Efficient entry into 2-substituted tetrahydroquinoline systems through alkylative ring expansion: Stereoselective formal synthesis of (±)-martinellic acid

Article abstract of DOI:10.1021/jo902540x

(Chemical Equation Presented) A new efficient synthesis of 2-substituted tetrahydroquinolines has been achieved by the domino reaction of N-indanyl(methoxy)amines, which consists of three types of reactions: elimination of an alcohol, the rearrangement of an aryl group, and the addition of an organolithium or magnesium reagent. The synthetic utility of this approach is demonstrated by the stereoselective formal synthesis of (±)- martinellic acid.

Full text of DOI:10.1021/jo902540x

pubs.acs.org/joc
Efficient Entry into 2-Substituted Tetrahydroquinoline Systems through
Alkylative Ring Expansion: Stereoselective Formal Synthesis of
(()-Martinellic Acid
Masafumi Ueda, Sayuri Kawai, Masataka Hayashi, Takeaki Naito, and
Okiko Miyata*
Kobe Pharmaceutical University, Motoyamakita, Higashinada,
Kobe 658-8558, Japan.
miyata@kobepharma-u.ac.jp
Received November 30, 2009
A new efficient synthesis of 2-substituted tetrahydroquinolines has been achieved by the domino
reaction of N-indanyl(methoxy)amines, which consists of three types of reactions: elimination of an
alcohol, the rearrangement of an aryl group, and the addition of an organolithium or magnesium
reagent. The synthetic utility of this approach is demonstrated by the stereoselective formal synthesis
of (()- martinellic acid.
Introduction
a significant subject of synthetic studies of biologically active
compounds. In constructing the 2-substituted tetrahydro-
quinoline, many synthetic methods have been reported,
including the hetero-Diels-Alder reaction,4 substituent in-
troduction to quinoline,5 electrophilic cyclization,6 and pal-
ladium-catalyzed annulations.7,8
We have developed a new methodology for the construc-
tion of 2-substituted tetrahydroquinolines from N-indanyl-
(methoxy)amines. This route involves a domino process via the
elimination of methanol, rearrangement of a metal arylmethyl-
amide, and subsequent addition of Grignard or organo-
lithium reagents to an intermediary imine. The method
described herein was successively applied to the stereoselec-
tive synthesis of a key intermediate used in the synthesis of
2-Substituted tetrahydroquinoline moieties are frequently
found in biologically active molecules.1 Several of these
compounds are naturally occurring. Dynemicin, a natural
antitumor antibiotic, has a complex structure built on the
tetrahydroquinoline system. Simple 2-alkyl and 2-arylethyl
tetrahydroquinolines have been isolated from Galipea offi-
cinalis; a reputed folk medicine known for its multiple
healing properties.2 Perhaps the most well-known examples
that comprise this molecular structure are the Martinella
alkaloids, martinelline, and martinellic acid, which exhibit
activities as bradykinin receptor antagonists.3 Many rela-
tively simple synthetic 2-substituted tetrahydroquinolines
are already used or have been tested as potential drugs.
Consequently, 2-substituted tetrahydroquinolines have been
(4) (a) Liu, H.; Dagousset, G.; Masson, G.; Retailleau, P.; Zhu, J. J. Am.
Chem. Soc. 2009, 131, 4598. (b) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am.
Chem. Soc. 2006, 128, 13070. (c) Powell, D. A.; Batey, R. A. Org. Lett. 2002,
4, 2913. (d) Hadden, M.; Nieuwenhuyzen, M.; Osborne, D.; Stevenson, P. J.;
Thompson, N. Tetrahedron Lett. 2001, 42, 6417. (e) Leardini, R.; Nanni, D.;
Tundo, A.; Zanardi, G.; Ruggieri, F. J. Org. Chem. 1992, 57, 1842.
(5) (a) Wee, A. G. H.; Liu, B.; Zhang, L. J. Org. Chem. 1992, 57, 4404. (b)
Goldstein, S. W.; Dambek, P. J. Synthesis 1989, 221.
(1) (a) Jones, G.. In Comprehensive Heterocyclic Chemistry II; Mckillop, A.,
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Norwich,
England, 1996; Vol. 5, p 167. (b) Katritzky, A. R.; Rachwal, S.; Rachwal, B.
Tetrahedron 1996, 52, 15031. (c) McAteer, C. H.; Balasubramanian, M.;
Muragan, R. In Comprehensive Heterocyclic Chemistry III; Katritzky, A. R.,
Ramsden, C. A., Scriven, E. F. V., Taylor, R. J. K., Eds.; Elsevier; Oxford, UK,
2007; Vol. 7, p 309.
(6) Raner, K. D.; Ward, A. D. Aust. J. Chem. 1991, 44, 1749.
(2) Jacquemond-Collet, I.; Bessiere, J. M.; Hannedouche, S.; Bertrand,
C.; Fouraste, I.; Moulis, C. Phytochem. Anal. 2001, 12, 312.
(3) Witherup, K. M.; Ransom, R. W.; Graham, A. C.; Bernard, A. M.;
Salvatore, M. J.; Lumma, W. C.; Anderson, P. S.; Pitzenberger, S. M.; Varga,
S. L. J. Am. Chem. Soc. 1995, 117, 6682.
(7) (a) Patil, N. T.; Wu, H.; Yamamoto, Y. J. Org. Chem. 2007, 72, 6577.
(b) Back, T. G.; Wulff, J. E. Angew. Chem., Int. Ed. 2004, 43, 6493.
(8) For other examples, see: Keller, P. A. In Comprehensive Heterocyclic
Chemistry III; Katritzky, A. R., Ramsden, C. A., Scriven, E. F. V., Taylor,
R. J. K., Eds.; Elsevier: Oxford, UK, 2007; Vol. 7, p 217.
914 J. Org. Chem. 2010, 75, 914–921
Published on Web 01/11/2010
DOI: 10.1021/jo902540x
r
2010 American Chemical Society

Ueda et al.
JOCArticle
TABLE 2. Reaction of N-Indanyl(methoxy)amines 3a-g with
TABLE 1. Reaction of N-Indanyl(methoxy)amine with R-Ma
AllylMgBra
entry
R-M
n-BuLi
PhLi
EtMgBr
PhMgBr
allylMgBr
PhCH2MgBr
p-MeC6H4MgBr
p-ClC6H4MgBr
product
yield (%)b
1
2
3
4
5
6
7
8
2a (R = n-Bu)
2b (R = Ph)
2c (R = Et)
64
68
34
84
92
82
84
81
2b (R = Ph)
2d (R = allyl)
2e (R = CH2Ph)
2f (R = p-MeC6H4)
2g (R = p-ClC6H4)
yield (%)b
aReaction conditions: 1 (0.3 mmol), RM (0.9 mmol) in Et2O (6 mL) at
rt. bIsolated yield
entry
substrate
R1
R2
R3
R4
4
5
6
1
2
3
4
5
6
7
3a
OMe
Cl
OH
H
H
H
H
H
H
Me
H
H
H
H
H
Me
H
H
H
H
H
H
H
Me
Ph
83
81
81
83
martinellic acid. We have previously demonstrated that the
domino reaction of N-benzylalkoxyamines with Grignard or
organolithium reagents gave aniline derivatives bearing a
branched alkyl group.9 In related works, the reaction of
N-indanyl(alkoxy)amines or indanone oximes with LiAlH4
or DIBALH gives rise to a reductive ring expansion that results
in the formation of the tetrahydroquinoline.10 Additionally,
Yamamoto’s group has reported that the organoaluminum-
promoted Beckmann rearrangement of oxime sulfonate fol-
lowed by either alkylation or reduction gave nitrogen-contain-
ing heterocycles.11 This method was applied to the preparation
of tetrahydroquinoline.
3b
3cc
3d
3ed
3fd
3gd
71e
30 f
14g
H
H
8
8
26
40
H
aReaction conditions: 3 (0.3 mmol), allylMgBr (0.9 mmol) in Et2O
(6 mL) at rt. bIsolated yield. callylMgBr (1.2 mmol) was used. dCis
isomer of 3e-g was used. eCis/trans = 1/2.7. fCis/trans = 1/3.0. gCis/
trans = 1/3.0.
TABLE 3. Reaction of N-Indanyl(methoxy)amines 3a-g with
PhMgBra
Results and Discussion
We first investigated the domino reaction of N-indanyl-
(methoxy)amines 1 as preliminary experiments (Table 1).
The reaction of indanylamine 1 with 3 equiv of n-BuLi
proceeded smoothly in Et2O at room temperature within
15 min to give the desired 2-n-butyltetrahydroquinoline 2a in
64% yield (entry 1). Similarly, phenyllithium gave the corre-
sponding product (entry 2). The treatment of 1 with either
phenyl or allyl magnesium bromide afforded the desired
2-substituted tetrahydroquinolines 2b and 2d in 84% and
92% yields, respectively (entries 4 and 5), while 2-ethyl-
tetrahydroquinoline 2c was obtained in low yield (entry 3).
