Tricyclic fused pyrazoles with a 'Click' 1,2,3-triazole substituent in position 3 are nanomolar CB1 receptor ligands

Article abstract of DOI:10.1055/s-0034-1379887

Structural modification of the potent conformationally constrained tricyclic pyrazole CB₁ ligand NESS0327 was achieved by replacing: (1) the chlorine substituent on the tricycle with a 3-fluoropropyl chain, and (2) the pyrazole 3-{[(piperidino)

Full text of DOI:10.1055/s-0034-1379887

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 817–826
paper
817
C. Zanato et al.
Paper
Synthesis
Tricyclic Fused Pyrazoles with a ‘Click’ 1,2,3-Triazole Substituent
in Position 3 Are Nanomolar CB1 Receptor Ligands
Chiara Zanatoa
HO
F
F
Maria Grazia Cascioa
Paolo Lazzari*b,c
Roger Pertweea
Andrea Testaa
Br
N
O
N
N
N
N
N
N
N
N
OEt
O
R
Cl
Cl
Cl
Cl
Cl
Cl
Matteo Zanda*a,d
R = Bn; Ki CB1 = 62.5 nM
R = 2,4-Cl2C6H4; Ki CB1 = 42.5 nM
a Kosterlitz Centre for Therapeutics, Institute of Medical Sciences,
University of Aberdeen, Foresterhill, AB25 2ZD, Scotland, UK
m.zanda@abdn.ac.uk
b PharmaNess Scarl, Parco Scientifico della Sardegna, Edificio 5,
Loc. Piscinamanna, 09010 Pula (CA), Italy
c KemoTech s.r.l., Parco Scientifico della Sardegna, Edificio 3,
Loc. Piscinamanna, 09010 Pula (CA), Italy
d C.N.R.-I.C.R.M., via Mancinelli 7, 20131 Milano, Italy
Received: 19.11.2014
Accepted: 12.12.2014
Published online: 16.01.2015
DOI: 10.1055/s-0034-1379887; Art ID: ss-2014-z0706-op
to its side effects, which included severe depression and
suicidal tendencies.13 Since then, the pharmaceutical indus-
try’s interest in cannabinoid ligands has somewhat de-
clined, whereas academic cannabinoid research has re-
mained vibrant. In particular, the relationship between
density, distribution, and functional modification of CB1 re-
ceptors and the onset of a pathological state is still not well
understood. For this reason the development of radio-li-
gands suitable for in vivo PET functional imaging of CB1 re-
ceptors has emerged as an important area of research in
medicine and drug development. A small number of PET ra-
diotracers14 based on the structure of rimonabant have
been synthesised, radiolabelled, and tested in vivo, but the
majority afforded unsatisfactory CNS-imaging capacity as a
consequence of their poor brain uptake. A few radiolabelled
CB1 PET ligands15 have also been tested in clinical trials on
humans.16 Recently, we described a new class of high-affin-
ity CB1 ligands A (Figure 1), bearing a ‘click’ N-(4-fluorobu-
tyl)-1,2,3-triazolyl function in position 3 of the pyrazolyl
ring, as candidate PET tracers.17 In agreement with previ-
ously reported data on rimonabant analogues having nitro-
gen- and oxygen-containing aromatic rings replacing the ri-
monabant-type hydrazide moiety in position 3 of the pyra-
zole ring,18 our results showed that the 1,2,3-triazole group
is well tolerated by the CB1 binding pocket, although the ef-
fect of varying the substituent in position 4 of the triazole
ring was not investigated. Taking into account the high CB1
affinity of NESS0327 (Figure 1), a conformationally con-
strained tricyclic pyrazole analogue of rimonabant, that
was reported to have CB1 affinity in the femtoMolar range,19
we have now extended our investigation to the 1-(2,4-di-
chlorophenyl)-1,4,5,6-tetrahydrobenzo[6,7]cyclohepta[1,2-
c]pyrazole-3-carboxamide structural scaffold for the devel-
opment of novel CB1 PET tracer candidates 1 (Figure 1).
Abstract Structural modification of the potent conformationally con-
strained tricyclic pyrazole CB1 ligand NESS0327 was achieved by replac-
ing: (1) the chlorine substituent on the tricycle with a 3-fluoropropyl
chain, and (2) the pyrazole 3-{[(piperidino)amino]carbonyl} substituent
with a 4-substituted 1,2,3-triazole group obtained by click chemistry
from an alkynyl precursor. Among the resulting compounds, two are
particularly promising candidates for [18F]radiolabelling and PET imag-
ing studies of the CB1 receptor, as they displayed Ki CB1 = 62.5 nM and
42.5 nM, respectively, in the same range as that displayed by rimon-
abant.
Key words cannabinoids, PET imaging, fluorine, Sonogashira reac-
tion, click chemistry
Cannabinoid receptors belong to the family of G-protein
coupled receptors (GPCRs).1 Two subgroups of cannabinoid
receptors have been discovered and extensively studied:
CB1 and CB2.2 Although CB1 receptors are predominantly lo-
calised in the central nervous system (CNS)2 while CB2 re-
ceptors are mostly present in the peripheral nervous sys-
tem (PNS),3 some studies have shown the presence of CB1
receptors in the PNS4 and of CB2 in the CNS, albeit in low
density.5 CB1 receptors have a prominent role in drug dis-
covery as they have been shown to play an important role
in a number of disorders, including chronic pain,6 depres-
sion,7 anxiety,8 stress,9 schizophrenia,10 and obesity.11 Con-
sequently, several cannabinoid ligands were developed as
drug candidates, including rimonabant (SR141716A),12
which is a pyrazole-core inverse agonist discovered by Sa-
nofi-Synthelabo (now Sanofi-Aventis) in 1994. Rimonabant
(Figure 1) was marketed in Europe as an anti-obesity drug,
but it was subsequently withdrawn from the market owing
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 817–826

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C. Zanato et al.
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Synthesis
Cl
Cl
O
O
HN
N
N
N
N
HN
N
N
Cl
Cl
Cl
Cl
rimonabant
(SR141716A)
NESS 0327
N
N
N
F
N
N
N
S
N
R
F
N
N
N
R
Cl
Cl
Cl
A
Cl
1a–l
this work
Figure 1 CB1 receptor ligands relevant to this work
In this work we describe: (1) the synthesis of tricyclic
fused pyrazoles 1 carrying a 3-fluoropropyl group as an ar-
omatic substituent and differently 4-substituted 1,2,3-tri-
azole groups in position 3 of the pyrazole ring; and (2) the
assessment of the CB1 and CB2 affinity of these new ligands.
Some of them, in particular 1g and 1l, showed excellent CB1
affinity in line with rimonabant, although selectivity vs.
CB2 was quite modest, suggesting that these compounds
may indeed have potential as PET tracers for imaging the
cannabinoid system in vivo.
The synthesis of target compounds 1 started from 3-
bromobenzaldehyde (2) (Scheme 1), which was submitted
to a Wittig olefination with (3-carboxypropyl)triphenyl-
phosphonium bromide affording the carboxylic acid 3 as a
mixture of E and Z geometric isomers.20 Catalytic hydroge-
nation of 3, over palladium on carbon catalyst provided the
saturated derivative 4, which was first transformed into the
corresponding acyl chloride and then submitted to an intra-
molecular Friedel–Crafts acylation promoted by aluminium
trichloride to give the benzosuberone 5.21 The latter was
subjected to Dieckmann reaction with diethyl oxalate in the
presence of sodium ethoxide20 to give the 1,3-diketo ester 6
as a tautomeric mixture, predominantly containing the
alkenylidene structure. Next, the tricarbonyl compound 6
and 2,4-dichlorophenylhydrazine were heated in ethanol to
afford the pyrazole 7.20 A solvent-free palladium-catalysed
Sonogashira cross coupling22 with prop-2-yn-1-ol afforded
the alkyne 8. A first attempt to hydrogenate the propargylic
alcohol 8 by employing palladium on carbon in ethyl ace-
tate under hydrogen (1 atm) resulted in a concomitant re-
ductive de-chlorination of the benzene ring. A second at-
tempt was carried out with the Wilkinson catalyst in ben-
zene (1 atm of H2) but, after 24 hours at 60 °C, only partial
hydrogenation to the corresponding alkene was observed
and the reaction did not proceed further. At this point we
opted for Raney nickel as catalyst23 under hydrogen (1 atm)
and when ethanol was used as the solvent we still obtained
a significant amount of de-chlorinated compounds, howev-
er, when tetrahydrofuran was used as the solvent we were
able to obtain the desired saturated product 9 in quantita-
tive yield. Next, the alcohol 9 was treated with the dehy-
droxy-fluorinating agent Deoxofluor24 affording the fluoro
ester 10 which was directly submitted to reduction with
lithium aluminium hydride. The resulting alcohol 11 was
oxidised with the Dess–Martin periodinane providing the
corresponding aldehyde 12. The latter was homologated
under Bestmann–Ohira alkynylation conditions25 leading to
the key alkyne intermediate 13.
