Synthesis of 7-oxo-dihydrospiro[indazole-5,4′-piperidine] acetyl-CoA carboxylase inhibitors

Article abstract of DOI:10.1021/jo202377g

Synthesis of oxo-dihydrospiroindazole-based acetyl-CoA carboxylase (ACC) inhibitors is reported. The dihydrospiroindazoles were assembled in a regioselective manner in six steps from substituted hydrazines and protected 4-formylpiperidine. Enhanced regios

Full text of DOI:10.1021/jo202377g

Article
pubs.acs.org/joc
Synthesis of 7-Oxo-dihydrospiro[indazole-5,4′-piperidine] Acetyl-
CoA Carboxylase Inhibitors
Scott W. Bagley,* James A. Southers, Shawn Cabral, Colin R. Rose, David J. Bernhardson,
David J. Edmonds, Jana Polivkova, Xiaojing Yang, Daniel W. Kung, David A. Griffith, and Scott J. Bader
Pfizer Worldwide Research & Development, Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: Synthesis of oxo-dihydrospiroindazole-based acetyl-CoA carboxylase (ACC) inhibitors is reported. The
dihydrospiroindazoles were assembled in a regioselective manner in six steps from substituted hydrazines and protected 4-
formylpiperidine. Enhanced regioselectivity in the condensation between a keto enamine and substituted hydrazines was
observed when using toluene as the solvent, leading to selective formation of 1-substituted spiroindazoles. The 2-substituted
spiroindazoles were formed selectively from alkyl hydrazones by ring closure with Vilsmeier reagent. The key step in the
elaboration to the final products is the conversion of an intermediate olefin to the desired ketone through elimination of HBr
from an O-methyl bromohydrin. This methodology enabled the synthesis of each desired regioisomer on 50−75 g scale with
minimal purification. Acylation of the resultant spirocyclic amines provided potent ACC inhibitors.
INTRODUCTION
■
Metabolic perturbations leading to hepatic and intramyocellular
lipid accumulation have been hypothesized to contribute to the
molecular pathogenesis of insulin resistance and type 2 diabetes
mellitus (T2DM).1 Acetyl-CoA carboxylase (ACC), a central
regulator of lipid metabolism, catalyzes the conversion of
acetyl-CoA to malonyl-CoA. Malonyl-CoA is an essential and
rate limiting substrate for the de novo synthesis of fatty acids.2
Furthermore, malonyl-CoA acts to control fatty acid oxidation
through allosteric inhibition of carnitine palmitoyltransferase 1,
which is responsible for movement of long chain fatty acyl-
Figure 1. Examples of Pfizer ACC inhibitors.
CoAs into the mitochondria for β-oxidation. Consequently,
inhibition of ACC is expected to simultaneously block de novo
ACC inhibitors, we were interested in preparing oxo-
lipogenesis and promote fatty acid oxidation. As a result,
dihydrospiroindazoles in which the ether linkage in 3 would
inhibition of ACC may offer a promising avenue for T2DM
be replaced by a methylene, obviating the retro-Michael ring-
treatment by reducing ectopic lipid accumulation and
opening. We also wished to incorporate regioselective synthetic
consequently improving insulin sensitization.3 Pfizer has been
routes to explore substitution at N1 and N2 of the pyrazole
pursuing ACC inhibitors (Figure 1) starting with a series of bis-
piperidine compounds, exemplified by CP-640186 (1),3 and
(indazole numbering), resulting in compounds of type A and B
spirochromanones such as 2.4,5 Most recently, the pyrazole
(Figure 2).
Retrosynthetic Analysis to N1 Alkyl Compounds. We
considered several possible routes to form the oxo-dihydrospir-
oindazole core and reasoned that a late-stage formation of the
spiropyranone (3) has been identified as a potent inhibitor of
ACC.6 The chromanone-like spirocyclic core of 3 is synthesized
through an efficient sequence of condensation reactions (via 4
and 5, Scheme 1).7 However, pyrazoles with alkyl substitution
central ketone ring, as used previously in the synthesis of 3,
would not be feasible.4 In addition, the SAR of 3 indicated that
on the isomeric nitrogen were not readily accessed through this
sequence and the SAR of that region of the molecule was left
unexplored. In addition, compound 3 is prone to a base-
bulky N-substituents would be preferred; therefore, routes
relying on alkylation were initially discounted in favor of
mediated retro-Michael type ring-opening reaction and
subsequent olefin migration resulting in the presumed open-
chain isomer 6. As part of our continued investigation into
Received: November 17, 2011
Published: January 12, 2012
© 2012 American Chemical Society
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a
Scheme 1. Retro-Michael Fate of 3 and Presumed Olefin
Isomer
Scheme 3. Synthesis of Key Olefin Intermediates
a
Reaction conditions: (a) MVK, PhCH3, 110 °C, p-TSA, Dean−Stark,
84%; (b) HC(NMe2)3 PhCH3, 110 °C, quant; (c) R-NHNH2.HCl,
AcOH, EtOH, 90 °C, see Table 1 for yields.
EtOH)8 using benzyl 4-formylpiperidine-1-carboxylate (12)
and MVK produced enone 13 in only modest yield; however,
use of p-TSA catalyzed acidic conditions with azeotropic
removal of water produced 13 in high yield (84%).9 Reaction of
13 with dimethylformamide dimethyl acetal (DMF-DMA) neat
or in solution (DMF or PhCH3) was unsuccessful; however,
the more reactive reagent tris(dimethylamino)methane10
(TDAM, 2 equiv) in refluxing PhCH3 gave enamine 14 in
quantitative yield. Formation of enamine 14 from enone 13 was
also successful with Bredereck’s reagent (t-butoxy bis-
(dimethylamino)methane) as the activated dimethylformamide
source.11
Figure 2. Desired regioisomeric pyrazole substitution.
regioselective condensation reactions using substituted hydra-
zines. Our retrosynthetic analysis to N1 alkyl compounds is
shown in Scheme 2, where analogs of 3, such as 7, would be
accessed from spiroketone 8 via deprotection of the amine and
a standard amide coupling. We believed that 8 could be
accessed from olefin 9, which was regarded as a key
intermediate because the expected steric and electronic
differentiation of the olefin carbons would allow for multiple
methods for the olefin to ketone transformation to be explored.
Achieving N1 Regioselective Condensation. Establish-
ing high levels of regioselectivity in the condensation of alkyl
hydrazines with enamine 14 was expected to be the key
determinant of success for this synthetic plan. The
condensation of 14 with various substituted hydrazine
hydrochlorides was first examined in refluxing EtOH in
presence of 2 equiv of AcOH.12 The observed regioselectivity
favoring the N1 alkyl isomer 15 over the N2 alkyl isomer 16
increased with the steric bulk of the alkyl group (Table 1),
varying from a ratio of 1.2:1 (15b/16b) with methyl hydrazine
hydrochloride to >50:1 (15e/16e) with t-butyl hydrazine
hydrochloride (t-BuNHNH2·HCl). This observed selectivity
was consistent with literature reports13 and confirmed by NOE
experiments. Under these conditions, phenyl hydrazine hydro-
chloride also showed high selectivity for 15f in 86% yield. Using
i-propyl hydrazine hydrochloride (i-PrNHNH2·HCl) alternate
conditions were investigated to obtain higher regioselectivity
(Table 1). Heating 14 and i-PrNHNH2·HCl in EtOH in the
presence of 2 equiv of AcOH resulted in a ratio of 11:1 15d/
16d (entry 4). Heating in EtOH without AcOH did not affect
the regioselectivity, returning a ratio of 11:1 (entry 7).
Switching the solvent to PhCH3 with 2 equiv of AcOH
improved the selectivity to 22:1 15d/16d (entry 8) while
refluxing in PhCH3 alone without AcOH raised the level of
selectivity to >30:1 15d/16d (entry 9). We were pleased to
note an improvement in the regioselectivity of the con-
densation between methyl hydrazine hydrochloride and
enamine 14 by 6-fold from 1.2:1 (entry 2) to 7:1 ratio of
15b/16b (entry 10) by heating in PhCH3 at reflux. At no time
did we observe 1,4-addition to the enone with any of the alkyl
hydrazines.
