A Nitrogen-Assisted One-Pot Heteroaryl Ketone Synthesis from Carboxylic Acids and Heteroaryl Halides

Article abstract of DOI:10.1021/acs.joc.6b00194

A practical and highly effective one-pot synthesis of versatile heteroaryl ketones directly from carboxylic acids and heteroaryl halides under mild conditions is reported. This method does not require derivatization of carboxylic acids (preparation of acid chlorides, Weinreb amides, etc.) or the use of any additives/catalysts. A wide substrate scope of carboxylic acids with high functional group tolerance has also been demonstrated. The results reveal that the presence of an α-nitrogen on the halide substrate greatly improves the desired ketone formation.

Full text of DOI:10.1021/acs.joc.6b00194

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Note
A Nitrogen-assisted One-pot Heteroaryl Ketone
Synthesis from Carboxylic Acids and Heteroaryl Halides
Krystyna Demkiw, Hirofumi Araki, Eric L Elliott, Christopher L. Franklin, Yoonjoo Fukuzumi,
Frederick Hicks, Kazushi Hosoi, Tadashi Hukui, Yoichiro Ishimaru, Erin O'Brien, Yoshimasa
Omori, Masahiro Mineno, Hideya Mizufune, Naotaka Sawada, Yasuhiro Sawai, and Lei Zhu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00194 • Publication Date (Web): 18 Mar 2016
Downloaded from http://pubs.acs.org on March 19, 2016
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The Journal of Organic Chemistry
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A Nitrogen-assisted One-pot Heteroaryl Ketone Synthesis
from Carboxylic Acids and Heteroaryl Halides
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Krystyna Demkiw,† Hirofumi Araki,‡ Eric L. Elliott,† Christopher L. Franklin,† Yoonjoo Fukuzumi,‡
Frederick Hicks,† Kazushi Hosoi,‡ Tadashi Hukui,‡ Yoichiro Ishimaru,‡ Erin O’Brien,† Yoshimasa Omoꢀ
ri,‡ Masahiro Mineno,*‡ Hideya Mizufune,‡ Naotaka Sawada,‡ Yasuhiro Sawai,‡ Lei Zhu*†
† Chemical Development Laboratories, Millennium Pharmaceuticals, Inc., a subsidiary of Takeda
Pharmaceutical Company Limited, 40 Landsdowne Street, Cambridge, MA 02139, USA
‡ Chemical Development Laboratories, CMC Center, Takeda Pharmaceutical Company Limited, 17ꢀ85,
Jusohonmachi 2ꢀchome, Yodogawaꢀku, Osaka 532ꢀ8686, Japan
ABSTRACT: A practical and highly effective oneꢀpot synthesis of versatile heteroaryl ketones directly
from carboxylic acids and heteroaryl halides under mild conditions is reported. This method does not
require derivatization of carboxylic acids (preparation of acid chlorides, Weinreb amides, etc.) or use of
any additives/catalysts. A wide substrate scope of carboxylic acids with high functional group tolerance
has also been demonstrated. The results revealed that the presence of an αꢀnitrogen on the halide subꢀ
strate greatly improved the desired ketone formation.
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Heteroaryl ketones are common structures in organic and medicinal chemistry;1 particularly pyridyl keꢀ
tones such as 1,1b a potent COXꢀ2 selective inhibitor, and 2, a key intermediate in the synthesis of TGFꢀ
β type 1 receptor inhibitor LY580276 (Figure 1).1c,d
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Figure 1. Pyridyl Ketones as a Pharmaceutically Active Compound (1) and an Intermediate (2)
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Among synthetic methods for heteroaryl ketones, the reactions between organometallic reagents and
carboxylic acid derivatives (e.g. acid chloride,1b,2 anhydride,3 ester,1c amide,1e,4,5 or nitrile6) are most
widely used. Direct conversion from carboxylic acids is less frequently employed, but is attractive due
to its practical advantages: step/atom efficiency, commercial availability of structurally diverse carboxꢀ
ylic acids, and potentially reduced reaction waste. Gilman first reported the direct conversion of carboxꢀ
ylic acids to ketones using excess organolithium reagents in 1933.7 The method has been applied to hetꢀ
eroaryl ketones, especially 2ꢀpyridyl ketones, by combining with halogenꢀmetal exchange of haloheterꢀ
ocycles.8 However, the main drawbacks of this method include poor functional group tolerance, excess
amount of reagents required, and cryogenic processing. Although various mild reactions using heteroarꢀ
yl Grignard reagents with nonꢀcarboxylic acid electrophiles have been reported1e,2,4,5,9–12 with an excelꢀ
lent functional group tolerance,2 Grignard reagents are less often used directly with carboxylic acids
than the analogous lithium reagents.13ꢀ15 This is likely due to the tendency of Grignard reagents to over
react, leading to the undesired tertiary alcohol.13,14 Recent publications have proposed the improved reꢀ
action of carboxylic acids and aryl metal species with modified Grignard reagents,15 nickelꢀcatalyzed
reactions with Grignard reagents,14 and a palladiumꢀcatalyzed coupling with aryl boronic acid.16 These
methods require a furnished Grignard reagent such as alkyl magnesium amide,15 addition of transition
metal catalyst,14,16 or additives such as di(Nꢀsuccinimidyl)carbonate.16 Moreover, the two Grignard
methods showed only examples using a commercially available phenyl magnesium reagent,14,15 and the
boronic acid reaction requires an extra borylation step.16 To our best knowledge, no example for a direct
ketone synthesis from a carboxylic acid and a pyridyl Grignard reagent has been reported. Therefore, a
convenient and functional group tolerant reaction from a carboxylic acid and a heteroaryl (especially
pyridyl) halide to the corresponding ketone is still in demand.
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Scheme 1. Highly Effective Synthesis of an Aryl-pyridyl Ketone
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2
3
4
1) iPrMgBr (carboxylate formation)
2) 2-I pyr.
O
O
5
3) iPrMgCl•LiCl (halogen-metal exchange
6
7
8
N
then, addition to carbonyl)
4) H+ (elimination)
OH
MeO
MeO
9
3
96%
O
THF, rt
O
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Recent development efforts in our labs focused on the effective preparation of arylꢀpyridyl ketone inꢀ
termediate 3. Treatment of 4ꢀ(methoxycarbonyl)benzoic acid with in situ generated 2ꢀ
pyridylmagnesium chloride provided 3 in 96% isolated yield (Scheme 1). This ketone synthesis is speꢀ
cifically attractive due to its practical advantages: tolerance of an ester group, no tertiary alcohol forꢀ
mation, one pot synthesis, and ambient reaction temperature. Encouraged by its potential in preparation
of highly valuable heteroaryl ketone moieties, investigation was carried out to further explore this transꢀ
formation. Herein, we disclose the reaction scope and limitations.
Table 1. Determining Optimal Reaction Conditions
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Entrya
R
Grignard 1
Grignard 2
(%)b
80
1
2
K
Na
Li
H
H
H
H
H
H
H
H
H
ꢀꢀ
ꢀꢀ
iPrMgCl•LiCl
iPrMgCl•LiCl
iPrMgCl•LiCl
iPrMgCl•LiCl
EtMgCl
87
87
99
86
93
95
59
69
93
90
89
3
ꢀꢀ
4
iPrMgBr
iPrMgBr
iPrMgBr
iPrMgBr
iPrMgBr
iPrMgBr
iPrMgBr
iPrMgBr
iPrMgCl•LiCl
5
6
EtMgBr
7
iPrMgBr
VinylMgCl
VinylMgBr
MeLi
8
9
10
11c
12c
ꢀꢀ
ꢀꢀ
a
Reaction was stirred for 15 min after Grignard 1 addition and 1 h after Grignard 2 addition. Reaction scale: 4 (500 mg) in 25 mL anhyꢀ
drous THF. bConversion to 6 was based on 4 (% conv = AUCꢀ6/(AUCꢀ4 + AUCꢀ6)) and determined by UHPLC (254 nm) of the reaction
mixture. cConsolidated Grignard reagent (2.75 eq.) was added in one portion.
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Our investigation began with a screening of the reaction conditions using benzoic acid inorganic salts or
the free acid (4) and 2ꢀiodopyridine (5) to prepare an arylꢀpyridyl ketone (6) (Table 1). The primary foꢀ
cus was to identify the optimal R group and Grignard reagent combination for clean conversion from 4
to 6. Alkaline metal (K, Na, Li) benzoates were treated with iPrMgCl•LiCl, in the presence of 5 (entries
1–3). HPLC analysis showed clean, but incomplete conversion to 6, likely due to low solubility of the
salts in THF. A counter ion (K vs. Na vs. Li) effect was not observed. The coupling reaction from magꢀ
nesium benzoate generated in situ with iPrMgBr was investigated by combining with a halogenꢀmetal
exchanging reaction. Compared to various Grignard reagents 2 (EtMgCl, EtMgBr, iPrMgBr, Vinylꢀ
MgCl, VinylMgBr), iPrMgCl•LiCl provided the best conversion yield (entry 4 vs. 5–9). The method
was also superior to the corresponding reaction with the other benzoic acid salts (K, Na, Li, entry 4 vs.
