Synthesis of the 5-fluoro-4-hydroxypentyl side chain metabolites of synthetic cannabinoids 5F-APINACA and CUMYL-5F-PINACA

Article abstract of DOI:10.1055/s-0037-1609914

An efficient method for the construction of the 5-fluoro-4-hydroxypentyl side chain common to a number of synthetic cannabinoid metabolites was developed. A series of hydroxyl protecting groups was examined to assess the viability as orthogonal protecting

Full text of DOI:10.1055/s-0037-1609914

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
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R. J. McKinnie et al.
Paper
Synthesis
Synthesis of the 5-Fluoro-4-hydroxypentyl Side Chain Metabolites
of Synthetic Cannabinoids 5F-APINACA and CUMYL-5F-PINACA
Ryan J. McKinnie
Tasneam Darweesh
Phoebe A. Zito
Terrell J. Shields Jr.
Mark L. Trudell*
Department of Chemistry, University of New Orleans,
New Orleans, LA 70148, USA
mtrudell@uno.edu
Received: 15.06.2018
Accepted after revision: 18.07.2018
Published online: 14.08.2018
DOI: 10.1055/s-0037-1609914; Art ID: ss-2018-m0418-op
O
N
O
N
N
N
H
H
Abstract An efficient method for the construction of the 5-fluoro-4-
hydroxypentyl side chain common to a number of synthetic cannabi-
noid metabolites was developed. A series of hydroxyl protecting groups
was examined to assess the viability as orthogonal protecting groups
for epoxidation and regioselective hydrofluorination. The 1-[5-fluoro-4-
(diphenyl-tert-butylsilyloxy)]pentyl tosylate was prepared in 67% overall
yield (six steps) from pent-4-en-1-ol and was employed for the synthe-
sis of the 4-hydroxy metabolites of the synthetic cannabinoid 5F-
APINACA and CUMYL-5F-PINACA.
N
N
X
X
1 X = H; APINACA
3 X = F; 5F-APINACA
2 X = H, CUMYL-PICA
4 X = F; CUMYL-5F-PINACA
O
O
Key Words cannabinoid, metabolite, hydrofluorination, epoxidation,
5F-APINACA, CUMYL-5F-PINACA
N
N
H
H
N
N
N
N
The N-alkylindazole carboxamides [Figure 1; APINACA
(1),1,2 CUMYL-PINACA (2)3,4] and the corresponding 5-fluo-
ro analogues [Figure 1, 5F-APINACA (3),1 CUMYL-5F-
PINACA (4)3,4] are members of a class of illicit and widely
abused synthetic cannabinoids (SCBs) that continue to pose
a major health risk throughout the world.5,6 Introduction of
a fluorine atom at the terminal carbon of the N-pentyl
chain of indazole congener has been shown to generally
lead to an increase in potency. The 5F-analogues have be-
come increasingly more prevalent as clandestine labs aim
to evade scheduling laws and introduce more potent syn-
thetic cannabinoids into the illicit drug market.
In order to understand the deleterious effects of these
synthetic cannabinoids it was interest to explore the psy-
chopharmacological effects of the metabolites. Studies have
shown that synthetic cannabinoids undergo a variety of
biotransformations and that some of these metabolites are
OH
OH
F
F
5F-4OH-APINACA (5)
5F-4OH-CUMYL-PINACA (6)
Figure 1 5F-Indazole carboxamide SCBs and 4-OH-metabolites
pharmacologically active.7,8 Forensic studies have identified
the major metabolites for many of the 5F-indazole carbox-
amides. The metabolites 59 and 610 resulting from the
mono-hydroxylation of the N-pentyl chain at the 4-position
adjacent to the terminal fluorine atom (Figure 1) are neu-
tral lipophilic molecules and would be expected to exhibit
CNS activity. In an effort to evaluate the pharmacologi-
cal/toxicological effects of the 5F-4OH-indazole carboxam-
ide metabolites it was necessary to develop a general syn-
thetic strategy that would allow for the construction of a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

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R. J. McKinnie et al.
Paper
Synthesis
variety of structurally diverse 5F-4OH-indazole carboxam-
ides. To this end, a suitably protected 5F-4OH-pentyl syn-
thon was required to serve as a general building block for
the flurohydrin side-chain. Herein the syntheses of a 5F-
4OH-pentyl synthon with application for the syntheses of
the 5F-4OH-APINACA metabolite (5) 5F-4OH-CUMYL-
PINACA metabolite (6) are described.
