Preparation of 3,4-Substituted-5-Aminopyrazoles and 4-Substituted-2-Aminothiazoles

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Article

Preparation of 3,4-substituted-5-aminopyrazoles

and 4-substituted-2-aminothiazoles.

Stepan Havel, Prashant Khirsariya, Naresh Akavaram, Kamil Paruch, and Benoit Jean-Pierre Carbain

J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02655 • Publication Date (Web): 21 Nov 2018

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Preparation of 3,4-substituted-5-aminopyrazoles and 4-substituted-2-aminothiazoles

†

,‡, #

Prashant Khirsariya,^†^,^‡Naresh Akavaram,^†^,^‡Kamil Paruch,^†^,^‡and Benoit

Stepan Havel,

†

,‡,#,*

Carbain

5

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†

‡

Department of Chemistry, CZ Openscreen, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.

International Clinical Research Center, St. Anne’s University Hospital Brno, Pekařská 53, 656 91 Brno, Czech Republic.

Abstract

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3-substituted-4-aryl-1H-pyrazol-5-amine

Pd-catalyzed

-arylation

R

N

R

O

R

O

cyclization

NH

Ar

CN

36 examples

Ar

CN

35 examples

NH₂

S

N

protection

borylation

R = Boc

R' = PMB

X = B(Pin)

NH₂

4-(hetero)aryl-thiazol-2-amine

Br

Suzuki

S

R

N

R'

coupling

S

NH₂

N

N-Boc-thiourea

condensation

N

X

deprotection

Ar

O

B

R = Boc

R' = PMB

X = B(MIDA)

21 examples

Br

O

protection

N

3,4-Substituted-5-aminopyrazoles and 4-substituted-2-aminothiazoles are frequently used

intermediates in medicinal chemistry and drug discovery projects. We report an expedient flexible

synthesis of 3,4-substituted-5-aminopyrazoles (35 examples), based on palladium-mediated α-

arylation of β-ketonitriles with aryl bromides. A library of 4-substituted-2-aminothiazoles (21

examples) was assembled by a sequence employing Suzuki coupling of newly prepared properly

protected pinacol ester and MIDA ester of 4-boronic acid-2-aminothiazole with (hetero)aryl halides.

Introduction

Heterocyclic 5-membered aromatic ring motifs can be found in numerous biologically active small

molecules. The 5-aminopyrazole scaffold has been used in compounds with diverse

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pharmacological activities, e.g. kinase inhibitors, antivirals, antifungals, etc. Likewise, the 2-

aminothiazole pharmacophore is an ubiquitous medicinal chemistry building block, employed in

several anticancer, neuroprotective and antiviral agents.²

Scheme 1: Typical synthetic approaches to 5-aminopyrazoles and 2-aminothiazoles.

O

N

R

N

N H

2

4

R

NH

4

R'

NH₂

S

O

R'

Br₂

H N NH₂

2

S

N

Br

NH₂

R

4

R'

R

5-Aminopyrazoles are generally synthesized from -ketonitriles and hydrazine (Scheme 1). α-

3

substituted β-ketonitriles can be prepared by several methods, e.g. cyanation of esters, electrophilic

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cyanation of silyl enol ethers or electrophilic cyanation of boron enolates. We envisioned that to

create a diverse library of 4-substituted-5-aminopyrazoles, a more expedient route would be based

on direct α-arylation of β-ketonitriles. Carbon nucleophiles, such as anions of active methylene

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compounds, can undergo copper-promoted α-arylation with aryl halides (the Hurtley reaction). This

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7b,8

copper-promoted α-arylation has been extensively used for β-diketones, esters and malonates,

and nitriles (cyanoacetates, malononitrile, arylnitriles).⁷^c^,⁸^e^,⁹Over the last three decades, palladium-

catalyzed α-arylations of β-diketones,¹⁰esters¹¹and nitriles¹²have been also reported. However,

analogous α-arylations of β-ketonitriles are very scarce: to our knowledge, only one example of

copper-mediated α-arylation of β-ketonitrile¹³and two substrate-specific arylations of β-ketonitriles

have been reported.¹⁴Of palladium-mediated arylations of β-ketonitriles, only two couplings with

benzoylacetonitrile and two specific electrophiles have been described in the literature.¹¹^b^,¹⁵Herein,

we report a modular palladium-catalyzed α-arylation of β-ketonitriles with a relatively broad substrate

scope.

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-Substituted-2-aminothiazoles are typically synthesized in 2 steps through bromination of ketones¹⁶

and subsequent condensation of the resulting α-bromoketones with thiourea¹⁷(Scheme 1).

However, in some cases, the desired ketones are not commercially available, or they are expensive.

Alternatively, the desired derivatization can be achieved on the already established thiazole ring via

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a metal-mediated cross-coupling (i.e. Sonogashira, Suzuki and Stille reactions) using properly

mono- or bis-protected/substituted 4-halothiazol-2-amines. Of note, the preparation of 4-boronic

acid-2-aminothiazole derivatives for ‘inverse’ Suzuki coupling with aryl halides has been reported

only in the patent literature.²¹Hereafter, we report the rapid and flexible synthesis of a library of 4-

(

hetero)aryl-2-aminothiazoles from 4-bromo-2-aminothiazole, which consists of protection,

borylation, Suzuki coupling and deprotection steps. The preparation of the heretofore unknown

protected 4-boronic acid MIDA ester-2-aminothiazole and its use in the Suzuki coupling with

(hetero)aryl halides, are also described.

RESULTS AND DISCUSSION

Synthesis of 3,4-substituted-5-aminopyrazoles. The synthesis of 3,4-substituted-5-

aminopyrazoles was achieved in three steps from commercially available esters and acetonitrile

(

Scheme 2). The synthesis commenced with the reaction of esters with acetonitrile in the presence

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of sodium hydride, yielding the corresponding β-ketonitriles. Then, we focused on the Pd-catalyzed

α-arylation of β-ketonitriles, allowing derivatization prior to the formation of the pyrazole ring.

Scheme 2: Synthetic route to 4-aryl-5-aminopyrazole derivatives.

.

N H H O

2

4

2

Pd(OAc)₂

ligand

CH SO H, EtOH

3

or AcOH

Cs CO

ArBr

N

NH

O

2

3

O

NaH

or HCl, EtOH

CN

NH₂

CH CN +

R

Oalkyl

R

3

THF

reflux

DMF

150 °C

reflux

Aryl

2a - 2aj

18 - 85 %

Aryl

1a - 1f

3a - 3ai

10 - 90 %

7

0 - 90 %

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Three different ligands were screened: PPh₃_,¹⁰^aXphos and tBuMePhos.¹⁰^bAs shown in Table 1

(entries 8, 19, 20, 22, 24 and 36), the reactions employing tBuMePhos provided the best yields. The

α-arylation was generally fast (reaction time ca. 30 min.) and provided the desired arylated

ketonitriles in moderate to good yields (Table 1). The panel of successfully coupled aryl bromide

substrates was relatively extensive (36 examples including bicyclic cores, electron poor/rich aromatic

systems and 4-bromopyridine). As demonstrated in Table 1 (entries 1 and 2), arylbromides proved

to be better coupling partners than the respective arylchlorides or iodides. α-arylations with 3-

bromothiophene, 5-bromopyrimidine were unsuccessful and in the particular case of 6-

bromoquinoline, the deacetylated product (i.e. 2-(quinolin-6-yl)acetonitrile) was isolated. The

pyrazole ring closure can be achieved using hydrazine hydrate in the presence of aqueous

hydrochloric acid in EtOH (entries 1, 3, 5, 6 and 30) or using a catalytic amount of methanesulfonic

acid in ethanol (in most cases). However, the latter protocol provided only low yields for substrates

possessing electron deficient aryls (Table 1, entries 3, 5, and 15). Moreover, in the cases of 4-

nitrophenyl- and 4-pyridyl-derivatives (Table 1, entries 4 and 36), only the deacetylated products,

i.e. 2-(4-nitrophenyl)acetonitrile and 2-(pyridin-4-yl)acetonitrile, were isolated. Unsuccessful

cyclization was also observed for hindered α-arylated β-arylacetonitriles (entries 34 and 35), in

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accordance to the report of Wei et al. Gratifyingly, when performing the cyclization in acetic acid,

the reaction yielded the desired aminopyrazoles (entries 4, 34 and 35), except for the 4-pyridyl-

derivative (entry 36). We reasoned that low-yielding/failed α-arylation coupling and cyclization

reactions, could be due to unwanted deacetylation of the α-arylated β-ketonitriles. This side reaction

would arise via addition of a nucleophile, e.g. dimethyl amine (from decomposition of DMF) or

hydrazine, to the ketone forming a tetrahedral intermediate which would collapse through a ‘retro-

_C_l_a_i_s_e_n_c_o_n_d_e_n_s_a_t_i_o_n_’_t_o_g_i_v_e_u_n_d_e_s_i_r_e_d_a_r_y_l_-_a_c_e_t_o_n_i_t_r_i_l_e_d_e_r_i_v_a_t_i_v_e_s₍_S_c_h_e_m_e₃₎_.23

Scheme 3: Possible mechanism for the deacetylation of the α-arylated β-ketonitriles (under basic

conditions).

'

retro Claisen condensation'

^-O Nu

O

CN

Aryl

CN

-

+

R

_N_u-

R

Nu

Aryl

Table 1: Conversion of β-ketonitriles to 4-aryl-5-aminopyrazoles: palladium-catalyzed α-arylation

and cyclization.

Pd(OAc)₂

(

a) tBuMePhos

or (b) PPh₃

or (c) XPhos

Cs CO

(d) CH SO H, EtOH

3

or (e) AcOH

or (f) HCl, EtOH

R

O

N

2

3

NH

CN

+

Aryl halide

CN

+

N2H4.H2O

R

Aryl

DMF

reflux

Aryl

2a - 2aj

^N^H2

150 °C

1a - 1f

3a - 3ai

α-arylated β-ketonitrile

Compound Yield (%)

aminopyrazole

entry

Compound

aryl halide

Yield

(%)

Compound

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X = I; 62^a

1

a

80^f

1

2

X

2a

X = Br; 70

3a

3b

R = CH

2

CH

3

a

X = Cl; 28

a

X = I; 38

1a

R = CH

X

F

2b

X = Br; 58

a

90^d

2

a

X = Cl; 0

d

1a

10

3

4

5

6

7

Br

CF3

NO2

2c

2d

2e

2f

70^a

3c

3d

3e

3f

f

R = CH

2

CH

3

85

₀d

1a

53^a

Br

e

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R = CH

1a

R = CH

75

35

d

f

N

26^a

60

1a

₄₆a

₁₆f

Br

COOH

R = CH

O

S

CH₃

1a

₄₃a

a

₇₀d

Br

2g

3g

R = CH

2

3

5

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3

4

1a

R = CH

b

c

85^d

8

9

OCH3

2h

3h

2

CH

0

1a

63^a

42^a

64^a

₄₅a

3i

3j

80^e

81^d

62^d

₆₃d

Br

OCF3

2i

2j

R = CH

2

CH

3

CH3

N

CH3

1a

10

R = CH

1a

1

Br

N

O

2k

3k

R = CH

O

S

NH

O

1a

CH3

2

2l

3l

R = CH

2

CH

3

Br

O

S

1a

₆₇a

₄₆d

1

3

N

2m

3m

R = CH

2

O

Br

S

Cl

O

1a

4

N

2n

55^a

3n

68^d

R = CH

2

CH

3

d

1a

R = CH

23

44

15

16

17

18

2o

2p

2q

2r

66^a

3o

3p

3q

3r

e

2

CH

3

Br

F

1a

₂₅a

₇₂d

O

Br

R = CH

1a

63^a

75^a

70^d

39^d

36^d

74^d

Br

R = CH

1a

R = CH

CF3

a

b

c

6

40

5

1a

19

2s

2t

3s

3t

Br

R = CH

6

COOCH3

a

b

1a

43

40

20

21

22

R = CH

Br

O

1a

R = CH

57^a

3u

56^e

N

2u

2

CH

3

a

1a

R = CH

76

63

2v

2w

2x

3v

3w

3x

52^d

22^d

52^d

b

2

CH

3

OCF3

OCH3

1a

23

66^a

R = CH

Br

a

c

1a

65

58

24

R = CH

Br

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OCH3

1

a

₅₄a

₅₇d

2

5

Br

2y

3y

R = CH

2

CH

3

OCH3

OH

1a

R = CH

2

6

7

2z

79^a

3z

64^d

2

CH

3

Br

1a

₂₇a

₆₅d

2

2aa

3aa

Br

F

R = CH

2

1

2

3

4

5

6

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

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8

9

0

1

2

3

4

5

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8

9

0

1

2

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4

5

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9

0

1

2

3

4

5

6

7

8

9

0

1a

28

2ab

2ac

50^a

3ab

3ac

36^d

R = CH

2

CH

3

Br

F3CO

Br

1a

₁₈a

₃₉f

29

R = CH

2

1b

30

Br

2ad

2ae

52^a

55^a

3ad

3ae

66^e

48^e

R =

1

c

d

e

31

32

33

F3C

1

63^a

3af

47^e

Br

2af

H3CO

R =

₅₄a

₆₂e

2ag

3ag

1

f

OCH3

d

0

3

Br

F

85^a

34

2ah

3ah

₃e

R =

1

O

S

CH3

₀d

Br

56^a

3

5

6

2ai

2aj

3ai

-

e

30

a

7

1

1a

Br

N

b

c

₀d,e,f

3

65

24

R = CH

; ^cXPhos; ^dCH H; ^eAcOH; HCl

SO

3 3

2 3

CH

a

tBuMePhos; ^bPPh

f

3

Synthesis of 4-substituted-2-aminothiazoles. Since (hetero)aryl halides are in general more

available and less expensive than the corresponding boronates, we envisioned assembling the

required library of 4-(hetero)aryl-2-aminothiazoles via Suzuki couplings where the thiazole would be

the boron-containing coupling partner. Our approach thus consists of the following steps: [1]

preparation of N,N-protected 4-bromo-2-aminothiazole, [2] boronate formation, [3] Suzuki coupling

and [4] deprotection.

