A study of Heck cyclization reactions to form phenanthridine ring systems

Article abstract of DOI:10.1016/j.tet.2008.02.044

A survey of conditions for the palladium catalyzed intramolecular Heck cyclization of protected amines has shown that the Herrmann-Beller palladacycle can be exploited under 'cationic' conditions to provide a robust and rapid route (<2 h) to the synthesis

Full text of DOI:10.1016/j.tet.2008.02.044

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 4468e4477
www.elsevier.com/locate/tet
A study of Heck cyclization reactions to form
phenanthridine ring systems
Lauren R. Donaldson a, David Haigh b, Alison N. Hulme a,
*
a School of Chemistry, The University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK
b GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK
Received 23 November 2007; received in revised form 25 January 2008; accepted 14 February 2008
Available online 11 March 2008
Abstract
A survey of conditions for the palladium catalyzed intramolecular Heck cyclization of protected amines has shown that the HerrmanneBeller
palladacycle can be exploited under ‘cationic’ conditions to provide a robust and rapid route (<2 h) to the synthesis of single double bond isomer
phenanthridines in excellent yield (76e99%). In addition, the same cyclization can be performed under ‘neutral’ conditions to provide phenan-
thridines with a double bond isomer profile suitable for exploitation in diversity-based applications. We have also shown that the highly reactive
(tBu3P)2Pd catalyst can induce cyclization at low temperatures (ꢀ50 ꢁC), giving similar results to the ‘neutral’ conditions, and offering an
alternative pathway for sensitive substrates.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Phenanthridines; Heck reaction; Natural product scaffold
1. Introduction
to the lengthy reaction times (typically 24e48 h) and high
temperatures (typically 110e160 ꢁC) required for the cycliza-
tion reaction. Our initial aims were thus twofold to develop
conditions, which might overcome these practical problems,
whilst at the same time promoting the cyclization of a range
of functionalized amine precursors to allow access to a diverse
library based upon the phenanthridine core unit.
The phenanthridine framework 1 lies at the heart of a number
of natural products including the Amaryllidaceae alkaloids such
as the antiviral lycorine 2;1,2 and the Papaveraceae benzophe-
nanthridine alkaloids such as the tubulin polymerization inhib-
itor chelidonine 33 and isochelidonine 4 (Fig. 1).4 These, and the
closely related class of phenanthridones, are known to exhibit
diverse biological activities,5 and thus present excellent targets
for natural product scaffold-based libraries.6 Whilst construc-
tion of the phenanthridone core, which lies at the heart of the
antibiotic pancratistatin, has received considerable attention,5a,b
the synthesis of phenanthridines is comparatively unstudied.
We were attracted to a Heck cyclization-based approach to
the phenanthridine framework as there is good precedent for
cis-stereocontrol in formation of the 6,6-ring junction in
related phenanthridone systems.7 However, we were con-
cerned that the conditions reported were potentially limiting
in a library-based approach to the phenanthridine core due
OH
HO
H
N
H
O
O
H
H
N
H
1
2
HO
HO
O
O
O
O
H
H
O
O
H
H
N
N
Me
Me
O
O
3
4
* Corresponding author. Tel.: þ44 131 650 4711; fax: þ44 131 650 4743.
E-mail address: alison.hulme@ed.ac.uk (A.N. Hulme).
Figure 1. Phenanthridine alkaloid natural products.
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.044

L.R. Donaldson et al. / Tetrahedron 64 (2008) 4468e4477
4469
2. Results and discussion
P
P
2.1. Catalyst screening studies
O
O
O
Pd
Pd
10
Figure 2. HerrmanneBeller palladacycle.
O
To find conditions, which might be applied to the rapid
synthesis of a phenanthridine library using the Heck reaction
(Scheme 1), we first surveyed a range of standard catalysts.
Sulfonamide 5a (P¼SO2Me, Table 1) was found to be readily
accessible through alkylation of commercially available
2-bromobenzylamine with 3-bromocyclohexene, followed by
protection as the methanesulfonamide (84% yield over two
steps). It provided an excellent substrate for catalyst screening
studies (Table 1).
bond isomers.11 Investigation of a range of bases at the optimum
reaction temperature (140 ꢁC) showed that DIPEA gave compa-
rable results to those obtained in the presence of MeNCy2,
however, Et3N, K2CO3 and 2,6-lutidine gave lower conversion
levels (entries 4e7). We were pleased to observe that a switch
in solvent from DMA to DMF (entry 8) resulted in similar or
even enhanced reactivity with almost total conversion in only
35 min. However, at the elevated reaction temperatures required
to ensure complete conversion (140e160 ꢁC), we encountered
serious problems with reproducibility, which we ascribed to
catalyst decomposition and the formation of inert palladium
black.12 The capricious nature of this catalyst system led us to
investigate other possible palladium sources.
The HerrmanneBeller palladacycle (10, Fig. 2) is well-
known as a highly effective source of Pd(0) for the arylation
of alkenes.13 Its reactivity at elevated temperatures has been
attributed to a slow release of Pd(0) into the reaction medium,
thus maintaining a constant level of the active catalytic species
throughout the reaction.14 Its use also has precedent in
intramolecular cyclization reactions.15 The application of 10
as a Pd(0) source in conjunction with the optimum base
MeNCy2 gave relatively rapid cyclization at a range of tem-
peratures (130e150 ꢁC), but led to a diminished selectivity
for the D1,2 double bond isomer (entries 9e11). With the
R'
R'
R'
Heck
H
cyclization
X'
R
R
R
H
P
N
N
NH2
P
X
X
Scheme 1. A Heck cyclization-based retrosynthetic analysis of a phenanthri-
dine library.
Using Pd(OAc)2/PCy3 under standard conditions (Table 1,
entries 1e3), the intramolecular Heck cyclization of 5a was
found to proceed to completion rapidly. In related intramolecu-
lar Heck cyclization reactions of benzamides, a range of double
bond isomers have been reported, including the bridgehead
D10b,1 (6a), D1,2 (7a) and D2,3 (8a) isomers.8,9 In this study,
none of the bridgehead double bond isomer was formed, and
the cis D1,2 isomer (7a) was observed as the major product,10
along with trace amounts of the D2,3 (8a) and D3,4 (9a) double
Table 1
Catalyst screening for the intramolecular Heck cyclization reaction of sulfonamide 5a (P¼SO2Me)
H
H
H
Heck
cyclization
H
P
H
P
H
P
H
P
N
N
N
N
N
P
Br
5a
6a
7a
8a
9a
Entry
Catalysta
Base (equiv)
T (ꢁC)
t (min)
Solvent
Conversionb (%)
Ratio (7a/8a/9a)
1
Pd(OAc)2/PCy3
Pd(OAc)2/PCy3
Pd(OAc)2/PCy3
Pd(OAc)2/PCy3
Pd(OAc)2/PCy3
Pd(OAc)2/PCy3
Pd(OAc)2/PCy3
Pd(OAc)2/PCy3
MeNCy2 (4)
MeNCy2 (4)
MeNCy2 (4)
Et3N (4)
130
140
150
140
140
140
140
140
130
140
150
140
140
140
70
60
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
DMF
DMF
DMF
DMF
DMF
DMF
99
99
98
58
98
87
d
95
85
98
88
76
99
99
77:14:9
96:2:2
95:3:2
2
3
30
70
4
90:2:8
92:5:3
5
DIPEA (4)
K2CO3 (4)
35
40
6
55:27:18
d
94:5:1
7
2,6-Lutidine (4)
MeNCy2 (4)
MeNCy2 (4)
MeNCy2 (4)
MeNCy2 (4)
AgF (1)
d
8
35
9
HerrmanneBeller (10)
HerrmanneBeller (10)
HerrmanneBeller (10)
HerrmanneBeller (10)
HerrmanneBeller (10)
HerrmanneBeller (10)
360
180
110
180c
120
70
39:38:23
44:31:25
52:16:32
65:23:12
67:18:15
85:13:2
10
11
12
13
14
a
Ag3PO4 (1)
Ag2CO3 (1)
[5 mol % Pd(0) source]/[10 mol % ligand].
