Development of a Practical Synthesis of a Pyrimidine Derivative with Fungicidal Activity

Article abstract of DOI:10.1021/acs.oprd.9b00130

A scalable synthesis of a pyrimidine fungicide lead was developed. The pyrimidine head, 1-(5-bromopyridin-2-yl)-2,2-dimethyl-1-(pyrimidin-5-yl)propan-1-ol, was prepared by metal-halogen exchange of 2-iodo-5-bromopyridine with i-PrMgCl followed by treatment with pivaloyl chloride (PivCl) in the presence of CuCN·2LiCl and subsequent addition of 5-lithiopyrimidine. The boronic acid tail, (4-(1-cyanocyclobutyl)-2-fluorophenyl)boronic acid, was prepared via treatment of 1-(4-bromo-3-fluorophenyl)cyclobutane-1-carbonitrile with i-PrMgCl and trimethylborate. The o-fluoro Grignard reagent formed during this reaction sequence was analyzed by two-drop calorimetry and accelerating rate calorimetry, which revealed minimal safety concerns for scale-up. Finally, the boronic acid tail was coupled with the pyrimidine head in the presence of catalytic palladium acetate [Pd(OAc)₂]/triphenylphosphine (PPh₃) to deliver the final product in >95% yield after crystallization.

Full text of DOI:10.1021/acs.oprd.9b00130

Article
pubs.acs.org/OPRD
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
Development of a Practical Synthesis of a Pyrimidine Derivative
with Fungicidal Activity
Sarah J. Ryan and Qiang Yang*
Product Design & Process R&D, Corteva Agriscience, 9330 Zionsville Road, Indianapolis, Indiana 46268, United States
ABSTRACT: A scalable synthesis of a pyrimidine fungicide lead was developed. The pyrimidine head, 1-(5-bromopyridin-2-
yl)-2,2-dimethyl-1-(pyrimidin-5-yl)propan-1-ol, was prepared by metal−halogen exchange of 2-iodo-5-bromopyridine with i-
PrMgCl followed by treatment with pivaloyl chloride (PivCl) in the presence of CuCN·2LiCl and subsequent addition of 5-
lithiopyrimidine. The boronic acid tail, (4-(1-cyanocyclobutyl)-2-fluorophenyl)boronic acid, was prepared via treatment of 1-
(4-bromo-3-fluorophenyl)cyclobutane-1-carbonitrile with i-PrMgCl and trimethylborate. The o-fluoro Grignard reagent formed
during this reaction sequence was analyzed by two-drop calorimetry and accelerating rate calorimetry, which revealed minimal
safety concerns for scale-up. Finally, the boronic acid tail was coupled with the pyrimidine head in the presence of catalytic
palladium acetate [Pd(OAc)2]/triphenylphosphine (PPh3) to deliver the final product in >95% yield after crystallization.
KEYWORDS: pyrimidine, fungicide, agrochemicals, lithiation of 5-bromopyridine, Grignard exchange,
Suzuki−Miyaura cross-coupling
raphy was required for purification of all intermediates as well as
the final product 1. These limitations of the discovery route
clearly necessitated a more scalable and cost-effective route to
support project needs.
INTRODUCTION
During the course of our investigations, pyrimidine derivative 1
(Figure 1) was found to have good activity against a key cereal
■
RESULTS AND DISCUSSION
■
During retrosynthetic analysis, we decided to maintain the
Suzuki−Miyaura cross-coupling as the last step to assemble the
final product 1, but via a more convergent approach that
reversed the identity of the boronic acid and aryl bromide cross-
coupling intermediates (Scheme 2). To enable this, focus was
placed on developing affordable and scalable methods for the
preparation of both pyrimidine head 7 and boronic acid tail 14.
Attempted Synthesis of Pyrimidine Head 7 via 12 or 6.
