A general strategy for the synthesis of difluoromethyl-containing pyrazoles, pyridines and pyrimidines

DOI: 10.1016/j.tet.2011.05.085

Source and publish data:

Tetrahedron p. 5663 - 5677 (2011)

Update date:2022-08-02

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Authors:

Iaroshenko, Viktor O.

Specowius, Verena

Vlach, Katharina

Vilches-Herrera, Marcelo

Ostrovskyi, Dmytro

Mkrtchyan, Satenik

Villinger, Alexander

Langer, Peter

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Article abstract of DOI:10.1016/j.tet.2011.05.085

Difluoromethyl-containing heteroannulated pyridines, pyrimidines and pyrazoles are prepared by a two step method. The regioselective cyclizations of electron-excessive aminoheterocycles, hydrazines and amidines with CF ₂Cl-substituted 1,3-dicarbonyl compounds provide the corresponding CF₂Cl-substituted heterocycles. Subsequent radical reactions with trimethylstannane or allyltrimethylstannane gave difluoromethyl-containing heteroannulated pyridines, pyrimidines and pyrazoles, respectively.

Full text of DOI:10.1016/j.tet.2011.05.085

Tetrahedron 67 (20 1 1 ) 5663e5677

Contents lists available at ScienceDirect

Tetrahedron

journal homepage: w ww.elsevier.com/locate/tet

A general strategy for the synthesis of diﬂuoromethyl-containing pyrazoles,

pyridines and pyrimidines

,b, ,

Viktor O. Iaroshenko ^a

^y, Verena Specowius ^a, Katharina Vlach ^a, Marcelo Vilches-Herrera ^a,

Dmytro Ostrovskyi ^a, Satenik Mkrtchyan ^a, Alexander Villinger ^a, Peter Langer ^a

,c,

€

Institut fur Chemie, Universitat Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany

^bDepartment of Chemistry, National Taras Shevchenko University, 62 Volodymyrska st., Kyiv-33 01033, Ukraine

€

Leibniz-Institut fur Katalyse an der Universitat Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany

a r t i c l e i n f o

a b s t r a c t

Article history:

Received 1 March 2011

Received in revised form 17 May 2011

Accepted 19 May 2011

Available online 27 May 2011

Diﬂuoromethyl-containing heteroannulated pyridines, pyrimidines and pyrazoles are prepared by a two

step method. The regioselective cyclizations of electron-excessive aminoheterocycles, hydrazines and

amidines with CF₂Cl-substituted 1,3-dicarbonyl compounds provide the corresponding CF₂Cl-substituted

heterocycles. Subsequent radical reactions with trimethylstannane or allyltrimethylstannane gave

diﬂuoromethyl-containing heteroannulated pyridines, pyrimidines and pyrazoles, respectively.

Keywords:

Cyclizations

Organoﬂuorine compounds

Regioselectivity

Purine isosteres

N-Heterocycles

1. Introduction

CO₂H

(CH₂)₃

The introduction of ﬂuorine-containing functional groups to

biomolecules often results in an improvement of the biological

activity.¹It has been demonstrated that CF₂H-containing molecules

possess strong anti-cancer activity. In general, compounds con-

taining CF₂-groups have been reported to exhibit herbicidal,²po-

tential antitumour³and antileishmanial activity.⁴Although

diﬂuoromethylated compounds have signiﬁcant applications in

drug and pesticide discovery, only a limited number of them are

synthetically available as compared to their CF₃analogues.

On the other side, there are a number of drugs on the market,

which contain a CF₂-group (Fig. 1).^5e9Pantoprazole (I) developed

by Altana Pharma (presently Nicomed) is a proton pump inhibitor

used for short-term treatment of erosion and ulceration of the

oesophagus caused by gastroesophageal reﬂux disease.⁵Eﬂorni-

HF₂C

Pantoprazole

Roflumilast

C₅H₁₁

III

CF₂H

D0870

VI Maraviroc

H₂N

CF₂H

H₂N

Eflornithine

thine

(a-diﬂuoromethylornithine or DFMO) IV, a rationally

designed ornithine decarboxylase inhibitor, is active against in-

fections with Trypanosoma gambiense. Eﬂornithine is a drug used

for the treatment of facial hirsutism (excessive hair)⁶as well as in

African trypanosomiasis (sleeping sickness).⁷

Fig. 1. Drugs containing a CF₂-group.

In general, molecules containing a CF₂-function are relatively

rare in the literature, due to the lack of synthetic methods available

for their introduction. A number of methods for the preparation of

CF₂-containing compounds have been developed in recent years.¹⁰

The commercial availability of several ﬂuorinating agents, such as

DAST, SF₄,¹¹SeF₄,¹²TBAF¹³and BrF₃,¹⁴has paved the way for the

* Corresponding authors. Fax: þ49 (0)381/498 6412; e-mail addresses: viktor.-

iaroshenko@uni-rostock.de (V.O. Iaroshenko), peter.langer@uni-rostock.de (P. Langer).

Tel./fax: þ380 44 537 32 53.

doi:10.1016/j.tet.2011.05.085

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V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 5663e5677

synthesis of various diﬂuorinated compounds. However, most of

these methods rely on harsh reaction conditions and aggressive

medias. Thus, the development of alternative synthetic approaches

to CF₂-containing molecules represents an important area of cur-

rent research.

CF₂Cl

ClF₂C

NH₂

1-5

2. Results and discussion

CF₂Cl

Continuing our research program¹⁵dedicated to the design and

synthesis of ﬂuorinated drug-like scaffolds and their functionali-

zation, we started the project reported herein. Our initial purpose

was to develop a facile and straightforward synthetic pathway to-

wards small heterocycles bearing CF₂H and CF₂R substituents in the

heteroaromatic ring. Based on the retrosynthetic analysis and our

previous experience in the synthesis of ﬂuorinated heterocycles,

based on cyclocondensation of electron-rich systems with ﬂuori-

nated 1,3-CCC- and 1,3-CNC-dielectrophiles, we envisaged the two-

step strategy depicted in Fig. 2. The ﬁrst step is built upon the initial

assembly of the heterocyclic scaffold by formal [2þ3] or [3þ3]-

cycloaddition reactions. As a second step, the exchange of the Cl-

atom by free radical conditions, using AIBN, Bu₃SnH or

Bu₃Sneallyl, was carried out.

OMe

NH₂

generated

in situ

Scheme 1. Synthesis of heteroannulated pyridines 7. Reagents and conditions: (i):

AcOH, reﬂux. (ii) CH₂Cl₂, argon, reﬂux, 2 h.

excellent yields (Table 1). At the same time, 5-aminoimidazoles 10,

in situ generated by our recently reported method,¹⁷reacted with 6

to give the 7-(chlorodiﬂuoromethyl)-imidazo[4,5-b]pyridines 11.

After construction of the condensed pyridine scaffolds, we have

concentrated our efforts on the functionalization of the CF₂eCl

bond by free radical reactions initiated by AIBN with Bu₃SnH or

Bu₃Sneallyl. This reaction takes place smoothly in dry benzene at

80 ^ꢀC and usually was ﬁnished within 18 h. All pyridines tested here

have shown high reactivity and gave the correspondent CF₂-

substituted pyridines 12, 13 in good to excellent yields (Scheme 2,

Table 2).

CF₂Cl

R₁

[3+3] or [2+3]

Het

NH₂

F₂

The bicyclic structures of scaffolds 12 and 13 were in accordance

with the NMR spectroscopic data. The assignments of scaffolds 12

free radical

HN NH₂

reduction reaction

Table 1

Yields of compounds 7, 11

Fig. 2. Retrosynthetic analysis.

Structure

CF₂Cl

Hereby, we report a general method for the synthesis of 4-CF₂R-

substituted heteroannulated pyridines as well as CF₂R-substituted

pyrimidines and pyrazoles. The syntheses follow a two step pro-

cedure, which consists of the formal [3þ3]- and [2þ3]-cyclization

of CF₂Cl-containing 1,3-CCC-dielectrophiles with electron-

excessive heteroaromatic systems, hydrazines and amidines. Sub-

sequently, radical-induced substitutions of the chlorine atom of the

CF₂Cl moiety using Bu₃SnH or Bu₃Sneallyl and AIBN are carried

out.¹⁶Previously, this method was used for the synthesis of com-

plex organic molecules,¹⁶but the scope and limitations have not yet

been studied.

CF₂Cl

OMe

CF₂Cl

Starting with electron-excessive aminoheterocycles available in

our laboratories (Fig. 3) and CF₂Cl-substituted 1,3-diketones, we

have elaborated a facile synthesis of g-CF₂Cl-substituted pyridines

7 (Scheme 1). The reaction proceeds in acetic acid under reﬂux

delivering the correspondent annulated pyridines in good to

CF₂Cl

a: R = 4-MeO-Benzyl,

b: R = Cyclohexyl,

c: R = t-Bu

NH₂

CF₂Cl

OMe

Me₂N

NH₂

CF₂Cl

NH₂

a: R= H,

a: R= Me,

b: R= Ph

b: R= Me

Fig. 3. Amines used for the synthesis of heteroanulated pyridines.

V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 5663e5677

5665

Table 1 (continued )

F₂C

Structure

CF₂Cl

Bu₃SnH

CF₂Cl

R¹

Bu₃SnAlyl

F₂C

7, 11

CF₂Cl

R¹

MeO

Scheme 2. Synthesis of pyridines 12 and 13. Reagents and conditions: (i): AIBN, C₆H₆,

18 h, 80 ^ꢀC.

CF₂Cl

and 13 were additionally conﬁrmed by X-ray crystal structure

analysis of compounds 12f and 13d (Figs. 4 and 5).¹⁸The 1-tert-

butyl-4-(1,1-diﬂuorobut-3-enyl)-6-methyl-1H-pyrrolo[2,3-b]pyri-

dine-3-carbonitrile 13d is, as expected, a plane molecule. In the

crystal, the angle F(1)C(13)F(2) is 105.0^ꢀand the angle C(5)C(13)

C(14) is 105.8^ꢀ, which are typical for CF₂ealkyl substituents. The

torsion angle C(2)C(5)eC(13)C(14) is 71.4^ꢀ(Fig. 5).

MeO

CF₂Cl

Table 2

Yields of compounds 12, 13

Structure

CF₂Cl

F₂C

12a

F₂C

CF₂Cl

12b

12c

F₂C

CF₂Cl

11a

OMe

CF₂Cl

F₂C

12d

12e

CF₂Cl

F₂C

MeO

CF₂Cl

F₂C

11b

12f

MeO

Yields of isolated products.

(continued on next page)

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V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 5663e5677

Table 2 (continued )

Table 2 (continued)

Structure

CF₂H

F₂C

12g

12h

13g

F₂C

MeO

F₂C

13h

12i

12j

MeO

F₂C

13i

13j

F₂C

13a

F₂C

13k

13l

13b

13c

OMe

F₂C

MeO

F₂C

13m

F₂C

13d

13e

Yields of isolated products.

For the synthesis of 4-(diﬂuoromethyl)pyrimidines we have

applied the same synthetic pathway as described above for the

synthesis of heteroannulated pyridines. As a model compound,

phenylamidine 14 was chosen. For the synthesis of the cyclic CF₂Cl-

precursors 16a,b we have used two different building blocks,

namely, CF₂Cl-substituted 1,3-diketones 6 and (E)-1-chloro-4-

ethoxy-1,1-diﬂuorobut-3-en-2-one 15 (Scheme 3). The reaction of

phenylamidine with CF₂Cl-substituted 1,3-dielectrophiles 6 and 15

afforded the 4-(chlorodiﬂuoromethyl)-2-phenylpyrimidines 16a,b

in good yields. The reaction with Bu₃SnH and Bu₃Sneallyl resulted

in the formation of the correspondent CF₂H- and CF₂Allyl-

substituted derivatives 17, 18 (Scheme 4).

F₂C

13f

The structure of pyrimidine 16b was unambiguously proved by

X-ray crystal structure analysis (Fig. 6).¹⁸The molecule has a plane

structure, the corresponding torsion angle N(1)C(1)eC(5)C(10) is

close to 0^ꢀ.

MeO

V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 5663e5677

5667

F₂C

Bu₃SnH

CF₂Cl

a: R=H (56%)

b: R= Me (50%)

Bu₃SnAlyl

F₂C

a: R=H (29%)

b: R= Me (45%)

Scheme 4. Synthesis of pyrimidines 17, 18. Reagents and conditions: (i): AIBN, C₆H₆,

18 h, 80 ^ꢀC.

Fig. 4. Molecular structure of compound 12f.

substituted pyrazoles, which is based on formal [3þ2]-cyclizations

of hydrazines with CF₂Cl-substituted 1,3-CCC-dielectrophiles fol-

lowed by functionalization of the CF₂Cl-group (Scheme 5).

ClF₂C

R₂

R₁-NH-NH₂

i or ii

ClF₂C

OEt

R₂

R₁

i or ii

R₁-NH-NH₂

Scheme 5. Synthesis of 3-chlorodiﬂuoromethyl-1H-pyrazoles 20. Reagents and con-

ditions: (i): EtOH, reﬂux, 5 h (ii): AcOH, 20 ^ꢀC.

Fig. 5. Molecular structure of compound 13d.

As the starting point, we have chosen two previously described

methods for the synthesis of pyrazole using diketones 6 and (E)-1-

chloro-4-ethoxy-1,1-diﬂuorobut-3-en-2-one 15. We have identiﬁed

two reported reaction conditions for the synthesis of pyrazoles,

namely, acetic acid at 20 ^ꢀC,²³and ethanol under reﬂux.

The reaction of hydrazines with 6 and 15 regioselectively

afforded the 3-(chlorodiﬂuoromethyl)-1H-pyrazoles 20 in 10e94%

yields (Table 3, Scheme 5). The yields are dependent on the choice

of the reaction medium. The modiﬁcation of the CF₂Cl-group, again

conducted using Bu₃SnH or Bu₃Sneallyl in the presence of AIBN,

led to the formation of the CF₂-substituted pyrazoles 21 and 22 in

fair yields (Scheme 6).

ClF₂C

NH₂

CF₂Cl

ClF₂C

OEt

a: R=H

(73%)

b: R= Me (71%)

NH₂

Scheme 3. Synthesis of pyrimidines 16. Reagents and conditions: (i): 1.1 equiv NaOAc,

xylol, 7.5 h, reﬂux.

Pyrazoles have a wide range of biological activities and occur in

numerous drugs. Pyrazoles are present in B-Raf inhibitors,¹⁹CARM1

inhibitors,²⁰CB1 receptor antagonists,²¹and EP1 receptor antago-

nists.²²Fluorinated pyrazoles are relatively rare. In spite of extensive

studies related to the biological activities of pyrazole derivatives,

syntheses of pyrazoles suffer from their poor regioselectivity, es-

pecially in the case of the condensation reaction of 1,3-diketones

with unsymmetrical hydrazines. Therefore, we were strongly en-

couraged to pursue the synthesis of a focused library of CF₂-

Fig. 6. Molecular structure of compound 16b.

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V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 5663e5677

Table 3

Yields of compounds 20

3.3. General procedure for the synthesis of compounds 7aen

A solution of chlorodiﬂuorodiketone (1.0 equiv) and amine

(1.0 equiv) in acetic acid (10 mL per 1 mmol of starting material)

was heated for 3e6 h under reﬂux. The solvent was evaporated, and

the obtained crude product was puriﬁed by column chromatogra-

phy to give the pure product.

R₁

R₂

% (20)^a

79 (ii)

94 (i)

0 (i,ii)

73 (ii)

47 (ii)

88 (ii)

73 (i)

4e(NO₂)C₆H₄

3.4. General procedure for the synthesis of compounds 12aej,

13aem, 17a,b, 18a,b, 21, 22a,b

4e(NO₂)C₆H₄

Yields of isolated products; in brackets: reactions conditions applied.

To a solution of chlorodiﬂuorinated heterocycle (0.5 equiv) and of

the stannane (1.25 equiv) in benzene (10 mL per 1 mmol of starting

material) was added AiBN (0.06 equiv). The mixture was heated for

16 h under reﬂux (TLC control). The solvent was evaporated and the

crude product was puriﬁed by column chromatography (silica gel,

heptanes/EtOAc, 100:1) to give the crude product. The residue was

puriﬁed by preparative chromatography (silica gel, heptane).

F₂C

Bu₃SnH

ClF₂C

21 (28%)

Bu₃SnAlyl

R₂

3.5. General procedure for the synthesis of compound 7j

F₂C

R₁

a: R=H (38%)

b: R= Me (40%)

A solution of 1.0 equiv of the chlorodiﬂuorodiketone and of

1.0 equiv of the amine in acetic acid (3 mL per 1 mmol of the

starting material) was added NaOAc (4 equiv). The mixture was

heated for 6 h under reﬂux. The solvent was evaporated, and the

obtained crude product was puriﬁed by column chromatography to

give the pure product.

R₂

Scheme 6. Synthesis of pyrazoles 21, 22. Reagents and conditions: (i): AIBN, C₆H₆, 18 h,

80 ^ꢀC.

In conclusion, we have elaborated a practical and short synthetic

route to CF₂-containing drug-like heteroannulated pyridines, py-

rimidines and pyrazoles using a new two step sequence. This pro-

tocol relies on the assembly of the CF₂Cl-containing heterocyclic

moiety by [3þ2]- and [3þ3]-cyclizations and subsequent sub-

stitution reactions by free radical conditions.

3.6. General procedure for the synthesis of compounds 16a,b

A solution of 1.0 equiv of the chlorodiﬂuorodiketone,1.0 equiv of

benzamidine and 1.1 equiv of sodium acetate in xylol (1 mL per

1 mmol of starting material) was heated at 139 ^ꢀC. The crude

product was poured into ice water. After standing for 12 h at room

temperature, the precipitate formed was ﬁltered, washed with

water and dried.

3. Experimental section

3.1. General comments

3.7. General procedure for the synthesis of compounds 20a,

20c, 20eef

Chemical yields refer to pure isolated substances. ¹H and ¹³C

NMR spectra were obtained using a Bruker DPX-300 spectrometer.

Chemical shifts of the ¹H and ¹³C NMR are reported in parts per

million using the solvent internal standard (CDCl₃7.26 ppm and

77.0 ppm, DMSO-d₆2.49 ppm and 39.7 ppm). IR spectra were

recorded on a PerkineElmer FTIR 1600 spectrometer for samples in

KBr discs. Mass spectra were obtained on a HewlettePackard HP

GC/MS 5890/5972 instrument (EI, 70 eV) by GC inlet or on an MX-

1321 instrument (EI, 70 eV) by direct inlet. Elemental analyses were

carried out at the Microanalytical laboratory of the University of

Rostock Germany. Melting points are uncorrected. The solvents

were purchased directly from ACROS and used without further

puriﬁcation. Analytical thin layer chromatography was performed

on 0.20 mm 60 A silica gel plates. Column chromatography was

performed using 60 A silica gel (60e200 mesh).