Scheme 2. Retrosynthesis of N1 Substituted Oxo-
dihydrospiroindazoles
Olefin 9 would be derived from condensation of substituted
hydrazines with enamine 10. A logical precursor to 10 was
spiroenone 11, which could be obtained via Robinson
annulation of a protected 4-formylpiperidine with methyl
vinyl ketone (MVK).5
RESULTS AND DISCUSSION
The synthesis of key olefin intermediate 15 is depicted in
Scheme 3. Robinson annulation under basic conditions (KOH,
■
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Table 1. Substituent and Solvent Effects on Regiochemistry
a
b
c
entry
compound
R
solvent
AcOH (equiv)
yield of 15/16 mixture (%)
ratio of 15/16
C7 ppm (15/16)
1
2
15a
H
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
PhCH3
PhCH3
PhCH3
2
87
89
58
77
79
86
63
74
86
62
−
6.59
15b/16b
15c/16c
15d/16d
15e/16e
15f/16f
15d/16d
15d/16d
15d/16d
15b/16b
Me
2
1.2:1
3.5:1
11:1
>50:1
>30:1
11:1
22:1
>30:1
7:1
6.38/6.54
6.39/6.53
6.43/6.57
6.68/6.57
6.53/6.66
6.43/6.57
6.43/6.57
6.43/6.57
d
3
Et
2
4
i-Pr
t-Bu
Ph
2
5
2
6
2
7
i-Pr
i-Pr
i-Pr
Me
−
2
8
9
−
−
10
6.38/6.54
a
b
Typical reaction conditions (General method A): 1 equiv of 14, 1.4 equiv of alkyl hydrazine HCl, 2 equiv of AcOH, EtOH, 2−18 h, reflux. Ratio
determined by NMR. Shift (in ppm) of diagnostic doublet signal from olefin proton at C7. Ethyl hydrazine oxalate salt used in place of
hydrochloride salt.
c
d
Selective N2 Alkyl Pyrazole Synthesis. With a method to
prepare N1 substituted 1,4-dihydrospiroindazoles in hand, we
turned our attention to the regioselective synthesis of the N2
substituted analogs. The N2 t-butyl derivative was targeted as a
direct comparison with compound 3 to evaluate the effect of
changing the ring oxygen to methylene. We hypothesized that
the same key spiroenone 13 could be utilized to access the
desired N2 derivatives by condensing with an alkyl hydrazine
first, creating a hydrazone, and attempting to close the pyrazole
ring with a formic acid equivalent, effectively reversing the
synthetic route used to prepare the N1 isomers. Condensation
of the spiroenone 13 with t-BuNHNH2·HCl in refluxing EtOH
provided hydrazone 17 in 70% yield. Installation of the
pyrazole carbon atom was attempted with DMF-DMA,14
TDAM and HC(OEt)3 but attempts to cyclize to the pyrazole
16e were unsuccessful and returned starting hydrazone.
Inspired by a literature report from Prasad,15 who reported
that an α-unsubstituted hydrazone can be condensed with
Vilsmeier reagent to produce a pyrazole ring, we successfully
reacted 17 with 3 equiv of Vilsmeier reagent (freshly prepared
from POCl3 in DMF at 0 °C) at 80 °C to deliver the desired
16e in 65% yield (Scheme 4). We now had developed two
proved inert to various hydroboration/oxidation conditions
(borane−THF,17 9-BBN18 and Pd-catalyzed catecholborane19).
Interestingly, Moorthy20 reported that an olefin could be
converted directly to an α-bromoketone by reaction with N-
bromosuccinimide (NBS) in the presence of DMSO and IBX;
however, when applied to 15d, the major product from this one
pot reaction was racemic trans-bromohydrin 18 (Scheme 5).
a
Scheme 5. Conversion of Olefin to Ketone
a
Scheme 4. Regioselective Formation of N2 t-Bu Pyrazole
a
Reaction conditions: (a) NBS, THF, H2O, rt; (b) Jones’ Reagent,
acetone, 0 °C; (c) Zn dust, THF, NH4Cl(aq), rt (61% for 3 steps); (d)
1-methyl-1,4-cyclohexadiene, 10% Pd/C (50% wet), 80 °C, then 1 N
HCl/Et2O, 95%.
Despite the lack of reactivity of 18 toward in situ oxidation by
IBX the regioselective formation of bromohydrin 18 offered a
very attractive way to access 20 through oxidation of olefin 15d.
Thus, treatment of 15d with 1 equiv of NBS in THF−water
(3:1) at room temperature provided 18 which was directly
oxidized with Jones’ reagent21 to furnish α-bromoketone 19.
Debromination with Zn dust in a biphasic mixture of THF/
aqueous NH4Cl (1:1) delivered spiroketone 20 in 61% yield
over 3 steps. This sequence from olefin 15d to spiroketone 20
(Scheme 5) was performed at room temperature, each reaction
taking no more than 1 h with purification necessary only after
the final debromination step. Protecting group removal under
transfer hydrogenation conditions (Pd/C, 1-methyl,1−4-cyclo-
hexadiene) followed by salt formation gave desired amine-HCl
a
Reaction conditions: (a) t-BuNHNH2·HCl, EtOH, reflux, 70%; (b)
POCl3, DMF 0 °C, then 17, 80 °C, 65%.
complementary synthetic routes designed to deliver either
pyrazole isomer in a regioselective manner.
Conversion of Olefin to Ketone. At this point the carbon
skeletons of both desired core structures were fully elaborated
and conversion of the olefin to the desired ketone was the
remaining functionalization to be completed. Initial attempts to
oxidize the N1-substituted olefin 15d directly to ketone 20 via
Wacker oxidation16 were unsuccessful. In addition, olefin 15d
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a
21 in 95% yield. This route could also be successfully applied to
the N2 alkyl regioisomer (e.g., 16e).
Scheme 6. Elimination Route to Ketone
Enabling Larger Scale Processes. While the conversion
of olefin to ketone was an efficient process using the three step
NBS/Jones oxidation/Zn reduction route, we wished to avoid
the hazards associated with the use of chromium-based
oxidation reagents. Identification of a viable alternative to the
Jones oxidation from 18 to 19 was not trivial, as many
traditional green oxidation methods such as TEMPO/NaOCl
returned 18. Stoichiometric reagents such as MnO2 and
activated sulfoxide processes such as Swern and Parikh-Doering
(pyridine-SO3) also proved ineffective. The only oxidation
process which proved successful was TPAP-NMO,22 giving
clean α-bromoketone 19 in less than 1 h at room temper-
ature.23 Notably, the use of acetonitrile as solvent was critical to
the success of this reaction. Even though we now had
developed a quick and effective alternative process for
converting the olefin 15d to ketone 20, the overall process
involved three redox reactions to achieve a net one oxidation
level change. Additionally, we were still producing Ru and Zn
waste, and although catalytic, TPAP can be expensive on a
larger scale. Thus, additional methods to convert the olefin 15d
to ketone 20 needed to be explored to develop a truly efficient
route. Particularly, we preferred to complete the conversion
from 15d to 20 with just a single oxidative step.
Capitalizing on the oxidation state of bromohydrin 18, we
hypothesized that base-promoted elimination of HBr from 18
could lead directly to the desired ketone 20. Usually, treatment
of a trans bromohydrin with a base strong enough to effect an
elimination reaction would deliver the epoxide24 instead of the
desired ketone 20. To avoid epoxide formation, we recognized
that we needed an O-alkyl bromohydrin.25 Utilizing the N2-
substituted olefin 16e, treatment with NBS in MeOH at room
temperature delivered the desired O-methyl bromohydrin 22
within minutes in 83% yield. Several conditions were screened
to promote the syn-elimination of HBr that would produce the
desired enol ether.26,27 It was found that treatment of 22 with
potassium tert-butoxide (2 equiv) in THF at room temperature
for 30 min gave enol ether 23 (not isolated), which upon
quenching with 2 N HCl produced ketone 24 in 88% yield over
two steps (Scheme 6a). Similar conditions were applied to N1
substituted olefins 15d and 15e. Interestingly, in a classic
demonstration of steric congestion, O-methyl bromohydrin 25a
required 18 h at room temperature or 1 h at 60 °C to complete
the elimination to the enol ether before the acidic workup
afforded 20, while 25b did not participate in the elimination
reaction even under prolonged heating in THF at reflux
(Scheme 6b).
a
Reaction conditions: (a) NBS, MeOH, PhCH3, rt, 86% (b) KOtBu,
THF, rt; (c) 2 N HCl, THF, rt, 88% over 2 steps; (d) 1-methyl-1,4-
cyclohexadiene, 10% Pd/C (50% wet), 80 °C, 95%; (e) 1H-indazole-
5-carboxylic acid, T3P, Et3N, DMF, rt, 72−75%; (f) (i) KOtBu, THF,
60 °C, 1 h or rt, 18 h; (ii) THF, 2 N HCl, rt, 89%.
This sequence also delivered high overall conversion with
water-soluble byproducts. Bypassing chromatography and
relying on aqueous workups allowed us to telescope the entire
route from spiroenone 29 to the desired HCl salt of amine 21
(Scheme 7). Spiroenone 29 was converted to the intermediate
enamine with TDAM in refluxing PhCH3 and, after only an
aqueous wash, taken directly into condensation with i-
PrNHNH2·HCl to form N1-substituted pyrazole olefin 30,
again purification required only an aqueous wash. Treatment of
compound 30 with NBS in MeOH delivered O-methyl
bromohydrin 31. Compound 31 was treated with potassium
tert-butoxide in THF at 60 °C for 1 h followed by treatment
with 1 N HCl, delivering the desired BOC-protected
spiroketone. Deprotection was effected by HCl in EtOAc
(AcCl/MeOH in EtOAc) and the HCl salt of 21 was collected
by filtration in 93% yield over five telescoped steps from BOC-
spiroenone 29 without chromatography on 50 g scale.