First, appropriate protecting groups for the aminothiazole that would be stable to aqueous basic

conditions (Suzuki coupling) and easily removable at the end of the synthetic sequence, were

identified. Suzuki couplings were performed on differently N,N-protected 4-bromo-2-aminothiazoles

followed by deprotections (under acidic conditions). In our hands, di-Boc²⁴and di-ethoxymethyl²⁵

protection could not be achieved in high yield. On the other hand, the protection with a single Boc

group facilitated the second protection through alkylation of the aminothiazole moiety. The

combination of Boc and ethoxymethyl protecting groups was productive for the Suzuki coupling

(substrate 5a in Table 2), but the deprotection step was low yielding. Gratifyingly, the combination

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of Boc and PMB protecting groups proved to be more satisfactory, allowing clean Suzuki coupling

and deprotection reactions in high yields (substrate 5b in Table 2).

Table 2: Amino-protecting groups effects on Suzuki coupling and deprotection reactions.

Aryl boronic acid/ester

Pd(dppf)Cl₂

K PO

(a) HCl

EtOH, 90 °C

S

R

N

S

R

N

S

3

4

NH₂

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

N

Boc

DME/H O

N

Boc

or (b) TFA

70 °C

N

Br

2

Ar

80 °C

5

a - 5b

6a - 6c'

7a - 7c

Suzuki step

deprotection step

entry

1

Compound

aryl boronic acid/ester

Compound

Yield (%)

Compound

Yield (%)

O

5a

B

N

O

6a

88

7a

7b

18^a

₂₇a

₂₄a

85^b

R = EtOCH

2

O

N

O

5a

N

2

B

6b

88

R = EtOCH

2

5a

3

4

HO

N

6c

90

78

R = EtOCH

2

B

7c

N

5b

6c’

R = PMB

a

HCl, EtOH, 90 °C; ^bTFA, 70 °C

The next step consisted of the conversion of compound 5b into the corresponding boronic ester.

Since the latter was needed in a relatively large quantity, 5-bromo-2-aminothiazole, which is

significantly less expensive than the 4-bromo isomer, was protected (compound 9) and converted

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into compound 5b, via a halogen-dance reaction (Scheme 4).

Scheme 4: Synthetic routes to 4-(hetero)aryl-2-aminothiazole derivatives.

Boc O, DMAP

CH2Cl2, rt

2

Br

S

N

S

PMB

Boc

^N^H2

N

then

N

PMBCl, Cs CO

2

3

9

DMF, 80 °C

6

5 %

LDA, THF, - 78 °C

0 %

8

EtOCH Cl, DIPEA

2

CH Cl , 80 °C

5a: 92 %

2

S

N

R

N

S

R

N

PMBCl, Cs2CO3

DMF, 80 °C

5b: 99 %

R'

N

Boc

Br

Boc O

DMAP

2

R = R' = H

4: R = H, R' = Boc

5a: R = CH OCH CH

5b: R = PMB

2

3

CH Cl , rt

2

80 %

n-BuLi

iPrOBPin

THF, -78 °C

Aryl halide

Pd(dppf)Cl₂

K PO

S

PMB

3

4

N

or Pd(OAc)₂

B Pin

O

N

Boc

DME/H O

80 °C

B

2

O

8

PCy₃

dioxane, 90 °C

S

PMB

S

TFA

N

NH₂

N

Boc

70 °C

N

Ar

6d - 6q

7d - 7q

36 - 80 % (2 steps)

70 - 92 %

The borylation reaction was achieved either by lithium-halogen exchange or Miyaura reaction²⁶

(Scheme 4). Of note, isolation of the boronate 8 (using standard work-up and purification by flash

chromatography on silica gel) did not afford the completely pure substance. However, the Suzuki

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coupling of the crude boronate 8 with a variety of (hetero)aryl halides was productive (14 examples,

Table 3). For heteroaryl chlorides (entry 12-13), the sequence Miyaura borylation-Suzuki coupling

was more efficient than the sequence lithiation borylation-Suzuki coupling. Finally, the deprotection

in neat TFA afforded the targeted aminothiazoles 7d – 7q in high yields (Table 3).

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5

6

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7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

Table 3: Substrates and yields for the borylation-Suzuki coupling sequence and the deprotection.

(a) n-BuLi

iPrOBPin

THF, -78 °C

Aryl halide

^P^d⁽^d^p^p^f⁾^C^l2

S

PMB

Boc

S

PMB

Boc

S

PMB

Boc

S

K PO

3

TFA

4

N

NH₂

N

^o^r⁽^b⁾^P^d⁽^O^A^c⁾2

O

N

DME/H O

N

70 °C

N

Br

B

2

Ar

B Pin

2

80 °C

2

5b

O

8

6d - 6q

7d - 7q

PCy₃

dioxane, 90 °C

Borylation + Suzuki coupling steps

deprotection step

Compound

entry

aryl halide

Compound

Yield (%)

80

1

2

Br

OCH3

6d

70^a

7d

65^a

60^a

7e

7f

75

N

6e

6f

Br

3

N

4

5

Br

COOEt

6g

6h

64^a

65^a

7g

7h

89

75

S

Br

N

Br

6

6i

60^a

7i

92

CF3

N

7

8

Br

N

6j

71^a

36^a

7j

79

84

N

O

Br

6k

7k

N

Br

9

6l

65 ^b

60 ^b

7l

75

70

F

Br

N

10

6m

7m

N

1

6n

6o

80^b

7n

75

78

Br

N

a

3

65

0

12

7o

7p

b

Cl

N

a

b

O

37

1

3

4

6p

6q

75

80

75

(THP removed)

Cl

N

1

Cl

75^b

7q

N

a

lithiation borylation; ^bMiyaura borylation

Next, we focused on the synthesis of 4-boronic acid-2-aminothiazole MIDA ester,²⁷hoping that it

would be sufficiently stable for purification (and easier handling). The MIDA-protected bromomethyl

acylboronate was synthesized according to the published protocol from vinylboronic acid MIDA

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29

ester, and used for condensation with N-Boc-thiourea 10 to provide the thiazole 11 (Scheme 5).

Subsequent protection with p-methoxybenzyl chloride afforded the desired MIDA ester 12, which

was stable to purification on silica gel and could be stored for months at room temperature under

nitrogen (Scheme 5). The structure of 12 was unambiguously confirmed by X-ray crystallography

(

crystallographic data are given in the Supporting Information). As shown in Table 4, MIDA ester 12

0

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6

7

8

9

0

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2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

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0

was also successfully used for Suzuki couplings with various (hetero)aryl bromides (7 examples). Of

note, the Suzuki coupling of the mono-protected MIDA ester 11 was significantly less effective (entry

8), demonstrating the necessity of di-protection of the aminothiazole.

Scheme 5: Preparation of aminothiazole MIDA ester boronate 12 and the following steps.

O

B

O

R' =

R'-Br

O

N

PMBCl

S

^N^E^t3

S

N

Boc

NH

^C^s^C^O3

2

R

N

NH₂

CH CN

3

NaH

H

R'

7

6

0 °C

3 %

80 °C

71 %

(

Boc) O

R = H

0: R = Boc

11

2

THF

°C to rt

1

0

32 %

Aryl halide

Pd(dppf)Cl₂

K3PO4

S

PMB

Boc

S

N

PMB

Boc

TFA

S

N

NH₂

N

DME/H2O

70 °C

B

Ar

80 °C

O

12

6d, 6e, 6r - 6v'

40 - 74 %

7d, 7e, 7r - 7v

O

28 - 93 %

O

Table 4: Substrates and yields of the Suzuki coupling with MIDA ester 12 and the deprotection.

Aryl bromide

Pd(dppf)Cl₂

S

R

K PO

S

N

R

TFA

S

N

3

4

N

NH₂

N

O

N

Boc

DME/H2O

80 °C

Boc

70 °C

B

Ar

O

12

6d, 6e, 6r - 6v'

7d, 7e, 7r - 7v

O

Suzuki step

Compound

deprotection step

entry

R

aryl halide

Yield (%)

Compound

Yield (%)

1

2

3

PMB

Br

6r

71

65

71

7r

93

Br

OCH3

N

6d

6e

7d

7e

80

75

Br

N

4

PMB

6s

74

7s

81

N

O

N

H3CO

Br

5

6

PMB

6t

55

40

7t

28

51

N

6u

7u

Br

N

Br

7

8

PMB

H

6v

71

40

7v

-

84

-

N

6v’

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CONCLUSION

In summary, an efficient palladium-mediated α-arylation of β-ketonitriles with a broad panel of aryl

bromides (36 examples) has been developed. This methodology enables a convenient access to

3,4-disubstituted-5-aminopyrazoles in 3 steps from readily available esters and acetonitrile. The

synthesis of a library of 4-substituted-2-aminothiazoles was accomplished via effective preparation

of N-Boc-N-PMB-thiazole-2-amine-4-boronic esters and their successful use in palladium-mediated

cross-couplings (21 examples).

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EXPERIMENTAL SECTION

General information

All commercial reagents were obtained from Merck and Fluorochem and were of the highest

available purity. Unless stated otherwise, chemicals were used as supplied without further

purification. Anhydrous solvents were obtained from Acros and were stored under nitrogen. Unless

noted otherwise, the reactions were carried out in oven-dried glassware under atmosphere of

nitrogen or argon. The progress of reactions was monitored by thin layer chromatography and was

conducted on plates pre-coated with silica gel (Merck 60 F₂₅₄). Eluent mixture ratios are quoted as

volume:volume. Visualization was done either by short wave (254 nm) or long wave (366 nm)

ultraviolet light. Flash column chromatography was carried out using silica gel from Merck, (technical

grade, pore size 60 Å, 230-400 mesh particle size, 40-63 μm particle size). Elution gradients are

quoted as ratios between solvents at the start and end of the elution. Melting points were determined

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1

with a Stuart Scientific SMP40 apparatus and are uncorrected. H, C{ H}, and F{ H} nuclear

magnetic resonance (NMR) spectra were obtained as methanol-d , chloroform-d, or DMSO-d

4

6

solutions and recorded at 300 or 500 MHz, 75 or 125 MHz and 282 or 471 MHz respectively, on a

13

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Bruker Avance III 500 spectrometer. Where C{ H} NMR data are not quoted, insufficient material

was available or problems obtaining adequate spectra were encountered. Chemical shifts are quoted

in parts per million () referenced to the appropriate deuterated solvent employed. Multiplicities are

indicated by s (singlet), d (doublet), t (triplet), q (quartet), p (pentet), sept (septet), m (multiplet) or

(br) broad, or combinations thereof. Coupling constant values are given in Hz. Homonuclear and

heteronuclear two dimensional NMR experiments were used where appropriate to facilitate

assignment of chemical shifts. IR spectra were recorded on a Bruker ALPHA FT-IR spectrometer.