Conversion was determined through analysis of the 1H NMR of the crude reaction mixture.
No significant change was observed after 180 min, even on leaving reaction for 24 h.
b
c

4470
L.R. Donaldson et al. / Tetrahedron 64 (2008) 4468e4477
1. CAN, MeOH
O
3. LiAlH4, Et2O
0 °C, 40 min
aim of suppressing double bond migration through a cationic
reaction pathway,16 we screened the use of a range of Ag(I)
salts (entries 12e14) as additives.17 We were pleased to dis-
cover that the use of Ag2CO3 in conjunction with the Herr-
manneBeller catalyst led to rapid conversion (70 min at
140 ꢁC), good double bond isomer ratios and excellent
reproducibility.
rt, 16 h
2. i. LiAlH4, Et2O
0 °C - rt, 1 h;
ii. silica, CH2Cl2
3 h
4. CBr4, PPh3,
Et2O, rt, 2 h
O
O
13
Br
14
(66% yield
(48% yield
over 2 steps)
over 2 steps)
5. o-BrPhCH2NH2•HCl,
DIPEA, MeCN, rt, 16 h
6. MeSO2Cl, Et3N,
CH2Cl2, rt, 3 h
2.2. Cyclization of a range of functionalized amines
H
10 (5 mol %)
A range of functionalized amine precursors 5bee (Boc,
Cbz, Bn, PMB) were synthesized from the same intermediate
as used in the formation of sulfonamide 5a in good to excel-
lent yields (81e90%). In all cases, our optimum conditions
employing the HerrmanneBeller catalyst 10 gave excellent
conversions to the phenanthridine core, strongly favouring
the D1,2 isomer (Table 2). With the exception of the PMB-pro-
tected amine precursor 5e, the reactions were complete in
<2 h. The Bn and PMB-protected analogues in particular
showed excellent selectivity for the D1,2 isomer.
H
Ag2CO3 (1 eq)
N
N
SO2Me
DMF, 140 °C, 2 h
SO2Me
Br
(99%)
11
12
(41% yield
over 2 steps)
Scheme 2. Synthesis and Heck cyclization of gem dimethyl analogue 12.
2.3. Diversity-based applications of the phenanthridine
cyclization reaction
The identity and ratios of the Boc and Cbz-protected prod-
ucts (7be9b and 7ce9c, respectively) were determined by
The synthesis of natural product-like libraries based on
strategies, which make use of the rapid introduction of stereo-
chemical and structural diversities,22 is the one which has
gained prominence in recent years as a means to efficiently
cover chemical space.23 The initial results obtained for the cy-
clization of sulfonamide 5a under ‘neutral’ conditions with the
HermanneBeller catalyst (Table 1, entry 10) offer consider-
able potential in this direction. In one step, the phenanthridine
core unit is formed, whilst at the same time the potential for
further diversification, through reaction of the newly formed
double bond at each of the three positions, D1,2, D2,3 and
1
direct correlation of their H NMR spectra with their sulfon-
amide counterparts (7ae9a), and the assignment of minor
peaks was confirmed by TOCSY experiments. For the Bn
and PMB products, extensive 2D NMR analysis confirmed
that the major product in each of these two cases was the
D1,2 isomer (7d and 7e, respectively), whilst the D2,3 and
D3,4 minor products were assigned by analogy with their sul-
fonamide counterparts.
In order to assess the utility of these conditions on a sub-
strate biased towards the formation of a single double bond
isomer, we chose to synthesize the gem dimethyl analogue
of the phenanthridine ring system, 11. The sulfonamide-pro-
tected cyclization precursor 12 was readily accessed (Scheme
2) through conversion of dimedone to the known enone
13,18,19 reduction of 13 to the corresponding enol and conver-
sion to allylic bromide 14,20,21 coupling of bromide 14 with
2-bromobenzylamine and finally sulfonamide protection of
the amine (six steps, 13% overall yield). Heck cyclization of
12 employing the HerrmanneBeller catalyst resulted in quan-
titative conversion in 2 h to a colourless solid, which was
shown to be the desired D1,2 3,3-dimethyl-tetrahydrophenan-
thridine 11.
D
3,4, is introduced. In combination with different amine pre-
cursors, a large and diverse compound library based on the
phenanthridine core might be rapidly assembled (Scheme 3).
Heck
Br
X
cyclization
n
Ar
Ar
n
NH2
N
Br
3 building blocks
3 further sites for
skeletal development
Scheme 3. Diversity oriented synthesis of a phenanthridine library.
To determine the potential versatility of such an approach, we
screened the use of the HerrmanneBeller catalyst across the full
range of amine precursors 5aee (Table 3). Whilst the Boc and
Cbz-protected substrates (5b and 5c) behaved in a similar
manner to 5a, giving a double bond isomer profile suitable for
diversity-based applications, the Bn and PMB-protected
substrates (5d and 5e) gave predominantly the D1,2 isomer.
The highly reactive catalyst (tBu3P)2Pd has been used to
conduct intermolecular Heck coupling reactions at rt.24 How-
ever, this catalyst system has limited precedent in intramolec-
ular Heck cyclizations,25 and only one example of its use at
Table 2
Cyclization reactions of a range of functionalized aminesa
Amine
P
t (min)
Yield (%)
Ratio (7/8/9)
5a
5b
5c
5d
5e
a
SO2Me
Boc
Cbz
70
120
120
120
160
99
99
99
92
76
85:13:2
83:15:2
92:6:2
100:0:0b
97:3:0
Bn
PMB
Reagents and conditions: aryl halide (1 equiv), palladacycle 10 (5 mol %),
Ag2CO3 (1 equiv), DMF, 140 ꢁC.
b
Minor isomer peaks could not be quantified.

L.R. Donaldson et al. / Tetrahedron 64 (2008) 4468e4477
4471
Table 3
Cyclization under neutral HerrmanneBeller conditionsa
catalysts showed no significant changes in selectivity. In sharp
contrast, our study demonstrates that in the intramolecular
Heck reaction where the two components are linked as the
protected benzylamine, the palladium catalyst plays a pivotal
role in double bond isomerism under otherwise identical con-
ditions (entry 8 vs entry 10, Table 1). Furthermore, when we
re-subjected the isolated D1,2 and D2,3 double bond isomers
(7a and 8a, respectively) to each of the optimized reaction
conditions, which should allow a base-catalyzed double
bond migration, each isomer was recovered unchanged even
after 48 h, strongly suggesting that the double bond ratios
are established at the time of cyclization. Indeed when the
reaction of the sulfonamide precursor 5a was monitored by
1H NMR, the double bond isomer ratio was found to be con-
sistent with the final ratio from the earliest timepoint measured
and did not show a significant deviation from this ratio through
the remainder of the reaction. These results suggest that the
double bond isomer ratio obtained in these intramolecular
Heck cyclization reactions is a product of the differing rates
of decomplexation of each catalyst compared to the rate of
hydropalladation/dehydropalladation in each case.30
Amine
P
t (h)
Yield (%)
Ratio (7/8/9)
5a
5b
5c
5d
5e
a
SO2Me
Boc
Cbz
3
3
3
5
5
98
95
99
93
93
44:31:25
36:38:26
33:39:28
83:8:9
Bn
PMB
74:13:13
Reagents and conditions: aryl halide (1 equiv), MeNCy2 (4 equiv), pallada-
cycle 10 (5 mol %), DMF, 140 ꢁC.
low temperatures (40 ꢁC) has been reported,25c with no exam-
ples of its application in a system similar to ours. We explored
the use of this catalyst with amine precursors 5aee (Table 4).
Whilst, the intermolecular reactions are typically conducted in
dioxane,24,26e28 the use of this solvent in our system led to
very low conversions. A simple solvent switch to MeCN gave
much more promising results and we observed complete conver-
sion of sulfonamide 5a to products 7ae9a at room temperature.
However, the Boc and Cbz-protected precursors required a
slightly elevated temperature (50 ꢁC) for the cyclization reac-
tion to proceed to completion. Intriguingly, the Bn and PMB-
protected substrates 5d and 5e showed little or no reactivity at
either temperature.