1–3). Vinyl magnesium reagents, rarely used for halogenꢀmagnesium exchange, were the least effective
(entries 8–9).17 Interestingly,18 the iodineꢀlithium exchange reaction with MeLi performed equally well
compared to the Grignard reagent (entry 10), and excellent conversion yield was obtained. In addition,
the same Grignard reagents (iPrMgBr, iPrMgCl•LiCl) were confirmed to be applicable to both the salt
formation and the iodineꢀmagnesium exchange reaction (entries 11–12).
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Table 2. Preparation of Heteroaryl Ketones
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a
b
c
Reaction was typically run for 4–5 h. 8 (1.1 eq.), iPrMgBr (1.05 eq.), iPrMgCl•LiCl (1.4 eq.). Extra 8 and iPrMgCl•LiCl used. Yield
without chromatography. dYield after chromatography. e(BINOLate)Bu2MgLi2 added as additive. fwt/wt assay.
To determine the scope of this reaction, acids 7a–b and halides 8a–j were reacted under the optimized
protocol (Table 1, entry 4). Benzoic acid (7a) reacted with 2ꢀiodopyridine (8a) and 2ꢀbromopyridine
(8a’) to afford 9a in 88% (8a) and 83% (8a’) yield respectively.2 Starting from picolinic acid (7b) and
iodobenzene (8b), 9a was obtained in a quite lower yield (46%) compared to the yield from 7a/8a. Conꢀ
sistent with literature,13,14 the reaction between 7a and 8b produced the desired product 9b in a poor
yield (26% determined by wt/wt assay) with notable byproduct formation.19 The remarkable yield difꢀ
ference between 9a and 9b led to a hypothesis that the nitrogen in 8 was critical for desired reactivity.5
The position of the nitrogen relative to the halogen in the heteroaryl halide was also found important
since 9c and 9d were not formed under the same reaction conditions that afforded 9a. A similar 2ꢀ
pyridyl effect was also reported for addition of a pyridyl Grignard reagent to an aldehyde.12 For other
heterocyclic nucleophiles, the reaction went smoothly whenever an αꢀnitrogen was present, and the deꢀ
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sired products were obtained in 79% (9e), 70% (8f→9f), 37% (8f’→9f) and 47% (9g) yield, respectiveꢀ
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5
ly. In contrast, heterocyclic nucleophiles without an αꢀnitrogen reacted sluggishly (9i and 9h) or not at
all (7a and 8j).
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9
Next, the effect of modifying functional groups on the acid substrates 10a–s was studied under the
standard reaction conditions using 2ꢀiodopyridine (5) (Table 3). Halogens were tolerated; 11a, 11b, and
11c were isolated with 94%, 80%, and 64% yield, respectively. The decreasing yields from 11a to 11c
are in agreement with increasing reactivity of Cl, Br, and I with iPrMgCl•LiCl;20 leading to the undeꢀ
sired competing halogen metal exchange over 5. The electron donating methoxy group showed no
change of benzoic acid reactivity and 11d was isolated in 94% yield. A critical intermediate bearing meꢀ
thyl group for the marketed allergy drug triprolidine,21 11e, was readily isolated without chromatogꢀ
raphy in 75% yield. The desired ester (11f and g) and nitrile (11h) products from substituted benzoic acꢀ
ids were obtained in good to excellent yields with high functional group tolerance.2 Distinctively, diacid
10i afforded bis ketone 11i when excess Grignard reagent was used. The targeted ketones containing an
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acidic proton for phenol (11j), acetamide (11k), and indole (11l) were also obtained with excess 5 and
the Grignard reagents in 62%, 82% and 90% yield respectively. A nitrogen or sulfur atom in carboxylic
acid 10 did not interfere with the reaction; 11m and 11n were prepared in moderate to good yields. Aliꢀ
phatic carboxylic acids (10o and 10p), underwent the same reaction to afford mono aryl ketone 11o and
11p in 76% and 82% isolated yield, respectively. A methyl ketone was found reactive towards iPrMgBr
and a tertiary alcohol 11q’ was the main product. Nitro substitution caused complication; 11r and 11s
were not observed by LC/MS.
Table 3. Functional Group Tolerance of the Reaction
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1) iPrMgBr (1.05 eq.)
2) 2-I pyr. (1.1 eq.) (5)
3) iPrMgCl•LiCl (1.2 eq.)
1
2
3
4
O
O
R
R
OH
THF, rt
N
11
10
5
6
7
8
O
O
O
O
MeO2C
9
N
N
N
N
X
MeO
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11ac (X = Cl) 94%,
11bc (X = Br) 80%
11cb,d (X = I) 64%
O
11eb,c
75%
O
11da,b,d
11fc,f (p-CO2Me) 96%
11gc (m-CO2Me) 90%
O
94%
O
O
N
N
N
N
HO
N
11hc
71%
O
N
NC
H
11ka,b,c
11ia,b,c
11ja,b,c
69%
O
O
82%
62%
O
N
O
S
N
11nb,d
NH
N
N
N
11mb,e
66%
O
11oc
11la,b,c
90%
O
88%
76%
O
O
O2N
N
N
N
N
11pc
11q 0%
11r (p-NO2) 0% 11s (o-NO2) 0%
complicated rxn mixture
11q'
O
OH
82%
complicated rxn mixture
Reaction was typically run for 2–5 h. aExtra iPrMgBr used. bExtra 5 and iPrMgCl•LiCl used. Yield without chromatography. Yield after
chromatography. ewt/wt assay. f11f identical to 3.
c
d
By considering the results of this study, the following reaction mechanism was hypothesized (Scheme 2).
The magnesium carboxylate and the secondly added Grignard reagent could form an aggregated magneꢀ
sium species 12, mediated by the adjacent nitrogen atom of heteroaryl halides, as explained by other
bimetallic magnesium reagents.12,22 Magnesium species 12 could accelerate the halogenꢀmetal exchange
to form the second magnesium complex 13 by bringing the halogen atom closer to the secondly added
Grignard reagent.3,12 The complex 13 could readily cause an addition of the Grignard reagent to the carꢀ
boxylate to form dimagnesium tetrahedral intermediate 14 which was stable to prevent undesirable terꢀ
tiary alcohol formation.5,23 The proposed mechanism was supported by the results on a comparison
study to prepare 9a from 8a versus 8b, and also the ketone syntheses from 2ꢀiodopyridine (8a) versus
the corresponding 3ꢀ or 4ꢀ isomers 8c–d or 2ꢀiodothiophene (8i) described in Table 2.12 The data sugꢀ
gested that the αꢀnitrogen coordinated to the Grignard reagent more effectively as a hard organometal
species, compared to the distant nitrogens and the softer sulfur atom. In addition, the formation of agꢀ
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gregated metal species such as 12 might contribute to promotion of the halogenꢀmetal exchange reaction
by vinyl magnesium reagents and MeLi (entry 8–10 in Table 1), which are uncommon for such exꢀ
change due to unsuitable reactivity. The fast halogenꢀmetal exchange based on the aggregated magnesiꢀ
um species 12 might also contribute to high functional group tolerance, e.g. ester and nitrile groups
(11f–h in Table 3).
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Scheme 2. Proposed Reaction Mechanism
Br
Mg
Br
Br
Mg
Mg
Pyridyl Grignard
addition to carbonyl
Halogen-Mg
exchange
O
O
O
O
N
R
R
N
N
O
R
Mg
Mg
I
O
Mg
Cl
i-Pr
Cl
Cl
12
13
14
In conclusion, a oneꢀpot synthesis of heteroaryl ketones from a group of heteroaryl halides and carboxꢀ
ylic acids was demonstrated. It was shown that the presence of an αꢀnitrogen on the halide substrate
greatly improved the reaction. This method allows direct access to ketones without going through addiꢀ
tional process intermediates (acid chloride, Weinreb amides, and etc.). Other highlights include a wide
substrate scope of carboxylic acids with high functional group tolerance, and mild reaction conditions.
EXPERIMENTAL SECTION
General. All chemicals were purchased commercially and used without further purification. Melting
point was measured on a microscopic melting point apparatus. NMR spectra were taken on a 500 MHz
NMR spectrometer with TMS as the internal standard. All UPLC analyses were performed on a UHPLC
system equipped with a BEH C18 (1.7 ꢁm, 2.1 x 50 mm) reverseꢀphase column with a flow rate of 1.0
mL/min. Purification of compounds were performed with an automated chromatography system using
preꢀpacked silica columns. High resolution mass spectrometry studies were performed on a Linear Trap
Quadropole (LTQ) mass spectrometer using an electrospray ion source in positive mode.
