Synthesis of 3-(hetero)aryl tetrahydropyrazolo[3,4-c]pyridines by Suzuki-Miyaura cross-coupling methodology

Article abstract of DOI:10.1021/jo5012015

A new synthetic route to 3-(heteroaryl) tetrahydropyrazolo[3,4-c]pyridines has been developed that uses the Suzuki-Miyaura cross-coupling of a triflate 6 with (hetero)aryl boronic acids or esters. Using Pd(OAc)₂ and XPhos or an XPhos precatalyst, a diverse range of substituents at the C3 position of the tetrahydropyrazolo[3,4-c]pyridine skeleton were prepared. The use of pivaloyloxymethyl and benzyl protection also offers the potential to differentially functionalize the pyrazole and tetrahydropyridine nitrogens.

Full text of DOI:10.1021/jo5012015

Note
pubs.acs.org/joc
Synthesis of 3‑(Hetero)aryl Tetrahydropyrazolo[3,4‑c]pyridines by
Suzuki−Miyaura Cross-Coupling Methodology
Paul D. Kemmitt,* Kevin Blades, Matthew R. Box, Stephanie Dickinson, Gillian M. Lamont,
Katrina Madden, William McCoull, and Jason Williams
AstraZeneca Oncology Innovative Medicines, Mereside, Alderley Park, Macclesfield Cheshire, SK10 4TG, United Kingdom
S
* Supporting Information
ABSTRACT: A new synthetic route to 3-(heteroaryl)
tetrahydropyrazolo[3,4-c]pyridines has been developed that
uses the Suzuki−Miyaura cross-coupling of a triflate 6 with
(hetero)aryl boronic acids or esters. Using Pd(OAc)2 and
XPhos or an XPhos precatalyst, a diverse range of substituents
at the C3 position of the tetrahydropyrazolo[3,4-c]pyridine
skeleton were prepared. The use of pivaloyloxymethyl and
benzyl protection also offers the potential to differentially
functionalize the pyrazole and tetrahydropyridine nitrogens.
etrahydropyrazolopyridine rings are widely used in
Tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-ol ring 7 is readily
Tmedicinal chemistry; in particular, compounds featuring made in 83% yield by reaction of ethyl 1-benzyl-3-
oxopiperidine-4-carboxylate with hydrazine hydrate.4 Initial
tetrahydropyrazolo[4,3-c]pyridines are reported to exhibit a
attempts at making the triflate 8 from N-phenyltrifluorometha-
nesulfonimide with DBU in DCM failed, but switching the
solvent to pyridine provided 8 in 54% yield.5 Finally, 6 was
made in 63% yield when sodium hydride was added to a
mixture of chloromethyl pivalate and 8. The structure of 6 was
confirmed by NOE experiments, which showed an enhance-
ment of the piperidine C7 proton signals when the methylene
on the POM was irradiated. This confirmed that alkylation had
occurred adjacent to the piperidine ring (as drawn in 6, Scheme
2).
With a route that allowed us access to multigram quantities
of versatile intermediate 6 in hand, we were able to study how it
performed during a Suzuki−Miyaura cross-coupling (SMC)
reaction. A brief catalyst screen using Pd(PPh3)4, Pd(dppf)Cl2,
Pd(dtbpf)Cl2, Pd(Amphos)Cl2, and Pd(OAc)2 with XPhos
identified that the most efficient conditions for the reaction of 6
(1 equiv) with a boronic acid or ester (1.2−1.5 equiv) were
Pd(OAc)2 (5 mol %), XPhos (10 mol %), and K2CO3, (3
equiv) in DME/water (3:1), at 80 °C. This afforded a range of
coupled products in 17−86% yields (Table 1, entries 9−17).6
Notably, boronic acids containing electron-donating groups all
coupled in good yields (entries 9−11). The synthesis of 11
represents a significantly more efficient synthesis of this aryl
substitution pattern seen in 2 (Scheme 1), an intermediate in
the synthesis of a Heat Shock Protein (HSP 90) inhibitor
(Figure 1).2 Those boronic acids containing electron-with-
drawing substituents at the para position were also well
tolerated (entries 12 and 13). However, boronic acids with an
ortho electron-withdrawing group were less successful. For
range of different biological properties depending on the
substitution pattern, for example, as a cannabinoid receptor
modulator1a or as a potential treatment for diabetes.1b
A
bioisostere, tetrahydropyrazolo[3,4-c]pyridine is less prevalent;
one example is reported to inhibit the activity of Heat Shock
Protein 902 (Figure 1).
Although 3-substituted tetrahydropyrazolo[4,3-c]pyridines
such as 1 can be readily prepared in a one-pot procedure
from tert-butyl 4-oxopiperidine-1-carboxylate and an acid
chloride (Scheme 1),3 the synthesis of tetrahydropyrazolo-
[3,4-c]pyridine derivatives of the type 2 are less efficiently
described. Their reported synthesis starts by forming the
lithium enolate of tert-butyl 3-oxopiperidine-1-carboxylate;
however, as this produces a mixture of enolates, subsequent
reaction with an acid chloride results in an inseparable mixture
of diketones 3 and 4. Consequently, reaction of this mixture
with hydrazine gives not only the desired 3-substituted
tetrahydropyrazolo[3,4-c]pyridine 2 but also a regioisomer
tetrahydropyrazolo[4,3-b]pyridine 5, often as an inseparable
mixture (Scheme 1).1a
As part of a drug discovery program, we were interested in 3-
(heteroaryl) tetrahydropyrazolo[3,4-c]pyridines but required an
approach that would allow for their synthesis as a single
regioisomer, ready variation of the C3 position and be
amenable to selective derivatization of the heterocyclic
nitrogens. We reasoned that synthesis of the triflate 6 would
open up cross-coupling chemistry and thus allow for the
incorporation of a wide variety of substituents at the C3
position. Suitable protection of the nitrogens with benzyl and
pivaloyloxymethyl (POM) would further provide scope for
selective functionalization of the heterocyclic nitrogens
(Scheme 2).