The synthesis of the target compounds 1a–l was com-
pleted by using a copper-catalysed azide-alkyne cycloaddi-
tion26 between 13 and a series of azides (Scheme 2).
We next tested the CB1 and CB2 affinity of compounds
1a–l. To that end, we performed [3H]CP55940 displacement
binding assays with membranes obtained from hCB1 and
hCB2 CHO cells using methods we have described previous-
ly.27 The results are summarised in Table 1 and affinity to
CB1 and CB2 are expressed as Ki values. All the compounds,
with the exception of 1b that showed higher affinity for the
CB2 receptor, evidenced nanomolar affinity for the CB1 re-
ceptor and moderate to low CB1/CB2 selectivity. Compounds
1g and 1l stand out for their high CB1 affinity, which was
comparable to that displayed by rimonabant. Moreover, Ki
CB1 values of both 1g and 1l were in line with the CB1 affin-
ity of NESS0327 as reported by Zhang et al.28 It is worth
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C. Zanato et al.
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Synthesis
Br
Br
Br
COOH
Br
COOH
O
iii
ii
i
vi
2
3
4
5
O
HO
Br
HO
Br
O
O
O
O
v
viii
vi
vii
N
N
N
N
N
OEt
OEt
N
O
OEt
OEt
O
Cl
Cl
Cl
Cl
Cl
6
7
8
9
Cl
F
F
F
F
O
ix
x
xi
N
N
N
N
N
N
N
N
OEt
OH
O
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
10
11
12
13
Scheme 1 Synthesis of alkyne 13. Reagents and conditions: (i) Ph3P+(CH2)3CO2H.Br-, t-BuOK, DMSO, r.t., overnight (80%); (ii) H2, Pd/C, EtOAc, AcOH, r.t.,
overnight; (iii) 1. (COCl)2, DMF, r.t., 1 h; 2. AlCl3, CH2Cl2, r.t., overnight (80% over 3 steps); (vi) diethyl oxalate, NaOEt, EtOH, r.t., overnight; (v) 2,4-di-
chlorophenylhydrazine hydrochloride, EtOH, reflux, overnight (50% over 2 steps); (vi) prop-2-yn-1-ol, PdCl2(PPh3)2, TBAF, 70 °C, 4 h (70%); (vii) H2, Raney
Ni, THF–H2O, r.t., 3 h; (viii) Deoxofluor, THF, CH2Cl2, r.t., 2 h (80% over 2 steps); (ix) LiAlH4, THF, r.t., 2 h (85%); (x) DMP, CH2Cl2, r.t., 3 h; (xi) dimethyl
1-diazo-2-oxopropylphosphonate, K2CO3, MeOH, r.t., overnight (90% over 2 steps).
F
noting that the originally reported femtoMolar CB1 affinity
of NESS032720 was not confirmed in literature by other au-
thors who determined for the same compound Ki CB1 values
in the range 18.4–126 nM.29 Relative to rimonabant, both
1g and 1l showed lower CB1/CB2 selectivity (Ki CB2/Ki CB1
<10).
In the light of their high CB1 affinities 1g,l are therefore
the most promising candidates for further development, in-
cluding their possible use as a PET tracer for imaging the
CB1 receptor in vivo.
N
N
Cl
Cl
13
i, ii or iii
In conclusion, we have described the structural modifi-
cation of the potent conformationally constrained tricyclic
pyrazole CB1 ligand NESS0327, which was achieved by re-
placing: (1) the chlorine substituent in the tricycle with a
3-fluoropropyl chain, which is amenable to radiofluorina-
tion, and (2) the pyrazole 3-{[(piperidino)amino]carbonyl}
substituent with a 4-substituted 1,2,3-triazole group ob-
tained by click chemistry from the alkynyl precursor 13.
Compounds 1g and 1l are particularly promising candidates
for [18F]radiolabelling and PET imaging studies of the CB1
receptor, as they displayed Ki CB1 = 62.5 nM and 42.5 nM,
respectively, in the same range as that displayed by rimon-
abant, although CB1/CB2 selectivity was fairly low for both
the novel derivatives. Moreover, Ki CB1 values of 1g and 1l
are in line with that of the reference analogue NESS0327,
F
N
N
N
N
N
R
Cl
Cl
1a–l
Scheme 2 Synthesis of CB1 ligands 1a–l. Reagents and conditions: (i)
TMSN3, CuSO4, sodium ascorbate, DMF–H2O, microwaves, 120 °C, 30
min (45% 1a); (ii) NaN3, CuSO4, sodium ascorbate, DMF–H2O, MeI,
120 °C, overnight (48% 1b); (iii) RN3, CuSO4, sodium ascorbate,
t-BuOH–H2O, r.t., overnight (60–82% 1c–l).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 817–826

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Table 1 CB1 and CB2 Affinities of Compounds 1a–l
Compound
R
Receptor affinity
Ki CB1 (nM)a (95% CL)b
Max. disp. (95% CL)b
Ki CB2 (nM)a (95% CL)b
Max. Disp. (95% CL)b
393.6
(217.4–712.6)
79.7
(67.7–91.7)
2212
(829.2–5903)
84.8
(57.0–112.5)
1a
1b
1c
1d
1e
H
2260.0
(361.6–14120)
87.8
(38.7–136.9)
1271
(998.8–1617)
99.6
(92.5–106.6)
Me
226.6
(141.2–363.8)c
71.3
(64.7–77.8)
1446
(1093–1912)
71.8
(65.8–77.8)
Pr
250.6
(144.1–435.6)
78.9
(69.5–88.3)
883.1
(544.4–1433)
78.8
(68.2–89.4
(CH2)4Me
458.0
(94.4–2221)
70.6
(44.4–96.8
935.0
(690.1–1267)
784.2
(476.1–92.3
116.3
(70.4–192.3)
62.8
(57.6–67.9)
685.3
(302.9–1550)
45.7
(36.8–54.6)
1f
62.5
(28.1–139.1)
60.2
(50.2–70.2)
358.4
(243.2–528.0)
60.8
(55.7–65.9)
1g
1h
Bn
Ph
415.0
(287.9–598.4)
49.5
(44.7–54.4)
d
d
–
–
OMe
338.1
(69.8–1637)
26.9
(11.4–42.5)
648.4
(218.4–1925)
30.4
(19.0–41.7)
1i
1j
112.7
(20.7–613.3)
27.9
(14.6–41.1)
1023
(122.1–8570)
25.5
(4.6–46.4)
CF3
MeO
Cl
91.9
(41.3–204.7)
47.8
(41.3–54.2)
508.6
(159.7–1620)
32.3
(24.2–40.4)
1k
1l
42.5
(24.4–74.1)
40.9
(36.6–45.2)
195.4
(126.0–303.0)
30.1
(26.6–33.7)
Cl
31.7
87.8
(83.1–92.4)
1400
(500–3700)
92.4
(70.4–114)
rimonabant (SR141716A)18
(22.4–45.0)e
a n = 4, unless otherwise indicated.
b CL = confidence limits.
c n = 12.
d Plateau could not be reached, n = 2.
e n = 24.
which some authors reported to be in the nM range29
whereas the original study had measured for the same
compound a Ki CB1 = 0.00035 nM.20
recorded using a Griffin melting point apparatus. All reactions were
carried out in oven- or flame-dried glassware under a N2 atmosphere,
unless stated otherwise. All commercially available reagents were
used as received. Reactions were magnetically stirred and monitored
by TLC on silica gel (60 F254 pre-coated glass plates, 0.25-mm thick-
ness). Visualisation was accomplished by irradiation with a UV lamp
and/or staining with ceric ammonium molybdate or KMnO4 solution.
Flash chromatography was performed on silica gel (60 Å, particle size
0.040–0.062 mm). Yields refer to chromatographically and spectro-
scopically pure compounds, unless stated otherwise.