It was envisaged that an appropriately functionalized
pentene derivative could be converted in the desired 5F-
4OH-pentyl synthon via an expoxidation followed by regi-
oselective hydrofluorination (Scheme 1). Commercially
available pent-4-en-1-ol (7) was selected as the starting
material for the construction of the 5F-4OH-pentyl side
chain synthon. As illustrated in Scheme 2, the hydroxyl
group of 7, was protected with series of representative pro-
tecting groups: the benzyl ether 8a,11 the trityl ether 8b,12
the benzoate ester 8c,13 and the MOM ether 8d.14 Each pro-
tected substrate 8a–d was obtained in high yield, then eval-
uated for its ability to withstand the conditions of the epox-
idation/hydrofluorination steps.
group of 8d was equally effective in the epoxidation reac-
tion to afford 9d (88%) but was not as well tolerated in sub-
sequent transformations. The epoxides 9a–d were convert-
ed into the fluorohydrins 10a–d by tetrabutylammonium
dihydrogen trifluoride18 (10 mol%) catalyzed regioselective
hydrofluorination with potassium hydrogen difluoride in
chlorobenzene. The solid-liquid phase transfer catalysis
conditions gave good yields of the corresponding 1-fluoro-
2-hydroxyfluorohydrins 10a–d. None of the other regioiso-
meric fluorohydrins 11a–d (4F-5OH) were observed when
the reactions were performed on a 2 mmol scale. The tetra-
butylammonium dihydrogen trifluoride catalyst was pre-
pared using a slightly modified procedure in a polyethylene
bottle. The salt was air stable and could be stored indefi-
nitely in an anhydrous environment. The benzyl ether
proved to be superior to the other protecting groups for the
hydrofluorination reaction, affording the fluorohydrin regi-
oselectively 10a19 in 95% yield (2 mmol scale). The benzyl
epoxide 9a was selected for large-scale preparation of the
fluorohydrin 10a for development of the synthesis of the
metabolites of 5F-APINACA and CUMYL-5F-PINACA. Upon
increasing the scale of the hydrofluorination to a 22 mmol
scale, a trace amount of the regioisomeric fluorohydrin 11a
was observed. However, this regioisomer could be easily re-
moved by column chromatography. The large-scale prepa-
ration of 10a proceeded in high yield (87%) from 9a and fur-
nished gram quantities of pure fluorohydrin regioisomer
10a to advance toward the synthesis of the metabolites 5
and 6.
X
X
X
epoxidation
hydrofluorination
OH
F
O
5F-4OH-pentyl synthon
Scheme 1 5F-4OH-pentyl synthon
The epoxidation of the known hydroxyl protected
alkenes 8a,11 8b,12 8c,13 and 8d14 was achieved with mCPBA
to furnish the previously reported corresponding epoxides
9a,11 9b,15 9c,16 and 9d17 in high yields.The benzyl ether 8a
proved to be the most robust protecting group, giving the
highest yield of the epoxide 9a (94%). The MOM protecting
The hydroxyl group in the fluorohydrin 10a necessitat-
ed the use of a protecting group that was orthogonal to the
benzyl ether and would be stable under hydrogenolysis
conditions. The tert-butyldiphenylsilyl ether was chosen to
protect the hydroxyl moiety of 10a. The fluorohydrin 10a
was treated with TBDPSCl and imidazole in dichlorometh-
OR
OR
OR
OR
OH
iii
ii
i
+
F
OH
F
O
OH
7
8a R = Bn (99%)
9a R = Bn (94%)
9b R = Tr (73%)
9c R = Bz (74%)
9d R = MOM (88%)
11a–d
(not observed)
10a R = Bn (87%)
10b R = Tr (69%)
10c R = Bz (41%)
10d R = MOM (66%)
8b R = Tr (84%)
8c R = Bz (86%)
8d R = MOM (81%)
OH
OBn
OTs
iv
v
vi
10a
OTBDPS
OTBDPS
F
OTBDPS
F
F
13 (99%)
14 (85%)
12 (98%)
5F-4OH-pentyl
synthon
Scheme 2 Synthesis of 5F-4OH-pentyl synthon. Reagents and conditions: (i) (a) BnBr, DIPEA, 150 °C; (b) TrCl, Et3N, CH2Cl2, r.t.; (c) BzCl, pyridine, CH2Cl2,
r.t.; (d) MOM-Cl, DIPEA, CH2Cl2, r.t.; (ii) mCPBA, CH2Cl2, r.t.; (iii) KHF2, Bu4N+H2F3– (cat.), PhCl, 120 °C; (iv) TBDPSCl, imidazole, CH2Cl2, r.t.; (v) H2, 10%
Pd/C, EtOH; (vi) TsCl, DMAP, Et3N, CH2Cl2, 0 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

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R. J. McKinnie et al.
Paper
Synthesis
anae under an argon atmosphere to give the TBDPS ether
12 (98%) in nearly quantitative yield. With the secondary
hydroxyl group orthogonally protected the deprotection of
the benzyl ether could be pursued. The benzyl ether was re-
moved via palladium-catalyzed hydrogenolysis at 50 °C and
1 atm (5 days) to provide the alcohol 13 in 99% yield. Short-
er reaction times could be achieved at higher pressures (2–
3 atm); however, the yield of alcohol 13 was slightly dimin-
ished and not as clean due to the undesired removal of the
TBDPS group. Conversion of the primary alcohol 13 into the
tosylate 14 was accomplished upon treatment of the alco-
hol with p-toluenesulfonyl chloride, 4-dimethylaminopyri-
dine, and triethylamine at 0 °C. This gave the desired to-
sylate in 85% yield and provided the TBDPS-protected 5F-4-
OH pentyl synthon 14 in 67% overall yield from 7 to be used
for the construction of the 5F-4OH metabolites 5 and 6.
