Two-stage sonogashira coupling method in the synthesis of auxin active acetylenes

Article abstract of DOI:10.3987/COM-07-11087

A sequential Sonogashira coupling of a protected acetylene precursor with aryl halides (5) followed by pyrazolyl iodides (14) allows efficient access to the unsymmetrical aryl-heteroarylacetylene (8). Subsequent regioselective lithiation exchange followed by dimethyl oxalate quench produced readily vicinal ketoesters (9) which show auxin effects in a wide variety of plant species.

Full text of DOI:10.3987/COM-07-11087

HETEROCYCLES, Vol. 71, No. 9, 2007
1967
HETEROCYCLES, Vol. 71, No. 9, 2007, pp. 1967 - 1974. © The Japan Institute of Heterocyclic Chemistry
Received, 20th April, 2007, Accepted, 25th May, 2007, Published online, 29th May, 2007. COM-07-11087
TWO-STAGE SONOGASHIRA COUPLING METHOD IN THE
SYNTHESIS OF AUXIN ACTIVE ACETYLENES
G. Wayne Craig,a* Martin Eberle,b Bruno Irminger,c Anegret
Schückenböhmer,c Yvette Laime,a and Patrick Müllerc
aSyngenta Crop Protection, CH-4002 Basel, Switzerland
Email: Gerald_Wayne.Craig@syngenta.com; Tel: +4161 323 2708
bCurrent address, Novartis AG, CH-4002, Basel, Switzerland
cFormer address, Sandoz AG, CH-4002, Basel, Switzerland
Abstract - A sequential Sonogashira coupling of a protected acetylene
precursor with aryl halides (5) followed by pyrazolyl iodides (14)
allows efficient access to the unsymmetrical aryl-heteroarylacetylene
(8). Subsequent regioselective lithiation exchange followed by
dimethyl oxalate quench produced readily vicinal ketoesters (9) which
show auxin effects in a wide variety of plant species.
Dedicated to Professor Kevin M. Smith, vice-chancellor of Louisiana
State University and recipient of the Robert Burns Woodward Award
on Lifetime Achievement at the International Conference on Porphyrins
and Pthalocyanines (ICPP- 4) held in Rome 2006.
INTRODUCTION
Throughout the agrochemical industry, synthetic chemistry has sought to solve the growing needs for
better and more efficient crop protection from harmful insects, fungi or pernicious plants. Strategies for
chemistry innovation are addressed through introduction of novel heterocycles,1a,1b application of new
technologies,2a or simple replacement of key atoms with biosteric equivalents.2b In this publication we
describe one such application of the ever growing usage of palladium coupling methodology in
agrochemistry.3
Palladium catalyzed coupling of terminal acetylenes via the Sonogashira reaction4a has become a
mainstay procedure in organic synthesis.4b The application to heterocycles, particularly pyrazoles have
shown unexpected problems due to vicinal functionality5a or deiodination5b but otherwise appear suitable

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HETEROCYCLES, Vol. 71, No. 9, 2007
for synthetic elaboration.6 Herein we describe a methodology to prepare stepwise unsymmetrical
bis-aryl-pyrazolylacetylenes followed by introduction of a desired vicinal ketoester. Although
alternative strategies exist for introduction of the acetylene unit into a molecule, they often rely on
transformation of preexisting functionality. An example is the Corey-Fuchs method7a which transforms
acetophenones (1a) from 2-chlorostyrenes (2a) with eventual elimination under strong basic conditions to
the desired acetylene (3). On the other hand the Ohira reagent,7b achieves this in a combined
retro-Claisen-Wittig reaction of benzaldehyde (4) presumably followed by mild β-elimination of
O
Cl
O
Ohira
ii)
i)
iii)
H
R
O
O
O
P
2a
3
4
1a R = -Me
1b R = -H
iv)
O
N+
iii)
v)
Cl
N
N+
Cl
N
2b
2c
Reagents and Conditions: i) PCl5, KOH. ii) n-butyllithium, THF. iii) MeOH, K2CO3. iv) Cl3CCO2Na,
DMF, rt. v) Zn metal, AcOH
Scheme 1
OH
OH
X
X
X
7a
I
i)
ii)
5a
Sonogashira
6a
retro-Favorskii
3a
TMS
7b
3a-6a X = 3-CF3
Reagents and Conditions: i) PdCl2(Ph3P)2, Cu (I) iodide, diisopropylamine, Ph3P, 60 ˚C, 7a. ii)
NaOH powder and distillation. 3a (X = 3-CF3), 62 % from 5a.
Scheme 2
diazonium ion to give the terminal acetylene.7c A non-Wittig variation is the formation of the vinyl
dichloride (2b) from benzaldehyde (1b) and mild treatment with sodium trichloroacetate followed by