1H (400.13 MHz), 13C (100.58 MHz), and 19F (376.45 MHz) NMR spec-
tra were recorded on a Bruker Avance III spectrometer. 1H NMR chem-
ical shifts are reported relative to the solvent resonance (CDCl3,
δ = 7.26). 13C NMR spectra were recorded with complete proton de-
coupling, and the chemical shifts are reported relative to the solvent
resonance (CDCl3, δ = 77.0). MS experiments were performed on an
Agilent Technologies 1200 Series HPLC system equipped with a DAD
and a 6120 MS detector composed by a ESI ionisation source and a
Single Quadrupole mass selective detector. A CEM Discover® System
was used to perform reaction with microwaves. Melting points were
5-(3-Bromophenyl)pent-4-enoic Acid (3)30
To a suspension of (3-carboxypropyl)triphenylphosphonium bromide
(30.0 g, 69.9 mmol, 1.2 equiv) in anhyd DMSO (20 mL), t-BuOK (17.3
g, 153.7 mmol, 2.2 equiv) was added. The mixture was stirred for 1 h
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 817–826

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Synthesis
at r.t., then a solution of 3-bromobenzaldehyde (2, 6.8 mL, 58.3 mmol,
1.0 equiv) in DMSO (30 mL) was added dropwise. The resulting mix-
ture was stirred overnight, poured into H2O (150 mL), and extracted
with CHCl3 (2 × 200 mL). The aqueous layer was acidified with concd
HCl and extracted with CHCl3 (2 × 200 mL). The combined organic
layers were washed with H2O (2 × 200 mL), dried (Na2SO4), filtered,
and the solvent was evaporated under reduced pressure. The crude
product was purified by flash chromatography (hexane–EtOAc, 7:3)
to give 3 (11.85 g, 80%) as a yellow oil as an E/Z diastereomeric mix-
ture; Rf = 0.25 (hexane–EtOAc, 6:4).
Ethyl 3-(2,4-Dichlorophenyl)-12-(3-hydroxyprop-1-ynyl)-3,4-di-
azatricyclo[8.4.0.02,6]tetradeca-1(14),2(6),4,10,12-pentaene-5-car-
boxylate (8)
A mixture of bromide 7 (3.0 g, 6.24 mmol, 1.0 equiv), prop-2-yn-1-ol
(0.36 mL, 6.24 mmol, 1.0 equiv), PdCl2(PPh3)2 (0.19 mmol, 131.4 mg,
0.03 equiv), and 1 M TBAF (18.7 mL, 18.7 mmol, 3.0 equiv) was stirred
at 70 °C for 4 h. Then the mixture was diluted with water (20 mL), ex-
tracted with EtOAc (2 × 50 mL), dried (Na2SO4), and filtered and the
solvent was evaporated under reduced pressure. The crude product
was purified by flash chromatography (CH2Cl2–MeOH, 95:5) to give 8
(2.0 g, 70%) as a white solid; mp 110–112 °C; Rf = 0.23 (hexane–EtOAc,
7:3).
5-(3-Bromophenyl)pentanoic Acid (4)30
1H NMR (400 MHz, CDCl3): δ = 1.44 (t, J = 7.1 Hz, 3 H), 1.97 (br s, OH),
2.25 (br s, 2 H), 2.65 (br s, 1 H), 2.67 (t, J = 6.5 Hz, 2 H), 3.24 (br s, 1 H),
4.47 (q, J = 7.1 Hz, 2 H), 4.49 (s, 2 H), 6.63 (d, J = 8.0 Hz, 1 H), 7.10 (dd,
J = 1.4, 8.0 Hz, 1 H), 7.35–7.44 (m, 3 H), 7.55 (d, J = 9.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.4, 20.7, 31.4, 32.4, 51.6, 61.1, 85.1,
88.4, 122.7, 123.7, 126.9, 128.1, 129.2, 129.3, 130.3, 130.6, 132.5,
132.9, 135.9, 136.0, 141.8, 142.0, 142.5, 162.8.
To a solution of pentenoic acid 3 (7.30 g, 28.7 mmol, 1.0 equiv) in
EtOAc (150 mL) and a catalytic amount of AcOH (0.5 mL), Pd/C (365.0
mg, 5% w/w) was added. The mixture was stirred under H2 (1 atm)
overnight and then filtered on a short pad of Celite; the solvent was
evaporated under reduced pressure. Compound 4 was obtained as yel-
low oil in a quantitative yield and was used without further purifica-
tion; Rf = 0.25 (hexane–EtOAc, 6:4).
MS (ESI): m/z calcd C24H2035Cl2N2O3: 455.1 [M + H]+, 457.1 [M + 2 +
H]+, 477.1 [M + Na]+, 479.1 [M + 2 + Na]+; found: 455.1 [M + H]+ (100),
457.1 [M + 2 + H]+ (70), 477.1 [M + Na]+ (20), 479.1 [M + 2 + Na]+ (15).
2-Bromo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (5)30
To an ice-cooled solution of carboxylic acid 4 (7.35 g, 28.7 mmol, 1.0
equiv), oxalyl chloride (2.46 mL, 28.7 mmol, 1.0 equiv) and a catalytic
amount of DMF (1.0 mL) were added, and then the mixture was
stirred for 1 h at r.t. The excess oxalyl chloride was removed under
reduced pressure and CH2Cl2 (5.0 mL) was added to the residue and
evaporated. This washing procedure was repeated (3 ×) then the
crude product was diluted with CH2Cl2 (5.0 mL) and added to a sus-
pension of AlCl3 (4.21 g, 31.0 mmol, 1.1 equiv) in CH2Cl2 (5.0 mL). The
mixture was stirred overnight at r.t., poured into ice, and extracted
with CH2Cl2 (3 × 100 mL). The combined organic layers were washed
with 5% aq NaHCO3 (200 mL) and H2O (2 × 200 mL), dried (Na2SO4),
and filtered and the solvent was evaporated under reduced pressure.
The crude product was purified by flash chromatography (hexane–
EtOAc, 9:1) to give 5 (5.46 g, 80%) as a yellow oil; Rf = 0.52 (hexane–
EtOAc, 9:1).
Ethyl 3-(2,4-Dichlorophenyl)-12-(3-hydroxypropyl)-3,4-diazatri-
cyclo[8.4.0.02,6]tetradeca-1(14),2(6),4,10,12-pentaene-5-carboxyl-
ate (9)
Raney Ni was washed with H2O until the washings were pH neutral
and transferred into a round-bottom flask. A solution of alkyne 8
(1.65 g, 3.60 mmol, 1.0 equiv) in THF (240 mL) was added, and the
mixture was degassed and then purged with H2 (3 ×). After stirring
for 3 h at r.t. the mixture was filtered through a short pad of Celite
and the solvent was evaporated under reduced pressure. Compound 9
was obtained as a white solid in a quantitative yield and was used
without further purification. Rf = 0.23 (hexane–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): δ = 1.45 (t, J = 7.1 Hz, 3 H), 1.65 (br s, OH),
1.90 (tt, J = 6.4, 13.0 Hz, 2 H), 2.27 (br s, 2 H), 2.61–2.79 (m, 5 H), 3.19
(br s, 1 H), 3.68 (t, J = 6.3 Hz, 2 H), 4.47 (q, J = 7.1 Hz, 2 H), 6.61 (d,
J = 7.9 Hz, 1 H), 6.88 (dd, J = 1.6, 7.9 Hz, 1 H), 7.15 (d, J = 1.6 Hz, 1 H),
7.39 (dd, J = 2.3, 8.4 Hz, 1 H), 7.42 (d, J = 2.3 Hz, 1 H), 7.54 (d, J = 8.4
Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.5, 20.7, 31.8, 31.9, 32.5, 33.8, 61.0,
62.3, 123.2, 126.1, 126.6, 127.0, 128.0, 129.9, 130.2, 130.7, 132.8,
135.7, 136.4, 141.8, 141.9, 142.4, 143.2, 163.0.
MS (ESI): m/z calcd C24H2435Cl2N2O3: 459.1 [M + H]+, 461.1 [M + 2 +
H]+, 481.1 [M + Na]+, 483.1 [M + 2 + Na]+; found: 459.1 [M + H]+ (100),
461.1 [M + 2 + H]+ (70), 481.1 [M + Na]+ (40), 483.1 [M + 2 + Na]+ (30).