Solid samples were measured neat and oily samples as films. High resolution mass spectra were

performed on an Agilent 6224 Accurate-Mass TOF LC-MS instrument. A dual electro-spray (or

multimode ion source) in positive (or negative) mode was chosen for high-resolution MS analysis

and the operating parameters were set as follows: nitrogen flow 5 L; min at 350°C, nebulizer 40 psig,

fragmentor voltage of 30 V, skimmer voltage of 65 V, vaporizer (only in case of MMI) 200°C or

capillary voltage (only in case of dESI) of 4 kV.

General procedures

General procedure A: Preparation of ketonitriles with NaH

To a solution of the appropriate ester (1 eq) and acetonitrile (1.2 eq, unless stated otherwise) in

anhydrous THF (2 mL per 1 mmol of ester, unless stated otherwise) was added under nitrogen NaH

(60 % suspension in mineral oil, 1.2 eq, unless stated otherwise) and the mixture was refluxed for 2

hours (unless stated otherwise). The reaction mixture was cooled to 0 °C, quenched with a 2M

aqueous HCl until pH neutral and extracted with EtOAc (5 mL per 1 mmol of ester). The organic

extracts were washed with brine (5 mL per mmol of ester), dried over MgSO , filtered and the solvent

4

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was evaporated in vacuo. The crude material was purified by flash column chromatography on silica

gel.

General procedure B: Palladium-mediated arylation of -ketonitriles

To a mixture of the appropriate -ketonitrile (1 eq), the appropriate aryl halide (1.1 or 1.2 eq), Cs CO

2

3

0

1

2

3

4

5

6

7

8

9

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2

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4

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6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

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2

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2

3

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9

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(

3 eq), tBuMePhos (0.025 - 0.1 eq) or XPhos (0.1 eq) or PPh (0.1 eq) and Pd(OAc) (0.025 - 0.05

3

2

eq) was added DMF (3 mL per 1 mmol of the substrate). The mixture was degassed for 10 min by

bubbling N or Ar. The resulting reaction mixture was refluxed for 30 min at 150 °C (unless stated

2

otherwise). When cooled to rt, the crude mixture was filtered to remove the excess of Cs CO , and

2

3

the filtrate was poured to a solution of 0.1 M HCl (20 mL per 1 mmol of the substrate) (unless stated

otherwise) and then diluted with EtOAc (20 mL per 1 mmol of the substrate). The organic phase was

extracted and washed with H O (3 x 20 mL per 1 mmol of the substrate) and brine (3 x 20 mL per 1

2

mmol of the substrate). The organic phase was dried over MgSO , filtered and the solvent was

4

evaporated in vacuo. The residue was purified by flash column chromatography on silica gel.

General procedure C1: Pyrazole formation in presence of CH SO H

3

A mixture of the appropriate 2-substituted-3-oxopentanenitrile (1 eq), N H .H O (1.1 - 2 eq) and

2

4

2

CH SO H (0.1 – 0.3 eq) in absolute EtOH (5 mL per 1 mmol of the substrate) was refluxed for 3

3

hours (unless stated otherwise). When cooled to rt, the solvent was evaporated in vacuo and the

residue was quenched with a saturated aqueous solution of NaHCO (20 mL per 1 mmol of the

3

substrate) and extracted with EtOAc (20 mL per 1 mmol of the substrate) (unless stated otherwise).

The organic extracts were washed with brine (2 x 20 mL per 1 mmol of the substrate), dried over

MgSO , filtered and the solvent was removed in vacuo. The crude material was purified by flash

4

column chromatography on silica gel.

General procedure C2: Pyrazole formation in AcOH

A mixture of the appropriate 2-substituted-3-oxopentanenitrile (1 eq) and N H .H O (1.1 eq, unless

2

4

2

stated otherwise) in AcOH (4 mL per 1 mmol of substrate) was refluxed for 4 hours (unless stated

otherwise) under N . When cooled to rt, the reaction mixture was quenched with a saturated aqueous

2

solution of NaHCO (40 mL per 1 mmol of the substrate) and extracted with EtOAc (40 mL per 1

3

mmol of the substrate) (unless stated otherwise). The organic extracts were washed with H O (40

2

mL per 1 mmol of the substrate) and brine (40 mL per 1 mmol of the substrate), dried over MgSO₄,

filtered and the solvent was removed in vacuo. The crude material was purified by flash column

chromatography on silica gel.

General procedure C3: Pyrazole formation in HCl

A mixture of the appropriate 2-substituted-3-oxopentanenitrile (1 eq), N H .H O (5 eq) and HCl (35

2

4

2

%, 10 eq) in EtOH (4 mL per 1 mmol of substrate, unless stated otherwise) was refluxed for 2 hours

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(unless stated otherwise) under an atmosphere of nitrogen. Ethanol was evaporated. The crude was

dissolved in EtOAc (20 mL per 1 mmol of the substrate) and a saturated aqueous solution of NaHCO₃

(20 mL per 1 mmol of the substrate) was added. The organic extract was washed with brine (20 mL

per 1 mmol of the substrate), dried over MgSO , filtered and the solvent was removed in vacuo. The

4

crude material was purified by flash column chromatography on silica gel.

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General

procedure

D1:

Suzuki

coupling

with

tert-butyl

(4-bromothiazol-2-

yl)(ethoxymethyl)carbamate or tert-butyl (4-bromothiazol-2-yl)(4-methoxybenzyl)carbamate

To a solution of the appropriate (hetero)aryl boronic acid or ester (1.1 eq) in DME (10 mL per 1 mmol

of the substrate) and H O (2 mL per 1 mmol of the substrate) under an atmosphere of nitrogen, were

2

added tert-butyl (4-bromothiazol-2-yl)(ethoxymethyl)carbamate or tert-butyl (4-bromothiazol-2-yl)(4-

methoxybenzyl)carbamate (1 eq), K PO (3.0 eq) and Pd(dppf)Cl (0.03 eq unless stated otherwise).

3

4

2

The reaction mixture was stirred at 80 °C for 3 h, then diluted with water (20 mL per 1 mmol of the

substrate) and extracted with EtOAc (2 × 40 mL per 1 mmol of the substrate). The combined organic

extracts were washed with H O (15 mL per 1 mmol of the substrate) and brine (15 mL per 1 mmol

2

of the substrate), dried over MgSO , filtered, and concentrated under reduced pressure. The residue

4

was purified by column chromatography to provide the desired target compound.

General procedure D2: Suzuki coupling with tert-butyl (4-methoxybenzyl)(4-(4,4,5,5-

tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-2-yl)carbamate or tert-butyl (4-methoxybenzyl)(4-

(

6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)thiazol-2-yl)carbamate

To a solution of tert-butyl (4-methoxybenzyl)(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazol-

-yl)carbamate or tert-butyl (4-methoxybenzyl)(4-(6-methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-

2

yl)thiazol-2-yl)carbamate (1 eq) in DME (10 mL per 1 mmol of the substrate) and H O (2 mL per 1

2

mmol of the substrate) under an atmosphere of nitrogen, were added the appropriate (hetero)aryl

halide (1.1 eq), K PO (3.0 eq) and Pd(dppf)Cl (0.1 eq). The reaction mixture was stirred at 80 °C

3

4

2

for 3 h (unless stated otherwise), then diluted with water (20 mL per 1 mmol of the substrate), and

extracted with EtOAc (2 × 40 mL per 1 mmol of the substrate). The combined organic extracts were

washed with H O (15 mL per 1 mmol of the substrate) and brine (15 mL per 1 mmol of the substrate),

2

dried over MgSO , filtered, and concentrated under reduced pressure. The residue was purified by

4

column chromatography to provide the desired target compound.

General procedure E1: deprotection with HCl

To a solution of tert-butyl (ethoxymethyl)(4-substituted thiazol-2-yl)carbamate (1 eq) in ethanol (16

mL per 1 mmol of the substrate) was added aqueous 3 M HCl (1 mL per 1 mmol of the substrate).

The reaction mixture was stirred at 90 °C for 12 h (unless stated otherwise), then the solvent was

evaporated under reduced pressure. The residue was stirred with 7 M NH in MeOH (5 mL per 1

3

mmol of the substrate) at 25 °C for 2 hours, then the solvent was evaporated under reduced

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pressure. The residue was purified by column chromatography to provide the desired target

compound.

General procedure E2: deprotection with TFA

Trifluoroacetic acid (4 mL per 1 mmol of the substrate unless stated otherwise) was added to a tert-

butyl (4-methoxybenzyl)(4-substitutedthiazol-2-yl)carbamate (1 eq) and stirred at 70 °C for 2 h, then

the solvent was evaporated under reduced pressure. The residue was quenched with a saturated

aqueous solution of NaHCO (30 mL per 1 mmol of the substrate) and extracted with CH Cl or

0

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2

3

4

5

6

7

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9

0

3

2

EtOAc (2 × 50 mL per 1 mmol of the substrate). The combined organic extracts were dried over

MgSO , filtered, and concentrated under reduced pressure. The residue was purified by column

4

chromatography to provide the desired target compound.

3-oxopentanenitrile (1a).

Prepared according to general procedure A with methyl propionate (3.82 g, 43.3 mmol), acetonitrile

(

6.8 mL, 130 mmol) and NaH (60 % suspension in mineral oil, 3.47 g, 87 mmol) in anhydrous THF

25 mL). Column chromatography (hexane:EtOAc; 4:1). The product was obtained as a colorless oil

-1

3.5 g, 0.036 mmol, 90 %). R = 0.32 (Hexane:EtOAc; 2:1); IR (cm ) 3347, 3170, 2974, 2209, 2180,

f

1

1653, 1594, 1460, 1370, 1064, 667; H NMR (500 MHz, Chloroform-d):  (ppm) 1.10 (t, J = 7.2 Hz,

13

1

3

H), 2.62 (q, J = 7.2 Hz, 2H), 3.47 (s, 2H); C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.5, 31.7,

-

3

5.7, 114.0, 198.2; HRMS (APCI-TOF) m/z: [M-H] Calcd for C H NO 96.0455; Found 96.0462.

5

6

CAS registry No. [33279-01-5]. H and ¹³C NMR spectra were consistent with those previously

1

reported in the literature.³⁰^a

3-cyclohexyl-3-oxopropanenitrile (1b).

Prepared according to general procedure A with methyl cyclohexanecarboxylate (1 g, 7.03 mmol),

acetonitrile (0.44 mL, 8.44 mmol) and NaH (60 % suspension in mineral oil, 0.338 g, 8.44 mmol) in

anhydrous THF (15 mL). Column chromatography (hexane:EtOAc; 1:0 to 1:1). The product was

obtained as a yellow-brown oil (0.776 g, 5.131 mmol, 73 %).

or

n-BuLi (2.36 M solution in hexane, 2.57 ml, 6.08 mmol) was added under nitrogen to a solution of

acetonitrile (0.48 mL, 9.11 mmol) in anhydrous THF (5 mL) at -78 ºC. The reaction mixture was

stirred at at -78 ºC for 30 min, then a solution of methyl cyclohexanecarboxylate (0.432 g, 3.04 mmol)

in anhydrous THF (5 mL) was added dropwise and the mixture was stired at -78 ºC for 2 hrs. The

reaction mixture was quenched with saturated aqueous solution NH Cl (10 mL) and extracted with

4

CH Cl (3 x 75 mL). The organic extracts were dried over MgSO , filtered and the solvent was

2

4

evaporated in vacuo. The residue was purified by flash column chromatography on silica gel

(hexane:EtOAc; 1:0 to 1:1). The product was obtained as yellow-brown oil (0.45 g, 2.98 mmol, 98

-1

%

). R = 0.27 (Hexane:EtOAc; 4:1); IR (cm ) 2930, 2855, 1719, 1450, 1389, 1317, 1293, 1144, 1069,

f

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1003, 872, 719; H NMR (500 MHz, DMSO-d )  (ppm) 1.14 – 1.45 (m, 5H), 1.65 – 1.73 (m, 1H),

6

13

1

.77 – 1.86 (m, 2H), 1.85 – 1.96 (m, 2H), 2.55 (tt, J = 11.1, 3.5 Hz, 1H), 3.49 (s, 2H); C{ H} NMR

(

126 MHz, DMSO-d )  (ppm) 25.4, 25.7, 28.3, 30.4, 50.1, 114.1, 200.5; HRMS (APCI-MMI) m/z:

6

-

[M-H] Calcd for C H NO 150.0924; Found 150.0923.

9

12

CAS registry No. [62455-70-3]. H and ¹³C NMR spectra were consistent with those previously

1

reported in the literature.⁴^a

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-oxo-3-(4-(trifluoromethyl)phenyl)propanenitrile (1c).