Received: May 29, 2014
Published: July 22, 2014
© 2014 American Chemical Society
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Note
Figure 1. Selected examples of bioactive compounds featuring the tetrahydropyrazolopyridine core.
Scheme 1. General Route to Tetrahydropyrazolo[4,3-c] and [3,4-c] Pyridines
Scheme 2. Synthesis of Intermediate 6
example, the ortho-trifluoromethyl analogue 14 was obtained in
17% yield, but more typically, they failed, e.g., ortho-
fluorophenylboronic acids. Similarly, the reaction of 3-
pyridylboronic acid also failed to produce any desired product,
although heterocyclic boronic acids or esters of quinoline,
indole, and pyrazole all coupled in good yields (entries 15−17).
In an effort to improve the range of substrates that would
undergo an SMC reaction with 6, we looked at using the XPhos
precatalyst 18 reported by Buchwald et al. as a suitable reagent
for coupling reactions of unstable boronic acids.7 We were
pleased to find that using 18 dramatically improved the SMC
reaction of 6 to such an extent that boronic acids or esters that
failed to couple when using Pd(OAc)2 and XPhos were now
isolated in excellent yields (Table 1, entries 19−24). For
example, when 6 was reacted with 2,4,5-trifluorophenylboronic
acid, 18 (2 mol %), K3PO4, (2 equiv), THF, water (3:1) at rt
for 30 min, 19 was isolated in 92% yield; similarly, other
challenging fluorinated arylboronic acids coupled in high yields
(entries 20 and 21). In some cases, higher catalyst loading was
required to achieve an efficient conversion. For example, only
16% of 22 was isolated when 6 was reacted with 3-
pyridylboronic acid and 4 mol % of 18 at 40 °C, but this
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Note
Table 1. Suzuki−Miyaura Cross-Coupling Reaction of 6
reagents and conditions
ArOTf 6
boronic acid/ester
precatalyst
base
solvent
temp
a
b
c
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1 equiv
1.2 equiv ArB(OH)2
1.5 equiv ArB(OH)2
1.2 equiv ArBPin
5 mol % Pd(OAc)2, 10 mol % XPhos
5 mol % Pd(OAc)2, 10 mol % XPhos
5 mol % Pd(OAc)2, 10 mol % XPhos
5 mol % Pd(OAc)2, 10 mol % XPhos
2 mol % 18
3 equiv K2CO3
3 equiv K2CO3
3 equiv K2CO3
3 equiv K2CO3
2 equiv K3PO4
2 equiv K3PO4
2 equiv K3PO4
2 equiv K3PO4
2 equiv K3PO4
DME:water 3:1
DME:water 3:1
DME:water 3:1
DME:water 3:1
THF:water 3:1
THF:water 3:1
THF:water 3:1
THF:water 3:1
THF:water 3:1
80 °C
80 °C
80 °C
80 °C
rt
d
e
f
1.5 equiv ArBPin
1.5 equiv ArB(OH)2
1.5 equiv ArB(OH)2
1.5 equiv ArB(OH)2
1.5 equiv ArB(OH)2
1.5 equiv ArBPin
8 mol % 18
rt
g
h
i
8 mol % 18
40 °C
40 °C
40 °C
4 mol % 18
4 mol % 18
Scheme 3. Examples of Derivatization of the Pyrazolo Tetrahydropyridine Skeleton
increased to 91% when 8 mol % of 18 was used. Similarly, when
8 mol % of 18 was used at rt, 2-(trifluoromethyl)phenylboronic
acid couples in an improved 76% yield (entry 14). Indeed,
reactions that proceeded in moderate yields with Pd(OAc)2 and
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Note
CDCl3) δ 19.2, 26.8, 38.8, 48.3, 49.4, 61.4, 70.2, 106.3, 118.7 (q, J =
322 Hz), 127.5, 128.5, 128.9, 137.6, 141.2, 150.5, 177.3; IR (DCM) ν
2976, 2808, 1743, 1448, 1217, 1138, 1034, 822 cm−1; HRMS (ESI-
TOF) calcd for C20H25F3N3O5S [M + H]+ m/z 476.1468, found
476.1462.
General Procedure for Suzuki Coupling of 6 with Pd(OAc)2
and XPhos (Method A). Pd(OAc)2 (5 mol %) was added to a
degassed mixture of the appropriate boronic acid or ester (1.2 equiv
unless stated otherwise), 6 (1 mmol), XPhos (10 mol %), and K2CO3
(3 equiv) in DME (7 mL) and water (2.3 mL) at rt under nitrogen,
and the resulting mixture was stirred at 80 °C for the time indicated.
After being allowed to cool to rt, the reaction mixture was diluted with
EtOAc (50 mL) and washed with water (20 mL) and brine (20 mL).
The organic layer was dried over MgSO4 and concentrated, and the
resulting residue was purified by silica gel chromatography.
General Procedure for Suzuki Coupling; Using XPhos
Precatalyst 18 (Method B). XPhos precatalyst 18 (2−8 mol %), 6
(261 mg, 0.55 mmol), and the appropriate boronic acid or ester (1.5
equiv unless stated otherwise) were added to THF (10 mL) and water
(3.3 mL), and the mixture was degassed for 10 min. To this was added
K3PO4 (233 mg, 1.10 mmol), and the reaction was stirred at rt to 40
°C for the time indicated. The reaction mixture was diluted with water
(50 mL) and extracted with ether (2 × 50 mL). The organic layer was
dried over MgSO4 and concentrated under reduced pressure, and the
resulting residue was purified by silica gel chromatography (0−60%
EtOAc in heptane) unless otherwise specified.