HETEROCYCLES, Vol. 71, No. 9, 2007
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halogen elimination of the vinyl dichloride (2b) with zinc metal and acetic acid to the desired
phenylacetylene (3) (Scheme1).7d Our strategy is exemplified by first halobenzene coupling with the
acetylene precursor (7a), followed by a second halopyrazole coupling both using Sonogashira conditions
(Scheme 2).
RESULTS AND DISCUSSION
We employed the method of Rossi et al. which was reproducible at large-scale conditions.8 In general,
readily available 1,1-dimethyl-2-propyn-1-ol (7a) was efficiently coupled with a variety of substituted
halobenzenes (5) in 69-90 % yields. The subsequent arylpropargylic alcohols (6) were then distilled
with added solid sodium hydroxide to give retro-Favorskii cleavage of acetone at an efficient rate to
inhibit polymerization. Next a second Sonogashira coupling with iodopyrazoles (14a, b, 16) allowed
synthetic entry to the desired unsymmetrical acetylene (8). A variety of substituted phenylacetylenes
coupled in typical yields of 65-85 % (Scheme 3). In contrast to alkylation conditions used in the
literature9a,9b for preparing the starting N-1-methyl-4-iodopyrazoles (14) and (16), we prepared them on
R
R
i
ii
N
N
14a or
16
NMe
NMe
O
F3C
F3C
O
MeO
8a R = Me
b R = H
9a R = Me
b R = H
Reagents and Conditions: i) PdCl2(Ph3P)2, Cu (I) iodide, Ph3P, diisopropylamine, 60 ˚C, 3a, (8a:
89 %, 8b: 67 %). ii) n-butyllithium, THF, -70 ˚C, dimethyl oxalate, -60 ˚C, (9a: 95.6 %, 9b: 90 %).
Scheme 3
large scale in three steps utilizing phase-transfer conditions (Scheme 4). Although both iodination and
alkylation steps resulted in mixtures of regioisomers (13a,b) and (14a,b) as observed by GC analysis, the
products are easily separated by solubility differences in n-hexane following the two-step process. This
permitted efficient purification of the desired pyrazole product in multigram quantities (14a) in 32 %
overall yield. Ideally, a one-pot-two-step-coupling methodology would be an optimal improvement but
this may require an amenable acetylene precursor where convenient in situ generation can be done.

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HETEROCYCLES, Vol. 71, No. 9, 2007
Me
Me
Me
i
ii
OMe
OMe
O
N
N
NH
N
+
I
I
Me
NH
NH
13a
13b
11
10a
iii
Me
Me
N
NMe
N
I
I
NMe
14a
14b
iii
i
ii
OMe
OMe
MeO
N
N
N
I
NH
NMe
NMe
OMe
10b
12
15
16
Reagents and Conditions: i) 24 % soln. hydrazine hydrate, AcOH, 30-85 ˚C (11; 60 %, 12, 90 %).
ii) HIO3, I2, CCl4, H2O-AcOH, 60 ˚C (14a, 26 %, 14b; 24 %; 16, 97 %). iii) n-Bu4NHSO4, Me2SO4,
NaOH (aq), CH2Cl2, (13a: b, 81%, 15: 53 %).
Scheme 4
Although trimethylsilylacetylene (7b) is a convenient acetylene precursor it is extremely expensive. On
the other hand Vasilevsky and Elguero10 have explored the direct usage of acetylene itself. They
addressed the volatility problem by application of higher boiling DMF and increased reactivity with the
use of stronger bases, however their conditions gave only modest 24-35 % yields when coupled to
pyrazoles in a one-pot-two-step-coupling strategy. Therefore we preferred to focus on a
sequential-two-stage-coupling process.
O
O
i) or
ii)
X
iii) iv) or
v) vi)
OMe
Cl
O
N
N
18
19
20
17a: X = -H
17b: X = Li or Cd
17c: X = -Br
N
N
N
N
MeO
Reagents and Conditions: i) AlCl3-ClCOCO2Me (17a). ii) ClCOCO2Me (17b). iii) trimethylsilyl
cyanide. iv) H2SO4-MeOH. v) LDA, THF, (17c), (20). vi) Amber lite-H+ resin, MeOH.
Scheme 5