A solution of 1.0 equiv of the chlorodiﬂuorodiketone or of (Z)-1-

chloro-4-ethoxy-1,1-diﬂuorbut-3-en-2-one and of 1.0 equiv of the

hydrazine in acetic acid (8 mL per 1 mmol of starting material) was

stirred for 2 h at room temperature. The solvent was evaporated,

and the crude product was puriﬁed by column chromatography to

give the pure product.

3.8. General procedure for the synthesis of compounds 20b, 20g

A solution of 1.0 equiv of the chlorodiﬂuorodiketone or of (Z)-1-

chloro-4-ethoxy-1,1-diﬂuorbut-3-en-2-one and of 1.0 equiv of the

hydrazine in ethanol (8 mL per 1 mmol of starting material) was

heated for 5 h under reﬂux and stirred for 12 h at room tempera-

ture. The solvent was evaporated, and the obtained crude product

was puriﬁed by column chromatography to give the pure product.

3.2. General procedure for the synthesis of compounds 6

3.8.1. 4-(Chlorodiﬂuoromethyl)-3,6-dimethyl-1-phenyl-1H-pyrazolo

[3,4-b]pyridine (7a). Brown solid isolated by recrystallization from

To a solution of NaH (1.1 equiv) in ether (2.0 mL/mmol SM) was

added acetophenone (1.0 equiv) at 0 ^ꢀC. The solution was stirred at

(1.0 equiv) was added. The temperature was allowed to rise to

20 ^ꢀC over 14 h. To the solution was added HCl (10%) and the

mixture was extracted with Et₂O. The organic layers were dried

over Na₂SO₄, ﬁltered and the ﬁltrate was concentrated in vacuo. The

residue was puriﬁed by chromatography (heptane/EtOAc) to give

the chlorodiﬂuoroketones.

acetic acid, mp 67e69 ^ꢀC; ¹H NMR (CDCl₃, 300 MHz):

¼2.74e2.75

(m, 6H, CH₃), 7.27e7.33 (m, 1H, CH), 7.44e7.53 (m, 3H, C_ArH),

8.19e8.22 (m, 2H, C_ArH). ¹³C NMR (CDCl₃, 75 MHz):

^ꢀC for 10 min before methyl 2-chloro-2,2-diﬂuoroacetate

d¼15.5

(t, J_C,F¼4.5 Hz, CH₃), 25.1 (CH₃), 108.3 (t, J_C,F¼2.2 Hz, C), 112.4

(t, J_C,F¼6.6 Hz, CH), 121.6 (CH), 124.3 (t, J_C,F¼35.0 Hz, C), 126.1, 129.0

(CH),137.4 (t, J_C,F¼28.6 Hz, CeCF₂Cl),139.0, 140.9, 152.0 (C). ¹⁹F NMR

(CDCl₃, 282 MHz):

2922 (w), 2851 (w),1681 (w),1595 (m),1573 (w),1502 (s),1438 (m),

¼ꢁ49.54 (CF₂Cl). IR (ATR, cm^ꢁ1):

¼3082 (w),

V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 5663e5677

5669

1412 (s), 1391 (w), 1378 (w), 1343 (s), 1305 (w), 1295 (w), 1271 (w),

1219 (s), 1162 (s), 1122 (s), 1071 (m), 1034 (m), 1009 (m). MS (EI,

70 eV): m/z (%)¼309 ([M^þ] [³⁷Cl], 51), 308 (34), 307 ([M^þ] [³⁵Cl],

100), 292 (16), 272 (52), 266 (22), 257 (11), 77 (16). HRMS (EI,

70 eV): calcd for C₁₅H₁₂N₃ClF₂([M^þ], [³⁵Cl]) 307.06823, found

307.067620. Anal. Calcd for C₁₅H₁₂ClF₂N₃(307.73): C, 58.55, H, 3.93,

N, 13.66. Found: C, 58.290, H, 3.960, N, 12.910.

298.0917. Anal. Calcd for C₁₄H₁₄ClF₂N₃(297.73): C, 56.48, H, 4.74, N,

14.11. Found: C, 55.350, H, 4.380, N, 13.810.

3.8.5. 1-tert-Butyl-4-(chlorodiﬂuoromethyl)-6-(4-methoxyphenyl)-

1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (7e). White solid isolated

recrystallization from acetic acid; mp 178e179 ^ꢀC; ¹H NMR (CDCl₃,

300 MHz):

2H, C_ArH), 7.85 (s, 1H, CH), 8.00 (s, 1H, CH), 8.03e8.08 (m, 2H, C_ArH).

¹³C NMR (CDCl₃, 75 MHz):

d¼1.90 (s, 9H, C(CH₃)₃), 3.89 (s, 3H, OCH₃), 7.01e7.06 (m,

3.8.2. 4-(Chlorodiﬂuoromethyl)-6-(4-methoxyphenyl)-3-methyl-1-

phenyl-1H-pyrazolo[3,4-b]pyridine (7b). White solid isolated by

recrystallization from acetic acid; mp 158e159 ^ꢀC; ¹H NMR (CDCl₃,

¼29.3 (C(CH₃)₃), 55.4 (OCH₃), 59.2

(C(CH₃)₃), 83.2 (C), 109.0 (t, J_C,F¼6.1 Hz, CH), 112.8 (t, J_C,F¼2.2 Hz, C),

114.4 (C), 115.6 (C^N), 124.4 (t, J_C,F¼290.5 Hz, CF₂Cl), 128.3 (CH),

130.9 (C), 136.0 (CH), 136.4 (t, J_C,F¼29.0 Hz, CeCF₂Cl), 143.3 (C),151.9

300 MHz):

¼2.77 (t, ³J¼1.9 Hz, 3H, CH₃), 3.89 (s, 3H, OCH₃),

7.01e7.04 (m, ³J¼8.9 Hz, 2H, C_ArH), 7.32 (t, ³J¼7.4 Hz, 1H, C_ArH),

(C),160.9 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ49.83 (CF₂Cl). IR (ATR,

7.51e7.57 (m, 2H, C_ArH), 7.79 (s, 1H, CH), 8.10e8.13 (m, 2H, C_ArH),

cm^ꢁ1):

¼3140 (w), 3089 (w), 2986 (w), 2931 (w), 2836 (w), 2632

8.30e8.32 (m, 2H, C_ArH). ¹³C NMR (CDCl₃, 75 MHz):

¼15.5 (t,

(w), 2271 (w), 2225 (s), 1750 (w), 1643 (w),1606 (w),1592 (m), 1575

(w), 1515 (s), 1465 (w), 1450 (w), 1440 (w), 1396 (s), 1365 (s), 1320

(s), 1297 (s), 1240 (w), 1204 (m), 1172 (m), 1061 (w), 1134 (s), 1117

(w), 1068 (w), 1033 (s), 1015 (w), 1007 (w). MS (EI, 70 eV): m/z (%)¼

391 ([M^þ], [³⁷Cl], 11), 390 (8), 389 ([M^þ], [³⁵Cl], 32), 335 (35), 334

(19), 333 (100). 298 (29). HRMS (EI, 70 eV): calcd for C₂₀H₁₈N₃ClF₂O

([M^þ], [³⁵Cl]) 389.11010, found 389.110212.

J_C,F¼4.4 Hz, CH₃), 55.4 (OCH₃), 108.6 (t, J_C,F¼2.2 Hz, C), 108.8 (t,

J_C,F¼6.6 Hz, CH), 114.3 (CH), 121.4 (CH), 124.4 (t, J_C,F¼290.5 Hz,

CF₂Cl), 125.9 (CH), 128.9 (CH), 129.0 (CH), 130.5 (C), 137.9 (t,

J_C,F¼29.2 Hz, CeCF₂Cl), 139.2 (C), 141.1 (C), 152.2 (C), 156.5 (C), 161.4

(C). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ49.55 (CF₂Cl). IR (ATR, cm^ꢁ1):

¼3107 (w), 3076 (w), 3040 (w), 3007 (w), 2938 (w), 2842 (w),

1593 (w), 1582 (w), 1568 (w), 1504 (w), 1493 (w), 1478 (w), 1458

(m), 1435 (w), 1417 (s), 1386 (w), 1347 (s), 1311 (w), 1297 (w), 1255

(w), 1236 (s), 1167 (w), 1157 (w), 1118 (m), 1084 (m), 1050 (w), 1042

(w), 1028 (m), 1002 (w). MS (EI, 70 eV): m/z (%)¼401 ([M^þ], [³⁷Cl],

35), 400 (25), 399 ([M^þ], [³⁵Cl], 100), 364 (14). HRMS (EI, 70 eV):

3.8.6. 1-tert-Butyl-4-(chlorodiﬂuoromethyl)-6-(4-chlorophenyl)-1H-

pyrrolo[2,3-b]pyridine-3-carbonitrile (7f). White solid isolated re-

crystallization from acetic acid; mp 244e245 ^ꢀC; ¹H NMR (CDCl₃,

300 MHz):

¼1.90 (s, 9H, C(CH₃)₃), 7.46e7.51 (m, 2H, C_ArH), 7.88 (s,

calcd for C₂₁H₁₆N₃ClF₂O ([M^þ],

[

³⁵Cl]) 399.09445, found

1H, CH), 8.01e8.06 (m, 3H, C_ArH). ¹³C NMR (CDCl₃, 75 MHz):

d¼29.3

399.094692. Anal. Calcd for C₂₁H₁₆ClF₂N₃O (399.82): C, 63.08, H,

4.03, N, 10.51. Found: C, 62.600, H, 3.620, N, 9.920.

(C(CH₃)₃), 59.4 (C(CH₃)₃), 83.4 (C), 109.4 (t, J_C,F¼6.6 Hz, CH), 113.6 (t,

J_C,F¼2.2 Hz, C), 115.0 (C^N), 124.2 (t, J_C,F¼291 Hz, CF₂Cl), 128.2 (CH),

129.2 (CH), 135.7 (C), 136.6 (t, J_C,F¼29.2 Hz, CeCF₂Cl), 136.7 (C),

3.8.3. 4-(Chlorodiﬂuoromethyl)-6-(4-chlorophenyl)-3-methyl-1-

phenyl-1H-pyrazolo[3,4-b]pyridine (7c). White solid isolated by re-

crystallization from acetic acid; mp 157e158 ^ꢀC; ¹H NMR (CDCl₃,

136.8 (CH), 148.2, 150.9 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

d¼ꢁ49.90.

IR (ATR, cm^ꢁ1):

¼3136 (w), 3094 (w), 2993 (w), 2945 (w), 2224 (s),

1756 (w), 1591 (w), 1514 (m), 1494 (m), 1471 (m), 1398 (s), 1370 (w),

1359 (w), 1320 (s), 1294 (w), 1275 (w), 1239 (m), 1203 (s), 1177 (w),

1163 (m), 1136 (s), 1116 (w), 1103 (w), 1090 (s), 1064 (m), 1038 (w),

1010 (s). MS (EI, 70 eV): m/z (%)¼397 ([M^þ], [³⁷Cl] [³⁷Cl], 16), 395

([M^þ], [³⁷Cl] [³⁵Cl], 16), 393 ([M^þ], [³⁵Cl] [³⁵Cl], 25), 339 (66), 337

(100), 303 (13), 302 (56). HRMS (ESI-TOF/MS): calcd for

C₁₉H₁₅Cl₂F₂N₃([MþH]^þ, [³⁵Cl] [³⁵Cl]) 394.0684, found 394.0689.

Anal. Calcd for C₁₉H₁₅Cl₂F₂N₃(394.25): C, 57.88, H, 3.83, N, 10.66.

Found: C, 57.900, H, 3.420, N, 9.980.

300 MHz):

¼2.79 (s, 3H, CH₃), 7.34 (t, ³J¼7.4 Hz,1H, C_ArH), 7.47e7.57

(m, 4H, C_ArH), 7.80 (s, 1H, CH), 8.08 (d, ³J¼8.5 Hz, 2H, C_ArH), 8.27 (d,

³J¼7.7 Hz, 2H, C_ArH).¹³C NMR (CDCl₃, 75 MHz):

¼15.5 (t, J_C,F¼4.4 Hz,

CH₃), 109.0 (t, J_C,F¼6.6 Hz, CH), 109.3 (t, J_C,F¼2.2 Hz, C), 121.5 (CH),

124.1 (t, J_C,F¼290.5 Hz, CF₂Cl),126.2 (CH),127.5 (C),128.7,129.0,129.2

(CH), 136.4 (d, J_C,F¼4.4 Hz, C), 138.3 (t, J_C,F¼29.2 Hz, CeCF₂Cl), 139.0,

141.2,152.1,155.5 (C).¹⁹F NMR (CDCl₃, 282 MHz):

d¼ꢁ49.62. IR (ATR,

cm^ꢁ1):

¼3061 (w), 2979 (w), 2937 (w), 2861 (w), 2355 (w), 2138

(w), 1592 (w), 1581 (w), 1562 (w), 1503 (s), 1489 (w), 1476 (w), 1456

(w), 1438 (w), 1418 (m), 1403 (m), 1388 (w), 1345 (s), 1312 (w), 1298

(w), 1268 (w), 1242 (s), 1176 (m), 1152 (m), 1026 (m), 1094 (w), 1084

(w), 1051 (m), 1031 (w), 1013 (w), 1002 (w). MS (EI, 70 eV): m/z (%)¼

407 ([M^þ], [³⁷Cl] [³⁷Cl],12), 405 ([M^þ], [³⁵Cl] [³⁷Cl], 67), 404 (28), 403

([M^þ], [³⁵Cl] [³⁵Cl],100), 402 (9), 368 (23). HRMS (EI, 70 eV): calcd for

C₂₀H₁₃N₃Cl₂F₂([M^þ], [³⁵Cl]) 403.04491, found 403.043839. Anal.

Calcd for C₂₀H₁₃Cl₂F₂N₃(404.24): C, 59.42, H, 3.24, N,10.39. Found: C,

58.996, H, 3.187, N, 10.144.

3.8.7. 4-(Chlorodiﬂuoromethyl)-1-cyclohexyl-6-methylds1H-pyrrolo

[2,3-b]pyridine-3-carbonitrile (7g). Brown solid isolated re-

crystallization from acetic acid; mp 173e174 ^ꢀC; ¹H NMR (CDCl₃,

300 MHz):

¼1.24e2.15 (m,10H, CH₂), 2.70 (s, 3H, CH₃), 4.81e4.90(m,

1H, CH), 7.31 (s, 1H, C_ArH), 7.90 (s, 1H, CH). ¹³C NMR (CDCl₃, 75 MHz):

¼24.5 (CH₃), 25.3, 25.5, 33.4 (CH₂), 54.2 (CH), 83.9 (C),111.0 (C),113.2

(t, J_C,F¼6.0 Hz, CH), 115.2 (C^N), 124.3 (t, J_C,F¼290.7 Hz, CF₂Cl), 134.6

(CH), 135.9 (t, J_C,F¼29.3 Hz, CeCF₂Cl), 147.3 (C), 154.5 (C). ¹⁹F NMR

(CDCl₃, 282 MHz):

¼ꢁ49.78 (CF₂Cl). IR (ATR, cm^ꢁ1):

¼3126 (w),

3.8.4. 1-tert-Butyl-4-(chlorodiﬂuoromethyl)-6-methyl-1H-pyrrolo

[2,3-b]pyridine-3-carbonitrile (7d). White solid isolated re-

crystallization from acetic acid; mp 161e162 ^ꢀC; ¹H NMR (CDCl₃,

2934 (m), 2857 (w), 2225 (s), 1693 (w), 1598 (w), 1581 (w), 1581 (w),

1537 (w), 1520 (s), 1494 (w), 1464 (w), 1451 (w), 1416 (w), 1394 (w),

1361 (w), 1348 (w),1332 (m),1306 (w),1291 (m), 1272 (w),1250 (w),

1223 (m),1210 (w),1191 (w),1172 (w),1146 (w),1123 (s),1028 (s). MS

(EI, 70 eV): m/z (%)¼325 ([M^þ], [³⁷Cl], 9), 323 ([M^þ], [³⁵Cl], 28), 288

(17), 243(35), 242(19), 241(100), 206(57). HRMS(ESI-TOF/MS):calcd

for C₁₆H₁₆ClF₂N₃Na ([MþNa]^þ, [³⁵Cl]) 346.0893, found 346.089.

300 MHz):

¼1.82 (s, 9H, C(CH₃)₃), 2.69 (s, 3H, CH₃), 7.29 (s, 1H, CH),

7.95 (s, 1H, CH). ¹³C NMR (CDCl₃, 75 MHz):

¼24.7 (CH₃), 29.1

(C(CH₃)₃), 59.1 (C(CH₃)₃), 82.8 (C), 112.4 (t, J_C,F¼6.1 Hz, CH), 115.4

(C^N), 121.6 (C), 124.3 (t, J_C,F¼290.5 Hz, CF₂Cl), 135.7 (t,

J_C,F¼29.2 Hz, CeCF₂Cl), 135.4 (CH), 148.0, 153.4 (C). ¹⁹F NMR (CDCl₃,

282 MHz):

¼ꢁ49.76. IR (ATR, cm^ꢁ1):

n¼3141 (w), 2988 (w), 2975

3.8.8. 1-(4-Methoxybenzyl)-4-(chlorodiﬂuoromethyl)-6-methyl-1H-

pyrrolo[2,3-b]pyridine-3-carbonitrile(7h). Brown solid isolated re-

crystallization from acetic acid; mp 104e106 ^ꢀC; ¹H NMR (CDCl₃,

(w), 2929 (w), 2225 (m), 1597 (w), 1579 (w), 1515 (m), 1483 (w),

1444 (w), 1395 (w), 1367 (w), 1356 (w), 1367 (w), 1314 (m), 1303

(w), 1217 (w), 1199 (w), 1055 (m), 1026 (s), 1036 (m), 1022 (m). MS

(EI, 70 eV): m/z (%)¼299 ([M^þ], [³⁷Cl], 12), 297 ([M^þ], [³⁵Cl], 37), 262

(10), 243 (49), 242 (22). 241 (100), 207 (21), 206 (100). HRMS (ESI-

TOF/MS): calcd for C₁₄H₁₄ClF₂N₃([MþH]^þ, [³⁵Cl]) 298.0918, found

300 MHz):

¼2.73 (s, 3H, CH₃), 3.79 (s, 3H, OCH₃), 5.44 (s, 2H, CH₂),

6.87e6.90 (m, 2H, ³J¼8.7 Hz, C_ArH), 7.23e7.26 (m, 2H, ³J¼8.7 Hz,

C_ArH), 7.34 (s, 1H, CH), 7.73 (s, 1H, CH). ¹³C NMR (CDCl₃, 75 MHz):

d¼24.5 (CH₃), 48.4 (CH₂), 55.3 (OCH₃), 84.4 (C), 110.9 (t, J_C,F¼2.2 Hz,

5670

V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 5663e5677

C), 113.3 (t, J_C,F¼5.5 Hz, CH), 114.5 (CH), 114.9 (C^N), 124.2 (t,

J_C,F¼290.5 Hz, CF₂Cl), 127.2 (C), 128.1 (C), 129.7 (CH), 136.1 (t,

1325 (w), 1312 (w), 1283 (w), 1225 (s), 1211 (w), 1172 (m), 1117 (s),

1082 (s), 1027 (s). MS (EI, 70 eV): m/z (%)¼279 ([M^þ], [³⁷Cl], 37), 278

(18), 277 ([M^þ], [³⁵Cl], 100), 244 (23), 242 (34). HRMS (ESI-TOF/MS):

calcd for C₁₀H₁₁ClF₂N₃S ([MþH]^þ, [³⁵Cl]) 278.0325, found 278.0325.