Initial investigations focused on the use of 5-cyanopyrimidine
(15) to introduce the pyrimidine moiety via nucleophilic
addition to nitrile cyanide ion. Intermediate 15 can be prepared
via treatment of 5-bromopyrimidine with potassium ferricyanide
at elevated temperatures.2 It was postulated that 15 could be
converted to 7 via consecutive addition of two Grignard reagents
to install the tert-butyl and pyridine motifs. Toward this end, two
parallel reactions were performed, wherein 15 was treated with t-
BuMgBr and Grignard reagent 5, respectively. Unfortunately,
neither reaction proceeded as planned. Instead, these reactions
produced the undesired dihydropyrimidines 16 and 17,
respectively, as the major products. This was attributed to
Grignard addition to the electron-deficient pyrimidine ring
system (Scheme 3).
Figure 1. Structure of 1.
pathogen, Septoria tritici (SEPTTR).1 To support further
evaluation of the biological efficacy of this compound, we
were tasked to identify and optimize scalable and cost-effective
routes to this molecule.
The discovery route was used to produce gram quantities of
compound 1 for initial regulatory and field biology studies, but
this route was not suitable for larger-scale synthesis (Scheme
1).1 The starting material, pyrimidine-5-carboxylic acid (2),
would be prohibitively expensive on large scale, presumably
because of its preparation from 5-bromopyrimidine via
cryogenic lithiation (−95 °C). Also, a number of trans-
formations in the discovery route utilized expensive conditions,
such as the formation of Weinreb amide 3 using N-ethyl-N′-(3-
(dimethylamino)propyl)carbodiimide hydrochloride (EDCI)
to ensure selectivity of the Grignard reaction and the two
sequential Pd-catalyzed cross-coupling reactions. In addition,
there were many low-yielding steps in the sequence: (1) the
addition of t-BuMgBr to ketone 6 (48% yield), (2) the
installation of the cyclobutyl ring (42% yield), and (3) the
Suzuki−Miyaura cross-coupling for the synthesis of 1 under
microwave conditions (54% yield). Finally, column chromatog-
From these results it was apparent that the pyrimidine was
more electrophilic than the nitrile substituent. In contrast, the
Grignard addition of 5 to 5-ketopyrimidine 6 in the discovery
route successfully provided the desired pyrimidine head 7, albeit
Special Issue: Corteva Agriscience
Received: March 22, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00130
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Scheme 1. Discovery Route to Compound 1
Scheme 2. Retrosynthetic Analysis toward the Synthesis of 1
in only 48% yield (Scheme 1). It was reasoned that a pyrimidine
bearing a ketone at the 5-position should serve as an appropriate
intermediate toward accessing target 1.
Vinamidinium salts, prepared from affordable starting
reagents, have been employed for the preparation of a variety
of pyrimidine products via condensation with formamidines.3
These salts offer a potentially cost-effective alternative for the
preparation of 1; however, the requisite 3-acylvinamidinium salt
was unprecedented in the literature, presumably because of side
reactions of the acyl group with the Vilsmeier−Haack reagent
during preparation. It was envisioned that these undesired side
reactions could be avoided by protecting the ketone as an
enamine to afford the desired vinamidinium dication and
therefore enable the cyclization with formamidine (Scheme 4).
To test this hypothesis, enamine 19 was prepared from
pinacolone via treatment with titanium tetrachloride and
pyrrolidine. The resulting enamine 19 was then treated with
phosphoryl chloride (POCl3) in N,N-dimethylmethanamide
(DMF) to afford the vinamidinium chloride, which precipitated
out as a white solid upon addition of sodium hexafluorophos-
B
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Scheme 3. Grignard Addition to 5-Cyanopyrimidine
Scheme 4. Proposed Approach to Ketone 12 via
Vinamidinium salt 18
of the pyrimidine head 7 via the addition of the Grignard reagent
5 to ketone 12. Unfortunately, the only product isolated from
this reaction was dihydropyrimidine 21. This was also the case
when the organolithium reagent was utilized (Scheme 5).
Scheme 5. Attempted Synthesis of 7 from 12
phate to give vinamidinium dihexafluorophosphate 18.
Vinamidinium salt 18 was then treated with formamidine
under a variety of conditions (Table 1). Between the two
possible cyclization pathways, it was expected that the undesired
aldehyde 20 would be disfavored because of the steric
interaction of the tert-butyl group with the aldehyde at the 3-
position. In addition, it was anticipated that tautomer 18a would
be more reactive than tautomer 18b. Interestingly, preliminary
results indicated that sodium ethoxide (NaOEt) in acetonitrile
(MeCN) favored the desired ketone 12 (entry 2), whereas
sodium hydroxide (NaOH) in DMF favored the undesired
aldehyde 20 (entry 4).
