Synthesis of Novel Fluoropicolinate Herbicides by Cascade Cyclization of Fluoroalkyl Alkynylimines

Article abstract of DOI:10.1021/acs.orglett.5b01176

The cascade cyclization of fluoroalkyl alkynylimines with primary amines has been modified to allow the synthesis of 4-amino-5-fluoropicolinates. Use of N-trityl and acetal protecting groups in the cyclization precursor led to 5-fluoropyridines that were

Full text of DOI:10.1021/acs.orglett.5b01176

Letter
pubs.acs.org/OrgLett
Synthesis of Novel Fluoropicolinate Herbicides by Cascade
Cyclization of Fluoroalkyl Alkynylimines
Peter L. Johnson,‡ James M. Renga,† Christopher V. Galliford,‡ Gregory T. Whiteker,*,‡
and Natalie C. Giampietro*,†
†Discovery Chemistry and ‡Process Chemistry, Dow AgroSciences, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
S
* Supporting Information
ABSTRACT: The cascade cyclization of fluoroalkyl alkynylimines with primary
amines has been modified to allow the synthesis of 4-amino-5-fluoropicolinates.
Use of N-trityl and acetal protecting groups in the cyclization precursor led to 5-
fluoropyridines that were easily deprotected to picolinaldehyde derivatives for
further elaboration to structures of interest as potential herbicides. This method
provided access to picolinic acids with alkyl or aryl substituents at the 6-position that were previously inaccessible via cross-
coupling chemistry.
icolinic acid herbicides have been an active area of
commercial interest for decades. Broadleaf herbicides of
this class function through an auxinic mode of action and are
widely used in cereal and pasture applications. Examples of
commercial picolinate herbicides include picloram1 and amino-
pyralid2 (Figure 1). More recently, new highly potent 6-
aminopyralid6 with F-TEDA, followed by cross-coupling
reactions, has been employed to access synthetic targets.7
This method has two major limitations. First, the electrophilic
fluorination step suffers from marginal conversion and high
reagent cost. Second, although many relatively simple aryl and
heteroaryl boronates are commercially available, species with
more complex substitution patterns are limited. As a result, far
fewer pyridyl targets with aliphatic groups at the 6-position
have been synthesized.
P
Attracted by a recent report of the synthesis of multiply
substituted 5-fluoropyridines by the cascade cyclization of
fluoroalkyl alkynylimines with primary amines,8 we envisioned
this method could provide access to new 5-fluoropicolinic acid
herbicide targets if the resulting 4-NHAr substituent could be
cleaved to an −NH2 group (Scheme 1). Although most
Scheme 1. Cascade Cyclization of Trifluoromethylalkynyl
Imines
Figure 1. Picolinic acid auxinic herbicides.
arylpicolinate herbicides, including Arylex active3 and DAS-
534,4 have been reported. These newer auxinic herbicides
provide effective control of broadleaf weeds with extremely low
use rates. The continued development of effective herbicidal
products which maximize crop yields is necessary to support
the growing world population and to counteract losses of arable
land.5
Continued investigation of structure−activity relationships
for the identification of new herbicides can be enabled by the
development of new synthetic methods. In addition, route
scoping for scale-up and synthesis of radiolabeled compounds
often require the development of new synthetic methods. We
were particularly interested in new strategies for the synthesis of
4-amino-3-chloro-5-fluoropicolinates with alkyl or aryl sub-
stituents at the 6-position because facile introduction of the 5-
fluoro substituent is challenging. Previously, fluorination of
reported examples of this cascade cyclization employed N-
phenyl imines, one example using a N-p-methoxyphenyl (PMP)
imine was described. We proposed that oxidative deprotection
of the resulting N-PMP group followed by pyridine ring
chlorination could lead to new herbicidal analogs.
We first explored this strategy for the synthesis of DAS-534.
Alkynylimine 2a was prepared by Sonogashira coupling of 1
with methyl propiolate in 74% yield. Cyclization of 2a with 4-
chlorobenzylamine using Cs2CO3 in THF at 80 °C gave
pyridine derivative 3a in 40% isolated yield. Oxidative removal9
Received: April 21, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01176
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Organic Letters
Letter
of the N-PMP group using NaIO4 was unsuccessful.
Fortunately, reaction of 3a with 2 equiv of 1,3-dichloro-5,5-
dimethylimidazolidine-2,4-dione (DCDMH) in CH3CN/H2O
gave the azaquinone, 4a, in 79% isolated yield (Scheme 2).
Scheme 3. Chlorination/Deprotection of N-PMP Acetal 3d
Scheme 2. Oxidative Deprotection−Chlorination Sequence
Hydrolysis of azaquinone 4a with aqueous sulfuric acid gave the
4-aminopyridine 5 in 85% yield. Chlorination of the pyridine
ring at the 3-position of 5 with 0.60 equiv of DCDMH gave 6
in 73% yield. Alternatively, 3a can be directly converted to 6 in
38% yield by one-pot deprotection−chlorination using 2 equiv
of DCDMH in CH3CN/H2O in the presence of H2SO4.
Hydrolysis of 6 with NaOH in MeOH gave DAS-534 in 11%
