Lewis acid catalyzed three-component hetero-Diels-Alder (Povarov) reaction of N-arylimines with strained norbornene-derived dienophiles

Article abstract of DOI:10.1021/jo9021106

(Chemical Equation Presented) Generally, the hetero-Diels-Alder reaction (Povarov reaction) of N-arylimine dienes are limited to reaction with activated, electron-rich alkenes. However, introduction of ring strain in the dienophile, as with moderately strained bicyclo[2.2.1]heptenes (norbornene), enables three-component Povarov reaction with in situ formed N-arylimines under Lewis acid catalyzed conditions (BF₃·OEt₂). The reactions proceed efficiently with a diverse set of commercially available anilines and benzaldehydes, as well as a variety of substituted norbornenes. The corresponding tetrahydroquinolines are formed with high complexity in a multicomponent fashion and are obtained in good yield and high diastereoselectivity. In addition, more reactive ethyl glyoxylate derived imines were utilized to achieve faster, room temperature reactions with norbornene. In all cases, attack of the N-arylimine dienes occurred exclusively from the exo-face of the norbornene ring, but the relative stereochemistry of the substituent α to the tetrahydroquinoline nitrogen, as well as the regioselectivity of reaction, was shown to depend upon subtle substituent effects on the aniline precursors. In most cases, a preference for the formation of exo-exo diastereomeric adducts was observed, but for reactions of ortho- or meta-substituted anilines, the formation of exo-endo adducts was also observed. These observations may be rationalized by two competing mechanistic models, involving either a concerted asynchronous [4 + 2]-like mechanism or a stepwise mechanism.

Full text of DOI:10.1021/jo9021106

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Lewis Acid Catalyzed Three-Component Hetero-Diels-Alder (Povarov)
Reaction of N-Arylimines with Strained Norbornene-Derived Dienophiles
Chris D. Smith, Julia I. Gavrilyuk, Alan J. Lough, and Robert A. Batey*
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, M5S 3H6 Canada
rbatey@chem.utoronto.ca
Received October 15, 2009
Generally, the hetero-Diels-Alder reaction (Povarov reaction) of N-arylimine dienes are limited to
reaction with activated, electron-rich alkenes. However, introduction of ring strain in the dienophile,
as with moderately strained bicyclo[2.2.1]heptenes (norbornene), enables three-component Povarov
reaction with in situ formed N-arylimines under Lewis acid catalyzed conditions (BF3 OEt2). The
3
reactions proceed efficiently with a diverse set of commercially available anilines and benzaldehydes,
as well as a variety of substituted norbornenes. The corresponding tetrahydroquinolines are formed
with high complexity in a multicomponent fashion and are obtained in good yield and high
diastereoselectivity. In addition, more reactive ethyl glyoxylate derived imines were utilized to
achieve faster, room temperature reactions with norbornene. In all cases, attack of the N-arylimine
dienes occurred exclusively from the exo-face of the norbornene ring, but the relative stereochemistry
of the substituent R to the tetrahydroquinoline nitrogen, as well as the regioselectivity of reaction, was
shown to depend upon subtle substituent effects on the aniline precursors. In most cases, a preference
for the formation of exo-exo diastereomeric adducts was observed, but for reactions of ortho- or
meta-substituted anilines, the formation of exo-endo adducts was also observed. These observations
may be rationalized by two competing mechanistic models, involving either a concerted asynchro-
nous [4 þ 2]-like mechanism or a stepwise mechanism.
Introduction
coupling of electron-deficient N-arylimines (2-azadienes) and
electron-rich alkenes (Scheme 1).3 The Povarov reaction is
usually promoted by either protic or Lewis acidic catalysis and
can be performed in a multicomponent fashion by the coupling
of alkenes, aldehydes, and anilines via in situ imine formation
and subsequent formal [4 þ 2]-cycloaddition. The formal [4 þ
2]-cycloaddition can be viewed as occurring either through a
concerted inverse-electron demand Diels-Alder reaction me-
chanism or via a stepwise Mannich-like reaction/intramolecu-
lar electrophilic aromatic substitution sequence. While a wide
variety of anilines and aldehydes are known to participate in
the Povarov reaction, the dienophile component is usually
limited to activated, electron-rich alkenes, such as cyclic and
acyclic enamines, enamides and enol ethers, and cyclic con-
jugated dienes.
Hetero-Diels-Alder reactions of azadienes constitute one of
the most convenient approaches to the synthesis of nitrogen
heterocycles.1 One variant of these reactions is the Povarov
reaction, in which tetrahydroquinolines2 are formed by the
(1) For a review on the hetero-Diels-Alder reaction, see: (a) Weinreb, S.
M. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L.
A., Eds.; Permagon Press: Oxford, 1991; Vol. 5; pp 401-449. (b) Boger, D. L. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A.,
Eds.; Permagon Press: Oxford, 1991; Vol. 5; pp 451-512. (c) Buonora, P.; Olsen,
J.-C.; Oh, T. Tetrahedron 2001, 57, 6099–6138. (d) Jorgensen, K. A. Angew.
Chem., Int. Ed. 2000, 39, 3558–3588. (e) Cycloaddition Reactions in Organic
Synthesis; Kobayashi, S., Jorgensen, K. A., Eds.; Wiley-VCH: Weinheim,
Germany, 2002; pp 151-209.
(2) For recent reviews of tetrahydroquinoline synthesis, see: (a) Katritz-
ky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron 1996, 52, 15031–15070. (b)
Kouznetsov, V. V.; Mendez, L. Y. V.; Gomez, C. M. M. Curr. Org. Chem.
2005, 9, 141–161.
Generally, the use of simple alkenes as dienophiles has met
with limited success in the Povarov reaction. However, the
limitation of requiring activated, electron-rich dienophiles
for the Povarov reaction can be overcome through the
(3) For reviews on the Povarov reaction, see: (a) Glushkov, V. A.;
Tolstikov, A. G. Russ. Chem. Rev. 2008, 77, 137–159. (b) Povarov, L. S.
Russ. Chem. Rev. 1967, 36, 656-670 and references cited therein.
702 J. Org. Chem. 2010, 75, 702–715
Published on Web 12/29/2009
DOI: 10.1021/jo9021106
r
2009 American Chemical Society

Smith et al.
JOCArticle
SCHEME 1. Formation of Tetrahydroquinolines from the
Povarov Reaction
SCHEME 2. Three-Component Povarov Reaction of N-Aryli-
mines with Norbornene
introduction of ring strain in the dienophile.4-7 Examples of
strained dienophiles used in the Povarov reaction include
methylenecyclopropanes and azetidines.4 The use of ring-
strained bicyclic alkenes provides another general strategy
for dienophile activation. Increasing the reactivity of alkenes
through the introduction of ring strain is known for many
reactions. Perhaps one of the most well-used classes
of moderately strained alkenes is bicyclo[2.2.1]heptenes
(norbornenes). For example, norbornene has recently been
used as an activated dienophile in 1,3-dipolar cycloadditions
of nitrile oxides8 and has been shown to be more reactive
toward allylic hydroxylamines in a thermal tandem Cope-
type hydroamination/[2,3]-rearrangement sequence.9 Nor-
bornene is also required as an additive in the palladium-
catalyzed Catellani reaction.10 There are few examples on the
use of norbornene as a dienophile in the Povarov reaction,
and selectivity effects in these reactions have not been
studied.5,6 We now report the use of moderately strained
bicyclo[2.2.1]heptenes11 as dienophile components in the
three-component Povarov reaction using Lewis acid cataly-
sis, including investigations on the regio- and diastereos-
electivity of these reactions, and the use of substituted
norbornenes. The resultant products have complex natural
product-like12 tetracyclic architectures that could have inter-
esting biological properties.
initial bond-forming event between C-6 and C-6a (Scheme 2).
However, the strong inherent preference of norbornene to react
via the exo-face would be expected to limit the observed
diastereomers to exo-endo-1 and exo-exo-1.14,15
Initial screening studies using a three-component coupling
approach revealed that a range of Lewis acids were capable
of promoting the reaction between methyl 4-aminobenzoate
2 (1.0 equiv), 4-bromobenzaldehyde 3 (1.1 equiv), and excess
Results and Discussion
The Povarov reaction of the parent bicyclo[2.2.1]heptene,
norbornene, can potentially lead to four possible diastereomers
of 1,13 arising from the facial selectivity of addition to either
face of norbornene and the relative stereochemistry of the
norbornene (Table 1). Using BF3 OEt2, exo-exo-1a was
3
obtained in 38% yield along with 3% of the corresponding
quinoline 5 and 11% of 6, presumably resulting from reduc-
tion of the in situ formed imine (Table 1, entry 1).16 Raising
the temperature to 45 °C increased the yield of 1a to
85% (Table 1, entry 2). Metal and lanthanide triflates
(4) For examples using activated strained alkenes, see: (a) Trifonov, L. S.;
Orahovats, A. S. Heterocycles 1984, 22, 355–364. (b) Stevenson, P. J.;
Nieuwenhuyzen, M.; Osborne, D. Chem. Commun. 2002, 444–445. (c) Shao,
L.-X.; Shi, M. Adv. Synth. Catal. 2003, 345, 963–966. (d) Shao, L.-X.; Xu, B.;
Shi, M. Org. Lett. 2003, 5, 579–582. (e) Lu, J.-M.; Shi, M. Org. Lett. 2007, 9,
1805–1808.
(5) Single examples on the use of norbornadiene and norbornene have
been reported, both of which are reported to occur via unusual endo-facial
attack on the alkene. See: (a) Destro, F.; Prato, M.; Lucchini, V. Tetrahedron
Lett. 1984, 25, 5573–5576. (b) Campos, P. J.; Lamaza, I.; Rodriguez, M. A.;
Canal, G. Tetrahedron Lett. 1997, 38, 6741–6744.
(6) A trifluoroacetic acid (1.0 equiv) promoted coupling of anilines,
aldehydes, and norbornene has been applied to the synthesis of bridged
phenanthridines; however, the diastereoselectivity of the reaction and rela-
tive stereochemistry of the adducts were not reported. See: Ralbovsky, J. L.;
Beckett, R. P. U.S. Patent 20080214537, September 4, 2008.
(11) (a) An indication of the strain release on going from a norbornene
system to a norbornane is apparent from the heat of hydrogenation, which
was determined to be -33.1 kcal mol-1. This strain release is 6 kcal mol-1
higher than the conversion of cyclohexene to cyclohexane: Turner, R. B.;
Meador, W. R.; Winkler, R. E. J. Am. Chem. Soc. 1957, 79, 4116–4121. (b)
The strain energy of norbornene has been recently calculated as 21.6 kcal
mol-1 (B3LYP/6-31G*): Khoury, P. R.; Goddard, J. D.; Tam, W. Tetra-
hedron 2004, 60, 8103–8112.
(12) For recent reviews on reactions suitable for diversity and target-
oriented synthesis, see: (a) Shaw, J. T. Nat. Prod. Rep. 2009, 26, 11–26. (b)
Nandy, J. P.; Prakesch, M.; Khadem, S.; Reddy, P. T.; Sharma, U.; Arya, P.
Chem. Rev. 2009, 109, 1999–2060.
(7) (a) For a related reaction of N-arylnitrilium salts with norbornene,
see: Moustafa, A. H.; Hitzler, M. G.; Lutz, M.; Jochims, J. C. Tetrahedron
1997, 53, 625–640. (b) For a related reaction using an azomethine ylide with
norbornene, see: Pohlhaus, P. D.; Bowman, R. K.; Johnson, J. S. J. Am.
Chem. Soc. 2004, 126, 2294–2295. (c) For a related metalloporphyrin-
catalyzed radical reaction of para-cyano-N,N-dimethylaniline with norbor-
nene, see: Dicken, C. M.; Lu, F.-L.; Bruice, T. C. Tetrahedron Lett. 1986, 27,
5967–5970.
(13) This assumes that syn-addition of the imine diene occurs across the
alkene of the norbornene.
(14) The following notation is used to differentiate between the possible
diastereomers. The first term results from the mode of facial selectivity for
addition to the norbornene system (exo or endo), while the second term (exo
or endo) is defined on the basis of the Diels-Alder reaction, where H-6 and
H-6a have a trans and cis relationship, respectively.
(15) Campos has suggested that a highly unusual endo-facial attack on the
norbornene occurs in reaction of N-(methoxymethyl)arylamines; see ref 5b.
We did not observe any formation of endo-endo-1 or endo-exo-1 diastereo-
mers in our study.
(8) Mayo, P.; Hecnar, T.; Tam, W. Tetrahedron 2001, 57, 5931–5941.
ꢀ
(9) Bourgeois, J.; Dion, I.; Cebrowski, P. H.; Loiseau, F.; Bedard, A.-C.;
Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 874–875.
(10) (a) Catellani, M.; Fagnola, M. C. Angew. Chem., Int. Ed. Engl. 1994,
33, 2421–2422. (b) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 119–122.
(16) This diastereomer was assigned based on comparison to other related
tetrahydroquinolines and their H-6-H-6a and H-6a-H-10a coupling con-
stants (typically J = 10-11 Hz and J = 8-9 Hz, respectively).
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TABLE 1. Optimization of Three-Component Povarov Reaction of 2, 3 and Norbornene
yield (%)a
entry
catalyst (mol %)
temp (°C)
(1a/5/6)b
1
2
3
4
5
6
7
8
BF3 OEt2 (20)
3
rt
38 (38:4:11)
85 (85:6:9)
42 (42:2:5)c
81 (81:6:13)
71 (71:6:10)
32 (32:4:9)
NRd
BF3 OEt2 (20)
45
45
45
45
45
45
45
3
Yb(OTf)3 (10)
Sc(OTf)3 (10)
Cu(OTf)2 (10)
TfOH (10)
CAN (10)e
BF3 OEt2 (20) þ DDQ (2 equiv)
36f
3
aYields determined by 1H NMR integration relative to 1,3,5-trimethoxybenzene as an internal standard. bDetermined by relative 1H NMR
f
integrations (H-6 or H-10a). c40% of the in situ formed imine present. dIn situ formed imine 4 (not shown) was isolated. ePerformed in CH3CN. Isolated
yield of quinoline 5.
were also competent catalysts (Table 1, entries 3-5), with
Sc(OTf)3 giving the highest yield. On the other hand, protic
acids such as triflic acid were less effective as catalysts
(Table 1, entry 6), perhaps due to competing oligomerization
reactions.6 For each of these reactions (Table 1, entries 1-6),
small amounts of quinoline 5 and amine 6 were also formed
in an approximately 1:2 ratio. The formation of these side
products is most likely the result of a hydrogen transfer
mechanism.17 Variation of the reaction stoichiometry, sol-
vent, and the temperature did not significantly affect the
formation of these side products. The use of cerium ammo-
nium nitrate (CAN),18 which can act as both a Lewis acid
and an oxidant, was unsuccessful (Table 1, entry 7). How-
the norbornene ring was observed;16 however, the relative
stereochemistry of the C-6 substituent with respect to C-6a/
C-10a was not always selective. Sole formation of the exo-
exo diastereomer of 1a-i was observed with all anilines
containing para substituents. X-ray crystallography of 1d
revealed an exo-exo relative stereochemistry19 and validated
the stereochemical assignment for all of the other exo-exo
diastereomers. Next, a survey of differentially substituted
chloroanilines was conducted. ortho-Chloroanilines gave a
mixture of diastereomers (Table 2, entries 10-12), with a
modest preference for the formation of the exo-exo-1 dia-
stereomer. Following separation of the diastereomers of 1l
by column chromatography, the stereochemistry of the
exo-endo diastereomer was confirmed by X-ray crystallogra-
phy.19 Unexpectedly, a complete reversal in diastereoselec-
tivity was observed for the reaction of the di-meta-
substituted 3,5-dichloroaniline, which exclusively afforded
exo-endo-1m (Table 2, entry 13). The use of 2,5-dichloroani-
line, which has both ortho- and meta-chloro substituents,
resulted in the preferential formation of the exo-exo diaster-
eomer 1n in a 76:24 dr (Table 2, entry 14). In this case, the
exo-exo directing effect of the ortho-chloro substituent ap-
pears to override the exo-endo directing effect of the meta-
chloro substituent. Modest regioselectivity was observed20
for the Povarov reaction with meta-substituted anilines
(Table 2, entries 15-17), although each regioisomer was
formed with remarkably high diastereoselectivity. The
3-substituted regioisomers were formed as the exo-exo-1 dia-
stereoisomers (g98:2), whereas the 1-substituted regioi-
somers were formed as the exo-endo-1 diastereoisomers
ever, a combination of BF3 OEt2 and DDQ led to the
3
exclusive formation of quinoline 5 (Table 1, entry 8). At-
tempts to apply the optimized BF3 OEt2-based conditions to
3
less reactive dienophiles such as cyclohexene and cyclopen-
tene were unsuccessful.
Application of the optimized conditions of BF3 OEt2
3
(20 mol %) in CH2Cl2 at 45 °C for 22 h to a variety of
commercially available aromatic aldehydes and anilines with
norbornene led to the formation of tetrahydroquinolines
1a-t in good to excellent yields (Table 2). The electronic
nature of the aniline and aromatic aldehyde had little effect
upon product formation. However, the position of the
substituents on the aniline did affect the diastereoselectivity
of the reaction. In all cases, exclusive exo-facial selectivity on
(17) For similar hydrogen transfer mechanisms, see: (a) Shindoh, N.;
Tokuyama, H.; Takemoto, Y.; Takasu, K. J. Org. Chem. 2008, 73, 7451–
7456. (b) Itoh, T.; Nagata, K.; Kurihara, A.; Miyazaki, M.; Ohsawa, A.
Tetrahedron Lett. 2002, 43, 3105–3108.
(18) For recent examples of CAN-catalyzed Povarov reactions, see: (a)
ꢀ
Sridharan, V.; Avendano, C.; Menendez, J. C. Synlett 2007, 1079–1082. (b)
Savitha, G.; Perumal, P. T. Tetrahedron Lett. 2006, 47, 3589–3593.
(19) For details of single-crystal X-ray analysis, see the Supporting
Information.
(20) Hayashi, R.; Cook, G. R. Org. Lett. 2007, 9, 1311–1314.
704 J. Org. Chem. Vol. 75, No. 3, 2010