Ethyl 2-{2-Bromo-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-
6-yl}-2-oxoacetate (6)30
Na metal (874 mg, 38.0 mmol, 2.0 equiv) was added in one small por-
tion to dry EtOH (100 mL) and the mixture was stirred until all the Na
had reacted. Ethyl oxalate (1.97 mL, 19.0 mmol, 1.0 equiv) was added,
followed by a solution of bromo-benzosuberone 5 (4.57 g, 19.0 mmol,
1.0 equiv) in dry EtOH (5.0 mL). The solution was stirred at r.t. over-
night then the mixture was slowly poured into ice, and 2 M aq HCl (10
mL) was added. The resulting mixture was extracted with CHCl3 (2 ×
100 mL), dried (Na2SO4), and filtered and the solvent was evaporated
under reduced pressure. Compound 6 was obtained as yellow oil in a
quantitative yield and was used without further purification; Rf =
0.45 (hexane–EtOAc, 9:1).
Ethyl 3-(2,4-Dichlorophenyl)-12-(3-fluoropropyl)-3,4-diazatricy-
clo[8.4.0.02,6]tetradeca-1(14),2(6),4,10,12-pentaene-5-carboxylate
(10)
Ethyl 12-Bromo-3-(2,4-dichlorophenyl)-3,4-diazatricyc-
lo[8.4.0.02,6]tetradeca-1(14),2(6),4,10,12-pentaene-5-carboxylate
(7)30
To an ice-cooled solution of alcohol 9 (1.4 g, 3.2 mmol, 1.0 equiv) in
CH2Cl2 (30 mL), 50% Deoxofluor in THF (2.0 mL, 4.8 mmol, 1.5 equiv)
was added. The mixture was stirred at r.t. for 2 h, then sat. aq NaHCO3
(30 mL) was added. The resulting mixture was extracted with CH2Cl2
(2 × 100 mL), dried (Na2SO4), and filtered and the solvent was evapo-
rated under reduced pressure. The crude product was purified by
flash chromatography (hexane–EtOAc, 7:3) to give fluorinated com-
pound 10 (1.18 g, 80%) as white solid; mp 100–102 °C; Rf = 0.50
(hexane–EtOAc, 7:3).
A stirred mixture of diketo ester 6 (4.57 g, 19.0 mmol, 1.0 equiv) and
2,4-dichlorophenylhydrazine hydrochloride (4.06 g, 19.0 mmol, 1.0
equiv) in EtOH (130 mL) was heated at 80 °C overnight. The mixture
was allowed to cool to r.t. and the solvent was removed under re-
duced pressure to give a red-orange solid that was purified by flash
chromatography (hexane–EtOAc, 9:1) to afford 7 (4.56 g, 50%) as a
pale orange solid; mp 90–92 °C; Rf = 0.60 (hexane–EtOAc, 9:1).
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Synthesis
1H NMR (400 MHz, CDCl3): δ = 1.45 (t, J = 7.1 Hz, 3 H), 1.95–2.09 (m, 2
H), 2.27 (br s, 2 H), 2.67–2.75 (m, 5 H), 3.20 (br s, 1 H), 4.47 (dt, JH-H = 5.9
Hz, JH-F = 47.2 Hz, 2 H), 4.47 (q, J = 7.1 Hz, 2 H), 6.63 (d, J = 7.9 Hz, 1 H),
6.88 (dd, J = 1.7, 7.9 Hz, 1 H), 7.15 (d, J = 1.7 Hz, 1 H), 7.39 (dd, J = 2.2,
8.4 Hz, 1 H), 7.42 (d, J = 2.2 Hz, 1 H), 7.54 (d, J = 8.4 Hz, 1 H).
1H NMR (400 MHz, CDCl3): δ = 1.94–2.10 (m, 2 H), 2.19–2.34 (m, 2 H),
2.65–2.80 (m, 4 H), 3.14 (br s, 2 H), 4.47 (dt, JH-H = 5.9 Hz, JH-F = 47.2
Hz, 2 H), 6.63 (d, J = 7.9 Hz, 1 H), 6.89 (dd, J = 1.7, 7.9 Hz, 1 H), 7.16 (d,
J = 1.5 Hz, 1 H), 7.43 (dd, J = 2.3, 8.4 Hz, 1 H), 7.49 (d, J = 1.3 Hz, 1 H),
7.50 (d, J = 8.5 Hz, 1 H), 10.2 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 14.5, 31.1 (d, JC-F = 5.3 Hz), 31.7 (d, JC-F
20.2 Hz), 31.8, 61.0, 82.5, 83.1 (d, JC-F = 165.1 Hz), 123.3, 126.2, 126.8,
127.1, 128.0, 130.0, 130.2, 130.7, 132.8, 135.8, 136.3, 141.7, 141.9 (2
C), 143.2, 163.0.
=
13C NMR (100 MHz, CDCl3): δ = 20.4, 31.1 (d, JC-F = 5.3 Hz), 31.2, 31.6
(d, JC-F = 19.8 Hz), 32.7, 83.1 (d, JC-F = 165.1 Hz), 121.7, 126.2, 126.3,
127.2, 128.2, 130.0, 130.2, 130.5, 132.6, 136.0, 136.3, 141.9, 142.1,
143.6, 148.9, 188.2.
19F NMR (376.45 MHz, CDCl3): δ = –220.0 (tt, J = 25.3, 47.1 Hz, 1 F).
19F NMR (376.45 MHz, CDCl3): δ = –220.0 (tt, J = 25.4, 47.2 Hz, 1 F).
MS (ESI): m/z calcd for C24H2335Cl2FN2O2: 461.1 [M + H]+, 463.1 [M + 2
+ H]+, 483.1 [M + Na]+, 485.1 [M + 2 + Na]+; found: 461.1 [M + H]+
(100), 463.1 [M + 2 + H]+ (65). 483.1 [M + Na]+ (100), 485.1 [M + 2 +
Na]+ (65).
MS (ESI): m/z calcd for C22H1935Cl2FN2O: 417.1 [M + H]+, 419.1 [M + 2 +
H]+; found: 417.1 [M + H]+ (100), 419.1 [M + 2 + H]+ (70).
3-(2,4-Dichlorophenyl)-5-ethynyl-12-(3-fluoropropyl)-3,4-diaza-
tricyclo[8.4.0.02,6]tetradeca-1(14),2(6),4,10,12-pentaene (13)
[3-(2,4-Dichlorophenyl)-12-(3-fluoropropyl)-3,4-diazatricy-
clo[8.4.0.02,6]tetradeca-1(14),2(6),4,10,12-pentaen-5-yl]methanol
(11)
K2CO3 (2.1 g, 15.1 mmol, 3.3 equiv) and dimethyl 1-diazo-2-oxopro-
pylphosphonate (1.37 mL, 9.16 mmol, 2.0 equiv) were added to an
ice-cold solution of aldehyde 12 (1.90 g, 4.58 mmol, 1.0 equiv) in
MeOH (50 mL). After 5 min the ice bath was removed, the mixture
was allowed to warm to r.t. and stirred for an additional 12 h. 5% aq
NaHCO3 solution (10 mL) was added and the aqueous layer was ex-
tracted with Et2O (2 × 50 mL). The combined organic layers were
washed with brine, dried (MgSO4), and filtered and the solvent was
evaporated under reduced pressure. The crude product was purified
by flash chromatography (hexane–EtOAc, 7:3) to give alkyne 13 (1.7
g, 90%) as a white solid; mp 112–114 °C; Rf = 0.72 (hexane–EtOAc,
6:4).
1H NMR (400 MHz, CDCl3): δ = 1.95–2.08 (m, 2 H), 2.25 (br s, 2 H),
2.49–2.82 (m, 6 H), 3.28 (s, 1 H), 4.47 (dt, JH-H = 5.9 Hz, JH-F = 47.2 Hz, 2
H), 6.61 (d, J = 7.8 Hz, 1 H), 6.87 (d, J = 6.6 Hz, 1 H), 7.14 (s, 1 H), 7.38
(dd, J = 2.2, 8.5 Hz, 1 H), 7.43 (d, J = 2.1 Hz, 1 H), 7.48 (d, J = 8.7 Hz, 1
H).