J_C,F¼29.2 Hz, CeCF₂Cl), 136.7 (CH), 147.7 (C), 155.0 (C), 159.8 (C). ¹⁹

NMR (CDCl₃, 282 MHz):

¼ꢁ49.76 (CF₂Cl). IR (ATR, cm^ꢁ1):

¼3099

(w), 3034 (w), 3001 (w), 2935 (w), 2838 (w), 2226 (s), 1753 (w),

1710 (m), 1612 (w), 1601 (w), 1578 (w), 1524 (w), 1513 (s), 1463 (w),

1441 (w), 1415 (m), 1385 (m), 1350 (m), 1328 (w), 1298 (m), 1245 (s),

1217 (m), 1175 (m), 1122 (br m), 1031 (s). MS (EI, 70 eV): m/z (%)¼

363 ([M^þ], [³⁷Cl], 6), 361 ([M^þ], [³⁵Cl], 17), 121 (100). HRMS (ESI-

TOF/MS): calcd for C₁₈H₁₄ClF₂N₃NaO ([MþNa]^þ, [³⁵Cl]) 384.0686,

found 384.0680.

3.8.12. 7-(Chlorodiﬂuoromethyl)-1,5-dimethyl-3-phenyl-1H-imidazo

[4,5-b]pyridine-2(3H)-thione (7l). Yellow solid isolated by column

chromatography (heptane/EtOAc, 10:1); mp 173e174 ^ꢀC; ¹H NMR

(CDCl₃, 300 MHz):

¼2.53 (s, 3H, CH₃), 4.14 (t, J_H,F¼2.3 Hz, 3H,

CH₃), 7.22 (s, 1H, CH), 7.48e7.61 (m, 5H, CH). ¹³C NMR (CDCl₃,

75 MHz):

¼23.9 (CH₃), 34.9 (t, J_C,F¼6.0 Hz, 3H, CH₃), 113.1 (t,

J_C,F¼6.6 Hz, CH), 119.0 (t, J_C,F¼2.2 Hz, C), 124.5 (t, J_C,F¼290.0 Hz,

CF₂Cl), 125.1 (t, J_C,F¼29.2 Hz, CeCF₂Cl), 128.4, 129.2 (CH), 134.7 (C),

3.8.9. 1-(4-Methoxybenzyl)-4-(chlorodiﬂuoromethyl)-6-(4-

chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (7i). Yellow

solid isolated recrystallization from acetic acid; mp 218e219 ^ꢀC; ¹H

147.2 (C), 152.9 (C), 173.4 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

d¼ꢁ49.50

(CF₂Cl). IR (ATR, cm^ꢁ1):

¼3047 (w), 2962 (w), 1811 (w), 1722 (w),

1607 (w), 1504 (s), 1442 (m), 1425 (m), 1387 (s), 1377 (w), 1355 (m),

1325 (s), 1294 (w), 1283 (w), 1219 (s), 1167 (w), 1147 (w), 1103 (m),

1073 (m), 1042 (s). MS (EI, 70 eV): m/z (%)¼341 ([M^þ], [³⁷Cl], 31),

340 (83), 339 ([M^þ], [³⁵Cl], 83), 338 (100), 304 (18), 302 (11). HRMS

(EI, 70 eV): calcd for C₁₅H₁₂N₃ClF₂S ([M^þ], [³⁵Cl]) 339.04030, found

339.039725. Anal. Calcd for C₁₅H₁₂ClF₂N₃S (339.79): C, 53.02, H,

3.56, N, 12.37. Found: C, 53.277, H, 3.693, N, 12.150.

NMR (CDCl₃, 300 MHz):

¼3.80 (s, 3H, OCH₃), 5.53 (s, 2H, CH₂),

6.88e6.93 (m, 2H, ³J¼8.7 Hz, C_ArH), 7.28e7.31 (m, 2H, ³J¼8.9 Hz,

C_ArH), 7.47e7.52 (m, 2H, ³J¼8.9 Hz, C_ArH), 7.85 (s,1H, CH), 7.90 (s,1H,

CH), 8.06e8.10 (m, 2H, ³J¼8.7 Hz, C_ArH). ¹³C NMR (CDCl₃, 75 MHz):

¼48.8 (CH₂), 55.3 (CH₃), 84.9 (C), 111.2 (t, J_C,F¼6.1 Hz, CH), 112.3 (t,

J_C,F¼2.2 Hz, C),114.5 (C^N),114.6 (CH),124.1 (t, J_C,F¼291.0 Hz, CF₂Cl),

127.0 (C), 128.3, 129.2, 129.8 (C_ArH), 136.0 (C), 136.4 (C), 137.0 (t,

J_C,F¼29.2 Hz, CeCF₂Cl), 138.0 (CH), 147.9 (C), 152.2 (C), 159.9 (C). ¹⁹

3.8.13. 5-(Chlorodiﬂuoromethyl)-7-(4-chlorophenyl)-1,3-

NMR (CDCl₃, 282 MHz):

¼ꢁ49.93 (CF₂Cl). IR (ATR, cm^ꢁ1):

¼3091

dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

(7m). White

(w), 3047 (w), 3004 (w), 2961 (w), 2936 (w), 2906 (w), 2837 (w),

2226 (s), 1682 (w), 1612 (w), 1588 (w), 1516 (m), 1496 (w), 1477 (w),

1467 (w),1456 (w),1440 (w),1425 (w),1413 (w),1406 (w),1382 (m),

1347 (w),1336 (w),1317 (w),1306 (w),1295 (w),1280 (w),1234 (m),

1208 (w), 1177 (m), 1159 (m), 1142 (m), 1129 (w), 1118 (w), 1105 (w),

1095 (m), 1072 (w), 1025 (s), 1010 (s). MS (EI, 70 eV): m/z (%)¼461

([M^þ], [³⁷Cl] [³⁷Cl], 1), 459 ([M^þ], [³⁷Cl] [³⁵Cl], 6), 457 ([M^þ], [³⁵Cl]

solid isolated recrystallization from acetic acid; mp 293 ^ꢀC; ¹H NMR

(CDCl₃, 300 MHz):

¼3.51 (s, 3H, CH₃), 3.84 (s, 3H, CH₃), 7.49e7.54

(m, ³J¼8.9 Hz, 2H, C_ArH), 7.86 (s, 1H, C_ArH), 8.06e8.11 (m, ³J¼8.9 Hz,

2H, C_ArH). ¹³C NMR (CDCl₃, 75 MHz):

(C), 111.3 (t, J_C,F¼9.4 Hz, CH), 123.3 (t, J_C,F¼290.5 Hz, CF₂Cl), 128.9

(C_ArH), 129.5 (C_ArH), 134.9 (C), 138.1 (C), 146.2 (t, J_C,F¼28.6 Hz,

CeCF₂Cl), 150.9 (C), 152.7 (C), 158.0 (C), 160.1 (C). ¹⁹F NMR (CDCl₃,

¼28.9 (CH₃), 30.7 (CH₃),104.5

[

³⁵Cl], 9), 122 (10), 121 (100). HRMS (ESI-TOF/MS): calcd for

282 MHz):

¼ꢁ50.19 (CF₂Cl). IR (ATR, cm^ꢁ1):

¼3092 (w), 3065 (w),

C₂₃H₁₅Cl₂F₂N₃NaO ([MþNa]^þ,

[ [

³⁵Cl] ³⁵Cl]) 480.0452, found

3042 (w), 2953 (w), 1716 (m), 1663 (br s), 1579 (m), 1556 (m), 1516

(w),1503 (w),1384 (w),1452 (w),1417 (w), 1404 (w),1387 (w),1367

(w),1349 (w),1306 (w),1289 (w), 1282 (w),1254 (w), 1199 (m), 1119

(s), 1085 (w), 1072 (w), 1009 (s). MS (EI, 70 eV): m/z (%)¼389 ([M^þ],

480.0451. Anal. Calcd for C₂₃H₁₅Cl₂F₂N₃O (458.29): C, 60.28, H, 3.30,

N, 9.17. Found: C, 58.896, H, 3.254, N, 8.860.

[

³⁷Cl] [³⁷Cl], 13), 387 ([M^þ], [³⁷Cl] [³⁵Cl], 67), 385 ([M^þ], [³⁵Cl] [³⁵Cl],

3.8.10. 7-(Chlorodiﬂuoromethyl)-5-(4-chlorophenyl)-N,N-dime-

thylthiazolo[4,5-b]pyridin-2-amine (7j). Brown solid isolated by

column chromatography (heptane/EtOAc, 20:1); mp 194e196 ^ꢀC;

100), 365 (15), 350 (50), 300 (24), 275 (39), 273 (60). HRMS (EI,

70 eV): calcd for C₁₆H₁₁N₃Cl₂F₂O₂([M^þ], [³⁵Cl] [³⁵Cl]) 385.01909,

found 385.019348.

¹H NMR (CDCl₃, 300 MHz):

¼3.31 (s, 6H, CH₃), 7.14 (d, 2H,

³J¼8.5 Hz, C_ArH), 7.55 (s, 1H, CH), 8.06 (d, 2H, ³J¼8.5 Hz, C_ArH). ¹³

NMR (CDCl₃, 75 MHz):

¼40.3 (CH₃), 107.5 (t, J_C,F¼5.0 Hz, CH), 118.8

3.8.14. 5-(Chlorodiﬂuoromethyl)-1,3,7-trimethylpyrido[2,3-d]pyrimi-

dine-2,4(1H,3H)-dione (7n). Yellow solid isolated recrystallization

(C), 124.7 (t, J_C,F¼290.5 Hz, CF₂Cl), 128.4, 128.8 (C_ArH), 131.5 (C),

from acetic acid; mp 273 ^ꢀC; ¹H NMR (CDCl₃, 300 MHz):

¼2.67 (s,

136.7 (C), 137.7 (t, J_C,F¼29.2 Hz, CeCF₂Cl), 154.4 (C), 166.6 (C), 171.1

(C). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ52.58. IR (ATR, cm^ꢁ1):

¼2928

3H, CH₃), 3.46 (s, 3H, CH₃), 3.72 (s, 3H, CH₃), 7.30 (s, 1H, C_ArH). ¹³

(w), 1681 (m), 1600 (s), 1539 (s), 1492 (s), 1414 (w), 1394 (w), 1365

(w),1349 (w),1272 (w), 1248 (w),1229 (m), 1167 (w), 1130 (m), 1105

(w), 1088 (s), 1043 (w), 1012 (w). MS (EI, 70 eV): m/z (%)¼377 ([M^þ],

NMR (CDCl₃, 75 MHz):

¼25.4 (CH₃), 28.7 (CH₃), 30.5 (CH₃),103.5 (t,

³J_C,F¼1.7 Hz, C), 114.9 (t, J_C,F¼9.0 Hz, CH), 123.3 (t, J_C,F¼290.5 Hz,

CF₂Cl), 116.9 (C_ArH), 145.0 (t, J_C,F¼28.6 Hz, CeCF₂Cl), 150.9 (C), 152.4

³⁷Cl] [³⁷Cl], 14), 375 ([M^þ], [³⁷Cl] [³⁵Cl], 72), 373 ([M^þ], [³⁵Cl] [³⁵Cl],

(C),158.3 (C),161.2 (C).¹⁹F NMR (CDCl₃, 282 MHz):

d¼ꢁ50.19 (CF₂Cl).

[

IR (ATR, cm^ꢁ1):

¼3393 (w), 3360 (w), 3230 (w), 3084 (w), 2997 (w),

97), 360 (31), 358 (44), 348 (14). 346 (72), 344 (100), 323 (15).

HRMS (ESI-TOF/MS): calcd for C₁₅H₁₁Cl₂F₂N₃NaS ([MþNa]^þ, [³⁵Cl]

2954 (w), 2917 (w), 2851 (w),1711 (s),1661 (br s),1592 (w),1567 (m),

1503 (w),1454 (w),1417 (m),1381 (w),1368 (w),1343 (m),1286 (m),

1263 (m), 1235 (w), 1213 (m), 1179 (m), 1118 (s), 1093 (w), 1065 (w),

1031 (w),1001 (w). MS (EI, 70eV): m/z (%)¼291 ([M^þ], [³⁷Cl], 28), 289

([M^þ], [³⁵Cl], 86), 269 (18), 254 (45), 204 (25),179 (33),177 (100),169

(13), 142 (12). HRMS (ESI-TOF/MS): calcd for C₁₁H₁₁N₃ClF₂O₂

([MþH]^þ, [³⁵Cl]) 292.0476, found 292.0476.

[

³⁵Cl]) 395.9911, found 395.9911. Anal. Calcd for C₁₅H₁₁Cl₂F₂N₃S

(374.24): C, 48.14, H, 2.96, N, 11.23. Found: C, 48.283, H, 2.951.

3.8.11. 7-(Chlorodiﬂuoromethyl)-1,3,5-trimethyl-1H-imidazo[4,5-b]

pyridine-2(3H)-thione (7k). Yellow solid isolated by column chro-

matography (heptane/EtOAc, 10:1); mp 90e92; ¹H NMR (CDCl₃,

300 MHz):

¼2.62 (s, 3H, CH₃), 3.84 (s, 3H, CH₃), 4.05 (t,

³J_H,F¼2.4 Hz, 3H, CH₃), 7.17 (s, 1H, CH). ¹³C NMR (CDCl₃, 75 MHz):

3.8.15. 3-(4-Methoxybenzyl)-7-(chlorodiﬂuoromethyl)-5-methyl-3H-

imidazo[4,5-b]pyridine (11a). Yellow solid isolated by column

chromatography (heptane/EtOAc, 20:1); mp 59e60 ^ꢀC; ¹H NMR

¼23.9 (CH₃), 30.8 (CH₃), 34.6 (t, J_C,F¼6.1 Hz, CH₃), 112.4 (t,

J_C,F¼6.6 Hz, CH), 118.9 (t, J_C,F¼2.2 Hz, C), 123.5 (t, J_C,F¼289.4 Hz,

CF₂Cl), 124.9 (t, J_C,F¼29.0 Hz, CeCF₂Cl), 146.7 (C), 152.3 (C), 172.9 (C).

(CDCl₃, 300 MHz):

¼2.72 (s, 3H, CH₃), 3.78 (s, 3H, OCH₃), 5.39 (s,

¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ49.71 (CF₂Cl). IR (ATR, cm^ꢁ1):

2H, CH₂), 6.85e6.87 (m, ³J¼8.9 Hz, 2H, C_ArH), 7.26e7.29 (m,

³J¼8.9 Hz, 3H, C_ArH), 8.03 (s, 1H, CH). ¹³C NMR (CDCl₃, 75 MHz):

¼3043 (w), 3010 (w), 2958 (w), 2922 (w), 2853 (w), 1825 (w), 1718

(w), 1610 (s), 1588 (w), 1472 (s), 1435 (s), 1409 (s), 1389 (s), 1359 (s),

d¼24.6 (CH₃), 46.8 (CH₂), 55.3 (OCH₃), 113.0 (t, J_C,F¼5.5 Hz, CH),

V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 5663e5677

5671

114.3 (CH), 126.6 (t, J_C,F¼291.1 Hz, CF₂Cl), 128.2 (t, J_C,F¼2.2 Hz, C),

129.5 (CH), 133.9 (t, J_C,F¼28.1 Hz, CeCF₂Cl), 144.3 (CH), 148.1 (C),

(18), 354 (15), 328 (10). HRMS (ESI-TOF/MS): calcd for

Calcd for C₂₀H₁₄ClF₂N₃(369.80): C, 64.96, H, 3.82, N, 11.36. Found:

C, 64.825, H, 3.939, N, 11.033.

₂₀H₁₅N₃ClF₂([MþH]^þ, [³⁵Cl]) 370.0917, found 370.0924. Anal.

154.2 (C),159.7 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ50.57 (CF₂Cl). IR

(ATR, cm^ꢁ1):

¼3070 (w), 3030 (w), 2955 (w), 2937 (w), 2916 (w),

2839 (w), 1613 (m), 1588 (m), 1510 (s), 1482 (m), 1463 (w), 1441 (w),

1434 (w), 1420 (w), 1397 (m), 1382 (m), 1364 (w), 1355 (w), 1287 (s),

1240 (s), 1217 (w), 1204 (m), 1179 (m), 1162 (w), 1133 (s), 1114 (w),

1096 (s), 1027 (m). MS (EI, 70 eV): m/z (%)¼339 ([M^þ], [³⁷Cl], 13),

339 ([M^þ], [³⁵Cl], 37),122 (12),121 (100). HRMS (EI, 70 eV): calcd for

C₁₆H₁₄N₃ClF₂O ([M^þ], [³⁵Cl]) 337.07880, found 337.078831.