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TABLE 2. Formation of Tetrahydroquinolines 1 from the BF3 OEt2-Catalyzed Three-Component Coupling Reaction of Anilines, Aromatic Aldehydes,
3
and Norbornenea
entry
aniline (R1)
aldehyde (R2)
product
yieldb (%)
drc (exo-exo:exo-endo)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4-CO2Me
4-CO2Me
H
4-CO2Me
4-CO2Me
4-OMe
4-Cl
4-Cl
4-Cl
2-Cl
2-Cl
2,4-Cl
3,5-Cl
2,5-Cl
3,4-Me
3-Cl
4-Br
H
H
3,4-Cl
4-NO2
4-Br
2-OMe
4-Br
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
60(85)d
74
76
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
g98:2
72:28
59:41
55:45
2:98
74(87)d
81
69
58
78e
82
3,4-Cl
4-Br
70e
59
3,4-Cl
3,4-Cl
3,4-Cl
3,4-Cl
4-Br
65
91
55
82
82
76
76:24
1o/1p
1q/1r
1s/1t
g98:2/e2:98f
g98:2/e2:98g
g98:2 /g 98:2h
4-Br
4-Br
3-F
aAniline (1.0 equiv), aldehyde (1.1 equiv), norbornene (2.0 equiv). bIsolated yields based on the aniline. cDetermined by the relative integrations of H-6
in the 1H NMR of the crude reaction mixture. dEstimated yield (by 1H NMR) in parentheses. e10% of the corresponding quinoline was isolated. fIsolated
as a 60:40 mixture of 2,3-Me (1o)/1,2-Me (1p). gIsolated as a 36:64 mixture of 3-Cl (1q)/1-Cl (1r) regioisomers. hIsolated as a 56:44 mixture of 3-F (1s)/1-F
(1t) regioisomers.
(g98:2). However, in the case of the reactions of meta-
fluoroaniline, only exo-exo-1 diastereomers were observed
for both regioisomers (Table 2, entry 17).
characteristic of the syn relationship of these protons in a
pseudo-axial-equatorial relationship. These observations
are in agreement with the observed 1H NMR coupling
constants of the exo and endo products in the furo[3,2-
c]quinolines and pyrrolo[3,2-c]quinolines previously studied
in our group.21
1H NMR analysis of the Povarov adducts 1 was generally
sufficient to distinguish between the exo-exo-1 and exo-endo-1
diastereomers. The most diagnostic observations for the de-
termination of the relative stereochemistry were the chemical
shift of the H-6 proton and the coupling constant between
protons H-6 and H-6a. The chemical shift of the H-6 proton
was consistently more downfield in the exo-endo series
by approximately 0.6 ppm (e.g., H-6; exo-endo = 4.16 ppm,
exo-exo = 3.50 ppm for 1l). The coupling constant values for
3JH6-6a were in the range of 4-5 Hz for theexo-endo series and
10-11 Hz in the exo-exo series (e.g., 3JH6-6a = 4.5 Hz for exo-
1
In several cases, additional H 2D ROESY experiments
were also used to confirm the relative stereochemical assign-
ments. For example, a comparison of the ROESY spectra for
both diastereomers of 1j revealed ROE enhancements for
both H-6a and H-10a with the proximal protons on the
ethano bridge of the norbornene ring (blue arrows) and
strong ROE enhancements between the H-6a and H-10a
protons (pink arrows), thus confirming that the tetrahydro-
quinoline core was attached to the exo-face of norbornene
(Figure 1). A strong ROE correlation between H-6 and the
proximal hydrogen of the methano bridge (red arrow) was
diagnostic for the exo-exo diastereoisomer. For the exo-endo
diastereoisomer, diagnostic strong ROE correlations were
observed between both H-6 and H-6a (red arrow) and a weak
ROE correlation between H-6 and H-10a (black arrow).
Substituted norbornenes were also investigated as part-
ners in the Povarov reaction (Table 3). Reaction with
norbornadiene 7a produced the corresponding exo-exo ad-
duct 8a in 35% yield (Table 3, entry 1). The formation of a
3
endo-1l and JH6-6a = 10.0 Hz for exo-exo-1l). For a rigid
cyclohexane, these coupling constant values are indicative of a
pseudo-axial-equatorial coupling and pseudo-axial-axial
coupling, respectively.
In addition to confirming the relative stereochemical
assignments, a comparison of the X-ray crystallographic
structures of compounds exo-exo-1d and exo-endo-1l re-
vealed that in both cases the tetrahydroquinoline ring adopts
a half-chair conformation, with the C-6 aryl substituent in a
pseudo-equatorial position.19 The torsional angle (H-6-C-
6-C-6a-H-6a) for the solid state structure of exo-exo-1d
was determined to be 165.5°, which is consistent with the
3
(21) (a) Simoncic, P. D.; Lin, D.; Smyj, R. P.; Lough, A. J.; Batey, R. A.
Chem. Commun. 1999, 651–652. (b) Powell, D. A.; Batey, R. A. Chem.
Commun. 2001, 2362–2363. (c) Powell, D. A.; Batey, R. A. Tetrahedron Lett.
2001, 42, 7935–7939. (d) Powell, D. A.; Batey, R. A. Org. Lett. 2002, 4, 2913–
2916. (e) Powell, D. A. Multi-component Hetero Diels-Alder Reaction of N-
Arylimines: Synthesis of Functionalized Tetrahydroquinolines and Total Synth-
esis of the Martinelline Alkaloids. Ph.D. Thesis, University of Toronto, 2003, pp
38-42.
observed JH6-6a coupling constants of 10-11 Hz for the
exo-exo series, with H-6 and H-6a adopting pseudo-axial
positions with an anti relationship. In contrast, the measured
(H-6-C-6-C-6a-H-6a) torsional angle for exo-endo-1l was
determined to be 43.8°, which is consistent with the observed
3JH6-6a coupling constants of 4-5 Hz for the exo-endo series,
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Substituent effects on the aniline-derived ring appear to
play a remarkable role upon the diastereoselectivity achieved
in these reactions. As for other Povarov reactions, there are
two general mechanisms that can be envisaged for the
formation of the adducts: (i) a concerted [4 þ 2]-like mechan-
ism or (ii) a stepwise Mannich-like process. For the [4 þ 2]-
like process, asynchronous C-6-C-6a and C-10a-C-10b
bond formation can be envisaged. For the [4 þ 2]-like mecha-
nism orienting the Lewis acid coordinated imine CdN and
imine C-Ar groups away from the bridging methylene
(C-11) of norbornene would be expected to minimize steric
interactions in the exo-exo-TS transition state (Figure 2a).
Reaction via exo-exo-TS would lead initially to interme-
diate 14, which after loss of a proton would lead to exo-exo-1.
An analogous [4 þ 2]-like transition state leading to exo-
endo-1 is unlikely on steric grounds. For the stepwise
Mannich-like mechanism, orienting the Lewis acid coordi-
nated imine CdN and imine C-Ar groups away from the
bridging methylene of norbornene, such that the CdN bond
is antiperiplanar to the norbornene CdC bond in the exo-
endo-TS, would minimize steric interactions (Figure 2b).
Reaction via exo-endo-TS would lead initially to intermedi-
ate 15 via C-6-C-6a bond formation. Bond rotation of 15 to
16, followed by C-10a-C-10b bond formation to 17 and
proton loss would then lead to exo-endo-1.
The diastereoselectivity observed in most cases suggests an
inherent preference for reaction via a concerted [4 þ 2]-like
transition state exo-exo-TS over the stepwise exo-endo-TS
transition state. This preference may be accounted for by
destabilization of the exo-endo-TS transition state due to the
greater charge separation and potentially increased steric
interaction between the N-Ar group and the norbornene,
relative to the exo-exo-TS transition state. Introduction of a
single meta-N-aryl substituent as for methyl and chlorine
(Table 2, entries 15 and 16) leads to the formation of
regioisomeric 1- and 3-substituted products, both formed
with very high, yet opposite, diastereoselectivities. Thus, for
formation of the 3-substituted regioisomers 1o, 1q, and 1s,
reaction occurs to give exclusive formation of the exo-exo-
isomers. In these cases, the presence of a meta substituent at
position R3 would not exert any significant additional steric
destabilization of the exo-exo-TS. On the other hand, forma-
tion of the 1-substituted regioisomers 1p and 1r occurs pre-
ferentially to give exclusive formation of the exo-endo-isomers.
In these cases, unfavorable steric interactions between the R1
substituent and the norbornene ring system in exo-exo-TS
would result in preferential reaction via exo-endo-TS. This
notion is further supported by the result obtained with the di-
meta-N-aryl-substituted case (R1/R3 = Cl) for which exclusive
formation of the diastereomer exo-endo-1m occurs. In the case
of the 1-fluoro-substituted regioisomer 1t, exclusive formation
of the exo-exo diastereomer was nevertheless observed, which
is not unexpected based on steric arguments since fluorine is
isosteric with hydrogen. Introduction of an ortho-N-aryl sub-
stituent R4 = Cl leads to an erosion in stereoselectivity, as
exemplified by the formation of diastereomeric mixtures for
1j, 1k, 1l, and 1n. In these cases, the presence of the R4 = Cl
substituent presumably results in the N-Ar ring tilting out of
the plane of the CdN system to avoid any destabilizing syn-
pentane-like interaction between the C-Cl and N-BF3 bonds
in exo-exo-TS (and exo-endo-TS). As a result, a concerted
[4 þ 2]-like mechanism is disfavored, and the differentiation
FIGURE 1. Relevant ROE enhancements for exo-exo-1j and exo-
endo-1j.
significant amount of amine 6 (25%) and quinoline 9 (10%)
was responsible for the low yield of 8a obtained. The unusual
formation of 9 most likely arises from an oxidation to the
3,4-dihydroquinoline followed by a retro-[4 þ 2]-cycloaddi-
tion. Both endo- and exo-dicyclopentadiene afforded the
corresponding tetrahydroquinolines 8b and 8c in 63 and
75% yield (Table 3, entries 2 and 3), respectively. In both
cases, an inseparable mixture of regioisomers (2:1) was
isolated. Of particular note is the high chemoselectivity
observed, as only reaction with the norbornene alkene bond
occurs, thus demonstrating the activating effect of increased
strain on the bicyclic skeleton. In order to simplify charac-
terization, the regioisomers of both 8b and 8c were subjected
to diimide reduction using potassium azodicarboxylate
(PADA) to give the reduced adducts 10 and 11, respectively
(Scheme 3).22 Reaction of endo-norbornene methanol 7d
gave 8d as a mixture of regioisomers (1.1:1) in a combined
yield of 50% (Table 3, entry 4).23 Interestingly, only one
regioisomer of 8e was isolated when the corresponding
p-nitrobenzoyl-protected substrate 7e was used (Table 3,
entry 5). Both the endo- and exo-isomers of cyclic anhy-
dride-substituted norbornene 7f were found to be completely
unreactive (entry 6), presumably due to the deactivating
effect of the electron-withdrawing carbonyl groups. How-
ever, the bis(methoxymethyl)-substituted norbornene 7g
proved to be more reactive, resulting in a 68% yield of 8g
(Table 3, entry 7).
An approach to complement the generally lower reactivity
of norbornenes (compared to electron-rich dienophiles) is to
utilize more reactive imines. The use of ethyl glyoxylate
derived imines led to faster reactions even at room tempera-
ture (Scheme 4). However, isolation of the ethyl ester sub-
stituted tetrahydroquinolines 12a and 12b (not shown)
proved to be difficult because of their instability in air and
in solution, resulting in lower yields.24 Instead, immediate
reduction of the crude Povarov reaction mixture using
LiAlH4 in THF led to adducts 13a and 13b, which were
isolated in 60 and 55% yield as a 5:1 and 4.5:1 mixture of
diastereoisomers, respectively. X-ray crystallography of the
major stereoisomer of 13a confirmed the exo-exo relative
stereochemical assignment.19
(22) For the preparation of potassium azodicarboxylate (PADA), see: (a)
Dieck, H. A.; Heck, R. F. J. Org. Chem. 1975, 40, 1083–1090. For PADA
reduction procedure, see: (b) Patterson, I.; Anderson, E. A.; Dalby, S. M.;
Lim, J. H.; Genovino, J.; Maltas, P.; Moessner, C. Angew. Chem., Int. Ed.
2008, 47, 3016–3020.
(23) In addition, no other side products were isolated as might have been
envisaged had an intramolecular trapping by the hydroxyl group occurred in
the case of a stepwise Povarov mechanism.
(24) The ethyl ester substituted tetrahydroquinolines 12a and 12b were
isolated with acceptable purity and in 44 and 40% yield, respectively. See the
Experimental Section for characterization data and the Supporting Informa-
tion for copies of 1H and 13C NMR spectra.
706 J. Org. Chem. Vol. 75, No. 3, 2010