3. Conclusions
These results suggest that this low-temperature cyclization
offers a viable route for the synthesis of more-sensitive mem-
bers of a phenanthridine library.
These catalyst screening studies allow the following
conclusions to be drawn: firstly, for applications of the Heck
cyclization reaction to give phenanthridine ring systems where
a single double bond isomer is required, the HerrmanneBeller
catalyst employed under cationic conditions (Ag2CO3) pro-
vides a >85:15 ratio of isomers in favour of the D1,2 isomer
in all cases. Excellent yields (76e99%) are obtained in short
reaction times (<160 min). Where the double bond migration
process is hindered (e.g., in the case of the gem dimethyl
precursor 15), a 99% yield of a single reaction product is
obtained under these conditions. Intriguingly, for sulfonamide
or carbamate-protected precursors, two further options of syn-
thetic utility have been revealed. Rapid cyclization (<5 h) to
give high yields (95e99%) of an approximately equal mixture
of three double bond isomers may be achieved using the Herr-
manneBeller catalyst under ‘neutral’ pathway conditions. The
potential for exploitation of this result on more sensitive sub-
strates is increased by using the highly reactive (tBu3P)2Pd cat-
alyst; here cyclization may be achieved at comparatively low
temperatures (rte50 ꢁC). These results offer considerable
potential for a diversity-based approach to a phenanthridine li-
brary, as in a single step both the phenanthridine core and the
potential for further structural diversity are introduced. We are
currently pursuing the application of this strategy to a natural
product-based library.
2.4. Preliminary mechanistic investigations
We have shown that the double bond isomer profile
obtained under each of the optimized conditions shows dra-
matic variation, e.g., from 92:6:2 to 33:39:28 for cyclization
of 5c. Beller has concluded that in the intermolecular Heck
reaction of arylbromides with cyclohexene and cyclopentene,
double bond migration is predominantly catalyzed by the
base used in the reaction and not by an HPdX complex.29 In
this simple intermolecular equivalent of our study, the choice
of solvent and base was shown to have an important influence
on the extent of CeC double bond migration, whilst different
Table 4
Cyclization under low-temperature conditionsa
Amine
P
Method
t (h)
Yield (%)
Ratio (7/8/9)
5a
SO2Me
A
B
9
4
99
99
12:65:23
55:41:4
5b
5c
5d
Boc
Cbz
Bn
A
B
40
7
50
95
34:43:22
34:37:29
A
B
40
7
64
85
53:34:13
36:5:59
A
B
72
40
No reaction
23
d
n.d.b
4. Experimental
5e
PMB
A
B
72
40
No reaction
No reaction
d
d
4.1. General
a
Reagents and conditions. Method A: aryl halide (1 equiv), Pd2(dba)3
(5 mol %), tBu3PHBF4 (10 mol %), MeNCy2 (4 equiv), MeCN, rt; method
B: As method A at 50 ꢁC.
All non-aqueous reactions were carried out under an atmo-
sphere of nitrogen using flame- or oven-dried glassware.
Unless otherwise noted, starting materials and reagents were
b
Not determined.

4472
L.R. Donaldson et al. / Tetrahedron 64 (2008) 4468e4477
obtained from commercial suppliers and were used without fur-
ther purification. CH2Cl2, Et3N and DIPEA were distilled from
calcium hydride. Et2O was dried and purified by passage
through activated alumina columns using a solvent purification
system from www.glasscontour.com. Anhydrous DMF and ace-
tonitrile were used as supplied by BakerDRY. Anhydrous 1,4-
dioxane was used as supplied by Aldrich. Purification by flash
column chromatography was carried out using Merck Kieselgel
60 silica gel as the stationary phase. IR spectra were measured
on a Biorad FTS-7 or PerkineElmer Paragon 1000 FT-IR spec-
trometer as thin films unless otherwise stated. 1H and 13C NMR
spectra were measured on a Bruker AC250 or Bruker DPX360;
J values are reported in hertz. Melting points were determined
on a Gallenkamp Electrothermal Melting Point apparatus and
are uncorrected. Fast atom bombardment (FAB) mass spectra
were obtained using a Kratos MS50TC mass spectrometer at
The University of Edinburgh. High performance liquid chroma-
tography (HPLC) was carried out using a Gilson instrument
fitted with a refractive index detector, using a microsorb
100e5 Si column (length 250 mm, i.d. 21.4 mm, particle size
5 mm). A standard flow rate of 8.0 cm3 minꢂ1 was used. All sol-
vents used for HPLC were filtered prior to use. Double bond
isomer ratios were assigned on the basis of the 1H NMR spectra,
which are included in Supplementary data.
NMR d (62.9 MHz, CDCl3) 139.5 (C), 132.5 (CH), 130.0 (CH),
129.6 (CH), 128.9 (CH), 128.2 (CH), 127.2 (CH), 123.7 (C),
52.3 (CH), 50.8 (CH2), 29.2 (CH2), 25.1 (CH2), 19.9 (CH2).
4.2.2. N-(2-Bromo-benzyl)-N-cyclohex-2-enyl-methanesul-
fonamide 5a
To a solution of N-(2-bromo-benzyl)-cyclohex-2-enyl-amine
hydrochloride (3.90 g, 14.6 mmol) in CH2Cl2 (50 mL) at 0 ꢁC
were added Et3N (6.20 mL, 43.8 mmol) and methanesulfonyl
chloride (3.40 mL, 43.8 mmol), and the reaction mixture was
warmed to rt and stirred for 16 h. The reaction mixture was
diluted with Et2O (30 mL) and washed with H2O (2ꢃ30 mL),
HCl (2ꢃ30 mL, 1 M aq) and NaHSO3 (2ꢃ30 mL, satd aq). The
organics were dried (MgSO4), concentrated under reduced pres-
sure and purified byflashchromatography(CH2Cl2/1% MeOH in
CH2Cl2). The resultant solid was washed with Et2O (3ꢃ30 mL)
and dried to afford sulfonamide-protected amine 5a as a colour-
less solid (4.95 g, 99%). Rf [3:1, hexane/EtOAc]¼0.46; mp
100 ꢁC; nmax (CHCl3)/cmꢂ1 1332, 1145; 1H NMR d (250 MHz,
CDCl3) 7.67 (1H, dd, J 7.8, 0.8), 7.49 (1H, dd, J 7.9, 1.2), 7.33
(1H, td, J 7.7, 1.2), 7.12 (1H, m), 5.98e5.93 (1H, m),
5.53e5.47 (1H, m), 4.66e4.57 (1H, m), 4.47 (1H, dd, J 17.7),
4.33 (1H, d, J 17.7), 2.97 (3H, s), 1.99e1.92 (3H, m),
1.70e1.34 (3H, m); 13C NMR d (62.9 MHz, CDCl3) 137.7 (C),
133.7 (CH), 132.1 (CH), 129.2 (CH), 128.4 (CH), 127.3 (CH),
126.5 (CH), 121.9 (C), 55.6 (CH), 47.5 (CH2), 39.4 (CH3), 28.7
(CH2), 24.2 (CH2), 21.4 (CH2); m/z (FAB, THIOG) 346
([81BrMþH]þ, 64%), 344 ([79BrMþH]þ, 68), 266 (80), 264
(85). HRMS (FAB, THIOG) found: [81BrMþH]þ, 346.0326;
C14H19NO2S81Br requires: 346.0301. Found: [79BrMþH]þ,
344.0346; C14H19NO2S79Br requires: 344.0320.
4.2. Preparation of protected amines 5aee
4.2.1. N-(2-Bromo-benzyl)-cyclohex-2-enyl-amine
hydrochloride
To a solution of 2-bromobenzylamine hydrochloride (6.00 g,
27.0 mmol) in MeCN (100 mL) at 0 ꢁC was added DIPEA
(18.8 mL, 108 mmol) and the reaction mixture was stirred for
5 min. 3-Bromocyclohexene (3.10 mL, 27.0 mmol) was added
and the reaction mixture stirred for 16 h at rt. The reaction mixture
was concentrated under reduced pressure and the residue taken up
in CH2Cl2 (50 mL) and washed with NaCl (3ꢃ50 mL, satd aq).