With amine 21 in hand in multigram quantities, we turned
our attention to N2 t-butyl amine 26. In this case, the use of
Vilsmeier reagent in the route to 26 prohibited the use of a
BOC group as protection for the amine, and we focused on
optimization of the route from CBZ-protected enone 13
(Schemes 3 and 5). On a large scale, the hydrazone 17 could be
isolated by filtration as its HCl salt. The hydrazone was free-
based and taken into the annulation reaction with freshly
prepared Vilsmeier reagent (POCl3/DMF). The crude olefin
Deprotection to amines 21 and 26 followed by amide
formation with 1H-indazole-5-carboxylic acid delivered the final
ACC inhibitors 27 and 28, respectively.28
At this point, we had efficient and practical routes to both
amines 21 and 26 with critical bond forming processes in five of
the total six steps from N-protected 4-formyl piperidine
through the amine deprotection. Our next step was to evaluate
each of these steps to maximize yields and practicality on larger
scale. For the synthesis of the N1 i-propyl-substituted amine 21,
we discovered that a switch to BOC protected spiroenone 2929
offered multiple improvements. The CBZ protected spiroenone
13, a thick, viscous oil, is difficult to handle whereas 29 is a free-
flowing solid. In addition, use of BOC as a protecting group
allows an acidic deprotection strategy, instead of a catalytic
hydrogenation, directly producing the desired amine HCl salt.
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a
Scheme 7. Scale up of 21
a
Reaction conditions: (a) HC(NMe2)3 PhCH3, 110 °C; (b) i-PrNHNH2·HCl, MeOH, PhCH3, 110 °C; (c) NBS, MeOH, PhCH3, rt; (d) (i) KOtBu,
THF 60 °C; (ii) 1 N HCl, rt; (e) AcCl, MeOH, EtOAc, 93% overall yield (5 steps).
16e was converted to O-methyl bromohydrin 22 and then to
the CBZ-protected spiroketone 24 through the previously
described elimination route, at which point the material was
subjected to chromatography. Spiroketone 24 was then
deprotected via catalytic transfer hydrogenation; subsequent
salt formation and recrystallization delivered 75 g of the pure
HCl salt of amine 26. Overall yield from enone 13 was 35%.
Alternate Method for Selective Pyrazole Alkylation. In
parallel with our efforts to develop routes to deliver the N1 and
N2 isomers with high regioselectivity, alkylation of the
unsubstituted pyrazole was also examined.30 We prepared
spiroketone 32 from olefin 15a via the NBS/Jones/Zn
reduction route (Scheme 6). Alkylation of ketone 32 with 2-
iodopropane in DMF with K2CO3 resulted in a 3.5:1 mixture of
N1 and N2 i-propyl pyrazoles 20 and 33. Alternatively,
Mitsunobu alkylation31 of spiroketone 32 with 2-propanol in
THF with diisopropylazadicarboxylate (DIAD) and triphenyl
phosphine (Ph3P) delivered exclusively N1-substituted ketone
20 in 91% yield (Scheme 8). We now had a second method
spiroindazoles and thus ACC inhibitors 27 and 28. A key
finding that enabled the development of a process friendly
scalable route was the use of NBS in MeOH to form an O-
methyl bromohydrin intermediate, which upon elimination/
enol ether hydrolysis allowed efficient access to a ketone
intermediate in high yield, thereby removing one full redox
cycle from the original synthetic route. This bromination/
elimination sequence provides an alternative to traditional
Wacker oxidation conditions without the need for metal
catalysis and an oxygen atmosphere. The routes developed
allowed synthesis of both amine 21 and amine 28 on a greater
than a50 g scale with minimal purification steps.
EXPERIMENTAL SECTION
■
General Experimental Details. Unless otherwise stated, all
reactants, reagents and solvents were obtained from commercial
sources and used without further purification. Data for 1H NMR
spectra are reported relative to residual solvent signals (for CDCl3, δH
= 7.27 ppm; for DMSO-d6, δH = 2.50 ppm) as follows: chemical shift
(δ ppm), multiplicity, coupling constant (Hz) and integration. The
multiplicities are denoted as follows: s, singlet; d, doublet; t, triplet; q,
quartet; spt, septet; m, multiplet; br s, broad singlet. Data for 13C
NMR spectra are reported in terms of chemical shift (δ ppm) relative
to residual solvent signals (for CDCl3, δH = 77.0 ppm; for DMSO-d6,
δH = 39.5 ppm). Flash chromatography was carried out on either a
Biotage SP purification system or a Combiflash Companion from
Teledyne Isco; Biotage SNAP, KPsil or Redisep Rf silica columns were
used. Except where otherwise noted, all reactions were run under an
inert atmosphere of nitrogen gas using anhydrous solvents at room
temperature (∼23 °C). The terms “concentrated” and “evaporated”
refer to the removal of solvent at reduced pressure on a rotary
evaporator with a water bath temperature not exceeding 60 °C.
Chloride ion determination was carried out by QTI, Whitehouse, NJ.
Benzyl 9-Oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate
(13). To a solution of benzyl 4-formylpiperidine-1-carboxylate (12)
(90 g, 363.9 mmol) in benzene (700 mL) in a 2 L 3 neck round-
bottom flask fitted with a Dean−Stark trap was added p-TSA
monohydrate (692 g, 36.4 mmol) and the mixture was heated to 70
°C. MVK (61.8 mL, 753 mmol) was added and the reaction mixture
was heated at reflux for 24 h collecting expelled water in the trap. The
reaction was cooled to ambient temperature and washed with
saturated NaHCO3(aq). The layers were separated and the organic
layer was dried over Na2SO4, filtered and concentrated. The resultant
dark-brown oil was purified by flash chromatography on silica gel,
eluting with a gradient of 0−100% EtOAc/heptane to afford 13 (91.7
g, 84%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.40−7.29 (m,
5H), 6.80 (d, J = 10.2 Hz, 1H), 5.96 (d, J = 10.2 Hz, 1H), 5.14 (s, 2H),
3.69−3.59 (m, 2H), 3.50 (ddd, J = 3.8, 8.3, 13.8 Hz, 2H), 2.51−2.41
(m, 2H), 1.97 (t, J = 6.8 Hz, 2H), 1.74−1.63 (m, 2H), 1.62−1.52 (m,
2H); 13C NMR (126 MHz, CDCl3) δ 198.9, 155.8, 155.2, 136.6,
128.5, 128.5, 128.0, 127.9, 67.2, 39.7, 34.8, 34.0, 33.4, 32.1; HR-MS
calcd for C18H21NO3 (m/z) [M + H]+ 300.1594, found 300.1594.
Benzyl 10-((Dimethylamino)methylene)-9-oxo-3-
azaspiro[5.5]undec-7-ene-3-carboxylate (14). To a solution of
compound 13 (15.2 g, 51 mmol) in PhCH3 (180 mL) was added
tris(dimethylamino)methane (22.2 g, 153 mmol). The mixture was
heated at reflux for 5 h and then allowed to cool to room temperature
a
Scheme 8. Selective Mitsunobu Alkylation at N1
a
Reaction conditions: (a) (i) NBS, THF, H2O, rt; (ii) Jones’ reagent,
acetone, 0 °C; (iii) Zn dust, THF, NH4Cl(aq), rt (58% for 3 steps); (b)
K2CO3, 2-iodopropane, DMF, rt, 65% of 3.5:1 isomeric mixture; (c) 2-
propanol, DIAD, Ph3P, THF, rt, 91%.
available for delivering selectively alkylated pyrazoles, one from
substituted hydrazines and another enabled for late stage
diversification.
CONCLUSION
■
We have described efficient and scalable routes to regiomeric
oxo-dihydro spiroindazoles 21 and 26 and their subsequent
conversion to 27 and 28 as ACC inhibitors. During this
exploration, we have shown a methodology to form alkyl
pyrazoles with complete regiocontrol. Selectivity in the
condensation between a keto-enamine and substituted
hydrazines was improved by use of PhCH3 as solvent, giving
nearly complete selectivity for the N1 isomer. The comple-
mentary N2 regioisomer was obtained by a reordering of the
synthetic steps and closing the pyrazole with Vilsmeier reagent.
These methods allowed us to access the desired oxo-dihydro
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overnight. The reaction solution was concentrated to provide 14 (18.0
g, >99%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.49 (s, 1H),
7.28−7.40 (m, 5H), 6.59 (d, J = 10.1 Hz, 1H), 6.01 (d, J = 10.1 Hz,
1H), 5.13 (s, 2H), 3.52−3.66 (m, 2H), 3.39−3.52 (m, 2H), 3.07 (s,
6H), 2.74 (s, 2H), 1.58−1.73 (m, 2H), 1.41−1.58 (m, 2H); 13C NMR
(126 MHz, CDCl3) δ 187.3, 155.6, 149.8, 149.6, 137.0, 130.8, 128.7,
128.2, 128.1, 99.9, 77.6, 77.3, 77.1, 67.3, 43.8, 40.4, 35.9, 35.4, 34.3;
HR-MS calcd for C21H26N2O3 (m/z) [M + H]+ 355.2016, found
355.2018.
pounds were prepared from compound 14 (1.18 g, 3.32 mmol) and
methyl hydrazine hydrochloride according to General Method A to
give a 1.2:1 mixture of 15b/16b (0.99 g, 89%).