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TABLE 3. Povarov Reactions of Substituted Norbornenesa
aConditions: aniline (1.0 equiv), aldehyde (1.1 equiv), norbornene (2.0 equiv), BF3 OEt2 (20 mol %), 45-75 °C, CH2Cl2, 22-72 h. bIsolated yields
3
based on the aniline. c10% of quinoline 9 and 25% of amine 6 were isolated. dFormed as a separable 1.1:1 mixture of 8- and 9-substituted regioisomers.
between the skewed exo-exo and exo-endo transition states is
low, leading to low intrinsic diastereoselectivity.
The regioselectivity of Povarov reactions with meta-sub-
stituted anilines is little studied.3 In the current study, the regio-
selectivity of formation of the 1-substituted to 3-substituted
adducts was roughly 2:1 for Cl (Table 2, entry 16), 4:5 for F
(Table 2, entry 17), and 2:3 for Me (Table 2, entry 15).
Interestingly, a comparable trend in regioselectivities with
intramolecular Friedel-Crafts reaction has been repor-
ted.20 In this study, an In(III)-promoted cyclization of
J. Org. Chem. Vol. 75, No. 3, 2010 707

Smith et al.
JOCArticle
FIGURE 2. Transition state models and mechanistic rationale for the formation of exo-exo-1 and exo-endo-1.
SCHEME 3. Reduction of Dicyclopentadiene Adducts 8b and 8c
of endo adducts.25 In general, the formation of endo adducts
is often believed to occur via an asynchronous concerted
pathway, whereas the corresponding formation of the more
thermodynamically stable exo adducts is believed to occur
via a stepwise pathway. However, for the reactions of
norbornenes, preferential formation of exo-exo adducts
occurs via an asynchronous concerted [4 þ 2] pathway. This
difference in selectivity can be attributed to the additional
steric constraints, in the respective transition states, imposed
by the bicyclic nature of the norbornene ring, particularly the
bridging methylene (C-11). Povarov reaction of norbornene
via the exo-endo transition state is operative only in cases
where meta and ortho substituents are present on the aniline
ring. To the best of our knowledge, this effect has not been
observed with other Povarov reactions.
Conclusion
SCHEME 4. Three-Component Povarov Reaction with Ethyl
Glyoxylate Derived Imines
In summary, bicyclo[2.2.1]hepta-5-ene systems are de-
monstrated to behave as activated dienophiles in the three-
component Povarov reaction. They have greater reactivity
than simple alkenes but lower reactivity than the dienophiles
typically used in the Povarov reaction. The products are
highly functionalized natural product-like tetracyclic sys-
tems, which may be useful as biologically relevant targets.
For example, they have been demonstrated as cannabinoid
receptor ligands with potential therapeutic implications for
inflammatory conditions, including pain, arthritis, and asth-
ma.6 The diastereoselectivity and regioselectivity of the
Povarov reactions of norbornenes are influenced by subtle
steric/electronic effects on the substitution pattern of the
meta-substituted aromatic rings onto a tethered allylic bro-
mide functionality led to the formation of a new six-mem-
bered ring. The regioselectivities of the corresponding
1-substituted and 3-substituted products were 2:1 from the
meta-Cl, 1:4 from the meta-F, and 1:2 from the meta-Me-
substituted precursors.
The results obtained in the present study are different than
those found for many known Povarov reactions, where
Lewis acidic catalysis leads preferentially to the formation
(25) The mechanistic pathway and diastereoselectivity for Povarov reac-
tions can also be dependent on other factors, such as the choice of Lewis acid,
the polarity of the solvent, and the nature of the diene and dienophile used.
708 J. Org. Chem. Vol. 75, No. 3, 2010

Smith et al.
JOCArticle
precursor anilines. Furthermore, the diastereoselectivity ob-
tained is shown to differ from that typically observed in
Lewis acid catalyzed Povarov reactions, a factor which is
attributed to additional steric interactions that occur in the
transition states for the norbornene-based reactions and the
competing concerted and stepwise pathways. Further inves-
tigations are ongoing to establish whether these selectivity
differences occur in a more general sense or whether other
strained alkenes, such as cyclobutenes and cyclopropenes,
can be used.
a colorless oil (53 mg, 76%): Rf = 0.61 (90:10 hexanes/EtOAc);
IR (thin film) νmax 3346, 3026, 2951, 2868, 1604, 1587, 1493,
1
1468, 1451, 1346, 1296, 1255, 1103, 751, 700 cm-1; H NMR
(400 MHz, CDCl3) δ 7.44 (2H, dd, J = 8.5, 1.5 Hz), 7.24-7.39
(4H, m), 6.99 (1H, dd, J = 7.5, 1.0 Hz), 6.80 (1H, ddd, J = 7.5,
1.5, 1.0 Hz), 6.56 (1H, dd, J = 8.0, 1.0 Hz), 3.68 (1H, br s), 3.57
(1H, d, J = 10.5 Hz), 2.67-2.71 (2H, m), 2.19 (1H, dd, J = 9.5,
9.5 Hz), 2.07 (1H, d, J = 4.5 Hz), 1.62-1.71 (2H, m), 1.38-1.56
(2H, m), 1.14-1.22 (1H, m), 1.10 (1H, tt, J = 10.0, 1.5 Hz); 13
C
NMR (100 MHz, CDCl3) δ 147.9, 144.5, 128.7, 128.6, 128.1,
127.8, 127.3, 126.3, 119.5, 115.4, 61.8, 53.9, 44.2, 42.6, 39.4, 34.1,
30.0, 29.3; MS (EIþ) m/e (rel intensity) 276 (24), 275 (100), 274
(20), 206 (74), 198 (60), 130 (24), 91 (31); HRMS (EI) m/e calcd
for C20H21N [Mþ] 275.1674, found 275.1673.
Experimental Section
Methyl 6-(3,4-dichlorophenyl)-5,6,6a,7,8,9,10,10a-octahydro-
7,10-methanophenanthridine-2-carboxylate (exo-exo-1d). Purifi-
cation by flash column chromatography on silica gel using a
gradient elution of 5 to 20% ethyl acetate in hexanes afforded
the title compound (79 mg, 74%) as a white solid: mp 223-224
°C; Rf = 0.26 (90:10 hexanes/EtOAc); IR (thin film) νmax 3356,
2950, 2864, 1713, 1605, 1435, 1256, 1010, 770 cm-1; 1H NMR
(300 MHz, CDCl3) δ 7.99 (1H, s), 7.70 (1H, ddd, J = 8.0, 2.0, 1.0
Hz), 7.54 (1H, d, J = 2.0 Hz), 7.45 (1H, d, J = 8.0 Hz), 7.25 (1H,
dd, J = 8.0, 2.0 Hz), 6.58 (1H, d, J = 8.5 Hz), 4.00 (1H, br s),
3.88 (3H, s), 3.60 (1H, d, J = 10.0 Hz), 2.77 (1H, d, J = 3.5 Hz),
2.70 (1H, d, J = 8.5 Hz), 2.12 (1H, dd, J = 9.5, 9.5 Hz), 2.06 (1H,
d, J = 4.0 Hz), 1.40-1.72 (4H, m), 1.15-1.24 (1H, m), 1.14 (1H,
d, J = 10.0 Hz); 13C NMR (75 MHz, CDCl3) δ 167.6, 150.7,
144.2, 132.9, 132.0, 131.1, 130.8, 129.9, 128.5, 127.4, 126.2,
121.1, 115.0, 60.1, 53.5, 51.9, 43.8, 43.1, 39.7, 34.0, 29.9, 29.1;
MS (EIþ) m/e (rel intensity) 403 (66), 402 (31), 401 (100), 398
(20), 396 (28), 371 (38), 369 (24), 368 (56), 333 (46), 331 (60), 308
(25), 306 (31), 275 (31), 256 (72), 238 (19), 236 (24), 188 (46), 164
(21), 91 (29); HRMS (EI) m/e (Mþ) calcd (for C22H2135Cl2NO2)
401.0956, found 401.0949.
Methyl 6-(4-nitrophenyl)-5,6,6a,7,8,9,10,10a-octahydro-7,10-
methanophenanthridine-2-carboxylate (exo-exo-1e). Purification
by flash column chromatography on silica gel using a gradient
elution of 5 to 20% ethyl acetate in hexanes afforded the title
compound (79 mg, 81%) as a yellow solid: mp 227-229 °C; Rf
= 0.08 (95:5 hexanes/EtOAc); IR (thin film) νmax 3355, 2951,
2870, 1709, 1606, 1520, 1435, 1347, 1302, 1257, 1197, 1104, 849,
773, 740, 700 cm-1; 1H NMR (300 MHz, CDCl3) δ 8.21 (2H, d,
J = 8.5 Hz), 7.98 (1H, s), 7.70 (1H, dd, J = 8.5, 1.0 Hz), 7.59
(2H, dd, J = 8.5 Hz), 6.61 (1H, d, J = 8.5 Hz), 4.13 (1H, br s),
3.87 (3H, s), 3.77 (1H, d, J = 9.5 Hz), 2.76 (1H, d, J = 3.5 Hz),
2.72 (1H, d, J = 9.0 Hz), 2.13 (1H, d, J = 9.5, 9.0 Hz), 2.08 (1H,
d, J = 3.5 Hz), 1.36-1.81 (4H, m), 1.09-1.28 (2H, m); 13C
NMR (100 MHz, CDCl3) δ 167.3, 151.2, 150.2, 147.6, 130.6,
128.6, 128.4, 126.0, 123.9, 121.1, 114.9, 60.3, 53.2, 51.7, 43.6,
43.1, 39.6, 33.8, 29.6, 28.9; MS (EIþ) m/e (rel intensity) 379 (17),
378 (100), 309 (26), 256 (16), 149 (18), 84 (16); HRMS (EI) m/e
calcd for C22H22N2O4 [Mþ] 378.1580, found 378.1563.
General Procedure for the Three-Component Povarov Reac-
tion. An oven-dried 2-5 mL microwave vial was charged with
the aniline (0.26 mmol, 1 equiv), aldehyde (0.29 mmol, 1.1 equiv),
and norbornene-based dienophile (0.39 or 0.52 mmol, 1.5 or
2.0 equiv), and freshly distilled CH2Cl2 (1.3 mL, 0.2 M) was
added followed by BF3 OEt2 (0.056 mmol, 0.2 equiv). The
3
microwave vial was purged with nitrogen before it was tightly
sealed, and the reaction mixture was heated to 45 °C for 22 h.
The reaction mixture was cooled to room temperature, treated
with a few drops of MeOH, and finally concentrated in vacuo.
The crude residue was dry loaded onto silica and purified by
silica gel flash chromatography.
Methyl 6-(4-bromophenyl)-5,6,6a,7,8,9,10,10a-octahydro-7,
10-methanophenanthridine-2-carboxylate (exo-exo-1a). Purifi-
cation by flash column chromatography on silica gel using a
gradient elution of 5 to 10% ethyl acetate in hexanes afforded
the title compound (65 mg, 60%) as a white solid: mp 215-216
°C; Rf = 0.26 (90:10 hexanes/EtOAc); IR (thin film) νmax 3339,
2958, 1700, 1607, 1510, 1436, 1322, 1291, 1260, 1009, 831, 777
cm-1; 1H NMR (300 MHz, CDCl3) δ 8.00 (1H, s), 7.70 (1H, ddd,
J = 8.5, 2.0, 1.0 Hz), 7.51 (2H, d, J = 8.5 Hz), 7.30 (2H, d, J =
8.5 Hz), 6.56 (1H, d, J = 8.5 Hz), 4.00 (1H, br s), 3.90 (3H, s),
3.60 (1H, d, J = 10.0 Hz), 2.77 (1H, d, J = 4.0 Hz), 2.69 (1H, d,
J = 9.0 Hz), 2.13 (1H, dd, J = 9.5, 9.5 Hz), 2.06 (1H, d, J = 4.0
Hz), 1.39-1.71 (4H, m), 1.14-1.22 (1H, m), 1.13 (1H, d, J =
10.0 Hz); 13C NMR (75 MHz, CDCl3) δ 167.6, 151.0, 142.9,
132.0, 130.8, 129.7, 128.5, 126.3, 121.9, 120.8, 115.0, 60.4, 53.6,
51.9, 43.9, 43.0, 39.7, 34.0, 29.9, 29.1; MS (EIþ) m/e (rel
intensity) 413 (24), 412 (100), 411 (36), 410 (99), 343 (59), 342
(55), 263 (16), 257 (15), 256 (85), 248 (16), 246 (16), 214 (20), 188
(48); HRMS (EI) m/e (Mþ) calcd for C22H2279BrNO2 411.0833,
found 411.0841.
Methyl 6-phenyl-5,6,6a,7,8,9,10,10a-octahydro-7,10-metha-
nophenanthridine-2-carboxylate (exo-exo-1b). Purification by
flash column chromatography on silica gel using a gradient
elution of 5 to 10% ethyl acetate in hexanes afforded the title
compound (65 mg, 74%) as a white solid: mp 171-172 °C; Rf =
0.33 (90:10 hexanes/EtOAc); IR (thin film) νmax 3395, 2950,
2871, 1717, 1699, 1606, 1455, 1301, 1259, 1230, 1175, 1104, 1003,
1
849, 775, 737, 699 cm-1; H NMR (300 MHz, CDCl3) δ 8.00
6-(4-Bromophenyl)-2-methoxy-5,6,6a,7,8,9,10,10a-octahydro-
7,10-methanophenanthridine (exo-exo-1f). Purification by flash
column chromatography on silica gel using a gradient elution of
2 to 5% ethyl acetate in hexanes afforded the title compound (66
mg, 69%) as a yellow solid: mp 128-130 °C; Rf = 0.40 (95:5
hexanes/EtOAc); IR (thin film) νmax 3341, 2951, 2868, 1700,
1612, 1502, 1465, 1281, 1245, 1161, 1098, 1071, 1043, 1009, 875,
823, 736, 690 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.48 (2H, d,
J = 8.5 Hz), 7.31 (2H, d, J = 8.5 Hz), 6.87 (1H, d, J = 2.0 Hz),
6.61 (1H, dd, J = 8.5, 2.5 Hz), 6.52 (1H, d, J = 8.5 Hz), 3.77 (3H,
s), 3.49 (2H, d, J = 10.5 Hz, H-2 þ NH), 2.65-2.70 (2H, m),
2.09 (1H, dd, J = 9.5, 9.5 Hz), 2.01 (1H, d, J = 3.5 Hz), 1.35-
(1H, s), 7.70 (1H, ddd, J = 8.5, 2.0, 1.0 Hz), 7.32-7.45 (5H, m),
6.55 (1H, d, J = 8.5 Hz), 4.08 (1H, br s), 3.87 (3H, s), 3.62 (1H, d,
J = 10.0 Hz), 2.77 (1H, d, J = 4.0 Hz), 2.70 (1H, d, J = 9.0 Hz),
2.20 (1H, dd, J = 9.5, 9.0 Hz), 2.10 (1H, d, J = 4.0 Hz), 1.35-
1.72 (4H, m), 1.11-1.34 (2H, m); 13C NMR (75 MHz, CDCl3) δ
167.7, 151.3, 143.9, 130.8, 128.8, 128.4, 128.0, 126.3, 120.5,
114.9, 61.0, 53.5, 51.8, 43.9, 43.0, 39.7, 34.0, 30.0, 29.1; MS
(EIþ) m/e (rel intensity) 334 (25), 333 (100), 332 (17), 265 (14),
264 (73), 256 (58), 188 (25), 169 (20), 91 (31); HRMS (EI) m/e
calcd for C22H23NO2 [Mþ] 333.1729, found 333.1729.
6-Phenyl-5,6,6a,7,8,9,10,10a-octahydro-7,10-methanophenan-
thridine (exo-exo-1c). Purification by flash column chromatog-
raphy on silica gel using a gradient elution of 3 to 5% ethyl
acetate in hexanes afforded the title compound (65 mg, 60%) as
1.72 (4H, m), 1.14-1.21 (1H, m), 1.10 (1H, d, J = 10.0 Hz); 13
C
NMR (100 MHz, CDCl3) δ 153.2, 143.3, 140.8, 131.5, 129.6,
128.2, 121.3, 115.8, 114.0, 111.8, 61.6, 55.7, 53.5, 44.4, 42.3, 39.1,
J. Org. Chem. Vol. 75, No. 3, 2010 709

