Synthesis of 8-substituted-6-phenyl-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolines using Pictet-Spengler and Bischler-Napieralski cyclisation methods

Article abstract of DOI:10.1016/j.tetlet.2018.06.041

In the following communication we report routes for the synthesis of a set of 8-substituted-6-phenyl-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolines. Pictet-Spengler and Bischler-Napieralski methodologies were employed on the relevant indazole precursors and the merits of the two cyclisation reactions for preparing these structures were assessed.

Full text of DOI:10.1016/j.tetlet.2018.06.041

Accepted Manuscript
Synthesis of 8-substituted-6-phenyl-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]iso-
quinolines using Pictet-Spengler and Bischler-Napieralski cyclisation methods
Robert D.M. Davies, Jennifer H. Pink, James S. Scott, Andrew Bailey
PII:
S0040-4039(18)30795-0
https://doi.org/10.1016/j.tetlet.2018.06.041
TETL 50079
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
27 April 2018
8 June 2018
15 June 2018
Please cite this article as: Davies, R.D.M., Pink, J.H., Scott, J.S., Bailey, A., Synthesis of 8-substituted-6-
phenyl-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolines using Pictet-Spengler and Bischler-Napieralski
cyclisation methods, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.06.041
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Tetrahedron Letters
Synthesis of 8-substituted-6-phenyl-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-
f]isoquinolines using Pictet-Spengler and Bischler-Napieralski cyclisation methods
Robert D.M. Davies, Jennifer H. Pink, James S. Scott, Andrew Bailey*
Medicinal Chemistry, Oncology, IMED Biotech Unit, AstraZeneca, Macclesfield SK10 4TG, United Kingdom
ARTICLE INFO
ABSTRACT
In the following communication we report routes for the synthesis of a set of 8-substituted-6-
phenyl-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolines. Pictet-Spengler and Bischler-
Napieralski methodologies were employed on the relevant indazole precursors and the merits of
the two cyclisation reactions for preparing these structures were assessed.
Article history:
Received
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinoline
Pictet-Spengler
Bischler-Napieralski
Hydroxy-substituted tetrahydroisoquinolines have been
explored as potential ligands in a variety of therapeutic areas,
such as dopamine antagonists, nitric oxide inhibitors, opioid K
antagonists and phenylethanolamine N-methyltransferase
(PNMT) inhibitors.1a-d However, the phenolic hydroxy group has
been associated with in vivo liabilities in many different
molecules investigated as oral drugs. To overcome these issues,
several reports have demonstrated the use of indazole as a
potential isostere of phenol which can offer benefits in terms of
pharmacokinetic profile.2a-c During a recent drug discovery
project we wished to investigate this in the context of a
6-hydroxytetrahydroisoquinoline scaffold and synthesize an
analogous series with the isosteric tricyclic indazole cores 1a-c
(Fig. 1). Traditional approaches to the tetrahydroisoquinoline
scaffold often utilise a Pictet-Spengler or Bischler-Napieralski
cyclisation to construct the piperidine ring.3 Substituted, electron-
rich phenols are well suited to this chemistry, however less
electron rich aromatic systems perform poorly, or not at all, in
the cyclisation step and literature precedent for electron poor
indazole rings participating in these cyclisations was notably
absent. Our first-generation route to these targets therefore
involved construction of the tetrahydroisoquinoline ‘core’
followed by elaboration of an o-toluidine functionality to the
appropriate indazole (Scheme 1).
i, ii
iii
3
2
iv-vi
viii
vii
4
1a
5
Scheme 1. Reagents and conditions: (i) NH4Cl, HATU, DIPEA, CH2Cl2, rt,
100%; (ii) H2, Pd/C, methanol, rt, 97%; (iii) BH3·Me2S, THF, reflux, 64%;
(iv) benzaldehyde, aq. phosphate buffer/MeCN, 50 °C; (v) TFA, 90 °C, 44%
(2 steps); (vi) Boc2O, Et3N, aq. dioxane, rt, 75%; (vii) KOAc, Ac2O,
Toluene/CHCl3, 60 °C, then 18-Crown-6, isoamylnitrite, 60 °C, 43%;
(viii) HCl, dioxane/MeOH, rt, 95%.
The o-toluidine intermediate 4 was formed in 6 steps from
commercially available 2-methyl-3-nitrophenylacetic acid. An
initial coupling using ammonium chloride as a source of
ammonia followed by catalytic hydrogenation of the nitro group
both proceeded in good yield, leading to amide 2. Reduction with
borane dimethylsulfide gave the phenethylamine 3 which was
then reacted with benzaldehyde in a Pictet-Spengler cyclisation
followed by Boc protection to yield intermediate 4. It is worth
noting that the Pictet-Spengler cyclisation of phenethylamines in
which the aryl ring is substituted by ‘NH2’ has poor literature
precedent. The method we followed (based on a report by Hailes
and co-workers4) allowed isolation of the intermediate imine
1a R1/R 2 = H
1b R1 = Me, R2 = H
1c R1/R 2 = Me
which
was
further
elaborated
into
the
desired
tetrahydroisoquinoline by heating in TFA. A modified Jacobsen
procedure involving 18-crown-6 as a phase transfer reagent was
Figure 1. Target tricyclic indazoles 1a-c