From these results it was apparent that Grignard reagents
preferentially add to the pyrimidine ring over either the nitrile
group in 15 or the tert-butyl ketone in 12. Closer inspection of
With acceptable conditions in hand for the preparation of
ketone 12, attention was next turned to validating the synthesis
Table 1. Condensation of Vinamidinium 18 with Formamidine
entry
conditions
product ratio (12:20)
1
2
3
4
5
EtOH (0.05 M), 6 equiv of NaOEt, 22 °C
MeCN (0.25 M), 1.5 equiv of NaOEt, 22 °C
MeCN (0.25 M), 1.5 equiv of NaOEt, 80 °C
DMF (0.17 M), 5 equiv of NaOH, 22 °C
EtOH (0.05 M), 5 equiv of NaOH, 22 °C
5:2
1:0
9:1
1:2
3:4
C
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Scheme 6. Observed Impurities during the Grignard Addition of t-BuMgBr to 6
Scheme 7. Attempted Synthesis of 13
the reaction of 6 with t-BuMgBr in the discovery sequence
revealed the presence of 22 and 23 as minor impurities,
indicating that the pyrimidine ring of 6 is also susceptible to
nucleophilic attack (Scheme 6). To avoid these types of side
reactions, it was decided to pursue a late-stage installation of the
pyrimidine moiety via ketone 13 for the preparation of
pyrimidine head 7.
Synthesis of 7 via 13. Initial attempts to synthesize 13 via
the addition of t-BuMgBr to 5-bromo-2-cyanopyridine (24)
were made. Interestingly, tert-butyl-substituted pyridine 25 was
the only product observed in a modest 22% isolated yield.
Knochel reported similar substitution reactions of Grignard
reagents with 4-cyanopyridines, and the Lewis acid boron
trifluoride etherate (BF3·Et2O) is typically required to facilitate
the displacement of cyanide.4 In our case, 24 underwent
substitution of cyanide ion with t-BuMgBr without the need for
Lewis acid activation of the pyridine ring (Scheme 7).
reagents, and once formed, it is unlikely that Mg can migrate
between the 2- and 5-positions of pyridine.
Literature results indicated that 2,5-dibromopyridine under-
goes selective Mg−Br exchange at the undesired 5-position.
However, we found that the desired regioisomer of the Grignard
reagent was produced using 2-iodo-5-bromopyridine (4). After
generation of the Grignard reagent with i-PrMgCl, PivCl and a 2
mol % loading of copper(I) cyanide bis(lithium chloride)
complex (CuCN·2LiCl) were concurrently added to afford the
desired ketone 13 in 67% yield after distillation (0.1 mmHg) at
100 °C, thus avoiding column chromatography.7 Compound 29
was isolated as the major product when the reaction was carried
out in the absence of CuCN·2LiCl, regardless of the order of
addition (Scheme 8). It was speculated that this product was
formed via acylation of the desired product, leading to
intermediate 28, which further reacted with an additional
Scheme 8. Generation of Ketone 13 from 4 and PivCl
Alternatively, ketone 13 could be accessed via the reaction of a
2-metallo-5-bromopyridine with PivCl. It is well-known that
treatment of 2,5-dibromopyridine with n-butyllithium (n-BuLi)
can give either the 2-lithio-5-bromopyridine or 5-lithio-2-
bromopyridine isomer depending on the reaction conditions.5
This is due to the kinetic preference of 2-lithio-5-bromopyridine
isomer followed by equilibration to the thermodynamically
stable 5-lithio-2-bromopyridine isomer. When lithiation is
carried out in a coordinating solvent, such as tetrahydrofuran
(THF), equilibration is rapid and 5-lithio-2-bromopyridine is
the preferred product. In contrast, when the reaction is carried
out in toluene at low concentrations, equilibration is slow at low
temperature, allowing selective interception of the kinetic
product, 2-lithio-5-bromopyridine. However, the low concen-
tration and cryogenic conditions required for generation of 2-
lithio-5-bromopyridine make this approach unattractive on a
large scale. Therefore, focus was placed on the generation of 5-
bromopyridin-2-ylmagnesium bromide.6 Grignard reagents are
more stable and less basic than the corresponding organolithium
D
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Scheme 9. Activation of 5-Bromopyrimidine (30)
Scheme 10. Synthesis of 14
equivalent of Grignard reagent. Copper suppressed this pathway
by rapid transmetalation with the Grignard reagent followed by
oxidative addition of the acyl chloride and reductive elimination.
