Carboxylation reaction of a highly functionalized vinylic anion: a case of unexpected stability and reactivity

Article abstract of DOI:10.1016/j.tetlet.2009.12.112

Attempts to prepare JNJ 26273364, a highly functionalized pyrazole-based CCK₁ receptor antagonist, using a carboxylation reaction led to a series of unexpected results. This work demonstrated the unique reactivity and stability of the highly fu

Full text of DOI:10.1016/j.tetlet.2009.12.112

Tetrahedron Letters 51 (2010) 1110–1113
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Carboxylation reaction of a highly functionalized vinylic anion: a case
of unexpected stability and reactivity
a
a
b
b
a
Laurent Gomez a, , Jiejun Wu , Neelakandha S. Mani , Sudip Basu , Josef Moravek , J. Guy Breitenbucher
*
a Johnson & Johnson Pharmaceutical Research and Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA
b Moravek Biochemicals, Inc., 577 Mercury Lane, Brea, CA 92821, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Attempts to prepare JNJ 26273364, a highly functionalized pyrazole-based CCK1 receptor antagonist,
using a carboxylation reaction led to a series of unexpected results. This work demonstrated the unique
reactivity and stability of the highly functionalized Z-alkene functionality present around the pyrazole.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 3 December 2009
Revised 18 December 2009
Accepted 18 December 2009
Available online 28 December 2009
1. Introduction
reagents, and the ester products can isomerize under the reaction
conditions.Toovercometheseliabilities, wethoughtthatasequential
In previous publications from our laboratories, structure–activ-
ity relationships (SAR) of a novel series of pyrazole-based CCK1
functionalization of a geminal dibromo-vinyl group could be a valu-
able synthetic approach. We wish to discuss herein the results of
ourvariousinvestigationstowardthedevelopmentofacarboxylation
reaction of a highly functionalized alkene.
1–4
receptor antagonists were described.5 This work led to the discov-
ery of JNJ 26273364 (Fig. 1) as a potent, safe and selective antago-
nist. As part of our continuing chemistry efforts, an alternative
synthetic route to this analog was required in order to optimize
the overall chemical yield. Our initial goal was to develop a syn-
thetic route that would require the use of a versatile intermediate
which could be used for additional applications. Indeed, accessing
such an intermediate would allow the medicinal chemists to apply
divergent syntheses in order to obtain various analogs with dis-
tinct structural modifications. In addition, the route should enable
a facile preparation of 14C radiolabeled material required to profile
and measure the absorption, distribution, metabolism, and elimi-
nation of the compound in animals (rats and dogs).
2. Results and discussion
Originally, JNJ 26273364 was synthesized in six steps as shown in
Scheme 1.5c,9 The major drawback from the original medicinal
chemistry route was that the light-promoted isomerization of the
E-alkene.
Indeed, this transformation provided the desired Z-alkene 1 in
low conversion (15% isolated yield) along with the E-alkene 7 as
the major isomer (20% isolated yield) (Scheme 1). In order to ad-
dress this problem, a new approach to the synthesis of this mate-
rial was explored.
We envisioned that JNJ 26273364 (1) could be prepared from
the key intermediate vinyl bromide 9 in a single step using a lith-
ium–halogen exchange reaction followed by carboxylation of the
corresponding vinylic anion (Fig. 2).
To first evaluate the validity of our initial strategy we decided to
access the precursor 9 from JNJ 26273364 itself (1), available in-
house in large quantities using a halodecarboxylation reaction of
The highly functionalized pyrazole possesses a unique trisubsti-
tuted Z-alkene functionality. Two of the major challenges associated
withthesynthesisofthisfunctionalgroupare(1)toutilizea synthetic
routewhichwillaffordtheproductwithhighstereoselectivityand(2)
to identify reaction conditions that are sufficiently mild to avoid any
isomerization. Three major synthetic routes have been developed to
access such a,b-unsaturated carboxylic acid moieties in the scientific
literature. The most common strategies involve the use of aromatic
aldehydes in the Perkin reaction,6 or substituted malonic acids
through the (Doebner) Knoevenagel reaction.7 Although these meth-
ods have beenwidely used, they primarily sufferfrom a poor selectiv-
Cl
ity generally favoring the E-isomer. Alternatively,
a,b-unsaturated
Cl
N
N
carboxylic acids can be accessed from the Horner–Wadsworth–Em-
mons phosphonoacetate reagents after hydrolysis of the esters.8
However, thisapproach necessitatesthe preparationofthe individual
Cl
O
O
1
O
OH
* Corresponding author. Tel.: +1 858 320 3383; fax: +1 858 4502089.
E-mail address: Igomez4@prdus.jnj.com (L. Gomez).
Figure 1. JNJ 26273364.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.112