General Procedure for Table 1. In order to prepare 6 phenyl(pyridinꢀ2ꢀyl)methanone, carboxylic acid
4 (500 mg, 4.094 mmol, 1.0 equiv) dissolved in anhydrous tetrahydrofuran (25.0 mL) was placed into a
reaction vessel at room temperature under a nitrogen atmosphere. Grignard 1 (4.299 mmol, 1.05 equiv)
was then added dropwise at room temperature and stirred for 15 minutes. 2ꢀIodopyridine (5.732 mmol,
1.4 equiv) was added followed by Grignard 2 (6.960 mmol, 1.7 equiv). The resulting solution was
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stirred at room temperature for 1 hour. Conversion to 6 was monitored by UPLC at a wavelength of 254
1
2
3
nm.
4
5
6
7
8
9
9a: Phenyl(pyridin-2-yl)methanone. In order to prepare phenyl(pyridinꢀ2ꢀyl)methanone (9a), benzoic
acid (500 mg, 4.094 mmol, 1.0 equiv) and anhydrous tetrahydrofuran (25.0 mL, 308 mmol) were added
to a reaction vessel at room temperature under a nitrogen atmosphere. The reaction was then cooled in
an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀmethyltetrahydrofuran, 1.5 mL, 4.299 mmol,
1.05 equiv) was added at a rate that kept the temperature below 15 °C. 2ꢀIodopyridine (0.61 mL, 5.732
mmol, 1.4 equiv) or 2ꢀbromopyridine (0.55 mL, 5.732 mmol, 1.4 equiv) was added to the reaction mixꢀ
ture followed by isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 5.4 mL, 6.960
mmol, 1.7 equiv). After 10 minutes (2ꢀiodopyridine) or 4 hours (2ꢀbromopyridine) of stirring, the reacꢀ
tion was quenched with saturated ammonium chloride aqueous solution (25 mL). The mixture was
washed with water (25 mL) and brine (25 mL). The organic layers were dried over sodium sulfate, filꢀ
tered, and concentrated in vacuo to afford a light yellow liquid. The residue was purified via column
chromatography with a gradient mobile phase of 0–60% ethyl acetate in hexanes to afford compound 9a
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1
(from 2ꢀiodopyridine, 658 mg, 88% or from 2ꢀbromopyridine, 624 mg, 83%) as a yellow oil. H NMR
(500 MHz, DMSOꢀd6) δ ppm 7.50–7.59 (m, 2 H) 7.61–7.75 (m, 2 H) 7.92–8.03 (m, 3 H) 8.07 (t, J =
7.73 Hz, 1 H) 8.72 (br d, J = 4.40 Hz, 1 H). 13C NMR (125 MHz, DMSOꢀd6) δ ppm 124.6, 127.2, 128.7,
131.0, 133.4, 136.5, 138.1, 149.0, 155.0, 193.9. HRMS calculated for C12H9NO [M + H]+ 184.0762,
found 184.0757.
9a: Phenyl(pyridin-2-yl)methanone. In order to prepare phenyl(pyridinꢀ2ꢀyl)methanone (9a), 2ꢀ
picolinic acid (500 mg, 4.061 mmol, 1.0 equiv) and anhydrous tetrahydrofuran (25.0 mL, 308 mmol)
were added to a reaction vessel at room temperature under a nitrogen atmosphere. The reaction was then
cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀmethyltetrahydrofuran, 1.5 mL,
4.264 mmol, 1.05 equiv) was added at a rate that kept the temperature below 15 °C. Iodobenzene (0.50
mL, 4.468 mmol, 1.1 equiv) was added to the reaction mixture followed by isopropylmagnesium chloꢀ
ride lithium chloride complex (1.3 M in THF, 3.7 mL, 4.874 mmol, 1.2 equiv). After 1 hour of stirring,
some starting material still remained, and then iodobenzene (0.14 mL, 1.218 mmol, 0.3 equiv) and isoꢀ
propylmagnesium chloride lithium chloride complex (1.3 M in THF, 1.6 mL, 2.032 mmol, 0.5 equiv)
were added. After another 3 hours or stirring, an additional amount of isopropylmagnesium chloride
lithium chloride complex (1.3 M in THF, 1.6 mL, 2.032 mmol, 0.5 equiv) was added. A calibration
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curve of the reference material was created, and after 5 hours of stirring, a weight/weight assay was carꢀ
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ried out in order to determine the yield of compound 9a (344.7 mg, 46%). NMRs consistent with 9a.
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9b: Benzophenone. In order to prepare benzophenone (9b), benzoic acid (500 mg, 4.094 mmol, 1.0
equiv) and anhydrous tetrahydrofuran (25.0 mL, 308 mmol) were added to a reaction vessel at room
temperature under a nitrogen atmosphere. The reaction was then cooled in an ice bath and isopropylꢀ
magnesium bromide (2.9 M in 2ꢀmethyltetrahydrofuran, 1.5 mL, 4.299 mmol, 1.05 equiv) was added at
a rate that kept the temperature below 15 °C. 2ꢀIodopyridine (918.8 mg, 4.504 mmol, 1.1 equiv) was
added to the reaction mixture followed by isopropylmagnesium chloride lithium chloride complex (1.3
M in THF, 3.8 mL, 4.913 mmol, 1.2 equiv). After 2 hours of stirring, it was determined that starting maꢀ
terial was remaining, and then the reaction was cooled to 10 °C, and 2ꢀiodopyridine (75.2 mg, 1.228
mmol, 0.3 equiv) was added to the reaction mixture followed by isopropylmagnesium chloride lithium
chloride complex (1.3 M in THF, 1.6 mL, 2.047 mmol, 0.5 equiv). Reaction was stirred for an additionꢀ
al 3 hours and was quenched with saturated sodium chloride solution (25 mL). The mixture was washed
with saturated ammonium chloride solution (25 mL) and brine (25 mL). The rganic layers were dried
over sodium sulfate, filtered, and concentrated in vacuo to afford a light yellow liquid. A calibration
curve with the reference material was created, and a weight/weight assay was carried out in order to deꢀ
termine the yield of compound 9b (26%). NMRs consistent with reference standards and those reported
in literature.
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9e: 4-Benzoyl-N,N-dimethyl-1H-imidazole-1-sulfonamide. In order to prepare 4ꢀbenzoylꢀN,Nꢀ
dimethylꢀ1Hꢀimidazoleꢀ1ꢀsulfonamide (9e), benzoic acid (500 mg, 4.094 mmol, 1.0 equiv) and anhyꢀ
drous tetrahydrofuran (25.0 mL, 308 mmol) were added to a reaction vessel at room temperature under a
nitrogen atmosphere. The reaction was then cooled in an ice bath and isopropylmagnesium bromide (2.9
M in 2ꢀmethyltetrahydrofuran, 1.5 mL, 4.229 mmol, 1.05 equiv) was added at a rate that kept the temꢀ
perature below 10 °C. 4ꢀiodoꢀN,Nꢀdimethylꢀimidazoleꢀ1ꢀsulfonamide (1.356 g, 4.504 mmol, 1.1 equiv)
was added to the reaction mixture followed by isopropylmagnesium chloride lithium chloride complex
(1.3 M in THF, 3.8 mL, 4.913 mmol, 1.2 equiv) was added. After 3.5 hours of stirring, the reaction was
quenched with water with saturated ammonium chloride solution (25 mL). The mixture was washed
with water (25 mL) and brine (25 mL). The organic layers were dried over sodium sulfate, filtered, and
1
concentrated in vacuo to afford compound 9e (905.7 mg, 79%) as a yellow solid; mp 130–131 °C. H
NMR (500 MHz, DMSOꢀd6) δ ppm 2.91 (s, 6 H) 7.53–7.59 (m, 2 H) 7.67 (t, J = 7.34 Hz, 1 H) 8.17 (d, J
13
= 7.83 Hz, 2 H) 8.31 (s, 1 H) 8.40 (s, 1 H). C NMR (125 MHz, DMSOꢀd6) δ ppm 38.4, 125.0, 128.8,
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130.3, 133.3, 137.4, 138.0, 141.6, 186.9. HRMS calculated for C12H13N3O3S [M + H]+ 280.0756, found
280.0749.
