A novel approach to functionalised 5,7,8,9-tetrahydropyrimido[4,5-b][1,4] diazepin-6-ones using intramolecular palladium-catalysed amidation

Article abstract of DOI:10.1016/j.tetlet.2012.03.125

The development of a novel palladium-catalysed amidation approach towards 5,7,8,9-tetrahydropyrimido[4,5-b][1,4]diazepin-6-one templates is highlighted. The route proceeds through the reaction of an amino amide, generated by 1,4-addition of an amine to an

Full text of DOI:10.1016/j.tetlet.2012.03.125

Tetrahedron Letters 53 (2012) 5049–5055
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel approach to functionalised 5,7,8,9-tetrahydropyrimido[4,5-b][1,4]
diazepin-6-ones using intramolecular palladium-catalysed amidation
Gregory R. Carr, James L. Feron, Paul D. Johnson, Craig A. Roberts, David A. Rudge, Iain Simpson,
⇑
Gail L. Wrigley
AstraZeneca, Oncology Innovative Medicines, Discovery Chemistry, Mereside, Alderley Park, Macclesfield SK10 4TG, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
The development of a novel palladium-catalysed amidation approach towards 5,7,8,9-tetrahydropyrim-
ido[4,5-b][1,4]diazepin-6-one templates is highlighted. The route proceeds through the reaction of an
amino amide, generated by 1,4-addition of an amine to an acrylamide, with 5-bromo-2,4-dichloropyrim-
idine and final palladium-catalysed cyclisation to provide the functionalised scaffold in up to 60% isolated
yield over three steps. The route offers efficiency advantages over the previously reported nitro-reduction
cyclisation approach to these molecules. It also provides alternative means to introduce bulky alkyl sub-
stituents at the amide nitrogen. The application of this route in the synthesis of a variety of analogues is
described.
Received 20 December 2011
Revised 19 March 2012
Accepted 29 March 2012
Available online 21 April 2012
Keywords:
Palladium
Amidation
Bicyclic
Ó 2012 Published by Elsevier Ltd.
Pyrimidine
Intramolecular
5,7,8,9-Tetrahydropyrimido[4,5-b][1,4]diazepin-6-ones have em-
erged as attractive molecular scaffolds for protein kinase inhibition1
and other important biological targets.2 Conventional synthetic
approaches to these molecules often rely on intramolecular reduc-
tive cyclisation of 5-nitropyrimidines3 (Scheme 1; disconnection
A), followed by further manipulation to incorporate R2. In this Letter
we exemplify a novel approach to these molecules that utilises an
intramolecular palladium-catalysed amidation reaction (Scheme
1; disconnection B).
disconnection A requires introduction of diversity element R2 after
the cyclisation reaction, which can be problematic when R2 is a
secondary alkyl group with the potential for mixtures of N- and
O-alkylated products to be formed. By developing disconnection
B, we hoped that we could incorporate R2 into the cyclisation
substrate thereby removing a potentially problematic chemical
transformation on the cyclised intermediate.
Our initial foray into the synthesis of the 5,7,8,9-tetrahydropy-
rimido[4,5-b][1,4]diazepin-6-one target core template
1 was
In 1996, Buchwald reported on the use of palladium-catalysis to
effect an intramolecular amidation for the formation of fused bicy-
clic ring systems.4 A limitation of this process was the low yields
under the reported reaction conditions for the formation of the
6,7-bicyclic motif (ꢀ5%). The scope of palladium-catalysed amida-
tion reactions was subsequently greatly extended through the
development of a catalytic system which utilised a Pd/Xantphos
mixture for intermolecular palladium-catalysed amidations.5 This
has also been applied successfully to intramolecular amidation
reactions to provide access to the previously elusive 6,7-bicyclic
systems in the formation of 1,5-diazepinones using substituted
bromo-benzenes with a pendant amide for the cyclisation.6
Herein we disclose the first example of 5-bromopyrimidines
as substrates in this type of cyclisation to provide access to
the 5,7,8,9-tetrahydropyrimido[4,5-b][1,4]diazepin-6-one scaffold.
through the conventional disconnection approach (Scheme 2).
Whilst this route was effective in delivering the desired com-
pound 1, the belief that we could achieve extra route efficiency
savings led us to investigate an alternative disconnection strategy.