HETEROCYCLES, Vol. 71, No. 9, 2007
1971
In the literature, vicinal ketoesters have been introduced by Friedel-Crafts acylation,11a homologation of
acylcyanides,11b hydrolysis of the acylation product with the Katritzky reagent,11c (20) or addition of an
organometallic11d intermediate to methyl chloroglyoxalate (Scheme 5).
For introduction of the vicinal
ketoester we chose the latter method due to compatibility with pyrazole functionality and convenient
availability of dimethyl oxalate. Therefore the acetylene parent (8a) was lithiated at -70 ˚C with
n-butyllithium in THF with subsequent warming to -60 ˚C and addition of dimethyl oxalate to quench the
lithiated pyrazole. The subsequent product (9a) was isolated in 95.6 % yield after routine workup via
water quench, followed by extraction and column chromatography. In the case of the unsubstituted
2H-pyrazole (8b), lithiation occurred regioselectively adjacent to the N-1-methyl group to give (9b) in
62 % yield. These compounds (9a, 9b) are representative of other substituted benzene analogs (X =
4-fluoro; 2,5-dimethyl; 2,5-dichloro; or 4-trifluoromethyl) that were synthesized and subsequently tested
in our biological screen. These compounds (9a, b) displayed auxin symptomology in a wide variety of
plant species which is similar to those reported by other known herbicides.12 Plant species that were most
affected were Solanum, Abutilon, Amaranthus, Chenopodium, Galium, Ipomoea and Solanum. These
plants showed typically twisting and distorted growth of leaf tips and shoots.
CONCLUSION
The foregoing synthetic methodology shows the general versatility of pyrazole modifications using
Sonogashira coupling reactions. The first stage efficiently makes use of the Sonogashira conditions to
couple arylhalides to an acetylene precursor in 69-90 % yields. A second stage retro-Favorskii liberates
phenyl acetylenes for coupling to iodopyrazoles in 65-85 %. Large scale application proved to have broad
compatibility with functionality for further synthetic elaborations. Moreover, phase-transfer alkylation
conditions gave efficient iodopyrazoles used in this scaled-up process. Although this methodology fails to
employ an optimal one-pot-two-step-coupling strategy, this application to other heterocycles certainly can
be expected to be a useful strategy for production of bis-heteroaryl-pyrazolylacetylenes and
bis-pyrazolyl-pyrazolylacetylenes.
EXPERIMENTAL
1
Melting points were determined with MRK MEL-TEMP II and are uncorrected. The H-NMR spectra
were taken with JEOL JNM-GSX 270 spectrometer. Chemical shifts are reported in reference to
tetramethylsilane as internal standard. GC analyses were carried out on a Varian 3300 gas chromatograph.
Flash column chromatography was performed on E. Merck silica gel 60 (70-230 mesh or 230-400 mesh).
General coupling procedure for preparation of 3-trifluoromethylphenylacetylene (3a).
After stirring a solution of copper (I) iodide (120 mg, 0.63 mmol), triphenylphosphine (120 mg, 0.46
mmol) and bis-triphenylphosphine palladium dichloride (120 mg, 0.17 mmol) in diisopropylamine (140
mL) under argon atmosphere for 5 min, a mixture of 3-iodotrifluoromethylbenzene (5a) (50.7 g, 0.18
mol) and 1,1-dimethyl-2-propyn-1-ol (7a) (27 g, 0.32 mol) was added which resulted in exothermic