The organics were combined, dried (MgSO4) and concentrated
under reduced pressure. The residue was taken up in CH2Cl2
(3 mL), HCl (30 mL, 1.0 M in Et2O, 30.0 mmol) added and the re-
sultant suspension filtered to afford the amine hydrochloride as
a colourless solid (7.15 g, 99%). Mp 142 ꢁC; 1H NMR
d (250 MHz, CD3OD) 7.79 (1H, dd, J 8.0, 1.3), 7.66 (1H, dd, J
7.6), 7.53 (1H, td, J 7.6, 1.3), 7.43 (1H, td, 7.9, 1.7), 6.29e6.23
(1H, m), 5.91e5.87 (1H, m), 4.46 (2H, s), 4.06e4.03 (1H, m),
2.28e2.18 (3H, m), 1.94e1.87 (3H, m); 13C NMR d (250 MHz,
CD3OD) 135.4 (CH), 133.0 (CH), 131.6 (CH), 131.1 (CH),
130.9 (C), 128.0 (CH), 124.5 (C), 120.7 (CH), 54.3 (CH), 46.9
(CH2), 24.8 (CH2), 23.9 (CH2), 18.8 (CH2); m/z (FAB, THIOG)
266 ([81BrMꢂH]þ, 86%), 264 ([79BrMꢂH]þ, 70), 262 (27), 239
(25), 238 (28.5), 186 (91), 184 (88). HRMS (FAB, THIOG) Found:
4.2.3. (2-Bromo-benzyl)-cyclohex-2-enyl-carbamic acid
tert-butyl ester 5b
To a suspension of N-(2-bromo-benzyl)-cyclohex-2-enyl-
amine hydrochloride (500 mg, 1.87 mmol) in CH2Cl2 (20 mL)
was added Et3N (395 mL, 2.81 mmol). After 10 min, the reaction
mixture was cooled to 0 ꢁC, Boc2O (613 mg, 2.81 mmol) in
CH2Cl2 (5 mL) was added and the reaction mixture was stirred
for a further 10 min. The reaction mixture was warmed to rt
and stirred for 16 h. The reaction mixture was diluted with
CH2Cl2 (20 mL), extracted with NaCl (3ꢃ20 mL, satd aq), dried
(MgSO4) and concentrated under reduced pressure. Flash
chromatography (10:1:0.1, hexane/EtOAc/Et3N) afforded
Boc-protected amine 5b as a colourless oil (685 mg, 90%). Rf
[3:1, hexane/EtOAc]¼0.8; mp 81 ꢁC; nmax (CHCl3)/cmꢂ1
1
3057, 3021, 1695, 1274, 1253; H NMR d (360 MHz, 318 K,
CDCl3) 7.51 (1H, d, J 7.7), 7.29e7.26 (2H, m), 7.11e7.07
(1H, m), 5.83 (1H, br s), 5.50 (1H, d, J 10.1), 4.90 (1H, br s),
4.38 (2H, br s), 2.10e1.81 (3H, m), 1.81e1.70 (1H, m), 1.55e
1.46 (2H, m), 1.35 (9H, s); 13C NMR d (90.6 MHz, 318 K,
CDCl3) 155.6 (C), 132.2 (CH), 131.7 (CH), 130.8 (C), 128.0
(CH), 127.7 (CH), 127.3 (CH), 126.9 (CH), 121.9 (C), 79.7
(C), 53.0 (CH), 52.6 (CH2), 28.0 (3ꢃCH3), 27.3 (CH2), 24.4
(CH2), 21.2 (CH2); m/z (FAB, THIOG) 368 ([81BrMþH]þ,
12%), 366 ([79BrMþH]þ, 15), 313 (33), 312 (68), 311 (39), 310
(70), 266 (28), 232 (57), 230 (51). HRMS (FAB, THIOG) found:
[
[
81BrMꢂH]þ, 266.0372; C13H15N81Br requires: 266.0369. Found:
79BrMꢂH]þ, 264.0383; C13H15N79Br requires: 264.0388. Free
amine: Rf [3:1, hexane/EtOAc]¼0.90; nmax (CH2Cl2)/cmꢂ1 3361,
1466, 1436, 1010, 747; 1H NMR d (250 MHz, CDCl3) 7.68 (1H,
dd, J 7.9, 1.3), 7.60 (1H, dd, J 7.7, 1.7), 7.43 (1H, td, J 7.4, 1.1),
7.26 (1H, td, J 7.6, 1.8), 5.97e5.87 (2H, m), 4.10 (1H, d, J 13.8),
4.03 (1H, d, J 13.8), 3.38 (1H, br s), 2.17e1.66 (6H, m); 13C

L.R. Donaldson et al. / Tetrahedron 64 (2008) 4468e4477
4473
[
Found:
366.1069.
81BrMþH]þ, 368.1046; C18H25NO821Br requires: 368.1050.
([81BrMþH]þ, 52%), 354 ([79BrMþH]þ, 47%), 329 (35), 327
(35), 276 (75), 274 (53), 184 (34), 171 (69), 169 (71). HRMS
(FAB, THIOG) found: [81BrMþH]þ, 356.0838; C20H23NO821Br
[
79BrMþH]þ, 366.1067; C18H25NO729Br requires:
requires: 356.0838. Found:
C20H23NO729Br requires: 354.0857.
[
79BrMþH]þ, 354.0856;
4.2.4. (2-Bromo-benzyl)-cyclohex-2-enyl-carbamic acid
benzyl ester 5c
To a suspension of NaH (143 mg, 60% dispersion in mineral
oil, 3.62 mmol) in DMF (10.0 mL) at 0 ꢁC was added
4.2.6. (2-Bromo-benzyl)-cyclohex-2-enyl-(4-methoxy-
benzyl)-amine 5e
N-(2-bromo-benzyl)-cyclohex-2-enyl-amine
hydrochloride
To a suspension of N-(2-bromo-benzyl)-cyclohex-2-enyl-
amine hydrochloride (750 mg, 2.81 mmol) in DMF (20 mL) at
0 ꢁC was added NaH (246 mg, 60% dispersion in mineral oil,
6.18 mmol) and the reaction mixture was stirred until homoge-
neous. The reaction mixture was warmed to rt and stirred for
30 min, and then cooled to 0 ꢁC, p-methoxybenzyl bromide
(614 mL, 4.21 mmol) was added and the reaction mixture stirred
for 15 min. Thereactionmixturewas warmed to rtand stirred for
16 h. Et2O (30 mL) was added, the organics washed with NaCl
(3ꢃ20 mL, satd aq), concentrated under reduced pressure and
purified by flash chromatography (100:1.5:0.1, hexane/EtOAc/
NH3) to afford PMB-protected amine 5e as a colourless oil
(912 mg, 84%). Rf [3:1, hexane/EtOAc]¼0.81; nmax (CHCl3)/
cmꢂ1 2857, 1541, 1508, 1457, 1248, 750; 1H NMR
d (360 MHz, CDCl3) 7.69 (1H, d, J 7.8), 7.47 (1H, dd, J 7.8),
7.31e7.25 (3H, m), 7.04 (1H, td, J 7.8, 1.7), 6.83 (2H, dd, J
6.7, 1.8), 5.85e5.82 (1H, m), 5.76 (1H, d, J 10.5), 3.76 (3H,
s), 3.75 (2H, m), 3.70 (1H, d, J 13.8), 3.55 (1H, d, J 13.8),
3.34 (1H, br s), 2.04e1.93 (3H, m), 1.83e1.75 (1H, m),
1.58e1.48 (2H, m); 13C NMR d (90.6 MHz, CDCl3) 158.3
(C), 139.6 (C), 132.2 (C), 132.1 (CH), 130.4 (CH), 130.1
(2ꢃCH), 129.4 (2ꢃCH), 127.7 (CH), 127.0 (CH), 123.9 (C),
113.4 (2ꢃCH), 55.0 (CH3), 54.9 (CH), 53.3 (CH2), 52.9
(CH2), 25.2 (CH2), 23.4 (CH2), 21.7 (CH2); m/z (FAB, THIOG)
389 ([81BrMþH]þ, 15%), 387 ([79BrMþH]þ, 43), 359 (53), 357
(54), 306 (43.9), 304 (41.2), 280 (21.8), 278 (24.4), 216 (35.9),
214 (21.0). HRMS (FAB, THIOG) found: [81BrMþH]þ,
388.1068; C21H25NO81Br requires: 388.1100. Found:
(500 mg, 1.65 mmol) in DMF (10.0 mL). The solution was