With a scalable synthesis of 13 in hand, we next focused on the
late-stage installation of pyrimidine to 13. Initial attempts to
generate Grignard reagent 31 from 5-bromopyrimidine (30)
with i-PrMgCl in THF at −20 °C resulted in the formation of
dihydropyrimidine 32 as the major product, resulting from
nucleophilic addition to the pyrimidine ring, along with a trace
amount of the desired Grignard reagent 31. Lowering the
reaction temperature did not improve the conversion to the
desired Grignard reagent.8 Turbo Grignard, i-PrMgBr·LiCl, was
used in place of i-PrMgCl in an attempt to favor the formation of
the desired Grignard reagent by increasing the rate of halogen-
metal exchange; however, 32 was still the only product observed.
As Grignard reagent 31 proved to be difficult to generate,
attention was turned to the generation of 5-lithiopyrimidine
(35). Organolithium reagent 35 was generated as the major
product at −95 °C via addition of 30 to n-BuLi (Scheme 9)9 and
then treated with ketone 13. Tertiary alcohol 7 was isolated in
57% yield after column chromatography, confirming the
feasibility of this strategy for the synthesis of the pyrimidine
head 7 for Suzuki−Miyaura cross-coupling. Unfortunately, the
low temperature required for selective lithiation (−95 °C) is
typically very difficult to achieve on scale in a batch mode
process and requires specialized equipment. To address this, the
stability of 35 at higher temperatures was investigated.
Preliminary results indicated that 35 was stable over time up
to −75 °C, although several impurities (including 33 and 34
resulting from the addition of organolithium reagents to the
pyrimidine ring system) were observed. Our results were also
consistent with the fenarimol fungicide process, in which 35 was
prepared at −75 °C under continuous flow conditions.10
The yield of the reaction of organolithium reagent 35 with
ketone 13 was increased to 70% by concurrent addition of n-
BuLi and 30 at −75 °C. It was reasoned that the successful
control of side reactions during the lithiation of 30 with n-BuLi
under continuous flow conditions in the fenarimol process
benefited from the concurrent addition of n-BuLi and 30. This
reaction was successfully scaled up to afford 48 g of pyrimidine
head 7 in 76% isolated yield after column chromatographic
purification. Preliminary results further demonstrated that the
desired product 7 could be purified via recrystallization from
ethyl acetate (EtOAc)/heptanes.
Synthesis of Boronic Acid 14. Boronic acid 14 or a similar
boron derivative such as pinacol boronic ester 36 was designed
to allow convergent access to the final product 1 via Suzuki−
Miyaura cross-coupling. Although pinacol boronic ester 36 was
successfully obtained via the 1,1′-bis(diphenylphosphino)-
ferrocene]palladium(II) dichloride [Pd(dppf)Cl2]-catalyzed
E
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borylation of 9 with pinacolborane in the presence of potassium
acetate (KOAc) in dioxane and coupled with 7 to afford the
desired product 1,11 there was interest in identifying a more
economical set of conditions for the preparation of this key
intermediate or its equivalent. Attempts to directly borylate 37
by lithiation with lithium diisopropylamide (LDA) followed by
treatment with trimethylborate did not result in the desired
product 14. The desired boronic acid 14 was obtained in 42%
isolated yield when aryl bromide 9 was treated with n-BuLi at
−78 °C and then quenched with trimethylborate.12 The low
yield was attributed to the formation of the major impurity 38,
which was likely formed via direct addition of n-BuLi to the
nitrile group. Alternatively, Grignard−halogen exchange was
investigated to overcome this undesired side reaction. To this
end, aryl bromide 9 was treated sequentially with i-PrMgCl and
trimethylborate to afford the desired boronic acid in 90%
isolated yield (Scheme 10). Further investigations revealed that
boronic acid 14 could be purified via pH adjustment during the
aqueous extractive workup to remove impurities, providing 97%
purity.