Prepared according to general procedure A with methyl 4-(trifluoromethyl)benzoate (1 g, 4.90 mmol),

acetonitrile (0.306 mL, 5.88 mmol) and NaH (60 % suspension in mineral oil, 0.235 g, 5.88 mmol) in

anhydrous THF (15 mL). Column chromatography (hexane:EtOAc; 1:0 to 7:3). The product was

obtained as a light brown solid (0.85 g, 3.99 mmol, 81 %). R = 0.60 (Hexane:EtOAc; 1:1); mp= 43 -

f

-1

4

5 °C; IR (cm ) 2957, 2912, 1688, 1601, 1409, 1396, 1325, 1218, 1168, 1128, 1108, 1065, 1006,

1

9

30, 835, 768; H NMR (500 MHz, Chloroform-d)  (ppm) 4.13 (s, 2H), 7.80 (d, J = 8.2 Hz, 2H), 8.05

13

1

(

d, J = 8.1 Hz, 2H); C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 29.8, 113.3, 123.3 (q, J = 272.6

Hz), 126.4 (q, J = 3.7 Hz), 129.0, 136.1 (q, J = 33.3 Hz), 137.0, 186.6; ¹⁹F{ H} NMR (471 MHz,

1

-

Chloroform-d)  (ppm) - 63.40. HRMS (APCI-MMI) m/z: [M-H] Calcd for C H F NO 212.0329; Found

10

5 3

212.0327.

1

CAS registry No. [72682-94-5]. H NMR spectrum was consistent with that previously reported in the

literature.³⁰^b

3

-(4-methoxyphenyl)-3-oxopropanenitrile (1d).

Prepared according to general procedure A with methyl 4-methoxybenzoate (1 g, 6.02 mmol),

acetonitrile (0.38 mL, 7.72 mmol) and NaH (60 % suspension in mineral oil, 0.309 g, 7.72 mmol) in

anhydrous THF (15 mL). Column chromatography (hexane:EtOAc; 1:0 to 7:3). The product was

obtained as yellow solid (0.781 g, 4.458 mmol, 74 %). R = 0.50 (Hexane:EtOAc; 1:1); mp = 123 -

f

-1

1

26 °C; IR (cm ) 1680, 1596, 1577, 1512,1463, 1450, 1438, 1421, 1391, 1323, 1307, 1262, 1222,

1

169, 1119, 1024, 1011, 1000, 928, 845, 816, 770, 631, 604; H NMR (500 MHz, Chloroform-d) 

13

1

(ppm) 3.89 (s, 3H), 4.01 (s, 2H), 6.95 – 7.01 (m, 2H), 7.86 – 7.93 (m, 2H). C{ H} NMR (126 MHz,

Chloroform-d)  (ppm) 29.1, 55.8, 114.2, 114.5, 127.4, 131.1, 164.9, 185.6; HRMS (APCI-MMI) m/z:

−

[

M−H] Calcd for C H NO 174.0561; Found 174.0559.

10

8

2

CAS registry No. [3672-47-7]. H and ¹³C NMR spectra were consistent with those previously

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_r_e_p_o_r_t_e_d_i_n_t_h_e_l_i_t_e_r_a_t_u_r_e_.4a

3

-(4-(tert-butyl)phenyl)-3-oxopropanenitrile (1e).

Prepared according to general procedure A with methyl 4-(trifluoromethyl)benzoate (1 g, 5.2 mmol),

acetonitrile (0.33 mL, 6.2 mmol) and NaH (60 % suspension in mineral oil, 0.248 g, 6.2 mmol) in

anhydrous THF (15 mL). Column chromatography (hexane:EtOAc; 1:0 to 7:3). The product was

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obtained as yellow solid (0.74 g, 3.68mmol, 70 %). R = 0.60 (Hexane:EtOAc; 1:1); mp = 71 - 75 °C;

f

-1

IR (cm ) 2957, 2920, 2855, 1687, 1600, 1462, 1046, 1396, 1330, 1312, 1267, 1226, 1197, 1106,

1

005, 930, 911, 836, 720, 585; H NMR (500 MHz, Chloroform-d)  (ppm) 1.35 (s, 9H), 4.05 (s, 2H),

13

1

7.49 – 7.57 (m, 2H), 7.83 – 7.91 (m, 2H); C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 29.4, 31.1,

−

3

5.5, 114.1, 126.3, 128.6, 131.9, 159.0, 186.8; HRMS (APCI-MMI) m/z: [M−H] Calcd for C H NO

13

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200.1081; Found 200.1079.

CAS registry No. [39528-62-6]. H and ¹³C NMR spectra were consistent with those previously

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_r_e_p_o_r_t_e_d_i_n_t_h_e_l_i_t_e_r_a_t_u_r_e_.30c

3-(3-methoxynaphthalen-2-yl)-3-oxopropanenitrile (1f).

Prepared according to general procedure A with methyl 3-methoxy-2-naphthoate (0.62 g, 2.87

mmol), acetonitrile (0.45 mL, 8.6 mmol) and NaH (60 % suspension in mineral oil, (230 mg, 5.7

mmol) in anhydrous THF (5 mL). Column chromatography (hexane:EtOAc; 4:1). The product was

-1

obtained as a pale white solid (520 mg, 2.3 mmol, 80 %). mp = 152 - 153 °C; IR (cm ) 2252, 1676,

1

339, 1145, 759; H NMR (500 MHz, DMSO-d )  (ppm) 4.08 (s, 3H), 4.18 (s, 2H), 7.43 (m, 1H),

6

13

1

7.59 (m, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.90 (d, J = 8.2 Hz, 1H), 8.39 (s, 1H); C{ H} NMR (126 MHz,

DMSO-d )  (ppm) 34.1, 56.0, 107.0, 114.6, 125.2, 126.2, 126.7, 128.1, 129.6, 129.8, 133.5, 137.2,

6

+

1

55.3, 188.8; HRMS (APCI-TOF) m/z: [M+H] Calcd for C H NO 226.0862; Found 226.0867.

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3-oxo-2-phenylpentanenitrile (2a).

Prepared according to general procedure B with 3-oxopentanenitrile (100 mg, 1.05 mmol),

iodobenzene (257 mg, 1.26 mmol, 0.141 mL), Cs CO (1.027 g, 3.15 mmol), tBuMePhos (9 mg, 0.03

2

3

mmol) and Pd(OAc) (7 mg, 0.03 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc;

2

5:1 to 1:1). The product was obtained as a yellow solid (113 mg, 0.651 mmol, 62 %).

or

Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol),

bromobenzene (390 mg, 2.47 mmol, 0.26 mL), Cs CO (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06

2

3

mmol) and Pd(OAc) (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc;

2

5

:1 to 1:1). The product was obtained as a yellow solid (250 mg, 1.47 mmol, 70 %). R = 0.45

f

-1

1

(

Hexane:EtOAc; 7:3); mp = 56 - 57 °C; IR (cm ) 2248, 1725, 1455, 1198, 1100, 748, 695; H NMR

(300 MHz, Chloroform-d)  (ppm) 1.03 (t, J = 7.2 Hz, 3H), 2.46 – 2.78 (m, 2H), 4.71 (s, 1H), 7.32 –

7

1

.47 (m, 5H); ¹³C{ H} NMR (75 MHz, Chloroform-d)  (ppm) 7.6, 33.2, 50.6, 116.4, 128.0, 129.2,

1

+

-

29.6, 130.0, 199.5; HRMS (APCI-TOF) m/z: [M+H] Calcd for C H NO 174.0913; Found [M-H]

11

12

74.0913.

CAS registry No. [6277-02-7]. H and ¹³C NMR spectra were consistent with those previously

1

reported in the literature.³⁰^d

or

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Prepared according to general procedure B with 3-oxopentanenitrile (100 mg, 1.05 mmol),

chlorobenzene (142 mg, 1.26 mmol, 0.128 mL), Cs CO (1.027 g, 3.15 mmol), tBuMePhos (9 mg,

2

3

0

.03 mmol) and Pd(OAc) (7 mg, 0.03 mmol) in DMF (3 mL). The reaction mixture was refluxed for

2

5

h at 150 °C. Column chromatography (hexane:EtOAc; 5:1 to 1:1). The product was obtained as a

yellow solid (50 mg, 0.289 mmol, 28 %).

0

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-(4-fluorophenyl)-3-oxopentanenitrile (2b).

Prepared according to general procedure B with 3-oxopentanenitrile (100 mg, 1.03 mmol), 1-bromo-

-fluorobenzene (215 mg, 1.23 mmol), Cs CO (5.87 g, 18.4 mmol), tBuMePhos (16 mg, 0.05 mmol)

4

2

3

and Pd(OAc) (6 mg, 0.03 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 10:1 to

2

3

:1). The product was obtained as yellow-orange oil (112 mg, 0.6 mmol, 58 %). R = 0.35

f

-1

(

EtOAc:MeOH; 5:1); IR (cm ) 1730, 1632, 1604, 1460, 1419, 1350, 1228, 1161, 1103, 1068, 1016,

1

820; H NMR (500 MHz, Chloroform-d)  (ppm) 1.06 (t, J = 7.2 Hz, 3H). 2.56 – 2.74 (m, 2H), 4.68

1

(

s. 1H), 7.09 – 7.17 (m, 2H), 7.35 – 7.42 (m, 2H); ¹³C{ H} NMR (126 MHz, Chloroform-d)  (ppm)

7.7, 33.4, 49.8, 116.4, 116.8 (d, J = 22 Hz), 125.9 (d, J = 3.4 Hz), 139.9 (d, J = 8.3 Hz), 163.3 (d. J

-

= 249,6 Hz), 199.4; HRMS (ESI-MMI) m/z: [M-H] Calcd for C H FNO 190.0674; Found 190.0672.

11

9

or

Prepared according to general procedure B with 3-oxopentanenitrile (100 mg, 1.03 mmol), 1-fluoro-

-iodobenzene (275 mg, 1.23 mmol), Cs CO (5.87 g, 18.4 mmol), tBuMePhos (16 mg, 0.05 mmol)

4

2

3

and Pd(OAc) (6 mg, 0.03 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 10:1 to

2

3:1). The product was obtained as yellow-orange oil (75 mg, 0.4 mmol, 38 %).

3-oxo-2-(4-(trifluoromethyl)phenyl)pentanenitrile (2c).

Prepared according to general procedure B with 3-oxopentanenitrile (0.156 g, 1.60 mmol), 1-bromo-

-(trifluoromethyl)benzene (0.365 g, 0.244 ml, 1.77 mmol), Cs CO (1.57 g, 4.82 mmol), tBuMePhos

4

2

3

(

50 mg, 0.16 mmol) and Pd(OAc) (9 mg, 0.04 mmol) in DMF (6 mL). Column chromatography

2

(hexane:EtOAc; 1:0 to 2:1). The product was obtained as a yelow solid (0.273 g, 1.13 mmol, 70 %);

-1

1

R = 0.21 (hexane:EtOAc; 2:1); mp = 75 - 78 °C; IR (cm ) 2219, 1613, 1323, 1113, 838, 538; H

f

NMR (500 MHz, Chloroform-d)  (ppm) 1.33 (t, J = 7.6 Hz, 3H), 2.73 (q, J = 7.6 Hz, 2H), 6.69 (s,

13

1

H), 7.67 (s, 4H); C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.9, 50.3, 115.9, 124.1 (q, J

= 272.1 Hz), 126.4 (q, J = 3.6 Hz), 126.8 (q, J = 3.7 Hz), 128.7, 128.7, 198.7; ¹⁹F{ H} NMR (471

1

-

MHz, Chloroform-d)  (ppm) -62.8; HRMS (APCI-TOF) m/z: [M-H] Calcd for C H F NO 240.0642;

12

9 3

Found 240.0642.

2-(4-nitrophenyl)-3-oxopentanenitrile (2d).

Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 4-

bromonitrobenzene (0.5 g, 2.5 mmol), Cs CO (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06 mmol)

2

3

and Pd(OAc) (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 4:1 to

2

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2:1). The product was obtained as a brown solid (0.24 g, 1.1 mmol, 53 %). R = 0.2 (EtOAc); mp =

f

-1

1

8

0 - 81 °C; IR (cm ) 2225, 1598, 1509,1334, 1107, 830, 732; H NMR (500 MHz, Chloroform-d) 

ppm) 1.11 (t, J = 7.2 Hz, 3H), 2.68 – 2.85 (m, 2H), 4.80 (s, 1H), 7.60 – 7.63 (m, 2H), 8.28 – 8.35

(

13

1

(m, 2H); C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 34.2, 50.1, 115.6, 124.8, 129.4, 136.7,

-

1

48.7, 198.0; HRMS (APCI-TOF) m/z: [M-H] Calcd for C H N O 217.0619; Found 217.0618.