L. Gomez et al. / Tetrahedron Letters 51 (2010) 1110–1113
1111
Cl
Cl
N
O
OLi
O
OH
Cl
N
O
N
a
b
c
OEt
O
O
N
O
O
Me
Cl
O
OEt
O
O
2
3
4
5
O
O
Cl
N
Cl
Cl
N
Cl
N
O
N
N
d
e
f
Cl
O
N
Z
Cl
O
OH
O
Cl
O
E
7
+
O
O
OH
6
7
O
O
1
Cl
Scheme 1. Original medicinal chemistry synthesis. Reagents and conditions: (a) diethyl oxalate, LiHMDS, Et2O, ꢀ78 °C to rt; (b) 2,5-dichlorophenylhydrazine, THF, TsOH,
40 °C, 74% over 2 steps; (c) DIBAL, THF, ꢀ78 °C to rt, 96%; (d) Dess–Martin periodinane, DCM, rt, 99%; (e) 3-chlorophenylacetic acid, NEt3, Ac2O, rt, 49%; (f) UV light, CHCl3,
yields: 1 (15%) and 7 (20%).
Cl
N
Cl
N
Cl
Cl
N
9
N
Cl
Cl
O
O
Br
O
1
O
O
OH
Figure 2. Proposed key transformation.
Table 1
Catalyst/solvent survey for the catalytic Hunsdiecker reaction
Cl
N
Cl
Cl
N
Cl
Cl
Cl
N
N
N
N
a
Cl
Cl
Cl
+
O
O
O
O
Br
COOH
Br
O
O
O
OH
9
1
10
Entry
Catalyst
Solvent
Products
Yields
1
2
3
4
5
NEt3
DCM
DCE
MeCN/H2O (97:3)
DCE
MeCN/H2O (97:3)
10
10
10
10
10
92a
100b
100b
100b
100b
Bu4N+OAcꢀ
Bu4N+OAcꢀ
Bu4NþOCðOÞCF3
LiOAc
ꢀ
Reagents and conditions: (a) NBS, rt, 5 min.
a
Isolated yield.
Determined by HPLC.
b
a
,b-unsaturated carboxylic acids (catalytic Hunsdiecker reaction)
(Table 1).
Treatment of compound 1 with a catalytic amount of triethyl-
increasing the rate of the reaction using alternative catalysts and/
or solvents (including LiOAc and MeCN/H2O as suggested from
the literature10) did not lead to detectable amounts of desired
product (Table 1).
An alternative synthesis of the key intermediate 9 was devised
which involved the use of pyrazole-3-carbaldehyde 6 as the start-
ing material (Scheme 2). This compound was also readily available
amine in dichloromethane followed by addition of N-bromosuccin-
imide rapidly afforded the corresponding brominated pyrazole 10
in 92% yield with no trace of desired product 9 (Table 1, entry 1).
Attempts to favor the desired halodecarboxylation event by
Cl
N
Cl
N
Cl
Cl
N
6
N
N
N
a
Cl
b
Cl
Cl
O
Br
O
O
O
Br
Br
11
O
O
O
9
Scheme 2. Corey-Fuchs/Suzuki strategy for the synthesis of intermediate 9. Reagents and conditions: (a) PPh3/CBr4, DCM, 0 °C, 20 min; (b) 3-chlorophenyl boronic acid,
Pd(PPh3)4, Na2CO3, dioxane/H2O (4:1), 70 °C, 12 h, 78%.