Potential safety hazards associated with o-fluoro Grignard
reagents are well-documented in the literature.13 These reactive
intermediates have been reported to form arynes via elimination,
which can potentially result in a runaway reaction. Two-drop
calorimetry analysis of the mixing of i-PrMgCl with aryl bromide
9 indicated an exotherm of −51.7 J/g, which was consistent with
the typical exotherm of the Grignard exchange. Accelerating rate
calorimetry (ARC) evaluation of the Grignard reagent from the
exchange of aryl bromide 9 with i-PrMgCl did not reveal
significant exothermic activity below 290 °C, indicating low
safety risk under the reaction conditions.
end, we evaluated palladium acetate [Pd(OAc)2] as an alternate
catalyst precursor in the presence of PPh3 in a variety of solvents
(Table 2). In all cases examined, the Suzuki product was formed
in over 90% yield when the reaction was conducted in a sealed
pressure vessel at or above 80 °C. However, when the reactions
using 1:1 THF/water and MeCN/water were repeated under
reflux in an open system, pyrimidine head 7 was not completely
consumed, and decomposition of boronic acid 14 was observed
by HPLC analysis. Among all of the evaluated conditions, the
reaction in 1:1 1,4-dioxane/water in the presence of Pd(OAc)2,
PPh3, and K2CO3 at 85 °C afforded the best yield and
reproducibility. These conditions were scaled up to a 10 g scale
successfully to afford the desired product 1 in quantitative yield
after recrystallization from 8 volumes of 1:7 EtOAc/heptanes.
Residual Pd was typically in the 1000−2000 ppm range when
the product 1 was isolated via recrystallization from EtOAc/
hexanes. While column chromatographic purification success-
fully afforded the desired product with nondetectable residual
Pd, it was desirable to develop a scalable isolation/purification
process that circumvented the need for column chromato-
graphic purification on a large scale. Several methods were tested
to remove the residual Pd (Table 3). Initial attempts using
activated charcoal did not significantly reduce the residual Pd
level (entry 2), nor did washing with aqueous ethylenediami-
netetraacetic acid (EDTA) solutions (entry 3). However, the
amount of Pd was reduced from 1710 to 350 ppm when the
crude product was stirred in the presence of aqueous sodium
hydrogen sulfite (NaHSO3) at 80 °C (entries 4−6). While
further reduction of the residual Pd was not attempted, it was
expected that the residual Pd level would continue to decrease
with additional aqueous NaHSO3 treatments.
Originally the synthesis of 9 was achieved in up to 42% yield
by treatment of 10 with 1,3-dibromopropane (11) in the
presence of sodium hydride (NaH) or potassium tert-butoxide
(KOt-Bu) in THF at 5 °C. Literature research showed that a
related analogue was synthesized in >70% yield by treatment of
the benzylnitrile with 11 using potassium carbonate (K2CO3) as
the base in the presence of a phase-transfer catalyst in acetone.14
Application of these literature conditions afforded the desired
product 9 in 60% yield after a silica gel plug purification (Scheme
11).
CONCLUSIONS
■
A scalable convergent route to fungicidal lead 1 was developed
(Scheme 12). The newly developed route avoided the use of the
expensive starting material pyrimidine-5-carboxylic acid. Inter-
mediate 13 was synthesized in 67% yield after distillation via
Grignard exchange of 4 with i-PrMgCl followed by reaction with
PivCl in the presence of a catalytic amount of CuCN·2LiCl.
Late-stage installation of the pyrimidine was achieved in good
yield via the concurrent addition of n-BuLi and 5-bromopyr-
imidine followed by treatment with ketone 13 at −75 °C.
Boronic acid 14 was prepared via halogen−metal exchange of
aryl bromide 9, thus avoiding the need for expensive palladium
cross-coupling conditions. The final coupling was achieved in
the presence of catalytic Pd(OAc)2/PPh3, affording the final
product in >95% yield after crystallization. Most column
chromatographic purifications were replaced with scalable
distillation or recrystallization processes. This route represents
a solid basis for further development of a process suitable for
larger-scale production.