With the synthon 14 in hand, the syntheses of the 4OH
metabolites of 5F-APINACA (3) and CUMYL-5F-PINACA (4)
were achieved in straightforward fashion (Scheme 3). Regi-
oselective N-alkylation of 1H-indazole-3-carboxylate 15
with the tosylate 14 afforded the N1-alkylated indazole 16
in 80% yield. Only trace amounts of what was presumed to
be the N2-alkylation product were observed.
The saponification of the methyl ester 16 afforded the
carboxylic acid 17 in nearly quantitative yield. The carbox-
ylic acid was converted into the adamantyl amide 18 via
carbodiimide-mediated coupling in 88% yield. The high
yield of the amide coupling was noteworthy, given that this
approach would allow for late stage diversification of the
metabolite structure thus affording easy access to a variety
of indazole carboxamide metabolites. Finally, the deprotec-
tion of the TBDPS ether of 18 was achieved in 87% yield
with TBAF in THF at 0 °C to give the 5F-4OH-APINACA me-
tabolite 5 in 57% overall yield from 15.
To demonstrate the utility of the approach, the 5F-4OH-
metabolite 6 of CUMYL-5F-PINACA (4) was synthesized in
similar fashion to the adamantyl congener 5 (Scheme 3).
Starting from the late intermediate acid 17, the cumyl am-
ide group was added via carbodiimide-mediated coupling
to furnish 19 in 99% yield. Subsequent removal of the TDPS
group with TBAF afforded the metabolite 6 in 81% yield and
64 % overall yield from 15.
In summary, we have developed an efficient method for
the gram-scale synthesis of a useful synthon 14 for the
preparation of the 4-hydroxylated side chain metabolites of
N-5-fluoropentylindazole carboxamides. The advantage of
this convergent synthetic approach is that derivatization of
the indazole carboxamide structure occurs late in the se-
quence following introduction of the metabolite side chain.
This should allow for the concise and efficient syntheses of
a variety of N-5-fluoropentylindazole carboxamide metab-
olites. The details of the syntheses of additional metabolites
as well as the pharmacological evaluation of these metabo-
lites will be reported elsewhere.
O
O
OCH3
OCH3
N
i
ii
N
N
N
H
OTBDPS
F
16 (80%)
15
O
N
O
OH
N
H
All reactions were carried out in oven-dried glassware under an N2
atmosphere, unless indicated otherwise. All chemicals were pur-
chased from Alfa Aesar, Sigma Aldrich, and VWR. Chromatography re-
fers to flash silica gel column chromatography [0.060–0.200mm (60
Å) silica gel from Sorbent Technology was used as the stationary
phase]. All chemicals were used as received without further purifica-
tion. 1H and 13C NMR spectra were recorded at r.t. in DMSO-d6 on a
Bruker 400 MHz instrument operating at a frequency of 300 MHz for
1H NMR, 75 MHz for 13C NMR and 282 MHz for 19F NMR. 1H chemical
shifts were referenced to the DMSO solvent signal (2.50 ppm) or the
CHCl3 signal (7.26 ppm). 13C chemical shifts were referenced to the
DMSO solvent signal (39.51 ppm) or the CHCl3 signal (77.16 ppm). At-
lantic Microlab, Inc., Norcross, GA performed all CHN microanalyses.
iii
N
N
N
OTBDPS
F
17 (99%)
OR
F
v
18 R = TBDPS (88%)
iv
5 R = H (87%)
O
N
H
N
N
The preparation of alkenes 8a–d and epoxides 9a–d is provided in the
Supporting Information.
OR
F
Tetrabutylammonium Dihydrogen Trifluoride (Bu4NH2F3)18
19 R = TBDPS (99%)
iv
Tetrabutylammonium hydrogen sulfate (2.0 g, 5.9 mmol) in CHCl3 (40
mL) was added to a polyethylene bottle equipped with a stir bar. The
reaction mixture was then treated with a solution of KHCO3 (591 mg,
5.9 mmol) in H2O (1.8 mL) and was allowed to stir at r.t. for 10 min.
Solid KHF2 (2.30 g, 29.5 mmol) was added and the mixture was
stirred for 1 h at r.t. The suspension was then vacuum filtered through
a glass microfiber filter in a Büchner funnel. The solids were washed
6 R = H (81%)
Scheme 3 Synthesis of 5F-4OH-metabolites 5 and 6. Reagents and con-
ditions: (i) t-BuOK, THF, 14, r.t., 48 h; (ii) NaOH/MeOH, 12 h, r.t, then aq
1 N HCl; (iii) adamantylamine, DIPEA, HOBt, EDC·HCl, DMF, 24 h, r.t.;
(iv) TBAF, THF, 0 °C, 24 h; (v) cumylamine, DIPEA, HOBt, EDC·HCl, DMF,
24 h, r.t.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

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R. J. McKinnie et al.
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Synthesis
with CHCl3 (30 mL) and the filtrate was transferred to a separatory
funnel. The organic layer was removed and concentrated under re-
duced pressure. As the volume of the solution was reduced, small
amounts of solid salts were formed, which were subsequently re-
moved by gravity filtration. The volume of the filtrate was further
concentrated under reduced pressure, and then dried under high vac-
uum for 24 h. The resulting colorless oil was used directly in subse-
quent reactions with no further purification; yield: 1.77 g (99%).
to r.t., then diluted by the addition of CH2Cl2 (30 mL), vacuum filtered
through a pad of Celite, and the filtrate was then concentrated under
reduced pressure. The resulting residue was purified by silica gel
flash chromatography (EtOAc/hexanes 2:3) to afford 10c as a clear,
viscous oil; yield: 249 mg (41%); Rf = 0.55 (EtOAc/hexanes 2:3).