(6-Benzyl-3-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-
pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (9). Using Method A;
the reaction mixture was stirred at 80 °C for 2 h. Isolated 9 as a white
solid, mp 115−116 °C (323 mg, 74%). 1H NMR (400 MHz, DMSO)
δ 1.08 (s, 9H), 2.73 (s, 4H), 3.61 (s, 2H), 3.74 (s, 2H), 3.79 (s, 3H),
5.91 (s, 2H), 6.97−7.01 (m, 2H), 7.25−7.3 (m, 1H), 7.32−7.39 (m,
4H), 7.62−7.67 (m, 2H); 13C NMR (101 MHz, DMSO) 22.0, 26.6,
38.2, 47.9, 49.9, 55.1, 60.6, 70.8, 112.2, 114.0, 125.9, 127.0, 127.4,
128.2, 128.6, 138.2, 139.2, 147.5, 158.8, 176.4; IR (DCM) ν 2972,
2934, 1737, 1613, 1530, 1454, 1249, 1127, 1030, 962 cm−1; HRMS
(ESI-TOF) calcd for C26H32N3O3 [M + H]+ m/z 434.2438, found
434.2438.
XPhos were also isolated in improved yields, (entries 11 and
17).
Removal of the N-benzyl protecting group either by
hydrogenation over palladium on charcoal (Scheme 3, 17 to
25) or by using chloroethyl chloroformate (ACE-Cl)8 (Scheme
3, 19 to 28) allows for selective functionalization of the
piperidine. For example, the reaction of 25 with benzoyl
chloride forms the amide 26, which is deprotected with 2 N
NaOH to afford 27 in 94% yield, and N-methylation of 28 by
reductive amination with formaldehyde, followed by removal of
the POM group, forms 29 in good overall yield, (Scheme 3).
In summary, we have described an improved approach
toward 3-(hetero)aryl substituted tetrahydropyrazolo[3,4-c]-
pyridines. The SMC reaction of the triflate 6 with a variety of
substituted boronic acids or esters afforded ready access to a
range of 3-(hetero)aryl products as single regioisomers.
Removal of the N-benzyl protecting group allows further
substitution of the core, and removal of the POM protecting
group gives the potential to increase diversity. The chemistry
described herein should extend the utility of this hitherto
under-reported heterocycle.
EXPERIMENTAL SECTION
■
6-Benzyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-ol
(7).4 Hydrazine hydrate (4.8 mL, 99.7 mmol) was added to a stirred
solution of ethyl 1-benzyl-3-oxopiperidine-4-carboxylate hydrochloride
(27 g, 90.7 mmol) and Et3N (12.6 mL, 90.7 mmol) in EtOH (300
mL), and the mixture was stirred at 80 °C for 90 min. The reaction
mixture was allowed to cool, and the precipitate was collected by
filtration, washed with EtOH (20 mL), and dried under vacuum to
1
give 7 as a white powder, mp 244 °C (dec) (17.3 g, 83%). H NMR
(400 MHz, DMSO) δ 2.32 (t, J = 5.7 Hz, 2H), 2.63 (t, J = 5.7 Hz,
2H), 3.31 (s, 2H), 3.65 (s, 2H), 7.22−7.3 (m, 1H), 7.34 (d, J = 4.4 Hz,
4H); 13C NMR (101 MHz, DMSO) δ 19.4, 48.7, 50.5, 60.9, 96.4,
126.9, 128.1, 128.7, 138.5, 139.0, 157.4; IR (DCM) ν 2792, 1599,
1264, 1118, 741 cm−1; HRMS (ESI-TOF) calcd for C13H16N3O [M +
H]+ m/z 230.1293, found 230.1291.
(6-Benzyl-3-(2-methoxyphenyl)-4,5,6,7-tetrahydro-1H-
pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (10). Using Method
A; from 1.5 equiv of 2-methoxyphenylboronic acid (228 mg, 1.50
mmol), and the reaction was heated to 80 °C for 20 min. Isolated 10
6-Benzyl-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl
Trifluoromethanesulfonate (8). N-Phenyl-bis(trifluoromethane-
sulfonimide) (26.9 g, 75.4 mmol) was added to a stirred solution of
7 (17.3 g, 75.4 mmol) in pyridine (100 mL), and the mixture was
stirred at rt for 24 h and then evaporated to dryness. The residue was
partitioned between ether (150 mL) and 2 M K2CO3 (100 mL). The
aqueous mixture was separated and extracted with ether (150 mL).
The ether extracts were combined, dried over MgSO4, and
concentrated, and the residue was purified by silica gel chromatog-
raphy (0−60% EtOAc in heptane) to give 8 as a colorless oil, which
1
as a yellow gum (435 mg, 86%). H NMR (400 MHz, CDCl3) δ 1H
NMR (400 MHz, CDCl3) δ 1.16 (s, 9H), 2.58 (t, J = 5.7 Hz, 2H), 2.73
(t, J = 5.7 Hz, 2H), 3.66 (s, 2H), 3.77 (s, 2H), 3.83 (s, 3H), 5.90 (s,
2H), 6.95 (d, J = 8.3 Hz, 1H), 6.99 (td, J = 7.5, 1.0 Hz, 1H), 7.26−7.37
(m, 4H), 7.37−7.42 (m, 2H), 7.48 (dd, J = 7.5, 1.8 Hz, 1H); 13C NMR
(101 MHz, CDCl3) δ 22.1, 27.0, 38.9, 48.8, 50.5, 55.4, 62.0, 70.9,
111.0, 115.8, 120.8, 122.5, 127.3, 128.4, 129.1, 129.5, 131.1, 138.2,
148.3, 157.2, 177.6; IR ν 2969, 2933, 1733, 1467, 1128 cm−1; HRMS
(ESI-TOF) calcd for C26H32N3O3 [M + H]+ m/z 434.2438, found
434.2440.
(6-Benzyl-3-(5-chloro-2,4-dimethoxyphenyl)-4,5,6,7-tetrahy-
dro-1H-pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (11). Using
Method A; (5-chloro-2,4-dimethoxyphenyl)boronic acid9(329 mg,
1.52 mmol, 1.5 equiv), and the reaction mixture was heated to 80 °C
for 2 h. Isolated 11 as a white solid (322 mg, 64%).