1
15b. H NMR (400 MHz, CDCl3) δ 7.38−7.35 (m, 4H), 7.35−
7.30 (m, 1H), 7.27 (s, 1H), 6.38 (d, J = 10.0 Hz, 1H), 5.88 (d, J = 9.8
Hz, 1H), 5.14 (s, 2H), 3.82 (s, 3H), 3.61−3.54 (m, 2H), 3.53−3.45
(m, 2H), 2.63 (s, 2H), 1.71−1.59 (m, 2H), 1.57−1.47 (m, 2H); 13C
NMR (101 MHz, CDCl3) δ = 155.1, 137.0, 136.7, 136.5, 135.8, 128.3,
127.8, 127.7, 114.2, 113.2, 66.8, 39.7, 35.6, 35.1, 34.8, 30.7; HR-MS
calcd for C20H23N3O2 (m/z) [M + H]+ 338.1863, found 338.1861.
16b. 1H NMR (400 MHz, CDCl3) δ 7.42−7.29 (m, 5H), 6.54 (dd,
J = 0.6, 10.0 Hz, 1H), 5.90 (d, J = 10.0 Hz, 1H), 5.14 (s, 2H), 3.83 (s,
2H), 3.66−3.54 (m, 2H), 3.53−3.39 (m, 2H), 2.62 (s, 2H), 1.69−1.59
(m, 2H), 1.55−1.44 (m, 2H) 13C NMR (101 MHz, CDCl3) δ 155.1,
147.2, 136.7, 135.7, 128.2, 127.7, 127.6, 127.0, 119.6, 113.4, 66.7, 39.8,
38.4, 35.5, 34.3, 30.6; HR-MS calcd for C20H23N3O2 (m/z) [M + H]+
338.1863, found 338.1863.
Benzyl 1,4-Dihydrospiro[indazole-5,4′-piperidine]-1′-car-
boxylate (15a). To a solution of compound 14 (9.13 g, 26.3
mmol) in EtOH (150 mL) was added hydrazine hydrate (1.53 mL,
31.5 mmol) and AcOH (1.50 mL, 26.3 mmol). The mixture was
heated for 2 h at reflux then cooled to ambient temperature,
concentrated and partitioned between EtOAc and water. The aqueous
phase was extracted with additional EtOAc. The combined organic
layers were washed with saturated NaHCO3(aq) and brine, dried over
Na2SO4, filtered and concentrated. The crude material was purified by
flash chromatography (100 g silica gel, 25−100% EtOAc/heptane
Alternate preparation of 15b and 16b: Compound 14 (419 mg, 1.18
mmol) was treated with methyl hydrazine hydrochloride according to
General Method B to yield a 7:1 mixture of compounds 15b and 16b
(247 mg, 62%).
1
gradient) to yield 15a (7.42 g, 87%) as a pale-yellow foam. H NMR
(400 MHz, CDCl3) δ 8.32 (br s, 1H), 7.40−7.30 (m, 5H), 7.28 (s,
1H), 6.58 (d, J = 10.0 Hz, 1H), 5.97 (d, J = 10.0 Hz, 1H), 5.15 (s, 2H),
3.64−3.54 (m, 2H), 3.53−3.43 (m, 2H), 2.65 (s, 2H), 1.69−1.58 (m,
2H), 1.56−1.44 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 155.3,
146.0, 137.2, 136.8, 128.4, 127.9, 127.8, 126.9, 118.8, 113.0, 67.0, 39.9,
Benzyl 1-ethyl-1,4-dihydrospiro[indazole-5,4′-piperidine]-
1′-carboxylate (15c) and benzyl 2-ethyl-2,4-dihydrospiro-
[indazole-5,4′-piperidine]-1′-carboxylate (16c). The title com-
pounds were prepared from compound 14 (1.18 g, 3.32 mmol) and
ethyl hydrazine oxalate (300 mg, 4.99 mmol) according to General
Method A to give a 3.5:1 mixture of 15c/16c (675 mg, 58%).
+
35.6, 34.8, 30; HR-MS calcd for C19H21N3O2 (m/z) [M + H]
324.1712, found 324.1711.
1
15c. H NMR (400 MHz, CDCl3) δ 7.41−7.29 (m, 5H), 7.23 (s,
Benzyl 1-Isopropyl-1,4-dihydrospiro[indazole-5,4′-piperi-
dine]-1′-carboxylate (15d) and Benzyl 2-Isopropyl-1,4-
dihydrospiro[indazole-5,4′-piperidine]-1′-carboxylate
(16d). General Method A. To a solution of compound 14 (1.18 g,
3.32 mmol) in EtOH (10 mL) was added AcOH (0.42 mL, 7.30
mmol) and i-PrNHNH2·HCl (535 mg, 4.84 mmol). The reaction was
heated at reflux for 18 h. The reaction was cooled to room
temperature, diluted with EtOAc and washed with 0.5 N citric acid,
water and brine. The combined organic layers were dried over
Na2SO4, filtered, and concentrated to obtain crude material, which was
purified by flash chromatography (10−80% EtOAc/heptane gradient,
50 g silica) to yield 930 mg (77%) of an 11:1 mixture of 15d and 16d.
For purposes of obtaining spectral data, the compounds were
separated by preparative HPLC (250 × 21.2 mm 5 μ Phenomenex
Cellulose-2, 5−100% EtOH/heptane gradient).
1H), 6.39 (dd, J = 0.6, 10.0 Hz, 1H), 5.85 (d, J = 10.0 Hz, 1H), 5.14 (s,
2H), 4.11 (q, J = 7.3 Hz, 2H), 3.67−3.40 (m, 4H), 2.63 (s, 2H), 1.68−
1.58 (m, 2H), 1.58−1.48 (m, 2H), 1.42 (t, J = 7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 155.6, 137.1, 136.7, 136.2, 128.7, 128.2, 128.1,
114.6, 113.6, 77.6, 77.2, 76.9, 67.3, 44.2, 40.1, 35.6, 35.2, 31.1, 16.0;
HR-MS calcd for C21H25N3O2 (m/z) [M + H]+ 352.2020, found
352.2020.
16c. 1H NMR (400 MHz, CDCl3) δ 7.40−7.27 (m, 5H), 7.05 (d, J
= 0.6 Hz, 1H), 6.53 (dd, J = 10.0, 0.6 Hz, 1H), 5.87 (d, J = 10.0 Hz,
1H), 5.12 (s, 2H), 4.07 (q, J = 7.3 Hz, 2H), 3.56 (dd, J = 6.7, 4.2 Hz,
2H), 3.50−3.36 (m, 2H), 2.58 (s, 2H), 1.66−1.58 (m, 2H), 1.48 (d, J
= 7.2 Hz, 2H), 1.44 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 155.6, 147.5, 137.1, 136.0, 128.7, 128.2, 128.0, 125.8, 120.1, 113.5,
77.6, 77.3, 76.9, 67.2, 47.0, 40.2, 34.8, 31.1, 15.9; HR-MS calcd for
C21H25N3O2 (m/z) [M + H]+ 352.2020, found 352.2022.
1
15d. H NMR (400 MHz, CDCl3) δ 7.38−7.29 (m, 5H), 7.25 (s,
1H), 6.43 (dd, J = 0.6, 10.0 Hz, 1H), 5.84 (d, J = 10.1 Hz, 1H), 5.14 (s,
2H), 4.47 (spt, J = 6.6 Hz, 1H), 3.62−3.45 (m, 4H), 2.62 (s, 2H),
1.68−1.59 (m, 2H), 1.57−1.51 (m, 2H), 1.49 (d, J = 6.8 Hz, 6H); 13C
NMR (100 MHz, CDCl3) δ 155.6, 137.1, 136.5, 136.0, 135.8, 128.7,
128.2, 128.1, 114.8, 113.5, 67.2, 50.6, 40.2, 35.6, 35.3, 31.0, 22.8; HR-
MS calcd for C22H27N3O2 (m/z) [M + H]+ 366.2176, found 366.2181.
Benzyl 1-Tert-butyl-1,4-dihydrospiro[indazole-5,4′-piperi-
dine]-1′-carboxylate (15e). The title compound was prepared
from compound 14 (442 mg, 1.25 mmol) and tert-butyl hydrazine
hydrochloride (218 mg, 1.75 mmol) according to General Method A
to give a > 50:1 mixture of 15e/16e (376 mg, 79%).
1H NMR (500 MHz, CDCl3) δ 7.39−7.35 (m, 4H), 7.33 (td, J =
8.7, 4.5 Hz, 1H), 7.21 (s, 1H), 6.68 (d, J = 10.2 Hz, 1H), 5.80 (d, J =
10.0 Hz, 1H), 5.14 (s, 2H), 3.62−3.53 (m, 2H), 3.52−3.44 (m, 2H),
2.60 (s, 2H), 1.64−1.60 (m, 11H), 1.55−1.49 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 155.3, 136.8, 135.5, 135.3, 134.3, 128.4, 127.9,
127.8, 117.3, 115.3, 67.0, 59.4, 40.0, 35.2, 34.3, 30.9, 30.3; HR-MS
calcd for C23H29N3O2 (m/z) [M + H]+ 380.2333, found 380.2338.