1H NMR (300 MHz, DMSO-d6): δ = 7.95 (d, J = 7.2 Hz, 2 H), 7.64 (t,
J = 7.5 Hz, 1 H), 7.54–7.46 (m, 2 H), 5.00 (d, J = 5.4 Hz, 1 H, OH), 4.39–
4.13 (m, 4 H), 3.75–3.63 (m, 1 H), 1.92–1.66 (m, 2 H), 1.59–1.35 (m, 2
H).
13C NMR (75 MHz, DMSO-d6): δ = 166.2, 133.7, 129.5, 129.2, 87.2 (d,
JC,F = 167.6 Hz), 68.7 (d, JC,F = 18.8 Hz), 65.1, 29.1 (d, JC,F = 6.5 Hz), 24.9.
19F NMR (282 MHz, DMSO-d6): δ = –225.3 (1 F, td, JH,F = 47.7 Hz,
JH,F = 18.9 Hz).
5-(Benzyloxy)-1-fluoropentan-2-ol (10a)19
To a flame-dried round-bottomed flask equipped with a stir bar were
added 2-[3-(benzyloxy)propyl]oxirane (9a;11 4.33 g, 22.5 mmol),
KHF2 (3.62 g, 22.5 mmol), Bu4NH2F3 (720 mg, 2.9 mmol), and chloro-
benzene (4.60 mL, 45.0 mmol). The round-bottomed flask was
equipped with a reflux condenser and heated at 120 °C until the
starting material was no longer detected by TLC. The reaction mixture
was allowed to cool to r.t., then diluted by the addition of CH2Cl2 (30
mL), vacuum filtered through a pad of Celite, and the filtrate was then
concentrated under reduced pressure. The residue was purified by sil-
ica gel flash chromatography (EtOAc/hexanes 2:3) to afford 10a as a
clear, viscous oil; yield: 4.15 g (87%); Rf = 0.49 (EtOAc/hexanes 2:3).
1H NMR (300 MHz, CDCl3): δ = 7.33 (m, 5 H), 4.52 (s, 2 H), 4.45–4.22
(m, 2 H), 3.91–3.81 (m, 1 H), 3.53 (t, J = 4.5 Hz, 2 H), 2.97 (br s, 1 H),
1.82–1.48 (m, 4 H).
13C NMR (75 MHz, DMSO-d6): δ = 139.1, 128.6, 127.8, 127.7, 87.3 (d,
JC,F = 167.5 Hz), 72.2, 70.1, 68.8 (d, JC,F = 18.5 Hz), 29.4 (d, JC,F = 6.5 Hz),
25.7.
1-Fluoro-5-(methoxymethoxy)pentan-2-ol (10d)
To a flame-dried round-bottomed flask equipped with a stir bar, 2-[3-
(methoxymethoxy)propyl]oxirane (9d;17 1.22 g, 8.32 mmol) were
added KHF2 (1.30 g, 16.64 mmol), Bu4NH2F3 (254 mg, 0.832 mmol),
and chlorobenzene (0.90 mL, 8.32 mmol). The round-bottomed flask
was equipped with a reflux condenser and heated at 120 °C until the
starting material was no longer detected by TLC. The reaction mixture
was allowed to cool to r.t., then diluted by the addition of CH2Cl2 (30
mL), vacuum filtered through a pad of Celite, and the filtrate was then
concentrated under reduced pressure. The residue was purified by sil-
ica gel flash chromatography (EtOAc/hexanes 4:6) to afford 10c as a
clear, viscous oil; yield: 745 mg (66%); Rf = 0.57 (EtOAc/hexanes 2:3).
1H NMR (300 MHz, DMSO-d6): δ = 4.91 (d, J = 5.4 Hz, 1 H), 4.52 (s, 2
H), 4.36–4.25 (m, 1 H), 4.20–4.09 (m, 1 H), 3.70–3.56 (m, 1 H), 3.42 (t,
J = 6.3 Hz, 2 H), 3.22 (s, 3 H), 1.71–1.22 (m, 4 H).
19F NMR (282 MHz, DMSO-d6): δ = –225.1 (1 F, td, JH,F = 47.9 Hz,
JH,F = 18.9 Hz).
13C NMR (75 MHz, DMSO-d6): δ = 96.1, 87.2 (d, JC,F = 167.5 Hz), 68.8
(d, JC,F = 18.7 Hz), 67.5, 54.9, 29.3 (d, JC,F = 6.4 Hz), 25.8.
19F NMR (282 MHz, DMSO-d6): δ = –225.1 (1 F, td, JH,F = 47.7 Hz,
JH,F = 18.9 Hz).