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HETEROCYCLES, Vol. 71, No. 9, 2007
warming to 70 ˚C. The reaction temperature was increased and maintained at 80 ˚C. Monitor by GC
showed the reaction completes within 1 h. The cooled reaction mixture was partitioned between EtOAc
and water and dried (anhydrous Na2SO4). Evaporation of the excess solvent gave an oil which was
combined with solid sodium hydroxide (3 g powdered pellets) and heating to 160 ˚C gave distillation of
acetone with formation of acetylene product (3a) which was distilled at 140 ˚C under slight vacuum (30
Torr) to give 18.3 g (59 % yield) (3a). 1H-NMR: (CDCl3) 7.40-7.79 (m, 4H), 3.15 (s, 1H).
General coupling procedure for the preparation of 1,3-dimethyl-4-(3-trifluoromethyl-
phenylethynyl)-1H-pyrazole (8a).
A typical procedure involves combining the triphenylphosphine (120 mg, 0.46 mmol), copper (I) iodide
(120 mg, 0.63 mmol) and bis-triphenylphosphine palladium dichloride (120 mg, 0.17 mmol) catalyst in
diisopropylamine (100 mL) with stirring under argon atmosphere for 5 min at rt. The pyrazolyl iodide
(14a) (12 g, 0.054 mol) and phenylacetylene (3a) (9.8 g, 0.057 mol) were added and the mixture warmed
to 80-85 ˚C. Monitor by GC showed the reaction completes within 3 h. The cooled solution was
filtered from iodide salts and the mixture partitioned between EtOAc and 2N HCl, followed by washing
with saturated aqueous NaHCO3. After drying of the organic layer (anhydrous Na2SO4) the solvent was
removed in-vacuo to give a residual oil which was chromatographed on silica gel. Isolated yield of (8a),
11.7 g (82 %). 1H-NMR: (CDCl3) 7.80-7.20 (m, 5H), 3.85, (s, 3H), 3.35 (s, 3H). Anal. Calcd for
C14H11F3N2: C, 63.63; H, 4.20; N, 10.60. Found: C, 62.21, H, 4.03; N, 11.03.
Preparation of 2-methyl-4-(3-trifluoromethylphenylethynyl)-2H-pyrazole (8b).
By the general procedure above reaction of pyrazolyliodide (16) (44 g, 0.21 mol) and phenylacetylene
(3a) (46.8 g, 0.27 mol) gave 35.5 g (67 %) (8b) after chromatography. 1H-NMR: (CDCl3) 7.75-7.40 (m,
6H), 3.95 (s, 3H). Anal. Calcd for C13H9F3N2: C, 62.40; H, 3.63; N, 11.20. Found: C, 62.20; H, 3.63;
N, 11.13.
General lithiation procedure for preparation of [2,5-dimethyl-4-(3-trifluoromethylphenylethynyl)-
2H-pyrazol-3-yl]-α-oxoacetic acid methyl ester (9a).
A typical procedure involved addition of n-butyllithium (60 mL, 1.6 M n-hexane soln., 0.096 mol) at -70
˚C to a solution of the pyrazole (8a) (23 g, 0.087 mol) in THF (120 mL) with mechanical stirring
continued for 90 min. Then a solution of dimethyl oxalate (31 g, 0.26 mol) in THF (120 mL) was added
all at once at -60 ˚C. The temperature rose to -30 ˚C with continued stirring. The reaction was allowed
to warm to rt overnight (12-15 h). The reaction was then quenched with water (50 mL) followed by
partition between Et2O and water and drying the organic phase (anhydrous Na2SO4). Chromatography
of the residual oil after evaporation of solvent on silica gel gave an isolated yield of 29.2g, (95.6 %) of 9a,
mp 66 ˚C. 1H-NMR: (CDCl3) 7.45-7.80 (m, 4H), 4.15 (s, 3H), 3,85 (s, 3H), 2.40 (s, 3H). Anal. Calcd for
C17H13F3N2O3: C, 58.29; H, 3.74; N, 8.00. Found: C, 58.61; H, 3.34; N, 8.33.
Preparation of [2-methyl-4-(3-trifluoromethylphenylethynyl)-2H-pyrazol-3-yl]-α-oxoacetic acid
methyl ester (9b).
By the general lithiation procedure above the reaction of pyrazole (8b) (9.5 g, 0.038 mol) gave similarly a

