
Nelson, K. L. J. Org. Chem. 1956, 21, 145–155.
Figure 1. X-ray structure of rac-3a and rac-4a.
(entries 3-9). TiCl4 gave a slightly higher yield, albeit lower
selectivity (entry 4). It is not surprising that a low conversion
was obtained with the use of ZnCl2, due to its weaker
oxophilicity (entry 5).9 A similar ratio of the final products
Org. Lett., Vol. 12, No. 8, 2010
1697

position with respect to the allyl group. As shown in Table
2, all substrates bearing different R substituents underwent
the astonishing behavior of 2h (entry 8), bearing a p-fluorine
substituent, may be attributed to the carbocation-fluorine
lone pair interaction in the σ-bridged carbocation.10 The most
para-electron-rich substituents facilitated the exceedingly
high selectivity of the ring contraction to give 3f, 3g, and 3l
(entries 6, 7, and 12). It is particularly noteworthy when the
sterically demanding o-methyl- or methoxyl-substituted
substrates 2m and 2n (entries 13 and 14) were used,
formation of rearranged products proceeded with excellent
selectivity. The exclusive rearrangement of 2n bearing the
o-methoxyl group may be interpreted by a possible oxonium
ion intermediate.11 Even for the reactive vinyl group in 2q
(entry 17), the corresponding product 3q was still isolated
in 22% yield. However, the reactive vinyl group also led to
several byproducts, requiring further optimization to extend
the functionality tolerence.
Table 2. Scope of N-Acyliminium Ion Cyclizationa,b
entry substrate
R
ratio (3:4)c yield% 3 (4)d
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
H
89:11
91:9
80:20
80:20
78:22
98:2
>99:1
90:10
89:11
86:14
86:14
97:3
78(7)
80(6)
70(15)
66(19)
68(19)
96(0)
88(0)
88e
m-CH3
m-OCH3
m-Cl
For insights into the cyclization/rearrangement cascade and
the stereochemistry outcome, a deuterium labeling experi-
ment was conducted (Scheme 3). The synthesis of amide
m-Br
p-OCH3
p-OTBDPS
p-F
p-Cl
p-CH3
p-CF3
p-CH2OTBS
o-CH3
o-OCH3
m-F
p-CO2Et
p-CHdCH2
9
79(7)
69(9)
77(12)
85(0)f
78(0)
86(0)
99e
10
11
12
13
14
15
16
17
Scheme 3. Isotopic Labeling Experiment
97:3
>99:1
50:50
75:25
91:9
80e,g,h
22(2)i
a Reaction condition: substrate (0.25 mmol), SnCl4 (0.375 mmol), CH2Cl2
(5 mL), rt, 2 h. b The stereochemistry assignments of 3b-q and 4b-q were
assigned by the similarity of their NMR spectra with those of 3a and 4a,
see Supporting Information for details. c Ratios were determined by 1H NMR
(300 MHz) of unpurified mixtures. d Yield of isolated products (the isolated
yield of 4 was in parentheses). e Two products were not separable on silica
gel column. f The product 3l was deprotected. g Isolated yield was based
on recovered starting material. h A white precipitate was observed during
the reaction; however, the substance 2p can be recovered in 50% yield
after workup. i Umoptimized yield; side products were not identified.
2a-d1 began with the regioselecitive hydroalumination of
2-propyn-1-ol by LiAlD4, followed by mesylation and the
copper-mediated coupling with 2-nitroiodobenzene to give
5 in 23% overall yield with 94% deuterium incorporation at
the C(2) of the alkene. The key SnCl4-promoted cationic
cyclization gave only two products 3a-d1 and 4a-d1 (both
retains 94% D incorporation at C(4)). There was no
deuterium scrambling at other positions of the products.
Interconversion between 3a-d1 and 4a-d1 was not observed
when they were individually resubjected to the reaction
conditions. These results indicate that the phenonium ion is
best invoked as intermediate in the ring contraction. The
stereochemical outcome relies on a chairlike cationic inter-
mediate, which may adopt a pseudoequatorial attack at C(4)
and C(5) by the incoming chloride to give 3a and 4a,
cyclization to give exclusively cis-products 3a-p and 4a-p
with good to excellent yields. The product distribution
favoring 3a-p implies the ring contraction was the major
pathway (path a, Scheme 2). For most of the cases in Table
Scheme 2. Proposed Pathway of Cationic Rearrangement
2, after the reaction of iminium ion with alkene, the positive
charge developed at C(4) can be further stabilized by the
aryl group through the phenonium ion. The fluorinated
substrate 2o (entry 15) can partially overcome the intrinsic
tendency (entry 1) due to the strong electron-withdrawing
inductive effect of fluorine at the meta-position. Nevertheless,
(10) (a) Rosenthal, J.; Schuster, D. I. J. Chem. Educ. 2003, 80, 679–
690. (b) For a recent review on fluorine compounds, see: O’Hagan, D. Chem.
Soc. ReV. 2008, 37, 308–319.
(11) (a) Oxonium ion: Manner, J. A. M.; Cook, J. A., Jr.; Ramsey, B. G.