Benzyl 1-Phenyl-1,4-dihydrospiro[indazole-5,4′-piperidine]-
1′-carboxylate (15f). The title compound was prepared from
compound 14 (424 mg, 1.20 mmol) and phenyl hydrazine
hydrochloride (242 mg, 1.67 mmol) according to General Method
A to give 15f (412 mg, 86%). 16f could not be isolated as a pure
compound. 1H NMR (500 MHz, CDCl3) δ 7.55−7.45 (m, 5H), 7.40−
7.30 (m, 6H), 6.54 (d, J = 10.0 Hz, 1H), 5.92 (d, J = 10.0 Hz, 1H),
5.16 (s, 2H), 3.69−3.59 (m, 2H), 3.56−3.46 (m, 2H), 2.71 (s, 2H),
1.69 (br s, 2H), 1.59 (br s, 2H); 13C NMR (126 MHz, CDCl3) δ
155.3, 139.5, 138.1, 137.0, 136.8, 136.5, 129.2, 128.5, 128.0, 127.9,
127.1, 123.3, 115.7, 115.3, 67.1, 39.9, 35.4, 34.7, 31.0 HR-MS calcd for
C25H25N3O2 (m/z) [M + H]+ 400.2020, found 400.2022.
1
16d. H NMR (400 MHz, CDCl3) δ 7.41−7.28 (m, 5H), 7.10 (s,
1H), 6.57 (d, J = 10.0 Hz, 1H), 5.89 (d, J = 10.0 Hz, 1H), 5.14 (s, 2H),
4.41 (spt, J = 6.7 Hz, 1H), 3.65−3.55 (m, 2H), 3.52−3.42 (m, 2H),
2.60 (s, 2H), 1.72−1.61 (m, 2H), 1.53−1.51 (m, 2H), 1.49 (d, J = 6.8
Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 155.3, 146.7, 136.9, 135.6,
128.4, 127.9, 127.8, 123.6, 119.9, 112.9, 67.0, 53.4, 40.0, 35.7, 34.5,
30.9, 23.0, 22.9; HR-MS calcd for C22H27N3O2 (m/z) [M + H]+
366.2176, found 366.2183.
Alternate Condition 1. Compound 14 (442 mg, 1.25 mmol) was
treated according to General Method A, omitting AcOH to deliver an
11:1 mixture of compounds 15d and 16d (289 mg, 63%).
Alternate Condition 2. Compound 14 (442 mg, 1.25 mmol) was
treated according to General Method A, with PhCH3 as solvent to
deliver a 22:1 mixture of compounds 15d and 16d (338 mg, 74%).
General Method B. Compound 14 (442 mg, 1.25 mmol) was
treated according to General Method A, with PhCH3 (without AcOH)
as solvent to deliver a > 30:1 mixture of compounds 15d and 16d (394
mg, 86%).
Benzyl 2-Tert-butyl-2,4-dihydrospiro[indazole-5,4′-piperi-
dine]-1′-carboxylate (16e). Compound 13 (3.40 g, 11.4 mmol)
was dissolved in EtOH (30 mL) and tert-butylhydrazine hydrochloride
Benzyl 1-Methyl-1,4-dihydrospiro[indazole-5,4′-piperidine]-
1′-carboxylate (15b) and Benzyl 2-Methyl-2,4-dihydrospiro-
[indazole-5,4′-piperidine]-1′-carboxylate (16b). The title com-
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(1.56 g, 12.5 mmol) was added. The mixture was heated at reflux for
18 h. The reaction was cooled to room temperature and concentrated
under reduced pressure to yield 17 as a tan oil that solidified on
standing.
HR-MS calcd for C14H21N3O (m/z) [M + H]+ 248.1757, found
248.1756.
Benzyl 6-Bromo-2-tert-butyl-7-methoxy-2,4,6,7-
tetrahydrospiro[indazole-5,4′-piperidine]-1′-carboxylate (22).
General Method C. To a solution of compound 16e (414 mg, 1.09
mmol) in methanol (15 mL) was added freshly recrystallized NBS
(194 mg, 1.09 mmol). The reaction was stirred for 30 min and
concentrated. The resultant oil was taken up in EtOAc and washed
with saturated Na2S2O3(aq) and 0.5 M NaOH. The organic phase was
dried over Na2SO4, filtered and concentrated. The crude material was
purified by flash chromatography (24 g silica gel, 0−100% EtOAc/
heptane gradient) to yield 22 (446 mg, 83%) as a clear oil.
To a suspension of compound 17 (4.21 g, 11.4 mmol) in
dichloromethane (200 mL) was added Et3N (1.90 mL, 13.6 mmol)
and the mixture was stirred for 30 min. The mixture was concentrated
and the resultant oil taken up in methyl t-butyl ether (MTBE, 200 mL)
and washed with water and brine. The organic phase was dried over
Na2SO4, filtered and concentrated. In a separate flask, DMF (50 mL)
was cooled to 0 °C and phosphorus(V)oxychloride (3.12 mL, 34.1
mmol) was added dropwise over 30 min. The mixture was stirred at 0
°C for 30 min and the free base of hydrazone 17 was added as a
solution in DMF (10 mL) in one portion. The resultant mixture was
stirred at 80 °C for 18 h. The mixture was cooled to room temperature
and diluted with MTBE (300 mL) and extracted with water. The
combined aqueous phases were extracted with additional MTBE. The
organic extracts were combined, washed with brine, dried over
Na2SO4, filtered and concentrated. The crude material was purified by
flash chromatography (10−80% EtOAc/heptane gradient, 40 g silica
1H NMR (400 MHz, CDCl3) δ 7.39−7.34 (m, 4 H), 7.34−7.30 (m,
1 H), 7.27 (s, 1 H), 5.14 (s, 2 H), 4.76 (d, J = 2.7 Hz, 1 H), 4.44 (d, J
= 2.2 Hz, 1 H), 3.81−3.72 (m, 1 H), 3.72−3.64 (m, 1 H), 3.59 (d, J =
0.5 Hz, 3 H), 3.32 (t, J = 9.5 Hz, 1 H), 3.24 (ddd, J = 13.7, 9.7, 3.7 Hz,
1 H), 2.61 (s, 2 H), 1.87 (br. s., 1 H), 1.78−1.67 (m, 3 H), 1.60 (s, 9
H); 13C NMR (126 MHz, CDCl3) δ 155.3, 143.8, 136.8, 128.4, 127.9,
127.8, 122.9, 112.6, 78.6, 67.0, 60.7, 58.5, 57.6, 40.1, 39.6, 36.9, 33.1,
29.9, 26.7; HR-MS calcd for C24H32BrN3O3 (m/z) [M + H]+
490.1700, found 490.1701.
1
gel) to yield 16e (3.64 g, 85%) as a clear oil. H NMR (400 MHz,
Benzyl 2-tert-Butyl-7-oxo-2,4,6,7-tetrahydrospiro[indazole-
5,4′-piperidine]-1′-carboxylate (24). To a solution of compound
22 (289 mg, 0.59 mmol) in THF (15 mL) cooled to 0 °C was added
dropwise potassium tert-butoxide (1.18 mL, 1 M in THF). The
mixture was then warmed to room temperature and stirred for 30 min
at which point 2 N HCl (5 mL) was added and stirring continued for
15 min. The reaction was diluted with water and extracted with
EtOAc. The organic layer was dried over Na2SO4, filtered and
concentrated. The crude material was purified by flash chromatog-
raphy (12 g silica, 10−100% EtOAc/heptane gradient) to yield 24
(206 mg, 88%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.40 (s, 1
H), 7.37−7.33 (m, 4 H), 7.33−7.29 (m, 1 H), 5.13 (s, 2 H), 3.53−3.47
(m, 4 H), 2.73 (s, 2 H), 2.59 (s, 0 H), 1.63 (s, 9 H), 1.60−1.52 (m, 0
H); 13C NMR (126 MHz, CDCl3) δ 191.8, 155.2, 145.0, 136.7, 128.4,
128.0, 127.8, 124.3, 123.4, 67.1, 60.2, 50.0, 39.7, 37.3, 35.3, 31.5, 29.8;
HR-MS calcd for C23H29N3O3 (m/z) [M + H]+ 396.2282, found
396.2287.
CDCl3) δ ppm 7.36−7.25 (m, 5H), 7.18 (s, 1H), 6.57 (d, J = 10.0 Hz,
1H), 5.86 (d, J = 10.0 Hz, 1H), 5.12 (s, 2H), 3.69−3.51 (m, 2H),
3.53−3.36 (m, 2H), 2.58 (s, 2H), 1.74−1.59 (m, 2H), 1.58−1.52 (m,
9H), 1.53−1.41 (m, 2H); 13C NMR (126 MHz, CDCl3) δ 155.3,
146.6, 136.8, 135.4, 128.4, 127.9, 127.8, 127.7, 127.7, 122.9, 120.0,
112.6, 66.9, 57.9, 39.9, 35.8, 34.4, 30.9, 29.8; HR-MS calcd for
C23H29N3O2 (m/z) [M + H]+ 380.2333, found 380.2334.