Scheme 11. Synthesis of 9
Suzuki−Miyaura Cross-Coupling of 7 and 14. The
assembly of the final product 1 in the discovery route was
performed under microwave conditions using aryl bromide 9
and pinacol boronic ester 8 as coupling partners in the presence
of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) as
the catalyst in toluene/EtOH/water. This reaction provided 1 in
54% yield after column chromatography to remove impurities,
residual palladium, and a large amount of pinacol byproduct.
The use of boronic acid 14 as a coupling partner circumvented
the need for removal of pinacol and therefore aided in the
development of nonchromatographic purification methods. In
addition, there was interest in identifying a less expensive
catalyst and a scalable method for palladium removal. To this
EXPERIMENTAL SECTION
■
General. All reagents were commercially available and used
as purchased without further purification. Unless otherwise
noted, all reactions were performed in round-bottom or jacketed
cylindrical flasks under nitrogen. 1H NMR spectra were
recorded on a Bruker Ultrashield 400 NMR spectrometer.
Mass spectra were obtained using a Waters Micromass ZQ mass
spectrometer. HPLC analysis was performed using an Agilent
1260 chromatograph with a YMC Pack-ODS-AQ column (4.6
mm × 150 mm, 5.0 μm, P/N 0415212347); mobile phase A:
F
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Table 2. Suzuki−Miyaura Cross-Coupling of 7 and 14
entry
solvent (ratio)
equiv of Pd(OAc)2
equiv of PPh3
temperature (°C)
isolated yield (%)
1
2
3
4
5
6
7
8
9
dioxane/water (5:2)
dioxane/water (1:1)
DMF/water (5:2)
DMF/water (1:1)
THF/water (5:2)
THF/water (1:1)
THF/water (1:1)
MeCN/water (5:2)
MeCN/water (1:1)
MeCN/water (1:1)
0.01
0.01
0.02
0.02
0.02
0.02
0.01
0.01
0.01
0.01
0.02
0.02
0.04
0.04
0.04
0.04
0.02
0.02
0.02
0.02
85
85
85
85
80
80
98
96
95
89
94
94
a
a
a
a
reflux (68)
85
85
ND
91
a
94
10
reflux
57
a
In-pot yield.
Preparation of 13. To a solution of 4 (20 g, 70.4 mmol) in
THF (140 mL) was added a 2 M solution of i-PrMgCl in THF
(42.3 mL, 85 mmol) at below −10 °C, and the reaction was
stirred at below −10 °C for 1 h. After this time the mixture was
cooled to −40 °C, and pivaloyl chloride (13 mL, 106 mmol) and
a 2 M solution of CuCN·2LiCl in THF (0.7 mL, 1.4 mmol) were
slowly added while the internal temperature was maintained
below −35 °C. The reaction mixture was allowed to warm to
room temperature over 30 min and stirred at room temperature
for an additional 2 h. After this time the reaction mixture was
quenched with 1 N NaOH (30 mL) to pH 10. The layers were
separated, and the aqueous phase was extracted with EtOAc (3
× 50 mL). The combined organic layers were dried over
anhydrous Na2SO4, filtered, and concentrated to provide a
brown oil. The oil was purified via distillation under reduced
pressure (0.1 mmHg, fractions collected at a bath temperature of
Table 3. Nonchromatographic Removal of Palladium from 1
residual Pd (ppm)
entry
conditions
starting level
ending level
1
2
3
4
5
6
control
activated charcoal
aqueous EDTA wash
NaHSO3, THF, 80 °C
NaHSO3, MeCN, 80 °C
NaHSO3, toluene, 80 °C
1710
1710
1710
1710
1710
1710
1710
1180
1710
350
425
350
water (0.5% formic acid), mobile phase B: MeCN (0.5% formic
acid); gradient: 30 to 95% B over 18 min, hold for 4 min, 95 to
30% B over 0.5 min, postrun equilibration for 2.5 min; flow rate:
1.0 mL/min; column temperature: 20 °C; UV detector: 265 nm.