Smith et al.
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33.9, 29.6, 29.1; MS (ESIþ) m/e (rel intensity) 387 (21), 386 (94),
385 (25), 384 (100); HRMS (ESI) m/e calcd for C21H22NO79Br
[M þ H]þ 384.0957, found 384.0948.
6.72 (1H, dd, J = 8.0, 8.0 Hz), 4.31 (1H, s), 4.20 (1H, d, J = 4.5
Hz), 3.04 (1H, d, J = 8.5 Hz), 2.23 (1H, d, J = 4.0 Hz), 2.12 (1H,
dd, J = 8.5, 4.5 Hz), 1.95 (1H, d, J = 2.0 Hz), 1.52-1.64 (2H,
m), 1.25-1.45 (2H, m), 0.98-1.09 (1H, m), 0.87 (1H, d, J = 10
Hz); 13C NMR (100 MHz, CDCl3) δ 143.4 (C), 141.7 (C), 131.6
(CH), 130.1 (C), 128.6 (CH), 128.2 (CH), 126.1 (CH), 120.9 (C),
119.8 (C), 119.1 (CH), 58.8 (CH), 50.8 (CH), 49.6 (CH), 47.0
(CH), 36.7 (CH), 34.8 (CH2), 31.3 (CH2), 28.4 (CH2); MS (EIþ)
m/e (rel intensity) 391 (20), 390 (22), 389 (100), 388 (39), 387 (86),
386 (27), 385 (21), 320 (61), 318 (41), 232 (45); HRMS (EI) m/e
calcd for C20H1979Br35ClN [Mþ] 387.0389, found 387.0371.
6-(4-Bromophenyl)-4-chloro-5,6,6a,7,8,9,10,10a-octahydro-7,
10-methanophenanthridine (exo-exo-1j). Purification by flash
column chromatography on silica gel using a gradient elution
of 2 to 4% ethyl acetate in hexanes afforded the title compound
(54 mg, 54%) as a white solid: mp 147-148 °C; Rf = 0.47 (98:2
hexanes/EtOAc); IR (thin film) νmax 3362, 3026, 2952, 2869,
1700, 1597, 1473, 1420, 1400, 1340, 1300, 1262, 1246, 1136, 1106,
2-Chloro-6-(2-methoxyphenyl)-5,6,6a,7,8,9,10,10a-octahydro-
7,10-methanophenanthridine (exo-exo-1g). Purification by flash
column chromatography on silica gel using a gradient elution of
3 to 5% ethyl acetate in hexanes afforded the title compound
(58 mg, 58%) as a colorless oil: Rf = 0.31 (95:5 hexanes/EtOAc);
IR (thin film) νmax 3357, 2954, 2870, 1688, 1599, 1494, 1455,
1287, 1244, 1028, 908, 816, 755 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 7.45 (1H, dd, J = 7.5, 2.0 Hz), 7.21-7.28 (2H, m), 6.97
(1H, ddd, J = 7.5, 1.5, 1.0 Hz), 6.87-6.94 (2H, m), 6.45 (1H, d,
J = 8.5 Hz), 4.21 (1H, d, J = 9.5 Hz), 3.82 (3H, s), 3.71 (1H, br
s), 2.69 (1H, d, J = 9.0 Hz), 2.60 (1H, d, J = 4.0 Hz), 2.24 (1H,
dd, J = 9.5, 9.0 Hz), 2.07 (1H, d, J = 4.0 Hz), 1.62-1.72 (2H,
m), 1.47-1.56 (1H, m), 1.37-1.44 (1H, m), 1.19-1.26 (1H, m),
1.09 (1H, ddd, J = 10.0, 2.0, 1.5 Hz); 13C NMR (100 MHz,
CDCl3) δ 157.1, 146.1, 132.0, 129.1, 128.33, 128.32, 127.8, 125.8,
123.4, 120.9, 116.3, 110.4, 55.4, 52.6, 51.9, 44.3, 43.2, 40.0, 34.2,
29.7, 29.3; MS (EIþ) m/e (rel intensity) 341 (45), 340 (42), 339
(100), 338 (26), 270 (35), 232 (37), 164 (25), 127 (25), 121 (22), 119
(27), 91 (32); HRMS (EI) m/e calcd for C21H2235ClNO [Mþ]
339.1382, found 339.1380.
6-(4-Bromophenyl)-2-chloro-5,6,6a,7,8,9,10,10a-octahydro-7,
10-methanophenanthridine (exo-exo-1h). Purification by flash
column chromatography on silica gel using a gradient elution
of 2 to 4% ethyl acetate in hexanes afforded the title compound
(78 mg, 78%) as a white solid: mp 140-142 °C; Rf = 0.31 (95:5
hexanes/EtOAc); IR (thin film) νmax 3356, 2952, 2870, 1487,
1457, 1406, 1340, 1294, 1256, 1071, 1010, 860, 820, 739 cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.49 (2H, d, J = 8.5 Hz), 7.29 (2H, d,
J = 8.5 Hz), 7.24 (1H, m), 6.94 (1H, ddd, J = 8.5, 2.5, 1.0 Hz),
6.49 (1H, d, J = 8.5 Hz), 3.66 (1H, br s), 3.49 (1H, d, J = 10.5
Hz), 2.65 (2H, d, J = 7.0 Hz), 2.09 (1H, dd, J = 10.5, 10.0 Hz),
2.02 (1H, d, J = 4.0 Hz), 1.33-1.72 (4H, m), 1.08-1.20 (2H, m);
13C NMR (100 MHz, CDCl3) δ 145.6, 143.1, 131.9, 129.8, 128.9,
128.5, 126.2, 124.2, 121.8, 116.6, 61.1, 53.6, 44.2, 42.7, 39.4, 34.1,
29.8, 29.2; MS (EIþ) m/e (rel intensity) 391 (24), 390 (25), 389
(100), 388 (32), 387 (82), 319 (57), 317 (43), 234 (28), 232 (85), 190
(20), 166 (23), 164 (56), 91 (36); HRMS (EI) m/e calcd for
C20H1979Br35ClN [Mþ] 387.0389, found 387.0381.
2-Chloro-6-(3,4-dichlorophenyl)-5,6,6a,7,8,9,10,10a-octahydro-
7,10-methanophenanthridine (exo-exo-1i). Purification by flash
column chromatography on silica gel using a gradient elution of
5 to 10% ethyl acetate in hexanes afforded the title compound
(84 mg, 82%) as an off-white solid: mp 177-178 °C; Rf = 0.53
(90:10 hexanes/EtOAc); IR (thin film) νmax 3359, 2953, 2870,
1599, 1489, 1457, 1401, 1332, 1290, 1256, 1126, 1030, 907, 812,
733 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.53 (1H, d, J = 2.0
Hz), 7.43 (1H, d, J = 8.0 Hz), 7.24-7.27 (2H, m), 6.95 (1H, dd,
J = 8.0, 1.5 Hz), 6.50 (1H, d, J = 8.5 Hz), 3.65 (1H, s), 3.49 (1H,
d, J = 10.0 Hz), 2.64-2.66 (2H, m), 2.07 (1H, dd, J = 9.5, 9.5
Hz), 2.03 (1H, d, J = 4.0 Hz), 1.37-1.72 (4H, m), 1.13-1.22
(1H, m), 1.13 (1H, d, J = 10.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 145.2, 144.4, 132.8, 131.9, 130.7, 129.9, 128.8, 128.5,
127.4, 126.3, 124.4, 116.6, 60.7, 53.5, 44.1, 42.7, 39.4, 34.1, 29.8,
29.1; MS (ESIþ) m/e (rel intensity) 382 (34), 380 (95), 378 (100);
HRMS (ESI) m/e calcd for C20H18N35Cl3 [M þ H]þ 378.0577,
found 378.0577.
1
1073, 1010, 974, 927, 818, 753, 733, 704 cm-1; H NMR (300
MHz, CDCl3) δ 7.50 (2H, d, J = 8.5 Hz), 7.32 (2H, d, J = 8.5
Hz), 7.18 (1H, d, J = 7.5 Hz), 7.10 (1H, d, J = 8.0 Hz), 6.71 (1H,
dd, J = 8.0, 8.0 Hz), 4.32-4.40 (1H, s), 3.53 (1H, d, J = 10.5
Hz), 2.67-2.73 (2H, m), 2.13 (1H, dd, J = 9.5, 9.5 Hz), 2.05 (1H,
d, J = 4.0 Hz), 1.36-1.73 (4H, m), 1.11-1.22 (1H, m), 1.12 (1H,
d, J = 10.0 Hz); 13C NMR (100 MHz, CDCl3) δ 143.1, 143.0,
131.9, 129.8, 128.8, 127.0, 126.4, 121.8, 119.9, 119.1, 60.6, 53.8,
44.5, 43.0, 39.6, 34.0, 29.9, 29.1; HRMS (EI) m/e calcd for
C20H1979Br35ClN [Mþ] 387.0389, found 387.0389.
4-Chloro-6-(3,4-dichlorophenyl)-5,6,6a,7,8,9,10,10a-octahydro-
7,10-methanophenanthridine (exo-endo-1k). Purification by flash
column chromatography on silica gel using a gradient elution of
1 to 5% ethyl acetate in hexanes afforded the title compound (26
mg, 26%) as a white solid: mp 163-164 °C; Rf = 0.46 (99:1
hexanes/EtOAc); IR (thin film) νmax 3358, 3065, 2954, 2924,
2870, 1598, 1576, 1470, 1417, 1395, 1361, 1279, 1130, 1030, 975,
907, 783, 732 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.56 (1H, d,
J = 2.0 Hz), 7.48 (1H, d, J = 11.0 Hz), 7.30 (1H, dd, J = 8.5, 2.0
Hz), 7.11 (1H, dd, J = 8.0, 1.0 Hz), 7.08 (1H, dd, J = 7.5, 0.5
Hz), 6.73 (1H, dd, J = 7.5, 7.5 Hz), 4.28 (1H, s), 4.20 (1H, d, J =
4.5 Hz), 3.04 (1H, d, J = 8.5 Hz), 2.23 (1H, d, J = 4.5 Hz), 2.12
(1H, dd, J = 8.5, 4.5 Hz), 1.95 (1H, d, J = 2.0 Hz), 1.54-1.60
(2H, m), 1.32-1.42 (2H, m), 1.03-1.09 (1H, m), 0.88 (1H, d, J =
10 Hz); 13C NMR (100 MHz, CDCl3) δ 143.1, 143.0, 132.7,
131.1, 130.5, 130.0, 128.8, 128.2, 126.2, 126.1, 119.9, 119.3, 58.5,
50.6, 49.6, 47.0, 36.7, 34.8, 31.3, 28.3; MS (EIþ) m/e (rel
intensity) 379 (84), 378 (39), 377 (100), 376 (27), 312 (25), 310
(64), 308 (64), 232 (55); HRMS (EI) m/e calcd for C20H18N35Cl3
[Mþ] 377.0505, found 377.0510.
4-Chloro-6-(3,4-dichlorophenyl)-5,6,6a,7,8,9,10,10a-octahydro-
7,10-methanophenanthridine (exo-exo-1k). Purification by flash
column chromatography on silica gel using a gradient elution of
1 to 5% ethyl acetate in hexanes afforded the title compound (33
mg, 33%) as a crystalline white solid: mp 148-150 °C; Rf = 0.51
(99:1 hexanes/EtOAc); IR (thin film) νmax 3359, 3059, 3023,
2956, 2922, 2871, 1596, 1572, 1466, 1416, 1399, 1336, 1302, 1289,
1253, 1105, 1029, 977, 819, 761, 731 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.56 (1H, d, J = 2.0 Hz), 7.25 (1H, d, J = 8.0 Hz), 7.28
(1H, dd, J = 8.0, 2.0 Hz), 7.19 (1H, d, J = 7.5 Hz), 7.12 (1H, dd,
J = 8.0, 1.0 Hz), 6.73 (1H, dd, J = 8.0, 8.0 Hz), 4.36 (1H, s), 3.54
(1H, d, J = 10.0 Hz), 2.68-2.72 (2H, m), 2.12 (1H, dd, J = 9.5,
9.5 Hz), 2.06 (1H, d, J = 4.0 Hz), 1.64-1.72 (1H, m), 1.51-1.62
(2H, m), 1.38-1.46 (1H, m), 1.17-1.24 (1H, m), 1.13 (1H, ddd,
J = 10.0, 2.0, 1.5 Hz); 13C NMR (100 MHz, CDCl3) δ 144.1,
142.6, 132.7, 131.7, 130.5, 129.8, 128.5, 127.2, 126.8, 126.2,
119.8, 119.1, 60.0, 53.5, 44.2, 42.8, 39.4, 33.8, 29.6, 28.9; MS
(EIþ) m/e (rel intensity) 379 (97), 378 (29), 377 (100), 310 (64),
308 (64), 232 (62), 164 (25); HRMS (EI) m/e calcd for
C20H18N35Cl3 [Mþ] 377.0505, found 377.0500.
6-(4-Bromophenyl)-4-chloro-5,6,6a,7,8,9,10,10a-octahydro-
7,10-methanophenanthridine (exo-endo-1j). Purification by flash
column chromatography on silica gel using a gradient elution of
2 to 4% ethyl acetate in hexanes afforded the title compound (16
mg, 16%) as a white solid: mp 205-207 °C; Rf = 0.71 (98:2
hexanes/EtOAc); IR (thin film) νmax 3367, 2956, 2873, 1599,
1478, 1417, 1364, 1298, 1281, 1127, 1070, 1007, 971, 842, 823,
1
797, 781, 739, 725 cm-1; H NMR (300 MHz, CDCl3) δ 7.54
(2H, d, J = 8.5 Hz), 7.35 (2H, d, J = 8.5 Hz), 7.05-7.13 (2H, m),
710 J. Org. Chem. Vol. 75, No. 3, 2010

