Microwave-assisted N-cyclopropylation of pyridinols with cyclopropyl boronic acid

Article abstract of DOI:10.1080/00397911.2010.539758

Copper(II)-mediated N-cyclopropylation of pyridinols involving copper(II) acetate, pyridine, and NaHMDS under microwave conditions in a dry air atmosphere is described. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.539758

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Microwave-Assisted N-Cyclopropylation
of Pyridinols with Cyclopropyl Boronic
Acid
Yashwant B. Tambe a , Somesh Sharma a , Arunendra Pathak a & L.
Krishnakanth Reddy a
a Jubilant Chemsys Limited, Noida, Uttar Pradesh, India
Accepted author version posted online: 21 Oct 2011. Version of
record first published: 11 Jan 2012
To cite this article: Yashwant B. Tambe, Somesh Sharma, Arunendra Pathak & L. Krishnakanth Reddy
(2012): Microwave-Assisted N-Cyclopropylation of Pyridinols with Cyclopropyl Boronic Acid, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
42:9, 1341-1348
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Synthetic Communications1, 42: 1341–1348, 2012
Copyright # Jubilant Chemsys Ltd.
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.539758
MICROWAVE-ASSISTED N-CYCLOPROPYLATION OF
PYRIDINOLS WITH CYCLOPROPYL BORONIC ACID
Yashwant B. Tambe, Somesh Sharma, Arunendra Pathak, and
L. Krishnakanth Reddy
Jubilant Chemsys Limited, Noida, Uttar Pradesh, India
GRAPHICAL ABSTRACT
Abstract Copper(II)-mediated N-cyclopropylation of pyridinols involving copper(II)
acetate, pyridine, and NaHMDS under microwave conditions in a dry air atmosphere is
described.
Keywords Copper (II) acetate; cyclopropyl boronic acid; MW; NaHMDS
INTRODUCTION
Medicinal and organic chemists have always searched for new groups and
functionalities that can provide some advantage and further the exploration in drug
discovery. In this respect, the cyclopropyl group has received incredible interest
because of its steric, electronic properties[1] and metabolic stability.[2] Introduction
of a cyclopropyl group is always a daunting task for chemists, utilizing a number
of steps. Organic chemists have used various methods for its introduction: (i) alky-
lation of alkoxide or phenoxide anion with cyclopropyl bromide,[3] (ii) methylena-
tion of vinyl ethers under Simmons–Smith conditions[4] and using sulfonium
ylids,[5] (iii) dehalomethylation of vinyl ether with dihalocarbene followed by
reductive elimination of halo,[6] (iv) alkylation of phenoxide with 1-iodo-1-
(phenylthio)cyclopropane, (iv) subsequent removal of phenylthio activating in
two steps,[7] and (v) cyclopropylation of aniline under reductive amination with
Received October 25, 2010.
Address correspondence to Somesh Sharma, Jubilant Chemsys Limited, B-34, Sector-58, Noida,
Uttar Pradesh, 201301, India. E-mail: somesh_sharma@jchemsys.com
1341

1342
Y. B. TAMBE ET AL.
(1-ethoxycyclopropoxy)trimethyl silane[8] and of cyclic amide and azoles using
tris-cyclopropylbismuth reagent.[9,10]
Cyclopropylation has been reported on the N-atom of indole, cyclic amides,
and azoles in copper(II)-assisted coupling reaction conditions.[11,12] However, these
substrates never posed a challenge for competitive product formation. On the other
hand, pyridinols, the substrate for our studies, has O- and N-atoms in the same ring,
and with Cu(II) coupling reagent (having affinity for both oxygen and nitrogen
atom), challenges in the product formation and distribution is expected.
RESULTS AND DISCUSSION
In this communication, we report our investigation of N-cyclopropylation on
substituted=unsubstituted=fused pyridinols. The preferred coupling product was
obtained in coupling conditions under microwave irradiation as depicted in
Scheme 1 and Table 1.
The effect of various substituents on the pyridyl system has been explored to
determine the feasibility of the reaction conditions in varying electronic environ-
ments. The work was also extended to fused pyridyl systems to reveal its generality
and viability. The promising results were obtained in the case of electron-donating
groups as compared to electron-withdrawing groups. No product formation is
observed in the cases of entries 2, 8, and 10, because of improper disposition of
hydroxyl with respect to nitrogen and hydrogen bonding. In all the examples, there
is a recovery of 10% of starting material under thermal conditions in contrast to
microwave conditions; however, no side product formation was observed in either
1
case. The desired product formation was further corroborated by H NMR and
13C NMR (on all examples) and heteronuclear multiple band correlation (HMBC)
on representative examples (entry 1). The reaction under microwaves (MW) resulted
in improved yields and shortened reaction time.
To see the influence of Li ion on product formation, LiHMDS was used as a
base. There was less product conversion, and the reaction was sluggish (Scheme 2).
This is due to better coordination of the Li ion with the oxygen atom in comparison
to the nitrogen atom.[13] There is slight improvement in the yield (2–5%) of the
product in the case of dry oxygen, and no conversion was observed in an inert
atmosphere.
Scheme 1.