The key amino amide 3 was synthesised through the 1,4-addition
of cyclopentylamine to N-methylacrylamide (2) (Scheme 3). Use
of a slight excess (1.1 equiv) of N-methylacrylamide (2) enabled
the isolation of pure compound 3 after ion exchange filtration,
which could be progressed directly into the subsequent reaction
with no requirement for column chromatography. The amine 3
underwent a smooth reaction with 5-bromo-2,4-dichloropyrimi-
dine, to provide an 85:15 mixture of the desired 4-substitued
product 4, along with the isomeric 2-substituted compound 5
which could be readily separated by flash silica gel chromatogra-
phy to provide the desired compound 4 in 73% isolated yield. To
effect the palladium-catalysed amidation reaction, we chose to
utilise Pd2dba3, Xantphos, Cs2CO3, 1,4-dioxane combination, previ-
ously reported to show good scope across a range of amidation
reactions.5 We were delighted to observe an efficient ring closure
of 4 to provide the 6,7-bicyclic system 1.
We rationalised that this approach could allow for
a more
convergent synthesis of the target molecules. Proceeding via
⇑
Corresponding author. Tel.: +440 1625 233261.
E-mail address: Gail.Wrigley@astrazeneca.com (G.L. Wrigley).
0040-4039/$ - see front matter Ó 2012 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2012.03.125

5050
G. R. Carr et al. / Tetrahedron Letters 53 (2012) 5049–5055
2
A
R
RO
NO2
O
HN
O
O
2
A
B
R
N
Br
Cl
N
1
R
N
N
1
1
R
R
B
N
N
N
N
N
N
Cl
Cl
Scheme 1. Disconnection strategies for the 5,7,8,9-tetrahydropyrimido[4,5-b][1,4]diazepin-6-one core.
reaction with 5-bromo-2,4-dichloropyrimidine, uniformly good to
excellent results were obtained (Table 1, entries 1–8, 40–80% over
two steps). Where the two steps were telescoped together, the
yields dropped off slightly (Table 1, entries 9–12, 27–44%), but this
was balanced by enhanced operational simplicity. All cyclisation
substrates provided the desired product in yields which ranged
from 18% (Table 1, entry 8) up to 95% (Table 1, entry 2).
O
O
O
N
O
O
O
a.
b.
NO2
NH2.HCl
HN
N
N
Cl
Where alternative acrylamide starting materials were commer-
cially available, the analogues were synthesised using our palla-
dium-catalysed coupling technique (Table 1, entries 13 and 14).
Previous in-house chemistry had shown that selective N-alkylation
of amides using isopropylbromide could be problematic, with the
formation of a mixture of N- and O-alkylated products.7 Therefore,
we were delighted to observe that the use of N-isopropyl acrylam-
ide (10) provided the desired product 8n in a reasonable yield (Ta-
ble 1, entry 14, 55%). It was observed that with the increasing steric
bulk of the amide substituent, the conditions/time required to
achieve cyclisation increased.
The b-methyl substituted compound 8o (Table 1, entry 15) was
available in racemic form by virtue of the starting acrylamide 11
containing the terminal methyl group. The 4-chloro displacement
step was low yielding, but did provide sufficient material for on-
ward chemistry. Exploration of a variety of other displacement
conditions failed to provide a significant improvement in the iso-
lated yield (K2CO3, acetone, 6%; Et3N, MeCN, 5%; DIPEA, MeCN,
4%; Et3N, CH2Cl2, no product). However, it was pleasing that the
ring closure did proceed in excellent yield.
c.
O
O
N
HN
d.
N
N
N
N
N
N
Cl
Cl
1
Scheme 2. Reagents and conditions: (a) Cyclopentanone, NaBH(OAc)3, NaOAc,
CH2Cl2, rt, 83%; (b) 2,4-dichloro-5-nitropyrimidine, K2CO3, acetone, rt, 53%; (c) Fe
powder, AcOH, 70 °C, 50%; (d) MeI, NaH, DMA, 0 °C to rt, 74%.
Comparison of our results from both routes showed that discon-
nection A delivered our core template 1 in 16% yield over four
steps, whilst disconnection B provided 1 in a superior 53% yield
in three steps.