11

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4-(1-cyano-2-oxobutyl)benzonitrile (2e).

Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 4-

bromobenzonitrile (450 mg, 2.4 mmol), Cs CO (1.95 g, 6.3 mmol), tBuMePhos (19 mg,0.06 mmol)

2

3

and Pd(OAc) (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 5:1 to

2

1:1). The product was obtained as a brown wax (110 mg, 0.55 mmol, 26 %). R = 0.10

f

-1

1

(

hexane:EtOAc; 1:1); IR (cm ) 2224, 2196, 1727, 1656, 1583, 1398, 1066, 1012, 821, 539; H NMR

(

500 MHz, DMSO-d )  (ppm) 1.11 (t, J = 7.2 Hz, 3H), 2.67 – 2.84 (m, 2H), 4.76 (s, 1H), 7.52 – 7.58

6

(m, 2H), 7.74 – 7.78 (m, 2H); ¹³C{ H} NMR (500 MHz, DMSO-d )  (ppm) 7.8, 34.1, 50.3, 113.7,

1

6

-

1

15.6, 118.0, 129.1, 133.4, 134.9, 198.2; HRMS (APCI-TOF) m/z: [M-H] Calcd for C H N O

12

9

2

197.0720; Found 197.0719.

4-(1-cyano-2-oxobutyl)benzoic acid (2f).

Prepared according to general procedure B with 3-oxopentanenitrile (0.21 g, 2.16 mmol), 4-

bromobenzoic acid (0.478 g, 2.38 mmol), Cs CO (2.82 g, 8.65 mmol), tBuMePhos (68 mg, 0.216

2

3

mmol) and Pd(OAc)₂(24 mg, 0.108 mmol) in DMF (6 mL). Column chromatography

(hexane:EtOAc:AcOH; 66:33:0.05 to 0:100:0.05). The product was obtained as a pale orange solid

-1

(

0.218 g, 1 mmol, 46 %). R = 0.74 (EtOAc:AcOH; 100:1); mp = 138 - 142 °C; IR (cm ) 2222, 1682,

f

1

602, 1423, 1383, 1368, 1318, 1282, 1242, 1187, 1070, 939, 859, 772, 751, 730; H NMR (500 MHz,

DMSO-d )  (ppm) 1.24 (t, J = 7.6 Hz, 3H), 2.64 (q, J = 7.6 Hz, 2H), 7.73 – 7.80 (m, 2H), 7.90 – 7.95

6

13

1

(

m, 2H), 12.04 (s, 1H), 12.69 (s, 1H); C{ H} NMR (126 MHz, DMSO-d )  (ppm) 12.2, 29.0, 85.3,

6

-

1

20.1, 126.6, 128.0, 129.4, 137.3, 166.9, 175.4; HRMS (APCI-MMI) m/z: [M-H] Calcd for C H NO

12 10

3

216.0666; Found 216.0665.

2-(4-(methylsulfonyl)phenyl)-3-oxopentanenitrile (2g).

Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 4-

bromophenyl methyl sulfone (0.58 g, 2.5 mmol), Cs CO (1.95 g, 6.3 mmol), tBuMePhos (19 mg,

2

3

0.06) and Pd(OAc) (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc;

2

:1 to 0:1). The product was obtained as a brown solid (0.22 g, 0.88 mmol, 43 %). R = 0.4

f

-1

(

hexane:EtOAc; 7:3); mp = 81 - 82 °C; IR (cm ) 3204, 3014, 2929, 2214, 1695, 1588, 1299, 1142,

1

1066, 960, 763, 525; H NMR (500 MHz, Chloroform-d)  (ppm) 1.09 (t, J = 7.2 Hz, 3H), 2.67 – 2.79

13

1

(

m, 2H), 3.08 (s, 3H), 4.81 (s, 1H), 7.60 – 7.65 (m, 2H), 8.00 – 8.04 (m, 2H); C{ H} NMR (126 MHz,

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Chloroform-d)  (ppm) 7.8, 34.2, 44.7, 50.2, 115.8, 128.8, 129.4, 136.0, 141.8, 198.3; HRMS (APCI-

-

TOF) m/z: [M-H] Calcd for C H NO S 250.0543; Found 250.0543.

12

3

2-(4-methoxyphenyl)-3-oxopentanenitrile (2h).

Prepared according to general procedure B with 3-oxopentanenitrile (0.197 g, 2.03 mmol), 4-

bromoanisole (0.379 g, 0.25 mL, 2.03 mmol), Cs CO (1.98 g, 6.08 mmol), tBuMePhos (63 mg, 0.2

0

1

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2

3

mmol) and Pd(OAc) (11 mg, 0.05 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc;

2

1

:0 to 1:1). The product was obtained as a pale yellow solid (0.221 g, 1.09 mmol, 54 %). R = 0.43

f

-1

(

hexane:EtOAc; 2:1); mp = 95 - 97 °C; IR (cm ) 2246, 1727, 1508, 1260, 1175, 1026, 814, 798, 551;

¹H NMR (500 MHz, Chloroform-d)  (ppm) 1.06 (t, J = 7.2 Hz, 3H), 2.60 (q, J = 7.2 Hz, 1H), 2.66 (q,

J = 7.2 Hz, 1H), 3.84 (s, 3H), 4.64 (s, 1H), 6.94 – 6.98 (m, 2H), 7.29 – 7.34 (m, 2H); ¹³C{ H} NMR

1

(126 MHz, Chloroform-d)  (ppm) 7.8, 33.1, 50.0, 55.6, 115.2, 116.7, 122.0, 129.3, 160.4, 199.9;

-

HRMS (APCI-TOF) m/z: [M-H] Calcd for C H NO 202.0874; Found 202.0875.

12

2

or

Prepared according to general procedure B with 3-oxopentanenitrile (0.225 g, 2.32 mmol), 4-

bromoanisole (0.5 g, 0.35 mL, 2.8 mmol), Cs CO (1.5 g, 4.6 mmol), XPhos (35 mg, 0.07 mmol) and

2

3

Pd(OAc) (16 mg, 0.07 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 1:0 to 1:1).

2

The product was obtained as a pale yellow solid (0.145 g, 0.7 mmol, 30 %).

or

Prepared according to general procedure B with 3-oxopentanenitrile (0.175 g, 1.8 mmol), 4-

bromoanisole (0.371 g, 0.25 mL, 1.98 mmol), Cs CO (1.76 g, 5.41 mmol), PPh (47 mg, 0.18 mmol)

2

3

and Pd(OAc) (10 mg, 0.045 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc; 1:0 to

2

1:1). The product was obtained as a pale yellow solid (0.095 g, 0.47 mmol, 23 %).

3-oxo-2-(4-(trifluoromethoxy)phenyl)pentanenitrile (2i).

Prepared according to general procedure B with 3-oxopentanenitrile (0.215 g, 2.21 mmol), 1-bromo-

-(trifluoromethoxy)benzene (0.587 g, 0.362 mL, 2.43 mmol), Cs CO (2.16 g, 6.64 mmol),

4

2

3

tBuMePhos (69 mg, 0.22 mmol) and Pd(OAc) (25 mg, 0.11 mmol) in DMF (6 mL). Column

2

chromatography (hexane:EtOAc; 1:0 to 1:1). The product was obtained as a brown wax (0.361 g,

-1

1

.40 mmol, 63 %). R = 0.31 (hexane:EtOAc; 2:1); IR (cm ) 3111, 2219, 1631, 1508, 1363, 1259,

f

1

204, 1151, 1069, 835, 760; H NMR (500 MHz, Chloroform-d)  (ppm) 1.07 (t, J = 7.2 Hz, 3H), 2.64

(dq, J = 18.6, 7.2 Hz, 1H), 2.73 (dq, J = 18.7, 7.2 Hz, 1H), 4.69 (s, 1H), 7.27 – 7.31 (m, 2H), 7.42 –

13

1

7.47 (m, 2H); C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.7, 33.6, 49.8, 116.1, 120.50 (q, J =

19

1

2

59.3 Hz), 122.0, 128.6, 129.7, 150.0, 199.0; F{ H} NMR (471 MHz, Chloroform-d)  (ppm) -57.90;

-

HRMS (APCI-TOF) m/z: [M-H] Calcd for C H F NO 256.0591; Found [M-H] 256.0590.

12

9

3

2

2-(4-(dimethylamino)phenyl)-3-oxopentanenitrile (2j).

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Prepared according to general procedure B with 3-oxopentanenitrile (0.205 g, 2.11 mmol), 4-bromo-

N,N-dimethylaniline (0.465 g, 2.32 mmol), Cs CO (2.06 g, 6.33 mmol), tBuMePhos (66 mg, 0.21

2

3

mmol) and Pd(OAc) (12 mg, 0.053 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc;

2

1

:0 to 1:1). The product was obtained as a pale orange solid (0.193 g, 0.89 mmol, 42 %). R = 0.36

f

-1

(

hexane:EtOAc; 2:1); mp = 109 - 110 °C; IR (cm ) 2979, 2900, 2245, 1720, 1610, 1523, 1446, 1365,

1

0

1

2

3

4

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6

7

8

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0

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0

1

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2

3

4

5

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7

8

9

0

1336, 1233, 1209, 1196, 1169, 1120, 1100, 1067, 949, 804, 789, 678; H NMR (500 MHz,

Chloroform-d)  (ppm) 1.02 (t, J = 7.2 Hz, 3H), 2.53 (dq, J = 18.5, 7.3 Hz, 1H), 2.64 (dq, J = 18.3,

_.₂_H_z_,₁_H₎_,₂_.₉₈₍_s_,₆_H₎_,₄_.₅₈₍_s_,₁_H₎_,₆_.₇₄₍_d_,_J₌₈_.₇_H_z_,₂_H₎_,₇_.₂₁₍_d_,_J₌₈_.₉_H_z_,₂_H₎_;13C{ H}

1

7

NMR (126 MHz, Chloroform-d)  (ppm) 7.9, 32.9, 40.6, 50.1, 113.3, 117.0, 128.9, 150.7, 200.3;

+

HRMS (APCI-MMI) m/z: [M+H] Calcd for C H N O 217.1335; Found 217.1338.

13

17

2

-(4-morpholinophenyl)-3-oxopentanenitrile (2k).

Prepared according to general procedure B with 3-oxopentanenitrile (0.171 g, 1.76 mmol), 1-bromo-

-chloro-4-fluorobenzene (0.406 g, 0.236 mL, 1.94 mmol), Cs CO (1.72 g, 5.28 mmol), tBuMePhos

3

2

3

(

55 mg, 0.18 mmol) and Pd(OAc) (10 mg, 0.044 mmol) in DMF (6 mL). No work-up, after filtration

2

the filtrate was evaporated and the residue was loaded on silica gel. Column chromatography

(hexane:EtOAc; 1:0 to 1:1). The product was obtained as an orange solid (0.293 g, 1.13 mmol, 64

-1

%

). R = 0.10 (hexane:EtOAc; 2:1); mp = 134 - 136 °C; IR (cm ) 2972, 2850, 2833, 2247, 1719,

f

1

606, 1519, 1448, 1385, 1351, 1268, 1239, 1168, 1113, 1068, 1049, 925, 824; H NMR (500 MHz,

Chloroform-d)  (ppm) 1.03 (t, J = 7.2 Hz, 3H), 2.54 (dq, J = 18.5, 7.2 Hz, 1H), 2.65 (dq, J = 18.5,

7.2 Hz, 1H), 3.15 – 3.22 (m, 4H), 3.82 – 3.89 (m, 4H), 4.60 (s, 1H), 6.91 (d, J = 8.9 Hz, 2H), 7.26 (d,

J = 8.9 Hz, 2H); ¹³C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.0, 48.8, 50.0, 66.8, 116.1,

1

+

1

16.8, 120.6, 129.0, 151.8, 200.0; HRMS (APCI-MMI) m/z: [M+H] Calcd for C H N O 259.1441;

15

19

2

Found 259.1448.

N-(4-(1-cyano-2-oxobutyl)phenyl)methanesulfonamide (2l).

Prepared according to general procedure B with 3-oxopentanenitrile (0.18 g, 1.85 mmol), N-(4-

bromophenyl)methanesulfonamide (0.51 g, 2.04 mmol), Cs CO (1.81 g, 5.56 mmol), tBuMePhos

2

3

(

58 mg, 0.185 mmol) and Pd(OAc) (21 mg, 0.093 mmol) in DMF (6 mL). Column chromatography

2

(hexane:EtOAc; 1:0 to 1:4). The product was obtained as an orange oil (0.224 g, 0.84 mmol, 45 %).