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9f: (1-Methyl-1H-pyrazol-3-yl)(phenyl)methanone. In order to prepare (1ꢀmethylꢀ1Hꢀpyrazolꢀ3ꢀ
yl)(phenyl)methanone (9f), benzoic acid (500 mg, 4.094 mmol, 1.0 equiv) and anhydrous tetrahydrofuꢀ
ran (25 mL, 308 mmol) were added to a reaction vessel at room temperature under a nitrogen atmosꢀ
phere. The reaction was then cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀ
methyltetrahydrofuran, 1.5 mL, 4.299 mmol, 1.05 equiv) was added at a rate that kept the temperature
below 15 °C. 3ꢀIodoꢀ1ꢀmethylꢀpyrazole (936.8 mg, 4.504 mmol, 1.1 equiv) was added to the reaction
mixture followed by isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 3.8 mL,
4.913 mmol, 1.2 equiv). At 1.5 hours, there was still starting material remaining, and additional amounts
of 3ꢀIodoꢀ1ꢀmethylꢀpyrazole (211.3 mg, 1.118 mmol, 0.3 equiv) and isopropylmagnesium chloride lithꢀ
ium chloride complex (1.3 M in THF, 1.6 mL, 2.047 mmol, 0.5 equiv) were added. After 4 hours of stirꢀ
ring, the reaction was quenched with saturated ammonium chloride solution (25 mL). The mixture was
washed with water (25 mL) and brine (25 mL). The organic layers were dried over sodium sulfate, filꢀ
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tered, and concentrated in vacuo to afford 9f (533mg, 70% yield) as a yellow oil. H NMR (500 MHz,
DMSOꢀd6) δ ppm 3.99 (s, 3 H) 6.88 (d, J = 2.45 Hz, 1 H) 7.50–7.57 (m, 2 H) 7.59–7.69 (m, 1 H) 7.90
13
(d, J = 1.96 Hz, 1 H) 8.16 (s, 1 H) 8.17–8.18 (m, 1 H). C NMR (125 MHz, DMSOꢀd6) δ ppm 39.8,
109.2, 128.7, 130.4, 133.0, 133.1, 137.7, 150.3, 187.2. HRMS calculated for C11H10N2O [M + H]+
187.0871, found 187.0866.
9f: (1-Methyl-1H-pyrazol-3-yl)(phenyl)methanone. In order to prepare (1ꢀmethylꢀ1Hꢀpyrazolꢀ3ꢀ
yl)(phenyl)methanone (9f), benzoic acid (500 mg, 4.094 mmol, 1.0 equiv) and anhydrous tetrahydrofuꢀ
ran (25.0 mL, 308 mmol) were added to a reaction vessel at room temperature under a nitrogen atmosꢀ
phere. The reaction was then cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀ
methyltetrahydrofuran, 1.5 mL, 4.299 mmol, 1.05 equiv) was added at a rate that kept the temperature
below 15 °C. 3ꢀBromoꢀ1ꢀmethylꢀpyrazole (725.1 mg, 4.504 mmol, 1.1 equiv) was added to the reaction
mixture followed by isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 3.8 mL,
4.913 mmol, 1.2 equiv). After 27 hours of stirring, the reaction was quenched with saturated ammonium
chloride solution (25 mL). The mixture was washed with water (25 mL) and brine (25 mL). The organic
layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford a yellow liquid. The
residue was purified via column chromatography with a gradient mobile phase of 0–60% ethyl acetate
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The Journal of Organic Chemistry
in hexanes to afford compound 9f (282.2 mg, 37% yield) as a colorless oil. NMR data consistent with
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9f.
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9g: Phenyl(thiazol-4-yl)methanone. In order to prepare phenyl(thiazolꢀ4ꢀyl)methanone (9g), benzoic
acid (500 mg, 4.094 mmol, 1.0 equiv) and anhydrous tetrahydrofuran (25.0 mL, 308 mmol) were added
to a reaction vessel at room temperature under a nitrogen atmosphere. The reaction was then cooled in
an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀmethyltetrahydrofuran, 1.5 mL, 4.229 mmol,
1.05 equiv) was added at a rate that kept the temperature below 10 °C. 4ꢀBromothiazole (0.40 mL,
4.504 mmol, 1.1 equiv) was added to the reaction mixture followed by isopropylmagnesium chloride
lithium chloride complex (1.3 M in THF, 3.8 mL, 4.913 mmol, 1.2 equiv). After 18.5 hours, starting
material was still remaining and 4ꢀbromothiazole (0.11 mL, 1.228 mmol, 0.3 equiv) and isopropylꢀ
magnesium chloride lithium chloride complex (1.3 M in THF, 1.6 mL, 2.047 mmol, 0.5 equiv) was addꢀ
ed. At 19.5 hours isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 3.8 mL, 4.913
mmol, 1.0 equiv) was added. The reaction stirred for a total of 24 hours and was then quenched with
water (25 mL) with some saturated ammonium chloride solution. The mixture was washed with water
(25 mL) and brine (25 mL). The organic layers were dried over sodium sulfate, filtered, and concentratꢀ
ed in vacuo to afford a dark oil. The residue was then was purified via column chromatography with a
gradient mobile phase of 0–60% ethyl acetate in hexanes to afford compound 9g (360 mg, 47%) as a
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dark yellow oil. H NMR (500 MHz, DMSOꢀd6) δ ppm 7.54–7.59 (m, 2 H) 7.65–7.70 (m, 1 H) 8.07–
8.12 (m, 2 H) 8.65 (d, J = 1.96 Hz, 1 H) 9.29 (d, J = 1.96 Hz, 1 H). 13C NMR (125 MHz, DMSOꢀd6) δ
ppm 128.8, 130.3, 130.5, 133.4, 137.5, 154.7, 155.6, 187.1. HRMS calculated for C10H7NOS [M + H]+
190.0327, found 190.0321.
9h: (1-Benzyl-1H-pyrazol-4-yl)(phenyl)methanone. In order to prepare (1ꢀbenzylꢀ1Hꢀpyrazolꢀ4ꢀ
yl)(phenyl)methanone (9h), benzoic acid (500 mg, 4.094 mmol, 1.0 equiv) and anhydrous tetrahydrofuꢀ
ran (25.0 mL, 308 mmol) were added to a reaction vessel at room temperature under a nitrogen atmosꢀ
phere. The reaction was then cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀ
methyltetrahydrofuran, 1.5 mL, 4.299 mmol, 1.05 equiv) was added at a rate that kept the temperature
below 10 °C. 1ꢀBenzylꢀ4ꢀiodoꢀ1Hꢀpyrazole (1280 mg, 4.504 mmol, 1.1 equiv) was added to the reaction
mixture followed by isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 3.8 mL,
4.913 mmol, 1.2 equiv). After 3 hours, there was still starting material remaining, and additional
amounts of 1ꢀBenzylꢀ4ꢀiodoꢀ1Hꢀpyrazole (350 mg, 1.228 mmol, 0.3 equiv) and isopropylmagnesium
chloride lithium chloride complex (1.3 M in THF, 1.6 mL, 2.047 mmol, 0.5 equiv) were added. At 24
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hours, there was still starting material remaining, and additional amounts of 1ꢀBenzylꢀ4ꢀiodoꢀ1Hꢀ
pyrazole (350 mg, 1.228 mmol, 0.3 equiv) and isopropylmagnesium chloride lithium chloride complex
(1.3 M in THF, 1.6 mL, 2.047 mmol, 0.5 equiv) were added. At 27 hours, there was still starting materiꢀ
al remaining, and additional amounts of 1ꢀBenzylꢀ4ꢀiodoꢀ1Hꢀpyrazole (581 mg, 2.047 mmol, 0.5 equiv)
and isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 1.6 mL, 2.047 mmol, 0.5
equiv) were added. The reaction stirred for a total of 28 hours and was then quenched with water (25
mL) with some saturated ammonium chloride solution. The mixture was washed with water (25 mL)
and brine (25 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacꢀ
uo to afford a yellow oil. The residue was purified via column chromatography with a gradient mobile
phase of 0–55% ethyl acetate in hexanes, followed by separation by Prep HPLC to afford compound 9h
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(200 mg, 20%) as a colorless oil. H NMR (500 MHz, DMSOꢀd6) δ ppm 5.41 (s, 1H), 6.27–6.37 (m,
1H), 7.28–7.49 (m, 4 H) 7.51–7.72 (m, 3 H) 7.74–7.85 (m, 1 H) 7.85–8.07 (m, 2 H) 8.39 (s, 1 H) 8.56
13
(s, 1 H). C NMR (125 MHz, DMSOꢀd6) δ ppm 69.1, 106.3, 129.0, 129.1, 129.2, 129.3, 129.5, 130.7,
134.1, 135.3, 135.6, 139.6, 194.1. HRMS calculated for C17H14N2O [M + H]+ 263.1184, found
263.1180.