Scheme 12. New Route to 1
G
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90−100 °C) to afford the desired product 13 as a clear oil (11.4
g, 67% yield). 1H NMR (400 MHz, CDCl3): δ 8.68 (dd, J = 2.3,
0.6 Hz, 1H), 7.92 (dd, J = 8.4, 2.3 Hz, 1H), 7.82 (dd, J = 8.4, 0.6
Hz, 1H), 1.43 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 205.4,
152.7, 148.8, 148.8, 148.7, 139.3, 125.1, 123.8, 44.1, 27.4. MS:
m/z 241 [M]+.
mL). The layers were separated, and the aqueous phase was
extracted with EtOAc (3 × 30 mL). The combined organic
layers were dried over anhydrous Na2SO4, filtered, and
concentrated to provide 14 as a yellow solid (7.48 g, 87%
yield). Mp: 92−98 °C. 1H NMR (500 MHz, DMSO-d6): δ 8.27
(s, 2H), 7.62 (t, J = 7.1 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 7.18 (d,
J = 10.1 Hz, 1H), 2.80−2.65 (m, 2H), 2.59 (q, J = 9.5 Hz, 2H),
2.33−2.09 (m, 1H), 2.08−1.87 (m, 1H). 13C NMR (126 MHz,
DMSO-d6): δ 166.12 (d, J = 245.8 Hz), 144.09 (d, J = 7.9 Hz),
136.54 (d, J = 9.8 Hz), 124.42, 121.49 (d, J = 2.6 Hz), 112.8,
112.6, 39.7, 34.17, 17.21. MS: m/z 219 [M]+.
Preparation of 1. A mixture of 7 (10 g, 31 mmol), 14 (7.8 g,
35.7 mmol), K2CO3 (8.6 g, 62 mmol), and PPh3 (0.33 g, 1.2
mmol) was purged with nitrogen for 15 min. Dioxane (34 mL),
degassed water (34 mL), and Pd(OAc)2 (0.14 g, 0.6 mmol) were
added, and the reaction mixture was heated at 85 °C for 4 h. The
reaction mixture was cooled to room temperature, and the layers
were separated. The aqueous phase was extracted with EtOAc (2
× 30 mL), and the combined organic layers were dried over
Na2SO4, filtered, and concentrated. The crude solid was
suspended in EtOAc (10 mL), and heptane (70 mL) was
added. The suspension was stirred at room temperature for 1 h
and filtered. The filter cake was dried under vacuum to provide
the desired product 1 as an off-white solid (12.8 g, 99% yield).
Mp: 152−156 °C. 1H NMR (400 MHz, CDCl3): δ 9.24 (s, 2H),
9.06 (s, 1H), 8.82−8.68 (m, 1H), 8.03−7.91 (m, 1H), 7.88 (dd,
J = 8.4, 0.7 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.41−7.20 (m, 2H),