J. Org. Chem. 1974, 39, 1199–1203. (b) The neighboring effect of the
methyl group is not clear. One proposed explanation is that the o-methyl
group may participate in the stabilization of phenonium ion through a C-H
hyperconjugation.
1698
Org. Lett., Vol. 12, No. 8, 2010

respectively.12 Furthermore, when Z-vinylsilane 7 was
exposed to the cyclization condition, alkene 8 was identified
as the major product due to loss of the silyl group through
an SE′ pathway (Scheme 4).13 It was determined that the
Scheme 6. Synthetic Transformations of 3a
Scheme 4. N-Acyliminium Ion Cyclization of Allylsilane 7
treatment of NaOEt, the homobenzylic chloride underwent
the facile elimination to give a terminal alkene 15. The
multifunctionalities in 15 and 16 allow a variety of trans-
formations for the access to important synthetic motifs as in
syntheses of isoschizogamine and the left domain of haplo-
phytine (Scheme 1).15 The current rearrangement comple-
ments published routes to these structures along with greater
structural diversity for future biological evaluation.
cation at C-ꢀ in Scheme 1c is indeed an intermediate, which
completes the cation relay process as the proof of concept.
To explore the ring size on the efficiency and understand
the origin of rearrangement, the cyclizations of 9 and 10 were
compared to 2a (Scheme 5). The low selectivity 53/47 of
In conclusion, the N-acyliminium ion, in cooperation with
a novel rearrangement, has been designed to initiate the
highly stereoselective 7-endo-trig/ring contraction cascade
as exemplified in the broad substrate scope on the construc-
tion of 4-substituted pyrrolo[1,2-a]quinolines. The mecha-
nistic study utilizing isotopic labeling and profound substit-
uent effects shed light on the development of other cationic
cyclization/ring contraction cascade. Structurally distinct
substrates for exploiting the current approach in the context
of asymmetric synthesis are currently ongoing in this
laboratory.
Scheme 5. N-Acyliminium Ion Cyclization of 9 and 10
Acknowledgment. The National Natural Science Founda-
tion of China (20702058 and 20872157), the Shanghai Rising
Star Program (08QA14079), Chinese Academy of Sciences,
and the start-up from Shanghai Institute of Organic Chem-
istry are gratefully acknowledged for financial support. We
thank Dr. Xiaodi Yang (Fudan University) for her assistance
with the X-ray analysis, Mr. Dong Wei for a partial study,
and Dr. Rob Hoen (Barcelona Science Park, Spain) for
invaluable discussions.
11 to 12 observed stands in contrast to the cyclization of 2a
to 3a (ratio: 89/11, 78% of 3a). Moreover, the cyclization
of acyclic substrate 10 afforded benzazepine 13 preferentially
to the corresponding rearranged tetrahydroquinoline 14.
These preliminary results clearly indicate that the dominance
in compound 3, as shown in Table 2, may not be solely
controlled by substituent on arene, and instead, a compensat-
ing steric effect arising from the rigidity of γ-lactam plays
a critical role in promoting the rearrangement.
Supporting Information Available: Complete experi-
mental details and characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL100220C
Finally, to further demonstrate the synthetic utility of the
current approach,14 the corresponding 3a was converted into
structurally versatile compounds (Scheme 6). With the
(14) For a recent catalytic cyclization of alkene with hydroxyamide by
Fe(OTf)3 in 1,4-dioxane, however, this protocol resulted in inseparable
alkene isomers; see: Komeyama, K.; Igawa, R.; Morimoto, T.; Takaki, K.
Chem. Lett. 2009, 38, 724–725.
(12) However, the origin of exceedingly high stereoselectivity needs to
be further investigated with the assistance of computational calculation.
(13) (a) It is tentatively assumed that the chlorinated product 3a was
generated from the cyclization of 2a derived from the desilylation of 7 in
the presence of SnCl4. (b) For the ꢀ-effect of the silyl group, see: Wierschke,
S. G.; Chandrasekhar, J.; Jorgensen, W. L. J. Am. Chem. Soc. 1985, 107,
1496–1500. (c) Fleming, I. In ComprehensiVe Organic Synthesis; Trost,
B. M., Fleming, I., Eds.; Pergamon Press: Oxford, U.K., 1991; Vol. 2, pp
563-593.
(15) For selected complex natural products bearing pyrroloquinoline,
see: (a) Haplophytine: Ueda, H.; Satoh, H.; Matsumoto, K.; Sugimoto, K.;
Fukuyama, T.; Tokuyama, H. Angew. Chem., Int. Ed. 2009, 48, 7600–7603.
(b) Nicolaou, K. C.; Dalby, S. M.; Li, S.; Suzuki, T.; Chen, D. Y.-K. Angew.
Chem., Int. Ed. 2009, 48, 7616–7620. (c) Isoschizogamine: Hubbs, J. L.;
Heathcock, C. H. Org. Lett. 1999, 1, 1315–1317. (d) For an advance
intermediate in the total synthesis of gephyrotoxin: Ito, Y.; Nakajo, E.;
Nakatsuka, M.; Saegusa, T. Tetrahedron Lett. 1983, 24, 2881–2884.
Org. Lett., Vol. 12, No. 8, 2010
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