3.8.19. 1-tert-Butyl-4-(diﬂuoromethyl)-6-(4-methoxyphenyl)-1H-

pyrrolo[2,3-b]pyridine-3-carbonitrile (12c). Yellow solid isolated by

preparative chromatography (heptane); mp 180e182 ^ꢀC; ¹H NMR

(CDCl₃, 300 MHz):

¼1.88 (s, 9H, C(CH₃)₃), 3.88 (s, 3H, OCH₃),

7.00e7.05 (m, ³J¼8.9 Hz, 2H, C_ArH), 7.26 (t, J_H,F¼55.0 Hz, 1H,

CF₂H), 7.84 (s, 1H, CH), 7.93 (s, 1H, CH), 8.04e8.08 (m, ³J¼8.9 Hz,

3.8.16. 3-(4-Chlorobenzyl)-7-(chlorodiﬂuoromethyl)-5-methyl-3H-

imidazo[4,5-b]pyridine (11b). Yellow oil isolated by preparative

2H, C_ArH). ¹³C NMR (CDCl₃, 75 MHz):

¼29.2 (C(CH₃)₃), 55.4

(OCH₃), 59.0 (C(CH₃)₃), 81.9 (CeChN), 110.2 (t, J_C,F¼6.6 Hz, CH),

111.8 (t, J_C,F¼240.4 Hz, CF₂), 114.3 (C_ArH), 115.2 (t, J_C,F¼4.4 Hz, C),

115.7 (C^N), 128.2 (C_ArH), 131.2 (C), 134.8 (t, J_C,F¼24.2 Hz, CeCF₂),

134.8 (C_ArH), 147.7 (C), 152.2 (C), 160.8 (C). ¹⁹F NMR (CDCl₃,

chromatography (heptane); ¹H NMR (CDCl₃, 300 MHz):

d¼2.73 (s,

3H, CH₃), 5.46 (s, 2H, CH₂), 7.26e7.28 (m, ³J¼8.7 Hz, 2H, C_ArH),

7.32e7.35 (m, ³J¼8.7 Hz, 3H, C_ArH), 8.09 (s, 1H, CH). ¹³C NMR (CDCl₃,

125 MHz):

¼24.6 (CH₃), 46.5 (CH₂), 113.2 (t, J_C,F¼5.5 Hz, CH), 124.2

282 MHz):

¼ꢁ113.81 (CF₂H). IR (ATR, cm^ꢁ1):

¼3137 (w), 2978

(t, J_C,F¼290.6 Hz, CF₂Cl), 128.2 (t, J_C,F¼2.7 Hz, C), 129.2 (CH), 129.3

(w), 2961 (w), 2934 (w), 2840 (w), 2220 (s), 1595 (m), 1579 (w),

1515 (s), 1472 (m), 1456 (w), 1417 (w), 1392 (w), 1367 (m), 1320

(s), 1305 (w), 1297 (m), 1246 (s), 1210 (w), 1198 (w), 1176 (s), 1135

(w), 1121 (w), 1110 (w), 1066 (w), 1024 (s). MS (EI, 70 eV): m/z

(%)¼355 ([M^þ], 31), 300 (18), 299 (100), 284 (10), 256 (12). HRMS

(ESI/TOF, MS): calcd for C₂₀H₁₉F₂N₃NaO ([MþNa]^þ) 378.1388,

found 378.1389.

(CH), 129.5 (C), 133.9 (C), 134.1 (t, J_C,F¼28.2 Hz, CeCF₂Cl), 144.2 (CH),

148.0 (C),154.3 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ50.62 (CF₂Cl). IR

(ATR, cm^ꢁ1):

¼3115 (w), 3068 (w), 3034 (w), 2923 (w), 2852 (w),

1736 (w), 1593 (s), 1507 (w), 1489 (s), 1431 (m), 1397 (m), 1382 (w),

1372 (w), 1353 (s), 1296 (w), 1285 (s), 1254 (w), 1213 (w), 1205 (w),

1189 (w), 1170 (w), 1129 (s), 1095 (m), 1011 (m). MS (EI, 70 eV): m/z

(%)¼345 ([M^þ], [³⁷Cl] [³⁷Cl], 8), 343 ([M^þ], [³⁷Cl] [³⁵Cl], 49), 341

([M^þ], [³⁵Cl] [³⁵Cl], 77), 307 (14), 306 (39), 127 (36), 125 (100), 89

(22). HRMS (ESI-TOF/MS): calcd for C₁₅H₁₂N₃Cl₂F₂([M^þ], [³⁵Cl])

342.0371, found 342.0373.

3.8.20. 1-Cyclohexyl-4-(diﬂuoromethyl)-6-methyl-1H-pyrrolo[2,3-b]

pyridine-3-carbonitrile (12d). White solid isolated by preparative

chromatography (heptane); mp 157e158 ^ꢀC; ¹H NMR (CDCl₃,

300 MHz):

¼1.23e2.14 (m, 10H, CH₂), 2.68 (s, 3H, CH₃), 4.79e4.90

3.8.17. 4-(Diﬂuoromethyl)-3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-

b]pyridine (12a). White solid isolated by preparative chromatog-

(m, 1H, CH), 7.18 (t, ³J_H,F¼54.8 Hz, 1H, CF₂H), 7.29 (s, 1H, CH), 7.84 (s,

1H, CH). ¹³C NMR (CDCl₃, 75 MHz):

¼24.6 (CH₃), 25.3, 25.5, 33.5

raphy (heptane); mp 75e76 ^ꢀC; ¹H NMR (CDCl₃, 300 MHz):

¼2.63

(CH₂), 54.1 (CH), 82.7 (CeChN), 111.8 (t, J_C,F¼240.0 Hz, CF₂H), 113.5

(t, J_C,F¼4.4 Hz, C), 114.5 (t, J_C,F¼6.6 Hz, CH), 115.7 (C^N), 133.3 (CH),

134.5 (t, J_C,F¼23.7 Hz, CeCF₂), 146.7 (C), 154.8 (C). 150.6 (C). ¹⁹F NMR

(t, ³J¼1.1 Hz, 3H, CH₃), 2.66 (s, 3H, CH₃), 6.89 (t, ³J¼55.0 Hz, 1H,

CF₂H), 7.09 (s, 1H, C_ArH), 7.19e7.24 (m, 1H, C_ArH), 7.40e7.45 (m, 2H,

C_ArH), 8.15e8.18 (m, ³J¼7.4 Hz, 2H, C_ArH). ¹³C NMR (CDCl₃, 75 MHz):

(CDCl₃, 282 MHz):

¼ꢁ113.70 (CF₂H). IR (ATR, cm^ꢁ1):

¼3123 (w),

¼14.9 (t, J_C,F¼3.3 Hz, CH₃), 25.1 (CH₃), 110.4 (t, J_C,F¼3.3 Hz, C), 112.9

3106 (w), 2941 (m), 2859 (w), 2217 (s), 1714 (w), 1596 (w), 1588 (w),

1523 (s), 1485 (w), 1468 (w), 1448 (w), 1416 (w), 1399 (w), 1386 (w),

1356 (m), 1324 (s), 1288 (s), 1272 (w), 1250 (w), 1197 (s), 1135 (s),

1111 (s), 1036 (s). MS (EI, 70 eV): m/z (%)¼289 (M^þ, 21), 208 (17),

207 (100). HRMS (ESI/TOF, MS): calcd for C₁₆H₁₈N₃F₂([MþH]^þ)

290.1463, found 290.1464.

(t, J_C,F¼240.0 Hz, CF₂H), 114.2 (t, J_C,F¼7.7 Hz, CH), 121.3 (C_ArH), 125.8

(C_ArH), 129.0 (C_ArH), 135.8 (t, J_C,F¼23.7 Hz, CeCF₂H), 139.2 (C), 141.1

(C), 151.7 (C), 159.2 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

d¼ꢁ111.78

(CF₂H). IR (ATR, cm^ꢁ1):

¼3088 (w), 3065 (w), 2959 (w), 2920 (w),

2857 (w), 1589 (w), 1504 (s), 1482 (w), 1458 (w), 1444 (w), 1415 (m),

1398 (w), 1375 (w),1347 (w), 1331 (w), 1302 (w),1271 (w), 1199 (w),

1141 (w), 1127 (w), 1080 (s), 1043 (w), 1028 (w), 1009 (w). MS (EI,

70 eV): m/z (%)¼273 ([M^þ], 100), 272 (29), 258 (23), 232 (15), 77

(15). HRMS (ESI-TOF/MS): calcd for C₁₅H₁₄F₂N₃[(MþH)^þ] 274.115,

found 274.1153. Anal. Calcd for C₁₅H₁₃F₂N₃(273.28): C, 65.93, H,

4.79, N, 15.38. Found: C, 66.066, H, 4.832, N, 14.783.

3.8.21. 1-(4-Methoxybenzyl)-4-(diﬂuoromethyl)-6-methyl-1H-pyr-

rolo[2,3-b]pyridine-3-carbonitrile (12e). White solid isolated by

preparative chromatography (heptane); mp 116e118 ^ꢀC; ¹H NMR

(CDCl₃, 300 MHz):

¼2.72 (s, 3H, CH₃), 3.79 (s, 3H, OCH₃), 5.43 (s,

2H, CH₂), 6.85e6.90 (m, ³J¼8.7 Hz, 2H, C_ArH), 7.18 (t, ³J_H,F¼54.8 Hz,

1H, CF₂H), 7.21e7.24 (m, ³J¼8.7 Hz, 2H, C_ArH), 7.32 (s, 1H, CH), 7.65

3.8.18. 6-(4-Chlorophenyl)-4-(diﬂuoromethyl)-3-methyl-1-phenyl-

1H-pyrazolo[3,4-b]pyridine (12b). White solid isolated by pre-

(s,1H, CH). ¹³C NMR (CDCl₃, 75 MHz):

d¼24.6 (CH₃), 48.2 (CH₂), 55.3

(OCH₃), 83.3 (CeChN), 111.7 (t, J_C,F¼240.0 Hz, CF₂H), 113.4 (t,

J_C,F¼4.4 Hz, C), 114.4 (C_ArH), 114.6 (t, J_C,F¼6.6 Hz, CH), 115.4 (C^N),

127.4 (C), 129.7 (C_ArH), 134.7 (t, J_C,F¼24.0 Hz, CeCF₂), 135.6 (CH),

parative chromatography (heptane); mp 152e154 ^ꢀC; ¹H NMR

(CDCl₃, 300 MHz):

¼2.73 (s, 3H, CH₃), 7.04 (t, J_H,F¼55.0 Hz, 1H,

CF₂H), 7.32 (t, ³J¼7.4 Hz, 1H, CH), 7.45e7.56 (m, 4H, C_ArH), 7.71 (s,

147.1 (C), 155.3 (C), 159.7 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ113.66

1H, C_ArH), 8.04e8.08 (m, 2H, C_ArH), 8.28e8.31 (m, 2H, C_ArH). ¹³C

(CF₂H). IR (ATR, cm^ꢁ1):

¼3131 (w), 3115 (w), 3067 (w), 3031 (w),

NMR (CDCl₃, 75 MHz):

¼14.9 (t, J_C,F¼3.0 Hz, CH₃), 110.7 (t,

3006 (w), 2967 (w), 2929 (w), 2835 (w), 2229 (s), 1711 (w), 1610

(w), 1584 (w), 1528 (m), 1509 (s), 1454 (w), 1439 (s), 1415 (s), 1381

(s), 1358 (w), 1324 (s), 1304 (w), 1291 (s), 1242 (s), 1196 (w), 1171

(w), 1161 (w), 1118 (w), 1107 (w), 1032 (s), 1005 (w). MS (EI, 70 eV):

m/z (%)¼327 ([M^þ], 27), 122 (9), 123 (100). HRMS (ESI/TOF, MS):

calcd for C₁₈H₁₆N₃F₂O ([MþH]^þ) 328.1256, found 328.1255. Anal.

Calcd for C₁₈H₁₅F₂N₃O (327.33): C, 66.05, H, 4.62, N, 12.84. Found: C,

65.731, H, 4.638, N, 12.426.

J_C,F¼8.0 Hz, CH), 111.5 (t, J_C,F¼3.3 Hz, C), 112.8 (t, J_C,F¼240.0 Hz,

CF₂), 121.1 (C_ArH), 125.9 (C_ArH), 128.7 (C_ArH), 129.0 (C_ArH), 129.1

(C_ArH), 136.2 (C), 136.7 (C), 137.7 (t, J_C,F¼24.0 Hz, CeCF₂), 139.2 (C),

141.3 (C), 151.7 (C), 155.6 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ112.03 (CF₂H). IR (ATR, cm^ꢁ1):

¼3107 (w), 3084 (w), 3063

(w), 2960 (w), 2921 (w), 2856 (w), 1593 (w), 1584 (w), 1569 (w),

1505 (s), 1490 (w), 1477 (m), 1459 (w), 1438 (w), 1417 (m), 1404

(w), 1393 (w), 1369 (w), 1359 (w), 1346 (m), 1331 (w), 1311 (w),

1295 (w), 1269 (m), 1223 (s), 1184 (w), 1174 (w), 1150 (s), 1129 (s),

1110 (w), 1093 (s), 1043 (w), 1032 (w), 1007 (s). MS (EI, 70 eV): m/

z (%)¼371 ([M^þ], [³⁷Cl], 34), 370 (28), 369 ([M^þ], [³⁵Cl], 100), 368

3.8.22. 1-(4-Methoxybenzyl)-6-(4-chlorophenyl)-4-(diﬂuoromethyl)-

1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (12f). Yellow solid isolated

by preparative chromatography (heptane); mp 184e185 ^ꢀC; ¹H

5672

V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 5663e5677

NMR (CDCl₃, 300 MHz):

¼3.79 (s, 3H, OCH₃), 5.51 (s, 2H, CH₂),

(w), 1418 (w), 1399 (w), 1385 (w), 1366 (w), 1355 (w), 1285 (s), 1241

6.87e6.90 (m, ³J¼8.7 Hz, 2H, C_ArH), 7.26 (t, J_H,F¼54.7 Hz, 1H,

CF₂H), 7.26e7.29 (m, ³J¼8.7 Hz, 2H, C_ArH), 7.46e7.49 (m, ³J¼8.7 Hz,

2H, C_ArH), 7.77 (s, 1H, CH), 7.89 (s, 1H, CH), 8.06e8.09 (m,

(s), 1213 (m), 1183 (w), 1173 (w), 1161 (w), 1096 (m), 1028 (s). MS (EI,

70 eV): m/z (%)¼303 ([M^þ], 50), 302 (11), 121 (100). HRMS (ESI/TOF,

MS): calcd for C₁₆H₁₆F₂N₃O ([MþH]^þ) 304.1251, found 304.1256.

Anal. Calcd for C₁₆H₁₅F₂N₃O (303.31): C, 63.36, H, 4.98, N, 13.85.

Found: C, 63.439, H, 5.212, N, 13.501.

³J¼8.7 Hz, 2H, C_ArH). ¹³C NMR (CDCl₃, 126 MHz):

¼48.6 (CH₂),

55.3 (OCH₃), 83.8 (CeChN), 111.4 (t, J_C,F¼7.2 Hz, CH), 111.6 (t,

J_C,F¼240.6 Hz, CF₂H), 114.5 (C_ArH), 114.8 (t, J_C,F¼4.3 Hz, C), 115.0

(C^N), 127.2 (C), 128.3 (CH), 129.1 (CH), 129.7 (CH), 135.5 (t,

J_C,F¼23.6 Hz, CeCF₂), 135.7 (C), 136.8 (C), 136.9 (CH), 147.4 (C),

3.8.26. 3-(4-Chlorobenzyl)-7-(diﬂuoromethyl)-5-methyl-3H-imidazo

[4,5-b]pyridine (12j). White solid isolated by preparative chroma-

tography (heptane); mp 92e93 ^ꢀC; ¹H NMR (CDCl₃, 300 MHz):

152.5 (C), 159.9 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

d¼ꢁ113.77 (CF₂H).

IR (ATR, cm^ꢁ1):

¼3105 (w), 2955 (w), 2919 (w), 2848 (w), 2221

¼2.70 (s, 3H, CH₃), 5.43 (s, 2H, CH₂), 7.21e7.32 (m, 5H, CH), 7.24 (t,

(s), 1611 (m), 1585 (w), 1574 (w), 1556 (w), 1520 (w), 1512 (s), 1477

(w), 1455 (w), 1445 (w), 1417 (w), 1406 (w), 1384 (m), 1354 (w),

1328 (w), 1315 (w), 1302 (w), 1292 (w), 1246 (s), 1217 (m), 1175 (s),

1150 (m), 1116 (w), 1104 (w), 1093 (s), 1078 (w), 1046 (m), 1026

(m), 1009 (m). MS (EI, 70 eV): m/z (%)¼425 ([M^þ], [³⁷Cl], 6), 423

([M^þ], [³⁵Cl], 17), 121 (100). HRMS (ESI/TOF, MS): calcd for

C₂₃H₁₆ClF₂N₃O ([MþNa]^þ, ³⁵Cl]) 446.0842, found 446.0842.

³J¼55.0 Hz, 1H, CF₂H), 7.99 (s, 1H, CH). ¹³C NMR (CDCl₃, 75 MHz):

¼24.6 (CH₃), 46.4 (CH₂), 111.4 (t, J_C,F¼239.0 Hz, CF₂H), 114.1 (t,

J_C,F¼5.5 Hz, CH), 129.2 (C_ArH), 130.1 (t, J_C,F¼5.0 Hz, C), 132.7 (t,

J_C,F¼23.7 Hz, CeCF₂), 134.2 (C), 134.3 (C), 143.8 (CH), 147.3 (C), 154.7

(C). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ116.05 (CF₂H). IR (ATR, cm^ꢁ1):

¼3063 (w), 2972 (w), 2926 (w), 2857 (w), 1805 (w), 1756 (w), 1593

(m), 1494 (s), 1444 (w), 1426 (w), 1413 (w), 1394 (w), 1384 (w), 1375

(w), 1367 (w), 1344 (w), 1332 (w), 1306 (w), 1286 (m), 1277 (w),

1234 (w), 1214 (s), 1197 (w), 1178 (s), 1153 (m), 1109 (w), 1089 (s),

1051 (s), 1017 (m). MS (EI, 70 eV): m/z (%)¼309 ([M^þ], [³⁷Cl], 35),

308 (50), 307 ([M^þ], [³⁵Cl], 94), 306 (100), 287 (13), 256 (15), 196

(23), 127 (32), 125 (96), 89 (22). HRMS (ESI/TOF, MS): calcd for

C₁₅H₁₂ClF₂N₃Na ([MþNa]^þ, [³⁵Cl]) 330.058, found 330.0581. Anal.

Calcd for C₁₅H₁₂ClF₂N₃(307.73): C, 58.55, H, 3.93, N,13.66. Found: C,

58.667, H, 3.983, N, 13.398.