9i: Phenyl(thiazol-5-yl)methanone. In order to prepare phenyl(thiazolꢀ5ꢀyl)methanone (9i), benzoic
acid (500 mg, 4.094 mmol, 1.0 equiv) and anhydrous tetrahydrofuran (25.0 mL, 308 mmol) were added
to a reaction vessel at room temperature under a nitrogen atmosphere. The reaction was then cooled in
an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀmethyltetrahydrofuran, 1.5 mL, 4.299 mmol,
1.05 equiv) was added at a rate that kept the temperature below 10 °C. 5ꢀBromothiazole (738.7 mg,
4.504 mmol, 1.1 equiv) was added to the reaction mixture followed by isopropylmagnesium chloride
lithium chloride complex (1.3 M in THF, 3.8 mL, 4.913 mmol, 1.2 equiv). The reaction stirred for a toꢀ
tal of 4.5 hours and was then quenched with water (25 mL) with some saturated ammonium chloride
solution. The mixture was washed with water (25 mL) and brine (25 mL). The organic layers were dried
over sodium sulfate, filtered, and concentrated in vacuo to afford a brown oil. The residue was purified
via column chromatography with a gradient mobile phase of 0–50% ethyl acetate in hexanes to afford
1
compound 9i (275 mg, 36%) as an orange oil. H NMR (500 MHz, DMSOꢀd6) δ ppm 7.56–7.66 (m, 2
H) 7.66–7.81 (m, 1 H) 8.21–8.31 (m, 2 H) 8.35–8.43 (m, 2 H). 13C NMR (125 MHz, DMSOꢀd6) δ ppm
128.8, 129.0, 131.2, 134.3, 135.2, 145.8, 167.3, 184.1. HRMS calculated for C10H7NOS [M + H]+
190.0327, found 190.0324.
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11a: (4-Chlorophenyl)(pyridin-2-yl)methanone. In order to prepare (4ꢀchlorophenyl)(pyridinꢀ2ꢀ
yl)methanone (11a), 4ꢀchlorobenzoic acid (500 mg, 3.193 mmol, 1.0 equiv) and anhydrous tetrahydroꢀ
furan (25.0 mL, 308 mmol) were added to a reaction vessel at room temperature under a nitrogen atꢀ
mosphere. The reaction was then cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀ
methyltetrahydrofuran, 1.2 mL, 3.353 mmol, 1.05 equiv) was added at a rate that kept the temperature
below 10 °C. 2ꢀIodopyridine (0.37 mL, 3.513 mmol, 1.1 equiv) was added to the reaction mixture folꢀ
lowed by isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 4.2 mL, 5.429 mmol,
1.7 equiv). The reaction was stirred at room temperature for 1 hour. Saturated ammonium chloride soluꢀ
tion (25 mL) was added to quench the reaction. The mixture was washed with saturated ammonium
chloride solution (25 mL) and brine (25 mL). The organic layers were dried over sodium sulfate, filꢀ
tered, and concentrated in vacuo to afford compound 11a (653.4 mg, 94% yield) as a yellow solid; lit.
mp 60–61 °C.24 1H NMR (500 MHz, DMSOꢀd6) δ ppm 7.55–7.63 (m, 1 H), 7.63–7.64 (m, 1 H), 7.67–
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7.72 (m, 1 H), 8.00–8.11 (m, 4 H), 8.64–8.84 (m, 1 H). C NMR (125 MHz, DMSOꢀd6) δ ppm 124.7,
127.5, 128.8, 133.0, 135.1, 138.3, 138.4, 149.1, 154.5, 192.5. HRMS calculated for C12H8ClNO [M +
H]+ 218.0373, found 218.0368.
11b: (4-Bromophenyl)(pyridin-2-yl)methanone. In order to prepare (4ꢀbromophenyl)(pyridinꢀ2ꢀ
yl)methanone (11b), 4ꢀbromobenzoic acid (500 mg, 2.487 mmol, 1.0 equiv) and anhydrous tetrahydroꢀ
furan (25.0 mL, 308 mmol) were added to a reaction vessel at room temperature under a nitrogen atꢀ
mosphere. The reaction was then cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀ
methyltetrahydrofuran, 0.90 mL, 2.162 mmol, 1.05 equiv) was added at a rate that kept the temperature
below 20 °C. 2ꢀIodopyridine (0.29 mL, 2.736 mmol, 1.1 equiv) was added to the reaction mixture folꢀ
lowed by isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 3.3 mL, 4.228 mmol,
1.7 equiv). The reaction stirred at room temperature for 2 hours. Water (25 mL) with a few drops of satꢀ
urated ammonium chloride solution was added to quench the reaction and the organic layer was then
extracted with water (2 x 25 mL) and brine (25 mL). The organic layers were dried over sodium sulfate,
filtered, and concentrated in vacuo to afford compound 11b (518.7 mg, 80% yield) as a white solid; lit.
mp (45–47 °C).25 1H NMR (500 MHz, DMSOꢀd6) δ ppm 7.68–7.79 (m, 3 H), 7.89–8.10 (m, 4 H), 8.73
(dd, J = 4.89, 0.98 Hz, 1 H). 13C NMR (125 MHz, DMSOꢀd6) δ ppm 124.7, 127.5, 127.6, 131.8, 133.1,
135.5, 138.2, 149.1, 154.4, 192.7. HRMS calculated for C12H8BrNO [M + H]+ 261.9868, found
261.9863.
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11c: (4-Iodophenyl)(pyridin-2-yl)methanone. In order to prepare (4ꢀiodophenyl)(pyridinꢀ2ꢀ
yl)methanone (11c), 4ꢀiodobenzoic acid (500 mg, 2.016 mmol, 1.0 equiv) and anhydrous tetrahydrofuꢀ
ran (25.0 mL, 308 mmol) were added to a reaction vessel at room temperature under a nitrogen atmosꢀ
phere. Isopropylmagnesium bromide (2.9 M in 2ꢀmethyltetrahydrofuran, 0.73 mL, 2.117 mmol, 1.05
equiv) was added dropwise and the reaction was stirred for 15 minutes. 2ꢀIodopyridine (0.30 mL, 2.822
mmol, 1.4 equiv) was added to the reaction mixture followed by isopropylmagnesium chloride lithium
chloride complex (1.3 M in THF, 2.6 mL, 3.427 mmol, 1.7 equiv). The reaction was stirred at room
temperature for 2 hours. Saturated ammonium chloride solution (25 mL) was added to quench the reacꢀ
tion. The mixture was washed with saturated ammonium chloride solution (25 mL) and brine (25 mL).
The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was
purified via column chromatography with a gradient mobile phase of 0–50% ethyl acetate in hexanes to
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afford compound 11c (395.5 mg, 64% yield) as an orange oil. H NMR (500 MHz, DMSOꢀd6) δ ppm
7.63–7.74 (m, 1 H), 7.75 (d, J = 7.34 Hz, 2 H), 7.90–8.03 (m, 3 H), 8.04–8.13 (m, 1 H), 8.64–8.80 (m, 1
13
H). C NMR (125 MHz, DMSOꢀd6) δ ppm 102.1, 124.7, 127.4, 132.8, 135.8, 137.6, 138.2, 149.1,
154.5, 193.1. HRMS calculated for C12H8INO [M + H]+ 309.9729, found 309.9732
11d: (4-Methoxyphenyl)(pyridin-2-yl)methanone. In order to prepare (4ꢀmethoxyphenyl)(pyridinꢀ2ꢀ
yl)methanone (11d), 4ꢀmethoxybenzoic acid (500 mg, 3.286 mmol, 1.0 equiv) and anhydrous tetrahyꢀ
drofuran (25.0 mL, 308 mmol) were added to a reaction vessel at room temperature under a nitrogen
atmosphere. Isopropylmagnesium bromide (2.9 M in 2ꢀmethyltetrahydrofuran, 2.4 mL, 6.901 mmol, 2.1
equiv) was added dropwise and the reaction stirred for 15 minutes. 2ꢀIodopyridine (0.49 mL, 4.601
mmol, 1.4 equiv) was added followed by isopropylmagnesium chloride lithium chloride complex (1.3 M
in THF, 4.3 mL, 5.587 mmol, 1.7 equiv). The reaction stirred at room temperature for 4 hours. Saturated
ammonium chloride solution (25 mL) was added to quench the reaction. The mixture was washed with
saturated ammonium chloride solution (25 mL) and brine (25 mL). The organic layers were dried over
sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via column chromatogꢀ
raphy with a gradient mobile phase of 0–55% ethyl acetate in hexanes to afford compound 11d (650 mg,
94% yield) as a white solid; lit. mp 60–61 °C.26 1H NMR (500 MHz, DMSOꢀd6) δ ppm 3.86 (s, 3 H),
7.08 (d, J = 8.80 Hz, 2 H), 7.65 (t, J = 6.17 Hz, 1 H), 7.89–7.97 (m, 1 H), 7.97–8.10 (m, 3 H), 8.71 (dd,
J = 4.89, 0.98 Hz, 1 H). 13C NMR (125 MHz, DMSOꢀd6) δ ppm 56.0, 114.1, 124.5, 126.8, 128.9, 133.6,
138.0, 148.9, 155.7, 163.7, 192.0. HRMS calculated for C13H11NO2 [M + H]+ 214.0868, found
214.0863.