1
solidified on standing, mp 112.4−114.5 °C (14.6 g, 54%). H NMR
(400 MHz, CDCl3) δ 2.61 (t, J = 5.8 Hz, 2H), 2.80 (t, J = 5.8 Hz, 2H),
3.52 (s, 2H), 3.72 (s, 2H), 7.26−7.41 (m, 5H); 13C NMR (101 MHz,
CDCl3) δ 19.0, 48.4, 49.9, 61.6, 104.2, 118.7 (q, J = 320 Hz), 127.6,
128.5, 129.0, 137.6, 140.3, 150.4; IR (DCM) ν 3187, 2808, 1426,
1332, 1215, 1137, 1051, 878 cm−1; HRMS (ESI-TOF) calcd for
C14H15F3N3O3S [M + H]+ m/z 362.0781, found 362.0786.
(6-Benzyl-3-(((trifluoromethyl)sulfonyl)oxy)-4,5,6,7-tetrahy-
dro-1H-pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (6). Sodium
hydride (1.94 g, 48.6 mmol, 60% mineral dispersion) was added
portionwise to a stirred solution of 8 (14.6 g, 40.5 mmol) and
chloromethyl pivalate (7.0 mL, 48.6 mmol) in THF (200 mL) at 0 °C,
under nitrogen. The solution was stirred at 0 °C for 20 min and then
quenched with saturated NH4Cl (125 mL) and extracted with heptane
(2 × 200 mL). The organic extracts were combined, dried over
MgSO4, and concentrated, and the residue was purified by silica gel
chromatography (10−40% EtOAc in heptane) to give 6 as a pale
Using Method B; XPhos precatalyst 18 (35 mg, 8 mol %). The
reaction was stirred at rt for 2 h and isolated 11 as a cream solid,
1
mp147−149 °C (259 mg, 94%). H NMR (400 MHz, CDCl3) δ 1.16
(s, 9H), 2.54 (t, J = 5.7 Hz, 2H), 2.72 (t, J = 5.7 Hz, 2H), 3.65 (s, 2H),
3.76 (s, 2H), 3.83 (s, 3H), 3.94 (s, 3H), 5.88 (s, 2H), 6.55 (s, 1H),
7.26−7.31 (m, 1H), 7.31−7.37 (m, 2H), 7.37−7.42 (m, 2H), 7.49 (s,
1H); 13C NMR (101 MHz, CDCl3) 22.1, 27.0, 38.9, 48.8, 50.4, 55.9,
56.3, 62.0, 70.8, 96.9, 114.0, 115.6, 115.9, 127.3, 128.4, 129.0, 131.8,
138.1, 138.3, 146.9, 155.8, 156.8, 177.6; IR 2968, 2933, 2874, 2847,
1736, 1607, 1437, 1327, 1278, 1209, 1128, 1030, 962 cm−1; HRMS
(ESI-TOF) calcd for C27H33ClN3O4 [M + H]+ m/z 498.2154, found
498.2158.
1
yellow gum (12.1 g, 63%); H NMR (400 MHz, CDCl3) δ 1.15 (s,
9H), 2.58 (t, J = 5.8 Hz, 2H), 2.77 (t, J = 5.8 Hz, 2H), 3.61 (s, 2H),
3.74 (s, 2H), 5.74 (s, 2H), 7.26−7.44 (m, 5H); 13C NMR (101 MHz,
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Note
(6-Benzyl-3-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-
pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (12). Using Method
A; the reaction was heated to 80 °C for 1 h. Isolated 12 as a white
dioxaborolan-2-yl)-1H-pyrazole (341 mg, 1.64 mmol), and K3PO4
(464 mg, 2.19 mmol) in THF (10 mL)/water (3.33 mL), and the
reaction was stirred for 30 min at 40 °C. Isolated 17 as a white solid,
mp 112.3 °C (354 mg, 79%). 1H NMR (400 MHz, DMSO) δ 1.07 (s,
9H), 2.62 (t, J = 5.1 Hz, 2H), 2.73 (t, J = 5.5 Hz, 2H), 3.58 (s, 2H),
3.72 (s, 2H), 3.87 (s, 3H), 5.87 (s, 2H), 7.22−7.31 (m, 1H), 7.3−7.41
(m, 4H), 7.69 (s, 1H), 7.98 (s, 1H); 13C NMR (101 MHz, DMSO) δ
21.0, 26.6, 38.2, 38.5, 47.8, 49.7, 60.5, 70.7, 112.1, 114.7, 127.0, 128.1,
128.2, 128.6, 136.1, 138.3, 138.7, 142.3, 176.5; IR (DCM) ν 2973,
2933, 1735, 1602, 1276, 1128 cm−1; HRMS (ESI-TOF) calcd for
C23H30N5O2 [M + H]+ m/z 408.2394, found 408.2394.
(6-Benzyl-3-(2,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-1H-
pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (19). Using Method
B; XPhos precatalyst 18 (9.6 mg, 2 mol %). The reaction was stirred at
rt for 30 min and isolated 19 as a yellow gum (258 mg, 92%).1H NMR
(400 MHz, CDCl3) δ 1.16 (s, 9H), 2.63 (t, J = 5.1 Hz, 2H), 2.76 (t, J =
5.7 Hz, 2H), 3.65 (s, 2H), 3.77 (s, 2H), 5.89 (s, 2H), 6.97 (td, J = 6.6,
9.8 Hz, 1H), 7.25−7.42 (m, 5H), 7.47 (ddd, J = 6.6, 8.9, 10.7 Hz, 1H);
13C NMR (176 MHz, CDCl3) δ 21.7 (d, J = 7.3 Hz), 26.9, 38.8, 48.6,
1
solid, mp 109.8 °C (435 mg, 86%). H NMR (400 MHz, CDCl3) δ
1.08 (s, 9H), 2.73 (s, 4H), 3.63 (s, 2H), 3.74 (s, 2H), 5.93 (s, 2H),
7.2−7.31 (m, 3H), 7.31−7.42 (m, 4H), 7.71−7.8 (m, 2H); 13C NMR
(101 MHz, DMSO) δ 21.9, 26.5, 38.2, 47.8, 49.8, 60.6, 70.8, 112.5,
115.5 (d, J = 21.5 Hz), 127.0, 128.1 (d, J = 8.1 Hz), 128.2, 128.6, 129.8
(d, J = 3 Hz), 138.2, 139.5, 146.8, 161.6 (d, J = 244 Hz), 176.4; IR
(DCM) ν 2973, 2931, 2802, 1735, 1527, 1488, 1112 cm−1; HRMS
(ESI-TOF) calcd for C25H29FN3O2 [M + H]+ m/z 422.2238, found
422.2236.