Benzyl 1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-
5,4′-piperidine]-1′-carboxylate (20). To a solution of compound
15d (4.93 g, 13.49 mmol) in 3:1 THF/water (120 mL) was added
freshly recrystallized NBS (2.63 g, 14.78 mmol). The clear orange
solution was stirred for 15 min then diluted with EtOAc (300 mL) and
washed with saturated Na2S2O3(aq), 1 M NaOH, water and brine. The
organic phase was dried over Na2SO4, filtered and concentrated. The
resultant bromohydrin 18 was dissolved in acetone (80 mL) and
cooled to 0 C. Jones’ reagent (13.5 mL) was added dropwise and the
reaction was stirred 1 h then cooled to 0 C. The reaction was
neutralized slowly with saturated NaHCO3(aq), filtered through Celite
and rinsed with EtOAc. The biphasic filtrate was separated and the
aqueous layer extracted with EtOAc. The combined organic phases
were washed with water and brine, dried over Na2SO4, filtered and
concentrated to give bromoketone 19 as off-white foam. Compound
19 was dissolved in THF (50 mL) and saturated NH4Cl(aq) (30 mL).
The mixture was treated with Zn powder (2.13 g, 32.6 mmol) and
stirred vigorously for 15 min. The reaction was diluted with EtOAc
and the phases were separated and the organic layer washed with water
and brine, dried over Na2SO4, filtered and concentrated. The crude
material was purified by flash chromatography (7−100% EtOAc/
heptanes gradient, 100 g silica gel) to yield 20 (3.13 g, 61% over 3
steps) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.41−7.28 (m,
6H), 5.39 (spt, J = 6.6 Hz, 1H), 5.13 (s, 2H), 3.59−3.51 (m, 2H),
3.50−3.43 (m, 2H), 2.75 (s, 2H), 2.54 (s, 2H), 1.55 (br. s., 4H), 1.46
(d, J = 6.3 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 187.8, 155.5,
137.0, 136.5, 133.1, 128.7, 128.3, 128.1, 127.2, 77.5, 67.4, 52.7, 51.0,
40.0, 38.1, 35.4, 31.8, 22.6; HR-MS calcd for C22H27N3O3 (m/z) [M +
H]+ 382.2125, found 382.2131.
1-Isopropyl-4,6-dihydrospiro[indazole-5,4′-piperidin]-7(1H)-
one hydrochloride (21). To a solution of compound 20 (416 mg,
1.09 mmol) in EtOAc (20 mL) was added 1-methyl-1,4-cyclo-
hexadiene (1.26 mL, 10.9 mmol) and 10% Pd/C (80 mg, 50% wet).
The resultant mixture was heated at reflux for 4 h. The reaction was
cooled to room temperature and filtered through Celite and rinsed
with EtOAc. The filtrate was treated with HCl (2 mL, 1 N in Et2O)
and concentrated to yield 21 (293 mg, 95%) as a white solid 1H NMR
(500 MHz, DMSO-d6) δ 8.89−8.67 (m, 2H), 7.47 (s, 1H), 5.27 (spt, J
= 6.6 Hz, 1H), 3.05 (br s, 4H), 2.79 (s, 2H), 2.62 (s, 2H), 1.71−1.60
(m, 4H), 1.36 (d, J = 6.6 Hz, 6H); 13C NMR (126 MHz, DMSO-d6) δ
187.1, 136.1, 132.1, 126.8, 51.5, 49.6, 38.8, 38.8, 36.2, 31.1, 30.1, 22.0,
2-tert-Butyl-4,6-dihydrospiro[indazole-5,4′-piperidin]-7(1H)-
one hydrochloride (26). To a solution of compound 24 (100 g, 253
mmol) in refluxing EtOAc (1 L) in a 2 L, 3-neck flask equipped with a
condenser and mechanical stirrer and flushed with N2 was added 20%
Pd(OH)2/C (7.10 g, 50% wet), and 1-methyl-1,4-cyclohexadiene
(63.1 mL, 506 mmol). The reaction mixture was heated at reflux for 1
h. MeOH (300 mL) was added and the mixture was cooled to ∼40 °C
and filtered through Celite. The filter cake was washed with a 1:1
mixture of MeOH/EtOAc (500 mL) and the combined filtrate was
concentrated. The crude free base was taken up in MeOH (45 °C) and
filtered. The filtrate was diluted with MeOH to a total volume of 300
mL in a 1 L, 3-neck flask, and stirred at 50 °C with a mechanical
stirrer. Hydrogen chloride (72.1 mL, 4 N in dioxane) was added
dropwise. Upon completion of the addition, the mixture was stirred at
50 °C for 40 min, then diluted with EtOH (500 mL) and the MeOH
was removed by distillation. Additional EtOH was added to keep a
constant volume and distillation continued until a ratio of ∼15:1
1
EtOH/MeOH (determined by H NMR) was reached. MeOH (20
mL) was added and the mixture was cooled slowly to room
temperature and stirred for 18 h. The precipitated solids were
collected by filtration, washed with EtOH and dried to yield 26 (75.3
g, 89%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.85 (br s,
2H), 7.83 (s, 1H), 3.04 (t, J = 5.7 Hz, 4H), 2.76 (s, 2H), 2.56 (s, 2H),
1.67−1.59 (m, 4H), 1.53 (s, 9H); 13C NMR (100 MHz, DMSO-d6) δ
190.75, 144.03, 125.69, 123.34, 59.61, 49.68, 38.98, 35.88, 31.43,
30.19, 29.36; HR-MS calcd for C15H23N3O (m/z) [M + H]+ 262.1914,
found 262.1914.
Benzyl 6-Bromo-1-isopropyl-7-methoxy-1,4,6,7-
tetrahydrospiro[indazole-5,4′-piperidine]-1′-carboxylate
(25a). The title compound was prepared from compound 15d (465
mg, 1.27 mmol) and NBS (226 mg, 1.27 mmol) according to General
1
Method C (563 mg, 93%) as a white solid. H NMR (400 MHz,
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CDCl3) δ 7.42−7.28 (m, 6H), 5.14 (s, 2H), 4.73 (d, J = 1.8 Hz, 1H),
4.41 (s, 1H), 4.33 (spt, J = 6.6 Hz, 1H), 3.87−3.74 (m, 1H), 3.70−
3.60 (m, 1H), 3.55 (d, J = 0.8 Hz, 3H), 3.36−3.26 (m, 1H), 3.22 (ddd,
J = 3.7, 9.8, 13.7 Hz, 1H), 2.69 (d, J = 15.8 Hz, 1H), 2.50 (d, J = 15.8
Hz, 1H), 1.82−1.63 (m, 4H), 1.50 (dd, J = 6.8, 8.4 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 155.2, 136.7, 136.3, 132.4, 128.4, 128.0, 127.8,
113.9, 77.5, 67.0, 58.3, 57.3, 50.8, 40.1, 39.6, 37.1, 32.2, 26.1, 22.6,
22.5; HR-MS calcd for C23H30BrN3O3 (m/z) [M + Na]+ 498.1363,
500.1345, found 498.1368, 500.1351.
and the resultant oil was taken up in MeOH (500 mL) and
concentrated (repeat 1x) to give olefin 30 as a thick orange oil.
Compound 30 was taken up in MeOH (550 mL) in a 1 L flask placed
in a water bath at ambient temperature. NBS (38.7 g, 217 mmol) was
added in 2 portions (slight exotherm) and the mixture was stirred for 1
h. The reaction was quenched with Na2S2O3(aq) (100 mL) and
MeOH was evaporated. The resultant slurry was partitioned between
EtOAc (100 mL), 2-methyltetrahydrofuran (2-MeTHF, 500 mL) and
water (100 mL). The organic phase was washed with 1 N NaOH(aq)
(2 × 80 mL), water (100 mL) and brine (100 mL). The combined
aqueous layers were washed with 2-MeTHF (200 mL) and the organic
phase was washed with water and brine (50 mL each). The organic
extracts were combined, dried over Na2SO4, filtered and concentrated.
The resultant oil was taken up in 2-MeTHF (300 mL) and PhCH3
(100 mL) and concentrated (repeat 2×) to give O-methylbromohy-
drin 31 as a thick orange gum. Compound 31 was taken up in THF
(300 mL) and potassium t-butoxide (414 mL, 1 M in THF) was added
at room temperature via an addition funnel. The resultant dark red
mixture was heated at 60 °C for 2 h then cooled to ambient
temperature. Hydrochloric acid (1 N, 476 mL) was added over 20 min
via an addition funnel and the mixture was stirred for 1 h and treated
with EtOAc (500 mL). The phases were separated and the organic
phase was washed with water. The combined aqueous phases were
extracted with additional EtOAc. The combined organic layers were
concentrated, taken up in a 1:1 mixture of THF/PhCH3 and
concentrated. The resultant orange oil was taken up in EtOAc (1 L)
and treated with charcoal (25 g) for 40 min. The charcoal was
removed by filtration through Celite, the filtercake washed with EtOAc
(1.5 L) and the filtrate concentrated. The residue was taken up in
EtOAc (660 mL) and MeOH (175 mL) and acetyl chloride (100 mL,
1.4 mol) was added dropwise over 20 min. The resultant mixture was
stirred for 5 h. The precipitate was collected by filtration and dried in a
vacuum oven to give compound 21 as a white solid (59.9 g, 93%
Benzyl 6-Bromo-1-tert-butyl-7-methoxy-1,4,6,7-
tetrahydrospiro[indazole-5,4′-piperidine]-1′-carboxylate
(25b). The title compound was prepared from compound 15d (324
mg, 0.85 mmol) and NBS (152 mg, 0.85 mmol) according to General
1
Method C (359 mg, 85%) as a white solid. H NMR (500 MHz,
CDCl3) δ 7.40−7.31 (m, 5H), 7.31 (s, 1H), 5.14 (s, 2H), 4.90 (d, J =
1.7 Hz, 1H), 4.47 (s, 1H), 3.92−3.77 (m, 1H), 3.75−3.66 (m, 1H),
3.52 (s, 3H), 3.27 (t, J = 10.7 Hz, 1H), 3.23−3.16 (m, 1H), 2.78 (d, J
= 15.9 Hz, 1H), 2.49 (d, J = 16.1 Hz, 1H), 1.92 (d, J = 12.9 Hz, 1H),
1.82−1.74 (m, 1H), 1.71−1.64 (m, 2H), 1.63 (s, 9H); 13C NMR (126
MHz, CDCl3) δ 155.2, 136.7, 135.4, 132.6, 128.4, 128.0, 127.8, 116.0,
78.6, 67.0, 61.0, 58.5, 56.3, 40.2, 39.7, 38.0, 35.9, 32.1, 29.8, 26.1; HR-
MS calcd for C24H32BrN3O3 (m/z) [M + H]+ 490.17, 492.1683, found
490.1708, 490.1691.