overall yield from 1, thus demonstrating the successful
application of the cascade cyclization sequence to the synthesis
of picolinate herbicides.
Scheme 4. Use of N-Trityl Protecting Group in Cascade
Cyclization Synthesis of DAS-534
Given the relatively low yield for cyclization of 2a to 3a, we
explored the use of alkynylimine substituents that could be
eventually converted to a carboxylic acid after cascade
cyclization (Table 1). Cyclization of the t-Bu ester 2b with 4-
Table 1. Effect of Alkynylimine Substituent on Cascade
Cyclization Yield with 4-Chlorobenzylamine (Conditions:
Cs2CO3, THF, 80 °C)
Ph3CNH2, CCl4, and CF3CO2H in the presence of PPh3 and
Et3N, followed by Sonogashira coupling. The initial report of
cascade cyclization of CF3-alkynylimines with primary amines
included the results of a solvent screen which showed that
ethers, such as THF and DME, gave higher selectivity to
fluoropyridine products.8a During our investigation, we found
that use of DMSO led to faster cyclization rates than THF with
no decrease in yield. Cyclization of 10 with 4-chlorobenzyl-
amine in DMSO proceeded in 81% yield to give N-trityl-
protected pyridine 11a. Both the N-trityl and acetal protecting
groups were hydrolyzed in 90% yield to give the 4-amino
picolinaldehyde 12a. Chlorination of aldehyde 12a with
DCDMH gave 3-chloro-4-amino picolinaldehyde 8 in 70%
yield.
R
pyridine
yield (%)
CO2Me
CO2tBu
2-Furyl
3a
3b
3c
3d
40
12
61
81
CH(OEt)2
By incorporating N-trityl and acetal protecting groups in 10,
the combined yield of the cascade cyclization and deprotection
steps was significantly improved. A variety of primary amines
were cyclized with 10 (Table 2) to yield 6-alkyl substituted
picolinaldehyde derivatives after deprotection. Notably, this
method allowed synthetic access to pyridine derivatives with
alkyl and cycloalkyl substituents at the 6-position that were
difficult to prepare by cross-coupling routes, due to the
instability and/or lack of accessibility of the requisite
organometallic reagent. Use of MeNH2 allowed access to the
6-H derivative 11b, whereas neo-pentylamine reacted with 10 to
form 6-tert-butylpyridine 11d. Cyclization of 10 with allylamine
gave the 6-vinyl derivatives 11g. Heterocyclic primary amines
were also tolerated. Notably, ethanolamine reacted with high
chemoselectivity at the amine functional group to give 6-
hydroxymethyl derivative 11j. Subsequent deprotection under
acidic conditions proceeded smoothly.
chlorobenzylamine occcurred in very low yield. The 2-
furylalkynylimine 2c underwent cyclization in higher yield,
but attempts to convert the resulting 2-furyl substituent
oxidatively to a carboxylic acid were unsuccessful. The acetal-
protected alkynylimine 2d cyclized efficiently in THF with 4-
chlorobenzylamine to give 3d in 81% yield (Scheme 3).
Removal of the N-PMP group was performed by a two-step
procedure. Reaction of 3d with DCDMH gave the 3-
chloroazaquinone derivative 7 in 30% yield. Subsequent
hydrolysis of the azaquinone and acetal groups with 1 M
H2SO4 gave the 4-amino picolinaldehyde 8 in 68% yield.
Pinnick oxidation of 8 gave DAS-534 in 72% yield.
Despite the improved cyclization yield obtained with the
acetal-protected alkynylimine, the low yielding oxidative
removal of the N-PMP group limited the utility of this method.
Use of an N-trityl protecting group was found to allow
deprotection in much higher yield than N-PMP (Scheme 4). N-
Trityl alkynylimine 9 was prepared analogously to 2d from
In summary, the utility of the cascade cyclization of
fluoroalkyl alkynylimines with primary amines has been
B
DOI: 10.1021/acs.orglett.5b01176
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of The Dow Chemical Company (“Dow”) or an affiliated company of
Dow.
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Table 2. Synthesis of Substituted 4-Amino-5-fluoro-6-
alkylpicolinaldehydes by Cascade Cyclization
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(10) Synthesis of 14C-labeled pyridines using this method will be
reported separately.
a
b
100 °C, 2.5 h. 60 °C, 3 h.
optimized for the synthesis of 4-amino-5-fluoropicolinates by
incorporating N-trityl and acetal protecting groups in the
cyclization precursor. The resulting pyridines were easily
deprotected to picolinaldehyde derivatives for further elabo-
ration to structures of interest as potential herbicides. This
method provides access to picolinic acids with alkyl or aryl
substituents at the 6-position that were previously inaccessible
by cross-coupling chemistry. In addition, radiolabeled com-
pounds can also be prepared by use of isotopically labeled
amines.10
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental data, characterization data, and spectra of
compounds. The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.orglett.5b01176.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: whitekgt2@dow.com.
*E-mail: ncgiampietro@dow.com.
Notes
The authors declare no competing financial interest.
REFERENCES
■
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C
DOI: 10.1021/acs.orglett.5b01176
Org. Lett. XXXX, XXX, XXX−XXX