3.8.23. 5-(4-Chlorophenyl)-7-(diﬂuoromethyl)-N,N-dimethylthiazolo

[4,5-b]pyridin-2-amine (12g). Yellow solid isolated by preparative

chromatography (heptane); mp 186e188 ^ꢀC; ¹H NMR (CDCl₃,

300 MHz):

¼3.30 (s, 6H, CH₃), 6.78 (t, J_H,F¼55.5 Hz, CF₂H),

7.40e7.43 (m, J¼8.9 Hz, 2H, C_ArH), 7.44 (s, 1H, CH), 8.04e8.08 (m,

J¼8.9 Hz, C_ArH). ¹³C NMR (CDCl₃, 75 MHz):

¼40.1 (CH₃), 109.3 (t,

J_C,F¼6.6 Hz, CH), 113.1 (t, J_C,F¼242.0 Hz, CF₂), 119.9 (t, J_C,F¼2.2 Hz, C),

128.3 (C_ArH), 128.8 (C_ArH), 135.2 (C), 135.7 (t, J_C,F¼24.2 Hz, CeCF₂),

137.0 (C), 154.2 (C), 166.3 (C), 171.2 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

3.8.27. 4-(1,1-Diﬂuorobut-3-enyl)-3,6-dimethyl-1-phenyl-1H-pyr-

azolo[3,4-b]pyridine (13a). Yellow solid isolated by preparative

chromatography (heptane); mp 51e52 ^ꢀC; ¹H NMR (CDCl₃,

¼ꢁ116.17 (CF₂H). IR (ATR, cm^ꢁ1):

¼2927 (w), 2859 (w), 2792 (w),

1600 (s), 1538 (s), 1492 (m), 1415 (w), 1403 (w), 1392 (w), 1369 (w),

1348 (w),1322 (w),1302 (w),1270 (w),1246 (w),1215 (w),1182 (w),

1133 (w), 1110 (w), 1091 (w), 1066 (w), 1034 (w), 1011 (m). MS (EI,

70 eV): m/z (%)¼341 ([M^þ], [³⁷Cl], 38), 339 ([M^þ], [³⁵Cl], 97), 326

(20), 324 (53), 312 (39), 310 (100). HRMS (ESI/TOF, MS): calcd for

C₁₅H₁₃F₂ClN₃O₂([MþH]^þ, [³⁵Cl]) 340.0481, found 340.0485.

300 MHz):

¼2.70 (t, J_H,F¼2.5 Hz, 3H, CH₃), 2.72 (s, 3H, CH₃),

2.96e3.10 (m, 2H, CH₂), 5.18e5.26 (m, 2H, CH₂), 5.74e5.88 (m, 1H,

CH), 7.11 (s, 1H, C_ArH), 7.26e7.31 (m, 1H, C_ArH), 7.47e7.53 (m, 2H,

C_ArH), 8.22e8.25 (m, 2H, C_ArH). ¹³C NMR (CDCl₃, 75 MHz):

d¼15.8 (t,

J_C,F¼6.0 Hz, CH₃), 25.1 (CH₃), 43.6 (t, J_C,F¼27.0 Hz, CH₂), 109.9 (t,

J_C,F¼2.8 Hz, C), 114.1 (t, J_C,F¼7.7 Hz, CH), 120.6 (t, J_C,F¼243.7 Hz, CF₂),

121.3 (CH₂),121.5 (C_ArH),125.8 (C_ArH),128.0 (t, J_C,F¼5.0 Hz, CH),128.9

3.8.24. 7-(Diﬂuoromethyl)-1,5-dimethyl-3-phenyl-1H-imidazo[4,5-

b]pyridine-2(3H)-thione (12h). White solid isolated by preparative

chromatography (heptane); mp 199e200 ^ꢀC; ¹H NMR (CDCl₃,

(C_ArH), 139.0 (t, J_C,F¼28.5 Hz, CeCF₂), 139.2, 141.1, 151.9, 158.6 (C). ¹⁹

NMR (CDCl₃, 282 MHz):

¼ꢁ93.05 (CF₂). IR (ATR, cm^ꢁ1):

¼3081

300 MHz):

¼2.52 (s, 3H, CH₃), 4.06 (t, ³J¼1.7 Hz, 3H, CH₃), 6.93

(w), 3065 (w), 3014 (w), 2985 (w), 2940 (w), 2921 (w), 2853 (w),

1643 (w), 1596 (s), 1584 (w), 1572 (w), 1504 (s), 1486 (w), 1456 (w),

1439 (w),1429 (w),1418 (m),1383 (w),1373 (w),1343 (m),1320 (w),

1306 (w), 1295 (w), 1284 (w), 1258 (s), 1201 (m), 1168 (w), 1152 (s),

1094 (s), 1068 (m), 1028 (m). MS (EI, 70 eV): m/z (%)¼314 (21), 313

([M^þ],100), 273 (10), 272 (57). HRMS (EI, 70 eV): calcd for C₁₈H₁₇N₃F₂

([M^þ]) 313.13851, found 313.138641. Anal. Calcd for C₁₈H₁₇F₂N₃

(313.14): C, 69.00, H, 5.47, N, 13.41. Found: C, 68.880, H, 5.470.

(t, ³J¼54.4 Hz,1H, CF₂H), 7.11 (s,1H, CH), 7.48e7.61 (m, 5H, C_ArH).¹³

NMR (CDCl₃, 75 MHz):

¼23.9 (CH₃), 34.0 (t, ³J_C,F¼4.4 Hz, CH₃),112.9

(t, J_C,F¼240.0 Hz, CF₂H),115.7 (t, J_C,F¼7.7 Hz, CH),120.7 (t, J_C,F¼2.8 Hz,

C),122.8 (t, J_C,F¼24.0 Hz, CeCF₂),128.4,129.2,129.2 (C_ArH),134.8 (C),

146.6 (C),153.0 (C),172.8 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ106.07

(CF₂H). IR (ATR, cm^ꢁ1):

¼3109 (w), 3053 (w), 3015 (w), 2953 (w),

2918 (w), 1621 (w), 1589 (w), 1504 (s), 1470 (w), 1438 (w), 1425 (m),

1405 (m), 1385 (m), 1357 (s), 1325 (s), 1295 (m), 1277 (w), 1230 (s),

1197 (s),1158 (w),1134 (s),1004 (w),1082 (s),1038 (s). MS (EI, 70 eV):

m/z (%)¼305 ([M^þ], 80), 304 (100), 290 (7), 289 (10), 77 (4). HRMS

(ESI/TOF, MS): calcd for C₁₅H₁₄N₃F₂S ([MþH]^þ) 306.0871, found

306.0871. Anal. Calcd for C₁₅H₁₃F₂N₃S (305.35): C, 59.00, H, 4.29, N,

13.76. Found: C, 58.914, H, 4.351, N, 13.313.

3.8.28. 4-(1,1-Diﬂuorobut-3-enyl)-6-(4-methoxyphenyl)-3-methyl-

1-phenyl-1H-pyrazolo[3,4-b]pyridine (13b). White solid isolated by

preparative chromatography (heptane); mp 94e96 ^ꢀC; ¹H NMR

(CDCl₃, 300 MHz):

¼2.73 (t, ³J¼2.3 Hz, 3H, CH₃), 3.02e3.15 (m, 2H,

CH₂), 3.88 (s, 3H, CH₃), 5.21e5.28 (m, 2H, CH₂), 5.76e5.91 (m, 1H,

CH), 7.02e7.05 (m, ³J¼9.1 Hz, 2H, C_ArH), 7.31 (t, ³J¼7.4 Hz, 1H, C_ArH),

7.54 (t, ³J¼7.4 Hz, 2H, C_ArH), 7.67 (s, 1H, C_ArH), 8.11e8.14 (m,

³J¼9.1 Hz, 2H, C_ArH), 8.32e8.36 (m, ³J¼8.7 Hz, 2H, C_ArH). ¹³C NMR

3.8.25. 3-(4-Methoxybenzyl)-7-(diﬂuoromethyl)-5-methyl-3H-imi-

dazo[4,5-b]pyridine (12i). White solid isolated by preparative

chromatography (heptane); mp 102e103 ^ꢀC; ¹H NMR (CDCl₃,

(CDCl₃, 75 MHz):

¼15.9 (t, J_C,F¼6.1 Hz, CH₃), 43.6 (t, J_C,F¼27.0 Hz,

300 MHz):

¼2.71 (s, 3H, CH₃), 3.78 (s, 3H, OCH₃), 5.38 (s, 2H, CH₂),

CH₂), 55.4 (OCH₃), 110.2 (t, J_C,F¼2.8 Hz, C), 110.5 (t, J_C,F¼8.3 Hz, CH),

114.3 (CH), 120.7 (t, J_C,F¼243.7 Hz, CF₂), 121.3 (CH), 121.4 (CH₂),

125.7 (C_ArH), 128.0 (t, J_C,F¼5.0 Hz, CH), 128.9 (C_ArH), 128.9 (C_ArH),

131.0 (C), 139.4 (C), 139.9 (t, J_C,F¼28.6 Hz, CeCF₂), 141.2 (C), 152.1 (C),

6.83e6.88 (m, ³J¼8.7 Hz, 2H, C_ArH), 7.24 (t, ³J¼55.0 Hz, 1H, CF₂H),

7.23e7.30 (m, 3H, C_ArH), 7.96 (s, 1H, CH). ¹³C NMR (CDCl₃, 75 MHz):

¼24.6 (CH₃), 46.6 (CH₂), 55.3 (OCH₃), 111.4 (t, J_C,F¼239.0 Hz, CF₂),

113.9 (t, J_C,F¼5.0 Hz, CH), 114.3 (CH), 127.6 (C), 129.4 (CH), 130.2 (t,

J_C,F¼5.0 Hz, C), 132.5 (t, J_C,F¼24.0 Hz, CeCF₂), 143.9 (CH), 147.4 (C),

156.1 (C), 161.2 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ93.05 (CF₂). IR

(ATR, cm^ꢁ1):

¼3116 (w), 3081 (w), 3011 (w), 2957 (w), 2929 (w),

154.4 (C), 159.6 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

d¼ꢁ116.01 (CF₂H).

2840 (w), 1645 (w), 1610 (w), 1593 (w), 1584 (w), 1566 (s), 1504 (s),

1481 (m), 1456 (w), 1441 (w), 1412 (s), 1388 (m), 1348 (m), 1325 (w),

1311 (w), 1295 (w), 1247 (w), 1230 (w), 1175 (w), 1167 (w), 1142 (w),

IR (ATR, cm^ꢁ1):

(w), 1611 (w), 1596 (w), 1584 (w), 1510 (s), 1465 (w), 1442 (w), 1432

¼3070 (w), 3029 (w), 2967 (w), 2939 (w), 2841

V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 5663e5677

5673

1130 (w), 1110 (w), 1088 (w), 1053 (m), 1027 (s). MS (EI, 70 eV): m/z

(%)¼406 ([M^þ], 27), 405 (100), 364 (27), 321 (7). HRMS (ESI-TOF/

MS): calcd for C₂₄H₂₂F₂N₃O [(MþH)^þ] 406.1725, found 406.1732.

399 ([M^þ], [³⁵Cl], (42), 345 (34), 344 (28), 343 (100), 342 (21), 304

(32), 302 (87), 290 (16). HRMS (ESI/TOF, MS): calcd for

C₂₂H₂₀ClF₂N₃Na [(MþNa)^þ, [³⁵Cl]) 422.1206, found 422.1202. Anal.

Calcd for C₂₂H₂₀ClF₂N₃(399.86): C, 66.08, H, 5.04, N,10.51. Found: C,

65.825, H, 5.206, N, 10.321.

3.8.29. 6-(4-Chlorophenyl)-4-(1,1-diﬂuorobut-3-enyl)-3-methyl-1-

phenyl-1H-pyrazolo[3,4-b]pyridine (13c). White solid isolated by

preparative chromatography (heptane); mp 124e126 ^ꢀC; ¹H NMR

3.8.32. 1-(4-Methoxybenzyl)-4-(1,1-diﬂuorobut-3-enyl)-6-methyl-

1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (13f). Yellow solid isolated

by preparative chromatography (heptane); mp 86e87 ^ꢀC; ¹H NMR

(CDCl₃, 300 MHz):

¼2.74 (t, ³J¼2.3 Hz, 3H, CH₃), 3.02e3.15 (m, 2H,

CH₂), 5.21e5.28 (m, 2H, CH₂), 5.77e5.91 (m, 1H, CH), 7.32 (t,

³J¼7.4 Hz, 1H, CH), 7.46e7.57 (m, 4H, C_ArH), 7.68 (s, 1H, C_ArH),

8.07e8.11 (m, ³J¼8.7 Hz, 2H, C_ArH), 8.29e8.32 (m, ³J¼8.7 Hz, 2H,

(CDCl₃, 300 MHz):

¼2.74 (s, 3H, CH₃) 3.07e3.21 (m, 2H, CH₂), 3.84

(s, 3H, OCH₃), 5.21e5.26 (m, 2H, CH₂), 5.47 (s, 2H, CH₂), 5.76e5.89

(m, 1H, CH), 6.90e6.95 (m, ³J¼8.7 Hz, 2H, C_ArH), 7.27e7.30 (m,

C_ArH). ¹³C NMR (CDCl₃, 75 MHz):

d¼15.9 (t, J_C,F¼6.0 Hz, CH₃), 43.3 (t,

J_C,F¼27.0 Hz, CH₂), 110.8 (t, J_C,F¼8.3 Hz, CH), 110.8 (t, J_C,F¼2.3 Hz, C),

120.7 (t, J_C,F¼243.7 Hz, CF₂), 121.4 (CH), 121.6 (CH₂), 126.0 (C_ArH),

128.2 (t, J_C,F¼5.0 Hz, CH), 128.8 (C_ArH), 129.0 (C_ArH), 129.1 (C_ArH),

136.1 (C), 136.9 (C), 139.2 (C), 140.3 (t, J_C,F¼28.1 Hz, CeCF₂), 141.3 (C),

³J¼8.7 Hz, 3H, C_ArH), 7.71 (s, 1H, CH). ¹³C NMR (CDCl₃, 75 MHz):

¼24.5 (CH₃), 43.2 (t, J_C,F¼27.0 Hz, CH₂), 48.2 (CH₂), 55.3 (OCH₃),

84.2 (CeChN), 112.1 (t, J_C,F¼3.3 Hz, C), 114.4 (CH), 114.9 (t,

J_C,F¼7.2 Hz, CH), 115.7 (C^N), 120.7 (t, J_C,F¼244.3 Hz, CF₂), 121.3

(CH₂), 127.4 (C), 128.0 (t, J_C,F¼4.8 Hz, CH), 129.7 (CH), 136.1 (CH),

138.0 (t, J_C,F¼28.6 Hz, CeCF₂), 147.4 (C), 154.8 (C), 159.7 (C). ¹⁹F NMR

151.9 (C), 155.2 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ93.64 (CF₂). IR

(ATR, cm^ꢁ1):

¼3115 (w), 3083 (w), 3020 (w), 2969 (w), 2929 (w),

2859 (w),1644 (w),1592 (m),1578 (m),1564 (w),1503 (s), 1489 (w),

1477 (w), 1456 (w), 1437 (w), 1412 (m), 1400 (m), 1387 (m), 1348

(m), 1324 (w), 1309 (w), 1294 (w), 1267 (w), 1249 (w), 1231 (w),

1166 (s), 1141 (w), 1129 (m), 1107 (w), 1095 (m), 1052 (s), 1021 (w),

1011 (w). MS (EI, 70 eV): m/z (%)¼411 ([M^þ], [³⁷Cl], 36), 410 (29),

409 ([M^þ], [³⁵Cl], 100), 370 (12), 368 (35). HRMS (ESI-TOF/MS):

calcd for C₂₃H₁₉ClF₂N₃([MþH]^þ, [³⁵Cl]) 410.123, found 410.1234.

Anal. Calcd for C₂₃H₁₈ClF₂N₃(409.86): C, 67.40, H, 4.43, N, 10.25.

Found: C, 67.463, H, 4.616, N, 9.744.

(CDCl₃, 282 MHz):

¼ꢁ93.80 (CF₂). IR (ATR, cm^ꢁ1):

¼3097 (w),

3076 (w), 3029 (w), 2937 (w), 2844 (w), 2222 (s), 1722 (w), 1644

(w), 1614 (w), 1595 (w), 1575 (m), 1530 (m), 1511 (s), 1493 (w), 1455

(w), 1442 (m), 1416 (s), 1388 (s), 1356 (m), 1326 (m), 1295 (s), 1246

(s),1211 (w), 1198 (w), 1182 (w), 1173 (s),1154 (m), 1007 (s),1025 (s),

1011 (w). MS (EI, 70 eV): m/z (%)¼367 ([M^þ], 28), 121 (100). HRMS

(ESI/TOF, MS): calcd for C₂₁H₂₀N₃F₂O ([MþH]^þ) 368.1569, found

368.1563.

3.8.33. 1-(4-Methoxybenzyl)-6-(4-chlorophenyl)-4-(1,1-diﬂuorobut-

3-enyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (13g). White solid

isolated by preparative chromatography (heptane); mp 158e159 ^ꢀC;

3.8.30. 1-tert-Butyl-4-(1,1-diﬂuorobut-3-enyl)-6-methyl-1H-pyrrolo

[2,3-b]pyridine-3-carbonitrile (13d). Yellow solid isolated by pre-

parative chromatography (heptane); mp 80e81 ^ꢀC; ¹H NMR (CDCl₃,

¹H NMR (CDCl₃, 300 MHz):

¼3.08e3.22 (m, 2H, CH₂), 3.80 (s, 3H,

300 MHz):

2H, CH₂), 5.18e5.24 (m, 2H, CH₂), 5.72e5.86 (m, 1H, CH), 7.16 (s, 1H,

C_ArH), 7.89 (s, 1H, CH). ¹³C NMR (CDCl₃, 75 MHz):

d¼1.81 (s, 9H, C(CH₃)₃), 2.66 (s, 3H, CH₃), 3.03e3.17 (m,

OCH₃), 5.19e5.24 (m, 2H, CH₂), 5.52 (s, 2H, CH₂), 5.74e5.88 (m, 1H,

CH), 6.88e6.91 (m, ³J¼8.7 Hz, 2H, C_ArH), 7.28e7.31 (m, ³J¼8.7 Hz, 2H,

C_ArH), 7.46e7.49 (m, ³J¼8.7 Hz, 2H, C_ArH), 7.78 (s,1H, CH), 7.79 (s,1H,

d¼24.7 (CH₃), 29.0

(CH₃), 43.2 (t, J_C,F¼27.0 Hz, CH₂), 58.8 (C(CH₃)₃), 82.4 (CeChN),

113.3 (t, J_C,F¼3.3 Hz, C), 114.1 (t, J_C,F¼7.3 Hz, CH), 116.2 (C^N), 120.7

(CH₂), 120.7 (t, J_C,F¼244.3 Hz, CF₂), 128.1 (t, J_C,F¼5.0 Hz, CH), 134.7

(CH), 137.5 (t, J_C,F¼28.6 Hz, CeCF₂), 147.8 (C), 153.2 (C). ¹⁹F NMR

CH), 8.07e8.09 (m, ³J¼8.7 Hz, 2H, C_ArH). ¹³C NMR (CDCl₃, 126 MHz):

¼43.3 (t, J_C,F¼27.0 Hz, CH₂), 48.6 (CH₂), 55.3 (OCH₃), 84.6

(CeChN),111.8 (t, J_C,F¼7.1 Hz, CH),113.6 (t, J_C,F¼2.4 Hz, C),114.5 (CH),

115.4 (C^N),120.8 (t, J_C,F¼244.6 Hz, CF₂),121.6 (CH₂),127.3 (C),127.9

(t, J_C,F¼4.8 Hz, CH), 128.4, 129.1, 129.8 (CH), 135.6, 136.9 (C), 137.4

(CDCl₃, 282 MHz):

¼ꢁ93.84 (CF₂). IR (ATR, cm^ꢁ1):

¼3156(w),

2980 (w), 2924 (w), 2220 (s), 1859 (w), 1784 (w), 1679 (w), 1649 (s),

1593 (w), 1580 (w), 1522 (s), 1473 (w), 1435 (w), 1425 (m), 1399 (w),

1290 (m), 1368 (s), 1356 (w), 1350 (w), 1320 (s), 1300 (w), 1266 (s),

1245 (m), 1232 (w), 1199 (s), 1164 (w), 1150 (s), 1111 (m), 1061 (s),

1034 (m), 1014 (m). MS (EI, 70 eV): m/z (%)¼303 ([M^þ], 32), 247

(58), 246 (30), 207 (19), 206 (100), 194 (23). HRMS (ESI/TOF, MS):

calcd for C₁₇H₁₉N₃F₃([MþH]^þ) 304.162, found 304.1617. Anal. Calcd

for C₁₇H₁₉F₂N₃(303.35): C, 67.31, H, 6.31, N, 13.85. Found: C, 67.309,

H, 6.396, N, 13.500.