Smith et al.
JOCArticle
2,4-Dichloro-6-(3,4-dichlorophenyl)-5,6,6a,7,8,9,10,10a-octa-
hydro-7,10-methanophenanthridine (exo-endo-1l). Purification
by flash column chromatography on silica gel using a gradient
elution of 100% hexanes to 5% ethyl acetate in hexanes afforded
the title compound (41 mg, 19%) as a white solid: mp 159-
160 °C; Rf = 0.40 (100% hexanes); IR (thin film) νmax 3358,
2955, 2924, 2872, 1573, 1475, 1396, 1278, 1130, 1030, 906, 858,
hexanes/EtOAc); IR (thin film) νmax 3358, 2956, 2926, 2870,
1587, 1449, 1415, 1265, 1157, 1130, 1031, 979, 906, 790, 734
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.54 (1H, d, J = 2.0 Hz),
7.49 (1H, d, J = 8.5 Hz), 7.28 (1H, dd, J = 8.5, 2.0 Hz), 7.07 (1H,
d, J = 8.5 Hz), 6.81 (1H, d, J = 8.5 Hz), 4.36 (1H, s), 4.17 (1H, d,
J = 4.5 Hz), 3.23 (1H, d, J = 9.0 Hz), 2.43 (1H, d, J = 4.0 Hz),
2.15-2.20 (1H, m), 1.96 (1H, d, J = 2.0 Hz), 1.04-1.62 (5H, m),
0.93 (1H, d, J = 10.0 Hz); 13C NMR (100 MHz, CDCl3) δ 144.5
(C), 142.3 (C), 133.2 (C), 132.8 (C), 131.3 (C), 130.6 (CH), 128.7
(CH), 127.5 (C), 126.7 (CH), 126.2 (CH), 120.2 (CH), 118.4 (C),
58.4 (CH), 50.7 (CH), 46.8 (CH), 45.2 (CH), 37.2 (CH), 35.4
(CH2), 31.0 (CH2), 28.5 (CH2); MS (EIþ) m/e (rel intensity) 413
(95), 412 (36), 411 (82), 345 (49), 344 (33), 343 (100), 342 (40), 341
(78), 266 (35), 239 (30), 237 (45), 200 (74), 198 (96), 187 (25), 161
(30), 67 (72); HRMS (EI) m/e calcd for C20H17NCl4 [Mþ]
411.0115, found 411.0124.
1,4-Dichloro-6-(3,4-dichlorophenyl)-5,6,6a,7,8,9,10,10a-octa-
hydro-7,10-methanophenanthridine (exo-exo-1n). Purification
by flash column chromatography on silica gel using a gradient
elution of 2 to 4% ethyl acetate in hexanes afforded the title
compound (38 mg, 36%) as a white foam: Rf = 0.57 (95:5
hexanes/EtOAc); IR (thin film) νmax 3379, 3049, 2955, 2926,
2872, 1587, 1564, 1471, 1394, 1276, 1166, 1130, 1030, 979, 906,
821, 788, 732 cm-1; 1H NMR (300 MHz, CDCl3) δ 7.33 (1H, d,
J = 8.0 Hz), 7.31 (1H, d, J = 2.0 Hz), 7.05 (1H, d, J = 8.5 Hz),
6.99 (1H, dd, J = 8.0, 2.0 Hz), 6.74 (1H, d, J = 8.5 Hz), 4.67 (1H,
s), 4.22 (1H, dd, J = 4.5, 2.0 Hz), 2.92 (1H, d, J = 9.0 Hz), 2.63
(1H, s), 2.25 (1H, s), 2.18 (1H, dd, J = 8.5, 4.5 Hz), 1.47-1.72
(4H, m), 1.25-1.36 (1H, m), 1.08 (1H, dd, J = 10.0, 1.5 Hz); 13C
NMR (100 MHz, CDCl3) δ 145.1 (C), 141.6 (C), 133.3 (C), 132.6
(C), 131.2 (C), 130.6 (CH), 129.0 (CH), 127.1 (CH), 125.9 (CH),
125.6 (C), 119.4 (CH), 117.6 (C), 57.7 (CH), 49.6 (CH), 44.6
(CH), 43.2 (CH), 42.6 (CH), 34.4 (CH2), 29.6 (CH2), 29.4 (CH2);
MS (EIþ) m/e (rel intensity) 413 (84), 411 (89), 409 (37), 407 (26),
382 (33), 380 (69), 378 (47), 345 (42), 343 (100), 341 (55), 268 (25),
266 (49), 239 (23), 237 (38), 200 (38), 198 (52); HRMS (EI) m/e
calcd for C20H17N35Cl4 [Mþ] 411.0115, found 411.0112.
6-(4-Bromophenyl)-2,3-dimethyl-5,6,6a,7,8,9,10,10a-octahy-
dro-7,10-methanophenanthridine (exo-exo-1o) and 6-(4-Bromo-
phenyl)-1,2-dimethyl-5,6,6a,7,8,9,10,10a-octahydro-7,10-metha-
nophenanthridine (exo-endo-1p). Purification of the crude
material (60:40 1o/1p) by flash column chromatography on
silica gel using a gradient elution of 2 to 4% ethyl acetate in
hexanes afforded two fractions containing an 89:11 mixture of
1o and 1p (19 mg, 16%) followed by three fractions containing a
27:73 mixture of 1o and 1p (58 mg, 49%) in the form of off-white
foams: Rf = 0.75 (90:10 hexanes/EtOAc); IR (thin film) νmax
3355, 3000, 2920, 2867, 1588, 1485, 1295, 1263, 1203, 1072, 1009,
831, 737 cm-1; 1H NMR (300 MHz, CDCl3) (1o) δ 7.48 (2H, d,
J = 8.5 Hz), 7.30 (2H, d, J = 8.5 Hz), 7.04 (1H, s), 6.38 (1H, s),
3.45-3.55 (1H, br s), 3.50 (1H, d, J = 10.0 Hz), 2.68 (1H, d, J =
3.5 Hz), 2.63 (1H, d, J = 9.0 Hz), 2.18 (3H, s), 2.15 (3H, s), 2.07
(1H, dd, J = 9.5, 9.5 Hz), 2.00 (1H, d, J = 4.0 Hz), 1.05-1.74
(4H, m); 13C NMR (100 MHz, CDCl3) (1o/1p) δ 145.0 (1p),
144.7 (1o), 143.5 (1o), 142.5 (1p), 135.6 (1p), 134.3 (1o), 131.5
(1o), 131.4 (1p), 129.6 (1o), 129.4 (1o), 128.9 (1p), 127.8 (1p),
127.4 (1p), 127.3 (1o), 125.2 (1p), 124.2 (1o), 121.3 (1o), 120.7
(1p), 116.5 (1o), 112.6 (1p), 61.3 (1o), 58.7 (1p), 53.6 (1o), 50.6
(1p), 44.6 (1p), 43.6 (1o), 42.6 (1p), 42.5 (1p), 42.3 (1o), 39.2 (1o),
34.2 (1p), 33.8 (1o), 29.8 (1p), 29.7 (1o), 29.5 (1p), 29.0 (1o), 20.1
(1p), 19.4 (1o), 19.0 (1o), 16.5 (1p); MS (EIþ) m/e (rel intensity)
384 (13), 383 (90), 382 (24), 381 (100), 314 (47), 312 (49), 226 (26),
158 (12), 86 (10), 84 (14); HRMS (EI) m/e calcd for C22H24N79Br
[Mþ] 381.1092, found 381.1102.
1
817, 734 cm-1; H NMR (400 MHz, CDCl3) δ 7.54 (1H, d,
J = 2.0 Hz), 7.48 (1H, d, J = 8.0 Hz), 7.28 (1H, dd, J = 8.5, 2.0
Hz), 7.12 (1H, d, J = 2.5 Hz), 7.07 (1H, d, J = 2.5 Hz), 4.25 (1H,
s), 4.16 (1H, d, J = 4.5 Hz), 3.00 (1H, d, J = 8.5 Hz), 2.25 (1H, d,
J = 4.5 Hz), 2.11 (1H, dd, J = 8.5, 4.5 Hz), 1.94 (1H, d, J = 2.5
Hz), 1.52-1.64 (2H, m), 1.31-1.42 (2H, m), 1.02-1.09 (1H, m),
0.90 (1H, d, J = 10 Hz); 13C NMR (100 MHz, CDCl3) δ 142.5
(C), 141.8 (C), 132.8 (C), 131.3 (C), 131.1 (C), 130.6 (CH), 128.7
(CH), 128.1 (CH), 126.2 (CH), 125.8 (CH), 123.4 (C), 120.1 (C),
58.4 (CH), 50.4 (CH), 49.6 (CH), 46.9 (CH), 36.7 (CH), 34.8
(CH2), 31.2 (CH2), 28.2 (CH2); MS (EIþ) m/e (rel intensity) 415
(15), 413 (60), 411 (80), 409 (70), 407 (50), 380 (100), 378 (75), 343
(38), 266 (22), 198 (20); HRMS (EI) m/e calcd for C20H17N35Cl4
[Mþ] 411.0115, found 411.0106.
2,4-Dichloro-6-(3,4-dichlorophenyl)-5,6,6a,7,8,9,10,10a-octa-
hydro-7,10-methanophenanthridine (exo-exo-1l). Purification by
flash column chromatography on silica gel using a gradient
elution of 100% hexanes to 5% ethyl acetate in hexanes followed
by an additional flash column using a gradient elution of 1 to 3%
ethyl acetate in hexanes afforded the title compound (101 mg,
46%) as a white solid: mp 198-199 °C; Rf = 0.22 (100%
hexanes); IR (thin film) νmax 3348, 2956, 2909, 2868, 1589,
1471, 1328, 1300, 1126, 1028, 871, 853, 816, 716 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 7.54 (1H, d, J = 2.0 Hz), 7.45
(1H, d, J = 8.5 Hz), 7.26 (1H, dd, J = 8.0, 2.0 Hz), 7.18 (1H, s),
7.12 (1H, d, J = 2.0 Hz), 4.32 (1H, s), 3.50 (1H, d, J = 10.0 Hz),
2.64-2.69 (2H, m), 2.11 (1H, dd, J = 9.5, 9.5 Hz), 2.06 (1H, d,
J = 4.0 Hz), 1.65-1.74 (1H, m), 1.51-1.60 (2H, m), 1.37-1.45
(1H, m), 1.15-1.23 (1H, m), 1.15 (1H, d, J = 10.0 Hz); 13C
NMR (100 MHz, CDCl3) δ 143.7 (C), 141.3 (C), 132.7 (C), 131.9
(C), 130.6 (CH), 129.7 (CH), 129.6 (C), 127.1 (CH), 126.9 (CH),
125.9 (CH), 123.3 (C), 120.0 (C), 59.9 (CH), 53.3 (CH), 44.3
(CH), 42.8 (CH), 39.4 (CH), 33.8 (CH2), 29.5 (CH2), 28.8 (CH2);
MS (EIþ) m/e (rel intensity) 415 (35), 413 (100), 412 (25), 411
(77), 345 (26), 343 (53), 341 (38), 268 (32), 266 (55), 200 (25), 198
(35), 86 (38), 84 (56); HRMS (EI) m/e calcd for C20H17N35Cl4
[Mþ] 411.0115, found 411.0105.
1,3-Dichloro-6-(3,4-dichlorophenyl)-5,6,6a,7,8,9,10,10a-octa-
hydro-7,10-methanophenanthridine (exo-endo-1m). Purification
by flash column chromatography on silica gel using a gradient
elution of 5 to 10% ethyl acetate in hexanes afforded the title
compound (101 mg, 91%) as a white foam: mp 48-49 °C; Rf =
0.52 (90:10 hexanes/EtOAc); IR (thin film) νmax 3381, 2953, 2871,
1589, 1570, 1468, 1390, 1332, 1294, 1256, 1175, 1131, 1104, 1029,
1
947, 906, 882, 835, 731 cm-1; H NMR (300 MHz, CDCl3) δ
7.32-7.36 (2H, m), 7.02 (1H, dd, J = 8.5, 2.0 Hz), 6.81 (1H, d, J
= 2.0 Hz), 6.42 (1H, d, J = 2.0 Hz), 4.09 (1H, d, J = 4.5 Hz), 3.97
(1H, s), 2.88 (1H, d, J = 9.0 Hz), 2.64 (1H, s), 2.20 (1H, s), 2.12
(1H, dd, J = 8.5, 4.5 Hz), 1.46-2.05 (4H, m), 1.26-1.33 (1H, m),
1.08 (1H, d, J= 10 Hz);13CNMR(100 MHz, CDCl3) δ146.1(C),
145.1 (C), 135.6 (C), 132.5 (C), 132.1 (C), 131.3 (C), 130.6 (CH),
129.1 (CH), 126.0 (CH), 122.7 (C), 119.7 (CH), 113.3 (CH), 58.0
(CH), 49.5 (CH), 44.3 (CH), 43.0 (CH), 41.9 (CH), 34.3 (CH2),
29.4 (2 ꢀ CH2); MS (EIþ) m/e (rel intensity) 415 (28), 413 (79), 411
(61), 345 (47), 343 (100), 239 (27), 237 (43), 198 (25); HRMS (EI)
m/e calcd for C20H17N35Cl4 [Mþ] 411.0115, found 411.0104.
1,4-Dichloro-6-(3,4-dichlorophenyl)-5,6,6a,7,8,9,10,10a-octa-
hydro-7,10-methanophenanthridine (exo-endo-1n). Purification
by flash column chromatography on silica gel using a gradient
elution of 2 to 4% ethyl acetate in hexanes afforded the title
compound (19 mg, 18%) as a colorless oil: Rf = 0.67 (95:5
6-(4-Bromophenyl)-3-chloro-5,6,6a,7,8,9,10,10a-octahydro-7,
10-methanophenanthridine (exo-exo-1q) and 6-(4-Bromophenyl)-
1-chloro-5,6,6a,7,8,9,10,10a-octahydro-7,10-methanophenanthri-
dine (exo-endo-1r). Purification of the crude material (36:64 1q/
J. Org. Chem. Vol. 75, No. 3, 2010 711