stirred for 30 min and then benzyl chloroformate (302 mL,
2.15 mmol) was added dropwise and the reaction mixture was
warmed to rt and stirred for 16 h. The reaction mixture was di-
luted with Et2O (20 mL), extracted with NaCl (3ꢃ20.0 mL,
satd aq), dried (MgSO4) and concentrated under reduced pres-
sure to give the crude product. Flash chromatography
(100:1:0.1 to 100:5:0.1, hexane/EtOAc/Et3N) afforded Cbz-
protected amine 5c as a colourless oil (570 mg, 86%). Rf
[10:1, hexane/EtOAc]¼0.54; mp 48 ꢁC; nmax (CHCl3)/cmꢂ1
1
3064, 3021, 1699, 1407, 1258; H NMR d (360 MHz, 323 K,
CDCl3) 7.52 (1H, d, J 5.8), 7.40e7.22 (7H, m), 7.11e7.08
(1H, m), 5.87e5.85 (1H, m), 5.48 (1H, d, J 10.2), 5.16 (2H, br
s), 4.89 (1H, br s), 4.51 (1H, d, J 17.4), 4.44 (1H, d, J 17.4),
2.11e1.84 (3H, m), 1.80e1.70 (1H, m), 1.70e1.47 (2H, m);
13C NMR d (90.6 MHz, 323 K, CDCl3) 156.4 (C), 138.4 (C),
136.7 (C), 132.4 (2ꢃCH), 128.3 (CH), 127.9 (CH), 127.7
(3ꢃCH), 127.6 (3ꢃCH), 127.1 (CH), 122.1 (C), 67.3 (CH2),
53.8 (CH), 47.7 (CH2), 28.1 (CH2), 24.5 (CH2), 21.2 (CH2);
m/z (FAB, 3-NOBA) 402 ([81BrMþH]þ, 35%), 400
([79BrMþH]þ, 38), 310 (22), 308 (22), 171 (69), 169 (50).
HRMS (FAB, THIOG) found:
[
81BrMþH]þ, 402.0821;
C21H23O281BrN requires: 402.0979. Found: [79BrMþH]þ,
400.0918; C21H23O279BrN requires: 400.0912.
4.2.5. Benzyl-(2-bromo-benzyl)-cyclohex-2-enyl-amine 5d
To a suspension of N-(2-bromo-benzyl)-cyclohex-2-enyl-
amine hydrochloride (750 mg, 2.47 mmol) in DMF (20 mL) at
0 ꢁC was added NaH (217 mg, 60% dispersion in mineral oil,
5.43 mmol) and the reaction mixture stirred for 30 min. Benzyl
bromide (382 mL, 3.21 mmol)was added dropwise, and thereac-
tion mixture warmed to rt and stirred for 16 h. Et2O (20 mL) was
added and the organics washed with NaCl (3ꢃ30 mL, satd aq),
dried (MgSO4), concentrated under reduced pressure and puri-
fied by flash chromatography (100:1:0.1, hexane/EtOAc/NH3)
to afford benzyl-protected amine 5d as a colourless oil
(712 mg, 81%). Rf [hexane]¼0.29; nmax (CHCl3)/cmꢂ1 3057,
3019, 1026; 1H NMR d (360 MHz, CDCl3) 7.71 (1H, dd, J 7.7,
1.6), 7.49 (1H, dd, J 8.0, 1.2), 7.40 (2H, d, J 7.4), 7.31e7.27
(3H, m), 7.27e7.21 (1H, m), 7.07 (1H, td, J 7.9, 1.8),
5.89e5.84 (1H, m), 5.79 (1H, d, J 10.4), 3.81 (1H, d, J 15.3),
3.78 (1H, d, J 14.0), 3.75 (1H, d, J 15.3), 3.63 (1H, d, J 14.0),
3.39e3.36 (1H, m), 2.08e1.95 (3H, m), 1.85e1.76 (1H, m),
1.64e1.42 (2H, m); 13C NMR d (90.6 MHz, CDCl3) 140.3
(C), 139.5 (C), 132.3 (CH), 130.4 (CH), 130.3 (CH), 130.2
(CH), 128.4 (2ꢃCH), 128.0 (2ꢃCH), 127.8 (CH), 127.2 (CH),
126.6 (CH), 124.0 (C), 55.2 (CH), 54.0 (CH2), 53.1 (CH2),
25.2 (CH2), 23.5 (CH2), 21.7 (CH2); m/z (FAB, THIOG) 356
[
79BrMþH]þ, 386.1121. C21H25NO79Br requires: 386.1120.
4.3. Heck cyclization conditions employed in Tables 2e4
4.3.1. Conditions for Table 2
To a degassed solution of the aryl halide (1 equiv) in DMF
were added palladacycle 10 (5 mol %) and Ag2CO3 (1 equiv),
and the reaction mixturewas heated at 140 ꢁC. At the conclusion
of the reaction (as judged by TLC), the mixture was allowed to
cool and then diluted with Et2O (20 mL) and washed with NaCl
(3ꢃ20 mL, satd aq). The organics were combined, dried
(MgSO4) and concentrated under reduced pressure to afford
the crude product, which was purified by column chromatogra-
phy to give the stated mixture of double bond isomers.
4.3.2. Conditions for Table 3
To a degassed solution of the aryl halide (1 equiv) in DMF
were added palladacycle 10 (5 mol %) and MeNCy2 (4 equiv),
and the reaction mixture was heated at 140 ꢁC. At the conclu-
sion of the reaction (as judged by TLC), the mixture was
allowed to cool and then diluted with Et2O (20 mL) and

4474
L.R. Donaldson et al. / Tetrahedron 64 (2008) 4468e4477
washed with NaCl (3ꢃ20 mL, satd aq). The organics were
combined, dried (MgSO4) and concentrated under reduced
pressure to afford the crude product, which was purified by
column chromatography to give the stated mixture of double
bond isomers.
NMR d (360 MHz, CDCl3) 7.37 (1H, d, J 7.8), 7.26 (1H, t, J
7.2), 7.19 (1H, t, J 7.3), 7.07 (1H, d, J 7.4), 5.83e5.80 (1H,
m), 5.61 (1H, dt, J 10.2, 1.0), 4.87e4.83 (1H, m), 4.59 (1H, d,
J 16.5), 4.26 (1H, d, J 16.5), 3.39 (1H, br s), 2.83 (3H, s),
2.43e2.38 (1H, m), 2.05e1.97 (1H, m), 1.94e1.76 (2H, m);
13C NMR d (90.6 MHz, CDCl3) 134.5 (C), 133.0 (CH), 132.4
(C), 127.3 (CH), 126.9 (CH), 126.1 (2ꢃCH), 125.8 (CH), 52.4
(CH), 43.3 (CH2), 39.8 (CH3), 34.1 (CH), 25.3 (CH2), 20.1
(CH2). This compound was also fully characterized by COSY,
HSQC and NOESY 2D NMR studies.
4.3.3. Conditions for Table 4
To a degassed solution of the aryl halide (1 equiv) and
MeNCy2 (4 equiv) in MeCN were added Pd2(dba)3
(5 mol %) and tBu3PHBF4 (10 mol %), and the reaction
mixture stirred at rt (or 50 ꢁC) for the indicated time. At the
conclusion of the reaction (as judged by TLC), the mixture
was diluted with Et2O (20 mL) and washed with NaCl
(3ꢃ20 mL, satd aq). The organics were combined, dried
(MgSO4) and concentrated under reduced pressure to afford
the crude product, which was purified by column chromatog-
raphy to give the stated mixture of double bond isomers.