With this more efficient route in hand, a number of derivatives
of the N-methylamide core were prepared (Table 1, entries 1–12).
In these cases where the 1,4-addition product was isolated prior to
Following on the initial success, we decided to investigate
whether further efficiency could be gained by the incorporation
HN
N
O
HN
N
O
HN
HN
O
a.
O
HN
b.
Br
N
N
N
N
Br
2
Cl
Cl
3
4
5
c.
N
O
N
N
N
Cl
1
Scheme 3. Reagents and conditions: (a) Cyclopentylamine, MeOH, 140 °C,
Xantphos (3 mol %), Cs2CO3, 1,4-dioxane, 100 °C, 80%.
lW, 91%; (b) 5-bromo-2,4-dichloropyrimidine, Et3N, MeCN, 100 °C, 73%; (c) Pd2dba3 (1 mol %),

G. R. Carr et al. / Tetrahedron Letters 53 (2012) 5049–5055
5051
of diversity at N-9 later in the synthesis. Any strategy here may
also allow for incorporation of more highly functionalised groups
at this position.8 To this end, attempts were made to cyclise the
unsubstituted compound 7p (Table 1, entry 16). Unfortunately, in
our hands using our ‘standard’ conditions, we were unable to
obtain the required 5,7,8,9-tetrahydropyrimido[4,5-b][1,4]diaze-
Table 1
Reagents and conditions: (a) Amine, MeOH, 140 °C,
l
W; (b) 5-bromo-2,4-dichloropyrimidine, Et3N, MeCN, rt; (c) Pd2dba3, Xantphos, Cs2CO3, 1,4-dioxane, 100 °C
2
R
O
2
2
R
R
2
R
HN
O
3
a.
b.
c.
HN
O
N
R
1
HN
O
3
R
3
N
R
R
Cl
N
N
1
N
N
R
3
HN
1
R
R
N
Cl
Br
6a-q
7a-q
8a-q
Entry
Acrylamide
Amine (NH2R1)
Methylamine
Product
Yielda (%) 6
Yielda,b (%) 7
Yielda (%) 8
O
N
N-Methylacrylamide (2)
N
N
N
N
N
N
N
1
99
54
26
R2 = Me, R3 = H
N
N
Cl
O
8a
N
2
3
4
5
6
7
2
2
2
2
2
2
Ethylamine
99
99
96d
96
98
79
66c
95
59
41
27
93
57
N
N
N
N
N
N
N
N
N
N
N
N
8b
Cl
O
N
Isopropylamine
Isobutylamine
Isoamylamine
Cyclohexylamine
78
8c
Cl
O
N
83e
Cl
O
8d
N
77
8e
8f
Cl
O
N
58
Cl
O
N
4-Aminotetrahydropyran
50
O
8g
Cl
(continued on next page)

5052
G. R. Carr et al. / Tetrahedron Letters 53 (2012) 5049–5055
Table 1 (continued)
Entry
Acrylamide
Amine (NH2R1)
Product
Yielda (%) 6
Yielda,b (%) 7
Yielda (%) 8
O
N
N
N
N
N
N
8
2
2
2
2
2-Methoxyethylamine
65d
84e
18
N
N
N
N
N
N
N
N
N
N
O
8h
Cl
O
N
31
9
sec-Butylamine
—
28
50
47
41
97
55g
82
NR
(2 steps)d,e,f
8i
Cl
O
N
27
10
11
12
13
14
15
16
2-Cyclopropylethylamine
Cyclobutylamine
Cyclopropanemethylamine
Cyclopentylamine
Cyclopentylamine
Cyclopentylamine
N/A
—
(2 steps)d,e,f
8j
Cl
O
N
32
—
(2 steps)d,e,f
8k
Cl
O
N
44
2
—
(2 steps)d,e,f
8l
Cl
O
N
N-Ethyl acrylamide (9)
R
71c
55c
6h
N
99
96
90
N/Ai
2 = Et, R3 = H
N
N
8m
Cl
O
N
N-Isopropyl
acrylamide (10)
R
N
2 = iPr, R3 = H
N
N
8n
Cl
N
O
N
N-Methyl
N
but-2-enamide (11)
R2 = Me, R3 = Me
N
N
8o
8p
Cl
O
N
NH
2
48c
N
Cl

G. R. Carr et al. / Tetrahedron Letters 53 (2012) 5049–5055
5053
Table 1 (continued)
Entry
Acrylamide
Amine (NH2R1)
Product
Yielda (%) 6
Yielda,b (%) 7
Yielda (%) 8
O
N
O
56
N
17
2
2,4-Dimethoxybenzylamine
—
53
(2 steps)d,f,j
N
N
O
Cl
8q
a
Isolated yield of desired compound.
b
The 4-substituted pyrimidine was readily separated from the undesired 2-substituted isomer by flash silica gel chromatography, yield quoted is that of the isolated
4-isomer.
c
Reaction carried out at reflux.