1-Fluoro-5-(trityloxy)pentan-2-ol (10b)
To a flame-dried round-bottomed flask equipped with a stir bar were
added 2-[3-(trityloxy)propyl]oxirane (9b;15 1.53 g, 4.47 mmol), KHF2
(699 mg, 8.94 mmol), Bu4NH2F3 (135 mg, 0.447 mmol), and chloro-
benzene (1.0 mL). The round-bottomed flask was equipped with a re-
flux condenser and heated at 120 °C until the starting material was
no longer detected by TLC. The reaction mixture was allowed to cool
to r.t., then diluted by the addition of CH2Cl2 (30 mL), vacuum filtered
through a pad of Celite, and the filtrate was then concentrated under
reduced pressure. The resulting residue was purified by silica gel
flash chromatography (EtOAc/hexanes 2:3) to afford 10b as a clear,
viscous oil; yield: 1.62 g (69%); Rf = 0.48 (EtOAc/hexanes 2:3).
1H NMR (300 MHz, DMSO-d6): δ = 7.34–7.23 (m, 15 H), 4.89 (d, J = 5.1
Hz, 1 H, OH), 4.35–4.23 (m, 1 H), 4.19–4.07 (m, 1 H), 3.63–3.48 (m, 1
H), 2.99 (t, J = 6.3 Hz, 2 H), 1.74–1.43 (m, 4 H).
13C NMR (75 MHz, DMSO-d6): δ = 144.4 (d, J = 9.2 Hz), 128.6, 128.3,
127.4, 87.2 (d, JC,F = 167.5 Hz), 77.3, 69.6, 68.8 (d, JC,F = 18.5 Hz), 29.4
(d, JC,F = 6.3 Hz), 25.9.
[5-(Benzyloxy)-1-fluoropentan-2-yloxy](tert-butyl)diphenylsi-
lane (12)
To a flame-dried round-bottomed flask equipped with a stir bar were
added a solution of 5-(benzyloxy)-1-fluoropentan-2-ol (10a; 2.04 g,
9.42 mmol) and imidazole (2.60 g, 37.7 mmol) in anhyd CH2Cl2 (70
mL), followed by the establishment of an argon atmosphere. TBDPS-Cl
(4.90 mL, 18.8 mmol) was added dropwise at 0 °C, the reaction mix-
ture was allowed to warm to r.t. and stirred for 2 h. The reaction mix-
ture was diluted with CH2Cl2 (30 mL), washed with H2O (100 mL), and
dried (Na2SO4). The solids were then removed by gravity filtration
and the solvent was removed under reduced pressure. The resulting
crude material was then purified by silica gel flash chromatography
(EtOAc/hexanes 1:9) to afford 12 as a clear, viscous oil; yield: 4.24 g
(98%); Rf = 0.73 (EtOAc/hexanes 1:9).
19F NMR (282 MHz, DMSO-d6): δ = –225.1 (1 F, td, JH,F = 47.4 Hz,
JH,F = 19.5 Hz).
1H NMR (300 MHz, CDCl3): δ = 7.72 (d, J = 6.0 Hz, 4 H), 7.48–7.31 (m,
11 H), 4.46 (s, 2 H), 4.37–4.35 (m, 1 H), 4.26–4.23 (m, 1 H), 3.98–3.92
(m, 1 H), 3.37 (t, J = 6.0 Hz, 2 H), 1.69–1.61 (m, 4 H), 1.11 (s, 9 H).
5-Fluoro-4-hydroxypentyl Benzoate (10c)
13C NMR (75 MHz, DMSO-d6): δ = 135.8, 133.6, 133.2, 130.2, 129.5 (d,
J = 17.7 Hz), 129.0 (d, J = 10.2 Hz), 128.1 (J = 7.0 Hz), 86.1 (dd,
JC,F = 169.0 Hz, JC,F = 14.2 Hz), 71.0 (dd, JC,F = 33.5 Hz, JC,F = 18.6 Hz),
64.8, 61.1, 29.6 (t, JC,F = 6.6 Hz), 28.3, 24.1, 19.4.
19F NMR (282 MHz, DMSO-d6): δ = –225.0 (1 F, td, JH,F = 47.4 Hz,
JH,F = 18.6 Hz).
To a flame-dried round-bottomed flask equipped with a stir bar were
added 3-(oxiran-2-yl)propyl benzoate (9c;16 457 mg, 2.16 mmol),
KHF2 (351 mg, 4.71 mmol), Bu4NH2F3 (92 mg, 0.216 mmol), and chlo-
robenzene (1.40 mL). The round-bottomed flask was equipped with a
reflux condenser and heated at 120 °C until the starting material was
no longer detected by TLC. The reaction mixture was allowed to cool
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R. J. McKinnie et al.
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Synthesis
4-(tert-Butyldiphenylsilyloxy)-5-fluoropentan-1-ol (13)
duced pressure. The crude residue was purified via silica gel flash
chromatography (EtOAc/hexanes 3:7) to afford 16 as a clear, viscous
oil; yield: 3.015 g (80%); Rf = 0.43 (EtOAc/hexanes 3:7).
1H NMR (300 MHz, DMSO-d6): δ = 8.06 (dt, J = 8.1, 0.9 Hz, 1 H), 7.68
(dt, J = 8.4, 0.9 Hz, 1 H), 7.52–7.28 (m, 12 H), 4.40 (t, J = 6.6 Hz, 2 H),
4.33–4.32 (m, 1 H), 4.18–4.16 (m, 1 H), 3.90 (s, 3 H), 3.85–3.75 (m, 1
H), 1.86–1.76 (m, 2 H), 1.42–1.34 (m, 2 H), 0.89 (m, 9 H).