4.4.2. Boc-functionalized phenanthridines 7be9b
4.4.2.1. (4aSR,10bSR)-4,4a,6,10b-Tetrahydro-3H-phenanthri
dine-5-carboxylic acid tert-butyl ester 7b (D1,2 isomer). Rf
[10:1, hexane/EtOAc]¼0.42; nmax (CHCl3)/cmꢂ1 3026, 1693,
1
1258, 913, 745; H NMR d (360 MHz, 323 K, CDCl3) 7.30
(1H, d, J 7.5), 7.25e7.17 (2H, m), 7.12 (1H, d, J 7.2), 6.17e
6.13 (1H, m), 5.87e5.83 (1H, m), 4.71 (1H, d, J 16.5), 4.41
(1H, br s), 4.39 (1H, d, J 16.5), 3.57 (1H, br s), 2.31e2.27
(1H, m), 2.15e2.05 (1H, m), 1.79e1.69 (1H, m), 1.61e1.40
(10H, m, 3ꢃCH3þCHCHD); 13C NMR d (90.0 MHz, 323 K,
CDCl3) 155.0 (C), 137.8 (C), 132.5 (C), 128.3 (CH), 128.1
(C), 127.6 (CH), 127.3 (CH), 126.8 (CH), 126.1 (CH), 125.9
(CH), 79.6 (CH), 43.5 (CH2), 37.3 (CH), 28.5 (3ꢃCH3), 25.3
(CH2), 24.2 (CH2); m/z (FAB, THIOG) 284 ([MꢂH]þ, 44%),
228 (66), 184 (49), 130 (25). HRMS (FAB, THIOG) found:
[MꢂH]þ, 284.1643; C18H22NO2 requires: 284.1650.
4.4. Data for phenanthridines 7e9
4.4.1. Sulfonamide-functionalized phenanthridines 7ae9a
4.4.1.1. (4aSR,10bSR)-5-Methanesulfonyl-3,4,4a,5,6,10b-hexa-
hydro-phenanthridine 7a (D1,2 isomer). Colourless oil. Rf [3:1,
hexane/EtOAc]¼0.38; tR [11:9, hexane/EtOAc] 15.9 min; nmax
(CHCl3)/cmꢂ1 3029, 1671, 1328, 1152; 1H NMR d (360 MHz,
CDCl3) 7.31 (1H, d, J 7.5), 7.26 (1H, t, J 7.8), 7.19 (1H, t, J
7.3), 7.10 (1H, d, J 7.5), 5.58 (1H, ddt, J 10.0, 4.8, 1.9),
5.86 (1H, dtd, J 10.0, 3.9, 1.7), 4.59 (1H, d, J 16.2), 4.43
(1H, d, J 16.2), 4.19 (1H, dt, J 8.4, 5.8), 3.66 (1H, br s),
2.74 (3H, s), 2.27e2.20 (2H, m), 1.87e1.81 (2H, m); 13C
NMR d (90.0 MHz, CDCl3) 136.9 (C), 131.1 (C), 128.5
(CH), 127.7 (CH), 127.6 (CH), 126.7 (CH), 126.3 (CH),
125.9 (CH), 52.1 (CH), 44.1 (CH2), 38.2 (CH3), 37.4 (CH),
25.1 (CH2), 24.0 (CH2); m/z (FAB, THIOG) 264 ([MþH]þ,
19%), 217 (25), 130 (79), 109 (38). HRMS (FAB, THIOG)
found: [MþH]þ, 264.1050. C14H18NO2S requires: 264.1058.
This compound was also fully characterized by COSY,
HSQC and NOESY 2D NMR studies.
4.4.2.2. Diagnostic data for 8b (D2,3 isomer). 1H NMR
d (360 MHz, 323 K, CDCl3) 5.73e5.65 (1H, m), 5.44e5.40
(1H, m), 4.55 (1H, d, J 10.9), 4.48 (1H, d, J 10.9), 3.21
(1H, t, J 4.8), 2.88 (1H, dd, J 29.3, 5.0), 2.67e2.55 (1H, m).
4.4.2.3. Diagnostic data for 9b (D3,4 isomer). 1H NMR
d (360 MHz, 323 K, CDCl3) 5.73e5.65 (1H, m), 5.53 (1H,
dd, J 10.2, 0.9), 5.09 (1H, br s), 4.86 (1H, d, J 16.8), 4.25
(1H, d, J 16.8), 3.30 (1H, br s), 2.45e2.38 (1H, m).
4.4.3. Cbz-functionalized phenanthridines 7ce9c
4.4.1.2. (4aSR,10bSR)-5-Methanesulfonyl-1,4,4a,5,6,10b-hexa-
hydro-phenanthridine 8a (D2,3 isomer). Colourless solid. Rf
[3:1, hexane/EtOAc]¼0.32; tR [11:9, hexane/EtOAc]
4.4.3.1. (4aSR,10bSR)-4,4a,6,10b-Tetrahydro-3H-phenanthri
dine-5-carboxylic acid benzyl ester 7c (D1,2 isomer). Rf [10:1,
hexane/EtOAc]¼0.34; nmax (CHCl3)/cmꢂ1 3030, 1698, 1410,
1
18.1 min; mp 140 ꢁC; H NMR d (360 MHz, CDCl3) 7.29e
1
7.23 (3H, m), 7.17 (1H, dd, J 6.5, 1.8), 5.69e5.66 (1H, m),
5.42 (1H, ddt, J 10.0, 5.1, 2.3), 4.53 (2H, s), 4.29 (1H, ddd, J
10.4, 4.0, 2.4), 3.26e3.22 (1H, m), 2.94 (3H, s), 2.92e2.85
(1H, m), 2.69e2.58 (1H, m), 2.28e2.23 (1H, m), 1.80e1.71
(1H, m); 13C NMR d (90.0 MHz, CDCl3) 135.6 (C), 128.5
(C), 127.3 (CH), 126.5 (CH), 126.4 (CH), 125.3 (CH), 124.9
(CH), 123.8 (CH), 51.7 (CH), 45.0 (CH2), 37.7 (CH3), 35.8
(CH), 27.9 (CH2), 26.5 (CH2). This compound was also fully
characterized by COSY, HSQC and NOESY 2D NMR studies.
1263; H NMR d (360 MHz, 323 K, CDCl3) 7.29e7.22 (6H,
m), 7.19e7.07 (2H, m), 7.01 (1H, d, J 6.1), 6.06e6.02 (1H,
m), 5.77e5.73 (1H, m), 5.12 (2H, s), 4.72 (1H, d, J 16.6), 4.41
(1H, br s), 4.36 (1H, d, J 16.6), 3.49 (1H, br s), 2.24e2.09
(1H, m), 2.07e1.95 (1H, m), 1.67e1.63 (1H, m), 1.56e1.48
(1H, m); 13C NMR d (90.6 MHz, 323 K, CDCl3) 155.5 (C),
137.6 (C), 136.9 (C), 132.0 (C), 128.4 (2ꢃCH), 128.3 (CH),
127.9 (CH), 127.8 (2ꢃCH), 127.6 (CH), 127.1 (CH), 127.0
(CH), 126.0 (CH), 126.0 (CH), 67.1 (CH2), 50.7 (CH), 43.6
(CH2), 37.2 (CH), 25.1 (CH2), 24.2 (CH2); m/z (FAB, THIOG)
320 ([MþH]þ, 24%), 318 ([MꢂH]þ, 51), 274 (37), 228 (26),
154 (61). HRMS (FAB, THIOG) found: [MꢂH]þ 318.1483;
C21H20NO2 requires: 318.1494.