6.16 (s, 1H), 2.97−2.82 (m, 2H), 2.75−2.56 (m, 2H), 2.49 (dq,
J = 11.7, 8.8 Hz, 1H), 2.25−2.03 (m, 1H), 1.08 (s, 9H). 13C
NMR (101 MHz, CDCl3): δ 161.18, 159.91, 156.81 (d, J = 9.2
Hz), 156.49, 156.42 (d, J = 4.5 Hz), 146.78 (d, J = 11.3 Hz),
137.04, 136.83, 130.91, 130.01, 124.29 (d, J = 13.6 Hz), 123.52,
121.98, 114.84, 79.52, 40.12, 39.80, 34.66, 26.27 (d, J = 9.4 Hz),
17.02. MS: m/z 417.1 [M + H]+.
Preparation of 7. To anhydrous THF (1.2 L) were added a
solution of 5-bromopyrimidine (41.4 g, 257.10 mmol) in
anhydrous THF (150 mL) and n-BuLi (102.2 mL, 257.10
mmol) concurrently while the internal temperature was
maintained below −70 °C with a dry ice/acetone bath. The
reaction mixture was stirred at approximately −75 °C for 1 h,
after which HPLC analysis indicated complete consumption of
5-bromopyrimidine. A solution of 13 (47.4 g, 196.6 mmol) in
anhydrous THF (50 mL) was added over 20 min, while the
internal temperature was maintained below −70 °C, at which
point HPLC analysis indicated 90% conversion of 13 to the
desired product 7. The reaction was quenched by slow addition
of a saturated aqueous solution of NH4Cl (100 mL), followed by
the addition of water (100 mL) and EtOAc (100 mL). The
mixture was allowed to warm to room temperature, and the
layers were separated. The organic layer was washed with a
saturated aqueous solution of NaCl (200 mL), dried over
anhydrous Na2SO4, filtered, and concentrated to a residue under
reduced pressure. The residue was purified by silica gel column
chromatography using 0−40% EtOAc/DCM as the eluent to
give the desired product 7 as a white solid (48.0 g, 98.2% HPLC
1
purity, 76% yield). Mp: 125−127 °C. H NMR (400 MHz,
CDCl3): δ 9.19 (s, 2H), 9.04 (s, 1H), 8.64 (d, J = 2.2 Hz, 1H),
7.87 (dd, J = 8.6, 2.2 Hz, 1H), 7.75−7.60 (m, 1H), 5.51 (s, 1H),
1.02 (s, 9H). 13C NMR (101 MHz, CDCl3): δ 159.7, 156.8,
156.4, 148.4, 139.1, 136.6, 123.5, 119.9, 79.6, 40.0, 26.1. MS: m/
z 322.0 [M + H]+.
Preparation of 9. To a 2 L four-neck round-bottom flask
fitted with a mechanical stirrer, a condenser, a nitrogen inlet, and
a thermocouple were added 10 (100 g, 468 mmol), 11 (81 mL,
560 mmol), K2CO3 (161 g, 1168 mmol), and acetone (1.0 L).
TBAB (15.06 g, 46.7 mmol) was added, and the reaction mixture
was heated at 55 °C, resulting in a dark-blue suspension that
changed to a purple color after 6 h of stirring. After 72 h of
stirring, the reaction mixture was cooled to room temperature
and filtered through a pad of Celite. The pad was rinsed with
acetone (2 × 200 mL), and the combined filtrate was
concentrated to dryness. The residue was passed through a
silica gel plug using 20% EtOAc/heptanes as the eluent. The
filtrates were concentrated to afford the desired product as a
AUTHOR INFORMATION
Corresponding Author
*E-mail: qiang.yang@corteva.com.
■
ORCID
Qiang Yang: 0000-0003-3762-5015
Author Contributions
The manuscript was written through contributions of both
authors. Both authors approved the final version of the
manuscript.
Notes
1
The authors declare no competing financial interest.
white crystalline solid (81 g, 68% yield). Mp: 47−50 °C. H
NMR (400 MHz, CDCl3): δ 7.58 (dd, J = 8.3, 7.1 Hz, 1H), 7.19
(dd, J = 9.4, 2.2 Hz, 1H), 7.11 (ddd, J = 8.3, 2.3, 0.8 Hz, 1H),
2.84 (dddd, J = 12.4, 7.1, 3.4, 1.4 Hz, 2H), 2.65−2.52 (m, 2H),
2.52−2.38 (m, 1H), 2.09 (dtt, J = 11.7, 9.1, 4.4 Hz, 1H). 13C
NMR (101 MHz, CDCl3): δ 159.24 (d, J = 249.0 Hz), 141.49
(d, J = 6.4 Hz), 134.06, 123.33, 122.59 (d, J = 3.6 Hz), 114.14 (d,
J = 23.7 Hz), 108.56 (d, J = 20.9 Hz), 39.71, 34.64, 16.96. MS:
m/z 254 [M]+.
Preparation of 14. A solution of 9 (10 g, 39.4 mmol) in dry
THF (70 mL) was cooled to 0 °C, and i-PrMgCl (23.6 mL of a 2
M solution in THF, 47.2 mmol) was slowly added while the
internal temperature was maintained at <5 °C. The reaction
mixture was stirred at 0 °C for 1 h, and B(OMe)3 (5.32 g, 51.2
mmol) was slowly added while the internal temperature was
maintained at <10 °C. The reaction mixture was stirred at 0 °C
for 30 min and quenched with saturated NH4Cl solution (20
ACKNOWLEDGMENTS
The authors thank Dr. Amaruka Hazari and Dr. Jayachandran
Devaraj for their assistance during this project.
■
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