1,4-Addition reactions were carried out in EtOH.
4-Chloro displacement reaction carried out in CH2Cl2.
d
e
f
Product from step a was used directly in step b. In these cases, the isolated yield over the two steps is given.
Reaction proceeded when transferred into a microwave apparatus and irradiated to 150 °C for 30 min.
Reaction was performed using K2CO3 in acetone.
3-Amino-N-methylpropanamide is commercially available (CAS 4874-18-4).
4-Chloro displacement reaction carried out in EtOH.
g
h
i
j
Initiator). The volatiles were removed under reduced pressure,
O
O
the residue diluted with MeOH (20 mL) and purified by strong cat-
ion exchange filtration (50 g SCX-2 cartridge) washing with MeOH
(100 mL) and eluting with 7 M methanolic NH3 (100 mL). The
eluted product was concentrated under reduced pressure to afford
the title compound 3 as a brown oil (3.09 g, 18.2 mmol, 91%). This
was used directly with no further purification. 1H NMR (400 MHz,
DMSO-d6) dH 7.79 (1H, br s), 3.29 (1H, br s), 2.95 (1H, pent,
J = 6.0 Hz), 2.65 (2H, t, J = 7.0 Hz), 2.55 (3H, d, J = 4.5 Hz), 2.17
(2H, t, J = 7.0 Hz), 1.73–1.64 (2H, m), 1.63–1.55 (2H, m), 1.51–
1.38 (2H, m), 1.30–1.21 (2H, m). MS (ES) m/z 171 [M+H]+.
N
N
a.
O
NH
N
N
N
N
N
O
Cl
8p
Cl
8q
Scheme 4. Reagents and condition: (a) TFA, CH2Cl2, rt, 79%.
Pyrimidine synthesis
pin-6-one core 8p. However, using 2,4-dimethoxybenzyl as a pro-
tecting group, with subsequent deprotection with TFA (Scheme 4),
gave access to 8p in reasonable yield (42% over 2 steps).
3-[(5-Bromo-2-chloropyrimidin-4-yl)-cyclopentylamino]-N-
methyl-propanamide (4)
2-Chloro-5-methyl-8,9-dihydro-7H-pyrimido[4,5-b][1,4]diaze-
pin-6-one (8p) underwent simple alkylation with various primary
alkyl halides9 to give a further range of functionalised 5,7,8,9-tetra-
hydropyrimido[4,5-b][1,4]diazepin-6-ones in good yields (Table 2).
It is envisaged that compounds 8r, 8u and 8v would have been prob-
lematic to prepare if N-9 functionality had been incorporated prior
to cyclisation (e.g., Table 2, entries 1, 4 and 5), due to potential com-
petitive reactions with the key palladium-catalysed cyclisation.
In conclusion, we have shown that 5,7,8,9-tetrahydropyrimi-
do[4,5-b][1,4]diazepin-6-ones can be readily synthesised by a
sequence of 1,4-addition, 4-chloro displacement of 5-bromo-2,4-
dichloropyrimidine and an intramolecular palladium-catalysed
amidation. The key intramolecular amidation reaction proceeds
for a number of differentially functionalised substrates. The method
offers yield and synthetic efficiency advantages over previously re-
ported routes to these molecules. It also provides an alternative
means to introduce bulky alkyl substituents (R2) at the amide posi-
tion. Furthermore, use of the 2,4-dimethoxybenzyl protecting group
allows for manipulation of the N-9 position at a later stage and
served to broaden the scope of this methodology further.