2
then used to take the o-toluidine functionality in 4 through to the
acyl protected indazole 5 in 43% yield.5 The synthesis was
completed by removal of the Boc and acyl protecting groups
under acidic conditions and target 1a was thus isolated in 8 steps
in an overall yield of 8%. Although ultimately successful, this
initial route carried an associated shortcoming in terms of the
early stage introduction of the phenyl ring via the aldehyde in the
Pictet-Spengler step. In the event that future work required
variation of this aryl substituent it was felt that such a sequence
would not prove optimal.
i
ii
10
11
iii
9b
In order to address this issue, we focused on the design of an
alternative approach which utilized a suitable, commercially
available indazole as a starting point. Ideally the intermediate in
question would be elaborated into the corresponding ethanamine,
thus potentially allowing formation of the targets via a late stage
Pictet-Spengler or Bischler-Napieralski cyclisation. Similar
reactions have been carried out on a range of predominantly
electron rich aryl and heteroaryl ethanamine analogues.6
Although unable to find precedent for such chemistry on an
indazole core, we were hopeful that this heterocycle would also
fit into the scope of the two cyclisation methods.
To achieve our objective, a diverse set of synthetic strategies
were employed to make the appropriate ‘indazole-substituted
ethanamine’ precursors 9a-c for use in these two approaches. The
methods of ring closure were then compared to determine the
most suitable route for preparing the target structures 1a-c.
Commercially available 4-bromoindazole was identified as an
appropriate starting point for synthesizing the three intermediate
ethanamines 9a-c which differed only in the nature of
substitution on the carbon adjacent to the amino group.
In the route to the unsubstituted methylene analogue 9a
(Scheme 2) 4-bromoindazole was first reacted under Heck
conditions with acrylamide to yield intermediate 6. Although the
yield for this step was moderate (52%), no 1,4 addition product
was observed and protection of the indazole nitrogen was found
to be unnecessary for this particular transformation.
Catalytic hydrogenation gave the saturated amide 7 which was
then converted to the corresponding Boc protected ethanamine
analogue 8 via a Hoffman rearrangement using lead tetraacetate
in tert-butanol.7 Attempts to replace lead tetraacetate with
alternative reagents for this transformation, such as
Scheme 3. Reagents and conditions: (i) Pd(OAc)2, isopropenyl acetate,
tributyltin methoxide, tri(o-tolyl)phosphine, toluene, 100 °C, 59%
(ii) Ti(i-PrO)4, (R)-tert-butanesulfinamide, THF, 65 °C then NaBH4, -48 °C,
51% (iii) HCl, MeOH/dioxane, rt, 100%.
Our route to the chiral α-methyl substituted analogue 9b
(Scheme 3) commenced using 4-bromoindazole in a Stille type
coupling with tributyltin methoxide and isopropenyl acetate to
yield ketone 10.8 In order to form the desired (R)-1-(1H-indazol-
4-yl)propan-2-amine 9b, this ketone was first condensed with
(R)-tert-butanesulfinamide to give the imine intermediate. In situ
reduction of the imine with sodium borohydride then gave a 51%
yield of the desired diastereoisomer 11, following HPLC
purification to remove 4% of the unwanted isomer (procedure
according to Ellman and co-workers, stereochemistry assignment
was based on the results therein for benzylmethyl ketone).9 The
synthesis was completed by acidic cleavage of the sulfinamide to
yield analogue 9b.
For introduction of the dimethyl substitution in target 9c
(Scheme 4) 4-bromoindazole was initially reacted under Negishi
conditions with 2-tert-butoxy-2-oxoethylzinc chloride to form
tert-butyl ester 12. This intermediate was converted to the
corresponding ethyl ester 13 via cleavage with TFA and then
heating the resultant acid (not isolated) in ethanol in the presence
of catalytic sulfuric acid. Formation of the tertiary alcohol 14 was
achieved by treating the ethyl ester with methylmagnesium
bromide.
We chose to employ a modified Ritter procedure with
chloroacetonitrile10 to access the desired 1-(1H-indazol-4-yl)-2-
methylpropan-2-amine from alcohol 14, the initially formed
chloroamide (not isolated) being easily converted to 9c using
thiourea.
bis(trifluoroacetoxy)iodobenzene
proved
unsuccessful.
Deprotection of 8 under acidic conditions then yielded 2-(1H-
indazol-4-yl)ethanamine 9a.
i
ii, iii
12
v, vi
13
i
ii
iv
7
6
14
9c
iii
iv
Scheme 4. Reagents and conditions: (i) 2-tert-butoxy-2-oxoethylzinc
chloride, DavePhos, Pd(dba)2, THF/toluene reflux, 49%; (ii) TFA, rt; (iii)
EtOH, cat H2SO4, reflux, 83% (2 steps); (iv) NaH, 0 °C, THF, then MeMgBr
-78 °C, 64%; (v) 2-chloroacetonitrile, AcOH, H2SO4, rt, 100%; (vi) thiourea,
EtOH/AcOH, reflux, 56%.
8
9a
Scheme 2. Reagents and conditions: (i) acrylamide, Pd(dtbpf)Cl2, TBACl, N-
cyclohexyl-N-methylcyclohexanamine, MeCN, 130 °C, MW, 52%; (ii) H2,
Pd/C, EtOH, rt, 95%; (iii) Pb(OAc)4, t-BuOH, 80 °C, 56%; (iv) TFA/CH2Cl2,
rt, 100%.