(6-Benzyl-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-
1H-pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (13). Using
Method A; the reaction was heated to 80 °C for 30 min. Isolated
13 as a white solid, mp 96.7 °C (372 mg, 79%). 1H NMR (400 MHz,
CDCl3) δ 1.16 (s, 9H), 2.75−2.91 (m, 4H), 3.66 (s, 2H), 3.78 (s, 2H),
5.90 (s, 2H), 7.27−7.44 (m, 5H), 7.65 (d, J = 8.2 Hz, 2H), 7.85 (d, J =
8.2 Hz, 2H); 13C NMR (101 MHz, CDCl3) 22.7, 26.9, 38.9, 48.7, 50.3,
61.8, 70.8, 113.9, 125.5 (q, J = 3.7), 127.1 (q, J = 252 Hz), 125.6,
126.8, 127.5, 128.5, 129.5 (q, J = 33 Hz), 137.1, 137.9, 139.6, 147.9,
177.5; IR (DCM) ν 3062, 3022, 2975, 2933, 2806, 2761, 1735, 1819,
1324, 1124 cm−1; HRMS (ESI-TOF) calcd for C26H29F3N3O2 [M +
H]+ m/z 472.2206, found 472.2209.
50.3, 61.8, 70.6, 105.9 (dd, J = 20.9, 28.4 Hz), 115.3, 117.7 (d, J = 17.2
Hz), 118.2 (dd, J = 5.9, 20 Hz), 127.4, 128.5, 128.9, 137.9, 139.2,
143.9, 146.9 (ddd, J = 3.2, 12.3, 236 Hz), 149.9 (dt, J = 1.8, 13.3, 252.3
Hz), 155.0 (dd, J = 7.7, 256 Hz), 177.4; IR ν 2973, 2929, 2873, 1739,
1531, 1470, 1139; HRMS (ESI-TOF) calcd for C25H27F3N3O2 [M +
H]+ m/z 458.2050, found 458.2050.
(6-Benzyl-3-(2-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-
1H-pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (14). Using
Method A; the reaction was heated to 80 °C for 6 h. Isolated 14 as
a colorless gum (83 mg, 17%).
(6-Benzyl-3-(2-fluorophenyl)-4,5,6,7-tetrahydro-1H-
pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (20). Using Method
B; XPhos precatalyst 18 (35 mg, 8 mol %). The reaction was stirred at
1
Using Method B; XPhos precatalyst 18 (35 mg, 8 mol %). The
reaction was stirred at rt for 3 h and isolated 14 as a colorless gum,
(198 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 1.16 (s, 9H), 2.44 (t, J
= 5.4 Hz, 2H), 2.75 (t, J = 5.3 Hz, 2H), 3.71 (s, 2H), 3.78 (s, 2H),
7.26−7.43 (m, 7H), 7.47 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.1 Hz, 1H),
7.74 (d, J = 7.8 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 20.5, 26.9,
38.8, 48.5, 50.0, 61.6, 70.3, 115.1, 123.9 (q, J = 274 Hz), 126.3 (q, J =
5.1 Hz) 127.4, 128.3, 128.4, 129.1, 129.8 (q, J = 30.3 Hz), 131.2, 132.0,
132.4, 137.9, 138.0, 148.4, 177.5; IR (DCM) ν 2960, 2931, 2872,
1738, 1441, 1315, 1165, 1130, 1036, 966 cm−1; HRMS (ESI-TOF)
calcd for C26H29F3N3O2 [M + H]+ m/z 472.2206, found 472.2210.
(6-Benzyl-3-(quinolin-6-yl)-4,5,6,7-tetrahydro-1H-pyrazolo-
[3,4-c]pyridin-1-yl)methyl Pivalate (15). Using Method A; the
reaction was heated to 80 °C for 30 min. Isolated 15 as a white solid,
mp 131.7 °C (236 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 1.17 (s,
9H), 2.85 (t, J = 5.6 Hz, 2H), 2.94 (t, J = 5.4 Hz, 2H), 3.69 (s, 2H),
3.80 (s, 2H), 5.94 (s, 2H), 7.28−7.46 (m, 6H), 8.1−8.23 (m, 4H),
8.89 (dd, J = 4.2, 1.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 22.8,
27.0, 38.9, 48.8, 50.4, 61.8, 70.8, 113.9, 121.4, 125.1, 127.4, 128.4,
128.5, 128.6, 129.0, 129.7, 131.9, 136.2, 138.0, 139.6, 148.0, 148.5,
150.4, 177.5; IR (DCM) ν 2973, 2931, 1735, 1276, 1126, 1108 cm−1;
HRMS (ESI-TOF) calcd for C28H31N4O2 [M + H]+ m/z 455.2441,
found 455.2441.
40 °C for 2 h and isolated 20 as an orange gum (214 mg, 94%). H
NMR (400 MHz, CDCl3) δ 1.16 (s, 9H), 2.66 (t, J = 5.3 Hz, 2H), 2.76
(t, J = 5.7 Hz, 2H), 3.66 (s, 2H), 3.77 (s, 2H), 5.91 (s, 2H), 7.07−7.2
(m, 2H), 7.27−7.44 (m, 6H), 7.61 (td, J = 7.5, 1.8 Hz, 1H); 13C NMR
(176 MHz, CDCl3) 21.7 (d, J = 6.9), 26.9, 38.8, 48.7, 50.3, 61.8, 70.7,
115.4, 115.9 (d, J = 22.1 Hz), 121.2 (d, J = 14.6 Hz), 124.1 (d, J = 3.1
Hz), 127.3, 128.4, 129.0, 129.7 (d, J = 8.1 Hz), 130.8 (d, J = 3.6 Hz),
138.0, 138.7, 145.7, 160.1 (d, J = 249), 177; IR (DCM) ν 2972, 2931,
2802, 1738, 1460, 1277, 1128, 1030, 966 cm−1; HRMS (ESI-TOF)
calcd for C25H29FN3O2 [M + H]+ m/z 422.2238, found 422.2241.