-1

R = 0.20 (hexane:EtOAc; 1:1); (cm ) 3273, 1680, 1601, 1510, 1448, 1395, 1318, 1296, 1238, 1145,

f

1

9

2

1

72, 908, 771, 754, 696; H NMR (500 MHz, Chloroform-d)  (ppm) 1.06 (t, J = 7.2 Hz, 3H), 2.57 –

.74 (m, 2H), 3.05 (s, 3H), 4.68 (s, 1H), 7.03 (s, 1H), 7.28 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.8 Hz,

13

1

H); C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.7, 33.6, 40.0, 49.9, 116.4, 121.0, 126.6, 129.6,

-

38.1, 199.4; HRMS (APCI-MMI) m/z: [M-H] Calcd for C H N O S 265.0652; Found 265.0652.

12

13

2

3

2-(4-(morpholinosulfonyl)phenyl)-3-oxopentanenitrile (2m).

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Prepared according to general procedure B with 3-oxopentanenitrile (0.1 g, 1 mmol), 4-[(4-

bromophenyl)sulfonyl]morpholine (0.26 g, 0.85 mmol), Cs CO (0.98 g, 3 mmol), tBuMePhos (16

2

3

mg, 0.05 mmol) and Pd(OAc) (12 mg, 0.05 mmol) in DMF (3 mL). Column chromatography

2

(hexane:EtOAc; 2:1 to 0:1). The product was obtained as a yellow wax (0.19 g, 0.57 mmol, 67 %).

1

R = 0.44 (hexane:EtOAc; 7:3); H NMR (500 MHz, Chloroform-d)  (ppm) 1.10 (t, J = 7.2 Hz, 3H),

f

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

2.65 – 2.86 (m, 2H), 3.02 – 3.08 (m, 4H), 3.74 – 3.77 (m, 4H), 4.78 (s, 1H), 7.58 – 7.65 (m, 2H), 7.81

13

1

–

7.84 (m, 2H); C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.5, 34.0, 45.9, 50.0, 66.1, 115.6,

+

1

28.9, 129.0, 134.9, 136.7, 198.1; HRMS (APCI-TOF) m/z: [M+H] Calcd for C H N O S 323.1060;

15

19

2

4

Found 323.1057.

3-oxo-2-(4-(piperidin-1-ylsulfonyl)phenyl)pentanenitrile (2n).

Prepared according to general procedure B with 3-oxopentanenitrile (100 mg, 1 mmol), 1-[(4-

bromophenyl)sulfonyl]piperidine (300 mg, 1 mmol), Cs CO (0.98 g, 3 mmol), tBuMePhos (16 mg,

2

3

0.05 mmol) and Pd(OAc)₂(12 mg, 0.05 mmol) in DMF (3 mL). Column chromatography

(hexane:EtOAc; 2:1 to 0:1). The product was obtained as a yellow wax (170 mg, 0.55 mmol, 55 %).

-1

1

R = 0.45 (hexane:EtOAc; 7:3); IR (cm ) 2201, 1687, 1337, 1161, 925, 737, 577; H NMR (500 MHz,

f

Chloroform-d)  (ppm) 1.08 (t, J = 7.2 Hz, 3H), 1.40 – 1.49 (m, 2H), 1.61 – 1.70 (m, 4H), 2.63 – 2.82

_m_,₂_H₎_,₂_.₉₇_–₃_.₀₅₍_m_,₄_H₎_,₄_.₇₉₍_s_,₁_H₎_,₇_.₅₅_–₇_.₆₀₍_m_,₂_H₎_,₇_.₈₀_–₇_.₈₃₍_m_,₂_H₎_;13C{1H} NMR

(

126 MHz, Chloroform-d)  (ppm) 7.8, 23.6, 25.4, 34.1, 47.1, 50.2, 115.9, 128.9, 129.0, 134.6, 138.0,

+

1

98.5; HRMS (APCI-TOF) m/z: [M+H] Calcd for C H N O S 321.1267; Found 321.1267.

16

21

2

3

2-(3-chloro-4-fluorophenyl)-3-oxopentanenitrile (2o).

Prepared according to general procedure B with 3-oxopentanenitrile (0.171 g, 1.76 mmol), 1-bromo-

-chloro-4-fluorobenzene (0.406 g, 0.236 mL, 1.94 mmol), Cs CO (1.72 g, 5.28 mmol), tBuMePhos

3

2

3

(

55 mg, 0.18 mmol) and Pd(OAc) (10 mg, 0.044 mmol) in DMF (6 mL). Column chromatography

2

(hexane:EtOAc; 1:0 to 2:1). The product was obtained as yellow wax (0.262 g, 1.16 mmol, 66 %). R_f

-

1

=

1

0.31 (hexane:EtOAc; 2:1); IR (cm ) 2979, 2205, 1733, 1701, 1620, 1591, 1530, 1499, 1463, 1350,

1

260, 1228, 1139, 1111, 1062, 945, 881, 822, 768, 710; H NMR (500 MHz, Chloroform-d)  (ppm)

.08 (t, J = 7.2 Hz, 3H), 2.60 – 2.80 (m, 2H), 4.63 (s, 1H), 7.21 (dd, J = 8.5, 8.5 Hz, 1H), 7.28 (ddd,

J = 8.7, 4.4, 2.4 Hz, 1H), 7.46 (dd, J = 6.6, 2.4 Hz, 1H); ¹³C{ H} NMR (126 MHz, Chloroform-d) 

1

(ppm) 7.7, 33.7, 49.3, 115.9, 117.9 (d, J = 21.8 Hz), 122.7 (d, J = 19.1 Hz), 127.0 (d, J = 4.5 Hz),

19

1

28.0 (d, J = 7.3 Hz), 130.5, 158.7 (d, J = 252.5 Hz), 198.7; F{ H} NMR (471 MHz, Chloroform-d)

-



(ppm) -113.68; HRMS (APCI-TOF) m/z: [M-H] Calcd for C H ClFNO 224.0284; Found 224.0283.

11

8

2-(benzo[d][1,3]dioxol-5-yl)-3-oxopentanenitrile (2p).

Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 5-bromo-

,3-benzodioxole (0.5 g, 0.3 mL, 2.5 mmol), Cs CO (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06

1

2

3

mmol) and Pd(OAc) (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc;

2

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2:1). The product was obtained as a yellow solid (0.15 g, 0.67 mmol, 25 %). R = 0.5 (hexane:EtOAc;

f

-1

1

2

:1); IR (cm ) 2248, 1724, 1466, 1240, 1032, 807; H NMR (500 MHz, Chloroform-d)  (ppm) 1.06

13

1

(

t, J = 7.2 Hz, 3H), 2.54 – 2.73 (m, 2H), 4.59 (s, 1H), 6.01 (s, 2H), 6.82 – 6.88 (m, 3H); C{ H} NMR

(126 MHz, Chloroform-d)  (ppm) 7.9, 33.2, 50.4, 102.0, 108.4, 109.3, 116.6, 122.0, 123.6, 148.7,

-

1

49.0, 199.7; HRMS (APCI-TOF) m/z: [M-H] Calcd for C H NO 216.0666; Found 216.0666.

12

10

3

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-3-oxopentanenitrile (2q).

Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 6-bromo-

2,3-dihydro-1,4-benzodioxine (0.53 g, 0.33 mL, 2.5 mmol), Cs CO (1.95 g, 6.3 mmol), tBuMePhos

2

3

(

19 mg, 0.06 mmol) and Pd(OAc) (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography

2

(hexane:EtOAc; 2:1). The product was obtained as a yellow solid (0.3 g, 1.3 mmol, 63 %). R = 0.5

f

-1

1

(

hexane:EtOAc; 2:1); mp = 86 - 88 °C; IR (cm ) 2218, 1626, 1508, 1344, 1283, 1063, 858, 749; H

NMR (300 MHz, Chloroform-d)  (ppm) 1.28 (t, J = 7.6 Hz, 3H), 2.47 – 2.83 (m, 2H), 4.29 (s, 4H),

13

1

6.25 (s, 1H), 6.77 – 7.05 (m, 3H); C{ H} NMR (75 MHz, Chloroform-d)  (ppm) 7.8, 33.1, 50.1, 64.5,

-

6

4.5, 116.6, 117.1, 118.5, 121.1, 123.0, 144.5, 144.6, 199.7; HRMS (APCI-TOF) m/z: [M-H] Calcd

for C H NO 230.0823; Found 230.0824.

13

12

3

2-(naphthalen-2-yl)-3-oxopentanenitrile (2r).

Prepared according to general procedure B with 3-oxopentanenitrile (0.176 g, 1.81 mmol), 2-

bromonaphtalene (0.413 g, 2 mmol), Cs CO (1.77 g, 5.44 mmol), tBuMePhos (57 mg, 0.18 mmol)

2

3

and Pd(OAc) (10 mg, 0.045 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc; 10:1

2

to 1:1). The product was obtained as a pale orange solid (0.304 g, 1.36 mmol, 75 %). R = 0.37

f

-1

(

hexane:EtOAc; 2:1); mp = 94 - 96 °C; IR (cm ) 3365, 3184, 3140, 3075, 2957, 2923, 2855, 1631,

1601, 1585, 1522, 1491, 1463, 1444, 1343, 1115, 1044, 1025, 944, 889, 860, 822, 794, 746, 729;

¹H NMR (500 MHz, Chloroform-d)  (ppm) 1.04 (t, J = 7.2 Hz, 3H), 2.62 (dq, J = 18.6, 7.2 Hz, 1H),

2.73 (dq, J = 18.6, 7.2 Hz, 1H), 4.85 (s, 1H), 7.44 (dd, J = 8.5, 2.1 Hz, 1H), 7.52 – 7.59 (m, 2H), 7.83

1

3

1

–

1

7.89 (m, 2H), 7.89 – 7.94 (m, 2H); C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.3, 51.0,

16.5, 124.9, 127.3, 127.3, 127.4, 127.7, 128.0, 128.2, 129.8, 133.4, 133.5, 199.6; HRMS (APCI-

+

TOF) m/z: [M+H] Calcd for C H NO 224.1070; Found 224.1072.

15

14

3-oxo-2-(3-(trifluoromethyl)phenyl)pentanenitrile (2s).

Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 1-bromo-

3

-(trifluoromethyl)benzene (0.55 g, 0.35 ml, 2.5 mmol), Cs CO (1.95 g, 6.3 mmol), tBuMePhos (19

2 3

mg, 0.06 mmol) and Pd(OAc) (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography

2

(hexane:EtOAc; 2:1). The product was obtained as a yelow oil (320 mg, 1.37 mmol, 65 %).

or

Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 1-bromo-

3

-(trifluoromethyl)benzene (0.55g, 0.35 ml, 2.5 mmol), Cs CO (1.95 g, 6.3 mmol), XPhos (28 mg,

2 3

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0.06 mmol) and Pd(OAc)₂(14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography

hexane:EtOAc; 2:1). The product was obtained as a yelow oil (282 mg, 1.17 mmol, 56 %).

(

or

Prepared according to general procedure B with 3-oxopentanenitrile (168 mg, 1.73 mmol), 1-bromo-

3

-(trifluoromethyl)benzene (0.43 g, 0.27 ml, 1.9 mmol), Cs CO (1.7 g, 5.2 mmol), PPh (44 mg, 0.17

2 3 3

0

1

2

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7

8

9

0

1

2

3

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7

8

9

0

1

2

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9

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8

9

0

1

2

3

4

5

6

7

8

9

0

mmol) and Pd(OAc) (22 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc;

2

-

1

2

1

3

:1). The product was obtained as a yelow oil (170 mg, 0.69 mmol, 40 %). IR (cm ) 2209, 1731,

1

629, 1165, 1121, 1074, 800, 698; H NMR (500 MHz, Chloroform-d)  (ppm) 1.10 (t, J = 7.2 Hz,

H), 2.85 – 2.59 (m, 2H), 4.75 (s, 1H), 7.64 – 7.57 (m, 2H), 7.66 (s, 1H), 7.69 (d, J = 7.2 Hz, 1H);

13

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C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.9, 50.2, 116.0, 123.7 (q, J = 272.5 Hz), 125.1

19

1

(q, J = 3.7 Hz), 126.4 (q, J = 3.6 Hz), 130.4, 131.2, 131.6, 132.3 (q, J = 32.9 Hz), 198.7; F{ H} NMR

+

(

471 MHz, Chloroform-d)  -62.82; HRMS (APCI-TOF) m/z: [M+H] Calcd for C H F NO 256.0591;

12

9

3

2

Found 256.0592.

methyl 3-(1-cyano-2-oxobutyl)benzoate (2t).

Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), methyl 3-

bromobenzoate (0.53 g, 2.5 mmol), Cs CO (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06 mmol) and

2

3

Pd(OAc) (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 2:1). The

2

product was obtained as a pale yelow oil (0.2 g, 0.87 mmol, 43 %);

or

Prepared according to general procedure B with 3-oxopentanenitrile (134 g, 1.38 mmol), methyl 3-

bromobenzoate (0.31 g, 1.45 mmol), Cs CO (1.41 g, 4.35 mmol), PPh (40 mg, 0.15 mmol) and

2

3

Pd(OAc) (20 mg, 0.08 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 2:1). The

2

-1

product was obtained as a pale yelow oil (127 mg, 0.55 mmol, 40 %). IR (cm ) 2210, 1727, 1693,

1

218, 755, 670; H NMR (500 MHz, Chloroform-d)  (ppm) 1.08 (t, J = 7.2 Hz, 3H), 2.70 (p, J = 7.2

Hz, 2H), 3.96 (d, J = 1.1 Hz, 3H), 4.76 (s, 1H), 7.50 – 7.59 (m, 1H), 7.59 – 7.65 (m, 1H), 8.05 – 8.14

13

1

(

m, 2H); C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.8, 50.4, 52.7, 116.2, 129.3, 130.0,

-

1

30.6, 130.7, 131.9, 132.4, 166.2, 199.0; HRMS (APCI-TOF) m/z: [M-H] Calcd for C H NO

13

12

3

230.0823; Found 230.0823.

2-(3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-3-oxopentanenitrile (2u).

Prepared according to general procedure B with 3-oxopentanenitrile (0.205 g, 2.11 mmol), 2-(3-

Bromophenyl)-5-methyl-1,3,4-oxadiazole (0.605 g, 2.53 mmol), Cs CO (2.06 g, 6.33 mmol),

2

3

tBuMePhos (66 mg, 0.21 mmol) and Pd(OAc) (24 mg, 0.1 mmol) in DMF (6 mL). Column

2

chromatography (hexane:EtOAc; 3:1 to 0:1). The product was obtained as a yellow-orange solid

-1

(0.307 g, 1.20 mmol, 57 %). R = 0.50 (EtOAc); Mp > 250 °C; IR (cm ) 2196, 1624, 1580, 1555,

f

1

493, 1450, 1420, 1381, 1344, 1288, 1265, 1239, 1071, 1044, 981, 891, 798, 753, 727, 682; H

NMR (500 MHz, DMSO-d )  (ppm) 1.25 (t, J = 7.6 Hz, 3H), 2.59 (s, 3H), 2.64 (q, J = 7.6 Hz, 2H),

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1

2

3

4

5

6

7

8

9

1

2

3

4

5

6

NMR (126 MHz, DMSO-d )  (ppm) 10.6, 12.2, 28.9, 84.8, 120.1, 123.6, 123.9, 124.4, 129.5, 129.8,

6

+

1

33.9, 163.8, 164.0, 174.8; HRMS (APCI-MMI) m/z: [M+H] Calcd for C H N O 254.0935; Found

14

12

3

2

254.0934.

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

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6

7

8

9

0

1

2

3

4

5

6

7

8

9

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9

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2-([1,1'-biphenyl]-3-yl)-3-oxopentanenitrile (2v).

Prepared according to general procedure B with 3-oxopentanenitrile (0.097 g, 1 mmol), 3-

bromobiphenyl (0.244 g, 0.175 Ml, 1.05 mmol), Cs CO (0.976 g, 3 mmol), PPh (27 mg, 0.1 mmol)

2

3

and Pd(OAc) (6 mg, 0.025 mmol) in DMF (3 mL). Reaction time: 1 h. Column chromatography

2

(hexane:EtOAc; 10:1 to 1:2). The product was obtained as a yellow-orange oil (0.136 g, 0.55 mmol,

1

63 %). R = 0.43 (hexane:EtOAc; 2:1); H NMR (500 MHz, Chloroform-d)  (ppm) 1.06 (t, J = 7.2 Hz,

f

3H), 2.57 – 2.79 (m, 2H), 4.75 (s, 1H), 7.35 – 7.42 (m, 2H), 7.44 – 7.53 (m, 3H), 7.56 – 7.65 (m, 4H);

13

1

C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.4, 50.8, 116.5, 126.8, 127.3, 128.1, 129.1,

+

130.1, 130.6, 140.0, 143.0, 199.5; HRMS (APCI-TOF) m/z: [M+H] Calcd for C H NO 250.1226;

17

16

Found 250.1222.

or

Prepared according to general procedure B with 3-oxopentanenitrile (0.139 g, 1.43 mmol), 3-

bromobiphenyl (0.4 g, 0.286 mL, 1.72 mmol), Cs CO (1.399 g, 4.29 mmol), tBuMePhos (45 mg,

2

3

0

.143 mmol) and Pd(OAc) (8 mg, 0.036 mmol) in DMF (3 mL). Reaction time: 1 h. Column

2

chromatography (hexane:EtOAc; 10:1 to 1:2). The product was obtained as a yellow-orange oil

(0.274 g, 1.1 mmol, 76 %).

3

-oxo-2-(3-(trifluoromethoxy)phenyl)pentanenitrile (2w).

Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 1-bromo-

-(trifluoromethoxy)benzene (0.6 g, 0.37 mL, 2.5 mmol), Cs CO (1.95 g, 6.3 mmol), tBuMePhos (19

3

2

3

mg, 0.06 mmol) and Pd(OAc) (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography

2

(

hexane:EtOAc; 2:1). The product was obtained as a yellow wax (0.35 g, 1.36 mmol, 66 %). R =

f

-1

1

0.55 (hexane:EtOAc; 7:3); IR (cm ) 2210, 1732, 1623, 1354, 1153, 698, 663; H NMR (500 MHz,

Chloroform-d)  (ppm) 1.08 (t, J = 7.2 Hz, 3H), 2.61 – 2.78 (m, 2H), 4.70 (s, 1H), 7.26 – 7.30 (m,

13

1

H), 7.35 – 7.37 (m, 1H), 7.49 (t, J = 8 Hz, 1H); C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8,

33.7, 50.2, 116.0, 120.6 (q, J = 258.2 Hz), 120.9, 121.8, 126.5, 131.3, 132.2, 150.1, 198.7; HRMS

-

(

APCI-TOF) m/z: [M-H] Calcd for C H F NO 256.0591; Found 256.0592.

12

9

3

2

2-(3-methoxyphenyl)-3-oxopentanenitrile (2x).

Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 3-

bromoanisole (0.46 g, 0.3 mL, 2.5 mmol), Cs CO (1.95 g, 6.3 mmol), XPhos (29 mg, 0.06) and

2

3

Pd(OAc) (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 2:1). The

2

product was obtained as a yellow oil (0.25 g, 0.12 mmol, 58 %). R = 0.6 (hexane:EtOAc; 7:3); IR

f

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(cm ) 2204, 1728, 1600, 1455, 1259, 1037, 780, 696; H NMR (500 MHz, Chloroform-d)  (ppm)

1

.05 (t, J = 7.2 Hz, 3H), 2.51 – 2.80 (m, 2H), 3.84 (s, 3H), 4.66 (s, 1H), 6.91 – 6.95 (m, 2H), 6.98 (d,

13

1

J = 7.7 Hz, 1H), 7.34 (t, J = 7.9 Hz, 1H); C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.9, 33.3,

50.9, 55.6, 113.8, 115.0, 116.5, 120.3, 130.9, 131.5, 160.7, 199.6; HRMS (APCI-TOF) m/z: [M-H]^-

Calcd for C H NO 202.0874; Found 202.0874.

12

2

0

1

2

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8

9

0

1

2

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4

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7

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0

or

Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 3-

bromoanisole (0.46 g, 0.3 mL, 2.5 mmol), Cs CO (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06

2

3

mmol) and Pd(OAc) (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc;

2

:1). The product was obtained as a yellow oil (0.27 g, 1.3 mmol, 65 %).

2

-(3,5-dimethoxyphenyl)-3-oxopentanenitrile (2y).

Prepared according to general procedure B with 3-oxopentanenitrile (0.201 g, 2.1 mmol), 1-bromo-

,5-dimethoxybenzene (0.494 g, 2.3 mmol), Cs CO (2.02 g, 6.2 mmol), tBuMePhos (65 mg, 0.21

3

2

3

mmol) and Pd(OAc) (23 mg, 0.1 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc;

2

1:0 to 2:1). The product was obtained as a yellow oil (0.263 g, 1.13 mmol, 54 %). R = 0.43

f

-1

(

hexane:EtOAc; 2:1); IR (cm ) 2941, 2840, 2204, 1729, 1594, 1458, 1430, 1347, 1325, 1299, 1205,

1

156, 1108, 1062, 836, 693; H NMR (500 MHz, Chloroform-d)  (ppm) 1.05 (t, J = 7.2 Hz, 3H), 2.56

(

dq, J = 18.6, 7.2 Hz, 1H), 2.69 (dq, J = 18.6, 7.3 Hz, 1H), 3.80 (s, 6H), 4.59 (s, 1H), 6.46 (dd, J =

13

1

2

.2 Hz, 1H), 6.51 (d, J = 2.1 Hz, 2H); C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.1, 51.0,

-

55.7, 101.1, 106.2, 116.3, 132.0, 161.8, 199.4; HRMS (APCI-TOF) m/z: [M-H] Calcd for C H NO

13

14

3

2

32.0979; Found 232.0979.

2

-(3-hydroxyphenyl)-3-oxopentanenitrile (2z).

Prepared according to general procedure B with 3-oxopentanenitrile (0.193 g, 1.99 mmol), 3-

bromophenol (0.378 g, 2.18 mmol), Cs CO (1.94 g, 5.96 mmol), tBuMePhos (62 mg, 0.2 mmol) and

2

3

Pd(OAc) (22 mg, 0.1 mmol) in DMF (6 mL). Column chromatography (hexane:EtOAc; 1:0 to 1:1).

2

The product was obtained as a light brown wax (0.298 g, 1.57 mmol, 79 %). R = 0.21

f

-1

(

hexane:EtOAc; 2:1); IR (cm ) 3395, 2982, 2257, 2209, 1722, 1591, 1489, 1456, 1349, 1277, 1220,

1

190, 1162, 1108, 998, 964, 871, 781, 695; H NMR (500 MHz, Chloroform-d)  (ppm) 1.05 (t, J =

7.2 Hz, 3H), 2.58 (dq, J = 18.6, 7.2 Hz, 1H), 2.69 (dq, J = 18.6, 7.2 Hz, 1H), 4.65 (s, 1H), 5.49 (s,

H), 6.87 (ddd, J = 8.1, 2.4, 1 Hz, 1H), 6.90 (dd, J = 2.1 Hz, 1H), 6.94 (d, J = 7.6 Hz, 1H), 7.29 (dd,

1

13

1

J = 7.8 Hz, 1H); C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.8, 33.3, 50.6, 114.9, 116.4, 116.6,

-

1

20.4, 131.1, 131.4, 156.9, 199.7; HRMS (APCI-TOF) m/z: [M-H] Calcd for C H NO 188.0717;

11 10

2

Found 188.0717.

2

-(4-fluoro-2-methylphenyl)-3-oxopentanenitrile (2aa).

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Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 2-bromo-

5

-fluorotoluene (466 mg, 2.47 mmol), Cs CO (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06 mmol)

2

3

and Pd(OAc) (14 mg, 0.06 mmol) in DMF (3 mL). Column chromatography (hexane:EtOAc; 5:1 to

2

1

:1). The product was obtained as a yellow solid (115 mg, 0.55 mmol, 27 %). R = 0.50

f

-1

1

(

Hexane:EtOAc; 2:1); mp = 117 - 119 °C; IR (cm ) 2202, 1729, 1495, 1253, 864, 815; H NMR (500

0

1

2

3

4

5

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7

8

9

0

1

2

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7

8

9

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8

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2

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4

5

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8

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3

4

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0

MHz, Chloroform-d)  (ppm) 1.01 (t, J = 7.2 Hz, 3H), 2.30 (s, 3H), 2.53 (q, J = 7.2 Hz, 2H), 4.78 (s,

13

1

H), 6.85 – 7.00 (m, 2H), 7.23 – 7.37 (m, 1H); C{ H} NMR (75 MHz, Chloroform-d)  (ppm) 7.8,

19.8 (d, J = 1.7 Hz), 33.6, 47.7, 114.3 (d, J = 21.8 Hz), 116.3, 118.5 (d, J = 21.6 Hz), 125.0 (d, J =

3.3 Hz), 130.9 (d, J = 8.8 Hz), 139.2 (d, J = 8.2 Hz), 163.0 (d, J = 249.2 Hz), 199.5; ¹⁹F{ H} NMR

1

-

(

282 MHz, Chloroform-d)  (ppm) -112.4; HRMS (APCI-TOF) m/z: [M-H] Calcd for C H FNO

12

11

204.0830; Found 204.0831.