13C NMR (75 MHz, DMSO-d6): δ = 162.8, 140.8, 135.7, 133.4 (d,
J = 13.8 Hz), 130.3, 128.1 (d, J = 4.8 Hz), 127.1, 123.6, 123.3, 121.6,
111.1, 86.0 (d, JC,F = 169.5 Hz), 71.6 (d, JC,F = 18.8 Hz), 52.0, 49.3, 30.1
(d, JC,F = 5.9 Hz), 27.1, 25.2, 19.3.
19F NMR (282 MHz, DMSO-d6): δ = –225.4 (1 F, td, JH,F = 47.1 Hz,
JH,F = 19.5 Hz).
To a 100 mL round-bottom flask equipped with a stir bar was added
10% Pd/C (520 mg, 4.88 mmol) was added. EtOH (50 mL) was added
under N2, followed by the addition of a solution of 12 (4.40 g, 9.77
mmol) in EtOH (5 mL). The reaction mixture was heated to 50 °C and
stirred under an atmosphere of H2 (1 atm) for 5 days until the starting
material was consumed. The suspension was vacuum filtered through
a pad of Celite and the filtrate was concentrated under reduced pres-
sure. The crude yellow oil was purified by flash chromatography
(EtOAc/hexanes 2:8) to afford 13 as a clear, viscous oil; yield: 3.51 g
(99%); Rf = 0.27 (EtOAc/hexanes 1:4).
1H NMR (300 MHz, CDCl3): δ = 7.70–7.67 (m, 4 H), 7.46–7.37 (m, 6 H),
4.37–4.30 (m, 1 H), 4.24–4.19 (m, 1 H), 3.95–3.89 (m, 1 H), 3.50 (t,
J = 6.0 Hz, 2 H), 1.59–1.51 (m, 4 H), 1.42 (br s, 1 H), 1.07 (s, 9 H).
13C NMR (75 MHz, DMSO-d6): δ = 135.8 (d, J = 3.1 Hz), 133.7 (d, J = 9.1
Hz), 130.2 (d, J = 5.9 Hz), 128.1 (d, J = 7.4 Hz), 86.1 (d, JC,F = 169.4 Hz),
72.1 (d, JC,F = 18.5 Hz), 61.0, 29.6 (d, JC,F = 6.4 Hz), 28.3, 27.2, 19.4.
19F NMR (282 MHz, DMSO-d6): δ = –225.1 (1 F, td, JH,F = 47.7 Hz,
JH,F = 19.2 Hz).
1-[(4-tert-Butyldiphenylsilyloxy)-5-fluoropentyl]-1H-indazole-3-
carboxylic Acid (17)
To a round-bottomed flask equipped with a stir bar was added 16
(3.02 g, 5.81 mmol) dissolved in MeOH (70 mL). A solution of aq 1 N
NaOH (12 mL) was added dropwise and the reaction mixture was al-
lowed to stir for 12 h at r.t. The solvent was removed under reduced
pressure. The residue was dissolved in H2O, acidified with dropwise
addition of aq 1 N HCl (pH 2), and extracted with EtOAc (3 × 25 mL).
The combined organic layers were dried (Na2SO4), filtered, and con-
centrated under reduced pressure to give 17 as a clear, viscous oil,
which was then used in the next step with no further purification;
yideld: 2.926 g (99%); Rf = 0.00 (EtOAc/hexanes 1:4).
1H NMR (300 MHz, DMSO-d6): δ = 12.92 (br s, 1 H, CO2H), 8.12 (d,
J = 8.4 Hz, 1 H), 7.70 (d, J = 8.7 Hz, 1 H), 7.57–7.31 (m, 12 H), 4.43 (t,
J = 6.0 Hz, 2 H), 4.38–4.37 (m, 1 H), 4.22–4.21 (m, 1 H), 3.89–3.80 (m,
1 H), 1.89–1.83 (m, 2 H), 1.46–1.43 (m, 2 H), 0.94 (s, 9 H).
13C NMR (75 MHz, DMSO-d6): δ = 163.9, 140.8, 135.6, 133.5 (d,
J = 15.1 Hz), 130.2, 128.1 (d, J = 6.2 Hz), 126.9, 123.5, 123.2, 121.9,
110.8, 86.0 (d, JC,F = 169.9 Hz), 71.6 (d, JC,F = 18.9 Hz), 49.2, 30.2 (d,
JC,F = 5.5 Hz), 27.1, 25.2, 19.3.
19F NMR (282 MHz, DMSO-d6): δ = –225.4 (1 F, td, JH,F = 47.9 Hz,
JH,F = 20.6 Hz).
4-(tert-Butyldiphenylsilyloxy)-5-fluoropentyl 4-Methylbenzene-
sulfonate (14)
To a round-bottomed flask equipped with a stir bar was added 13
(4.80 g, 13.3 mmol) and anhyd CH2Cl2 (100 mL). The reaction mixture
was then stirred and cooled to 0 °C in an ice bath followed by the se-
quential portionwise addition of 4-dimethylaminopyridine (997 mg,
7.99 mmol) and p-TsCl (3.10 g, 16.0 mmol). Et3N (1.90 mL, 13.3 mmol)
was added dropwise and the mixture was stirred at 0 °C for 20 h. The
mixture was diluted with Et2O (100 mL) and allowed to stir for an ad-
ditional 30 min. The resulting precipitate was removed by filtration.