3
Path A
Ethylamines 9a-c
Targets
1a-c
i
Path A
(Pictet-Spengler)
Path B
i
ii, iii, iv
16
iv
ii
18 R = H
17 R = H
v
v
20 R = Boc
19 R = Boc
Scheme 6. Reagents and conditions: (i) benzaldehyde, TFA, 130 °C, MW,
32% (17 and 18, mixed isomers); (ii) benzoyl chloride, DIPEA, CH2Cl2/THF,
rt; (iii) POCl3, P2O5, reflux; (iv) NaBH4, MeOH/THF, 3 steps, 87% (17 and
18, mixed isomers); (v) Boc2O, MeOH, rt, (19, 47% and 20, 29%).
Path B
(Bischler-Napieralski)
iii
15a-c
For substrate 9a there was little difference between the two
methods; the Bischler-Napieralski sequence gave the slightly
higher overall yield (66%), whereas the shorter Pictet-Spengler
step (61%) required long microwave reaction times (30 h) at
elevated temperature (130 °C).
Scheme 5. Reagents and conditions: (i) benzaldehyde, TFA, 130 °C, MW;
(ii) benzoyl chloride, DIPEA, CH2Cl2/THF, rt; (iii) POCl3, P2O5, reflux;
(iv) NaBH4, MeOH/THF, rt.
Table 1
Formation of α-methyl analogue 1b from 9b under Pictet-
Spengler conditions in TFA was also found to require a long
microwave reaction time at high temperature and resulted in a
similar yield of the cyclized material (59%). For this example,
however, the Bischler-Napieralski sequence (Path B) gave a
lower overall recovery of 44% from ethanamine 9b, mostly due
to a low conversion (49%) of amide 15b to target 1b. It should
also be noted that for both methods the stereochemistry of the
major product 1b was confirmed by nOe experiments and shown
to exhibit ‘cis’ arrangement of the phenyl and methyl substituents
(Fig. 2). The analogous trans compound (not isolated) was only
observed in trace amounts in the crude reaction mixtures.
For the dimethyl substituted precursor 9c, cyclisation via Path
A using the same Pictet-Spengler conditions (microwave heating
at 130 °C in TFA) enabled us to isolate target 1c in 91% yield.12
However, on this occasion we were unable to form 1c using the
Bischler-Napieralski (Path B) ‘sequence’. Heating under the
POCl3/P2O5 conditions resulted in loss of nitrogen from the
tertiary centre of amide 15c, leading to decomposition of the
starting material.
Having focused our initial investigations on the derivatives of
2-(1H-indazol-4-yl)ethanamine 9a-c as a starting point for the
Pictet-Spengler and Bischler-Napieralski cyclisations, we then
attempted the same chemistry on the isomeric 2-(1H-indazol-6-
yl)ethanamine 16 (prepared using a similar synthetic route to 9a,
see ESI), as shown in Scheme 6. On this occasion both the ‘Path
A’ and ‘Path B’ cyclisation protocols resulted in a mixture of the
2 possible regioisomers (17 and 18) accessible from starting
material 16 (Scheme 6). The Bischler-Napieralski sequence gave
the better overall yield of 87 % as a 5:3 ratio of 17 to 18, whereas
from the Pictet-Spengler step we isolated 32% of a 3:1 ratio in
favour of the same isomer.
Yields for Path A and Path B cyclisation routes
R1, R2
Path A (%)
Path B (%)
H, H (1a)
61
59
91
66
44
-
Me, H (1b)
Me, Me (1c)
The three ‘indazole-substituted ethanamine’ analogues 9a-c
prepared as described above were then assessed in the two
cyclisation pathways shown in Scheme 5. Results for the Pictet-
Spengler reaction (Path A) and the three step Bischler-
Napieralski ‘sequence’ (Path B) are reported (Table 1). It should
be noted that the yields quoted in Table 1 for Path B are overall
yields, over the three steps (ii, iii and iv) shown in Scheme 5.
Initial efforts to react 9a with benzaldehyde in a Pictet-
Spengler cyclisation (Path A) focused on the use of mild
conditions, such as stirring in dichloromethane with TFA at room
temperature. Although these reagents have proved successful for
converting analogous indole analogues11 they yielded only
recovered starting materials when applied to 9a. More forcing
conditions, microwave heating at 130 °C in TFA were identified
as a suitable method for this step, giving 1a in a yield of 61%.
Alternatively, using Path B, starting material 9a could first be
converted to the amide 15a using benzoyl chloride (91%) and
then cyclized using Bischler-Napieralski methodology. For the
cyclisation step we resorted to heating in POCl3 in the presence
of P2O5. This resulted in an effective transformation to the
intermediate dihydroisoquinoline (not isolated). A 73% yield of
target 1a from amide 15a was obtained following reduction of
the dihydroisoquinoline with sodium borohydride, giving an
overall yield of 66% for these three steps from 9a (Table 1).
The mixture of isomers obtained from the Bischler-
Napieralski path was converted to the corresponding Boc
protected compounds, allowing facile separation of 19 and 20
using silica gel chromatography. The structures of these two
regioisomers were assigned using 1H NMR (based on the
observed ortho coupling for the indazole ‘aryl’ protons in isomer
19).
In summary, we have reported the synthesis of a small set of
8-substituted-6-phenyl-,7,8,9-tetrahydro-3H-pyrazolo[4,3-
f]isoquinolines. The strategy of constructing this scaffold via
either Pictet-Spengler or Bischler-Napieralski cyclisation
methodology proved successful and to the best of our knowledge
represents the first reported examples of these traditional
reactions on an indazole core. For the ethanamine analogue
lacking substitution on the carbon adjacent to the amino group
(9a) there was little to choose between the two routes under
n.O.e
Figure 2. Cis stereochemistry of 1b