2-tert-Butyl-1′-(1H-indazole-5-carbonyl)-4,6-dihydrospiro-
[indazole-5,4′-piperidin]-7(2H)-one (27). General Method D.
To a solution of compound 26 (70 mg, 0.27 mmol) and 1H-indazole-
5-carboxylic acid (48 mg, 0.30 mmol) was added Et3N (75 μL, 0.54
mmol) and T3P (0.31 mL, 50% in EtOAc). The resultant mixture was
stirred for 4 h at room temperature. The mixture was diluted with
EtOAc and washed with water and brine. The organic phase was dried
over Na2SO4, filtered and concentrated. The crude material was
purified by flash chromaotgraphy (12 g silica gel, 25−100% EtOAc/
heptane gradient) to yield 27 (81 mg, 75%) as a white solid. 1H NMR
(500 MHz, CDCl3) δ 8.20−8.13 (m, 1H), 7.86 (s, 1H), 7.58−7.53 (m,
1H), 7.49−7.46 (m, 1H), 7.42 (s, 1H), 3.94−3.39 (m, 4H), 2.79 (s,
2H), 2.66 (s, 2H), 1.81−1.46 (m, 13H); 13C NMR (126 MHz,
CDCl3) δ 191.7, 170.6, 144.9, 135.1, 128.8, 126.4, 124.5, 123.3, 120.4,
110.2, 60.3, 50.0, 37.7, 35.6, 31.9, 31.7, 29.8, 18.6, 17.3; HR-MS calcd
for C23H27N5O2 (m/z) [M + H]+ 406.2238, found 406.2229.
1′-(1H-indazole-5-carbonyl)-1-isopropyl-4,6-dihydrospiro-
[indazole-5,4′-piperidin]-7(1H)-one (28). The title compound was
prepared from compound 21 (75 mg, 0.3 mmol) and 1H-indazole-5-
carboxylic acid (54 mg, 0.33 mmol) according to General Method D
1
overall yield; 1.8 equiv of HCl salt by Cl ion analysis). H and 13C
spectra obtained were consistent with previous batches of compound
21. For characterization purposes, a small amount of both compound
30 and compound 31 were isolated and purified and the data are listed
below.
tert-Butyl-1-isopropyl-1,4-dihydrospiro[indazole-5,4′-piperi-
1
dine]-1′-carboxylate (30). H NMR (500 MHz, CDCl3) δ 7.26 (s,
1H), 6.43 (d, J = 10.0 Hz, 1H), 5.85 (d, J = 10.0 Hz, 1H), 4.48 (spt, J
= 6.6 Hz, 1H), 3.53−3.38 (m, 4H), 2.63 (s, 2H), 1.66−1.58 (m, 2H),
1.55−1.51 (m, 2H), 1.50 (d, J = 6.8 Hz, 6H), 1.48 (s, 9H); 13C NMR
(126 MHz, CDCl3) δ 154.8, 136.5, 135.7, 135.6, 114.3, 113.3, 79.4,
50.3, 39.5, 35.4, 35.0, 30.7, 28.4, 22.6; HR-MS calcd for C19H29N3O2
(m/z) [M + H]+ 332.2333, found 332.2339.
1
to yield 28 (85 mg, 72%) as a white solid. H NMR (500 MHz,
DMSO-d6) δ 13.17 (s, 1 H), 8.08 (s, 1 H), 7.77 (s, 1 H), 7.52 (d, J =
8.8 Hz, 1 H), 7.41 (s, 1 H), 7.32 (dd, J = 1.4, 8.6 Hz, 1 H), 5.22 (spt, J
= 6.6 Hz, 1 H), 3.76−3.30 (m, 4 H), 2.76 (s, 2 H), 2.57 (s, 2 H), 1.46
(br s, 4 H), 1.31 (d, J = 6.4 Hz, 6 H); 13C NMR (126 MHz, DMSO-
d6) δ 187.9, 169.3, 144.0, 139.8, 136.2, 134.2, 132.5, 128.2, 127.2,
125.2, 122.1, 119.7, 110.0, 51.6, 50.1, 38.5, 37.9, 30.4, 22.2; HR-MS
calcd for C22H25N5O2 (m/z) [M + H]+ 392.2081, found 392.2088.
Large Scale Synthesis of 1-Isopropyl-4,6-dihydrospiro-
[indazole-5,4′-piperidin]-7(1H)-one Hydrochloride (21). To a
solution of compound 29 (55.0 g, 207 mmol) in PhCH3 (410 mL) was
added tris(dimethylamino)methane (72 mL, 415 mmol) and the
resultant mixture was heated at reflux for 4 h then allowed to stir at
ambient temperature for 18 h. The mixture was concentrated and the
resulting slurry was taken up in PhCH3 (400 mL) and concentrated to
a yellow solid. The yellow solid was taken up again in PhCH3 (500
mL) and heated to 90 °C. To this solution was added i-
PrNHNH2·HCl (29.8 g, 269 mmol) as a solution in MeOH (75
mL) over 30 min. The mixture was heated at reflux for 4 h and allowed
to cool to ambient temperature overnight. Most of the solvent was
removed via distillation and the residue was cooled to room
temperature and taken up in 10% citric acid(aq) (100 mL) and
EtOAc (500 mL) and the layers were separated. The organic phase
was washed with 10% citric acid(aq) (100 mL), water and brine. The
combined aqueous washes were extracted with additional EtOAc (200
mL). The organic phases were combined and washed with water and
brine. The solution was dried over Na2SO4, filtered and concentrated
tert-Butyl-6-bromo-1-isopropyl-7-methoxy-1,4,6,7-
tetrahydrospiro[indazole-5,4′-piperidine]-1′-carboxylate (31).
1H NMR (500 MHz, CDCl3) δ 7.32 (s, 1H), 4.71 (d, J = 1.7 Hz, 1H),
4.41 (s, 1H), 4.31 (spt, J = 6.6 Hz, 1H), 3.72−3.62 (m, 1H), 3.55 (br s,
4H), 3.27−3.18 (m, 1H), 3.12 (ddd, J = 13.7, 9.6, 3.5 Hz, 1H), 2.67
(d, J = 15.9 Hz, 1H), 2.47 (d, J = 15.9 Hz, 1H), 1.79−1.61 (m, 4H),
1.48 (dd, J = 10.0, 6.6 Hz, 6H), 1.44 (s, 9H); 13C NMR (126 MHz,
CDCl3) δ 154.7, 136.3, 132.3, 114.0, 99.7, 79.5, 77.5, 58.4, 57.3, 50.7,
39.6, 37.2, 37.1, 32.3, 28.4, 26.1, 22.6, 22.5; HR-MS calcd for
C20H32BrN3O3 (m/z) [M + H]+ 442.1700, 444.1682, found 442.1710,
444.1692.
Benzyl 7-Oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperi-
dine]-1′-carboxylate (32). To a solution of 15a (608 mg, 1.88
mmol) in a 3:1 mixture of THF/water (20 mL) was added freshly
recrystallized NBS (335 mg, 1.88 mmol). The reaction was stirred for
30 min and diluted with EtOAc and washed with saturated
Na2S2O3(aq). The organic phase was dried over Na2SO4, filtered
and concentrated. The resultant white solid was taken up in acetone
(20 mL), cooled to 0 °C and treated with Jones’ reagent (2.0 mL).
The reaction was stirred for 1 h, neutralized with saturated
KH2PO4(aq) and stirred for 20 min. The acetone was evaporated
and the resultant slurry was diluted with water and extracted three
times with EtOAc. The combined organic extracts were concentrated.
The resultant tan oil was taken up in 1:1 THF/saturated NH4Cl(aq)
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The Journal of Organic Chemistry
Article
(20 mL) and treated with Zn dust (369 mg, 5.64 mmol) with vigorous
stirring for 30 min. The reaction was diluted with water and EtOAc
and the layers separated. The organic phase was washed with brine,
dried over Na2SO4, filtered and concentrated. The crude material was
purified by flash chromatography (24 g silica gel, 20−100% EtOAc/
(3) Harwood, H. J. Jr.; Petras, S. F.; Shelly, L. D.; Zaccaro, L. M.;
Perry, D. A.; Makowski, M. R.; Hargrove, D. M.; Martin, K. A.; Tracey,
W. R.; Chapman, J. G.; Magee, W. P.; Dalvie, D. K.; Soliman, V. F.;
Martin, W. H.; Mularski, C. J.; Eisenbeis, S. A. J. Biol. Chem. 2003, 278,
37099−37111.