Benzyl and p-substituted phenyl magnesium bromide also
worked well to furnish the desired products 2e-g in good
yields (entries 6-8). This observation deserves parti-
cular attention, because tetrahydroquinolines carrying vari-
ous substituents can be effectively synthesized in short reac-
tion time.
yield (%)b
entry
substrate
R1
R2
R3
R4
7
5
1
2
3
4
5
6
7
3a
OMe
Cl
OH
H
H
H
H
H
H
Me
H
H
H
H
H
Me
H
H
H
H
H
H
H
Me
Ph
89
84
87
3b
3cc
3d
81
3ed
3fd
3gd
81e
33 f
18f
H
H
11
18
H
aReaction conditions: 3 (0.3 mmol), PhMgBr (0.9 mmol) in Et2O
(6 mL) at rt. bIsolated yield. callylMgBr (1.2 mmol) was used. dCis isomer
of 3e-g was used. eCis/trans = 1/12. Trans isomer was selectively
obtained.
f
To further study the scope and limitations of this process,
we investigated the substituent effects in the domino reaction
of N-indanyl(methoxy)amines 3a-g with allylmagnesium
bromide (Table 2). 5-Substituted indanylamines 3a-c bear-
ing electron-donating or -withdrawing groups afforded the
corresponding 2-allyltetrahydroquinolines 4a-c in good
yields (entries 1-3). Similar results were achieved with
6- or 2-methylindanylamines 3d and 3e (entries 4 and 5).
However, indanylamines 3f and 3g bearing the methyl or
phenyl group at the 3-position gave the 4-substituted
tetrahydroquinolines 4 in low yields, accompanied by
indanones 5 and indanylamines 6 as side products
(entries 6 and 7). It is noteworthy that the protection of
the hydroxyl group is not necessary for this reaction
system (entry 3).
We next investigated the domino reaction of N-indanyl-
(methoxy)amines 3a-g with phenylmagnesium bromide. It
is one of the advantages that this reaction can introduce
directly the aryl group into the 2-position of quinoline
nucleus. As shown in Table 3, these reactions proceeded
(9) (a) Miyata, O.; Ishikawa, T.; Ueda, M.; Naito, T. Synlett 2006, 2219.
(b) Mukhopadhyay, P. P.; Miyata, O.; Naito, T. Synlett 2007, 1403.
(10) (a) Cho, H.; Iwama, Y.; Sugimoto, K.; Kwon, E.; Tokuyama, H.
Heterocycles 2009, 78, 1183. (b) Booth, S. E.; Jenkins, P. R.; Swain, C. J.
J. Chem. Soc., Chem. Commun. 1993, 147.
(11) Maruoka, K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane, S.;
Hattori, K.; Yamamoto, H. J. Am. Chem. Soc. 1983, 105, 2831.
J. Org. Chem. Vol. 75, No. 3, 2010 915

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SCHEME 1. Possible Reaction Pathway
SCHEME 2. Synthetic Strategy
on the stannyl radical addition-cyclization reactions of
imine derivatives, we have recently developed an asymmetric
total synthesis of martinellic acid based on the RACE
reaction of a chiral oxime ether.17 However, these synthetic
methods have unsatisfactory chemical yields and stereo-
selectivity. We have focused our efforts on the stereoselective
synthesis of martinellic acid and investigated the domino
reaction of tricyclic methoxyamine 8 leading to a key inter-
mediate 9 reported by Snider and co-workers (Scheme 2).18
Snider succeeded in the synthesis of (()-martinellic acid
via an intermediate 9 using [3þ2] dipolar cycloaddition of an
azomethineylide as a key reaction.18 However, [3þ2] dipolar
cycloaddition gave the undesired stereoisomer (3%), in
addition to the desired 3a,4-trans-3a,9b-cis-product (57%).
Recently, Lovely has reported the synthesis of (-)-martinel-
lic acid by a similar route. Similarly, in the dipolar cycload-
dition, the undesired stereoisomer was obtained as a side
product (9%).16 The tricyclic methoxyamine 8 for the domi-
no reaction was prepared from commercially available acetal
10 (Scheme 3). Lithiation of bromoacetal 10 with n-BuLi and
subsequent treatment with DMF gave 93% of aldehyde 11,
which was subjected to vinylation with vinylmagnesium
bromide and acetylation of the resulting allyl alcohol pro-
viding 12 in 85% yield. Treatment of 12 with 10% HCl
in EtOH afforded aldehyde 13. Condensation of 13 with
N-benzylglycine hydrochloride generated azomethine yilide,
which spontaneously underwent [3þ2] cycloaddition to give
indenopyrrolidine 14 in 78% yield. Hydrolysis of acetate,
oxidation of alcohol with MnO2, and condensation with
O-methylhydroxyamine hydrochloride furnished oxime
ether 17. Finally, stereoselective reduction of oxime moiety
was accomplished by borane-pyridine complex and tri-
cyclic methoxyamine 8 in 36% (99% brsm).
effectively to give 7a-g in good yields except for 3-substi-
tuted indanylamine 3f and 3g.
According to our previous report on the domino reaction,9a
we propose the possible reaction pathway as shown in Scheme 1.
Initially, N-indanyl(methoxy)amines 1 and 3 are chelated with
organolithium or Grignard reagent to generate the intermediate
Athat is converted into the imines Bvia elimination of an alkoxy
group and rearrangement of an aryl group. Finally, the addition
of organolithium and magnesium reagents to the imines B
would produce 2-substituted tetrahydroquinolines 2, 4, and 7.
In the case of indanylamines 3f and 3g, the Grignard reagent
would possibly attack the benzyl proton to generate the inter-
mediate D, which should undergo hydrolysis to give the
indanones 5. On the other hand, the allylation of D could yield
amino indanes 6 carrying an allyl group. Although it seems
reasonable to speculate that 5 and 6 would be obtained via the
route shown in Scheme 1, we are currently unable to offer a
detailed explanation of the influence of the 3-substituent on this
domino reaction.
To demonstrate the synthetic utility of the alkylative ring
expansion, we performed an efficient formal synthesis of (()-
martinellic acid. Over the past decade, considerable effort
has been devoted to the synthesis of the martinella alka-
loids.12 The pyrrolo[3,2-c]quinoline core of the martinella
alkaloids has been prepared by several synthetic routes.
Furthermore, asymmetric total synthesis of martinellines
was reported by several groups.13-16 As part of our studies
With the substrate for key reaction in hand, we next
investigated the domino reaction of 8 with allylmagnesium
bromide (Scheme 4). As expected, the reaction proceeded
smoothly and stereoselectively in 30 min to give the desired
pyrroloquinoline 18 in 94% yield as a sole product. The
high stereoselectivity of this reaction is explained by the
allylation from the less hindered convex face of the cis-
pyrroloquinoline intermediate E. The bromination of 18
followed by hydroboration-oxidation of the resulting
(12) Nyerges, M. Heterocycles 2004, 63, 1685 and references cited therein.
(13) Ma, D.; Xia, C.; Jiang, J.; Zhang, J. Org. Lett. 2001, 3, 2189.
(14) Ma, D.; Xia, C.; Jiang, J.; Zhang, J.; Tang, W. J. Org. Chem. 2003,
68, 442.
(15) Ikeda, S.; Shibuya, M.; Iwabuchi, Y. Chem. Commun. 2007, 504.
(16) Badarinarayana, V.; Lovely, C. J. Tetrahedron Lett. 2007, 48, 2607.
(17) Shirai, A.; Miyata, O.; Tohnai, N.; Miyata, M.; Procter, D. J.;
Sucunza, D.; Naito, T. J. Org. Chem. 2008, 73, 4464.
(18) Snider, B. B.; Ahn, Y.; O’Hare, S. M. Org. Lett. 2001, 3, 4217.
916 J. Org. Chem. Vol. 75, No. 3, 2010

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JOCArticle
SCHEME 3. Synthesis of Tricyclic Methoxyamine 8
SCHEME 4. Formal Synthesis of (()-Martinellic Acid
bromide 19 afforded pyrrolo[3,2-c]quinoline 9, which is a
key intermediate used in the synthesis of (()-martinellic
acid.
General Procedure for Domino Elimination-Rearrangement-
Addition Reaction of 1-(Methoxyamino)indan (1) with Organo-
metallic Reagents. To a solution of 1 (49 mg, 0.3 mmol) in Et2O
(6.0 mL) was added organometallic reagent (0.9 mmol) under an
argon atmosphere at room temperature. After being stirred at
the same temperature for 15 min, the reaction mixture was
diluted with H2O and extracted with CHCl3. The organic phase
was dried over MgSO4 and concentrated under reduced pres-
sure. Purification of the residue by PTLC (hexane:AcOEt = 5:1)
afforded tetrahydroquinolines 2a-g.