4
11. See for example (a) Hadjaz, F.; Besret, S.; Martin-Nizard, F.;
Yous, S.; Dilly, S.; Lebegue, N.; Chavatte, P.; Duriez, P.;
consideration. For mono (9b) or dimethyl (9c) substituted
structures, our preferred cyclisation conditions favoured
formation of the targets via the Pictet-Spengler reaction.
Berthelot, P.; Carato, P. Eur. J. Med. Chem. 2011, 46, 2575-2585.
(b) Weiqin Jiang, Xuqing Zhang, and Zhihua Sui. Org. Lett. 2003,
5, 43-46.
Acknowledgments
12. This Pictet-Spengler approach was used to react 9c with 4-bromo-
2-fluoro-6-methoxybenzaldehde to give the corresponding
tricyclic indazole in 88% yield. For details see PCT Int. Appl.
(2017), WO2017182495, 166 pp.
We would like to thank Howard Beeley, Paul Davey, Scott
Boyd, David Whittaker and Peter Barton for analytical support.
Supplementary Data
Supplementary material (experimental procedures and
characterization data including 1H NMR, 13C NMR spectra for all
isolated compounds) associated with this article can be found in
the online version.
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5
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Synthesis of 8-substituted-6-phenyl-6,7,8,9-tetrahydro-3H-pyrazolo
[4,3-f]isoquinolines using Pictet-Spengler and Bischler-Napieralski
cyclisation methods.
Leave this area blank for abstract info.
Robert D. M. Davies, Jennifer H. Pink, James S. Scott, Andrew Bailey*
Path A
(Pictet-Spengler)
9a-c
a R 1/R 2 = H
b R1 = Me, R2 = H
c R1/R 2 = Me
1a-c
Path B
(Bischler-Napieralski)
15a-c

6
HIGHLIGHTS
Pictet-Spengler or Bischler-Napieralski used to construct a
tricyclic indazole core
Conditions develop to allow indazoles to undergo these
cyclisations
Cis stereochemistry prefered in the case of α-methyl indazole
ethanamines