MICROWAVE-ASSISTED N-CYCLOPROPYLATION
1343
Table 1. Copper(II)-catalyzed N-cyclopropylation of various pyridinol derivatives
Yield (%) (time in h)
conventional heating
(90–95 ꢀC)
Yield (%) (time in h)
microwave heating
Entry
Substrate
Product
(120 ꢀC)
1
2
40 (24)
75 (2)
No conversion
No conversion
3
4
48 (24)
30 (26)
80 (2)
65 (2.5)
5
6
45 (18)
40 (18)
80 (2)
75 (2)
7
8
9
45 (22)
No conversion
40 (24)
75 (2.5)
No conversion
74 (2)
10
No conversion
No conversion
Notes. Reaction conditions: Substrate (1.0 equiv.), cyclopropyl boronic acid (2.0 equiv.), Cu(OAc)2 (1.0
equiv.), pyridine (5.0 equiv.), NaHMDS (1.0 equiv.), dry air, and toluene.

1344
Y. B. TAMBE ET AL.
Scheme 2.
CONCLUSION
In summary, we have successfully demonstrated copper-mediated N-cyclopro-
pylation on substituted fused or unfused pyridinol systems in MW conditions.
Efforts are under way to develop this chemistry for O-cyclopropylation with other
transition-metal catalysts and ligands.
EXPERIMENTAL
1H NMR, HMBC, and 13C NMR spectra were recorded on a Bruker 400-MHz
Ultrashield Advance II 400 model. The chemical shifts are reported in d parts per mil-
lion (ppm) relative to tetramethylsilane (TMS). The Fourier transform (FT)-infrared
(IR) spectra were recorded on a Perkin-Elmer FT-IR system Spectrum Bx. Mass spec-
tra were recorded on a SQD-3100 Waters instrument for positive ion mode with
Acquity ultrahigh performance liquid chromatography (UPLC) for purity. The lab-
oratory-grade solvents and reagents were used without further purification. Thin-layer
chromatography (TLC) was performed on silica-gel 60F254 precoated plates (250-mm
layers). TLC visualization was performed with ultraviolet (UV) light. A Biotage
Initiator Sixty Exp 355434 instrument was used to carry out the reaction under micro-
waves. Flash chromatography was performed using Biotage SNAP cartridge KP-Sil
10g on the Biotage system in MeOH=dichloromethane (DCM). Purity of the isolated
compound is more than 95% by TLC.
Conventional Heating Condition
Pyridinol or quinolinol (5.0 mmol, 1.0 eq), cyclopropylboronic acid
(10.0 mmol, 2.0 eq), copper(II) acetate (5.0 mmol, 1.0 eq), pyridine (25.0 mmol, 5.0
eq), and toluene (10 mL) were added to a 25-mL round-bottom flask. To the mixture,
NaHMDS (5.0 mmol, 1.0 eq) was added under nitrogen atmosphere. Dry air was
introduced to the reaction mixture. The mixture was stirred at 100 ꢀC for 24 h under
an atmosphere of dry air, and then allowed to cool to ambient temperature. The
reaction mass was passed through a celite pad. The celite pad was washed with ethyl
acetate (2 ꢁ 5 mL). The organic layer was washed with water (2 ꢁ 5 mL), dried over
anhydrous Na2SO4, and concentrated in vacuo. Purification was done on Biotage
SNAP cartridge KP-Sil (10 g) using Biotage system in MeOH=DCM solvent system
to afford the desired N-cyclopropyl pyridinone or quinolinone.

MICROWAVE-ASSISTED N-CYCLOPROPYLATION
1345
Microwave Heating Condition
Similar reaction conditions (molar concentration and atmosphere) were main-
tained in microwave vial (10–20 ml) to carry out the reaction in a Biotage MW. The
MW reactions were carried out at 1-g scale in 5 ml of toluene. The purification was
done as described previously.
1-Cyclopropylpyridin-2(1H)-one (1)
1H NMR (400 MHz, DMSO-d6): d 7.50 (d, 1H, J ¼ 6.8 Hz), 7.36 (t, 1H,
J ¼ 7.2 Hz), 6.34 (d, 1H, J ¼ 9.2 Hz), 6.15 (t, 1H, J ¼ 6.8 Hz), 3.35 (m, 1H), 0.96
(m, 2H), 0.81 (m, 2H) ppm; 13C NMR (100 MHz, MeOD): d 165.13, 140.41,
137.61, 118.99, 107.03, 32.25, and 5.86 ppm; MS: m=z ¼ 136.06 (M þ 1); HRMS:
obs. 136.0688, cal. 136.0762; IR (neat, cmꢂ1): 1636, 1547, 1399, 1362, 1257, 1183,
1068, 1018, 856, 524.
1-Cyclopropylpyridin-4(1H)-one (3)
1H NMR (400 MHz, CDCl3): d 7.43 (d, 2H, J ¼ 7.6 Hz), 6.34 (d, 2H,
J ¼ 7.6 Hz), 3.39 (m, 1H), 1.08 (m, 2H), 1.00 (m, 2H) ppm; 13C NMR (100 MHz,
CDCl3): d 179.35, 140.78, 118.46, 36.96 and 7.11 ppm; MS: m=z ¼ 136.04 (M þ 1);
HRMS: obs. 136.0675, cal. 136.762; IR (neat, cmꢂ1): 1638, 1545, 1458, 1400,
1362, 1256, 1199, 1183, 1068, 1018, 884, 856, 694, 524.
1-Cyclopropyl-2-oxo-1,2-dihydropyridine-4-carbonitrile (4)