1112
L. Gomez et al. / Tetrahedron Letters 51 (2010) 1110–1113
Table 2
Lithium–bromide exchange/carboxylation sequence
Cl
Cl
Cl
Cl
N
N
9
N
Step a: Reagent
N
Cl
Cl
O
O
Step b: Electrophile
R
Br
O
O
R = CO2H; 1
R = CHO; 15
Entry
Reagents
Electrophile
T (°C)
Time (min)
Results
aa
bb
10
1
2
3
4
5
6
7
tert-BuLi
tert-BuLi
tert-BuLi
n-BuLi/TMEDA
i-PrMgCl
CO2 gas
Dry ice
CO2 gas
CO2 gas
CO2 gas
CO gas
CO gas
ꢀ78
ꢀ78
ꢀ78
ꢀ78
25
2
9 + ND
9 + ND
ND
9 + ND
9
2
5
10
120
24 h
10
10
10
120
120
Pd(OAc)2/dppf/MeOH/DMF
PdCl2/PPh3
50
70
9
ND
NBu3/H2O
a
Reaction time for step a.
Reaction time for step a; ND: presence of unknown byproducts.
b
in-house as a precursor to JNJ 26273364. Treatment of 6 with tri-
phenylphosphine and carbon tetrabromide in dichloromethane at
0 °C for 20 min afforded after flash column chromatography the
desired product 11 in 99% yield. A subsequent Suzuki cross-cou-
pling reaction in the presence of tetrakis(triphenylphosphine)pal-
ladium and 3-chloro-phenylboronic acid provided the Z-alkene
product 9 as a single stereoisomer in 78% isolated yield. The stereo-
chemistry of the alkene was unambiguously assigned using 2D
NMR spectroscopy and NOESY studies.
Lithium–bromide exchange of the vinyl bromide 9 was the
key step. This transformation was investigated using various re-
agents, solvents, and temperatures. The results are shown in Ta-
ble 2. Our initial attempt involved the use of tert-butyl lithium
for 2 min at ꢀ78 °C followed by addition of CO2 gas. Under these
reaction conditions, recovered starting material along with
uncharacterized byproducts was detected (entry 1). Similar re-
sults were obtained when CO2 gas was replaced with dry ice
(entry 2). Increasing the lithium–bromide exchange reaction
time (step a) from 2 to 5 min led to complete consumption of
the starting material but no trace of product (entry 3). Using
alternative bases, such as n-butyl lithium with TMEDA (entry
4) or i-PrMgCl (entry 5) were also unsuccessful as the desired
product was not detected. To probe the reactivity of the precur-
sor 9 to undergo carbonylation reaction, two sets of conditions
were investigated using different palladium catalysts in the pres-
ence of CO gas (entries 6 and 7). Unfortunately, none of these
reactions afforded the desired aldehyde product 15.
Isolation and 2D NMR structural determination of the common
major byproduct from the reactions revealed compound 12 (Fig. 3)
which is a constitutional isomer of the targeted compound 1. With
the assumption that the formation of compound 12 follows the
proposed mechanism (Fig. 3), a few observations can be made:
(1) the lithium–bromide exchange was indeed occurring, (2) the
vinylic anion was unstable under the reaction conditions and (3)
deprotonation of the aryl ring (inter- or intramolecular) appeared
to be favored, leading to CO2 incorporation at the aromatic ring in-
stead of at the vinylic group (Fig. 3).
It was hypothesized that reaction conditions that would allow
for a greater stability of the vinylic anion (intermediate i) should
provide, after quenching with CO2, good conversion to the desired
product. Two variables (i.e., temperature and reaction time) were
examined and the results are summarized in Table 3. Using a mix-
ture of THF/Et2O/pentane (4:1:1; so-called Trapp mixture) and
Et2O/liquid nitrogen, intermediate 9 was treated with tert-butyl
lithium at ꢀ116 °C for 1 min followed by addition of CO2 gas or
dry ice. Under these conditions, none of the rearranged product
12 was isolated and 15% of the desired product was isolated along
with recovered starting material and unsubstituted alkene 13 (Ta-
ble 3, entry 1). It should be noted that no isomerization to the E-al-
kene was observed under these reaction conditions. This result
Cl
N
Cl
N
N
n-BuLi
N
Cl
Cl
O
O
Li
Br
O
H
O
Cl
i
Cl
9
Cl
Cl
CO2
gas
N
ii
N
fast
N
N
Cl
Cl
O
O
H
H
12
O
Li
O
Cl
HOOC
Cl
Figure 3. Proposed mechanism for the formation of 12.