A solution of ester 10 (2.47 g, 5.36 mmol, 1.0 equiv) in THF (53.0 mL)
was added to a suspension of LiAlH4 (223.8 mg, 5.90 mmol, 1.1 equiv)
in THF (53.0 mL) at 0 °C. The mixture was warmed to r.t. and stirred
for 2 h. The solution was cooled to 0 °C and quenched with H2O (5.4
mL), 15% aq NaOH (11 mL), and H2O (5.4 mL). After vigorously stirring
for 1 h, the mixture was filtered on a short pad of silica, dried
(Na2SO4), and filtered, and the solvent was evaporated under reduced
pressure. The crude product was purified by flash chromatography
(hexane–EtOAc, 1:1) to give fluorinated alcohol 11 (1.92 g, 85%) as
white solid; mp 104–106 °C; Rf = 0.25 (hexane–EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): δ = 1.95–2.08 (m, 2 H), 2.19–2.26 (m, 2 H),
2.39 (t, J = 7.6 Hz, OH), 2.62 (br s, 4 H), 2.72 (t, J = 7.6 Hz, 2 H), 4.47 (dt,
JH-H = 5.8 Hz, JH-F = 47.2 Hz, 2 H), 4.79 (d, J = 5.8 Hz, 2 H), 6.62 (d, J = 7.9
Hz, 1 H), 6.87 (dd, J = 1.7, 7.9 Hz, 1 H), 7.13 (d, J = 1.7 Hz, 1 H), 7.35
(dd, J = 2.2, 8.5 Hz, 1 H), 7.43 (d, J = 2.0 Hz, 1 H), 7.44 (d, J = 4.2 Hz, 1
H).
13C NMR (100 MHz, CDCl3): δ = 20.8, 31.0, 31.1 (d, JC-F = 5.4 Hz), 31.7
(d, JC-F = 19.8 Hz), 32.7, 80.1, 83.1 (d, JC-F = 165.0 Hz), 123.5, 126.2,
126.8, 126.9, 128.0, 130.0, 130.3, 130.4, 130.6, 132.6, 135.0, 135.4,
136.5, 141.2, 141.5, 141.9.
13C NMR (100 MHz, CDCl3): δ = 20.3, 31.1 (d, JC-F = 5.4 Hz), 31.2, 31.7
(d, JC-F = 19.8 Hz), 32.8, 57.7, 83.1 (d, JC-F = 165.0 Hz), 118.2, 126.1,
127.0, 127.4, 128.0, 129.9, 130.3, 130.5, 132.7, 135.0, 136.8, 141.1,
141.7, 142.1, 151.
19F NMR (376.45 MHz, CDCl3): δ = –220.0 (tt, J = 25.3, 47.2 Hz, 1 F).
MS (ESI): m/z calcd for C23H1935Cl2FN2: 413.1 [M + H]+, 415.1 [M + 2 +
19F NMR (376.45 MHz, CDCl3): δ = –219.9 (tt, J = 25.2, 47.1 Hz, 1 F).
H]+; found: 413.1 [M + H]+ (100), 415.1 [M + 2 + H]+ (70).
MS (ESI): m/z calcd for C22H2135Cl2FN2O: 419.1 [M + H]+, 421.1 [M + 2 +
H]+; found: 419.1 [M + H]+ (100), 421.1 [M + 2 + H]+ (70).
Synthesis of Benzylic and Aliphatic Azides;31 General Procedure
NaN3 (2.0 equiv) in H2O (0.1 mL/mmol) was added to a stirred solu-
tion of the benzylic/aliphatic bromide (1.0 equiv) in THF (2.5
mL/mmol). The resulting suspension was stirred at 80 °C for 3 h. The
mixture was extracted with CH2Cl2, washed with water and brine,
dried (Na2SO4), and filtered, and the solvent was evaporated under re-
duced pressure. The azide was obtained in quantitative yield and was
used without further purification and isolation.
3-(2,4-Dichlorophenyl)-12-(3-fluoropropyl)-3,4-diazatricy-
clo[8.4.0.02,6]tetradeca-1(14),2(6),4,10,12-pentaene-5-carbalde-
hyde (12)
To a solution of alcohol 11 (1.91 g, 4.58 mmol, 1.0 equiv) in CH2Cl2 (12
mL), Dess–Martin periodinane (DMP, 2.33 g, 5.50 mmol, 1.2 equiv)
was added at 0 °C The mixture was warmed to r.t. and stirred for 3 h.
Then sat. aq NaHCO3 (93 mL) and Na2S2O3 (5.2 g, 33.4 mmol, 7.3
equiv) were added. After stirring for 1 h, the phases were separated
and the aqueous phase was extracted with CH2Cl2 (3 × 100 mL). The
combined organic extracts were washed with brine (2 × 100 mL),
dried (Na2SO4), and evaporated under reduced pressure. Aldehyde 12
was obtained as a white solid in a quantitative yield and was used
without further purification; Rf = 0.70 (hexane–EtOAc, 6:4).
Synthesis of Aromatic Azides;31 General Procedure
A solution of aromatic amine (1.0 equiv) in MeCN (2 mL/mmol) was
cooled to 0 °C and t-BuONO (1.5 equiv) followed by TMSN3 (1.5 equiv)
were added dropwise. The resulting solution was stirred at r.t. for 1 h.
The mixture was concd under vacuum, diluted with hexane, and fil-
tered on a short pad of silica gel. The azide was obtained in quantita-
tive yield and was used without further purification and isolation.
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Synthesis
3-(2,4-Dichlorophenyl)-12-(3-fluoropropyl)-5-(1H-1,2,3-triazol-4-
yl)-3,4-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2(6),4,10,12-pen-
taene (1a)
HRMS: m/z [M + H]+ calcd for C24H23Cl2FN5: 470.1309; found:
470.1305.
To solution of alkyne 13 (70 mg, 0.17 mmol, 1.0 equiv) and TMSN3
(0.02 mL, 0.2 mmol, 1.2 equiv) in DMF–H2O (4:1, 2.0 mL), CuSO4 (1.4
mg, 0.008 mmol, 0.05 equiv) and sodium ascorbate (14.0 mg, 0.07
mmol, 0.4 equiv) were added. The mixture was placed in a microwave
reactor and irradiated for 30 min at 120 °C. The solution was cooled,
ice was added, and it was extracted with EtOAc (3 × 5 mL). The organ-
ic layers were washed with H2O, brine, dried (Na2SO4), and filtered
and the solvent was evaporated under reduced pressure. The crude
product was purified by flash chromatography (hexane–EtOAc, 6:4)
to give triazole 1a (34.8 mg, 45%) as a white solid; mp 94–96 °C; Rf =
0.20 (hexane–EtOAc, 1:1).
1H NMR (400 MHz, CDCl3): δ = 1.98–2.10 (m, 2 H), 2.30 (br s, 2 H),
2.69–2.86 (m, 4 H), 2.88 (br s, 2 H), 4.48 (dt, JH-H = 5.9 Hz, JH-F = 47.2
Hz, 2 H), 6.68 (d, J = 7.8 Hz, 1 H), 6.90 (d, J = 7.5 Hz, 1 H), 7.17 (s, 1 H),
7.39 (dd, J = 1.8, 8.3 Hz, 1 H), 7.45 (d, J = 1.8 Hz, 1 H), 7.57 (d, J = 8.4
Hz, 1 H), 8.19 (s, 1 H).
Compounds 1c–l; General Synthetic Procedure
Sodium ascorbate (0.2 equiv) and CuSO4 (0.04 equiv) were added to a
solution of alkyne 13 (1.0 equiv) and the appropriate azide (1.0 equiv)
in t-BuOH–H2O (2:1, 12 mL per mmol). The mixture was stirred at r.t.
for 24 h. Sat. aq NH4Cl (10 mL/mmol) was added and the aqueous lay-
er was extracted with EtOAc. The organic layer was washed with
brine, dried (Na2SO4), and filtered and the solvent was evaporated un-
der reduced pressure.
3-(2,4-Dichlorophenyl)-12-(3-fluoropropyl)-5-(1-propyl-1H-1,2,3-
triazol-4-yl)-3,4-diazatricyclo[8.4.0.02,6]tetradeca-
1(14),2(6),4,10,12-pentaene (1c)
The crude product was purified by flash chromatography (hexane–
EtOAc, 6:4) to give triazole 1c (40 mg, 65%) as a white solid; mp 122–
124 °C; Rf = 0.40 (hexane–EtOAc, 6:4).
1H NMR (400 MHz, CDCl3): δ = 1.02 (t, J = 7.4 Hz, 3 H), 1.97–2.11 (m, 2
H), 2.01 (dd, J = 7.2, 14.4 Hz, 2 H), 2.27–2.39 (m, 2 H), 2.70–2.82 (m, 4
13C NMR (100 MHz, CDCl3): δ = 21.1, 31.1 (d, JC-F = 5.3 Hz), 31.5, 31.7
(d, JC-F = 19.5 Hz), 32.7, 83.1 (d, JC-F = 165.0 Hz), 118.8, 126.2, 127.1,
127.2, 128.1, 130.0, 130.4, 130.7, 132.8, 135.5, 136.5, 141.5 (2 C),
141.9, 142.0 (2 C), 142.9.