Conclusions
We have shown that the domino elimination-
rearrangement-addition reaction of N-indanyl(methoxy)-
amines proceeds smoothly to give the tetrahydroquinolines
bearing various types of substituents. Furthermore, we have
succeeded in the stereoselective formal synthesis of (()-
martinellic acid.
2-Butyl-1,2,3,4-tetrahydroquinoline (2a).19 A colorless oil. IR
(neat): 3408 cm-1. 1H NMR (300 MHz, CDCl3): δ 6.95 (1H, br t,
J = 8.0 Hz), 6.94 (1H, br d, J = 8.0 Hz), 6.59 (1H, td, J = 8.0,
1.0 Hz), 6.46 (1H, dd, J = 8.0, 1.0 Hz), 3.60 (1H, br s), 3.27-3.18
(1H, m), 2.81 (1H, ddd, J = 16.0, 11.0, 5.5 Hz), 2.71 (1H, dt, J =
16.0, 5.5 Hz), 2.00-1.91 (2H, m), 1.65-1.31 (6H, m), 0.93 (3H, t,
J = 7.0 Hz). 13C NMR (75 MHz, CDCl3): δ 144.7, 129.2, 126.6,
121.4, 116.8, 114.0, 51.6, 36.4, 28.1, 27.9, 26.4, 22.8, 14.1. HRMS
m/z: calcd for C13H19N (Mþ) 189.1516, found 189.1529.
Experimental Section
1
General. Melting points are uncorrected. H and 13C NMR
spectra were recorded at 300 or 500 MHz and at 75 or 125 MHz,
respectively. IR spectra were recorded with FTIR appa-
ratus. Mass spectra were obtained by EI or CI methods.
Medium-pressure column chromatography (MCC) was per-
1,2,3,4-Tetrahydro-2-phenylquinoline (2b).19 A colorless oil.
IR (neat): 3402 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.57-7.21
€
formed with Lobar grosse B (E. Merck 310-25, Lichroprep
Si60). Preparative TLC separations (PTLC) were carried out on
precoated silica gel plates (E. Merck 60F254). All the reagents
and solvents were used as received from the manufacturer.
(19) Amiot, F.; Cointeaux, L.; Silve, E. J.; Alexakis, A. Tetrahedron 2004,
60, 8221.
J. Org. Chem. Vol. 75, No. 3, 2010 917

Ueda et al.
JOCArticle
(5H, m), 6.97 (1H, br t, J = 8.0 Hz), 6.96 (1H, br d, J = 8.0 Hz),
6.64 (1H, br t, J = 8.0 Hz), 6.52 (1H, br d, J = 8.0 Hz), 4.42 (1H,
dd, J = 9.0, 3.5 Hz), 4.00 (1H, br s), 2.91 (1H, br ddd, J = 16.0,
10.0, 5.5 Hz), 2.71 (1H, br dt, J = 16.0, 5.5 Hz), 2.18-1.93 (2H,
m). 13C NMR (75 MHz, CDCl3): δ 144.7, 144.6, 129.2, 128.5,
127.3, 126.8, 126.4, 120.7, 117.0, 113.9, 56.1, 30.9, 26.2. HRMS
m/z: calcd for C15H15N (Mþ) 209.1203, found 209.1203.
2-Ethyl-1,2,3,4-tetrahydroquinoline (2c).20 A colorless oil. IR
(neat): 3402 cm-1. 1H NMR (300 MHz, CDCl3): δ 6.96 (1H, br t,
J = 8.0 Hz), 6.95 (1H, br d, J = 8.0 Hz), 6.60 (1H, br t, J = 8.0
Hz), 6.50 (1H, br d, J = 8.0 Hz), 3.21-3.13 (1H, m), 2.87-2.68
(2H, m), 2.02-1.93 (1H, m), 1.66-1.49 (3H, m), 0.99 (3H, t, J =
7.0 Hz). 13C NMR (75 MHz, CDCl3): δ 129.2, 126.7, 121.4,
116.9, 114.0, 53.0, 29.4, 27.6, 26.4, 10.0. HRMS m/z: calcd for
C11H15N (Mþ) 161.1204, found 161.1211.
phase was dried over MgSO4 and concentrated under reduced
pressure. Purification of the residue by PTLC (hexane:AcOEt =
5:1 or 2:1) afforded 4a-g, 5f, 5g, 6f, and 6g.
1,2,3,4-Tetrahydro-6-methoxy-2-(2-propenyl)quinoline (4a).
A colorless oil. IR (neat): 3398 cm-1 1H NMR (300 MHz,
.
CDCl3): δ 6.59 (1H, br d, J = 8.0 Hz), 6.57 (1H, br s), 6.44 (1H,
d, J = 8.0 Hz), 5.90-5.76 (1H, m), 5.16 (1H, br d, J = 17.5 Hz),
5.14 (1H, br d, J = 9.5 Hz), 3.72 (3H, s), 3.28-3.19 (1H, m), 2.84
(1H, ddd, J = 17.0, 11.0, 6.0 Hz), 2.76-2.67 (1H, m), 2.37-2.28
(1H, m), 2.23-2.13 (1H, m), 2.00-1.92 (1H, m), 1.69-1.56 (1H,
m). 13C NMR (75 MHz, CDCl3) δ 151.8, 138.5, 135.0, 122.5,
117.8, 115.2, 114.5, 112.8, 55.7, 50.8, 41.0, 28.3, 26.6. HRMS
m/z: calcd for C13H17NO (Mþ) 203.1310, found 203.1314.
6-Chloro-1,2,3,4-tetrahydro-2-(2-propenyl)quinoline (4b). A
1
colorless oil. IR (neat): 3413 cm-1. H NMR (300 MHz, CD-
1,2,3,4-Tetrahydro-2-(2-propenyl)quinoline (2d).21 A colorless
oil. IR (neat): 3402 cm-1. 1H NMR (300 MHz, CDCl3): δ 6.95
(1H, br t, J = 8.0 Hz), 6.94 (1H, br d, J = 8.0 Hz), 6.60 (1H, br t,
J = 8.0 Hz), 6.46 (1H, br d, J = 8.0 Hz), 5.93-5.73 (1H, m), 5.16
(1H, br d, J = 17.0 Hz), 5.15 (1H, br d, J = 11.0 Hz), 3.78 (1H,
br s), 3.36-3.23 (1H, m), 2.92-2.74 (2H, m), 2.40-2.09 (2H, m),
2.03-1.90 (1H, m), 1.73-1.59 (1H, m). 13C NMR (75 MHz,
CDCl3): δ 144.5, 134.9, 129.2, 126.7, 121.2, 117.9, 117.0, 114.0,
50.4, 41.1, 28.2, 26.4. HRMS m/z: calcd for C12H15N (Mþ)
173.1204, found 173.1204.
Cl3): δ 6.91 (1H, br s), 6.90 (1H, br d, J = 8.0 Hz), 6.38 (1H, d,
J = 8.0 Hz), 5.88-5.74 (1H, m), 5.16 (1H, br d, J = 15.5 Hz),
5.15 (1H, br d, J = 11.0 Hz), 3.87 (1H, br s), 3.32-3.23 (1H, m),
2.85-2.65 (2H, m), 2.38-2.29 (1H, m), 2.21-2.11 (1H, m),
1.99-1.91 (1H, m), 1.66-1.53 (1H, m). 13C NMR (75 MHz,
CDCl3): δ 143.0, 134.7, 128.7, 126.5, 122.6, 121.2, 118.1, 114.9,
50.4, 40.9, 27.7, 26.2. HRMS m/z: calcd for C12H1435ClN (Mþ)
207.0814, found 207.0821.
1,2,3,4-Tetrahydro-2-(2-propenyl)-6-quinolinol (4c). A color-
less oil. IR (neat): 3602, 3367 cm-1 1H NMR (300 MHz,
.
1,2,3,4-Tetrahydro-2-(phenylmethyl)quinoline (2e).22 A color-
less oil. IR (neat): 3408 cm-1. 1H NMR (300 MHz, CDCl3): δ
7.37-7.20 (5H, m), 6.97-6.89 (2H, m), 6.59 (1H, br t, J = 7.5
Hz), 6.39 (1H, br d, J = 7.8 Hz), 3.73 (1H, br s), 3.50 (1H, tdd,
J = 8.7, 5.1, 2.7 Hz), 2.89-2.65 (4H, m), 2.07-1.96 (1H, m),
1.79-1.64 (1H, m). 13C NMR (75 MHz, CDCl3): δ 144.3, 138.5,
129.2, 128.6, 126.7, 126.5, 121.2, 117.1, 114.2, 52.6, 43.0, 28.2,
26.1. HRMS m/z: calcd for C16H17N (Mþ) 223.1360, found
223.1371.