HETEROCYCLES, Vol. 71, No. 9, 2007
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yield of 8 g (62 %) of 9b, mp 79 ˚C. 1H-NMR: (CDCl3) 7.78-7.41 (m, 5H), 4.21 (s, 3H), 3.88 (s, 1H).
Anal. Calcd for C16H11F3N2O3: C, 57.15; H, 3.30; N, 8.33. Found: C, 58.01; H, 3.34; N, 8.23.
General condensation procedure for preparation of 3-methyl-1H-pyrazole (11).
To 3-oxobutyraldehyde dimethyl acetal (10a) (132 g, 1.0 mol) was added hydrazine hydrate (210 mL,
24 % soln., 1.0 mol,) with cooling maintained at 10 ˚C. Then acetic acid (60 mL) was slowly added
allowing the temperature to rise to 30 ˚C. After complete addition, the bath temperature was adjusted to
85 ˚C for 1.5 h until the reaction was judged completed as monitored by GC. Removal of low boiling
components by rotary evaporation followed by vacuum distillation of the residue through a Vigreux
column gave the main fractions (85-100 ˚C / 30 Torr) corresponding to an unresolved mixture of pyrazole
1
tautomers (11) 73 g, (60 % yield). H-NMR: (CDCl3) 8.20 (br s, 1H), 7.49 (s, 1H), 6.10 (s, 1H), 2.35 (s,
3H).
Preparation of 1H-pyrazole (12).
By the general condensation procedure above, treatment of 1,1,3,3-tetramethoxypropane (10b) (220 g, 1.0
mol) with hydrazine hydrate (210 mL 24 % soln., 1.0 mol) and acetic acid (240 mL) gave a 90 % yield of
12. 1H-NMR: (CDCl3) 8.20 (br s, 1H), 7.50 (s, 1H), 6.10 (s, 1H).
General iodination procedure for preparation of 4-iodo-3-methyl-1H-pyrazole (13a) and
3-iodo-2-methyl-1H-pyrazole (13b).
The pyrazole (11) (105 g, 1.20 mol) was dissolved in acetic acid (240 mL), CCl4 (100 mL), iodine (145 g,
0.29 mol) and water (240 mL) containing iodic acid (45 g, 0.24 mol). The two-phase mixture was stirred
vigorously which gave exothermic warming to 50 ˚C. The reaction was completed by GC monitor after 90
min. Sodium bisulfite (aq) (100 mL, 1 M soln.) was added to decolorize the solution followed by
addition of NaOH (aq) (340 mL, 50 % soln.) to basify. The granular salt mixture was removed by
filtration and the liquid filtrate extracted with EtOAc (2 x 500 mL). Drying of the organic layers over
anhydrous Na2SO4 followed by filtration and evaporation gave (13a, b) as an amorphous solid mixture,
216 g, (81 % yield), mp 112 ˚C. 1H-NMR: (CDCl3) 7.50 (s, 1H), 7.40 (s, 1H), 2.35 (2 x s, 3H)
General phase-transfer-alkylation procedure for preparation of 4-iodo-1,3-dimethyl-1H-pyrazole
(14a) and 4-iodo-1,5-dimethyl-1H-pyrazole (14b).
The pyrazole mixture of isomers (13a, 13b) (215 g, 1.03 mol) were dissolved in CH2Cl2 (1 L) containing
tetra-n-butylammonium hydrogen sulfate (0.10 mol), NaOH (aq) (500 mL, 2 M soln.) and dimethyl
sulfate (141 g, 1.12 mol). Vigorous stirring at rt showed after exothermic reaction two resolved product
peaks by GC. The organic phase was separated and washed with brine and dried (anhydrous Na2SO4).
The solvent after filtration was then evaporated to an oil which was stirred with n-hexane and decanted
from the insoluble portion. The pyrazole fractions were concentrated after several extractions to give
pyrazole (14a), 57.8 g, (26 %), 1H-NMR: (CDCl3) 7.40 (s, 1H), 3.85 (s, 3H), 2.30 (s, 3H) and (14b), 55.8
g, (24 %) yield. 1H-NMR: (CDCl3) 7.60 (s,1H), 3.95 (s, 3H).
Preparation of 1-methyl-1H-pyrazole (15).
By the general phase-transfer procedure above for (14a,b) the reaction of pyrazole (12) gave 53 % yield

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HETEROCYCLES, Vol. 71, No. 9, 2007
of (15). 1H-NMR: (CDCl3) 8.20 (br s, 1H), 7.60 (s, 1H), 7.50 (s, 1H), 3.90 (s, 3H).
Preparation of 4-iodo-1-methyl-1H-pyrazole (16).
By the general iodination procedure above for (13a,b) the reaction of pyrazole (15) (34.9 g, 0.43 mol)
gave 44.1 g, 99 % yield of (16), mp 57 ˚C. 1H-NMR: (CDCl3) 7.62 (s, 1H), 7.50 (s, 1H), 3.92 (s, 3H).
ACKNOWLEDGEMENTS
The authors would also like to thank our chemistry colleague Joe Bamberg formerly from Sandoz Crop
Protection, Palo Alto, currently with Hoffmann La Roche, Palo Alto who brought the auxin effects to our
attention. We also express our appreciation to Dr. Clemens Lamberth and Dr. Andrew Edmunds,
Syngenta Crop Protection for their comments concerning this manuscript.
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