(6-Benzyl-3-(2,5-difluorophenyl)-4,5,6,7-tetrahydro-1H-
pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (21). Using Method
B; XPhos precatalyst 18 (17 mg, 4 mol %). The reaction was stirred at
40 °C for 30 min and isolated 21 as a yellow gum (217 mg, 91%). 1H
NMR (400 MHz, CDCl3) δ 1.16 (s, 9H), 2.66 (t, J = 5.2 Hz, 2H), 2.76
(t, J = 5.7 Hz, 2H), 3.66 (s, 2H), 3.77 (s, 2H), 5.90 (s, 2H), 6.94−7.11
(m, 2H), 7.27−7.42 (m, 6H); 13C NMR (101 MHz, CDCl3) 21.8 (d, J
= 7.5), 27.0, 38.9, 48.7, 50.3, 61.9, 70.7, 115.4, 116.0 (dd, J = 24.2, 8.6
Hz), 116.9 (dd, J = 25.4, 8.8 Hz), 116.9 (dd, J = 24.8, 4.3 Hz), 122.6
(dd, J = 17.6, 8.3 Hz), 127.4, 128.5, 129.0, 138.0, 139.1, 144.8, 156.1
(dd, J = 248, 2.0 Hz), 156.1 (dd, J = 244.4, 2.0 Hz), 177.5; IR (DCM)
ν 2972, 2931, 2804, 1738, 1468, 1127, 972 cm−1; HRMS (ESI-TOF)
calcd for C25H28F2N3O2 440.2144 [M + H]+ m/z, found 440.2147.
(6-Benzyl-3-(pyridin-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo-
[3,4-c]pyridin-1-yl)methyl Pivalate (22). Using Method B; XPhos
precatalyst 18 (35 mg, 8 mol %). The reaction was stirred at 40 °C for
3 h and purified by silica gel chromatography (40−100% EtOAc in
heptane, followed by 10% MeOH) to give 22 as a pale brown gum
(219 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 1.16 (s, 9H), 2.82 (s,
4H), 3.65 (s, 2H), 3.78 (s, 2H), 5.90 (s, 2H), 7.26−7.43 (m, 6H), 8.06
(dt, J = 1.9, 7.9 Hz, 1H), 8.55 (dd, J = 1.7, 4.8 Hz, 1H), 8.91−9.04 (m,
1H); 13C NMR (101 MHz, CDCl3) δ 22.2, 27.0, 38.9, 48.7, 50.4, 61.8,
70.7, 113.8, 123.5, 127.5, 128.5, 129.0, 129.6, 133.9, 137.9, 139.6,
146.5, 147.9, 148.8, 177.5; IR (DCM) ν 3061, 2972, 2931, 1736, 1277,
1128, 1032, 966 cm−1; HRMS (ESI-TOF) calcd for C24H29N4O2
405.2285 [M + H]+ m/z, found 405.2285.
(6-Benzyl-3-(1H-indol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo-
[3,4-c]pyridin-1-yl)methyl Pivalate (16). Using Method A; the
reaction was heated to 80 °C for 30 min. Isolated 16 as a white solid,
1
mp 82.4 °C (313 mg, 71%). H NMR (400 MHz, CDCl3) δ 1.15 (s,
9H), 2.80 (t, J = 5.3 Hz, 2H), 2.87 (t, J = 5.3 Hz, 2H), 3.66 (s, 2H),
3.78 (s, 2H), 5.91 (s, 2H), 6.55 (ddd, J = 3.0, 2.0, 0.9 Hz, 1H), 7.14−
7.2 (m, 1H), 7.25−7.44 (m, 6H), 7.63 (dd, J = 8.5, 1.6 Hz, 1H), 7.92−
7.99 (m, 1H), 8.29 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 22.7,
27.0, 38.9, 48.8, 50.5, 61.8, 70.9, 103.1, 111.2, 113.2, 119.2, 121.5,
124.6, 125.5, 127.3, 128.1, 128.5, 129.0, 135.6, 138.1, 139.0, 150.7,
177.7; IR (DCM) ν 3409, 3239, 2973, 2931, 1735, 1444, 1276, 1126,
1110, 1029, 966 cm−1; HRMS (ESI-TOF) calcd for C27H31N4O2 [M +
H]+ m/z 443.2442, found 443.2441.
(6-Benzyl-3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-
1H-pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (17). Using
Method A; the reaction was heated to 80 °C for 2 h. Isolated 17
(267 mg, 66%) as a white solid.
Using Method B; from 6 (520 mg, 1.09 mmol), XPhos precatalyst
18 (68.8 mg, 0.09 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-
(6-Benzyl-3-(thiophen-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo-
[3,4-c]pyridin-1-yl)methyl Pivalate (23). Using Method B; XPhos
precatalyst 18 (35 mg, 8 mol %). The reaction was stirred at rt for 20
min and isolated 23 as a white solid, mp 134.1−135.7 °C (200 mg,
1
89%). H NMR (400 MHz, CDCl3) δ 1.15 (s, 9H), 2.71−2.88 (m,
4H), 3.63 (s, 2H), 3.77 (s, 2H), 5.88 (s, 2H), 7.27−7.42 (m, 6H),
7686
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The Journal of Organic Chemistry
Note
7.47−7.55 (m, 2H); 13C NMR (101 MHz, CDCl3) 22.2, 26.9, 38.9,
48.7, 50.2, 61.7, 70.8, 113.3, 121.4, 125.6, 126.4, 127.4, 128.5, 129.0,
134.7, 138.2, 139.0, 177.5; IR (DCM) ν 2972, 2802, 1736, 1462, 1277,
1126, 1034, 964 cm−1; HRMS (ESI-TOF) calcd for C23H28N3O2S
410.1897 [M + H]+ m/z, found 410.1898.