CDCl3): δ 6.49 (1H, br d, J = 8.0 Hz), 6.48 (1H, br s), 6.39
(1H, br d, J = 8.0 Hz), 5.89-5.75 (1H, m), 5.15 (1H, br d, J =
17.5 Hz), 5.14 (1H, br d, J = 9.5 Hz), 3.95 (1H, br s), 3.23-3.20
(1H, m), 2.80 (1H, ddd, J = 16.5, 11.0, 5.5 Hz), 2.67 (1H, dt, J =
16.5, 5.5 Hz), 2.36-2.28 (1H, m), 2.22-2.12 (1H, m), 1.98-1.90
(1H, m), 1.68-1.55 (1H, m). 13C NMR (75 MHz, CDCl3): δ
147.5, 138.4, 135.0, 123.1, 117.9, 116.0, 115.6, 113.9, 50.9, 41.0,
28.3, 26.5. HRMS m/z: calcd for C12H15NO (Mþ) 189.1153,
found 189.1153.
1,2,3,4-Tetrahydro-2-(4-methylphenyl)quinoline (2f).23 A color-
1,2,3,4-Tetrahydro-7-methyl-2-(2-propenyl)quinoline (4d). A
1
less oil. IR (neat): 3415 cm-1. H NMR (300 MHz, CDCl3): δ
1
colorless oil. IR (neat): 3402 cm-1. H NMR (300 MHz, CD-
7.30-7.23 (2H, m), 7.15 (2H, br d, J=5.1Hz), 7.08-6.96 (2H, m),
6.64 (1H, br t, J = 7.2 Hz), 6.52 (1H, br d, J = 7.8 Hz), 4.39 (1H,
dd, J = 9.3, 3.3 Hz), 3.99 (1H, br s), 2.92 (1H, ddd, J = 16.2, 10.2,
5.4 Hz), 2.73 (1H, dt, J = 16.3, 4.8 Hz), 2.35 (3H, s) 2.14-1.90
(2H, m). 13C NMR (75 MHz, CDCl3): δ 144.8, 141.8, 137.0,
129.24, 129.19, 126.8, 126.4, 120.8, 117.0, 113.9, 56.0, 31.0,
26.5, 21.0. HRMS m/z: calcd for C16H17N (Mþ) 223.1361,
found 223.150.
Cl3): δ 6.83 (1H, d, J = 7.5 Hz), 6.42 (1H, br d, J = 7.5 Hz), 6.30
(1H, br s), 5.88-5.74 (1H, m), 5.15 (1H, br d, J = 17.5 Hz), 5.14
(1H, br d, J = 10.0 Hz), 3.61 (1H, s), 3.30-3.22 (1H, m),
2.83-2.64 (2H, m), 2.41-2.10 (2H, m), 2.20 (3H, s), 1.98-1.89
(1H, m), 1.67-1.54 (1H, m). 13C NMR (75 MHz, CDCl3): δ
144.3, 136.3, 135.0, 129.0, 118.2, 117.9, 117.8, 114.6, 50.4, 41.1,
28.3, 26.0, 21.0. HRMS m/z: calcd for C13H17N (Mþ) 187.1360,
found 187.1360.
1,2,3,4-Tetrahydro-2-(4-chlorophenyl)quinoline (2g).24 A color-
less oil. IR (neat): 3410 cm-1. 1H NMR (300 Hz, CDCl3): δ 7.35-
7.27 (4H, m), 7.05-6.97 (2H, m), 6.66 (1H, br t, J = 7.5 Hz), 6.55
(1H, br d, J = 7.8 Hz), 4.42 (1H, brdd, J = 9.0, 3,0 Hz), 4.00(1H,
br s), 2.91 (1H, ddd, J = 16.2, 10.2, 5.1 Hz), 2.71 (1H, dt, J =
16.2, 5.1 Hz), 2.15-2.03 (1H, m), 2.01-1.87 (1H, m). 13C NMR
(75 MHz, CDCl3): δ 144.4, 143.3, 132.9, 129.3, 128.6, 127.9,
126.9, 120.8, 117.4, 114.0, 55.5, 30.9, 26.1. HRMS m/z: calcd for
C15H1435ClN (Mþ) 243.0814, found 243.0820.
General Procedure for Domino Elimination-Rearrangement-
Addition Reaction of 1-(Methoxyamino)indans with AllylMgBr.
To a solution of 3a-g (0.3 mmol) in Et2O (6.0 mL) was added
allylmagnesium bomide (1 mol/L in THF, 0.9 mL, 0.9 mmol)
under an argon atmosphere at room temperature. After being
stirred at the same temperature for 15 min, the reaction mixture
was diluted with H2O and extracted with CHCl3. The organic
cis-1,2,3,4-Tetrahydro-3-methyl-2-(2-propenyl)quinoline (4e).
A colorless oil. IR (neat): 3410 cm-1 1H NMR (300 MHz,
.
CDCl3): δ 6.95 (1H, br t, J = 7.5 Hz), 6.94 (1H, br d, J = 7.5
Hz), 6.60 (1H, br t, J = 7.5 Hz), 6.46 (1H, br d, J = 7.5 Hz),
5.88-5.74 (1H, m), 5.15 (1H, br d, J = 16.0 Hz), 5.14 (1H, br d,
J = 11.5 Hz), 3.38-3.21 (1H, m), 2.95 (1H, dd, J = 16.0, 6.5
Hz), 2.47 (1H, dd, J = 16.0, 5.5 Hz), 2.30-2.22 (1H, m),
2.17-2.07 (2H, m), 0.94 (3H, d, J = 7.0 Hz). 13C NMR (75
MHz, CDCl3): δ 143.8, 135.5, 129.8, 126.6, 120.2, 117.8, 117.1,
113.9, 53.6, 36.8, 34.5, 29.7, 14.1. HRMS m/z: calcd for C13H17N
(Mþ) 187.1360, found 187.1363.
trans-1,2,3,4-Tetrahydro-3-methyl-2-(2-propenyl)quinoline (4e).
A colorless oil. IR (neat): 3410 cm-1 1H NMR (300 MHz,
.
CDCl3): δ 6.95 (1H, br t, J = 7.5 Hz), 6.94 (1H, br d, J = 7.5
Hz), 6.59 (1H, br t, J = 7.5 Hz), 6.46 (1H, br d, J = 7.5 Hz),
5.89-5.75 (1H, m), 5.18 (1H, br d, J = 15.0 Hz), 5.14 (1H, br d,
J = 10.0 Hz), 3.96 (1H, br s), 2.94 (1H, td, J = 8.0, 3.5 Hz),
2.75 (1H, dd, J = 15.0, 4.5 Hz), 2.54-2.44 (2H, m), 2.07 (1H, dt,
(20) Wang, Z.-J.; Deng, G.-J.; Li, Y.; He, Y.-M.; Tang, W.-J.; Fan, Q.-H.
Org. Lett. 2007, 9, 1243.
J = 13.0, 8.0 Hz), 1.87-1.70 (1H, m), 1.03 (3H, d, J = 6.5 Hz). 13
C
(21) Meyers, A. I.; Milot, G. J. Org. Chem. 1993, 58, 6538.
(22) Wang, D.-W.; Wang, X.-B.; Wang, D.-S.; Lu, S.-M.; Zhou, Y.-G.;
Li, Y.-X. J. Org. Chem. 2009, 74, 2780.
(23) Han, Z.-Y.; Xiao, H.; Chen, X.-H.; Gong, L.-Z. J. Am. Chem. Soc.
2009, 131, 9182.
(24) Guo, Q.-S.; Du, D.-M.; Xu, J. Angew. Chem., Int. Ed. 2008, 47, 759.
NMR (75 MHz, CDCl3): δ 144.0, 135.1, 129.0, 126.7, 120.8, 118.2,
116.7, 113.5, 56.0, 38.8, 35.0, 31.3, 18.2. HRMS m/z: calcd for
C13H17N (Mþ) 187.1360, found 187.1379.
1,2,3,4-Tetrahydro-4-methyl-2-(2-propenyl)quinoline (4f). The
cis-4f and trans-4f were inseparable (cis:trans = 1:3). A colorless
918 J. Org. Chem. Vol. 75, No. 3, 2010

Ueda et al.