(4) (a) Corbett, J. W.; Freeman-Cook, K. D.; Elliot, R.; Vajdos, F.;
Rajamohan, F.; Kohls, D.; Marr, E.; Zhang, H.; Tong, L.; Tu, M.;
Murdande, S.; Doran, S. D.; Houser, J. A.; Song, W.; Jones, C. J.;
Coffey, S. B.; Buzon, L.; Minich, M. L.; Dirico, K. J.; Tapley, S.;
McPherson, R. K.; Sugarman, E.; Harwood, H. J. Jr.; Esler, W. Bioorg.
Med. Chem. Lett. 2010, 20, 2383. (b) Corbett, J. W.; Elliott, R. L.; Bell,
A. Spiroketone acetyl-CoA carboxylase inhibitors. WO08065508;
2008.
1
heptane gradient) to yield 32 (371 mg, 58%) as a white solid. H
NMR (500 MHz, CDCl3) δ 7.66 (s, 1H), 7.41−7.29 (m, 5H), 5.14 (s,
2H), 3.63−3.42 (m, 4H), 2.81 (s, 2H), 2.61 (s, 2H), 1.58 (br s, 4H);
13C NMR (126 MHz, CDCl3) δ 155.2, 136.7, 128.5, 128.0, 128.0,
127.9, 67.1, 49.8, 39.7, 38.0, 35.2, 31.1; HR-MS calcd for C19H21N3O3
(m/z) [M + H]+ 340.1656, found 340.1661.
Benzyl 1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-
5,4′-piperidine]-1′-carboxylate (20) and Benzyl 2-Isopropyl-7-
oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-car-
boxylate (33) (Alkylation Method). To a solution of compound 32
(100 mg, 0.30 mmol) in DMF (5 mL) was added K2CO3 (49 mg, 0.35
mmol) and 2-iodopropane (44 μL, 0.44 mmol). The mixture was
stirred for 18 h. The reaction was diluted with MTBE and washed with
water and brine. The organic phase was dried over Na2SO4, filtered
and concentrated. The crude material was purified by flash
chromatography (12 g silca gel, 0−100% EtOAc/heptane gradient)
to yield compound 20 (57 mg, 51%) and compound 33 (16 mg, 14%).
The spectra of 20 prepared via this method match those shown
(5) For a recent review see: Corbett, J. W. Expert Opin. Ther. Pat.
2009, 19, 943−956.
(6) Freeman-Cook, K. D.; Amor, P.; Bader, S.; Buzon, L. M.; Coffey,
S. B.; Corbett, J. W.; Dirico, K. J.; Doran, S. D.; Elliott, R. L.; Esler, W;
Guzman-Perez, A.; Henegar, K. E.; Houser, J. A.; Jones, C. S.;
Limberakis, C; Loomis, K.; McPherson, K.; Murdande, S.; Nelson, K.
L.; Phillion, D.; Pierce, B. S.; Song, W.; Sugarman, E.; Tapley, S.; Tu,
M.; Zhao, Z. J. Med. Chem. 2011, DOI: 10.1021/jm201503u.
(7) Synthesis of spirochromanone and spirotetralone structures have
been reported: (a) Chu, G.-H.; Le Bourdonnec, B.; Gu, M.; Saeui, C.
T.; Dolle, R. E. Tetrahedron 2009, 65, 5161−5167. (b) Claremon, D.
A.; Ponticello, G. S.; Selnick, H. G. Spirocycles useful as Class III
antiarrhythmic agents. U.S. Patent 5,439,914, August 8, 1995.
(8) Pandey, A.; Seroogy, J.; Volkots, D.; Smyth, M. S.; Rose, J.;
Mehrotra, M. M.; Heath, J.; Ruhter, G.; Schotten, T.; Scarborough, R.
M. Bioorg. Med. Chem. Lett. 2001, 11, 1293−1296.
1
previously. Compound 33 spectroscopic data: H NMR (500 MHz,
CDCl3) δ 7.39−7.30 (m, 5H), 7.29 (s, 1H), 5.13 (s, 2H), 4.58 (spt, J =
6.7 Hz, 1H), 3.50 (t, J = 5.7 Hz, 4H), 2.73 (s, 2H), 2.59 (s, 2H), 1.62−
1.51 (m, 10H); 13C NMR (126 MHz, CDCl3) δ 191.6, 155.2, 145.1,
128.5, 128.0, 127.9, 125.1, 123.6, 67.1, 55.2, 50.0, 39.7, 37.4, 35.3, 31.4,
22.9; HR-MS calcd for C22H27N3O3 (m/z) [M + H]+ 382.2125, found
382.2125.
(9) Heathcock, C. H.; Ellis, J. E.; McMurry, J. E.; Coppolino, A.
Tetrahedron Lett. 1971, 52, 4995−4996.
(10) (a) Martin, S. F.; Moore, D. R. Tetrahedron Lett. 1976, 4459.
(b) Bredereck, H.; Effenberger, F.; Brendle, T. Angew. Chem., Int. Ed.
Engl. 1966, 5, 132. (c) Bredereck, H.; Effenberger, F.; Brendle, T.;
Muffler, H. Chem. Ber. 1968, 101, 1885.
(11) Bredereck, H.; Simchen, G.; Hoffmann, H.; Horn, P.; Wahl, R.
Angew. Chem., Int. Ed. Engl. 1967, 6, 356−357.
(12) (a) Menozzi, G.; Mosti, L.; Schenone, P. J. Heterocycl. Chem.
1984, 21, 1437−1440. (b) Molteni, V.; Hamilton, M. M.; Mao, L.;
Crane, C. M.; Termin, A. P.; Wilson, D. M. Synthesis 2002, 12, 1669−
1674.
Benzyl 1-Isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-
5,4′-piperidine]-1′-carboxylate (20) (Mitsunobu Alkylation
Method). To a solution of compound 32 (100 mg, 0.30 mmol) in
THF (10 mL) was added 2-propanol (34 μL, 0.44 mmol), Ph3P (101
mg, 0.38 mmol) and DIAD (80 μL, 0.38 mmol) and the mixture was
stirred for 18 h. The reaction was diluted with EtOAc and washed with
water and brine. The organic phase was dried over Na2SO4, filtered
and concentrated. The crude material was purified by flash
chromatography (12 g silica gel, 0−100% EtOAc/heptane gradient)
1
to yield compound 20 (102 mg, 91%) as a white solid. H and 13C
spectra obtained were consistent with previous batches of compound
20.
(13) Fustero, S.; Sanchez-Rosello, M.; Barrio, P.; Simon-Fuentes, A.
Chem. Rev. 2011, 111, 6984−7034.
ASSOCIATED CONTENT
■
(14) Kennedy, L. J. Synlett 2008, 4, 600−604.
S
* Supporting Information
(15) Xu, D. D.; Lee, G. T.; Jiang, X.; Prasad, K.; Repic, O.; Blacklock,
T. J. J. Heterocycl. Chem. 2005, 42, 131−135.
1H and 13C NMR spectra for all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) Tsuji, J.; Nagashima, H.; Hori, K. Tetrahedron Lett. 1982, 23,
2679−2682.
(17) Wu, H.; Bernard, D.; Chen, W.; Strahan, G. D.; Deschamps, J.
R.; Parrish, D. A.; Lewis, J. W.; MacKerell, A. D. Jr.; Coop, A. J. Org.
Chem. 2005, 70, 1907−1910.
AUTHOR INFORMATION
■
Corresponding Author
*Scott.W.Bagley@Pfizer.com
(18) Cheney, D. L.; Paquette, L. A. J. Org. Chem. 1989, 54, 3334−
3347.
Notes
(19) Evans, D. A.; Fu, G. C.; Hoveyda, A. H. J. Am. Chem. Soc. 1992,
The authors declare no competing financial interest.
114, 6671−6679.
(20) Moorthy, J. N.; Senapati, K; Singhal, N. Tetrahedron Lett. 2009,
50, 2493−2496.
ACKNOWLEDGMENTS
■
We thank Aaron Smith for helpful discussions, Kathleen Farley
for NMR assistance, as well as James Bradow and Qi Yan for
analytical and separation services. We are grateful to Bridge
Organics Co., SynCom BV and WuXi AppTec, Inc. for
resynthesis. In addition, we thank Bill Esler, Suvi Orr and
Vincent Mascitti for their help with the manuscript.
(21) Fillion, E.; Trepanier, V. E.; Mercier, L. G.; Remorova, A. A.;
Carson, R. J. Tetrahedron Lett. 2005, 46, 1091−1094.
(22) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 7, 639−666.
(23) Yield for the NBS/TPAP oxidation/Zn reduction pathway was
60% (3 steps), comparable to the NBS/Jones oxidation/Zn reduction
(61%, 3 steps).
(24) Askin, D.; Angst, C.; Danishefsky, S. J. Org. Chem. 1985, 50,
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