4.4.1.3. (4aSR,10bSR)-5-Methanesulfonyl-1,2,4a,5,6,10b-hexa-
hydro-phenanthridine 9a (D3,4 isomer). Colourless oil. Rf [3:1,
1
hexane/EtOAc]¼0.39; tR [11:9, hexane/EtOAc] 15.4 min; H

L.R. Donaldson et al. / Tetrahedron 64 (2008) 4468e4477
4475
4.4.3.2. Diagnostic data for 8c (D2,3 isomer). 1H NMR
d (360 MHz, 323 K, CDCl3) 5.69e5.65 (1H, m), 5.41e5.37
(1H, m), 4.65 (1H, d, J 16.6), 4.59 (1H, d, J 16.6), 3.20
(1H, br s), 2.88e2.81 (1H, m), 2.63e2.55 (1H, m).
4.4.5.2. Diagnostic data for 8e (D2,3 isomer). 1H NMR
d (360 MHz, CDCl3) 5.68e5.65 (1H, m), 5.56e5.53 (1H,
m), 3.98 (1H, d, J 13.2), 3.18 (1H, br s), 2.71e2.65 (1H, m).
4.4.5.3. Diagnostic data for 9e (D3,4 isomer). 1H NMR
d (360 MHz, CDCl3) 5.96e5.91 (1H, m), 5.90e5.84 (1H,
m), 4.05 (1H, J 13.3), 3.11 (1H, br s).
1
4.4.3.3. Diagnostic data for 9c (D3,4 isomer). H NMR
d (360 MHz, 323 K, CDCl3) 5.75e5.71 (1H, m), 5.55 (1H, d,
J 9.7), 4.95 (1H, d, J 16.6), 4.33 (1H, d, J 16.6), 3.33 (1H, br s).
4.5. Synthesis and cyclization of gem dimethyl analogue 12
4.4.4. Bn-functionalized phenanthridines 7de9d
4.5.1. 5,5-Dimethyl-cyclohex-2-enol20
4.4.4.1. (4aSR,10bSR)-5-(Benzyl)-3,4,4a,5,6,10b-hexahydro-
phenanthridine7d(D1,2 isomer). Rf [10:1, hexane/EtOAc]¼0.44;
nmax (CHCl3)/cmꢂ1 3025, 1642, 1602, 1260; 1H NMR
d (360 MHz, CDCl3) 7.35 (2H, d, J 7.0), 7.29e7.20 (4H, m),
7.19 (1H, t, J 7.6), 7.10 (1H, t, J 7.6), 6.89 (1H, d, J 7.6),
6.06e6.02 (1H, ddt, J 9.8, 4.2, 1.8), 5.73e5.70 (1H, ddt, J
9.8, 5.5, 2.4), 3.89 (1H, d, J 13.3), 3.75 (1H, d, J 15.6), 3.66
(1H, d, J 13.3), 3.58 (1H, br s), 3.54 (1H, d, J 15.6), 3.14
(1H, ddd, J 10.6, 5.2, 2.5), 2.21e2.07 (2H, m), 1.86e1.77
(1H, m), 1.69e1.61 (1H, m); 13C NMR d (90.0 MHz, CDCl3)
139.0 (C), 137.7 (C), 133.4 (C), 128.8 (CH), 128.7 (2ꢃCH),
128.2 (2ꢃCH), 127.7 (CH), 127.4 (CH), 126.9 (CH), 126.4
(2ꢃCH), 125.2 (CH), 58.4 (CH2), 56.1 (CH), 50.9 (CH2), 37.8
(CH), 24.3 (CH2), 19.4 (CH2); m/z (FAB, THIOG) 276
([MþH]þ, 76%), 200 (35), 184 (55), 154 (93), 136 (83).
HRMS (FAB, THIOG) found: [MþH]þ 276.1755; C20H22N re-
quires: 276.1754. This compound was also fully characterized
by COSY, HSQC and NOESY 2D NMR studies.
To a solution of enone 1319 (661 mg, 5.32 mmol) in Et2O
(12 mL) at 0 ꢁC was added portionwise LiAlH4 (201 mg,
5.32 mmol). The reaction mixture was stirred at 0 ꢁC for
40 min and then quenched by the addition of Na2SO4$5H2O
portionwise. Thereactionmixturewasfilteredand the filtratevig-
orously stirredwithpotassium sodiumtartate(50 mL, satdaq) for
1 h. The organic phase was separated and the aqueous phase
washed with Et2O (3ꢃ40 mL). The combined organics were
dried(MgSO4) andconcentratedunder reducedpressuretoafford
5,5-dimethyl-cyclohex-2-enol as a colourless oil (525 mg, 72%).
Rf [3:1, hexane/EtOAc]¼0.37; nmax (CHCl3)/cmꢂ1 3336, 2952,
1
1650, 1454, 1089, 1037, 725; H NMR d (250 MHz, CDCl3)
5.71 (2H, s), 4.29e4.22 (1H, m), 1.88e1.57 (3H, m), 1.31 (1H,
dd, J 12.3, 8.7), 1.00 (3H, s), 0.92 (3H, s); 13C NMR
d (62.9 MHz, CDCl3) 129.1 (CH), 128.0 (CH), 66.2 (CH), 45.3
(CH2), 38.9 (CH2), 31.2 (CH3), 30.7 (C), 26.0 (CH3); m/z
(FAB, THIOG) 149 ([MþNa]þ, 33%), 127 ([MþH]þ, 5), 125
([MꢂH]þ, 12), 124 (18), 111 (53). HRMS (FAB, THIOG) found:
[MꢂH]þ, 125.0968; C8H13O requires: 125.0966.
4.4.4.2. Diagnostic data for 8d (D2,3 isomer). 1H NMR
d (360 MHz, CDCl3) 5.70e5.67 (1H, m), 5.58e5.55 (1H,
m), 2.74e2.65 (1H, m).
4.5.2. 3-Bromo-5,5-dimethyl-cyclohex-2-ene 14
To a stirred solution of 5,5-dimethyl-cyclohex-2-enol
(2.00 g, 15.8 mmol) and CBr4 (11.1 g, 33.3 mmol) in Et2O
(75 mL) at 0 ꢁC was added PPh3 (8.00 g, 33.3 mmol). The reac-
tion mixture was warmed to rt and stirred for 2 h. The reaction
mixture was filtered and the filtrate concentrated under reduced
pressure to afford a colourless solid and yellow oil. These were
washed with pentane (2ꢃ100 mL) and the combined washings
dried (MgSO4) and concentrated under reduced pressure to
afford bromide 14 as a pale yellow oil (2.00 g, 67%). This mate-
rial was found to be unstable to flash chromatography and thus
was used without further purification. Rf [3:1, hexane/
4.4.4.3. Diagnostic data for 9d (D3,4 isomer). 1H NMR
d (360 MHz, CDCl3) 5.96e5.92 (1H, m), 5.89e5.86 (1H, m).
4.4.5. PMB-functionalized phenanthridines 7ee9e
4.4.5.1. (4aSR,10bSR)-5-(4-Methoxy-benzyl)-3,4,4a,5,6,10b-
hexahydro-phenanthridine 7e (D1,2 isomer). Rf [10:1, hexane/
EtOAc]¼0.23; nmax (CHCl3)/cmꢂ1 3024, 1647, 1609, 1511;
1H NMR d (360 MHz, CDCl3) 7.33e7.29 (3H, m), 7.18 (1H,
t, J 7.3), 7.10 (1H, t, J 7.6), 6.96 (1H, d, J 7.6), 6.90e6.88
(2H, m), 6.12e6.08 (1H, m), 5.79e5.76 (1H, m), 3.89 (1H,
d, J 13.0), 3.82 (3H, s), 3.80 (1H, d, J 16.1), 3.67 (1H, d, J
13.0), 3.62 (1H, br s), 3.59 (1H, d, J 16.1), 3.12 (1H, ddd, J
10.6, 5.4, 2.6), 2.20e2.00 (2H, m), 1.90e1.63 (2H, m); 13C
NMR d (90.0 MHz, CDCl3) 158.6 (C), 137.7 (C), 133.4 (C),
130.9 (C), 129.9 (2ꢃCH), 128.8 (CH), 127.6 (CH), 127.4
(CH), 126.4 (CH), 126.3 (CH), 125.2 (CH), 113.6 (2ꢃCH),
57.7 (CH2), 55.9 (CH), 55.1 (CH3), 50.8 (CH2), 37.8 (CH),
24.4 (CH2), 19.2 (CH2); m/z (FAB, THIOG) 306 ([MþH]þ,
56%), 305 ([M]þ, 58), 304 ([MꢂH]þ, 69), 251 (12.4), 184
(46.1). HRMS (FAB, 3-NOBA) found: [M]þ 305.1779;
C21H23NO requires: 305.1780. This compound was also fully
characterized by COSY, HSQC and NOESY 2D NMR studies.