Smith et al.
JOCArticle
1r) by flash column chromatography on silica gel using a
gradient elution of 2 to 4% ethyl acetate in hexanes afforded
one fraction containing 1q (13 mg, 13%), one fraction contain-
ing an 84:16 mixture of 1q and 1r (29 mg, 29%), two fractions
containing a 5:95 mixture of 1q and 1r (28 mg, 28%), and one
fraction containing 1r (14 mg, 13%). exo-exo-1q: Isolated as a
colorless oil; Rf = 0.57 (90:10 hexanes/EtOAc); IR (thin film)
113.7 (C, 2JC-F = 18 Hz), 110.5 (CH, 4JC-F = 2.5 Hz), 105.7
(CH, JC-F = 23 Hz), 59.4 (CH), 51.1 (CH), 42.5 (CH), 42.4
2
(CH), 40.1 (CH), 39.6 (CH), 33.8 (CH2), 30.2 (CH2), 28.7 (CH2).
Methyl 6-(4-bromophenyl)-5,6,6a,7,10,10a-hexahydro-7,10-
methanophenanthridine-2-carboxylate (exo-exo-8a) and Methyl
2-(4-bromophenyl)quinoline-6-carboxylate (9). Synthesized ac-
cording to the general procedure. Purification by flash column
chromatography on silica gel using a gradient elution of 10 to
30% ethyl acetate in hexanes afforded exo-exo-8a followed by 9.
exo-exo-8a: Isolated (38 mg, 34%) as a yellow foam; Rf = 0.25
(90:10 hexanes/EtOAc); IR (thin film) νmax 3340, 2958, 1698,
νmax 3358, 2953, 2870, 1597, 1487, 1460, 1294, 1087, 1072, 1010,
922, 906, 823, 732 cm-1; H NMR (300 MHz, CDCl3) δ 7.49
(2H, dd, J = 8.5, 2.0 Hz), 7.29 (2H, dd, J = 8.5, 2.0 Hz), 7.18
(1H, d, J = 8.0 Hz), 6.76 (1H, dd, J = 8.0, 2.0 Hz), 6.56 (1H, d,
J = 2.0 Hz), 3.67 (1H, s), 3.53 (1H, d, J = 10.0 Hz), 2.61-2.65
(2H, m), 2.10 (1H, dd, J = 9.5, 9.5 Hz), 2.03 (1H, d, J = 3.5 Hz),
1.09-1.71 (6H, m); 13C NMR (100 MHz, CDCl3) δ 147.7, 142.8,
131.7, 131.4, 129.6, 129.5, 125.4, 121.6, 119.3, 114.9, 60.7, 53.4,
43.5, 42.6, 39.3, 33.8, 29.6, 29.0; MS (EIþ) m/e (rel intensity) 389
(85), 387 (65), 320 (88), 318 (72), 232 (35), 166 (27), 164 (60), 68
(31), 67 (100); HRMS (EI) m/e calcd for C20H1979Br35ClN [Mþ]
387.0389, found 387.0388. exo-endo-1r: Isolated as a colorless
oil; Rf = 0.45 (90:10 hexanes/EtOAc); IR (thin film) νmax 3377,
3061, 2953, 2924, 2870, 1593, 1577, 1485, 1292, 1072, 1010, 986,
1
1
1624, 1500, 1328, 1288, 1278, 1017, 883, 776 cm-1; H NMR
(400 MHz, CDCl3) δ 8.06 (1H, s), 7.72 (1H, dd, J = 8.0, 1.0 Hz),
7.52 (2H, d, J = 8.5 Hz), 7.31 (2H, d, J = 8.5 Hz), 6.64 (1H, d,
J = 8.0 Hz), 6.31 (1H, dd, J = 5.5, 3.0 Hz), 6.05 (1H, dd, J=5.5,
3.0 Hz), 4.12 (1H, s), 3.88 (3H, s), 3.63 (1H, d, J = 10.0 Hz), 3.34
(1H, s), 2.65 (1H, s), 2.56 (1H, d, J = 8.5 Hz), 1.98 (1H, dd, J =
9.5, 9.0 Hz), 1.62 (1H, d, J = 9.0 Hz), 1.36 (1H, ddd, J = 9.0, 2.0,
1.5 Hz); 13C NMR (75 MHz, CDCl3) δ 167.3, 150.6, 142.6,
137.4, 136.4, 131.8, 130.4, 129.4, 128.4, 126.1, 121.8, 120.8,
114.6, 62.4, 51.7, 48.0, 47.9, 44.8, 43.4, 39.2; MS (EIþ) m/e (rel
intensity) 411 (4), 409 (4), 345 (51), 344 (85), 343 (88), 342 (79),
341 (24), 312 (22), 310 (20), 203 (12), 189 (10), 188 (100); HRMS
(EI) m/e calcd for C22H2079BrNO2 [Mþ] 409.0677, found
409.0679. Compound 9: Isolated (10 mg, 10%) as a white foam;
Rf=0.08 (90:10 hexanes/EtOAc); IR (thin film) νmax 2957, 2946,
2871, 1694, 1565, 1480, 1341, 1073, 1009, 985, 839, 742 cm-1; 1H
NMR (400 MHz, CDCl3) δ 8.59 (1H, d, J = 2.0 Hz), 8.33 (1H, d,
J =2.0 Hz), 8.31 (1H, d, J =2.0 Hz), 8.17 (1H, d, J = 9.0 Hz),
8.09 (2H, d, J = 8.5 Hz), 7.91 (1H, d, J = 8.5 Hz), 7.67 (2H, d,
J = 9.0 Hz), 4.00 (3H, s); 13C NMR (100 MHz, CDCl3) δ 166.6,
158.0, 150.1, 138.2, 137.9, 132.1, 130.6, 129.9, 129.3, 129.2, 127.9,
126.3, 124.6, 119.1, 52.4;MS(EIþ) m/e (rel intensity) 343 (90), 341
(93), 312 (78), 310 (83), 284 (24), 282 (23), 203 (62), 202 (29), 86
(65), 84 (100), 51 (24), 49 (75), 44 (66), 32 (39); HRMS (EI) m/e
calcd for C17H1279BrNO2 [Mþ] 341.0051, found 341.0049.
910, 835, 754, 727 cm-1; H NMR (300 MHz, CDCl3) δ 7.39
1
(2H, dd, J = 8.5, 2.0 Hz), 7.11 (2H, d, J = 8.5 Hz), 6.89 (1H, dd,
J = 8.0, 8.0 Hz), 6.79 (1H, dd, J = 8.0, 1.0 Hz), 6.39 (1H, dd,
J = 8.0, 1.0 Hz), 4.09 (1H, d, J = 5.0 Hz), 3.90 (1H, s), 2.91 (1H,
d, J = 9.0 Hz), 2.70 (1H, s), 2.20 (1H, s), 2.13 (1H, dd, J = 8.5,
5.0 Hz), 1.74 (1H, d, J = 10.0 Hz), 1.47-1.65 (3H, m),
1.25-1.31 (1H, m), 1.07 (1H, ddd, J = 10.0, 1.5, 1.5 Hz); 13C
NMR (100 MHz, CDCl3) δ 145.9, 144.4, 135.1, 131.6, 128.7,
127.1, 124.3, 120.9, 119.9, 113.5, 58.6, 49.9, 44.2, 43.0, 42.3, 34.3,
29.6, 29.5; MS (EIþ) m/e (rel intensity) 389 (100), 388 (28), 387
(87), 322 (25), 320 (92), 318 (66), 232 (46), 164 (34); HRMS (EI)
m/e calcd for C20H1979Br35ClN [Mþ] 387.0389, found 387.0371.
6-(4-Bromophenyl)-3-fluoro-5,6,6a,7,8,9,10,10a-octahydro-7,
10-methanophenanthridine (exo-exo-1s) and 6-(4-Bromophenyl)-
1-fluoro-5,6,6a,7,8,9,10,10a-octahydro-7,10-methanophenanthri-
dine (exo-exo-1t). Purification of the crude material (56:44 1s/1t)
by flash column chromatography on silica gel using a gradient
elution of 2 to 3% ethyl acetate in hexanes afforded one fraction
containing 1s (4.4 mg, 4.5%) followed by five fractions contain-
ing a 59:41 mixture of 1s and 1t (68 mg, 70%) and finally one
fraction containing 1t (2.2 mg, 2.2%). exo-exo-1s: Isolated as a
colorless oil; Rf = 0.52 (90:10 hexanes/EtOAc); IR (thin film)
exo-exo-8b and 6-(4-Bromophenyl)-2-chloro-6,6a,7,7a,8,9,10,
10a,11,11a-octahydro-5H-7,11-methanocyclopenta[j]phenanthri-
dine (10). Synthesized according to the general procedure with
the exception that the reaction was heated to 50 °C for 60 h.
Purification of the crude material (∼2:1 mixture of
regioisomers) by flash column chromatography on silica gel
using an elution of 5% ethyl acetate in hexanes afforded exo-
exo-8b as a 2.7:1 mixture of regioisomers (145 mg, 63%) in the
form of a yellow foam: Rf = 0.51 (90:10 hexanes/EtOAc); IR
(thin film) νmax 3357, 3041, 2947, 2885, 2849, 1590, 1487, 1453,
ν
max 3362, 3028, 2953, 2870, 1616, 1510, 1487, 1298, 1157, 1107,
;
1072, 1010, 908, 839, 783, 732 cm-1 1H NMR (300 MHz,
CDCl3) δ 7.49 (2H, dd, J = 8.5, 2.0 Hz), 7.30 (2H, dd, J =
8.5, 2.0 Hz), 7.17-7.24 (1H, m, H1), 6.50 (1H, ddd, J = 8.5, 8.0,
2.5 Hz, H2), 6.28 (1H, dd, J = 10.0, 2.5 Hz, H4), 3.70 (1H, s),
3.54 (1H, d, J=10.5 Hz), 2.61-2.65 (2H, m), 2.06 (1H, dd, J=
9.5, 9.5 Hz), 2.03 (1H, d, J = 4.0 Hz), 1.37-1.71 (4H, m),
1.09-1.26 (2H, m); 19F (376 MHz, CDCl3) δ -117.6; 13C NMR
1340, 1295, 1254, 1071, 1010, 907, 862, 818, 732, 702, 641 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.48 (4H, d, J = 8.5 Hz), 7.27
(4H, d, J = 8.5 Hz), 7.14-7.19 (2H, m), 6.93 (2H, dd, J = 8.5,
1.0 Hz), 6.47 (2H, d, J = 8.5 Hz), 5.60-5.70 (3H, m), 5.36-5.39
(1H, m), 3.62 (1H, s), 3.58 (1H, d, J = 10.5 Hz), 3.47 (1H, d, J =
10.0 Hz), 3.20-3.26 (1H, m), 3.03-3.08 (1H, m), 2.76 (2H, m),
2.65-2.73 (2H, m), 2.50-2.57 (2H, m), 2.34-2.45 (2H, m),
2.10-2.20 (4H, m), 1.79-1.94 (3H, m), 1.73 (1H, d, J = 10.0
Hz), 1.34-1.39 (2H, m); 13C NMR (100 MHz, CDCl3) δ 145.8,
145.6, 142.7, 142.6, 131.96, 131.90, 131.7, 131.67, 131.66, 131.4,
129.7, 129.6, 129.5, 129.0, 128.1, 127.2, 125.9, 125.8, 124.1,
123.9, 121.5, 116.3, 116.2, 61.6, 60.3, 53.0, 52.5, 48.6, 47.5,
45.7, 45.3, 44.1, 42.5, 42.3, 41.7, 38.9, 37.2, 36.8, 36.0, 32.5,
32.3 (only 41 of 42 expected carbon signals are resolved at 100
MHz). The mixture of regioisomers was subjected to diimide
reduction following a literature procedure.22 To a colorless
solution of exo-exo-8b (77 mg, 0.18 mmol) in dry CH2Cl2 (4.0
mL) was added in three portions potassium azodicarboxylate
(283 mg, 0.460 mmol) at reflux. The yellow suspension was
treated with glacial AcOH (220 μL, 4.1 mmol) over 2 h, after
which the reaction mixture was heated at reflux for 22 h. The
white suspension was filtered by gravity, and the filtrate was
1
(100 MHz, CDCl3) δ 161.3 (C, JC-F = 241 Hz), 147.3 (C,
3JC-F = 8.0 Hz), 142.9 (C), 131.7 (CH), 129.6 (CH, 3JC-F = 9.5
4
Hz), 129.5 (CH), 122.5 (C, JC-F = 3.0 Hz), 121.5 (C), 106.0
(CH, 2JC-F = 21 Hz), 101.8 (CH, 2J = 24 Hz), 60.7 (CH), 53.4
(CH), 43.4 (CH), 42.7 (CH), 39.2 (CH), 33.7 (CH2), 29.6 (CH2),
29.0 (CH2); MS (EIþ) m/e (rel intensity) 373 (10), 371 (15), 304
(17), 302 (16), 216 (12), 148 (38), 68 (18), 67 (100); HRMS (EI) m/
e calcd for C20H1979BrFN [Mþ] 371.0685, found 371.0675. exo-
exo-1t: Isolated as a colorless oil; Rf = 0.47 (90:10 hexanes/
1
EtOAc); H NMR (300 MHz, CDCl3) δ 7.46 (2H, d, J = 8.5
Hz), 7.17-7.33 (2H, m), 6.90-6.98 (1H, m), 6.44-6.51 (1H, m),
6.32 (1H, d, J = 8.0 Hz), 3.85 (1H, s), 3.80 (1H, d, J = 8.5 Hz),
2.76-2.80 (2H, m), 2.03-2.07 (2H, m), 1.45-1.71 (3H, m),
1.18-1.26 (2H, m), 1.09 (1H, d, J = 10.0 Hz); 19F (376 MHz,
CDCl3) δ -113.6; 13C NMR (100 MHz, CDCl3) δ 162.3 (C,
1JC-F = 242 Hz), 147.9 (C, 3JC-3 F = 9.5 Hz), 143.5 (C), 131.6
(CH), 129.3 (CH), 127.1 (CH, JC-F = 10.5 Hz), 121.3 (C),
712 J. Org. Chem. Vol. 75, No. 3, 2010