1346
Y. B. TAMBE ET AL.
1H NMR (400 MHz, DMSO-d6): d 7.77 (d, 1H, J ¼ 7.2 Hz), 6.99 (d, 1H,
J ¼ 1.2 Hz), 6.46 (dd, 1H, J ¼ 1.6 Hz, 7.2 Hz), 3.33 (m, 1H), 1.00 (m, 2H), 0.87 (m,
2H) ppm; 13C NMR (100 MHz, MeOD): d 162.90, 139.96, 124.81, 124.67, 115.45,
105.72, 32.79, and 5.93 ppm; MS: m=z ¼ 161.22 (M þ 1); HRMS: obs. 161.0805,
cal. 161.0715; IR (neat, cmꢂ1): 2244, 1662, 1587, 1514, 1330, 1302, 1200, 1032,
876, 792, 737, 627.
1-Cyclopropyl-4,6-dimethylpyridin-2(1H)-one (5)
1H NMR (400 MHz, DMSO-d6): d 5.97 (s, 1H), 5.91 (s, 1H), 2.76 (m, 1H), 2.37
(s, 3H), 2.02 (s, 3H), 1.08 (m, 2H), 0.72 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3):
d 165.30, 150.15, 147.32, 117.03, 109.56, 27.73, 21.03, 20.51, and 10.32 ppm; MS:
m=z ¼ 164.18 (M þ 1); HRMS: obs. 164.1022, cal. 164.1075; IR (neat, cmꢂ1): 1656,
1577, 1548, 1347, 1240, 1033, 892, 823, 613, 525.
1-Cyclopropyl-4,8-dimethylquinolin-2(1H)-one (6)
1H NMR (400 MHz, CDCl3): d 7.46 (d, 1H, J ¼ 7.6 Hz), 7.32 (d, 1H,
J ¼ 7.2 Hz), 7.13 (t, 1H, J ¼ 7.6 Hz), 6.44 (s, 1H), 3.44 (m, 1H), 2.72 (s, 3H), 2.38
(s, 3H), 1.20 (m, 2H), 0.60 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d 166.31,
146.69, 141.35, 133.91, 126.93, 123.51, 122.66, 122.42, 121.45, 32.67, 22.44, 19.35,
and 12.44 ppm; MS: m=z ¼ 214.26 (M þ 1); HRMS: obs. 214.1290, cal. 214.123; IR
(neat, cmꢂ1): 1650, 1583, 1440, 1381, 1277, 1165, 1025, 862, 747.
1-Cyclopropyl-7-methoxyquinolin-4(1H)-one (7)

MICROWAVE-ASSISTED N-CYCLOPROPYLATION
1347
1H NMR (400 MHz, DMSO-d6): d 8.06 (d, 1H, J ¼ 8.8 Hz), 7.88 (d, 1H,
J ¼ 7.6 Hz), 7.36 (d, 1H, J ¼ 6.0 Hz), 7.02 (dd, 1H, J ¼ 2.4 Hz, 8.8 Hz), 5.92 (d, 1H,
J ¼ 8.0 Hz), 3.92 (s, 3H), 3.49 (m, 1H) 1.20 (m, 2H), 1.00 (m, 2H) ppm; 13C NMR
(100 MHz, MeOD): d 178.31, 163.23, 143.91, 143.51, 127.25, 119.89, 113.87,
108.23, 98.39, 54.84, 33.86, and 7.16 ppm; MS: m=z ¼ 216.14 (M þ 1); HRMS: obs.
216.1132, cal. 216.1025.
1-Cyclopropylquinolin-4(1H)-one (9)
1H NMR (400 MHz, DMSO-d6): d 8.15 (dd, 1H, J ¼ 1.2 Hz, 8.0 Hz), 8.03 (d,
1H, J ¼ 8.8 Hz), 7.98 (d, 1H, J ¼ 8.0 Hz), 7.77 (m, 1H), 7.41 (t, 1H, J ¼ 7.6 Hz),
6.00 (d, 1H, J ¼ 7.6 Hz), 3.53 (m, 1H), 1.19 (m, 2H), 1.02 (m, 2H) ppm; 13C NMR
(100 MHz, MeOD): d 178.82, 144.22, 141.55, 132.32, 125.41, 124.06, 116.93,
108.42, 33.95, 7.22 ppm; MS: m=z ¼ 186.08 (M þ 1), HRMS: obs. 186.0938, cal.
186.0919.
ACKNOWLEDGMENT
We are thankful to Jubilant Chemsys Limited for funding our research work
and providing the infrastructure support.
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