(CH), 138.9 (t, J_C,F¼28.6 Hz, CeCF₂), 147.7 (C), 152.0 (C), 159.9 (C). ¹⁹

NMR (CDCl₃, 282 MHz):

¼ꢁ113.76 (CF₂). IR (ATR, cm^ꢁ1):

¼3098

(w), 3076 (w), 2952 (w), 2920 (w), 2837 (w), 2217 (s),1739 (w),1722

(w), 1704 (w), 1642 (w), 1611 (w), 1594 (w), 1584 (m), 1513 (s), 1478

(w), 1464 (w), 1455 (w), 1442 (w), 1415 (s), 1405 (w), 1387 (m), 1365

(w), 1347 (w), 1332 (w), 1305 (w), 1294 (w), 1275 (w), 1247 (s), 1227

(m),1212 (w),1172 (s),1147 (w),1137 (w),1122 (w),1112 (w),1092 (s),

1033 (s), 1012 (w). MS (EI, 70 eV): m/z (%)¼465 ([M^þ], [³⁷Cl], 6), 463

([M^þ], [³⁵Cl], 17), 121 (100). HRMS (ESI/TOF, MS): calcd for

C₂₆H₂₁N₃ClF₂O ([MþH]^þ, [³⁵Cl]) 464.1336, found 464.1335. Anal.

Calcd for C₂₆H₂₀ClF₂N₃O (463.91): C, 67.31, H, 4.35, N, 9.06. Found: C,

67.389, H, 4.452, N, 8.517.

3.8.31. 1-tert-Butyl-6-(4-chlorophenyl)-4-(1,1-diﬂuorobut-3-enyl)-

1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (13e). White solid isolated

by preparative chromatography (heptane); mp 190e191 ^ꢀC; ¹H

NMR (CDCl₃, 300 MHz):

¼1.89 (s, 9H, C(CH₃)₃), 3.10e3.23 (m, 2H,

3.8.34. 7-(1,1-Diﬂuorobut-3-enyl)-1,3,5-trimethyl-1H-imidazo[4,5-b]

pyridine-2(3H)-thione (13h). White solid isolated by preparative

chromatography (heptane); mp 100e101 ^ꢀC; ¹H NMR (CDCl₃,

CH₂), 5.21e5.27 (m, 2H, CH₂), 5.76e5.90 (m, 1H, CH), 7.45e7.48 (m,

³J¼8.7 Hz, 2H, C_ArH), 7.76 (s, 1H, CH), 8.01 (s, 1H, C_ArH), 8.03e8.05

(m, ³J¼8.7 Hz, 2H, C_ArH). ¹³C NMR (CDCl₃, 75 MHz):

d¼29.3

300 MHz):

¼2.59 (s, 3H, CH₃), 2.98e3.12 (m, 2H, CH₂), 3.83 (s, 3H,

(C(CH₃)₃), 43.3 (t, J¼27.0 Hz, CH₂), 59.1 (C(CH₃)₃), 83.1 (CeChN),

111.0 (t, J_C,F¼7.7 Hz, CH), 114.9 (t, J_C,F¼3.3 Hz, C), 115.9 (C^N), 120.8

(t, J_C,F¼244.8 Hz, CF₂), 121.5 (CH), 128.0 (t, J_C,F¼5.0 Hz, CH), 128.2,

129.1 (CH), 135.4 (C), 136.2 (CH), 137.2 (C), 138.5 (t, J_C,F¼28.6 Hz,

CH₃), 3.98 (t, ³J¼2.6 Hz, 3H, CH₃), 5.22e5.29 (m, 2H, CH₂),

5.73e5.87 (m, 1H, CH), 7.03 (s, 1H, C_ArH). ¹³C NMR (CDCl₃, 75 MHz):

¼23.9 (CH₃), 30.7 (CH₃), 34.8 (t, J_C,F¼8.3 Hz, CH₃), 43.2 (t,

³J_C,F¼27.0 Hz, CH₂), 114.6 (t, J_C,F¼7.7 Hz, CH),120.0 (t, J_C,F¼243.0 Hz,

CeCF₂), 149.0 (C), 150.6 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

d¼ꢁ93.80

CF₂), 120.3 (t, J_C,F¼2.2 Hz, C), 121.7 (CH), 126.7 (t, J_C,F¼29.0 Hz,

(CF₂). IR (ATR, cm^ꢁ1):

¼3137 (w), 3086 (w), 2987 (w), 2921 (w),

CeCF₂), 127.6 (t, J_C,F¼5.0 Hz, CH), 146.4 (C), 152.0 (C), 172.5 (C). ¹⁹

2223 (s), 1747 (w), 1645 (w), 1583 (w), 1568 (w), 1518 (s), 1495 (w),

1470 (w), 1396 (s), 1366 (s), 1316 (s), 1293 (w), 1279 (w), 1268 (w),

1235 (w), 1207 (s), 1152 (w), 1124 (w), 1103 (w), 1089 (m), 1054 (w),

1040 (w), 1012 (w). MS (EI, 70 eV): m/z (%)¼401 ([M^þ], [³⁷Cl], 14),

NMR (CDCl₃, 282 MHz):

¼ꢁ86.55 (CF₂). IR (ATR, cm^ꢁ1):

¼3093

(w), 3051 (w), 2941 (w), 2916 (w), 1643 (m), 1615 (m), 1469 (s), 1435

(w), 1408 (br m), 1390 (w), 1361 (s), 1322 (s), 1309 (w), 1282 (m),

1260 (w), 1223 (w), 1215 (w), 1174 (w), 1157 (m), 1108 (m), 1077 (m),

5674

V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 5663e5677

1022 (w), 1003 (s). MS (EI, 70 eV): m/z (%)¼283 ([M^þ], 100), 282

(16), 268 (22), 232 (11), 220 (11), 219 (44), 218 (63). HRMS (ESI/TOF,

MS): calcd for C₁₃H₁₅N₃F₂NaS ([MþNa]^þ) 306.0847, found

306.0849. Anal. Calcd for C₁₃H₁₅F₂N₃S (283.34): C, 55.11, H, 5.34, N,

14.83. Found: C, 55.268, H, 5.522, N, 14.619.

3H, CH₃), 3.27e3.41 (m, 2H, CH₂), 3.80 (s, 3H, OCH₃), 5.11e5.19 (m,

2H, CH₂), 5.40 (s, 2H, CH₂), 5.68e5.82 (m, 1H, CH), 6.68e6.91 (m,

³J¼8.9 Hz, 2H, C_ArH), 7.27e7.31 (m, ³J¼8.9 Hz, 2H, C_ArH), 7.97 (s, 1H,

CH). ¹³C NMR (CDCl₃, 75 MHz):

d¼24.6 (CH₃), 42.3 (t, J¼26.0 Hz,

CH₂), 46.6 (CH₂), 55.3 (OCH₃), 114.3 (t, J_C,F¼6.1 Hz, CH), 120.5 (t,

J_C,F¼243.7 Hz, CF₂), 120.6 (CH₂), 127.7 (C), 128.7 (t, J_C,F¼5.0 Hz, CH),

129.3 (t, J_C,F¼4.4 Hz, C), 129.5 (CH), 135.4 (t, J_C,F¼27.5 Hz, CeCF₂),

143.3 (CH), 147.5 (C), 154.1 (C), 159.6 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

3.8.35. 7-(1,1-Diﬂuorobut-3-enyl)-1,5-dimethyl-3-phenyl-1H-imi-

dazo[4,5-b]pyridine-2(3H)-thione (13i). White solid isolated by

preparative chromatography (heptane); mp 184e185 ^ꢀC; ¹H NMR

¼ꢁ95.75 (CF₂). IR (ATR, cm^ꢁ1):

¼3078 (w), 2954 (w), 2930 (w),

(CDCl₃, 300 MHz):

¼2.50 (s, 3H, CH₃), 3.05e3.18 (m, 2H, CH₂), 4.07

2837 (w), 1717 (w), 1675 (w), 1644 (w), 1612 (w), 1588 (m), 1513 (s),

1492 (w), 1463 (w), 1435 (w), 1396 (w), 1381 (m), 1357 (m), 1300

(w), 1284 (m), 1246 (s), 1194 (w), 1176 (w), 1156 (w), 1109 (w), 1071

(m), 1029 (s). MS (EI, 70 eV): m/z (%)¼343 ([M^þ], 21), 122 (10), 121

(100). HRMS (ESI/TOF, MS): calcd for C₁₉H₁₉F₂N₃NaO [(MþNa)^þ]

366.1388, found 366.1393.

(t, ³J¼2.6 Hz, 3H, CH₃), 5.27e5.35 (m, 2H, CH₂), 5.79e5.92 (m, 1H,

CH), 7.08 (s, 1H, C_ArH), 7.49e7.68 (m, 5H, C_ArH). ¹³C NMR (CDCl₃,

75 MHz):

¼23.9 (CH₃), 30.7 (CH₃), 34.8 (t, ³J_C,F¼8.3 Hz, CH₃), 43.2

(t, J_C,F¼27.0 Hz, CH₂), 114.6 (t, J_C,F¼7.7 Hz, CH),120.0 (t,

J_C,F¼243.0 Hz, CF₂), 120.3 (t, J_C,F¼2.2 Hz, C), 121.7 (CH), 126.7 (t,

J_C,F¼29.0 Hz, CeCF₂), 127.6 (t, J_C,F¼5.0 Hz, CH), 146.4 (C), 152.0 (C),

172.5 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

d¼ꢁ86.18 (CF₂). IR (ATR,

3.8.39. 3-(4-Chlorobenzyl)-7-(1,1-diﬂuorobut-3-enyl)-5-methyl-3H-

imidazo[4,5-b]pyridine (13m). Yellow oil isolated by preparative

cm^ꢁ1):

¼3049 (w), 2956 (w), 2923 (w), 2853 (w), 1713 (w), 1614

(m), 1503 (s), 1483 (w), 1470 (w), 1442 (w), 1425 (s), 1394 (s), 1381

(w), 1358 (m), 1320 (w), 1294 (w), 1286 (w), 1255 (w), 1229 (w),

1219 (w), 1171 (w), 1143 (w), 1128 (w), 1108 (w), 1075 (s), 1028 (s),

1007 (m). MS (EI, 70 eV): m/z (%)¼345 ([M^þ], 100), 344 (47), 330

(18), 281 (50), 280 (67), 254 (12). HRMS (EI, 70 eV): calcd for

C₁₈H₁₇N₃F₂S ([M^þ]) 345.11058, found 345.110147.

chromatography (heptane); ¹H NMR (CDCl₃, 300 MHz):

3H, CH₃), 3.27e3.40 (m, 2H, CH₂), 5.10e5.18 (m, 2H, CH₂), 5.42 (s,

2H, CH₂), 5.67e5.81 (m, 1H, CH), 7.22e7.31 (m, 5H, C_ArH), 7.99 (s,

¼2.67 (s,

1H, CH). ¹³C NMR (CDCl₃, 126 MHz):

¼24.5 (CH₃), 42.2 (t,

J¼27.9 Hz, CH₂), 46.3 (CH₂), 114.4 (t, J_C,F¼6.7 Hz, CH), 120.4 (t,

J_C,F¼244.3 Hz, CF₂), 120.5 (CH₂), 128.6 (t, J_C,F¼5.3 Hz, CH), 129.0

(C_ArH), 129.1 (C_ArH), 129.3 (t, J_C,F¼3.6 Hz, C), 134.2 (C), 134.3 (C),

135.5 (t, J_C,F¼28.6 Hz, CeCF₂), 143.1 (CH), 147.4 (C), 154.3 (C). ¹⁹F

3.8.36. 5-(1,1-Diﬂuorobut-3-enyl)-1,3,7-trimethylpyrido[2,3-d]py-

rimidine-2,4(1H,3H)-dione (13j). Whitesolid isolated bypreparative

chromatography (heptane); mp 88e90 ^ꢀC; ¹H NMR (CDCl₃,

NMR (CDCl₃, 282 MHz):

¼ꢁ95.68 (CF₂). IR (ATR, cm^ꢁ1):

¼3080

(w), 3019 (w), 2954 (w), 2923 (w), 2854 (w), 1730 (w), 1714 (w),

1697 (w), 1681 (w), 1644 (w), 1591 (s), 1539 (w), 1491 (s), 1463 (w),

1431 (w), 1410 (w), 1396 (w), 1381 (m), 1358 (m), 1288 (s), 1233 (w),

1194 (s), 1155 (s), 1072 (w), 1029 (w), 1015 (m). MS (EI, 70 eV): m/z

(%)¼349 ([M^þ], [³⁷Cl], 8), 347 ([M^þ], [³⁵Cl], (32), 222 (60), 127 (31),

125 (100), 89 (18). HRMS (ESI/TOF, MS): calcd for C₁₈H₁₆ClF₂N₃Na

([MþNa)^þ, [³⁵Cl]) 370.0893, found 370.089.

300 MHz):

CH₃), 3.72 (s, 3H, CH₃), 5.13e5.19 (m, 2H, CH₂), 5.69e5.83 (m, 1H,

CH), 7.23 (s, 1H, CH). ¹³C NMR (CDCl₃, 75 MHz):

¼2.63 (s, 3H, CH₃), 3.30e3.43 (m, 2H, CH₂), 3.45 (s, 3H,

¼25.2 (CH₃), 28.7

(CH₃), 30.4 (CH₃), 41.3 (t, J¼24.8 Hz, CH₂), 104.7 (t, J_C,F¼2.2 Hz, C),

117.1 (t, J_C,F¼11.0 Hz, CH), 120.7 (CH₂), 121.2 (t, J_C,F¼245.4 Hz, CF₂),

129.0 (t, J_C,F¼5.0 Hz, CH),147.4 (t, J_C,F¼27.5 Hz, CeCF₂),151.0 (C),152.1

(C), 159.5 (C), 164.3 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ91.50 (CF₂).

IR (ATR, cm^ꢁ1):

n¼3366 (w), 3120 (w), 3080 (w), 2957 (w), 1713 (s),

3.8.40. 4-(Chlorodiﬂuoromethyl)-2-phenylpyrimidine (16a). Orange-

1666 (m), 1641 (w), 1614 (w), 1593 (s), 1565 (s), 1500 (m), 1451 (w),

1416 (s), 1382 (w), 1355 (s), 1329 (w), 1284 (w), 1263 (w), 1254 (w),

1234 (w), 1196 (w), 1171 (w), 1154 (w), 1140 (w), 1078 (s), 1025 (w),

1009 (w). MS (EI, 70 eV): m/z (%)¼295 ([M^þ], 24), 275 (35), 274 (32),

254 (34), 231 (21), 230 (100), 190 (26), 189 (38), 162 (49), 161 (31).

HRMS (ESI/TOF, MS): calcd for C₁₄H₁₆F₂N₃O₂[(MþH)^þ] 296.1205,

found 296.1206. Anal. Calcd for C₁₄H₁₅F₂N₃O₂(295.28): C, 56.94, H,

5.12, N, 14.23. Found: C, 57.082, H, 5.411, N, 13.797.

yellow solid isolated recrystallization from water; mp 139 ^ꢀC; ¹H

NMR (CDCl₃, 300 MHz):

¼7.46 (d, J_H,H¼5.1 Hz, 1H, CH), 7.51e7.53

(m, 3H, Ar), 8.50e8.53 (m, 2H, Ar), 9.00 (d, ³J_H,H¼5.1 Hz, 1H, CH). ¹³

NMR (CDCl₃, 75 MHz):

¼113.0 (t, J_C,F¼3.3 Hz, CH) 123.6 (t,

¹J_C,F¼291.1 Hz, CF₂Cl), 128.6, 128.7, 131.6 (C_ArH), 136.2 (C_Ar), 159.6

(CH), 160.2 (t, J_C,F¼30.8 Hz, CeCF₂Cl), 165.4 (C). ¹⁹F NMR (CDCl₃,

282 MHz):

¼ꢁ58.28 (CF₂Cl). IR (ATR, cm^ꢁ1):

¼3201 (w), 3134 (w),

3066 (w), 3045 (w), 2962 (w), 2922 (w), 2851 (w), 1965 (w), 1909

(w), 1621 (w), 1601 (w), 1588 (w), 1559 (m), 1520 (m), 1458 (w),

1430 (m), 1390 (s), 1368 (m), 1322 (m), 1308 (m), 1298 (m), 1276

(m), 1185 (w), 1172 (w), 1144 (s), 1093 (s), 1067 (s), 1025 (m), 1002

(m). MS (EI, 70 eV): m/z (%)¼242 ([M]^þ, [³⁷Cl], 32), 240 ([M]^þ, [³⁵Cl],

100), 241 (12), 205 (15), 155 (91), 104 (12), 103 (22), 77 (13).HRMS

(EI, 70 eV): calcd for C₁₁H₇ClF₂N₂([M]^þ, [³⁵Cl]) 240.02603, found

240.025859.