1
EtOAc]¼0.46; nmax (CHCl3)/cmꢂ1 1437, 1120, 723, 694; H
NMR d (250 MHz, CDCl3) 5.90e5.84 (1H, m), 5.75e5.71
(1H, m), 4.79e4.77 (1H, m), 2.14e1.88 (3H, m), 1.80e1.70
(1H, m), 1.02 (3H, s), 0.96 (3H, s); 13C NMR d (62.9 MHz,
CDCl3) 129.0 (CH), 128.2 (CH), 47.5 (CH), 46.7 (CH2), 38.1
(CH2), 31.9 (C), 30.7 (CH3), 25.4 (CH3).
4.5.3. N-(2-Bromo-benzyl)-5,5-dimethylcyclohex-
2-enyl-amine
To a suspension of 2-bromobenzylamine hydrochloride
(412 mg, 1.85 mmol) in MeCN (20 mL) was added DIPEA
(1.30 mL, 7.40 mmol) and the reaction mixture stirred for
10 min. Bromide 14 (700 mL, 3.70 mmol) was added dropwise
and the reaction mixture stirred at rt for 16 h. The reaction

4476
L.R. Donaldson et al. / Tetrahedron 64 (2008) 4468e4477
1
mixturewasconcentratedunderreducedpressureandtheresidue
taken up in CH2Cl2 (20 mL) and washed with NaCl (3ꢃ20 mL,
satd aq). The combined organics were dried (MgSO4) and con-
centrated under reduced pressure to afford N-(2-bromo-ben-
nmax (CHCl3)/cmꢂ1 2957, 1332, 1153; H NMR d (360 MHz,
CDCl3) 7.32 (1H, d, J 7.5), 7.24 (1H, t, J 7.3), 7.20 (1H, t, J
7.9), 7.10 (1H, d, J 7.3), 6.03 (1H, dd, J 10.0, 5.6), 5.59 (1H, d,
J 10.0), 4.60 (1H, d, J 16.2), 4.43 (1H, d, J 16.2), 4.41 (1H, dd,
J 15.5, 6.2), 3.59 (1H, t, J 5.6), 2.87 (3H, s), 1.64e1.60 (2H,
m), 1.15 (3H, s), 0.94 (3H, s); 13C NMR d (90.6 MHz, CDCl3)
138.7 (CH), 136.3 (C), 130.3 (C), 127.9 (CH), 127.3 (CH),
126.1 (CH), 126.0 (CH), 123.7 (CH), 49.8 (CH), 43.3 (CH2),
39.0 (CH3), 38.2 (CH2), 36.6 (CH), 34.0 (C), 30.3 (CH3), 28.3
(CH3); m/z (FAB, THIOG) 292 ([MþH]þ, 100%), 291 ([M]þ,
82), 213 (44), 197 (40), 165 (12), 130 (15), 94 (89). HRMS
(FAB, THIOG) found: [MþH]þ, 292.1371; C16H22NO2S re-
quires: 292.1371.
zyl)-5,5-dimethylcyclohex-2-enyl-amine as
a
brown oil
(340 mg, 63%). Rf [3:1, hexane/EtOAc]¼0.37; nmax (CHCl3)/
cmꢂ1 3307, 1776, 1651, 1466, 1025, 750; 1H NMR
d (360 MHz, CDCl3) 7.53 (1H, dd, J 7.9, 1.2), 7.46 (1H, dd, J
6.1, 1.6), 7.28 (1H, t, J 7.4, 6.1), 7.11 (1H, td, J 7.8, 1.6),
5.76e5.70 (2H, m), 3.92 (2H, s), 3.31e3.24 (1H, m), 1.92
(1H, dd, J 17.8, 3.4), 1.79e1.71 (2H, m), 1.23 (1H, t, J 10.6),
1.00 (3H, s), 0.92 (3H, s); 13C NMR d (90.6 MHz, CDCl3)
139.6 (C), 132.5 (CH), 130.0 (CH), 128.4 (CH), 128.3 (CH),
127.3 (CH), 127.2 (CH), 123.7 (C), 52.0 (CH), 50.7 (CH2),
43.2 (CH2), 39.0 (CH2), 31.8 (CH3), 30.2 (C), 25.4 (CH3); m/z
(FAB, THIOG) 296 ([81BrMþH]þ, 96%), 294 ([79BrMþH]þ,
100), 239 (25), 188 (33), 186 (51), 171 (42), 169 (48). HRMS
(FAB, THIOG) found: [81BrMþH]þ, 296.0845;C15H21N81Br re-
quires: 296.0837. Found: [79BrMþH]þ, 294.0848; C15H21N79Br
requires: 294.0857.
Acknowledgements
We thank the EPSRC (DTA award to L.R.D.), GlaxoS-
mithKline and the SCI (Messel Scholarship to L.R.D.) for
financial support for this work.
Supplementary data
4.5.4. N-(2-Bromo-benzyl)-N-5,5-dimethylcyclohex-2-enyl-
methanesulfonamide 12
Experimental procedure for cyclizations in Tables 2e4.
Confirmations of double bond isomers and ring junction
To N-(2-bromo-benzyl)-5,5-dimethylcyclohex-2-enyl-amine
(180 mL, 0.62 mmol) in CH2Cl2 (5 mL) at 0 ꢁC were added
Et3N (262 mL, 1.87 mmol) and methanesulfonyl chloride
(214 mL, 1.87 mmol). The reaction mixture was warmed to rt
and stirred for 3 h. The reaction mixture was extracted with
HCl (2ꢃ10 mL, 1 M aq) and then with NaOH (2ꢃ10 mL, 1 M
aq), and the combined organics dried (MgSO4), concentrated un-
der reduced pressure and purified by flash chromatography (10:1
to5:1,hexane/EtOAc)toaffordsulfonamide12asa colourlessoil
(150 mg, 65%). Rf [3:1, hexane/EtOAc]¼0.77; nmax (CHCl3)/
1
stereochemistry. H and 13C NMR spectra for all compounds.
1H NMR integrals supporting ratios in Tables 2e4. Supple-
mentary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2008.02.044.
References and notes
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1
cmꢂ1 1335, 1159, 913, 745; H NMR d (360 MHz, CDCl3)
7.66 (1H, d, J 7.0), 7.50 (1H, dd, J 8.0, 1.2), 7.32 (1H, td, J 7.6,
0.7), 7.11 (1H, J 7.6, 1.8), 5.89e5.83 (1H, dddd, J 10.3, 5.2,
2.7, 2.5), 5.49 (1H, dd, J 10.3, 1.3), 4.63e4.47 (1H, m), 4.45
(1H, d, J 17.6), 4.31 (1H, d, J 17.6), 2.98 (3H, s), 1.92e1.83
(1H, m), 1.75e1.68 (1H, m), 1.68e1.60 (1H, m), 1.30e1.25
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127.4 (CH), 125.1 (CH), 122.0 (C), 54.9 (CH), 47.7 (CH2),
40.8 (CH2), 39.5 (CH3), 38.2 (CH2), 31.7 (CH3), 31.0 (C), 24.8
(CH3); m/z (FAB, THIOG) 374 ([81BrMþH]þ, 80%), 372
([79BrMþH]þ, 93), 294 (49), 292 (53), 264 (23), 262 (12), 171
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ThegeneralprocedureforTable 2 wasemployedusingsulfon-
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L.R. Donaldson et al. / Tetrahedron 64 (2008) 4468e4477
4477
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