Smith et al.
JOCArticle
concentrated in vacuo. Purification by flash column chroma-
tography on silica gel using 5% ethyl acetate in hexanes afforded
exo-exo-10: isolated (56 mg, 60%) as a white solid; mp 156-158
°C; Rf = 0.50 (90:10 hexanes/EtOAc); IR (thin film) νmax 3362,
2948, 2879, 1590, 1488, 1455, 1407, 1339, 1295, 1257, 1118, 1087,
lated (22 mg, 26%) as a yellow solid; mp >225 °C; Rf = 0.28
(65:35 hexanes/EtOAc); IR (thin film) νmax 3452 (br O-H),
3338 (N-H), 2950, 2872, 1703, 1605, 1505, 1486, 1435, 1300,
1259, 1196, 1130, 1105, 1071, 1010, 909, 825, 771, 732 cm-1; 1H
NMR (400 MHz, CDCl3) δ 7.96 (1H, s), 7.70 (1H, d, J = 8.5
Hz), 7.49 (2H, d, J = 8.5 Hz), 7.30 (2H, d, J = 8.5 Hz), 6.57 (1H,
d, J = 8.5 Hz), 4.03 (1H, s), 3.87 (3H, s), 3.68 (1H, d, J = 10.0
Hz), 3.55-3.67 (1H, m), 3.40-3.49 (1H, m), 2.77 (1H, d, J = 4.0
Hz), 2.64 (1H, d, J = 9.0 Hz), 2.43 (1H, dd, J = 9.5, 9.0 Hz),
2.03-2.29 (2H, m), 1.94 (1H, ddd, J = 12.5, 5.0, 4.5 Hz), 1.75
(1H, d, J = 10.0 Hz), 1.27 (1H, d, J = 11.0 Hz), 0.89-0.97 (1H,
m), 0.88(1H, t, J =5.5Hz);13C NMR (100 MHz, CDCl3) δ167.3
(C), 150.7 (C), 142.2 (C), 131.9 (CH), 130.5 (CH), 129.3 (CH),
128.4 (CH), 125.7 (C), 121.9 (C), 120.8 (C), 114.8 (CH), 64.1
(CH2), 59.9 (CH), 51.7 (CH3), 45.7 (CH), 44.1 (CH), 43.2 (CH),
41.8 (CH), 41.2 (CH), 35.3 (CH2), 33.6 (CH2); MS (EIþ) m/e (rel
intensity) 443 (37), 441 (59), 425 (46), 424 (19), 423 (62), 345 (24),
344 (100), 343 (26), 342 (87), 188 (37); HRMS (EI) m/e calcd for
C23H2479BrNO3 [Mþ] 441.0940, found 441.0939. exo-exo-8d0:
Isolated (20 mg, 24%) as a white solid; mp 196-200 °C; Rf =
0.18 (65:35 hexanes/EtOAc); IR (thin film) νmax 3488 (O-H),
3317 (N-H), 2945, 2909, 2878, 1684, 1601, 1511, 1486, 1434,
1071, 1010, 907, 862, 818, 732 cm-1 1H NMR (300 MHz,
;
CDCl3) δ 7.49 (2H, d, J = 8.5 Hz), 7.29 (2H, d, J = 8.5 Hz),
7.19 (1H, d, J = 1.0 Hz), 6.94 (1H, dd, J = 8.5, 1.5 Hz), 6.50 (1H,
d, J = 8.5 Hz), 3.66 (1H, s), 3.55 (1H, d, J = 10.0 Hz), 2.91 (1H,
d, J = 9.0 Hz), 2.52-2.64 (2H, m), 2.34-2.43 (1H, m), 2.35 (1H,
dd, J = 10.0, 9.5 Hz), 1.92 (1H, d, J = 4.5 Hz), 1.78 (1H, d, J =
10.0 Hz), 1.54-1.71 (5H, m), 1.40 (1H, d, J = 10.0 Hz),
1.25-1.43 (1H, m); 13C NMR (100 MHz, CDCl3) δ 145.7,
142.7, 131.7, 129.6, 129.5, 127.6, 125.8, 124.0, 121.6, 116.3,
61.2, 47.5, 46.7, 45.8, 45.2, 44.3, 38.9, 36.9, 29.0, 26.9, 26.6;
MS (EIþ) m/e (rel intensity) 429 (100), 428 (27), 427 (84), 320
(25), 272 (47); HRMS (EI) m/e calcd for C23H23N79Br35Cl [Mþ]
427.0702, found 427.0707.
exo-exo-8c and 6-(4-Bromophenyl)-2-chloro-6,6a,7,7a,8,9,10,
10a,11,11a-octahydro-5H-7,11-methanocyclopenta[j]phenanthri-
dine (11). Synthesized according to the general procedure with
the exception that the reaction was heated to 50 °C for 41 h.
Purification of the crude material (∼2:1 mixture of regioi-
somers) by flash column chromatography on silica gel using a
gradient elution of 50 to 80% dichloromethane in hexanes
afforded exo-exo-8c as a 2:1 mixture of regioisomers (173 mg,
75%) in the form of an off-white foam: Rf = 0.42 (90:10
hexanes/EtOAc); IR (thin film) νmax 3363, 3040, 2940, 2844,
1598, 1486, 1454, 1284, 1251, 1113, 1071, 1011, 907, 857, 821,
808, 735 cm-1. 1H NMR (400 MHz, CDCl3) δ 7.50 (4H, d, J =
8.5 Hz), 7.30 (4H, d, J = 8.5 Hz), 7.25-7.27 (2H, m overlaps
with residual chloroform peak), 6.93-6.97 (2H, m), 6.51 (2H, d,
J = 8.5 Hz), 5.53-5.71 (3H, m), 5.36-5.38 (1H, m), 3.66 (1H, s,
NH), 3.65 (1H, s, NH), 3.52 (1H, d, J = 10.5 Hz), 3.49 (1H, d,
J = 10.5 Hz), 2.80-2.83 (1H, m), 2.49-2.74 (5H, m), 2.45 (1H,
s), 2.36-2.46 (2H, m), 2.09-2.18 (3H, m), 1.97-2.02 (1H, m),
1.80-1.86 (2H, m), 1.74 (1H, s), 1.25-1.29 (4H, m). The mixture
of regioisomers was subjected to diimide reduction following a
literature procedure.22 To a colorless solution of exo-exo-8c (46
mg, 0.11 mmol) in dry CH2Cl2 (2.5 mL) was added in three
portions potassium azodicarboxylate (169 mg, 0.873 mmol) at
reflux. The yellow suspension was treated with glacial AcOH
(140 μL, 2.4 mmol) over 2 h, after which the reaction mixture
was heated at reflux for 22 h. The white suspension was filtered
by gravity, and the filtrate was concentrated in vacuo to afford
exo-exo-11: isolated (40 mg, 86%) as an off-white solid; mp
176-179 °C; Rf = 0.40 (90:10 hexanes/EtOAc); IR (thin film)
1301, 1256, 1246, 1126, 1105, 1051, 1009, 902, 832, 773, 724 cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.93 (1H, s), 7.70 (1H, d, J = 8.5
Hz), 7.49 (2H, d, J = 8.5 Hz), 7.28 (2H, d, J = 8.5 Hz), 6.57 (1H,
d, J = 8.5 Hz), 4.02 (1H, s), 3.86 (3H, s), 3.70-3.77 (2H, m), 3.61
(1H, d, J = 9.5 Hz), 3.00 (1H, d, J = 9.0 Hz), 2.85 (1H, d, J = 2.0
Hz), 2.25-2.30 (1H, m), 2.03-2.11 (1H, m), 1.79 (1H, dd, J =
12.0, 5.0 Hz), 1.72 (1H, d, J = 9.0 Hz), 1.45 (1H, dd, J = 5.0, 4.5
Hz), 1.27 (1H, d, J = 8.0 Hz), 0.65-0.73 (1H, m); 13C NMR (100
MHz, CDCl3) δ 167.3 (C), 151.1 (C), 142.6 (C), 131.8 (CH), 130.1
(CH), 129.4 (CH), 128.3 (CH), 126.1 (C), 121.7 (C), 120.9 (C),
114.8 (CH), 64.0 (CH2), 60.4 (CH), 53.9 (CH), 51.6 (CH3), 44.4
(CH), 42.3 (CH), 40.0 (CH), 35.9 (CH), 35.4 (CH2), 32.8 (CH2);
MS (EIþ) m/e (rel intensity) 443 (41), 442 (22), 441 (57), 344 (100),
343 (20), 342 (89), 188 (22); HRMS (EI) m/e calcd for
C23H2479BrNO3 [Mþ] 441.0940, found 441.0941.
Methyl 6-(4-bromophenyl)-8-{[(4-nitrobenzoyl)oxy]methyl}-
5,6,6a,7,8,9,10,10a-octahydro-7,10-methanophenanthridine-2-car-
boxylate (exo-exo-8e). Synthesized according to the general
procedure with the exception that 1.05 equiv of norbornene 7e
was used and the reaction was first stirred at 60 °C for 22 h and
then after addition of 0.7 mL of CH3CN was stirred at 75 °C for
16 h. Purification by flash column chromatography on silica gel
using a gradient elution of 10 to 25% ethyl acetate in hexanes
afforded the title compound (82 mg, 52%) as a yellow solid: mp
212-213 °C; Rf = 0.29 (80:20 hexanes/EtOAc); IR (thin film)
ν
max 3346, 2953, 2870, 1716, 1606, 1527, 1435, 1274, 1103, 719
νmax 3353, 3058, 2942, 2861, 1590, 1487, 1455, 1406, 1340, 1296,
cm-1; 1H NMR (400 MHz, CDCl3) δ 8.24 (2H, d, J = 9.0 Hz),
7.98 (1H, s), 7.71 (2H, d, J = 9.0 Hz), 7.70 (1H, d, J = 8.5 Hz),
7.23-7.30 (4H, m), 6.57 (1H, d, J = 8.5 Hz), 4.42 (1H, dd, J =
11.5, 6.0 Hz), 4.10-4.18 (1H, m), 3.99 (1H, s), 3.87 (3H, s), 3.65
(1H, d, J = 10.5 Hz), 2.85 (1H, d, J = 4.0 Hz), 2.68 (1H, d, J =
9.0 Hz), 2.47 (1H, dd, J = 9.5, 9.0 Hz), 2.40-2.47 (1H, m), 2.23
(1H, d, J = 3.0 Hz), 2.02 (1H, ddd, J = 12.0, 5.0, 4.5 Hz), 1.81
(1H, d, J = 10.0 Hz), 1.34 (1H, d, J = 10.5 Hz), 1.01 (1H, ddd,
J = 12.0, 5.0, 2.0 Hz); 13C NMR (100 MHz, CDCl3) δ 167.2 (C),
164.1 (C), 150.7 (C), 150.5 (C), 142.1 (C), 134.9 (C), 131.6 (CH),
130.4 (CH), 130.2 (CH), 129.5 (CH), 128.5 (CH), 125.2 (C),
123.6 (CH), 121.8 (C), 120.9 (C), 114.9 (CH), 65.7 (CH2), 60.0
(CH), 51.7 (CH3), 45.9 (CH), 44.0 (CH), 42.8 (CH), 41.1 (CH),
37.8 (CH), 35.0 (CH2), 32.9 (CH2); MS (ESIþ) m/e (rel intensity)
594 (17), 593 (53), 592 (19), 591 (55); HRMS (ESI) m/e calcd for
C30H27N2O679Br [M þ H]þ 591.1125, found 591.1101.
1259, 1249, 1193, 1111, 1085, 1072, 1010, 906, 860, 816, 733
cm-1; 1H NMR (300 MHz, CDCl3) δ 7.50 (2H, d, J = 8.5 Hz),
7.30 (2H, d, J = 8.5 Hz), 7.25 (1H, s), 6.95 (1H, dd, J = 8.5, 1.5
Hz), 6.51 (1H, d, J = 8.5 Hz), 3.66 (1H, s), 3.50 (1H, d, J = 10.5
Hz), 2.57 (1H, d, J = 9.0 Hz), 2.41 (1H, s), 1.82-2.05 (3H, m),
1.72-1.80 (3H, m), 1.60-1.69 (1H, m), 0.82-1.35 (5H, m); 13
C
NMR (100 MHz, CDCl3) δ 145.4, 143.0, 131.7, 129.6, 128.7,
128.3, 126.0, 124.0, 121.5, 116.2, 60.9, 52.5, 48.2, 47.7, 46.8, 43.6,
43.2, 32.2, 32.1, 28.1, 27.3; MS (EIþ) m/e (rel intensity) 429
(100), 428 (25), 427 (81), 320 (76), 318 (55), 272 (45); HRMS (EI)
m/e calcd for C23H23N79Br35Cl [Mþ] 427.0702, found 427.0683.
Methyl 6-(4-bromophenyl)-8-(hydroxymethyl)-5,6,6a,7,8,9,10,
10a-octahydro-7,10-methanophenanthridine-2-carboxylate (exo-
exo-8d) and Methyl 6-(4-bromophenyl)-9-(hydroxymethyl)-
5,6,6a,7,8,9,10,10a-octahydro-7,10-methanophenanthridine-2-car-
boxylate (exo-exo-8d0). Synthesized according to the general
procedure. Purification of the crude material (1:1.1 mixture of
regioisomers 8d/8d0) by flash column chromatography on silica
gel using a gradient elution of 35 to 50% ethyl acetate in hexanes
afforded exo-exo-8d followed by exo-exo-8d0. exoexo-8d: Iso-
Methyl 8,9-bis(methoxymethyl)-6-(4-methylphenyl)-5,6,6a,7,
8,9,10,10a-octahydro-7,10-methanophenanthridine-2-carboxy-
late (exo-exo-8g). Synthesized according to the general proce-
dure. Purification by flash column chromatography on silica gel
J. Org. Chem. Vol. 75, No. 3, 2010 713