JOCArticle
oil. IR (neat): 3402 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.12
(1/4H, br d, J = 8.0 Hz), 7.02 (3/4H, br d, J = 8.0 Hz), 6.96 (1H,
br t, J = 8.0 Hz), 6.65 (1/4H, br t, J = 8.0 Hz), 6.62 (3/4H, br t,
J = 8.0 Hz), 6.48 (3/4H, br d, J = 8.0 Hz), 6.46 (1/4H, br d, J =
8.0 Hz), 5.92-5.75 (1H, m), 5.17 (1H, br d, J = 17.5 Hz), 5.16
(1H, br d, J = 10.0 Hz), 3.94 (1H, br s), 3.42-3.31 (1H, m),
3.00-2.88 (1H, m), 2.39-2.25 (1H, m), 2.22-2.12 (1H, m), 1.97
(2/4H, ddd, J = 13.0, 6.0, 3.0 Hz), 1.71-1.67 (6/4H, m), 1.32 (3/
4H, d, J = 7.0 Hz), 1.27 (9/4H, d, J = 7.0 Hz). 13C NMR (75
MHz, CDCl3): δ 143.8, 135.0, 134.9, 129.0, 126.8, 126.7, 126.5,
118.0, 117.9, 117.2, 117.0, 114.1, 113.9, 50.6, 45.9, 41.5, 41.3,
38.6, 35.3, 30.8, 30.0, 24.6, 20.2. HRMS m/z: calcd for C13H17N
(Mþ) 187.1360, found 187.1370.
6.43 (1H, d, J = 8.0 Hz), 4.40 (1H, dd, J = 9.0, 3.5 Hz), 4.02 (1H,
br s), 2.86 (1H, ddd, J = 17.0, 10.0, 5.5 Hz), 2.67 (1H, dt, J =
17.0, 5.5 Hz), 2.14-2.05 (1H, m), 2.00-1.88 (1H, m). 13C NMR
(75 MHz, CDCl3): δ 144.3, 143.2, 128.8, 128.6, 127.5, 126.6,
126.4, 122.3, 121.4, 114.9, 56.0, 30.4, 26.1. HRMS m/z: calcd for
C15H1435ClN (Mþ) 243.0814, found 243.0795.
1,2,3,4-Tetrahydro-2-phenyl-6-quinolinol (7c). A colorless oil.
1
IR (neat): 3602, 3388 cm-1. H NMR (300 MHz, CDCl3): δ
7.41-7.25 (5H, m), 6.54 (1H, br d, J = 8.0 Hz), 6.53 (1H, br s),
6.45 (1H, d, J = 8.0 Hz), 4.35 (1H, dd, J = 9.5, 3.0 Hz), 4.14 (1H,
br s), 2.90 (1H, ddd, J = 16.0, 11.5, 6.5 Hz), 2.69 (1H, dt, J =
16.0, 5.0 Hz), 2.14-2.04 (1H, m), 2.02-1.91 (1H, m). 13C NMR
(75 MHz, CDCl3): δ 147.4, 144.8, 138.9, 128.5, 127.4, 126.6,
122.5, 116.0, 115.2, 114.0, 56.6, 31.0, 26.6. HRMS m/z: calcd for
C15H15NO (Mþ) 225.1153, found 225.1156.
(1r,3r)-2,3-Dihydro-3-methyl-2-(2-propenyl)-1H-inden-1-amine
1
(6f). A colorless oil. IR (neat): 3360, 3286 cm-1. H NMR (300
MHz, CDCl3): δ 7.26-7.17 (4H, m), 5.84-5.70 (1H, m), 5.12 (1H,
br d, J = 16.0 Hz), 5.11 (1H, br d, J = 11.0 Hz), 3.17-3.05 (1H,
m), 2.50 (1H, dd, J = 13.0, 7.5 Hz), 2.41-2.28 (2H, m), 1.94 (2H,
1,2,3,4-Tetrahydro-7-methyl-2-phenylquinoline (7d). A color-
less oil. IR (neat): 3415 cm-1. 1H NMR (300 MHz, CDCl3): δ
7.44-7.23 (5H, m), 6.87 (1H, d, J = 7.5 Hz), 6.46 (1H, br d, J =
7.5 Hz), 6.33 (1H, br s), 4.38 (1H, dd, J = 9.0, 3.0 Hz), 3.93 (1H,
br s), 2.85 (1H, ddd, J = 16.0, 10.0, 5.5 Hz), 2.67 (1H, dt, J =
16.0, 5.0 Hz), 2.23 (3H, s), 2.12-1.88 (2H, m). 13C NMR (75
MHz, CDCl3): δ 144.9, 144.5, 136.5, 129.1, 128.5, 127.3, 126.5,
118.0, 117.9, 114.5, 56.2, 31.1, 25.9, 21.1. HRMS m/z: calcd for
C16H17N (Mþ) 223.1360, found 223.1370.
br s), 1.52 (1H, dd, J= 13.0, 10.0 Hz), 1.32 (3H, d, J= 7.0Hz). 13
C
NMR (75 MHz, CDCl3): δ 146.8, 134.1, 127.4, 126.5, 123.2, 122.6,
118.6, 62.6, 50.9, 45.5, 35.7, 19.4. HRMS m/z: calcd for C13H17N
(Mþ) 187.1360, found 187.1335.
1,2,3,4-Tetrahydro-4-phenyl-1-(2-propenyl)quinoline (4g). The
cis-4g and trans-4g were inseparable (cis:trans = 1:3). A colorless
oil. IR (neat): 3418 cm-1 1H NMR (300 MHz, CDCl3): δ
.
cis-1,2,3,4-Tetrahydro-3-methyl-2-phenylquinoline (7e).
A
colorless oil. IR (neat): 3411 cm-1.1H NMR (300 MHz, CD-
Cl3): δ 7.35-7.26 (5H, m), 7.02 (1H, br t, J = 7.5 Hz), 7.00 (1H,
br d, J = 7.5 Hz), 6.65 (1H, br t, J = 7.5 Hz), 6.56 (1H, br d, J =
7.5 Hz), 4.52 (1H, d, J = 4.0 Hz), 4.14 (1H, br s), 2.97 (1H, dd,
J = 16.0, 5.0 Hz), 2.50 (1H, dd, J = 16.0, 6.5 Hz), 2.34-2.29
(1H, m), 0.82 (3H, d, J = 7.0 Hz). 13C NMR (75 MHz, CDCl3):
δ 144.2, 142.9, 129.7, 128.1, 127.2, 127.1, 126.9, 120.4, 117.1,
113.7, 59.4, 33.4, 31.9, 15.1. HRMS m/z: calcd for C16H17N
(Mþ) 223.1360, found 223.1362.
7.35-6.87 (7H, m), 6.60 (3/4H, br t, J = 8.0 Hz), 6.58 (3/4H,
br d, J = 8.0 Hz), 6.53 (1/4H, br d, J = 8.0 Hz), 6.52 (1/4H, br t,
J = 8.0Hz), 5.91-5.67(1H, m), 5.22-5.10(2H, m), 4.19 (3/4H, t,
J = 5.0 Hz), 4.14 (1/4H, dd, J = 12.0, 5.5 Hz), 3.51 (1/4H, dddd,
J = 11.0, 8.0, 5.5, 3.0 Hz), 3.19 (3/4H, tt, J = 8.5, 5.5 Hz),
2.41-2.09 (2H, m), 2.00-1.95 (7/4H, m), 1.86 (1/4H, q, J = 12.0
Hz,). 13C NMR (75 MHz, CDCl3): δ 147.4, 145.7, 144.8, 144.6,
134.8, 134.5, 130.6, 129.7, 128.7, 128.55, 128.49, 128.1, 127.4,
127.1, 126.4, 125.9, 125.1, 122.1, 118.3, 118.0, 117.4, 117.1, 114.1,
50.9, 45.5, 44.4, 41.8, 41.2, 40.9, 39.2, 36.5. HRMS m/z: calcd for
C18H19N (Mþ) 249.1517, found 249.1516.
(1r,3r)-2,3-Dihydro-3-phenyl-2-(2-propenyl)-1H-inden-1-amine
(6g). A colorless oil. IR (neat): 3360, 3291 cm-1. 1H NMR (300
MHz, CDCl3): δ 7.34-7.16 (8H, m), 6.88 (1H, br d, J = 7.5 Hz),
5.88-5.74 (1H, m), 5.15 (1H, br d, J = 16.0 Hz), 5.14 (1H, br d,
J = 11.5 Hz), 4.25 (1H, t, J = 8.0 Hz), 2.74 (1H, dd, J = 12.5, 7.5
Hz), 2.51-2.38 (2H, m), 2.14 (2H, br s), 2.00 (1H, dd, J = 12.5,
10.5 Hz). 13C NMR (75 MHz, CDCl3):δ145.2, 144.3, 134.0, 130.9,
128.5, 128.4, 127.6, 126.9, 126.5, 125.1, 122.7, 118.9, 93.2, 62.8,
52.5, 48.1, 45.4. HRMS m/z: calcd for C18H20N (M þ Hþ)
250.1580, found 250.1594.