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The Journal of Organic Chemistry
11e: Pyridin-2-yl(p-tolyl)methanone. In order to prepare pyridinꢀ2ꢀyl(pꢀtolyl)methanone (11e), 4ꢀ
methylbenzoic acid (500 mg, 3.672 mmol, 1.0 equiv) and anhydrous tetrahydrofuran (25.0 mL, 308
mmol) were added to a reaction vessel at room temperature under a nitrogen atmosphere. The reaction
was then cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀmethyltetrahydrofuran, 1.3
mL, 3.856 mmol, 1.05 equiv) was added at a rate that kept the temperature below 10 °C. 2ꢀIodopyridine
(0.43 mL, 4.040 mmol, 1.1 equiv) was added to the reaction mixture. Isopropylmagnesium chloride
lithium chloride complex (1.3 M in THF, 3.4 mL, 4.407 mmol, 1.2 equiv) was then added at a rate that
kept the temperature below 10 °C. The reaction was stirred at room temperature for 2.5 hours. Starting
material was still present and additional 2ꢀiodopyridine (0.12 mL, 1.102 mmol, 0.3 equiv) was added to
the reaction mixture followed by isopropylmagnesium chloride lithium chloride complex (1.3 M in
THF, 1.4 mL, 1.836 mmol, 0.5 equiv). The reaction was stirred at room temperature for an additional 2
hours. Water (25 mL) with a few drops of saturated ammonium chloride solution was added to quench
the reaction and the organic layer was then extracted with water (2 x 25) and brine (25 mL). The organic
layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford compound 11e (563
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mg, 78% yield) as a brown oil. H NMR (500 MHz, DMSOꢀd6) δ ppm 2.40 (s, 3 H), 7.35 (d, J = 7.75
Hz, 2 H), 7.62–7.68 (m, 1 H), 7.86–7.96 (m, 3 H), 8.06 (td, J = 7.70, 1.71 Hz, 1 H), 8.72 (dq, J = 4.89,
13
0.98 Hz, 1 H). C NMR (125 MHz, DMSOꢀd6) δ ppm 21.7, 124.5, 127.0, 129.3, 131.2, 133.8, 138.1,
144.0, 149.0, 155.3, 193.4. HRMS calculated for C13H11NO [M + H]+ 198.0919, found 198.0915.
11f: Methyl 4-picolinoylbenzoate. In order to prepare methyl 4ꢀpicolinoylbenzoate (11f), monoꢀmethyl
terephthalate (500 mg, 2.775 mmol, 1.0 equiv) and anhydrous tetrahydrofuran (25.0 mL, 308 mmol)
were added to a reaction vessel at room temperature under a nitrogen atmosphere. The reaction was then
cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀmethyltetrahydrofuran, 1.0 mL,
2.914 mmol, 1.05 equiv) was added at a rate that kept the temperature below 15 °C. 2ꢀIodopyridine
(0.33 mL, 3.053 mmol, 1.1 equiv) was added to the reaction mixture. Isopropylmagnesium chloride
lithium chloride complex (1.3 M in THF, 2.6 mL, 3.330 mmol, 1.2 equiv) was then added at a rate that
kept the temperature below 15 °C. The reaction was stirred at room temperature for 3 hours 30 minutes.
Starting material remained, and additional isopropylmagnesium chloride lithium chloride complex (1.3
M in THF, 1.1 mL, 1.388 mmol, 0.5 equiv). After at total of 4.5 hours, water (25 mL) with a few drops
of saturated ammonium chloride solution was added to quench the reaction and the organic layer was
extracted with water (2 x 25) and brine (25 mL). The organic layers were dried over sodium sulfate, filꢀ
tered, and concentrated in vacuo to afford compound 11f (642 mg, 96% yield) as an offꢀwhite solid; mp
1
117–119 °C. H NMR (500 MHz, DMSOꢀd6) δ ppm 3.91 (s, 3 H) 7.70–7.73 (m, 1 H) 8.06–8.12 (m, 6
H) 8.74 (d, J = 4.88 Hz, 1 H). 13C NMR (125 MHz, DMSOꢀd6) δ ppm 53.0, 124.7, 127.7, 129.3, 131.2,
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133.3, 138.3, 140.4, 149.2, 154.2, 166.1, 193.5. HRMS calculated for C14H11NO3 [M + H]+ 242.0817,
found 242.0811.
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11g: Methyl 3-picolinoylbenzoate. In order to prepare methyl 3ꢀpicolinoylbenzoate (11g), monoꢀ
methyl isophthalate (500 mg, 2.775 mmol, 1.0 equiv) and anhydrous tetrahydrofuran (25.0 mL, 308
mmol) were added to a reaction vessel at room temperature under a nitrogen atmosphere. The reaction
was then cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀmethyltetrahydrofuran, 1.0
mL, 2.914 mmol, 1.05 equiv) was added at a rate that kept the temperature below 10 °C. 2ꢀIodopyridine
(0.33 mL, 3.053 mmol, 1.1 equiv) was added to the reaction mixture. Isopropylmagnesium chloride
lithium chloride complex (1.3 M in THF, 2.6 mL, 3.330 mmol, 1.2 equiv) was then added at a rate that
kept the temperature below 10 °C. The reaction was stirred at room temperature for 30 minutes. Water
(25 mL) with a few drops of saturated ammonium chloride solution was added to quench the reaction
and the organic layer was extracted with water (2 x 25) and brine (25 mL). The organic layers were
dried over sodium sulfate, filtered, and concentrated in vacuo to afford compound 11g (600 mg, 90%
yield) as a white solid. Purity was determined by a w/w NMR assay, as some pyridine was present in the
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sample; mp 108–109 °C. H NMR (500 MHz, DMSOꢀd6) δ ppm 3.89 (s, 3 H), 7.66–7.77 (m, 2 H),
8.02–8.16 (m, 2 H), 8.19–8.30 (m, 2 H), 8.53 (s, 1 H), 8.75 (dd, J = 4.89, 0.98 Hz, 1 H). 13C NMR (125
MHz, DMSOꢀd6) δ ppm 52.9, 124.8, 127.6, 129.3, 130.0, 131.6, 133.5, 135.6, 136.9, 138.3, 149.1,
154.3, 166.0, 192.8. HRMS calculated for C14H11NO3 [M + H]+ 242.0817, found 242.0810.
11h: 4-Picolinoylbenzonitrile. In order to prepare 4ꢀpicolinoylbenzonitrile (11h), 4ꢀcyanobenzoic acid
(500 mg, 3.398 mmol, 1.0 equiv) and anhydrous tetrahydrofuran (25.0 mL, 308 mmol) were added to a
reaction vessel at room temperature under a nitrogen atmosphere. The reaction was then cooled in an ice
bath and isopropylmagnesium bromide (2.9 M in 2ꢀmethyltetrahydrofuran, 1.2 mL, 3.568 mmol, 1.05
equiv) was added at a rate that kept the temperature below 10 °C. 2ꢀIodopyridine (0.40 mL, 3.738
mmol, 1.1 equiv) was added to the reaction mixture. Isopropylmagnesium chloride lithium chloride
complex (1.3 M in THF, 4.4 mL, 5.777 mmol, 1.7 equiv) was then added at a rate that kept the temperaꢀ
ture below 10 °C. The reaction was stirred at room temperature for 3 hours. Water (25 mL) with a few
drops of saturated ammonium chloride solution was added to quench the reaction and the organic layer
was then extracted with water (2 x 25) and brine (25 mL). The organic layers were dried over sodium
sulfate, filtered, and concentrated in vacuo to afford compound 11h (502 mg, 71% yield) as a white solꢀ
id; lit. mp 118–121 °C.27 1H NMR (500 MHz, DMSOꢀd6) δ ppm 7.64–7.80 (m, 1 H), 7.96–8.06 (m, 2
13
H), 8.06–8.19 (m, 4 H), 8.68–8.80 (m, 1 H). C NMR (125 MHz, DMSOꢀd6) δ ppm 115.1, 118.7,
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124.8, 127.9, 131.5, 132.5, 138.4, 140., 149.2, 153.7, 192.9. HRMS calculated for C13H8N2O [M + H]+
209.0715, found 209.0708.
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11i: 1,4-Phenylenebis(pyridin-2-ylmethanone). In order to prepare 1,4ꢀphenylenebis(pyridinꢀ2ꢀ
ylmethanone) (11i), terephthalic acid (500 mg, 3.010 mmol, 1.0 equiv) and anhydrous tetrahydrofuran
(25.0 mL, 308 mmol) were added to a reaction vessel at room temperature under a nitrogen atmosphere.