Smith et al.
JOCArticle
using a gradient elution of 10 to 30% ethyl acetate in hexanes
afforded the title compound (95 mg, 68%) as a white solid: mp
176-178 °C; Rf = 0.05 (80:20 hexanes/EtOAc); IR (thin film)
EtOAc); IR (thin film) νmax 3380 (br O-H), 3359 (N-H), 2950,
2869, 2830, 1605, 1504, 1463, 1256, 1159, 1129, 1040, 998, 908,
850, 809, 731 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.69 (1H, d,
J = 3.0 Hz), 6.59 (1H, dd, J = 8.5, 3.0 Hz), 6.53 (1H, d, J = 8.5
Hz), 3.76-3.87 (2H, m), 3.75 (3H, s), 3.05-3.10 (1H, m), 2.88
(1H, d, J = 8.5 Hz), 2.55-2.85 (1H, br s), 2.22 (1H, d, J = 4.5
Hz), 2.14 (1H, d, J = 2.0 Hz), 1.90 (1H, dd, J = 8.5, 4.0 Hz),
1.36-1.66 (4H, m), 1.19-1.28 (1H, m), 0.92 (1H, d, J = 10.0
Hz); 13C NMR (100 MHz, CDCl3) δ 153.0 (C), 140.6 (C), 129.7
(C), 116.2 (CH), 114.7 (CH), 112.2 (CH), 65.7 (CH2), 56.8 (CH),
55.6 (CH3), 48.1 (CH), 46.9 (CH), 45.3 (CH), 36.6 (CH), 35.0
(CH2), 31.5 (CH2), 28.5 (CH2); MS (ESIþ) m/e (rel intensity) 261
(23), 260 (100); HRMS (ESI) m/e calcd for C16H21NO2 [M þ
H]þ 260.1645, found 260.1639. exo-exo-13a: Isolated (206 mg,
49%) as colorless needles; mp 92-94 °C; Rf = 0.28 (50:50
hexanes/EtOAc); IR (thin film) νmax 3242 (N-H), 3201 (br
O-H), 2951, 2868, 2827, 1611, 1501, 1458, 1340, 1238, 1202,
νmax 3336, 3061, 3024, 2949, 2922, 2891, 2833, 2810, 1705, 1606,
1487, 1435, 1298, 1251, 1197, 1126, 1103, 1010, 910, 823, 771, 732
cm-1; 1H NMR (300 MHz, CDCl3) δ 8.00 (1H, s), 7.69 (1H, dd, J
= 8.0, 1.0 Hz), 7.48 (2H, d, J = 8.5 Hz), 7.26 (2H, d, 8.5 Hz), 6.55
(1H, d, J = 8.5 Hz), 4.02 (1H, br s), 3.87 (3H, s), 3.62 (1H, d, J =
9.5 Hz), 3.47 (1H, dd, J = 9.0, 6.0 Hz), 3.36 (3H, s), 3.29-3.35
(2H, m), 3.23 (3H, s), 3.16-3.21 (1H, m), 2.76 (1H, d, J = 9.0
Hz), 2.70 (1H, s), 2.04-2.23 (2H, m), 2.02 (1H, s), 1.87-1.95 (1H,
m), 1.46 (1H, d, J = 11.0 Hz), 1.38 (1H, d, J = 11.0 Hz); 13C
NMR (100 MHz, CDCl3) δ 167.3, 150.6, 142.6, 131.8, 130.6,
129.3, 128.4, 125.7, 121.7, 120.7, 114.7, 72.6, 72.4, 60.1, 58.7, 58.5,
52.9, 51.6, 46.4, 45.3, 44.8, 43.5, 43.3, 29.6; MS (ESIþ) m/e (rel
intensity) 502 (100), 500 (97), 470 (23), 468 (18); HRMS (ESI) m/e
calcd for C26H3079BrNO4 [M þ H]þ 500.1430, found 500.1411.
Ethyl 2-methoxy-5,6,6a,7,8,9,10,10a-octahydro-7,10-ethano-
phenanthridine-6-carboxylate (exo-exo-12a). To a solution of
p-anisidine (31 mg, 0.25 mmol) in dry CH2Cl2 (1.3 mL) was
added ethyl glyoxylate (45 wt % solution in toluene, 55 μL, 0.25
mmol). After stirring at room temperature for 2.5 h, norbornene
(49 mg, 0.51 mmol) was added in one portion followed by
1
1164, 1119, 1082, 1039, 986, 904, 848, 826, 787, 734 cm-1; H
NMR (300 MHz, CDCl3) δ 6.79 (1H, d, J = 2.0 Hz), 6.54-6.63
(2H, m), 3.84 (1H, dd, J = 10.5, 3.0 Hz), 3.75 (3H, s), 3.54 (1H,
dd, J = 10.5, 10.0 Hz), 2.79 (1H, dd, J = 8.5, 3.0 Hz), 2.58-2.62
(2H, m), 2.12 (1H, s), 1.77 (1H, dd, J = 9.0, 9.0 Hz), 1.27-1.74
(7H, m), 1.07 (1H, d, J = 10.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 153.0 (C), 139.3 (C), 128.6 (C), 116.2 (CH), 113.9
(CH), 112.0 (CH), 65.9 (CH2), 57.4 (CH), 55.6 (CH3), 45.5 (CH),
43.5 (CH), 43.2 (CH), 40.7 (CH), 34.3 (CH2), 29.5 (CH2), 29.3
(CH2); MS (EIþ) m/e (rel intensity) 259 (14), 241 (15), 240 (35),
229 (16), 228 (100), 160 (37); HRMS (EI) m/e calcd for
C16H21NO2 [Mþ] 259.1572, found 259.1566.
Ethyl 2-methyl-5,6,6a,7,8,9,10,10a-octahydro-7,10-methano-
phenanthridine-6-carboxylate (exo-exo-12b). To a solution of
p-toluidine (81 mg, 0.76 mmol) in dry CH2Cl2 (3.5 mL) was
added ethyl glyoxylate (45 wt % solution in toluene, 200 μL, 0.91
mmol). After stirring at room temperature for 15 min, norbor-
nene (143 mg, 1.51 mmol) was added in one portion followed by
dropwise addition of BF3 OEt2 (7.0 μL, 0.056 mmol). The
3
reaction was stirred at room temperature for 5 h and then
treated with saturated aqueous NaHCO3. The reaction mixture
was extracted with CH2Cl2 (3 ꢀ 5 mL), and then the combined
organic extracts were dried with Na2SO4, filtered, and concen-
trated in vacuo. Purification of the crude material by flash
column chromatography on silica gel using a gradient elution
of 10 to 30% ethyl acetate in hexanes afforded the title com-
pound (34 mg, 44%) as a brown foam: Rf = 0.37 (80:20 hexanes/
EtOAc); IR (thin film) νmax 3366, 2949, 2868, 2829, 1734, 1623,
1570, 1501, 1465, 1205, 1118, 1035, 847, 813, 702 cm-1 1H
;
NMR (400 MHz, CDCl3) δ 6.71 (1H, d, J = 8.5 Hz), 6.60 (1H,
dd, J = 8.5, 2.5 Hz), 6.56 (1H, d, J = 8.5 Hz), 4.15 (2H, q, J =
7.0 Hz), 3.88 (1H, br s), 3.74 (3H, s), 3.50 (1H, d, J = 6.5 Hz),
2.70 (1H, d, J = 9.0 Hz), 2.46 (1H, d, J = 4.0 Hz), 2.37-2.43
(1H, m), 1.34 (1H, d, J = 3.0 Hz), 1.53-1.69 (3H, m), 1.40-1.44
(2H, m), 1.22 (3H, dd, J = 7.0, 7.0 Hz), 1.05 (1H, ddd, J = 10.0,
2.0, 1.5 Hz); 13C NMR (100 MHz, CDCl3) δ 173.3 (C), 153.3 (C),
138.7 (C), 128.6 (C), 116.3 (CH), 114.0 (CH), 112.2 (CH), 61.0
(CH2), 58.7 (CH3), 55.5 (CH), 45.9 (CH), 45.1 (CH), 44.1 (CH),
42.1 (CH), 34.1 (CH2), 30.1 (CH2), 28.9 (CH2), 14.2 (CH3); MS
(ESIþ) m/e (rel intensity) 301 (100), 228 (34); HRMS (ESI) m/e
calcd for C18H23NO3 [M þ H]þ 302.1750, found 302.1748.
(2-Methoxy-5,6,6a,7,8,9,10,10a-octahydro-7,10-methanophe-
nanthridin-6-yl)methanol (13a). To a solution of p-anisidine (201
mg, 1.63 mmol) in dry CH2Cl2 (8 mL) was added ethyl glyox-
ylate (45 wt % solution in toluene, 450 μL, 2.04 mmol). After
stirring at room temperature for 20 min, norbornene (306 mg,
3.25 mmol) was added in one portion followed by dropwise
dropwise addition of BF3 OEt2 (19 μL, 0.15 mmol). The reac-
3
tion was stirred at room temperature for 5 h and then concen-
trated in vacuo. Purification of the crude material by flash
column chromatography on silica gel using a gradient elution
of 4 to 12% ethyl acetate in hexanes afforded the title compound
(85 mg, 40%) as a colorless oil: Rf = 0.35 (90:10 hexanes/
EtOAc); IR (thin film) νmax 3368, 2950, 2869, 1734, 1616, 1507,
1
1473, 1369, 1297, 1253, 1196, 1027, 814 cm-1; H NMR (300
MHz, CDCl3) δ 6.95 (1H, s), 6.80 (1H, d, J = 8.0 Hz), 6.54 (1H,
d, J = 8.0 Hz), 4.16 (2H, q, J = 7.0 Hz), 3.90-4.05 (1H, br s),
3.55 (1H, d, J = 6.5 Hz), 2.68 (1H, d, J = 9.0 Hz), 2.46 (1H, d,
J = 3.0 Hz), 2.36-2.44 (1H, m), 2.35 (1H, d, J = 2.5 Hz), 2.23
(3H, s), 1.26-1.71 (5H, m), 1.23 (3H, t, J = 7.0 Hz), 1.07 (1H,
ddd, J = 10.0, 2.0, 1.5 Hz); 13C NMR (100 MHz, CDCl3) δ
173.3 (C), 142.4 (C), 129.3 (CH), 128.6 (C), 127.2 (C), 126.9
(CH), 115.5 (CH), 61.0 (CH2), 58.5 (CH), 46.1 (CH), 45.2 (CH),
43.7 (CH), 42.2 (CH), 34.1 (CH2), 30.1 (CH2), 28.9 (CH2), 20.7
(CH), 14.2 (CH3); MS (ESIþ) m/e (rel intensity) 286 (100), 212
(24); HRMS (ESI) m/e calcd for C18H23NO2 [M þ H]þ
286.1801, found 286.1802.
(2-Methyl-5,6,6a,7,8,9,10,10a-octahydro-7,10-methanophenan-
thridin-6-yl)methanol (13b). To a solution of p-toluidine (93 mg,
0.87 mmol) in dry CH2Cl2 (3.5 mL) was added ethyl glyoxylate
(45 wt % solution in toluene, 210 μL, 0.95 mmol). After stirring
at room temperature for 10 min, norbornene (163 mg, 3.25
mmol) was added in one portion followed by dropwise addition
addition of BF3 OEt2 (41 μL, 0.32 mmol). The reaction was
3
stirred at room temperature for 4 h and then concentrated in
vacuo. The crude residue was dissolved in dry THF (4 mL) and
then transferred by cannula to a cooled (0 °C) suspension of
LiAlH4 (195 mg, 4.88 mmol) in dry THF (8 mL). The reaction
mixture was warmed to room temperature and stirred over-
night, after which the mixture was cooled in an ice bath and
subjected to a Fieser workup (successive dropwise addition of
200 μL of H2O, 200 μL of 15% NaOH solution, and 600 μL of
H2O). The resultant granular suspension was stirred at room
temperature for 2 h, filtered through a pad of Celite, and the
filtrate was concentrated in vacuo. Purification of the crude
material by flash column chromatography on silica gel using a
gradient elution of 25 to 50% ethyl acetate in hexanes afforded
exo-endo-13a followed by exo-exo-13a. exo-endo-13a: Isolated
(48 mg, 11%) as a brown foam; Rf = 0.37 (50:50 hexanes/
of BF3 OEt2 (22 μL, 0.17 mmol). The reaction was stirred at
3
room temperature for 4 h and then concentrated in vacuo. The
crude residue was dissolved in dry THF (4 mL) and then
transferred by cannula to a cooled (0 °C) suspension of LiAlH4
(104 mg, 2.60 mmol) in dry THF (4 mL). The reaction mixture
was slowly warmed to room temperature and stirred overnight,
after which the mixture was cooled in an ice bath and subjected
714 J. Org. Chem. Vol. 75, No. 3, 2010

Smith et al.
JOCArticle
to a Fieser workup (successive dropwise addition of 105 μL of
H2O, 105 μL of 15% NaOH solution, and 315 μL of H2O). The
resultant granular suspension was stirred at room temperature
for 2 h, filtered through a pad of Celite, and the filtrate was
concentrated in vacuo. Purification of the crude material by
flash column chromatography on silica gel using a gradient
elution of 20 to 35% ethyl acetate in hexanes afforded exo-endo-
13b followed by exo-exo-13b. exo-endo-13b: Isolated (22 mg,
10%) as a brown foam; Rf = 0.47 (65:35 hexanes/EtOAc); IR
(thin film) νmax 3380 (br O-H), 3366 (N-H), 2952, 2921, 2869,
1615, 1508, 1455, 1372, 1297, 1278, 1039, 908, 812, 732 cm-1; 1H
NMR (400 MHz, CDCl3) δ 6.93 (1H, s), 6.80 (1H, dd, J = 8.0,
2.0 Hz), 6.52 (1H, d, J = 8.0 Hz), 3.77-3.89 (2H, m), 3.07-3.14
(1H, m), 2.87 (1H, d, J = 8.5 Hz), 2.24 (3H, s), 2.21 (1H, d, J =
4.5 Hz), 2.15 (1H, d, J = 2.0 Hz), 1.92 (1H, dd, J = 8.5, 4.0 Hz),
1.34-1.66 (6H, m), 1.18-1.27 (1H, m), 0.92 (1H, d, J = 10.0
Hz); 13C NMR (100 MHz, CDCl3) δ 144.2 (C), 130.2 (CH),
128.6 (C), 128.3 (C), 126.7 (CH), 115.5 (CH), 65.8 (CH2), 56.7
(CH), 48.2 (CH), 46.5 (CH), 45.4 (CH), 36.7 (CH), 35.0 (CH2),
31.6 (CH2), 28.5 (CH2), 20.6 (CH3); MS (ESIþ) m/e (rel
intensity) 245 (19), 244 (100); HRMS (ESI) m/e calcd for
C16H21NO [M þ H]þ 244.1695, found 244.1696. exo-exo-13b:
Isolated (94 mg, 45%) as an off-white solid; mp 112-114 °C;
Rf = 0.34 (65:35 hexanes/EtOAc); IR (thin film) νmax 3350 (br
O-H), 3325 (N-H), 3017, 2946, 2869, 1615, 1508, 1455, 1359,
1294, 1256, 1082, 1040, 1025, 909, 813, 733 cm-1; 1H NMR (400
MHz, CDCl3) δ 7.01 (1H, s), 6.80 (1H, d, J = 8.0 Hz), 6.52 (1H,
d, J = 8.0 Hz), 3.81 (1H, dd, J = 10.5, 3.0 Hz), 3.52 (1H, dd, J =
10.5, 8.5 Hz), 2.79 (1H, dd, J = 8.5, 3.0 Hz), 2.55-2.59 (2H, m),
2.24 (3H, s), 2.11 (1H, d, J = 3.5 Hz), 1.76 (1H, dd, J = 9.0, 9.0
Hz), 1.54-1.71 (2H, m), 1.52 (1H, dt, J = 10.0, 1.5 Hz),
1.27-1.42 (2H, m), 1.05 (1H, dt, J = 10.0, 1.5 Hz); 13C NMR
(100 MHz, CDCl3) δ 142.9, 129.0, 128.3, 127.3, 126.8, 115.5,
65.9, 57.1, 45.6, 43.3, 43.1, 40.8, 34.3, 29.5, 29.3, 20.7; MS (ESIþ)
m/e (rel intensity) 245 (27), 244 (100); HRMS (EI) m/e calcd for
C16H21NO [M þ H]þ 244.1695, found 244.1702.
Acknowledgment. The Natural Science and Engineering
Research Council (NSERC) of Canada funded this research.
C.D.S. acknowledges receipt of a NSERC PGSD3 scholar-
ship. We thank Dr. Alex Young (University of Toronto) for
mass spectral analysis.
1
Supporting Information Available: Copies of H and 13C
NMR spectra for all new compounds. Experimental procedures
and characterization data for all precursors and isolated side
products. Crystallographic data for compounds exo-exo-1d,
exo-endo-1l, and exo-exo-13a. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 3, 2010 715