The solution was then washed sequentially with 10% aq CuSO4 (2 × 50
mL), 10% aq NaHCO3 (2 × 50 mL), and brine (50 mL). The organic layer
was dried (MgSO4), filtered, and concentrated under reduced pres-
sure. The crude material was then purified by silica gel flash chroma-
tography (EtOAc/hexanes 2:8) to afford 14 as a clear, viscous oil;
yield: 4.42 g (85%); Rf = 0.38 (EtOAc/hexanes 1:4).
1H NMR (300 MHz, CDCl3): δ = 7.73 (d, J = 6.3 Hz, 2 H), 7.62 (d, J = 6.0
Hz, 4 H), 7.44–7.31 (m, 8 H), 4.28–4.07 (m, 3 H), 3.93–3.82 (m, 2 H),
2.44 (s, 3 H), 1.71–1.61 (m, 2 H), 1.51–1.43 (m, 2 H), 1.03 (s, 9 H).
Anal. Calcd for C23H30FN3O2: C, 69.15; H, 7.57; N, 10.52. Found: C,
68.94; H, 7.83; N, 10.49.
13C NMR (75 MHz, DMSO-d6): δ = 145.2, 135.7 (d, J = 3.8 Hz), 133.4 (d,
J = 8.3 Hz), 130.5, 130.3 (d, J = 6.1 Hz), 128.2 (d, J = 8.6 Hz), 127.9, 85.9
(d, JC,F = 169.5 Hz), 71.4 (d, JC,F = 18.8 Hz), 60.2, 28.8 (d, JC,F = 6.4 Hz),
28.3, 27.2, 24.2, 19.3.
19F NMR (282 MHz, DMSO-d6): δ = –225.4 (1 F, td, JH,F = 47.9 Hz,
JH,F = 19.2 Hz).
1-[4-(tert-Butyldiphenylsilyloxy)-5-fluoropentyl]-N-(adamantyl)-
1H-indazole-3-carboxamide (18)
To a round-bottomed flask equipped with a stir bar were added 17
(530 mg, 1.05 mmol), 1-adamantanamine (225 mg, 1.20 mmol), ED-
C·HCl (230 mg, 1.20 mmol), 1-hydroxybenzotriazole (162 mg, 1.20
mmol), DIPEA (1.10 mL, 6.10 mmol), and anhyd DMF (40 mL). The re-
action mixture was stirred for 24 h at r.t. The reaction was quenched
by the addition of H2O (40 mL) and the mixture was extracted with
EtOAc (3 × 25 mL). The combined organic layers were dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude materi-
al was then purified via silica gel flash chromatography (EtOAc/hex-
anes 7:3) to give 18 as a clear oil; yield: 590 mg (88%); Rf = 0.70
(EtOAc/hexanes 3:7).
1H NMR (300 MHz, DMSO-d6): δ = 8.14 (d, J = 8.4 Hz, 1 H), 7.59 (d,
J = 9.0 Hz, 1 H), 7.53–7.46 (m, 4 H), 7.40–7.29 (m, 7 H), 7.23 (t, J = 7.5
Hz, 1 H), 7.00 (br s, 1 H), 4.43–4.38 (m, 1 H), 4.33 (t, J = 6.6 Hz, 2 H),
4.18 (d, J = 4.2 Hz, 1 H), 3.84–3.75 (m, 1 H), 2.07 (s, 8 H), 1.85–1.76 (m,
2 H), 1.65 (s, 5 H), 1.42–1.35 (m, 2 H), 0.92 (s, 9 H), 0.89 (s, 2 H).
Methyl 1-[4-(tert-Butyldiphenylsilyloxy)-5-fluoropentyl]-1H-in-
dazole-3-carboxylate (16)
A solution of methyl indazole-3-carboxylate (15; 2.09 g, 7.35 mmol)
in anhyd THF (60 mL) was added to a round-bottomed flask equipped
with a stir bar and then cooled to 0 °C in an ice bath. Solid t-BuOK
(1.31 g, 11.0 mmol) was added slowly to the reaction mixture, which
was then allowed to warm to r.t. and stirred for 1 h. The mixture was
cooled to 0 °C, followed by dropwise addition of a solution 14 (3.67 g,
7.35 mmol) in THF (5 mL). The mixture was then warmed to r.t. and
stirred for 48 h. The reaction was quenched by the addition of H2O
(60 mL) and then extracted with EtOAc (3 × 50 mL). The combined or-
ganic layers were dried (Na2SO4), filtered, and concentrated under re-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

F
R. J. McKinnie et al.
Paper
Synthesis
1-(5-Fluoro-4-hydroxypentyl)-N-(adamantyl)-1H-indazole-3-car-
1H NMR (300 MHz, DMSO-d6): δ = 8.04 (d, J = 8.4 Hz, 1 H), 7.95 (br s, 1
H), 7.74 (d, J = 8.4 Hz, 1 H) 7.44–7.39 (m, 3 H), 7.30–7.14 (m, 4 H), 5.02
(d, J = 5.1 Hz, 1 H), 4.50 (t, J = 7.2 Hz, 2 H), 4.35–4.25 (m, 1 H), 4.19–
4.09 (m, 1 H), 3.74–3.62 (m, 1 H), 2.10–1.85 (m, 2 H), 1.71 (s, 6 H),
1.50–1.28 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 161.5, 148.1, 141.0, 137.7, 128.5,
127.0, 126.4, 125.2, 122.7, 122.5, 122.2, 110.8, 88.2 (d, JC,F = 167.6 Hz),
68.6 (d, JC,F = 18.8 Hz), 55.6, 49.1, 30.0, 29.7 (d, JC,F = 6.1 Hz), 26.2.