H), 2.99 (br s, 2 H), 4.41 (t, J = 7.1 Hz, 2 H), 4.47 (dt, JH-H = 5.9 Hz, JH-F
=
47.2 Hz, 2 H), 6.66 (d, J = 7.8 Hz, 1 H), 6.89 (dd, J = 1.7, 7.9 Hz, 1 H),
7.17 (d, J = 1.5 Hz, 1 H), 7.39 (dd, J = 2.3, 8.4 Hz, 1 H), 7.45 (d, J = 2.2
Hz, 1 H), 7.51 (d, J = 8.5 Hz, 1 H), 7.99 (s, 1 H).
19F NMR (376.45 MHz, CDCl3): δ = –219.9 (tt, J = 25.3, 47.2 Hz, 1 F).
MS (ESI): m/z calcd for C23H2035Cl2FN5: 456.1 [M + H]+, 458.1 [M + 2 +
13C NMR (100 MHz, CDCl3): δ = 11.1, 20.9, 23.7, 31.1 (d, JC-F = 5.5 Hz),
31.7 (d, JC-F = 19.8 Hz), 31.8, 32.8, 52.0, 83.1 (d, JC-F = 162.0 Hz), 118.9,
121.0, 126.0, 127.1, 127.3, 127.4, 129.9, 130.3, 130.7, 132.8, 135.2,
136.8, 141.2, 142.0, 142.5, 142.7, 142.9.
H]+; found: 456.1 [M + H]+ (100), 458.1 [M + 2 + H]+ (70).
HRMS: m/z [M + H]+ calcd for C23H21Cl2FN5: 456.1153; found:
456.1149.
19F NMR (376.45 MHz, CDCl3): δ = –219.9 (tt, J = 25.3, 47.1 Hz, 1 F).
MS (ESI): m/z calcd for C26H2635Cl2FN5: 498.1 [M + H]+, 500.1 [M + 2 +
3-(2,4-Dichlorophenyl)-12-(3-fluoropropyl)-5-(1-methyl-1H-
1,2,3-triazol-4-yl)-3,4-diazatricyclo[8.4.0.02,6]tetradeca-
1(14),2(6),4,10,12-pentaene (1b)
H]+; found: 498.1 [M + H]+ (100), 500.1 [M + 2 + H]+ (70).
HRMS: m/z [M + H]+ calcd for C26H27Cl2FN5: 498.1622; found:
A solution of NaN3 (102 mg, 1.5 mmol, 6.0 equiv), CuSO4 (8.0 mg, 0.05
mmol, 0.2 equiv), and sodium ascorbate (24.8 mg, 0.125 mmol, 0.5
equiv) in DMF–H2O (1:1, 8.0 mL) was stirred for 5 min at r.t. Then a
solution of alkyne 13 (103 mg, 0.25 mmol, 1.0 equiv) in DMF (1 mL)
and MeI (0.1 mL, 0.58 mmol, 1.6 equiv) were added and the resulting
mixture was stirred overnight at 120 °C. The solution was cooled and
extracted with EtOAc (3 × 20 mL). The organic layers were washed
with H2O, brine, dried (Na2SO4), and filtered and the solvent was
evaporated under reduced pressure. The crude product was purified
by flash chromatography (hexane–EtOAc, 6:4) to give triazole 1b
(56.2 mg, 48%) as a white solid; mp 88–90 °C; Rf = 0.25 (hexane–
EtOAc, 6:4).
1H NMR (400 MHz, CDCl3): δ = 1.96–2.09 (m, 2 H), 2.23–2.37 (m, 2 H),
2.69–2.83 (m, 4 H), 2.30 (br s, 2 H), 4.17 (s, 3 H), 4.47 (dt, JH-H = 5.9 Hz,
JH-F = 47.2 Hz, 2 H), 6.66 (d, J = 7.8 Hz, 1 H), 6.88 (dd, J = 1.7, 7.9 Hz, 1
H), 7.16 (d, J = 1.3 Hz, 1 H), 7.38 (dd, J = 2.3, 8.5 Hz, 1 H), 7.45 (d, J = 2.2
Hz, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 7.96 (s, 1 H).
498.1611.
3-(2,4-Dichlorophenyl)-12-(3-fluoropropyl)-5-(1-pentyl-1H-1,2,3-
triazol-4-yl)-3,4-diazatricyclo[8.4.0.02,6]tetradeca-
1(14),2(6),4,10,12-pentaene (1d)
The crude product was purified by flash chromatography (hexane–
EtOAc, 6:4) to give triazole 1d (35 mg, 60%) as a white solid; mp 133–
135 °C; Rf = 0.65 (hexane–EtOAc, 6:4).
1H NMR (400 MHz, CDCl3): δ = 0.92 (t, J = 7.1 Hz, 3 H), 1.22–1.47 (m, 4
H), 1.86–2.13 (m, 4 H), 2.25–2.40 (m, 2 H), 2.64–2.85 (m, 4 H), 3.03 (br
s, 2 H), 4.43 (t, J = 7.1 Hz, 2 H), 4.48 (dt, JH-H = 5.9 Hz, JH-F = 47.2 Hz, 2
H), 6.66 (d, J = 7.8 Hz, 1 H), 6.89 (dd, J = 1.6, 7.8 Hz, 1 H), 7.16 (d, J = 1.3
Hz, 1 H), 7.38 (dd, J = 2.3, 8.4 Hz, 1 H), 7.45 (d, J = 2.2 Hz, 1 H), 7.51 (d,
J = 8.5 Hz, 1 H), 7.98 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 13.8, 20.9, 22.1, 28.6, 30.0, 31.1 (d, JC-F
5.4 Hz), 31.7 (d, JC-F = 19.8 Hz), 31.8, 32.8, 50.4, 83.1 (d, JC-F = 165.0
Hz), 119.0, 121.0, 126.0, 127.1, 127.4, 128.0, 130.0, 130.3, 130.7,
132.8, 135.2, 136.8, 141.2, 142.0, 142.5, 142.7, 142.9.
=
13C NMR (100 MHz, CDCl3): δ = 20.9, 31.1 (d, JC-F = 5.4 Hz), 31.7 (d, JC-F
=
19.9 Hz), 31.8, 32.8, 36.7, 83.1 (d, JC-F = 165.0 Hz), 118.9, 122.2, 126.1,
127.1, 127.4, 128.0, 129.9, 130.3, 130.7, 132.8, 135.2, 136.8, 141.2,
142.0, 142.6, 142.7, 142.8.
19F NMR (376.45 MHz, CDCl3): δ = –219.9 (tt, J = 25.3, 47.2 Hz, 1 F).
19F NMR (376.45 MHz, CDCl3): δ = –219.9 (tt, J = 25.3, 47.2 Hz, 1 F).
MS (ESI): m/z calcd for C28H3035Cl2FN5: 526.2 [M + H]+, 528.2 [M + 2 +
H]+; found: 526.2 [M + H]+ (100), 528.2 [M + 2 + H]+ (65).
HRMS: m/z [M + H]+ calcd for C28H31Cl2FN5: 526.1935; found:
526.1924.
MS (ESI): m/z calcd for C24H2235Cl2FN5: 470.1 [M + H]+, 472.1 [M + 2 +
H]+; found: 470.1 [M + H]+ (100), 472.1 [M + 2 + H]+ (70).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 817–826

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Synthesis
5-[1-(But-3-enyl)-1H-1,2,3-triazol-4-yl]-3-(2,4-dichlorophenyl)-
12-(3-fluoropropyl)-3,4-diazatricyclo[8.4.0.02,6]tetradeca-
1(14),2(6),4,10,12-pentaene (1e)
13C NMR (100 MHz, CDCl3): δ = 20.9, 31.1 (d, JC-F = 5.3 Hz), 31.7 (d, JC-F
=
19.7 Hz), 31.8, 32.8, 54.3, 83.1 (d, JC-F = 165.0 Hz), 118.0, 190.0, 126.1,
127.1, 127.3, 128.0, 128.4 (2 C), 128.8, 129.1 (2 C), 130.0, 130.3, 130.7,
132.8, 134.5, 135.3, 136.6, 136.7, 141.3, 142.0, 142.7, 142.9.