3.8.37. 5-(1,1-Diﬂuorobut-3-enyl)-7-methylpyrido[2,3-d]pyrimidine-

2,4(1H,3H)-dione (13k). White solid isolated by preparative chro-

matography (heptane); mp 208e209 ^ꢀC; ¹H NMR ((CD₃)₂CO,

300 MHz):

(m, 2H, CH₂), 5.71e5.85 (m, 1H, CH), 7.27 (s, 1H, CH), 10.29 (s, 1H,

NH), 10.51 (s, 1H, NH). ¹³C NMR ((CD₃)₂CO, 75 MHz):

¼2.59 (s, 3H, CH₃), 3.30e3.44 (m, 2H, CH₂), 5.12e5.21

¼24.4 (CH₃),

41.2 (t, J¼24.8 Hz, CH₂), 104.4 (t, J_C,F¼2.8 Hz, C), 117.1 (t, J_C,F¼11.0 Hz,

CH), 121.5 (t, J_C,F¼244.3 Hz, CF₂), 120.3 (CH₂), 129.7 (t, J_C,F¼5.0 Hz,

CH), 147.2 (t, J_C,F¼27.5 Hz, CeCF₂), 149.7 (C), 154.5 (C), 160.8 (C),

3.8.41. 4-(Chlorodiﬂuoromethyl)-6-methyl-2-phenylpyrimidine

(16b). Orange-brown solid isolated recrystallization from water;

165.7 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ92.38 (CF₂). IR (ATR,

mp 58e59 ^ꢀC; ¹H NMR (CDCl₃, 300 MHz):

¼2.69 (s, 3H, CH₃), 7.32

cm^ꢁ1):

¼3207 (w), 3078 (w), 3023 (w), 2873 (w), 1693 (br s), 1601

(s, 1H, CH), 7.49e7.51 (m, 3H, Ar), 8.50e8.53 (m, 2H, Ar). ¹³C NMR

(m), 1566 (s), 1467 (w), 1440 (w), 1394 (s), 1372 (w), 1352 (m), 1316

(w), 1263 (s), 1211 (w), 1182 (w), 1157 (w), 1131 (w), 1114 (w), 1101

(w), 1084 (w), 1062 (w), 1033 (w). MS (EI, 70 eV): m/z (%)¼267

([M^þ], 26), 247 (45), 246 (64), 232 (27), 227 (26), 226 (66), 203 (70),

202 (100), 176 (70). HRMS (ESI/TOF, MS): calcd for C₁₂H₁₀F₂N₃O₂

[(MꢁH)^ꢁ] 266.0747, found 266.0753.

(CDCl₃, 75 MHz):

¼24.8 (CH₃), 112.5 (t, J_C,F¼3.3 Hz, CH), 123.9 (t,

¹J_C,F¼291.1 Hz, CF₂Cl), 127.3, 128.6, 131.3 (C_ArH), 136.5 (C_Ar), 160.0 (t,

²J_C,F¼30.0 Hz, CeCF₂Cl), 165.0, 170.1 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ58.17 (CF₂Cl). IR (ATR, cm^ꢁ1):

¼3365 (w), 3168 (w), 3067 (w),

2964 (w), 1660 (w), 1623 (w), 1590 (w), 1576 (m), 1546 (m), 1460

(w), 1448 (w), 1405 (w), 1370 (s), 1289 (w), 1260 (w), 1213 (m), 1202

(m), 1175 (w), 1148 (m), 1120 (s), 1091 (s), 1071 (m), 1027 (m). MS

(EI, 70 eV): m/z (%)¼256 ([M]^þ, [³⁷Cl], 34), 254 ([M]^þ, [³⁵Cl], 100),

255 (15), 219 (17), 169 (62), 104 (28), 103 (22). HRMS (EI, 70 eV):

calcd for C₁₂H₉ClF₂N₂([M]^þ, [³⁵Cl]) 254.04168, found 254.041507.

3.8.38. 3-(4-Methoxybenzyl)-7-(1,1-diﬂuorobut-3-enyl)-5-methyl-

3H-imidazo[4,5-b]pyridine (13l). Yellow oil isolated by preparative

chromatography (heptane); ¹H NMR (CDCl₃, 300 MHz):

d¼2.71 (s,

V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 5663e5677

5675

Anal. Calcd for C₁₂H₉ClF₂N₂(254.66): C, 56.60, H, 3.56, N, 11.00.

Found: C, 56.610, H, 3.143, N, 10.834.

(EI, 70 eV): m/z (%)¼260 ([M]^þ, 68), 259 (100), 239 (36), 104 (31),

103 (14), 77 (12). HRMS (EI, 70 eV): calcd for C₁₅H₁₄F₂N₂([M]^þ)

259.10413, found 259.104744. Anal. Calcd for C₁₅H₁₄F₂N₂(260.28):

C, 69.22, H, 5.42. Found: C, 68.870, H, 5.440.

3.8.42. 4-(Diﬂuoromethyl)-2-phenylpyrimidine (17a). White-yel-

low solid isolated by preparative chromatography (heptane); mp

55e57 ^ꢀC; ¹H NMR (CDCl₃, 300 MHz):

¼6.61 (t, ²J_H,F¼54.9 Hz, 1H,

3.8.46. 3-(Chlorodiﬂuoromethyl)-1H-pyrazole (20a). Colourless oil

CF₂H), 7.46e7.48 (m, 1H, CH), 7.49e7.51 (m, 3H, Ar), 8.46e8.49 (m,

isolated by column chromatography (heptane/EtOAc, 5:1); ¹H NMR

2H, Ar), 8.97 (d, J_H,H¼4.9 Hz, 1H, CH). ¹³C NMR (CDCl₃, 75 MHz):

(CDCl₃, 300 MHz):

¼6.63 (d, ⁴J_H,F¼2.5 Hz,1H, CH), 7.69e7.70 (m,1H,

¼112.9 (t, ¹J_C,F¼242.1 Hz, CF₂H), 114.3 (t, J_C,F¼3.0 Hz, CH), 128.4,

CH),11.99 (s,1H, NH). ¹³C NMR (CDCl₃, 63 MHz):

¼103.5 (CH),123.1

128.7, 131.3 (C_ArH), 136.6 (C_Ar), 159.0 (CH), 160.5 (t, J_C,F¼26.7 Hz,

(t,¹J_C,F¼284.7 Hz, CF₂Cl),130.3 (CH),147.6 (t, ²J_C,F¼31.6 Hz, CeCF₂Cl).

CeCF₂H), 164.9 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

(ATR, cm^ꢁ1):

d¼ꢁ119.11 (CF₂). IR

¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ47.1 (CF₂Cl). IR (ATR, cm^ꢁ1):

¼3167

¼3139 (w), 3092 (w), 3070 (w), 3046 (w), 2956 (w),

(m), 3065 (w), 2979 (m), 2933 (m), 2848 (w), 2774 (w), 2703 (w),

2533 (w), 2342 (w), 2141 (w),1635 (w),1553 (w),1481 (w),1372 (m),

1304 (s),1242(w),1226 (m),1117 (s),1079(s),1053 (s). MS (EI, 70eV):

m/z (%)¼154 ([M]^þ, [³⁷Cl], 5),152 ([M]^þ, [³⁵Cl],15),117 (100), 39 (13).

2922 (w), 2871 (w), 2853 (w),1587 (w),1566 (s),1531 (w),1520 (w),

1462 (w), 1435 (w), 1396 (s), 1353 (m), 1335 (m), 1307 (w), 1294 (w),

1252 (w), 1178 (w), 1155 (w), 1120 (m), 1090 (m), 1045 (s), 1025 (s),

1002 (m). MS (EI, 70 eV): m/z (%)¼206 ([M]^þ, 100), 207 (13), 155

(77), 104 (12), 103 (22), 77 (13). HRMS (EI, 70 eV): calcd for

C₁₁H₈F₂N₂([M]^þ) 206.06501, found 206.064908.

HRMS (ESI-TOF/MS): calcd for C₄H₃ClF₂N₂([MþH]^þ,

[

³⁵Cl])

153.0026, found 153.0025. Anal. Calcd for C₄H₃ClF₂N₂(152.53): C,

31.50, H, 1.98, N, 18.37. Found: C, 31.556, H, 1.934, N, 17.438.

3.8.43. 4-(Diﬂuoromethyl)-6-methyl-2-phenylpyrimidine (17b). Colo-

3.8.47. 3-(Chlorodiﬂuoromethyl)-1-phenyl-1H-pyrazole(20b). Yellow

oil isolated by column chromatography (heptane/EtOAc, 100:

urless oil isolated by preparative chromatography (heptane); ¹H NMR

(CDCl₃, 300 MHz):

¼2.66 (s, 3H, CH₃), 6.58 (t, J_H,F¼55.0 Hz, 1H,

1/10:1); ¹H NMR (CDCl₃, 300 MHz):

¼6.77 (d, J_H,F¼2.1 Hz, 1H,

CF₂H), 7.33 (s, 1H, CH), 7.47e7.51 (m, 3H, Ar), 8.46e8.49 (m, 2H, Ar).

CH), 7.48 (s, 5H, Ar), 7.66 (d, J_H,F¼1.9 Hz, 1H, CH). ¹³C NMR (CDCl₃,

¹³C NMR (CDCl₃, 75 MHz):

¼24.7 (CH₃),113.1 (t, ¹J_C,F¼241.8 Hz, CF₂H),

75 MHz):

¼108.3 (t, J_C,F¼2.7 Hz, CH), 119.9 (CH), 120.8 (t,

113.8 (t, ³J_C,F¼3.3 Hz, CH), 128.4, 128.6, 131.1 (C_ArH), 136.9 (C_Ar), 160.2

¹J_C,F¼286.0 Hz, CF₂Cl), 126.5, 128.9, 129.4 (C_ArH), 137.5 (t,

²J_C,F¼33.4 Hz, CeCF₂Cl), 139.2 (C_Ar). ¹⁹F NMR (CDCl₃, 282 MHz):

(t, J_C,F¼26.4 Hz, CeCF₂H), 164.5 (C), 169.4 (C). ¹⁹F NMR (CDCl₃,

282 MHz):

¼ꢁ119.20. IR (ATR, cm^ꢁ1):

¼3068 (w), 3043 (w), 2959

¼ꢁ43.2 (CF₂Cl). IR (ATR, cm^ꢁ1):

¼3144 (w), 3112 (w), 3066 (w),

(w), 2925 (w), 2872 (w), 2855 (w), 1593 (m), 1578 (m), 1556 (m), 1497

(w), 1459 (w), 1445 (w), 1409 (s), 1395 (s), 1373 (s), 1331 (m), 1287 (w),

1201 (w), 1174 (m), 1157 (w), 1137 (m), 1092 (s), 1049 (s), 1028 (s), 1002

(m). MS (EI, 70 eV): m/z (%)¼220 ([M]^þ, 100), 221 (14), 169 (44), 104

(21), 103 (16). HRMS (EI, 70 eV): calcd for C₁₂H₁₀F₂N₂([M]^þ)

220.08066, found 220.080431.

1598 (m), 1533 (m), 1502 (s), 1459 (m), 1397 (s), 1331 (s), 1272 (m),

1228 (s), 1147 (w), 1133 (w), 1097 (w), 1083 (w), 1072 (w), 1027 (m).

MS (EI, 70 eV): m/z (%)¼230 ([M]^þ, [³⁷Cl], 20), 228 ([M]^þ, [³⁵Cl], 57),

194 (12), 193 (100), 173 (43), 77 (18), 51 (12). HRMS (EI, 70 eV): calcd

for C₁₀H₇ClF₂N₂([M]^þ, [³⁵Cl]) 228.02603, found 248.025981. Anal.

Calcd for C₁₂H₉ClF₂N₂(228.63): C, 52.53, H, 3.09, N, 12.25. Found: C,

52.790, H, 2.890, N, 12.210.

3.8.44. 4-(1,1-Diﬂuorobut-3-enyl)-2-phenylpyrimidine

(18a). Yellow oil isolated by preparative chromatography (hep-

3.8.48. 3-(Chlorodiﬂuoromethyl)-5-methyl-1H-pyrazole (20d). White-

yellow solid isolated by column chromatography (heptane/EtOAc,

tane); ¹H NMR (CDCl₃, 300 MHz):

¼3.12e3.26 (m, ³J_H,F¼7.2 Hz, 2H,

CH₂), 5.18e5.26 (m, 2H, CH₂), 5.73e5.87 (m, J_H,F¼7.0 Hz, 1H, CH),

10:1/5:1); mp 83e84 ^ꢀC; ¹H NMR (CDCl₃, 300 MHz):

¼2.32 (d,

7.46 (d, ³J_H,H¼5.1 Hz, 1H, CH), 7.50e7.52 (m, 3H, Ar), 8.48e8.51 (m,

⁶J_H,F¼0.6 Hz, 3H, CH₃), 6.28 (s, 1H, CH), 12.41 (s, 1H, NH). ¹³C NMR

2H, Ar), 8.93 (d, J_H,H¼5.1 Hz, 1H, CH). ¹³C NMR (CDCl₃, 75 MHz):

(CDCl₃, 63 MHz):

¼10.6 (CH₃), 102.5 (t, J_C,F¼2.1 Hz, CH), 123.1 (t,

40.1 (t, J_C,F¼25.3 Hz, CH₂), 114.5 (t, J_C,F¼4.1 Hz, CH), 119.7 (t,

¹J_C,F¼284.7 Hz, CF₂Cl),142.2 (C),147.8 (t, ²J¼31.4 Hz, CeCF₂Cl).¹⁹F NMR

¹J_C,F¼243.2 Hz, CF₂), 121.2 (CH₂), 128.2 (t, J_C,F¼5.5 Hz, CH), 128.4,

(CDCl₃, 282 MHz):

¼ꢁ46.91 (CF₂Cl). IR (ATR, cm^ꢁ1):

¼3182 (w), 3140

128.6, 131.2 (C_ArH), 136.8 (C_Ar), 158.8 (CH), 162.3 (t, J_C,F¼30.5 Hz,

(w), 3098 (w), 3030 (w), 2980 (w), 2937 (w), 2876 (w), 2781 (w), 1582

(w),1477 (w),1423 (m),1382 (w),1306 (w),1221 (s),1162 (m),1112 (m),

1072 (s), 1031 (m). MS (EI, 70 eV): m/z (%)¼168 ([M]^þ, [³⁷Cl], 6), 166

([M]^þ, [³⁵Cl], 19), 131 (100). HRMS (ESI-TOF/MS): calcd for C₅H₅ClF₂N₂

([MþH]^þ, [³⁵Cl]) 166.0182, found 166.0183. Anal. Calcd for C₅H₅ClF₂N₂

(166.56): C, 36.06, H, 3.03, N, 16.82. Found: C, 36.354, H, 2.992, N,

15.639.

CeCF₂), 164.7 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

d¼ꢁ100.37 (CF₂Cl). IR

(ATR, cm^ꢁ1):

¼3070 (w), 3045 (w), 2984 (w), 2925 (w), 1645 (w),

1588 (w), 1563 (s), 1460 (w), 1428 (m), 1386 (s), 1347 (m), 1333 (m),

1314 (m),1286 (w),1260 (w), 1243 (w),1172 (m), 1143 (m),1108 (w),

1090 (m),1064 (m),1044 (m),1029 (m). MS (EI, 70 eV): m/z (%)¼246

([M]^þ, 18), 245 (100), 225 (17), 104 (18), 103 (11), 77 (12). HRMS

(ESI-TOF/MS): calcd for C₁₄H₁₂F₂N₂([MþH]^þ) 247.1041, found

247.1042. Anal. Calcd for C₁₄H₁₂F₂N₂(246.26): C, 68.28, H, 4.91, N,

11.38. Found: C, 68.417, H, 4.952, N, 11.122.

3.8.49. 3-(Chlorodiﬂuoromethyl)-1,5-dimethyl-1H-pyrazole (20e).

Yellow oil isolated by column chromatography (heptane/EtOAc,

10:1); ¹H NMR (CDCl₃, 300 MHz):

¼2.28, 3.80 (s, 3H, CH₃), 6.25 (s,

3.8.45. 4-(1,1-Diﬂuorobut-3-enyl)-6-methyl-2-phenylpyrimidine

(18b). Colourless oil isolated by preparative chromatography

1H, CH). ¹³C NMR (CDCl₃, 63 MHz):

¼11.1, 36.6 (CH₃), 103.2 (CH),

123.1 (t, J_C,F¼284.5 Hz, CF₂Cl), 140.1 (C), 145.9 (t, J_C,F¼31.6 Hz,

(heptane); ¹H NMR (CDCl₃, 300 MHz):

3.10e3.24 (m, 2H, CH₂), 5.17e5.26 (m, 2H, CH₂), 5.72e5.86 (m, 1H,

CH), 7.33 (s, 1H, CH), 7.45e7.50 (m, 3H, Ar), 8.47e8.51 (m, 2H, Ar).

¼2.65 (s, 3H, CH₃),

CeCF₂Cl). ¹⁹F NMR (CDCl₃, 282 MHz):

cm^ꢁ1):

¼ꢁ46.82 (CF₂Cl). IR (ATR,

¼3138 (w), 2952 (w), 1553 (w), 1463 (w), 1433 (w), 1426

(w), 1407 (w), 1381 (w), 1298 (w), 1201 (s), 1173 (m), 1116 (m), 1090

(m), 1036 (m), 1000 (s). MS (EI, 70 eV): m/z (%)¼182 ([M]^þ, [³⁷Cl],

14), 180 ([M]^þ, [³⁵Cl], 42), 146 (19), 145 (100). HRMS (EI, 70 eV):

calcd for C₆H₇ClF₂N₂([M]^þ, [³⁵Cl]) 180.02603, found 180.026362.