19F NMR (282 MHz, DMSO-d6): δ = –225.2 (1 F, td, JH,F = 56.1 Hz,
JH,F = 18.9 Hz).
MS (ESI): m/z = 384.7 [M + H]+.
boxamide (5F-4OH-APINACA; 5)9
To a round-bottomed flask equipped with a stir bar was added 18
(528 mg, 0.828 mmol), an argon atmosphere was established, and an-
hyd THF (30 mL) was added to the flask via syringe. The reaction mix-
ture was then cooled to 0 °C followed by the dropwise addition of a
solution of 1.0 M TBAF in THF (1.70 mL, 1.66 mmol). The mixture was
then warmed to r.t. and stirred for 24 h. The mixture was dissolved in
EtOAc (25 mL) and washed with H2O (3 × 20 mL). The organic layer
was dried (Na2SO4), filtered, and the solvent was removed under re-
duced pressure. The crude material was then purified via silica gel
flash chromatography (EtOAc/hexanes 7:3) to afford 5 as a clear, crys-
talline solid; yield: 288 mg (87%); mp 57–58 °C; Rf = 0.54 (EtOAc/hex-
anes 3:7).
Anal. Calcd for C22H26FN3O2: C, 68.91; H, 6.83; N, 10.96. Found: C,
68.75; H, 6.91; N, 10.80.
1H NMR (300 MHz, DMSO-d6): δ = 8.13 (d, J = 8.1 Hz, 1 H), 7.73 (d, J =
8.4 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1 H), 7.23 (t, J = 7.5 Hz, 1 H), 7.11 (br s, 1
H), 4.99 (d, J = 5.1 Hz, 1 H), 4.46 (t, J = 7.2 Hz, 2 H), 4.32–4.23 (m, 1 H),
4.17–4.07 (m, 1 H), 3.72–3.59 (m, 1 H), 2.08–2.05 (m, 9 H), 1.98–1.81
(m, 2 H), 1.65 (br s, 6 H), 1.44–1.27 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 161.5, 141.0, 137.9, 126.9, 122.7,
122.3, 110.8, 87.1 (d, JC,F = 168.0 Hz), 68.6 (d, JC,F = 18.8 Hz), 51.6, 49.0,
41.6, 36.4, 29.6 (d, JC,F = 6.0 Hz), 29.4, 26.1
Acknowledgment
The authors express their gratitude for technical support provided by
the UNO Mass Spectrometry Facility under the direction of Professor
David C. Podgorski.
19F NMR (282 MHz, DMSO-d6): δ = –225.3 (1 F, td, JH,F = 47.9 Hz,
JH,F = 18.9 Hz).
MS (ESI): m/z = 400.9 [M + H]+.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609914.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Anal. Calcd for C23H30FN3O2: C, 69.15; H, 7.57; N, 10.52. Found: C,
68.94; H, 7.83; N, 10.49.
References
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To a round-bottomed flask equipped with a stir bar was added 17
(531 mg, 1.05 mmol), cumylamine (0.199 mL, 1.38 mmol), EDC·HCl
(224 mg, 1.17 mmol), 1-hydroxybenzotriazole (163 mg, 1.21 mmol),
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addition of H2O (40 mL) and the mixture was extracted with EtOAc
(3 × 25 mL). The combined organic layers were dried (Na2SO4), fil-
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was then purified via silica gel flash chromatography (EtOAc/hexanes
7:3) to give 18 as a clear colorless oil; yield: 649 mg (99%); Rf = 0.76
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H), 7.61 (d, J = 8.4 Hz, 1 H), 7.55–7.17 (m, 16 H), 4.38 (t, J = 6.9 Hz, 2
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1-(5-Fluoro-4-hydroxypentyl)-N-(2-phenylpropan-2-yl)-1H-inda-
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To a round-bottomed flask equipped with a stir bar was added 19
(605 mg, 0.97 mmol), an argon atmosphere was established, and an-
hyd THF (30 mL) was added to the flask via a syringe. The reaction
mixture was then cooled to 0 °C, followed by the dropwise addition of
a solution of 1.0 M TBAF in THF (1.95 mL, 1.95 mmol). The mixture
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solved in EtOAc (25 mL) and washed with H2O (3 × 20 mL). The organ-
ic layer was dried (Na2SO4), filtered, and the solvent was removed un-
der reduced pressure. The crude material was then purified via silica
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and colorless wax; yield: 302 mg (81%); Rf = 0.62 (EtOAc/hexanes 7:3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G

G
R. J. McKinnie et al.
Paper
Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G