trans-1,2,3,4-Tetrahydro-3-methyl-2-phenylquinoline (7e). A
colorless oil. IR (neat): 3420 cm-1. 1H NMR (300 MHz, CDCl3):
δ 7.35-7.19 (5H, m), 7.01-6.97 (2H, m), 6.63 (1H, br t, J = 7.5
Hz), 6.47 (1H, br d, J = 7.5 Hz), 3.95 (1H, br s), 3.93 (1H, d,
J = 8.5 Hz), 2.79 (1H, dd, J = 16.0, 8.5 Hz), 2.59 (1H, dd, J =
16.0, 11.0 Hz), 2.13-1.98 (1H, m), 0.82 (3H, d, J = 6.5 Hz). 13
C
NMR (75 MHz, CDCl3): δ 144.5, 143.4, 129.1, 128.4, 127.6,
127.5, 126.8, 120.8, 116.9, 113.3, 63.3, 35.3, 33.8, 18.5. HRMS
m/z: calcd for C16H17N (Mþ) 223.1360, found 223.1366.
trans-1,2,3,4-Tetrahydro-4-methyl-2-phenylquinoline (7f). A
1
colorless oil. IR (neat): 3391 cm-1. H NMR (300 MHz, CD-
Cl3): δ 7.42-7.25 (5H, m), 7.08 (1H, br t, J = 7.5 Hz), 7.01 (1H,
br d, J = 7.5 Hz), 6.67 (1H, br t, J = 7.5 Hz), 6.54 (1H, br d, J =
7.5 Hz), 4.46 (1H, dd, J = 10.0, 4.0 Hz), 4.08 (1H, br s),
2.97-2.87 (1H, m), 2.03 (1H, ddd, J = 13.0, 10.0, 5.5 Hz),
1.84 (1H, dt, J = 13.0, 4.0 Hz), 1.35 (3H, d, J = 7.0 Hz). 13C
NMR (75 MHz, CDCl3): δ 144.8, 144.0, 128.8, 128.5, 127.4,
126.9, 126.6, 126.1, 117.1, 114.0, 52.1, 38.2, 29.9, 24.1. HRMS
m/z: calcd for C16H17N (Mþ) 223.1360, found 223.1370.
trans-1,2,3,4-Tetrahydro-2,4-diphenylquinoline (7g). A color-
less oil. IR (neat): 3391 cm-1. 1H NMR (300 MHz, CDCl3): δ
7.32-7.05 (11H, m), 6.88 (1H, br d, J = 8.0 Hz), 6.64 (1H, br d,
J = 8.0 Hz), 6.63 (1H, br t, J = 8.0 Hz), 4.32 (1H, dd, J = 10.0,
5.0 Hz), 4.15 (1H, t, J = 5.0 Hz), 2.30 (1H, ddd, J = 13.5,
10.0, 5.0 Hz), 2.18 (1H, dt, J = 13.5, 5.0 Hz). 13C NMR
(75 MHz, CDCl3): δ 146.9, 144.8, 144.4, 130.5, 128.6, 128.5,
128.3, 127.6, 127.4, 126.6, 126.1, 122.2, 117.2, 114.0, 51.9, 41.7,
39.0. HRMS m/z: calcd for C21H19N (Mþ) 285.1516, found
285.1542.
General Procedure for Domino Elimination-Rearrangement-
Addition Reaction of 1-(Methoxyamino)indans with PhMgBr. To
a solution of 3a-g (0.3 mmol) in Et2O (6.0 mL) was added
phenylmagnesium bromide (3 mol/L in THF, 0.3 mL, 0.9 mmol)
under an argon atmosphere at room temperature. After being
stirred at the same temperature for 15 min, the reaction mixture
was diluted with H2O and extracted with CHCl3. The organic
phase was dried over MgSO4 and concentrated under reduced
pressure. Purification of the residue by PTLC (hexane:AcOEt =
5:1 or 2:1) afforded 7a-g, 5f, and 5g.
1,2,3,4-Tetrahydro-6-methoxy-2-phenylquinoline (7a). A color-
1
less oil. IR (neat): 3393 cm-1. H NMR (300 MHz, CDCl3): δ
7.39-7.20 (5H, m), 6.62 (1H, d, J = 8.0 Hz), 6.60 (1H, br s), 6.47
(1H, br d, J = 8.0 Hz), 4.34 (1H, dd, J = 9.5, 2.5 Hz), 3.72 (3H, s),
2.91 (1H, ddd, J = 16.5, 10.5, 5.0 Hz), 2.70 (1H, dt, J = 16.5,
5.0 Hz), 2.13-1.90 (2H, m). 13C NMR (75 MHz, CDCl3): δ 151.8,
144.8, 138.9, 128.5, 127.3, 126.5, 122.0, 115.1, 114.6, 113.0, 56.5,
55.8, 31.1, 26.7. HRMS m/z: calcd for C16H17NO (Mþ) 239.1310,
found 239.1326.
6-Chloro-1,2,3,4-Tetrahydro-2-phenylquinoline (7b). A color-
less oil. IR (neat): 3419 cm-1. 1H NMR (300 MHz, CDCl3): δ
7.35-7.23 (5H, m), 6.95 (1H, br s), 6.94 (1H, br d, J = 8.0 Hz),
2-(Diethoxymethyl)benzaldehyde (11). To a solution of bro-
mide 10 (1.6 g, 6.2 mmol) in THF (16 mL) was added
n-buthyllithium (1.6 mol/L in n-hexane, 4.3 mL, 6.8 mmol)
under an argon atmosphere at -70 °C. After being stirred at
the same temperature for 30 min, DMF (5.7 mL, 73.4 mmol) was
J. Org. Chem. Vol. 75, No. 3, 2010 919

Ueda et al.
JOCArticle
added slowly dropwise keeping the same temperature and
stirring continued for 30 min. The reaction mixuture was stirred
at room temperature for 30 min, poured into saturated aqueous
NH4Cl (100 mL), and extracted with Et2O. The organic phase
was washed with brine, dried over MgSO4, and concentrated
under reduced pressure. Purification of the residue by column
chromatography on SiO2 (n-hexane:AcOEt = 10:1) afforded
aldehyde 11 (1.2 g, 93%) as a colorless oil. 1H NMR (300 MHz,
CDCl3): δ 10.50 (1H, s), 7.92 (1H, br d, J = 8.0 Hz), 7.69 (1H, br
d, J = 8.0 Hz), 7.58 (1H, br t, J = 8.0 Hz), 7.47 (1H, br t, J = 8.0
Hz), 5.96 (1H, s), 3.72 (1H, q, J = 7.0 Hz), 3.69 (1H, q, J = 7.0
Hz), 3.59 (1H, q, J = 7.0 Hz), 3.56 (1H, q, J = 7.0 Hz), 1.23
(6H, t, J = 7.0 Hz). The spectral data were identical with those
reported in the literature.25
MgSO4 and concentrated under reduced pressure. Purification
of the residue by PTLC (n-hexane:AcOEt = 3:1) afforded 14
(40.8 mg, 78%) as a colorless oil and an inseparable 3:2 mixture
of 3a,4-trans-3a,8b-cis and 3a,4-cis-3a,8b-cis isomers. IR (neat):
1729 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.44-7.06 (9H, m),
6.06-6.03 (1H, m), 4.40 (2/5H, d, J = 7.0 Hz), 4.23 (3/5H, d,
J = 7.0 Hz), 4.06 and 3.84 (6/5H, ABq, J = 12.0 Hz), 4.06 and
3.72 (4/5H, ABq, J = 12.0 Hz), 3.53-3.42 (1H, m), 3.03-2.80
(1H, m), 2.65-2.49 (1H, m), 2.15 (9/5H, s), 2.06 (6/5H, s),
1.83-1.71 (2H, m). 13C NMR (75 MHz, CDCl3): δ 170.8, 145.2,
143.8, 140.4, 139.5, 139.2, 129.3, 129.0, 128.9, 128.2, 128.1,
127.7, 126.9, 126.0, 125.0, 124.8, 83.2, 75.9, 71.4, 70.6, 60.4,
59.2, 54.6, 54.1, 50.0, 45.4, 29.2, 24.8, 21.1, 20.8. HRMS m/z:
calcd for C20H21NO2 (Mþ) 307.1571, found 307.1569.
r-Ethenyl-2-(diethoxymethyl)benzenemethanol Acetate (12).
To a solution of 11 (4.9 g, 23.6 mmol) in THF (34 mL) was
added vinylmagnesium bromide (1 M in THF, 58.9 mL, 58.9
mmol) under an argon atmosphere at 0 °C. After being stirred at
the same temperature overnight, the reaction mixture was
diluted with H2O and extracted with CHCl3. The organic phase
was dried over MgSO4 and concentrated under reduced pressure
to give the crude allyl alcohol that was subjected to the following
reaction without further purification. To a solution of the crude
allyl alcohol (5.6 g, 23.6 mmol) in pyridine (7.6 mL) was added
Ac2O (8.9 mL, 94.2 mmol) under a nitrogen atmosphere at room
temperature. After being stirred at room temperature overnight,
the reaction mixture was diluted with H2O and extracted with
CHCl3. The organic phase was washed with H2O, dried over
MgSO4, and concentrated under reduced pressure. Purification
of the residue by column chromatography on SiO2 (n-hexane:
AcOEt = 10:1) afforded 12 (5.6 g, 85%) as a colorless oil. IR
(3ar,8br)-1,2,3,3a,4,8b-Hexahydro-1-(phenylmethyl)indeno-
[1,2-b]pyrrol-4-ol (15). To a solution of 14 (202.3 mg, 0.66 mmol)
in MeOH (3.0 mL) was added K2CO3 (50 mg, 0.36 mmol) under
a nitrogen atmosphere at room temperature. After being stirred
at the same temperature for 3 h, the reaction mixture was diluted
with H2O and extracted with CHCl3. The organic phase was
dried over MgSO4 and concentrated under reduced pressure.