CDCl3) δ 1.21 (s, 9H), 2.55 (t, J = 4.8, Hz, 2H), 3.03 (t, J = 5.7 Hz,
2H), 4.04 (s, 2H), 5.93 (s, 2H), 6.99 (td, J = 6.5, 9.8 Hz, 1H), 7.46
(ddd, J = 6.7, 8.9, 10.7 Hz, 1H); 13C NMR (176 MHz, CDCl3) δ 18.8
(d, J = 9.86 Hz), 26.9, 38.8, 39.7, 41.7, 70.1, 106.0 (dd, J = 20.9, 28.4
Hz), 113.1, 116.5 (dt, J = 5.6, 16.9 Hz), 118.4 (dd, J = 5.0, 20.1 Hz),
132.7, 144.5, 147.0 (ddd, J = 3.1, 12.8, 246 Hz), 150.4 (dt, J = 13.5,
254 Hz), 154.9 (dd, J = 8.4, 248. Hz), 177.9; IR (DCM) ν 2974, 2935,
1738, 1531, 1468, 1279, 1182, 1134, 1034, 966, 843 cm−1; HRMS
(ESI-TOF) calcd for C18H21F3N3O2 368.1581 [M + H]+ m/z, found
368.1581.
(6-Benzyl-3-(4-formylphenyl)-4,5,6,7-tetrahydro-1H-
pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (24). Using Method
B; XPhos precatalyst 18 (35 mg, 8 mol %). The reaction was stirred at
1
40 °C for 8 h and isolated 24 as an orange gum (177 mg, 75%). H
NMR (400 MHz, CDCl3) δ 1.16 (s, 9H), 2.79−2.89 (m, 4H), 3.66 (s,
2H), 3.78 (s, 2H), 5.91 (s, 2H), 7.28−7.44 (m, 5H), 7.84−7.98 (m,
4H), 10.02 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 22.8, 27.0, 38.9,
48.7, 50.3, 61.8, 70.8, 114.3, 127.0, 127.5, 128.5, 129.0, 130.1, 135.4,
137.9, 139.6, 139.7, 147.9, 177.5, 191.9; IR (DCM) ν 2970, 2931,
2870, 1738, 1700, 1608, 1277, 1211, 1127, 1034, 966 cm−1; HRMS
(ESI-TOF) calcd for C26H30N3O3 432.2282 [M + H]+ m/z, found
432.2286.
6-Methyl-3-(2,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-1H-
pyrazolo[3,4-c]pyridine (29). Formaldehyde (37 wt % solution in
water) (0.262 mL, 3.22 mmol) was added to a stirred solution of 28
(296 mg, 0.81 mmol) in DCM (10 mL) and MeOH (1 mL) at rt.
After 15 min, sodium triacetoxyborohydride (426 mg, 2.01 mmol) was
added, and the mixture was stirred at rt for 1 h, diluted with DCM (50
mL), and washed with saturated NaHCO3 (50 mL). The aqueous
layer was reextracted with DCM (2 × 75 mL), and the organic extracts
were combined, dried over MgSO4, filtered, and evaporated to afford a
pale orange gum (276 mg, 90%). This was dissolved in MeOH (5
mL), and 2 N NaOH (2.2 mL, 4.01 mmol) was added. The resulting
solution was stirred at rt for 2 h. The reaction mixture was
concentrated, diluted with EtOAc (20 mL), and washed with water
(5 mL), and saturated NH4Cl (15 mL). The organic layer was
evaporated, and the residue was purified by ion exchange
chromatography, using an SCX column (1 M NH3/MeOH) to give
(3-(1-Methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-1H-
pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (25). A mixture of
10% palladium on charcoal (13.32 mg) and 17 (340 mg, 0.83 mmol)
in EtOH (10 mL) was stirred under an atmosphere of hydrogen at rt
for 17 h. The reaction mixture was filtered through Celite, the filtrate
was evaporated, and the residue was purified by silica gel
chromatography (0−5% MeOH in DCM) to give 25 as a white
solid, mp 105 °C (216 mg, 82%). 1H NMR (400 MHz, CDCl3) δ 1.19
(s, 9H), 2.64 (t, J = 5.7 Hz, 2H), 3.08 (t, J = 5.7 Hz, 2H), 3.93 (s, 3H),
3.99 (s, 2H), 5.89 (s, 2H), 7.69 (s, 1H), 7.79 (d, J = 0.57 Hz, 1H); 13C
NMR (101 MHz, CDCl3) δ 23.0, 27.0, 38.9, 39.0, 41.8, 43.4, 70.5,
113.0, 115.6, 127.6, 137.3, 139.4, 143.7, 177.7; IR (DCM) ν 3415,
3319, 2973, 2933, 1731, 1600, 1276, 1130 cm−1; HRMS (ESI-TOF)
calcd for C16H24N5O2 318.1930 [M + H]+ m/z, found 318.1928.
(6-Benzoyl-3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-
1H-pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (26). A solution
of benzoyl chloride (0.072 mL, 0.62 mmol) in DCM (2 mL) was
added to a solution of 25 (187 mg, 0.59 mmol) and Et3N (0.090 mL,
0.65 mmol) in DCM (5 mL) at 0 °C under nitrogen. The resulting
solution was allowed to warm to rt over 1 h, concentrated, and purified
by silica gel chromatography (10−50% EtOAc in heptane) to give 26
as a colorless gum (233 mg, 94%). 1H NMR (500 MHz, DMSO at 373
K) δ 1.11 (9H, s), 2.69 (2H, t), 3.69 (2H, t), 3.86 (3H, s), 4.77 (2H,
s), 5.93 (2H, s), 7.41−7.51 (5H, m), 7.66 (1H, d), 7.89 (1H, s); 13C
NMR (126 MHz, DMSO) δ 20.9, 26.0, 37.7, 37.8, 70.2, 111.9, 114.0,
126.1, 127.5, 127.8, 129.0, 135.6, 135.7, 136.4, 142.2, 169.6, 175.9, two
carbons obscurred by DMSO); IR (DCM) ν 2975, 2935, 2871, 1735,
1635, 1600, 1430, 1294, 1122 cm−1; HRMS (ESI-TOF) calcd for
C23H28N5O3 422.2187 [M + H]+ m/z, found 422.2187.