To
a stirred solution of 5-bromo-2,4-dichloropryimidine
(0.737 g, 3.23 mmol) in MeCN (25 mL) was added Et3N (0.42 mL,
3.00 mmol) and 3-(cyclopentylamino)-N-methyl-propanamide (3)
(0.500 g, 2.94 mmol) as a solution in MeCN (5 mL). The mixture
was heated at 100 °C for 4 h to give a mixture of isomers [85%
desired 4-subsituted (4), 15% undesired 2-substituted (5)]. The sol-
vent was removed under reduced pressure and the residue was ta-
ken up in EtOAc (100 mL) and H2O (100 mL). The organics were
removed and the aqueous further extracted with EtOAc (2 Â
50 mL). The combined organics were washed with H2O (200 mL),
brine (200 mL), dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash silica gel chromatogra-
phy (40 g silica cartridge, 0–10% MeOH/CH2Cl2) to afford the title
compound 4 (0.775 g, 2.14 mmol, 73%) as a brown oil. 1H NMR
dH (400 MHz, DMSO-d6) 8.38 (1H, s), 7.72 (1H, br q, J = 4.5 Hz),
4.57 (1H, pent, J = 8.0 Hz), 3.65 (2H, t, J = 7.0 Hz), 2.53 (3H, d,
J = 4.5), 2.33 (2H, t, J = 7.0 Hz), 1.90–1.77 (2H, m), 1.75–1.57 (4H,
m), 1.57–1.45 (2H, m). MS (ES) m/z 363 [35Cl 81Br (M+H)]+.
Aminoamide synthesis
Palladium-catalysed amidation
3-(Cyclopentylamino)-N-methyl-propanamide (3)
2-Chloro-9-cyclopentyl-5-methyl-5,7,8,9-tetrahydro-6H-
pyrimido[4,5-b][1,4]diazepin-6-one (1)
A solution of N-methylacrylamide (2) (1.88 g, 22.0 mmol) and
cyclopentylamine (1.98 mL, 20.0 mmol) in MeOH (14 mL) was
heated under microwave irradiation to 140 °C for 30 min (Biotage
3-[(5-Bromo-2-chloropyrimidin-4-yl)-cyclopentylamino]-N-me
thyl-propanamide (4) (300 mg, 0.83 mmol), Pd2(dba)3 (8 mg,

5054
G. R. Carr et al. / Tetrahedron Letters 53 (2012) 5049–5055
Table 2
(101 MHz, DMSO-d6) dC 171.12, 156.09, 153.99, 151.37, 123.85,
Reagents and conditions: (a) NaH, R1-X, DMA, 0 °C to rt
58.76, 44.88, 36.10, 33.75, 27.51, 24.00. MS (ES) m/z 281 [35Cl
(M+H)]+. HRMS (ES+) calcd for C13H18ON435Cl [M+H]+ 281.11637,
found 281.11649.
O
O
N
N
a.
Alkylation of 2-chloro-5-methyl-8,9-dihydro-7H-pyrimido[4,5-
b][1,4]diazepin-6-one (8p)
NH
N
1
R
N
N
N
N
2-Chloro-9-(2-fluoroethyl)-5-methyl-7,8-dihydropyrimido[4,5-
b][1,4]diazepin-6-one (8t)
Cl
Cl
8 p
8 r-v
To a cooled (ice/water bath) suspension of NaH (60% dispersion
in mineral oil; 15 mg, 0.38 mmol) in DMA (1 mL) was added a solu-
tion of 2-chloro-5-methyl-8,9-dihydro-7H-pyrimido[4,5-b][1,4]
diazepin-6-one (8p) (65 mg, 0.31 mmol) in DMA (1 + 0.5 mL wash)
{CARE: effervescence}. The resultant mixture was stirred under N2
in an ice bath for 1 h. Neat 1-bromo-2-fluoroethane (40 mL,
0.54 mmol) was then added and stirring continued overnight,
allowing the mixture to gradually warm to ambient temperature.