Purification of the residue by column chromatography on SiO2
(n-hexane:AcOEt = 2:1) afforded 15 (171.3 mg, 98%) as a
colorless oil and an inseparable 3:2 mixture of 3a,4-trans-3a,
8b-cis and 3a,4-cis-3a,8b-cis isomers. IR (neat): 3595 cm-1. 1H
NMR (300 MHz, CDCl3): δ 7.48 (1H, br d, J = 8.0 Hz),
7.37-7.14 (8H, m), 5.02 (2/5H, br d, J = 2.5 Hz), 4.82 (3/5H,
d, J = 7.0 Hz), 4.30 (2/5H, d, J = 7.5 Hz), 4.15 and 3.37 (6/5H,
ABq, J = 13.0 Hz), 4.05 and 3.66 (4/5H, ABq, J = 13.0 Hz),
3.79 (3/5H, d, J = 7.0 Hz), 3.11-3.01 (6/5H, m), 2.91-2.79 (4/
5H, m), 2.54-2.42 (1H, m), 2.20-2.05 (1H, m), 1.94-1.83 (3/
5H, m), 1.72-1.60 (2/5H, m). 13C NMR (75 MHz, CDCl3): δ
146.4, 144.7, 143.7, 142.3, 139.3, 138.5, 129.0, 128.9, 128.6,
128.5, 128.18, 128.15 127.0, 126.9, 125.6, 125.2, 125.0, 81.7,
75.0, 72.2, 71.4, 59.1, 58.2, 55.8, 54.4, 53.4, 48.7, 29.0, 22.0.
HRMS m/z: calcd for C18H19NO (Mþ) 265.1466, found
265.1455.
cis-2,3,3a,8b-Tetrahydro-1-(phenylmethyl)indeno[1,2-b]pyrrol-
4(1H )-one (16). To a solution of 15 (1.95 g, 7.36 mmol) in Et2O
(86 mL) was added MnO2 (2.50 g) under a nitrogen atmosphere
at room temperature. After being stirred at the same temperature
for 20 h, the reaction mixture was filtered through a pad of Celite
and the filtrate was concentrated under reduced pressure. Puri-
fication of the residue by column chromatography on SiO2
(n-hexane:AcOEt = 5:1) afforded 16 (1.32 g, 68%) as a colorless
oil. IR (neat): 1714 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.74
(1H, br d, J = 8.0 Hz), 7.60 (1H, br t, J = 8.0 Hz), 7.45 (1H, br d,
J = 8.0 Hz), 7.44 (1H, br t, J = 8.0 Hz), 7.38-7.24 (5H, m), 4.44
(1H, d, J = 6.5 Hz), 4.03 and 3.81 (2H, ABq, J = 13.0 Hz), 3.31
(1H, ddd, J = 11.0, 6.5, 5.0 Hz), 2.75-2.62 (2H, m), 2.25 (1H,
ddt, J = 13.0, 11.0, 6.5 Hz), 1.99 (1H, dtd, J = 13.0, 6.5, 5.0 Hz).
13C NMR (75 MHz, CDCl3): δ 153.4, 138.9, 136.9, 134.8, 128.9,
128.8, 128.4, 127.2, 126.7, 123.8, 100.0, 66.1, 58.2, 53.7, 51.9,
27.5. HRMS m/z: calcd for C18H17NO (Mþ) 263.1310, found
263.1296.
1
(neat): 1742 cm-1. H NMR (300 MHz, CDCl3): δ 7.64-7.28
(4H, m), 6.67 (1H, br d, J = 5.0 Hz), 6.02 (1H, ddd, J = 17.5,
10.5, 5.0 Hz), 5.80 (1H, s, CH), 5.26 (1H, dt, J = 17.5, 1.5 Hz),
5.21 (1H, dt, J = 10.5, 1.5 Hz), 3.72 (1H, q, J = 7.0 Hz), 3.69
(1H, q, J = 7.0 Hz), 3.58 (1H, q, J = 7.0 Hz), 3.52 (1H, q, J =
7.0 Hz), 2.08 (3H, s), 1.26 (3H, t, J = 7.0 Hz), 1.18 (3H, t, J = 7.0
Hz). 13C NMR (75 MHz, CDCl3): δ 169.8, 137.2, 136.4, 128.6,
127.7, 127.6, 126.5, 116.1, 99.4, 71.8, 62.5, 60.8, 21.1, 15.11,
15.06. HRMS m/z: calcd for C16H22O4 (Mþ) 278.1517, found
278.1533.
r-Ethenyl-2-formylbenzenemethanol Acetate (13). To a solu-
tion of 12 (165 mg, 0.6 mmol) in EtOH (5.4 mL) was added 10%
HCl (1.1 mL) under a nitrogen atmosphere at room tempera-
ture. After being stirred at the same temperature for 4 h, the
reaction mixture was diluted with H2O and extracted with
CHCl3. The organic phase was washed with H2O, dried over
MgSO4, and concentrated under reduced pressure. Purification
of the residue by column chromatography on SiO2 (n-hexane:
AcOEt = 10:1) afforded 13 (101.6 mg, 84%) as a colorless oil.
IR (neat): 1743, 1700 cm-1. 1H NMR (300 MHz, CDCl3): δ 10.3
(1H, s), 7.88 (1H, br d, J = 8.0 Hz), 7.61 (1H, br t, J = 8.0 Hz),
7.57 (1H, br d, J = 8.0 Hz), 7.49 (1H, br t, J = 8.0 Hz), 7.05 (1H,
br d, J = 5.5 Hz), 6.14-6.03 (1H, m), 5.24 (1H, br d, J = 10.5
Hz), 5.23 (1H, br d, J = 17.0 Hz), 2,13 (3H, s). 13C NMR (75
MHz,, CDCl3): δ 192.0, 169.4, 140.7, 136.0, 133.8, 133.1, 132.1,
128.2, 127.6, 117.0, 72.1, 20.9. HRMS m/z: calcd for C10H9O2
(Mþ - 43) 161.0602, found 161.0606.
(3ar,4r,8br)-1,2,3,3a,4,8b-Hexahydro-4-methoxyamino-1-
(phenylmethyl)indeno[1,2-b]pyrrole (8). To a solution of 16 (1.7
g, 6.4 mmol) in MeOH (200 mL) were added MeONH2 HCl (1.1
3
(3ar,8br)-1,2,3,3a,4,8b-Hexahydro-1-(phenylmethyl)indeno-
[1,2-b]pyrrol-4-ol 4-Acetate (14). To a solution of 13 (35.4 mg,
0.17 mmol) and N-benzylglycine hydrochloride (49.4 mg, 0.24
mmol) in toluene (3.0 mL) was added Et3N (0.06 mL, 0.41
mmol) under a nitrogen atmosphere at room temperature. After
being refluxed for 5 h, the reaction mixture was diluted with H2O
and extracted with CHCl3. The organic phase was dried over
g, 12.8 mmol) and AcONa (1.1 g, 12.8 mmol) under a nitrogen
atmosphere at room temperature. After being stirred at the same
temperature for 24 h, the reaction mixture was concentrated
under reduced pressure. The residue was diluted with H2O and
extracted with CHCl3. The organic phase was washed with H2O,
dried over MgSO4, and concentrated under reduced pressure to
give the crude oxime ether 17, which was subjected to the
following reaction without further purification. To a solution
of the crude oxime ether 17 (1.87 g, 6.4 mmol) and pyridine-
borane complex (2 mL, 21.1 mmol) in EtOH (15 mL) was added
(25) Chezal, J. M.; Moreau, E.; Desbois, N.; Blache, Y.; Chavignon, O.;
Teulade, J. C. Tetrahedron Lett. 2004, 45, 553.
920 J. Org. Chem. Vol. 75, No. 3, 2010

Ueda et al.
JOCArticle
slowly 10% HCl (20 mL) at -10 °C under a nitrogen atmo-
sphere. After the reaction mixture was stirred at room tempera-
ture for 48 h, Na2CO3 was added. The reaction mixture was
diluted with H2O and extracted with CHCl3. The organic phase
was washed with H2O, dried over MgSO4, and concentrated
under reduced pressure. Purification of the residue by column
chromatography on SiO2 (n-hexane:AcOEt = 3:1) afforded 8
(686 mg, 36%, 99% brsm) and oxime ether 17 (1.19 g, 63%).