The crude product was purified by flash chromatography (hexane–
EtOAc, 6:4) to give triazole 1e (25 mg, 60%) as a white solid; mp 138–
140 °C; Rf = 0.80 (hexane–EtOAc, 6:4).
1H NMR (400 MHz, CDCl3): δ = 1.93–2.12 (m, 2 H), 2.22–2.41 (m, 2 H),
2.61–2.82 (m, 6 H), 3.03 (br s, 2 H), 4.48 (dt, JH-H = 5.9 Hz, JH-F = 47.2
Hz, 2 H), 4.50 (t, J = 7.1 Hz, 2 H), 5.09–5.21 (m, 2 H), 5.81 (ddt, J = 6.8,
10.2, 17.0 Hz, 1 H), 6.65 (d, J = 7.8 Hz, 1 H), 6.88 (d, J = 7.8 Hz, 1 H),
7.16 (s, 1 H), 7.38 (dd, J = 2.0, 8.5 Hz, 1 H), 7.44 (d, J = 2.1 Hz, 1 H), 7.51
(d, J = 8.4 Hz, 1 H), 7.99 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 20.9, 31.1 (d, JC-F = 5.4 Hz), 31.7 (d, JC-F
19.8 Hz), 31.8, 32.8, 34.4, 49.7, 83.1 (d, JC-F = 164.9 Hz), 118.5, 119.0,
121.1, 126.1, 127.1, 127.4, 128.0, 129.9, 130.3, 130.7, 132.8, 133.2,
135.2, 136.8, 141.2, 142.0, 142.5, 142.7, 142.9.
19F NMR (376.45 MHz, CDCl3): δ = –220.0 (tt, J = 25.3, 47.2 Hz, 1 F).
MS (ESI): m/z calcd for C30H2635Cl2FN5: 546.2 [M + H]+, 548.2 [M + 2 +
H]+; found: 546.2 [M + H]+ (100), 548.2 [M + 2 + H]+ (70).
HRMS: m/z [M + H]+ calcd for C30H27Cl2FN5: 546.1628; found:
546.1613.
3-(2,4-Dichlorophenyl)-12-(3-fluoropropyl)-5-{1-[(4-methoxy-
phenyl)methyl]-1H-1,2,3-triazol-4-yl}-3,4-diazatricy-
clo[8.4.0.02,6]tetradeca-1(14),2(6),4,10,12-pentaene (1h)
=
The crude product was purified by flash chromatography (hexane–
EtOAc, 6:4) to give triazole 1h (50 mg, 78%) as a white solid; mp 70–
72 °C; Rf = 0.60 (hexane–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): δ = 1.93–2.11 (m, 2 H), 2.24–2.40 (m, 2 H),
2.66–2.80 (m, 4 H), 3.08 (br s, 2 H), 3.82 (s, 3 H), 4.47 (dt, JH-H = 5.9 Hz,
JH-F = 47.2 Hz, 2 H), 5.53 (s, 2 H), 6.64 (d, J = 7.9 Hz, 1 H), 6.88 (d, J = 9.5
Hz, 1 H), 6.91 (d, J = 8.6 Hz, 2 H), 7.16 (s, 1 H), 7.30 (d, J = 9.5 Hz, 2 H),
7.36 (dd, J = 2.0, 8.5 Hz, 1 H), 7.43 (d, J = 2.2 Hz, 1 H), 7.47 (d, J = 8.4
Hz, 1 H), 7.85 (s, 1 H).
19F NMR (376.45 MHz, CDCl3): δ = –220.0 (tt, J = 25.3, 47.2 Hz, 1 F).
MS (ESI): m/z calcd for C27H2635Cl2FN5: 510.1 [M + H]+, 512.1 [M + 2 +
H]+, 532.1 [M + Na]+, 534.1 [M + 2 + Na]+; found: 510.1 [M + H]+ (100),
512.2 [M + 2 + H]+ (70) 532.1 [M + Na]+ (45), 534.1 [M + 2 + Na]+ (30).
HRMS: m/z [M + H]+ calcd for C27H27Cl2FN5: 510.1622; found:
510.1613.
13C NMR (100 MHz, CDCl3): δ = 20.9, 29.7, 31.1 (d, JC-F = 5.4 Hz), 31.7
(d, JC-F = 19.7 Hz), 31.8, 32.8, 53.8, 55.4, 83.1 (d, JC-F = 165.0 Hz), 114.5
(2 C), 119.0, 120.8, 126.0, 126.5, 127.0, 127.4, 128.0, 129.9, 130.0 (2
C), 130.3, 130.7, 132.8, 135.2, 136.8, 141.2, 142.0, 142.7, 142.8, 160.0.
5-[1-(Cyclohexylmethyl)-1H-1,2,3-triazol-4-yl]-3-(2,4-dichloro-
phenyl)-12-(3-fluoropropyl)-3,4-diazatricyclo[8.4.0.02,6]tetradeca-
1(14),2(6),4,10,12-pentaene (1f)
19F NMR (376.45 MHz, CDCl3): δ = –219.9 (tt, J = 25.3, 47.2 Hz, 1 F).
The crude product was purified by flash chromatography (hexane–
EtOAc, 6:4) to give triazole 1f (62 mg, 76%) as a white solid; mp 174–
176 °C; Rf = 0.68 (hexane–EtOAc, 6:4).
MS (ESI): m/z calcd for C31H2835Cl2FN5O: 576.2 [M + H]+, 578.2 [M + 2 +
H]+; found: 576.2 [M + H]+ (100), 578.2 [M + 2 + H]+ (70).
1H NMR (400 MHz, CDCl3): δ = 0.95–1.13 (m, 2 H), 1.16–1.35 (m, 4 H),
1.63–1.82 (m, 4 H), 1.88–2.13 (m, 3 H), 2.27–2.42 (m, 2 H), 2.62–2.83
(m, 4 H), 3.03 (br s, 2 H), 4.25 (d, J = 7.2 Hz, 2 H), 4.47 (dt, JH-H = 5.9 Hz,
JH-F = 47.2 Hz, 2 H), 6.66 (d, J = 7.8 Hz, 1 H), 6.88 (dd, J = 1.4, 7.8 Hz, 1
H), 7.16 (d, J = 0.9 Hz, 1 H), 7.38 (dd, J = 2.2, 8.4 Hz, 1 H), 7.44 (d, J = 2.2
Hz, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 7.95 (s, 1 H).
13C NMR (100 MHz, CDCl3): δ = 20.9, 25.5 (2 C), 26.1, 30.5 (2 C), 31.1
(d, JC-F = 5.4 Hz), 31.7 (d, JC-F = 19.7 Hz), 31.8, 32.8, 38.8, 56.5, 83.1 (d,
JC-F = 165.0 Hz), 110.0, 121.5, 126.0, 127.1, 127.5, 128.0, 129.9, 130.3,
130.7, 132.8, 135.2, 136.8, 141.1, 142.0, 141.4, 142.7, 142.9.
HRMS: m/z [M + H]+ calcd for C31H29Cl2FN5O: 576.1728; found:
576.1720.
3-(2,4-Dichlorophenyl)-12-(3-fluoropropyl)-5-(1-phenyl-1H-1,2,3-
triazol-4-yl)-3,4-diazatricyclo[8.4.0.02,6]tetradeca-
1(14),2(6),4,10,12-pentaene (1i)
The crude product was purified by flash chromatography (hexane–
EtOAc, 6:4) to give triazole 1i (64 mg, 65%) as a white solid; mp 90–
92 °C; Rf = 0.65 (hexane–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): δ = 1.94–2.12 (m, 2 H), 2.26–2.44 (m, 2 H),
2.65–2.84 (m, 4 H), 3.10 (br s, 2 H), 4.48 (dt, JH-H = 5.8 Hz, JH-F = 47.2
Hz, 2 H), 6.69 (d, J = 7.8 Hz, 1 H), 6.90 (dd, J = 1.4, 7.8 Hz, 1 H), 7.18 (s,
1 H), 7.40 (dd, J = 2.2, 8.4 Hz, 1 H), 7.45–7.49 (m, 2 H), 7.54 (d, J = 8.4
Hz, 1 H), 7.58 (d, J = 7.5 Hz, 2 H), 7.83 (d, J = 7.5 Hz, 2 H), 8.47 (s, 1 H).
19F NMR (376.45 MHz, CDCl3): δ = –219.9 (tt, J = 25.3, 47.2 Hz, 1 F).