L. Gomez et al. / Tetrahedron Letters 51 (2010) 1110–1113
1113
Table 3
Optimization of the lithium–bromide/carboxylation reactiona
Cl
Cl
Cl
N
Cl
Cl
Cl
N
9
N
N
N
N
Cl
Cl
Cl
a- Base
+
O
O
O
b- Electrophile
O
H
Br
O
O
O
OH
1
13
Entry
Base
Reaction time (min)
Step a/step b
T (°C)
Electrophile
% Conversion
1
9
13
1
2
tert-BuLi
tert-BuLi
1/20
5/20
ꢀ116
ꢀ116
CO2 gas or dry ice
CO2 gas
15
8
0
77
0
71 (48b)
a
All reactions were carried out under the following reaction conditions: 1.2 equiv of base in a THF/Et2O/pentane mixture (4:1:1) at the indicated temperature under N2
atmosphere.
b
Isolated yield.
suggested that at very low temperature (ꢀ116 °C), the stability of
the vinyl anion had been improved but that the lithium–bromide
exchange reaction had become slower. The reaction time was ex-
tended to 5 min and under these conditions the desired JNJ
26273364 was isolated in 48% yield after flash column chromatog-
raphy (Table 3, entry 2).
Supplementary data
Supplementary data (experimental procedures and character-
ization data for all unknown compounds) associated with this arti-
cle can be found, in the online version, at doi:10.1016/
j.tetlet.2009.12.112.
In summary, a stereoselective synthesis of JNJ 26273364 was
developed which involved a carboxylation reaction of intermediate
9. The study conducted for the synthesis of this key starting material
9 led to the design of a tandem Corey-Fuchs/Suzuki sequence to af-
ford the desired Z-alkene as a single stereoisomer. Optimization of
the lithium–bromide exchange reaction required very low tempera-
ture (ꢀ116 °C) in order to stabilize the vinyl anion. Upon quenching
the reaction mixture with CO2 gas, the Z-alkene isomer was isolated
in48%isolatedyieldwithoutanytraceof isomerization product. This
protocol was also successfully applied to the synthesis of [14C]-la-
beled JNJ 26273364 from 14CO2 in a single step.11 This method high-
lights the fact that despite the high degree of functionalization of the
triarylpyrazole precursor 9, carefully chosen reaction conditions
were identifiedthatallowedfor theregiospecificcarboxylationreac-
tion. This temperature controlled transformation could also be ex-
panded to other types of electrophiles which could in turn
facilitate our medicinal chemistry efforts.
References and notes
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2. Jorpes, E.; Mutt, V. Acta Physiol. Scand. 1966, 66, 196–202.
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4. (a) Varga, G. Curr. Opin. Investig. Drugs 2002, 3, 621–626; (b) Herranz, R. Med.
Res. Rev. 2003, 23, 559–605; (c) Varga, G.; Balint, A.; Burghardt, B.; D’Amato, M.
Br. J. Pharmacol. 2004, 141, 1275–1284; (d) Peter, S. A. S.; D’Amato, M.;
Beglinger, C. Dig. Dis. 2006, 24, 70–82.
5. (a) McClure, K.; Hack, M.; Huang, L.; Sehon, C.; Morton, M.; Li, L.; Barrett, T. D.;
Shankley, N.; Breitenbucher, J. G. Bioorg. Med. Chem. Lett. 2006, 16, 72–76; (b)
Sehon, C.; McClure, K.; Hack, M.; Morton, M.; Gomez, L.; Li, L.; Barrett, T. D.;
Shankley, N.; Breitenbucher, J. G. Bioorg. Med. Chem. Lett. 2006, 16, 77–80; (c)
Gomez, L.; Hack, M.; McClure, K.; Sehon, C.; Huang, L.; Morton, M.; Li, L.;
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9. Barrett, Terrance D.; Breitenbucher, J. Guy; Gomez, Laurent; Hack, Michael D.;
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Acknowledgment
10. (a) Roy, S. Tetrahedron 2000, 56, 1369–1377; (b) Roy, S. J. Org. Chem. 2002, 67,
7861–7864.
We thank Leslie Gomez and Dr. Alice Lee-Dutra for their contri-
butions to the editing of this manuscript.
11. Experimental details for the preparation of [14C]-labeled JNJ 26273364 can be
found in the Supplementary data.