6.46 (1H, d, J = 8.0 Hz), 5.83 (1H, dtd, J = 18.5, 10.0, 5.0 Hz),
5.21 (1H, br d, J = 18.5 Hz), 5.20 (1H, br d, J = 10.0 Hz), 4.31
and 3.11 (2H, ABq, J = 13.0 Hz), 4.22, (1H, br s), 3.19 (1H, br t,
J = 9.0 Hz), 3.14 (1H, br d, J = 5.5 Hz), 2.88 (1H, br t, J = 8.5
Hz), 2.58-2.52 (1H, m), 2.13 (1H, q, J = 8.5 Hz), 2.05-1.84
(3H, m), 1.64-1.56 (1H, m). 13C NMR (75 MHz, CDCl3):
δ143.8, 140.0, 135.1, 134.1, 131.0, 128.5, 128.1, 126.7, 121.2,
118.6, 115.5, 107.2, 63.7, 57.6, 51.33, 51.26, 39.4, 38.3, 25.5.
HRMS m/z: calcd for C21H2379BrN2 (Mþ) 382.1044, found
382.1057.
A colorless oil. IR (neat): 3253 cm-1 1H NMR (500 MHz,
.
CDCl3): δ 7.39-7.17 (8H, m), 7.07 (1H, br d, J = 8.0 Hz), 4.59
(1H, d, J = 8.0 Hz), 4.30 (1H, br s), 4.13 (1H, d, J = 8.0 Hz), 4.09
and 3.75 (2H, ABq, J = 13.0 Hz), 3.61 (3H, s), 3.27 (1H, dt, J =
10.0, 8.0 Hz), 3.00 (1H, ddd, J = 10.0, 6.5, 4.0 Hz), 2.58 (1H,
td, J = 10.0, 6.5 Hz), 1.93-1.84 (2H, m). NOESY: NOE was
observed between 3a-H (δ 3.27) and 4-H (δ 4.59), 3a-H (δ 3.27)
and 8b-H (δ 4.13), 4-H (δ 4.59) and 8b-H (δ 4.13). 13C NMR
(125 MHz, CDCl3): δ 144.4, 141.6, 139.7, 129.2, 128.3, 128.2,
127.7, 127.1, 125.5, 125.2, 71.5, 64.1, 61.4, 60.3, 55.4, 46.2, 24.0.
HRMS m/z: calcd for C19H22N2O (Mþ) 294.1731, found
294.1709.
(3ar,4β,9br)-8-Bromo-2,3,3a,4,5,9b-hexahydro-1-(phenyl-
methyl)-1H-pyrrolo[3,2-c]quinoline-4-propanol (9). To a solution
of 19 (27.7 mg, 0.07 mmol) in THF (1 mL) was added thexylBH2
(0.8 mol/L, 0.088 mL, 0.07 mmol) under an argon atmosphere
at 0 °C. After being stirred at the same temperature for 1 h,
thexylBH2 (0.8 mol/L, 0.088 mL, 0.07 mmol) was added. After
being stirred at the same temperature for 1 h, thexylBH2
(0.8 mol/L, 0.088 mL, 0.07 mmol) was added. After being stirred
at the same temperature for 1 h, MeOH (0.07 mL), aq NaOH
(3 mol/L, 0.023 mL, 0.07 mmol), and 30% H2O2 (0.007 mL, 0.07
mmol) were added at 0 °C. After being stirred at room tempera-
ture for 3 h, the reaction was quenched by 10% HCl, and the
reaction mixture was diluted with H2O and extracted with
CHCl3. The organic phase was washed with H2O, dried over
MgSO4, and concentrated under reduced pressure. Purification
of the residue by PTLC (AcOEt) afforded 19 (19.7 mg, 70%) as a
white solid. IR (CHCl3): 3625, 3433 cm-1. 1H NMR (500 MHz,
CDCl3): δ 7.27-7.20 (6H, m), 7.14 (1H, dd, J = 8.5, 2.5 Hz),
6.48 (1H, d, J = 8.5 Hz), 4.30 (1H, d, J = 12.5 Hz), 3.71 (2H, t,
J = 6.0 Hz), 3.22 (1H, br t, J = 8.5 Hz), 3.17 (1H, m), 3.15 (1H,
br d, J = 12.5 Hz), 2.87 (1H, td, J = 9.0, 3.5 Hz), 2.14 (1H, br q,
J = 9.0 Hz), 2.02-1.94 (2H, m), 1.80-1.65 (3H, m), 1.59 (1H, br
q, J = 9.0 Hz), 1.53-1.47 (1H, m). 13C NMR (125 MHz,
CDCl3): δ 144.0, 140.0, 134.0, 131.0, 128.6, 128.1, 126.8,
121.8, 115.8, 107.7, 63.6, 62.9, 57.9, 52.6, 51.5, 39.4, 30.0, 28.7,
25.9. HRMS m/z: calcd for C21H2579BrN2O (Mþ) 400.1149,
found 400.1163.
(3ar,4β,9br)-2,3,3a,4,5,9b-Hexahydro-1-(phenylmethyl)-4-(2-
propenyl)-1H-pyrrolo-[3,2-c]quinoline (18). To a solution of 8
(670 mg, 2.3 mmol) in Et2O (46 mL) was added allylmagnesium
bromide (1 M in Et2O, 0.9 mL, 0.9 mmol) under an argon
atmosphere at room temperature. After being stirred at the same
temperature for 30 min, the reaction mixture was diluted with
H2O and extracted with CHCl3. The organic phase was washed
with H2O, dried over MgSO4, and concentrated under reduced
pressure. Purification of the residue by MCC (n-hexane:
AcOEt = 5:1) afforded 18 (655 mg, 94%) as a colorless oil. IR
(neat): 3415 cm-1. 1H NMR (500 MHz, CDCl3): δ 7.27-7.18 (5H,
m), 7.13 (1H, br d, J = 8.0 Hz), 7.07 (1H, br t, J = 8.0 Hz), 6.63
(1H, br t, J = 8.0 Hz), 6.58 (1H, br d, J = 8.0 Hz), 5.85 (1H, dtd,
J = 17.5, 10.0, 5.0 Hz), 5.21 (1H, br d, J =17.5Hz), 5.20(1H, br d,
J = 10.0 Hz), 4.37 and 3.10 (2H, ABq, J = 13.0 Hz), 3.22 (1H, br t,
J = 9.0 Hz), 3.17 (1H, d, J = 5.5 Hz), 2.88 (1H, br t, J = 8.5 Hz),
2.58-2.54 (1H, m), 2.13 (1H, q, J = 8.5 Hz), 1.99 (3H, m),
1.92-1.90 (1H, m), 1.62-1.56 (1H, m). 13C NMR (125 MHz,
CDCl3): δ 144.8, 140.3, 135.4, 131.9, 128.5, 128.3, 128.0, 126.6,
119.2, 118.3, 116.0, 114.0, 64.1, 57.6, 51.4, 39.7, 38.4, 29.7, 25.6.
HRMS m/z: calcd for C21H24N2 (Mþ) 304.1938, found 304.1925.
(3ar,4β,9br)-8-Bromo-2,3,3a,4,5,9b-hexahydro-1-(phenyl-
methyl)-4-(2-propenyl)-1H-pyrrolo[3,2-c]quinoline (19). To a
solution of 18 (91.2 mg, 0.3 mmol) in DMF (3 mL) was added
N-bromosuccinimide (51.6 mg, 0.3 mmol) under a nitrogen
atmosphere at room temperature. After being stirred at the
same temperature for 24 h, the reaction mixture was diluted with
H2O and extracted with CHCl3. The organic phase was washed
with H2O, dried over MgSO4, and concentrated under reduced
pressure. Purification of the residue by PTLC (n-hexane:
AcOEt = 5:1) afforded 19 (88 mg, 79%) as a colorless oil. IR
(CHCl3): 3415 cm-1. 1H NMR (300 MHz, CDCl3): δ 7.27-7.25
(5H, m), 7.20 (1H, d, J = 1.5 Hz), 7.13 (1H, dd, J = 8.0, 1.5 Hz),
Acknowledgment. We acknowledge Grants-in-Aid for
Scientific Research (B) (T.N.) and Scientific Research (C)
(O.M.) from the Japan Society for the Promotion of Science
and for Young Scientists (B) (M.U.) from the Ministry of
Education, Culture, Sports, Science and Technology of
Japan. Our thanks are also directed to the Science Research
Promotion Fund of the Japan Private School Promotion
Foundation for a research grant.
Supporting Information Available: Experimental procedure
and characterization data for 1 and 3a-g, and 1H and 13C NMR
spectra of all obtained compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 3, 2010 921