The mixture was quenched by addition of a saturated aqueous
solution of NH4Cl (0.5 mL) and stirred for 15 min. This was then
partitioned between CH2Cl2 (10 mL) and H2O (10 mL). The organic
layer was separated and the aqueous further extracted with CH2Cl2
(5 mL). The combined organics were evaporated to afford the title
compound 8t (86 mg, >95%) as a waxy off-white solid. 1H NMR dH
(400 MHz, DMSO-d6) 8.18 (1H, s), 4.62–4.77 (2H, m), 3.88–3.97
(2H, m), 3.81 (2H, m), 3.19 (3H, s) 2.71 (2H, m). MS (ES) m/z 259
Entry Alkyl halide
Product
Yielda (%)
O
N
N
N
N
N
N
1
2
3
4
5
Benzyl bromide
89
N
N
N
N
N
N
N
N
N
N
8r
Cl
O
N
57
S
4-Chloromethyl-2-
methylthiazole
(90% by LC–
MS)
N
8s
Cl
O
[
35Cl (M+H)]+.
N
1-Bromo-2-fluoroethane
>95
>95
62
Acknowledgements
F
8t
We thank Jonathan Eden and Robin Wood for supporting syn-
thesis and the Structure Purity Group at Alderley Park for assis-
tance in analysis. We would also like to acknowledge Professor
Joe Sweeney for assistance with the drafting of this article.
Cl
O
N
Bromoacetonitrile
N
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8u
8v
Cl
O
N
Propargyl chloride
Cl
a
Isolated yield of the desired compound, without any purification. Unless stated
the material was P95% by LC–MS.
0.01 mmol), Xantphos (15 mg, 0.02 mmol) and Cs2CO3 (392 mg,
1.20 mmol) were combined in 1,4-dioxane (10 mL) in a round
bottomed flask, fitted with a reflux condenser. The apparatus
was evacuated under vacuum and backfilled with N2 (x3) before
the resulting solution was heated to 100 °C. After 4 h, a further
portion of Pd2(dba)3 (8 mg, 0.01 mmol) and Xantphos (15 mg,
0.02 mmol) were added and heating continued for a further
2.5 h. The reaction mixture was cooled to room temperature, con-
centrated under reduced pressure and pre-loaded onto silica gel
for purification by flash chromatography (40 g silica cartridge,
0–10% CH2Cl2/MeOH) to give the title compound 1 (187 mg,
0.67 mmol, 80%) as a yellow solid. Mp, 141–143 °C. 1H NMR
(400 MHz, DMSO-d6) dH 8.13 (1H, s), 4.74 (1H, pent, J = 8.2 Hz),
3.69–3.60 (2H, m), 3.17 (3H, s), 2.67–2.59 (2H, m), 1.94–1.80
2. CCR4 or TARC and/or MDC function regulators: (a) Furukubo, S.; Miyazaki, H.;
Nakajima, T.; Ikeda, Y.; Morokuma, K.; Nakamaki, C. PCT Int. Appl.
WO2008146914; Chem. Abstr. 2008, 150, 20139; (b) Kokubo, S.; Miyazaki, H.;
Nakajima, T.; Ikeda, Y.; Morokuma, K.; Nakamaki, C. Jpn. Kokai Tokkyo Koho
JP2010126496; Chem. Abstr. 2010, 153, 37180; (c) Kokubo, S.; Miyazaki, H.;
Nakajima, T.; Ikeda, Y.; Morokuma, K.; Nakamaki, C. Jpn. Kokai Tokkyo Koho
JP2010208945; Chem. Abstr. 2010, 153, 431393. .
3. Deng, X.; Yang, Q.; Kwiatkowski, N.; Sim, T.; McDermott, U.; Settleman, J. E.; Lee,
J.; Gray, N. S. ACS Med. Chem. Lett. 2011, 2, 195–200.
4. Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525–7546.
(2H, m), 1.75–1.64 (2H, m), 1.64–1.49 (4H, m).13
C NMR

G. R. Carr et al. / Tetrahedron Letters 53 (2012) 5049–5055
5055
5. Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043–6048.
6. Cropper, E. L.; Yuen, A.; Ford, A.; White, A. J. P.; (Mimi) Hii, K. K. Tetrahedron
2009, 65, 525–530.
7. Unpublished results from within our laboratories showed that under a variety of
alkylation conditions a mixture of N- and O-alkylated products was obtained.
8. Unpublished results from within our laboratories showed that the key
cyclisation failed with more highly functionalised N-9 substituents. For
example, attempts to cyclise when R1 was 3-furylmethyl led to decomposition
of the starting material.
9. In our hands, attempts to alkylate secondary alkyl halides proved more
problematic than the primary examples recorded.