The reaction was then cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀ
methyltetrahydrofuran, 2.2 mL, 6.320 mmol, 2.1 equiv) was added at a rate that kept the temperature
below 10 °C. 2ꢀIodopyridine (0.71 mL, 6.621 mmol, 2.2 equiv) was added to the reaction mixture folꢀ
lowed by isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 5.6 mL, 7.223 mmol,
2.4 equiv). After an hour of stirring, it was determined that starting material was remaining, and the reꢀ
action was cooled to 10 °C, and 2ꢀiodopyridine (0.32 mL, 3.010 mmol, 1 equiv) was added to the reacꢀ
tion mixture followed by isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 2.5
mL, 3.311 mmol, 1.1 equiv). Reaction was stirred for an additional 19 hours, was cooled in an ice bath,
and then quenched with water (25 mL) causing a white solid to crash out. The pH of the solution was
adjusted to 9 with saturated ammonium chloride solution and an additional 10 mL of water was added.
The reaction was then filtered to afford compound 11i (540 mg, 62%) as a white solid; lit. mp 172–174
°C.25 1H NMR (500 MHz, DMSOꢀd6) δ ppm 7.72 (ddd, J = 6.85, 4.89, 1.96 Hz, 2 H) 8.01–8.17 (m, 8 H)
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8.75 (dt, J = 4.52, 1.41 Hz, 2 H). C NMR (125 MHz, DMSOꢀd6) δ ppm 124.2, 127.2, 130.0, 137.8,
139.3, 148.7, 153.8, 193.2. HRMS calculated for C18H12N2O2 [M + H]+ 289.0977, found 289.0968.
11j: (4-Hydroxyphenyl)(pyridin-2-yl)methanone. In order to prepare (4ꢀhydroxyphenyl)(pyridinꢀ2ꢀ
yl)methanone (11j), 4ꢀhydroxybenzoic acid (500 mg, 3.620 mmol, 1.0 equiv) and anhydrous tetrahydroꢀ
furan (25.0 mL, 308 mmol) were added to a reaction vessel at room temperature under a nitrogen atꢀ
mosphere. The reaction was then cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀ
methyltetrahydrofuran, 2.6 mL, 7.602 mmol, 2.1 equiv) was added at a rate that kept the temperature
below 15 °C. 2ꢀIodopyridine (0.42 mL, 3.982 mmol, 1.1 equiv) was added to the reaction mixture folꢀ
lowed by isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 3.3 mL, 4.344 mmol,
1.2 equiv). The reaction was stirred at room temperature for 3 hours. Starting material remained and adꢀ
ditional 2ꢀiodopyridine (0.65 mL, 6.154 mmol, 1.7 equiv) and isopropylmagnesium chloride lithium
chloride complex (1.3 M in THF, 6.1 mL, 7.964 mmol, 2.2 equiv) were added. The reaction was heated
to 30 °C and stirred for 16 hours. Water (25 mL) with a few drops of saturated ammonium chloride soꢀ
lution was added to quench the reaction and the organic layer was then extracted with water (2 x 25) and
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brine (25 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to
afford compound 11j 500 mg, 69% yield as a yellow oil. 1H NMR (500 MHz, DMSOꢀd6) δ ppm 6.87 (s,
1 H), 6.88 (s, 1 H), 7.57–7.66 (m, 1 H), 7.84–7.97 (m, 3 H), 7.99–8.07 (m, 1 H), 8.70 (dt, J = 5.14, 1.10
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Hz, 1 H), 10.46 (br s, 1 H). C NMR (125 MHz, DMSOꢀd6) δ ppm 115.5, 124.3, 126.5, 127.4, 133.9,
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137.9, 148.8, 156.1, 162.8, 191.9. HRMS calculated for C12H9NO2 [M + H]+ 200.0712, found 200.0709.
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11k: N-(4-Picolinoylphenyl)acetamide. In order to prepare Nꢀ(4ꢀpicolinoylphenyl)acetamide (11k), 4ꢀ
acetamidobenzoic acid (500 mg, 2.7906 mmol, 1.0 equiv) and anhydrous tetrahydrofuran (25.0 mL, 308
mmol) were added to a reaction vessel at room temperature under a nitrogen atmosphere. The reaction
was then cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀmethyltetrahydrofuran, 2.0
mL, 5.8604 mmol, 2.1 equiv) was added at a rate that kept the temperature below 15 °C. 2ꢀIodopyridine
(0.42 mL, 3.9069 mmol, 1.4 equiv) was added to the reaction mixture followed by isopropylmagnesium
chloride lithium chloride complex (1.3 M in THF, 3.6 mL, 4.7441 mmol, 1.7 equiv). The reaction was
stirred at room temperature for 20 hours. Starting material was still present and additional 2ꢀ
iodopyridine (0.42 mL, 3.9069 mmol, 1.4 equiv) was added to the reaction mixture followed by isoꢀ
propylmagnesium chloride lithium chloride complex (1.3 M in THF, 3.6 mL, 4.7441 mmol, 1.7 equiv).
The reaction was stirred a room temperature for an additional 2 hours. Water (25 mL) with a few drops
of saturated ammonium chloride solution was added to quench the reaction and the organic layer was
then extracted with water (2 x 25) and brine (25 mL). The organic layers were dried over sodium sulꢀ
fate, filtered, and concentrated in vacuo to afford compound 11k (550 mg, 82% yield) as a light brown
1
solid; mp (dec) 143–145 °C. H NMR (500 MHz, DMSOꢀd6) δ ppm 2.10 (s, 3 H), 7.65 (dd, J = 6.60,
5.62 Hz, 1 H), 7.73 (d, J = 8.80 Hz, 2 H), 7.84–7.97 (m, 1 H), 7.97–7.98 (m, 1 H), 8.00 (s, 1 H), 8.02–
13
8.18 (m, 1 H), 8.63–8.79 (m, 1 H), 10.32 (s, 1 H). C NMR (125 MHz, DMSOꢀd6) δ ppm 24.7, 118.3,
124.5, 126.8, 130.7, 132.6, 138.0, 144.2, 148.9, 155.6, 169.5, 192.2. HRMS calculated for C14H12N2O2
[M + H]+ 241.0977, found 241.0959.
11l: (1H-Indol-2-yl)(pyridin-2-yl)methanone. In order to prepare (1Hꢀindolꢀ2ꢀyl)(pyridinꢀ2ꢀ
yl)methanone (11l), indoleꢀ2ꢀcarboxylic acid (500 mg, 3.103 mmol, 1.0 equiv) and anhydrous tetrahyꢀ
drofuran (25.0 mL, 308 mmol) were added to a reaction vessel at room temperature under a nitrogen
atmosphere. The reaction was then cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀ
methyltetrahydrofuran, 2.2 mL, 6.516 mmol, 2.1 equiv) was added at a rate that kept the temperature
below 10 °C. 2ꢀIodopyridine (0.36 mL, 3.413 mmol, 1.1 equiv) was added to the reaction mixture folꢀ
lowed by isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 2.9 mL, 3.723 mmol,
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The Journal of Organic Chemistry
1.2 equiv) at a rate that kept the temperature below 5 °C. After 3 hours 30 minutes, there was still startꢀ
ing material remaining, and isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 2.9
mL, 3.723 mmol, 1.2 equiv) was added. In another hour, 2ꢀIodopyridine (0.10 mL, 0.9308 mmol, 0.3
equiv) was added to the reaction mixture followed by isopropylmagnesium chloride lithium chloride
complex (1.3 M in THF, 1.2 mL, 1.551 mmol, 0.5 equiv). In another hour, 2ꢀIodopyridine (0.10 mL,
0.9308 mmol, 0.3 equiv) was added to the reaction mixture followed by isopropylmagnesium chloride
lithium chloride complex (1.3 M in THF, 1.2 mL, 1.551 mmol, 0.5 equiv). The reaction stirred for a toꢀ
tal of 22 hours and was then quenched with water (25 mL) with some saturated ammonium chloride soꢀ
lution. The mixture was washed with water (25 mL) and brine (25 mL). The organic layers were dried
over sodium sulfate, filtered, and concentrated in vacuo to afford compound 11l (617.6 mg, 90%) as an
orange solid; mp 146–148 °C. 1H NMR (500 MHz, DMSOꢀd6) δ ppm 7.09 (ddd, J = 8.19, 6.97, 0.98 Hz,
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1 H) 7.25–7.38 (m, 1 H) 7.47–7.59 (m, 1 H) 7.65–7.81 (m, 2 H) 7.86 (dd, J = 1.96, 0.98 Hz, 1 H) 8.06–
13
8.12 (m, 2 H) 8.80–8.91 (m, 1 H) 11.96 (br s, 1 H). C NMR (125 MHz, DMSOꢀd
6
) δ ppm 113.3,
114.6, 120.8, 123.6, 124.0, 126.4, 127.5, 127.6, 134.3, 138.1, 138.5, 149.4, 154.8, 183.3. HRMS calcuꢀ
lated for C14H10N2O [M + H]+ 223.0871, found 223.0866.