¹³C NMR (CDCl₃, 75 MHz):

¼24.7 (CH₃), 40.2 (t, ²J_C,F¼24.8 Hz, CH₂),

114.0 (t, ³J_C,F¼4.4 Hz, CH), 119.9 (t, ¹J_C,F¼243.2 Hz, CF₂), 121.1 (CH₂),

128.4 (C_ArH), 128.5 (t, J_C,F¼5.5 Hz, CH), 128.5, 131.0 (C_ArH), 137.1

(C_Ar), 161.0 (t, J_C,F¼30.3 Hz, CeCF₂), 164.4, 169.2 (C). ¹⁹F NMR

(CDCl₃, 282 MHz):

¼ꢁ100.5 (CF₂). IR (ATR, cm^ꢁ1):

¼3081 (w),

3.8.50. 3-(Chlorodiﬂuoromethyl)-5-methyl-1-phenyl-1H-pyrazole

3069 (w), 2985 (w), 2959 (w), 2925 (w), 2855 (w), 1645 (w), 1592

(m), 1577 (m), 1548 (m), 1558 (w), 1429 (w), 1372 (s), 1318 (w), 1268

(s), 1197 (w), 1175 (w), 1140 (w), 1071 (w), 1060 (w), 1028 (m). MS

(20f). Yellow oil isolated by column chromatography (heptane/

EtOAc, 10:1); ¹H NMR (CDCl₃, 300 MHz):

¼2.33 (d, J_H,F¼0.6 Hz,

3H, CH₃), 6.44 (s, 1H, CH), 7.42e7.49 (m, 5H, Ar). ¹³C NMR (CDCl₃,

5676

V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 5663e5677

75 MHz):

¼12.3 (CH₃), 104.4 (t, J_C,F¼1.9 Hz, CH), 123.1 (t,

5H, Ar). ¹³C NMR (CDCl₃, 63 MHz):

¼12.4 (CH₃), 41.4 (t,

¹J_C,F¼285.0 Hz, CF₂Cl), 125.3, 128.6, 129.2 (C_ArH), 138.9 (C_Ar), 140.7

²J_C,F¼26.3 Hz, CH₂), 104.5 (t, J_C,F¼2.3 Hz, CH), 119.0 (t,

(C), 147.5 (t, J_C,F¼31.6 Hz, CeCF₂Cl). ¹⁹F NMR (CDCl₃, 282 MHz):

¹J_C,F¼236.9 Hz, CF₂), 120.2 (CH₂), 125.1, 128.2, 129.1 (C_ArH), 129.3 (t,

¼ꢁ47.23 (CF₂Cl). IR (ATR, cm^ꢁ1):

¼3136 (w), 3066 (w), 2966 (w),

³J_C,F¼5.0 Hz, CH), 139.3 (C_Ar), 140.0 (C), 148.7 (t, J_C,F¼33.6 Hz,

2928 (w), 1598(w), 1549 (w), 1503 (m), 1449 (m), 1317 (w), 1295

(w), 1277 (w), 1210 (s), 1149 (m), 1087 (s), 1073 (s), 1041 (w), 1017

(m), 1001 (s). MS (EI, 70 eV): m/z (%)¼244 ([M]^þ, [³⁷Cl], 8), 242

([M]^þ, [³⁵Cl], 26), 208 (12), 207 (100), 77 (27), 51 (16). HRMS (ESI-

TOF/MS): calcd for C₁₁H₉ClF₂N₂([MþH]^þ, [³⁵Cl]) 243.0495, found

243.0495. Anal. Calcd for C₁₁H₉ClF₂N₂(242.65): C, 54.45, H, 3.74, N,

11.54. Found: C, 54.846, H, 3.759, N, 11.332.

CeCF₂). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ92.05 (CF₂Cl). IR (ATR,

cm^ꢁ1):

¼3137 (w), 3079 (w), 3021 (w), 2985 (w), 2958 (w), 2925

(w), 2872 (w), 2856 (w),1645 (w),1598 (w),1552 (w),1503 (s),1481

(w), 1465 (w), 1450 (m), 1429 (w), 1378 (m), 1327 (w), 1318 (w),

1295 (w), 1270 (m), 1247 (w), 1198 (m), 1171 (m), 1138 (m), 1114 (w),

1063 (m), 1016 (s). MS (EI, 70 eV): m/z (%)¼248 ([M]^þ, 51), 247 (57),

228 (18), 227 (42), 207 (100), 157 (30). HRMS (ESI-TOF/MS): calcd

for C₁₄H₁₄F₂N₂([MþNa]^þ) 271.1017, found 271.1020.

3.8.51. 5-(Chlorodiﬂuoromethyl)-3-methyl-1-(4-nitrophenyl)-1H-

pyrazole (20g). Orange-brown solid isolated by column chroma-

tography (heptane/EtOAc, 10:1); mp 52e53 ^ꢀC; ¹H NMR (CDCl₃,

Acknowledgements

300 MHz):

¼2.36 (s, 3H, CH₃), 6.65 (s, 1H, CH), 7.68e7.73 (m, 2H,

Financial support by the State of Mecklenburg-Vorpommern

(scholarship for D.O.) and by the BMBF (grant No. 03IS2081A)

funding for Dr. Iaroshenko is gratefully acknowledged.

Ar), 8.31e8.36 (m, 2H, Ar). ¹³C NMR (CDCl₃, 63 MHz):

¼13.3 (CH₃),

109.9 (t, J_C,F¼2.7 Hz, CH), 120.5 (t, J_C,F¼285.6 Hz, CF₂Cl), 124.4

(C_ArH), 126.5 (t, ⁵J_C,F¼1.8 Hz, C_ArH), 138.0 (t, ²J_C,F¼33.4 Hz, CeCF₂Cl),

144.2,147.4,150.1 (C). ¹⁹F NMR (CDCl₃, 282 MHz):

¼ꢁ42.93 (CF₂Cl).

IR (ATR, cm^ꢁ1):

¼3122(w), 3091 (w), 2932 (w), 2863 (w), 1612 (w),

Supplementary data

1597 (m), 1555 (w), 1523 (s), 1503 (s), 1454 (m), 1438 (m), 1382 (w),

1343 (s), 1314 (m), 1275 (m), 1193 (m), 1154 (m), 1099 (m), 1075 (s),

1017 (s), 1002 (s). MS (EI, 70 eV): m/z (%)¼289 ([M]^þ, [³⁷Cl], 33), 287

([M]^þ, [³⁵Cl], 90), 252 (63), 206 (100), 205 (25), 165 (17), 75 (16).

HRMS (EI, 70 eV): calcd for C₁₁H₈ClF₂N₃O₂([M]^þ, [³⁵Cl]) 287.02676,

found 287.025954. Anal. Calcd for C₁₁C₈ClF₂N₃O₂(287.65): C, 45.93,

H, 2.80. Found: C, 45.528, H, 2.509.

Supplementary data associated with this article can be found, in

the online version, at doi:10.1016/j.tet.2011.05.085.

References and notes

ꢀ

1. (a) Resnati, G. Tetrahedron 1993, 49, 9385e9393; (b) Begue, J.-P.; Bonnet-Del-

ꢀ

pon, D. In Chimie Bioorganique et Medicinale du Fluor; CNRS: Paris, 2005; (c)

Hiyama, T. Organoﬂuorine Compounds. Chemistry and Application; Springer:

Berlin, 2000; (d) Kleemann, A.; Engel, J.; Kutscher, B.; Reichert, D. Pharmaceu-

tical Substances: Syntheses, Patents, Applications; Thieme: Stuttgart, 2001; (e)

Ismail, F. M. D. J. Fluorine Chem. 2002, 118, 27e35; (f) Krisch, P. Modern Fluo-

roorganic Chemistry; Wiley-VCH: Weinheim, 2004.

2. Goure, W. F.; Leschinsky, K. L.; Wratten, S. J.; Chupp, J. P. J. Agric. Food Chem.

1991, 39, 981e986.

3.8.52. 3-(Diﬂuoromethyl)-1-phenyl-1H-pyrazole (21). Colourless

oil isolated by preparative chromatography (heptane); ¹H NMR

(CDCl₃, 300 MHz):

¼6.63 (t, J_H,F¼53.6 Hz, 1H, CF₂H), 6.74e6.75

(m, 1H, CH), 7.44e7.51 (m, 5H, Ar), 7.71 (m, 1H, CH). ¹³C NMR (CDCl₃,

63 MHz):

¼107.3 (t, J_C,F¼2.3 Hz, CH), 108.5 (t, J_C,F¼235.5 Hz,

3. Ojima, I.; Lin, S.; Slater, J. C.; Wang, T.; Pera, P.; Bernacki, R. J.; Ferlin, C.; Scambia,

G. Bioorg. Med. Chem. 2000, 8, 1619e1628.

CF₂H), 124.9, 128.8, 129.4 (C_ArH), 136,2 (t, J_C,F¼30.0 Hz, CeCF₂H),

138.9 (C_Ar), 140.1 (t, J_C,F¼1.6 Hz, CH). ¹⁹F NMR (CDCl₃, 282 MHz):

4. Ferreira, S. B.; Cost, M. S.; Boechat, N.; Bezerra, R. J. S.; Genestra, M. S.; Canto-

Cavalheiro, M. M.; Kover, W. B.; Ferreira, V. F. Eur. J. Org. Chem. 2007, 42,

1388e1395.

¼ꢁ109.77 (CF₂). IR (ATR, cm^ꢁ1):

¼3142 (w), 3111 (w), 3066 (w),

2957 (w), 2925 (w), 2854 (w),1620 (w),1597 (w),1545 (w),1503 (s),

1465 (w), 1458 (w), 1401 (m), 1370 (m), 1344 (w), 1329 (m), 1296

(w), 1275 (w), 1208 (m), 1177 (w), 1159 (w), 1132 (m), 1081 (s), 1072

(s), 1035 (s), 1025 (s), 1006 (s). MS (EI, 70 eV): m/z (%)¼194 ([M]^þ,

100), 193 (34), 173 (12), 116 (12), 77 (23), 51 (16). HRMS (ESI-TOF/

MS): calcd for C₁₀H₈F₂N₂([M]^þ) 195.0728, found 195.0728.

€

5. (a) Schonig, E.; Taubert, D. Gastrointestinale Erkrankungen In Pharmakother-

apiedKlinische Pharmakologie, 13 Auﬂage; Lemmer, B., Brune, K., Eds.; 2007;

pp 325e335 Heidelberg: Springer Verlag, 2004; (b) Watson, T. D.; Stark, J. E.;

Vesta, K. S. Ann. Pharmacother. 2006, 40, 758e761; (c) The Merck Index. An

Encyclopaedia of Chemicals, Drugs and Biologicals, 14 Auﬂage; 2006 1209e1210.

6. Wolf, J. E.; Shander, D.; Huber, F.; Jackson, J.; Lin, C. S.; Mathes, B. M.; Schrode, K.

Int. J. Dermatol. 2007, 46, 94e108.

7. Pepin, J.; Milord, F.; Guern, C.; Schechter, P. J. Lancet 1987, 2, 1431e1433.

8. Bundschuh, D. S.; Eltze, M.; Barsig, J.; Wollin, L.; Hatzelmann, A.; Beume, R. J.

Pharmacol. Exp. Ther. 2001, 297, 280e290.

9. (a) Abel, S.; Back, D. J.; Vourvahis, M. Antiviral Therapy 2009, 14, 607e622; (b)

Levy, J. A. AIDS 2009, 23, 147e160; (c) Biswas, P.; Tambussi, G.; Lazzarin, A.

Expert Opinion on Pharmacotherapy 2007, 8, 923e933; (d) Stephenson, J. JAMA

2007, 297, 1535e1536; (e) Emmelkamp, J. M.; Rockstroh, J. K. Eur. J. Med. Res.

2007, 12, 409e417.

10. Olah, G. A.; Chambers, R. R.; Prakash, G. K. S. Synthetic Fluorine Chemistry;

Wiley: New York, NY, 1992.

11. Middleton, W. J. J. Org. Chem. 1975, 40, 574e578.

12. Olah, G. A.; Nojima, M.; Kerekes, I. J. Am. Chem. Soc. 1974, 96, 925e927.

13. Martinez, G. A.; Barcina, O. J.; Rys, A. Z.; Subramanian, L. R. Tetrahedron Lett.

1992, 33, 7787e7788.

14. Sasson, R.; Hagooly, A.; Rozen, S. Org. Lett. 2003, 5, 769e771.

15. (a) Iaroshenko, V. O.; Sevenard, D. V.; Kotljarov, A. V.; Volochnyuk, D. M.;

Tolmachev, A. O.; Sosnovskikh, V. Y. Synthesis 2009, 731e740; (b) Iaroshenko,

V. O.; Wang, Y.; Sevenard, D. V.; Volochnyuk, D. M. Synthesis 2009,

1851e1857; (c) Iaroshenko, V. O.; Wang, Y.; Zhang, B.; Volochnyuk, D. M.;

Sosnovskikh, V. Y. Synthesis 2009, 2393e2402; (d) Iaroshenko, V. O. Synthesis

2009, 3967e3974; (e) Mkrtchyan, S.; Iaroshenko, V. O.; Dudkin, S.; Ge-

vorgyan, A.; Vilches-Herrera, M.; Ghazaryan, G.; Volochnyuk, D.; Ostrovskyi,

D.; Ahmed, Z.; Villinger, A.; Sosnovskikh, V. Y.; Langer, P. Org. Biomol. Chem.

2010, 8, 5280e5284; (f) Iaroshenko, V. O.; Mkrtchyan, S.; Volochnyuk, D. M.;

Langer, P.; Sosnovskikh, V. Y.; Ostrovskyi, D.; Dudkin, S.; Kotljarov, A. V.;

Miliutina, M.; Savych, I.; Tolmachev, A. A. Synthesis 2010, 2749e2759; (g)

Ostrovskyi, D.; Iaroshenko, V. O.; Ali, I.; Mkrtchyan, S.; Villinger, A.; Tol-

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Mkrtchyan, S.; Ghazaryan, G.; Hakobyan, A.; Maalik, A.; Supe, L.; Villinger, A.;

Tolmachev, A.; Ostrovskyi, D.; Sosnovskikh, V. Y.; Langer, P. Synthesis 2011,

3.8.53. 3-(1,1-Diﬂuorobut-3-enyl)-1-phenyl-1H-pyrazole (22a). Colo-

urless oil isolated by preparative chromatography (heptane); ¹H

NMR (CDCl₃, 300 MHz):

¼3.07e3.21 (m, J_H,F¼7.0 Hz, 2H, CH₂),

5.20e5.29 (m, 2H, CH₂), 5.83e5.97 (m, ⁴J_H,F¼7.0 Hz, 1H, CH), 6.63 (d,

⁴J_H,F¼2.5 Hz, 1H, CH), 7.29e7.49 (m, 3H, Ar), 7.66e7.71 (m, 2H, Ar),

7.89 (d, J_H,F¼2.5 Hz, 1H, CH). ¹³C NMR (CDCl₃, 75 MHz):

d¼41.5 (t,

²J_C,F¼26.4 Hz, CH₂), 105.5 (t, ³J_C,F¼2.2 Hz, CH), 118.9 (t, ¹J_C,F¼237.1 Hz,

CF₂), 119.5 (CH), 120.4 (CH₂), 127.1, 127.8 (C_ArH), 129.2 (t, ³J_C,F¼5.0 Hz,

CH), 129.5 (C_ArH), 139.8 (C_Ar), 150.0 (t, J_C,F¼33.6 Hz, CeCF₂). ¹⁹F

NMR(CDCl₃, 282 MHz):

¼ꢁ92.05 (CF₂). IR (ATR, cm^ꢁ1):

¼3150 (w),

3081 (w), 3050 (w), 3022 (w), 2957 (w), 2923 (w), 2872 (w), 2854

(w), 1645 (w), 1601 (m), 1529 (w), 1497 (s), 1473 (w), 1463 (w), 1429

(w), 1416 (w), 1382 (m), 1327 (w), 1281 (s), 1244 (m), 1171 (m), 1153

(m), 1086 (m), 1072 (m), 1045 (s). MS (EI, 70 eV): m/z (%)¼234 ([M]^þ,

38), 233 (34), 213 (18), 194 (13), 193 (100), 77 (19). HRMS (EI, 70 eV):

calcd for C₁₃H₁₂F₂N₂([M]^þ) 234.09631, found 234.096137.

3.8.54. 3-(1,1-Diﬂuorobut-3-enyl)-5-methyl-1-phenyl-1H-pyrazole

(22b). Colourless oil isolated by preparative chromatography

(heptane); ¹H NMR (CDCl₃, 300 MHz):

¼2.33 (d, ⁶J_H,F¼0.6 Hz, 3H,

CH₃), 3.03e3.17 (m, ³J_H,F¼7.2 Hz, 2H, CH₂), 5.22e5.28 (m, 2H, CH₂),

5.83e5.96 (m, ⁴J_H,F¼7.0 Hz, 1H, CH), 6.37 (s, 1H, CH), 7.40e7.50 (m,

V.O. Iaroshenko et al. / Tetrahedron 67 (2011) 5663e5677

5677

469e480; (i) Iaroshenko, V. O.; Ostrovskyi, D.; Petrosyan, A.; Mkrtchyan, S.;

Villinger, A.; Langer, P. J. Org. Chem. 2011, 2899e2903.

Morales, T.; Woessner, R.; Randolph, N.; Lyssikatos, J.; Olivero, A. Bioorg. Med.

Chem. Lett. 2008, 18, 4692e4695.

16. (a) Osipov, S. N.; Burger, K. Tetrahedron Lett 2000, 41, 5659e5662; (b) Reutrakul,

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Chem. 2004, 69, 6913e6915; (c) Hagooly, Y.; Cohen, O.; Rozen, S. Tetrahadron

Lett. 2009, 50, 392e394.

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Tolmachev, A.; Langer, P. Synlett 2010, 2299e2303.

20. Purandare, A. V.; Chen, Z.; Huynh, T.; Pang, S.; Geng, J.; Vaccaro, W.; Poss, M. A.;

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18. Crystallographic data (excluding structure factors) for the structures reported in

thispaperhavebeendepositedwiththeCambridgeCrystallographicDataCentreas

supplementary publication CCDC-821637 (7b), CCDC-821639 (12f), CCDC-821638

(13d) and CCDC-821636 (16b) and can be obtained free of charge on application

to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: þ44(1223)336033; e-mail:

deposit@ccdc.cam.ac.uk, or via www.ccdc.cam.ac.uk/data_request/cif

19. Hansen, J. D.; Grina, J.; Newhouse, B.; Welch, M.; Topalov, G.; Littman, N.;

Callejo, M.; Gloor, S.; Martinson, M.; Laird, E.; Brandhuber, B. J.; Vigers, G.;

22. (a) Hall, A.; Billinton, A.; Bristow, A. K.; Brown, S. H.; Clayton, N. M.; Chowd-

hury, A.; Cutler, L.; Giblin, G. M. P.; Goldsmith, P.; Hayhow, T. G.; Kilford, I. R.;

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3392e3399.

23. Song, L.; Chu, Q.; Zhu, S. J. Fluorine Chem. 2001, 107, 107e112.

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Article abstract of DOI:10.1016/j.tet.2011.05.085

Full text of DOI:10.1016/j.tet.2011.05.085

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