1
29 as a orange gum (183 mg, 85%). H NMR (400 MHz, CDCl3) δ
2.52 (s, 3H), 2.67−2.76 (m, 2H), 2.79 (t, J = 5.6, 5.6 Hz, 2H), 3.60 (s,
2H), 7.04 (td, J = 10.2, 10.1, 6.6 Hz, 1H), 7.38 (ddd, J = 10.7, 8.6, 6.8
Hz, 1H), 10.27 (s, 1H); 13C NMR (176 MHz, DMSO) δ 21.2 (d, J =
7.0 Hz), 45.2, 52.5, 106.5 dd, J = 28.2, 22.8 Hz), 111.7, 117.3 (d, J =
15.8 Hz), 146.1 (dd, J = 242, 8.8 Hz), 148.6 (dd, J = 248, 14.1 Hz),
154.0 (d, J = 256 Hz), IR (DCM) ν 2943, 2926, 2852, 2795, 1527,
1472, 1190, 1084, 881, 820 cm−1; HRMS (ESI-TOF) calcd for
C13H13F3N3 268.1056 [M + H]+ m/z, found 268.1057.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for all synthesized compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: paul.kemmitt@astrazeneca.com. Phone: +44(0) 1625
233250.
■
(3-(1-Methyl-1H-pyrazol-4-yl)-4,5-dihydro-1H-pyrazolo[3,4-
c]pyridin-6(7H)-yl)(phenyl)methanone (27). 2 N NaOH (2.2 mL,
4.01 mmol) was added to a solution of 26 (128 mg, 0.30 mmol) in
MeOH (5 mL), and the solution was stirred at rt for 2 h. The reaction
mixture was concentrated, diluted with EtOAc (20 mL), and washed
with water (5 mL) and saturated NH4Cl (15 mL). The organic layer
was evaporated, and the residue was purified by preparative HPLC
(Waters XBridge Prep C18 OBD column, 5 μ silica, 50 mm diameter,
100 mm length, 5−95% H2O/1% NH3 to MeCN) to give 27 as a pale
Notes
The authors declare no competing financial interest.
REFERENCES
■
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1
yellow gum (85 mg, 91%). H NMR (500 MHz, DMSO at 373 K) δ
2.70 (t, J = 5.8 Hz, 2H), 3.72 (t, J = 5.3 Hz, 2H), 3.87 (s, 3H), 4.62 (s,
2H), 7.39−7.5 (m, 5H), 7.69 (s, 1H), 7.88 (s, 1H), 12.36 (s, 1H); 13C
NMR (126 MHz, DMSO at 373 K) δ 20.8, 37.9, 42.1, 43.0, 108.3,
112.1, 126.1, 126.9, 127.8, 128.9, 133.9, 135.4, 135.9, 142.9, 169.4; IR
(DCM) ν 3211, 2929, 1625, 1436 cm−1; HRMS (ESI-TOF) calcd for
C17H18N5O 308.1511 [M + H]+ m/z, found 308.1510.
(2) Mantegani, S.; Brasca, M. G.; Casuscelli, F.; Ferguson, R.; Posteri,
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(3-(2,4,5-Trifluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo-
[3,4-c]pyridin-1-yl)methyl Pivalate (28). ACE-Cl (0.052 mL, 0.48
mmol) was added to a stirred solution of 19 (253 mg, 0.55 mmol) in
DCM (10 mL), and the solution was stirred at rt for 1 h. MeOH (10
mL) was added, and the solution was stirred at rt for 17 h. The
reaction mixture was evaporated, and the residue was purified by silica
gel chromatography (0−10% MeOH in DCM) to give 28 as a pale
1
yellow solid, mp 93.7−95.7 °C (176 mg, 87%). H NMR (400 MHz,
7687
dx.doi.org/10.1021/jo5012015 | J. Org. Chem. 2014, 79, 7682−7688

The Journal of Organic Chemistry
Note
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(9) 5-Chloro-2,4-dimethoxyphenyl)boronic acid was prepared as
follows: butyllithium (3.60 mL, 5.76 mmol) was added to a solution of
1-bromo-5-chloro-2,4-dimethoxybenzene10 (1.38 g, 5.49 mmol) in
THF (30 mL) at −70 °C, under nitrogen; after 5 min, trimethyl borate
(0.612 mL, 5.49 mmol) was added dropwise and the resulting solution
was stirred at −70 °C for a further 30 min. The reaction mixture was
quenched with 2 M HCl (10 mL) and extracted into EtOAc (75 mL),
and the organic layer was washed with water (50 mL) and saturated
brine (50 mL), dried over MgSO4, filtered, and evaporated to afford a
solid that was triturated with ether, filtered, and dried under vacuum to
give (5-chloro-2,4-dimethoxyphenyl)boronic acid as a white solid, mp
1
134−136 °C (656 mg, 55%). H NMR (400 MHz, DMSO) 3.88 (s,
3H), 3.92 (s, 3H), 6.74 (s, 1H), 7.53 (s, 1H), 7.57 (s, 2H); 13C NMR
(101 MHz, DMSO) 55.9, 56.1, 96.9, 112.3, 135.9, 157.1, 164.1, C-B
not seen; GCMS (EI) m/z [M − HBO2] calcd for C8H9ClO2
172.0291; found 172.0297.
(10) Yang, Y.; Escobedo, J. O.; Wong, A.; Schowalter, C. M.; Touchy,
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Chem. 2005, 70, 6907.
7688
dx.doi.org/10.1021/jo5012015 | J. Org. Chem. 2014, 79, 7682−7688