11m: Di(pyridin-2-yl)methanone. In order to prepare di(pyridinꢀ2ꢀyl)methanone (11m), benzoic acid
(500 mg, 4.061 mmol, 1.0 equiv) and anhydrous tetrahydrofuran (25.0 mL, 308 mmol) were added to a
reaction vessel at room temperature under a nitrogen atmosphere. The reaction was then cooled in an ice
bath and isopropylmagnesium bromide (2.9 M in 2ꢀmethyltetrahydrofuran, 1.5 mL, 4.264 mmol, 1.05
equiv) was added at a rate that kept the temperature below 20 °C. 2ꢀIodopyridine (0.61 mL, 5.686
mmol, 1.4 equiv) was added to the reaction mixture followed by isopropylmagnesium chloride lithium
chloride complex (1.3 M in THF, 5.3 mL, 6.904 mmol, 1.7 equiv). After 2 hours of stirring starting maꢀ
terial still remained, and then isopropylmagnesium chloride lithium chloride complex (1.3 M in THF,
1.6 mL, 2.031 mmol, 0.5 equiv) was added. A calibration curve of the reference material was created
and after 5 hours of stirring, a weight/weight assay was carried out in order to determine the yield of
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compound 11m (496.4 mg, 66%). H NMR (500 MHz, DMSOꢀd6) δ ppm 7.64 (t, J = 6.23 Hz, 2 H)
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7.95–8.00 (m, 2 H) 8.04 (t, J = 7.58 Hz, 2 H) 8.64–8.73 (m, 2 H). C NMR (125 MHz, DMSOꢀd6) δ
ppm 124.8, 127.1, 137.5, 149.4, 154.7, 194.1. HRMS calculated for C11H8N2O [M + H]+ 185.0715,
found 185.0710.
11n: Pyridin-2-yl(thiophen-2-yl)methanone. In order to prepare pyridinꢀ2ꢀyl(thiophenꢀ2ꢀ
yl)methanone (11n), thiopheneꢀ2ꢀcarboxylic acid (500 mg, 3.902 mmol, 1.0 equiv) and anhydrous tetraꢀ
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hydrofuran (25.0 mL, 308 mmol) were added to a reaction vessel at room temperature under a nitrogen
atmosphere. The reaction was then cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀ
methyltetrahydrofuran, 1.4 mL, 4.097 mmol, 1.05 equiv) was added at a rate that kept the temperature
below 10 °C. 2ꢀIodopyridine (0.46 mL, 4.292 mmol, 1.1 equiv) was added to the reaction mixture folꢀ
lowed by isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 3.6 mL, 4.682 mmol,
1.2 equiv). After 1 hour 30 minutes, there was still starting material remaining, and then 2ꢀiodopyridine
(0.21 mL, 1.171 mmol, 0.3 equiv) and isopropylmagnesium chloride lithium chloride complex (1.3 M in
THF, 1.5 mL, 1.951 mmol, 0.5 equiv) were added. In another two hours, isopropylmagnesium chloride
lithium chloride complex (1.3 M in THF, 1.5 mL, 1.951 mmol, 0.5 equiv) was added. In another hour,
2ꢀiodopyridine (0.21 mL, 1.171 mmol, 0.3 equiv) and isopropylmagnesium chloride lithium chloride
complex (1.3 M in THF, 1.5 mL, 1.951 mmol, 0.5 equiv) were added. At the 5 hour time mark, addiꢀ
tional amounts of 2ꢀiodopyridine (0.21 mL, 1.171 mmol, 0.3 equiv) and isopropylmagnesium chloride
lithium chloride complex (1.3 M in THF, 1.5 mL, 1.951 mmol, 0.5 equiv) were added. The reaction
stirred for a total of 24 hours and was then quenched with water (25 mL) with some saturated ammoniꢀ
um chloride solution. The mixture was washed with water (25 mL) and brine (25 mL). The organic layꢀ
ers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford a dark orange liquid.
The residue was purified via column chromatography with a gradient mobile phase of 0–60% ethyl aceꢀ
tate in hexanes to afford compound 11n (648 mg, 88%) as a yellow oil. 1H NMR (500 MHz, DMSOꢀd6)
δ ppm 7.29 (dd, J = 5.14, 3.67 Hz, 1 H) 7.70–7.73 (m, 1 H) 8.06–8.13 (m, 3 H) 8.32–8.35 (m, 1 H)
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8.79–8.82 (m, 1 H). C NMR (125 MHz, DMSOꢀd6) δ ppm 123.9, 127.9, 128.5, 137.3, 138.1, 138.4,
139.8, 149.1, 153.7, 183.4. HRMS calculated for C10H7NOS [M + H]+ 190.0327, found 190.0326.
11o: 2-Phenyl-1-(pyridin-2-yl)ethanone. In order to prepare 2ꢀphenylꢀ1ꢀ(pyridinꢀ2ꢀyl)ethanone (11o),
2ꢀphenylacetic acid (500 mg, 3.672 mmol, 1.0 equiv) and anhydrous tetrahydrofuran (25.0 mL, 308
mmol) were added to a reaction vessel at room temperature under a nitrogen atmosphere. The reaction
was then cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀmethyltetrahydrofuran, 1.3
mL, 3.856 mmol, 1.05 equiv) was added at a rate that kept the temperature below 15 °C. 2ꢀIodopyridine
(0.43 mL, 4.040 mmol, 1.1 equiv) was added to the reaction mixture followed by isopropylmagnesium
chloride lithium chloride complex (1.3 M in THF, 3.4 mL, 4.407 mmol, 1.2 equiv) was added at a rate
that kept the temperature below 10 °C. After 3 hours of stirring, the reaction was quenched with water
that contained some saturated sodium ammonium solution (25 mL). The mixture was washed with water
(25 mL) and brine (25 mL). The organic layers were dried over sodium sulfate, filtered, and concentratꢀ
ed in vacuo to afford compound 11o (550.1 mg, 76%) as a brown oil. 1H NMR (500 MHz, DMSOꢀd6) δ
ppm 4.53 (s, 2 H) 7.21–7.44 (m, 5 H) 7.69 (t, J = 5.97 Hz, 1 H) 7.88–8.09 (m, 2 H) 8.79 (dd, J = 4.89,
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13
0.98 Hz, 1 H). C NMR (125 MHz, DMSOꢀd6) δ ppm 43.86, 122.3, 126.9, 128.3, 128.7, 130.4, 135.6,
138.1, 149.7, 153.0, 199.2. HRMS calculated for C13H11NO [M + H]+ 198.0919, found 198.0913.
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11p: 3-Phenyl-1-(pyridin-2-yl)propan-1-one. In order to prepare 3ꢀphenylꢀ1ꢀ(pyridinꢀ2ꢀyl)propanꢀ1ꢀ
one (11p), 3ꢀphenylpropanoic acid (500 mg, 3.330 mmol, 1.0 equiv) and anhydrous tetrahydrofuran
(25.0 mL, 308 mmol) were added to a reaction vessel at room temperature under a nitrogen atmosphere.
The reaction was then cooled in an ice bath and isopropylmagnesium bromide (2.9 M in 2ꢀ
methyltetrahydrofuran, 1.2 mL, 3.496 mmol, 1.05 equiv) was added at a rate that kept the temperature
below 15 °C. 2ꢀIodopyridine (0.39 mL, 3.663 mmol, 1.1 equiv) was added to the reaction mixture folꢀ
lowed by isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 3.1 mL, 3.995 mmol,
1.2 equiv). After 2 hours of stirring, the reaction was quenched with saturated ammonium chloride
aqueous solution (25 mL). The mixture was washed with water (25 mL) and brine (25 mL). The organic
layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford compound 11p
(577.7 mg, 82%) as a yellow oil. 1H NMR (500 MHz, DMSOꢀd6) δ ppm 2.96 (t, J = 7.58 Hz, 2 H) 3.51
(t, J = 7.58 Hz, 2 H) 7.01–7.35 (m, 5 H) 7.65 (ddd, J = 7.34, 4.40, 1.47 Hz, 1 H) 7.89–8.10 (m, 2 H)
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8.71 (d, J = 5.07 Hz, 1 H). C NMR (125 MHz, DMSOꢀd6) δ ppm 29.8, 39.2, 121.7, 126.3, 128.2,
128.7 (2C), 138.0, 141.8, 149.6, 153.2, 200.8. HRMS calculated for C14H13NO [M + H]+ 212.1075,
found 212.1071.
ASSOCIATED CONTENT
Supporting Information
Copies of 1H and 13C NMR spectra are available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* Email: lei.zhu@takeda.com
* Email: masahiro.mineno@takeda.com
ACKNOWLEDGMENT
Special thanks are given to Qing Lu from Analytical Development Laboratories at Millennium Pharmaꢀ
ceuticals, Inc. for assistance in compound characterization.
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