MS (ESI): m/z calcd for C30H3235Cl2FN5: 552.2 [M + H]+, 554.2 [M + 2 +
H]+; found: 552.2 [M + H]+ (100), 554.2 [M + 2 + H]+ (65).
HRMS: m/z [M + H]+ calcd for C30H33Cl2FN5: 552.2092; found:
13C NMR (100 MHz, CDCl3): δ = 20.9, 31.1 (d, JC-F = 5.3 Hz), 31.7 (d, JC-F
=
552.2098.
18.0 Hz), 31.8, 32.8, 83.1 (d, JC-F = 165.0 Hz), 119.1, 119.2, 120.4 (2 C),
126.1, 127.1, 127.3, 128.0, 128.7, 129.8 (2 C), 130.0, 130.4, 130.7,
132.9, 135.3, 136.8, 137.1, 141.3, 142.0, 142.5, 142.9, 143.3.
19F NMR (376.45 MHz, CDCl3): δ = –219.9 (tt, J = 25.3, 47.2 Hz, 1 F).
5-(1-Benzyl-1H-1,2,3-triazol-4-yl)-3-(2,4-dichlorophenyl)-12-(3-
fluoropropyl)-3,4-diazatricyclo[8.4.0.02,6]tetradeca-
1(14),2(6),4,10,12-pentaene (1g)
The crude product was purified by flash chromatography (hexane–
EtOAc, 6:4) to give triazole 1g (47 mg, 82%) as a white solid; mp 75–
77 °C; Rf = 0.50 (hexane–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): δ = 1.96–2.11 (m, 2 H), 2.24–2.40 (m, 2 H),
2.68–2.80 (m, 4 H), 3.09 (br s, 2 H), 4.47 (dt, JH-H = 5.9 Hz, JH-F = 47.2
Hz, 2 H), 5.60 (s, 2 H), 6.65 (d, J = 7.8 Hz, 1 H), 6.88 (dd, J = 1.8, 7.9 Hz,
1 H), 7.16 (d, J = 1.5 Hz, 1 H), 7.33–7.41 (m, 6 H), 7.43 (d, J = 2.2 Hz, 1
H), 7.48 (d, J = 8.5 Hz, 1 H), 7.93 (s, 1 H).
MS (ESI): m/z calcd for C29H2435Cl2FN5: 532.1 [M + H]+, 534.1 [M + 2 +
H]+; found: 532.1 [M + H]+ (100), 534.1 [M + 2 + H]+ (70).
HRMS: m/z [M + H]+ calcd for C29H25Cl2FN5: 532.1466; found:
532.1458.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 817–826

825
C. Zanato et al.
Paper
Synthesis
3-(2,4-Dichlorophenyl)-12-(3-fluoropropyl)-5-{1-[4-(trifluoro-
methyl)phenyl]-1H-1,2,3-triazol-4-yl}-3,4-diazatricy-
clo[8.4.0.02,6]tetradeca-1(14),2(6),4,10,12-pentaene (1j)
13C NMR (100 MHz, CDCl3): δ = 20.9, 31.1 (d, JC-F = 5.3 Hz), 31.7 (d, JC-F
=
19.3 Hz), 31.8, 32.8, 83.1 (d, JC-F = 165.0 Hz), 119.2, 123.0, 126.1, 127.1,
127.3, 128.0, 128.3, 128.5, 129.5, 130.0, 130.4, 130.7 (2 C), 132.8,
133.6, 135.3, 136.3, 136.7, 141.4, 142.0, 142.2, 142.7, 142.9.
The crude product was purified by flash chromatography (hexane–
EtOAc, 6:4) to give triazole 1j (39 mg, 75%) as a white solid; mp 88–
90 °C; Rf = 0.68 (hexane–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): δ = 1.94–2.13 (m, 2 H), 2.29–2.44 (m, 2 H),
2.65–2.83 (m, 4 H), 3.12 (br s, 2 H), 4.48 (dt, JH-H = 5.9 Hz, JH-F = 47.2
Hz, 2 H), 6.68 (d, J = 7.8 Hz, 1 H), 6.91 (dd, J = 1.6, 7.9 Hz, 1 H), 7.18 (d,
J = 1.3 Hz, 1 H), 7.41 (dd, J = 2.3, 8.4 Hz, 1 H), 7.48 (d, J = 2.2 Hz, 1 H),
7.53 (d, J = 8.5 Hz, 1 H), 7.67–7.83 (m, 2 H), 8.03–8.18 (m, 2 H), 8.53 (s,
1 H).
19F NMR (376.45 MHz, CDCl3): δ = –219.9 (tt, J = 25.3, 47.2 Hz, 1 F).
MS (ESI): m/z calcd for C29H2235Cl4FN5: 600.1 [M + H]+, 602.1 [M + 2 +
H] + , 603.1 [M + 3 + H]+, 604.1 [M + 4 + H]+; found: 600.1 [M + H] +
(100), 602.2 [M + 2 + H]+ (80), 603.1[M + 3 + H]+, 604.1 [M + 4 + H]+.
HRMS: m/z [M + H]+ calcd for C29H23Cl4FN5: 600.0686; found:
600.0692.
13C NMR (100 MHz, CDCl3): δ = 20.9, 31.1 (d, JC-F = 5.3 Hz), 31.7 (d, JC-F
19.8 Hz), 31.8, 32.8, 83.1 (d, JC-F = 165.0 Hz), 117.3 (q, JC-F = 4.0 Hz),
118.9, 119.3, 123.3 (q, JC-F = 272.9 Hz), 123.4, 125.9 (q, JC-F = 3.4 Hz),
=
Acknowledgment
We thank the European Commission for financial support (Industry
Academia Partnerships and Pathways project ‘PET BRAIN’, Contract
No 251482) and the EPSRC National Mass Spectrometry Service Cen-
tre (Swansea, UK), for performing HRMS analyses. We also wish to
thank Ms. Serena Montanari for carrying out some preliminary ex-
periments and Mrs Lesley A. Stevenson for technical support.
126.1, 127.1, 127.2, 128.1, 130.0, 130.4, 130.6 (2 C), 132.5 (q, JC-F
33.2 Hz), 132.8, 135.4, 136.7, 137.4, 141.4, 142.0, 142.1, 143.0, 143.8.
19F NMR (376.45 MHz, CDCl3): δ = –219.9 (tt, J = 25.3, 47.2 Hz, 1 F),
62.9 (s, 3 F).
=
MS (ESI): m/z calcd for C30H2335Cl2F4N5: 600.1 [M + H]+, 602.1 [M + 2 +
H]+; found: 600.1 [M + H]+ (100), 602.1 [M + 2 + H]+ (65).
HRMS: m/z [M + H]+ calcd for C30H24Cl2F4N5: 600.1339; found:
600.1347.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0034-1379887.
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3-(2,4-Dichlorophenyl)-12-(3-fluoropropyl)-5-[1-(2-methoxyphe-
nyl)-1H-1,2,3-triazol-4-yl]-3,4-diazatricyclo[8.4.0.02,6]tetradeca-
1(14),2(6),4,10,12-pentaene (1k)
References
The crude product was purified by flash chromatography (hexane–
EtOAc, 6:4) to give triazole 1k (38 mg, 60%) as a white solid; mp 128–
130 °C; Rf = 0.62 (hexane–EtOAc, 7:3).
1H NMR (400 MHz, CDCl3): δ = 1.96–2.13 (m, 2 H), 2.26–2.45 (m, 2 H),
2.64–2.87 (m, 4 H), 3.10 (br s, 2 H), 3.93 (s, 3 H), 4.48 (dt, JH-H = 5.9 Hz,
JH-F = 47.2 Hz, 2 H), 6.68 (d, J = 7.8 Hz, 1 H), 6.90 (dd, J = 7.7 Hz, 1 H),
7.06–7.22 (m, 3 H), 7.34–7.51 (m, 3 H), 7.56 (d, J = 8.4 Hz, 1 H), 7.87
(d, J = 1.4, 7.9 Hz, 1 H), 8.58 (s, 1 H).
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=
20.0 Hz), 31.8, 32.8, 56.0, 83.1 (d, JC-F = 164.9 Hz), 112.3, 119.1, 121.2,
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3-(2,4-Dichlorophenyl)-5-[1-(2,4-dichlorophenyl)-1H-1,2,3-tri-
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EtOAc, 6:4) to give triazole 1l (41 mg, 75%) as a white solid; mp 76–
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 817–826