2-(naphthalen-1-yl)-3-oxopentanenitrile (2ab).

Prepared according to general procedure B with 3-oxopentanenitrile (200 mg, 2.1 mmol), 1-

bromonaphtalene (0.51 g, 0.35 mL, 2.5 mmol), Cs CO (1.95 g, 6.3 mmol), tBuMePhos (19 mg, 0.06

2

3

mmol) and Pd(OAc) (14 mg, 0.06 mmol) in DMF (3 mL) for 3 h. Column chromatography

2

(hexane:EtOAc; 2:1). The product was obtained as a brown oil (0.23 g, 1 mmol, 50 %). R = 0.60

f

-1

1

(

hexane:EtOAc; 2:1); IR (cm ) 2200, 1726, 1398, 1350, 1109, 773; H NMR (500 MHz, DMSO-d ) 

6

(ppm) 1.0 (t, J = 7.2 Hz, 3H), 2.5 – 2.6 (m, 2H), 5.3 (s, 1H), 7.5 – 7.7 (m, 3H), 7.7 (d, J = 7.1 Hz, 1H),

13

1

7

.9 – 8.0 (m, 3H); C{ H} NMR (126 MHz, DMSO-d )  (ppm) 7.9, 33.1, 49.1, 116.6, 122.8, 125.8,

6

-

1

26.5, 126.9, 127.9, 128.0, 129.5, 130.5, 130.7, 134.4, 200.1; HRMS (APCI-TOF) m/z: [M-H] Calcd

for C H NO 222.0924; Found 222.0924.

15 12

3-oxo-2-(2-(trifluoromethoxy)phenyl)pentanenitrile (2ac).

Prepared according to general procedure B with 3-oxopentanenitrile (0.122 g, 1.26 mmol), 1-bromo-

2-(trifluoromethoxy)benzene (0.363 g, 1.51 mmol), Cs CO (1.23 g, 3.77 mmol), tBuMePhos (0.039

2

3

g, 0.125 mmol) and Pd(OAc) (0.007 g, 0.03 mmol) in DMF (3 mL). Column chromatography

2

(hexane:EtOAc; 0:1 to 1:1). The product was obtained as a yellow oil (0.059 g, 0.023 mmol, 18 %).

1

R = 0.50 (Hexane:EtOAc; 2:1); H NMR (500 MHz, Chloroform-d)  (ppm) 1.10 (t, J = 7.2 Hz, 3H),

f

2

1

.56 – 2.77 (m, 2H), 5.03 (s, 1H), 7.32 – 7.37 (m, 1H), 7.38 (dd, J = 7.6, 1.4 Hz, 1H), 7.43 – 7.50 (m,

13

1

H), 7.52 (dd, J = 7.7, 1.8 Hz, 1H); C{ H} NMR (126 MHz, Chloroform-d)  (ppm) 7.7, 34.3, 44.4,

15.6, 120.1, 120.5 (q, J = 260 Hz), 122.9, 127.6, 130.5, 131.1, 146.8, 198.1; HRMS (APCI-TOF)

+

m/z: [M+H] Calcd for C H F NO 258.0736; Found 258.0737.

12

11

3

2

3-cyclohexyl-3-oxo-2-phenylpropanenitrile (2ad).

Prepared according to general procedure B with 3-cyclohexyl-3-oxopropanenitrile(100 mg, 0.661

mmol), bromobenzene (76.4 µL, 0.727 mmol), Cs CO (646 mg, 1.983 mmol), tBuMePhos (20.7 mg,

2

3

0

.066 mmol) and Pd(OAc) (7.4 mg, 0.033mmol) in DMF (3.5 mL). Column chromatography

2

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(hexane:EtOAc; 9:1 to 4:1). The product was obtained as a yellow solid (78 mg, 0.343 mmol, 52 %).

-1

R = 0.50 (EtOAc:MeOH; 1:1); mp = 93 − 101 °C; IR (cm ) 3267, 3054, 2931, 2850, 2204, 1618,

f

1

495, 1448, 1356, 1343, 1258, 1087, 1068, 1029, 929, 893, 759, 746, 691; H NMR (500 MHz,

Chloroform-d)  (ppm) 1.14 – 1.29 (m, 3H), 1.29 – 1.47 (m, 2H), 1.60 – 1.81 (m, 5H), 2.65 (tt, J =

1

2

1.2, 3.2 Hz, 1H), 4.78 (s, 1H), 7.35 – 7.48 (m, 5H); ¹³C{ H} NMR (126 MHz, DMSO-d )  (ppm)

6

0

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5.2, 25.5, 25.6, 28.8, 29.2, 48.6, 49.4, 116.5, 128.3, 129.3, 129.7, 129.9, 201.7; HRMS (APCI-TOF)

-

m/z: [M-H] Calcd for C H NO 226.1237; Found 226.1236.

15

16

3-oxo-2-phenyl-3-(4-(trifluoromethyl)phenyl)propanenitrile (2ae).

Prepared according to general procedure B with 3-oxo-3-(4-(trifluoromethyl)phenyl)propanenitrile

(100 mg, 0.469 mmol), bromobenzene (54.3 µL, 0.516 mmol), Cs CO (459 mg, 1.41 mmol),

2

3

tBuMePhos (15 mg, 0.047 mmol) and Pd(OAc) (5 mg, 0.023 mmol) in DMF (3.5 mL). Column

2

chromatography (hexane:EtOAc; 1:0 to 7:3). The product was obtained as light brown solid (74 mg,

-1

0

.256 mmol, 55 %). R = 0.40 (EtOAc:MeOH; 10:1); mp = 99 − 101 °C; IR (cm ) 3074, 2220, 1610,

f

1047, 1349, 1323, 1289, 1264, 1244, jj1176, 1151, 1128, ,1115, 1069, 1053, 1014, 835, 755, 735,

1

696; H NMR (300 MHz, Chloroform-d)  (ppm) 5.55 (s, 1H), 7.37 – 7.47 (m, 5H), 7.73 (d, J = 8.3

13

1

Hz, 2H), 8.05 (d, J = 8.2 Hz, 2H); C{ H} NMR (75 MHz, Chloroform-d)  (ppm) 47.3, 116.2, 123.3

q, J = 272.9 Hz), 126.2 (q, J = 3.7 Hz), 128.4, 128.9 (q, J = 12.2 Hz), 129.6, 129.7, 129.8 (q, J = 3.4

(

19

1

Hz), 130.0, 136.5, 188.4; F{ H} NMR (282 MHz, Chloroform-d)  (ppm) -63.5; HRMS (APCI-TOF)

-

m/z: [M-H] Calcd for C H F NO 288.0642; Found 288.0642.

16

9 3

3-(4-methoxyphenyl)-3-oxo-2-phenylpropanenitrile (2af).

Prepared according to general procedure B with 3-(4-methoxyphenyl)-3-oxopropanenitrile (100 mg,

0.57 mmol), bromobenzene (66 µL, 0.63 mmol), Cs CO (558 mg, 1.71 mmol), tBuMePhos (18 mg,

2

3

0

.057 mmol) and Pd(OAc) (6.4 mg, 0.029mmol) in DMF (3.5 mL). Column chromatography

2

(hexane:EtOAc; 4:1 to 3:1). The product was obtained as light brown wax (90 mg, 0.358 mmol, 63

-1

%

). R = 0.60 (Hexane:EtOAc; 1:1); IR (cm ) 2933, 2204, 1677, 1598, 1573, 1511, 1494, 1452, 1422,

f

1

317, 1263, 1236, 1171, 1119, 1023, 934, 854, 845, 823, 750, 737, 636; H NMR (300 MHz,

Chloroform-d)  3.83 (s, 3H), 5.58 (s, 1H), 6.87 – 6.94 (m, 2H), 7.32 – 7.47 (m, 5H), 7.89 – 7.98 (m,

1

3

1

2

1

2

H). C{ H} NMR (75 MHz, Chloroform-d)  46.4, 55.7, 114.4, 117.0, 126.5, 128.2, 129.0, 129.6,

+

31.0, 131.8, 164.6, 187.4. HRMS (APCI-TOF) m/z: [M+H] Calcd for C H NO 252.1019; Found

16

14

2

52.1019.

1

CAS registry No. [5415-11-2]. H NMR spectrum was consistent with that previously reported in the

literature.³⁰^e

3-(4-(tert-butyl)phenyl)-3-oxo-2-phenylpropanenitrile (2ag).

Prepared according to general procedure B with 3-(4-(tert-butyl)phenyl)-3-oxopropanenitrile (100

mg, 0.497 mmol), bromobenzene (57 µL, 0.547 mmol), Cs CO (487 mg, 1.49 mmol), tBuMePhos

2

3

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(16 mg, 0.05 mmol) and Pd(OAc) (6 mg, 0.025 mmol) in DMF (3.5 mL). Column chromatography

2

(hexane:EtOAc; 9:1 to 4:1). The product was obtained as light brown oil (75 mg, 0.27 mmol, 54 %).R_f

-1

=

1

0.60 (Hexane:EtOAc; 3:1); IR (cm ) 2963, 2251, 1686, 1602, 1564, 1455, 1409, 1365, 1291, 1268,

1

233, 1195, 1109, 1025, 1012, 938, 861, 818, 757, 745, 720, 698; H NMR (300 MHz, Chloroform-

13

1

d)  1.32 (s, 9H), 5.60 (s, 1H), 7.30 – 7.33 (m, 3H), 7.43 – 7.51 (m, 4H), 7.87 – 7.95 (m, 2H). C{ H}

0

1

2

3

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1

2

3

4

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7

8

9

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1

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1

2

3

4

5

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2

3

4

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NMR (75 MHz, Chloroform-d)  31.0, 35.4, 46.6, 116.8, 126.1, 128.4, 129.1, 129.4, 129.7, 130.8,

+

1

31.2, 158.6, 188.5. HRMS (APCI-TOF) m/z: [M+H] Calcd for C H NO 278.1539; Found

19

20

278.1539.

2-(4-fluorophenyl)-3-(3-methoxynaphthalen-2-yl)-3-oxopropanenitrile (2ah).

Prepared according to general procedure B with 3-(3-methoxynaphthalen-2-yl)-3-oxopropanenitrile

0.3 g, 1.33 mmol), 1-bromo-4-fluorobenzene (0.28 mg, 0.18 mL, 1.6 mmol), Cs CO (1.30 g, 4

(

2

3

mmol), tBuMePhos (13 mg, 0.04 mmol) and Pd(OAc) (9 mg, 0.04 mmol) in DMF (3 mL) for 1.5 h.

2

Column chromatography (hexane:EtOAc; 5:1 to 1:1). The product was obtained as a white solid

-1

(

0.36 g, 1.13 mmol, 85 %). R = 0.60 (hexane:EtOAc ; 1:1); mp = 176 - 177 °C; IR (cm ) 2216, 1615,

f

1

1599, 1505, 1346, 1214, 830, 811; H NMR (500 MHz, DMSO-d )  (ppm) 3.94 (s, 3H), 7.27 (t, J =

6

8.8 Hz, 2H), 7.43 (t, J = 7.5 Hz, 1H), 7.50 (s, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.82 (dd, J = 8.6, 5.5 Hz,

13

1

2

H), 7.90 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.1 Hz, 1H), 8.06 (s, 1H), 12.19 (s, 1H); C{ H} NMR (126

MHz, DMSO-d )  (ppm), 55.8, 88.6, 106.3, 115.2, 115.4, 120.3, 124.3, 126.5, 126.6, 127.6 (d, J =

6

15.5 Hz), 128.1, 129.1, 129.1, 130.2, 135.0, 154.4, 160.6 (d, J = 244.4 Hz), 165.5; HRMS (APCI-

+

TOF) m/z: [M+H] Calcd for C H FNO 320.1081; Found 320.1081.

20

15

2

3

-(3-methoxynaphthalen-2-yl)-2-(4-(methylsulfonyl)phenyl)-3-oxopropanenitrile (2ai).

Prepared according to general procedure B with 3-(3-methoxynaphthalen-2-yl)-3-oxopropanenitrile

0.21 mg, 0.93 mmol), 4-bromophenyl methyl sulfone (0.25 g, 1.12 mmol), Cs CO (0.91 g, 2.8

(

2

3

mmol), tBuMePhos (0.01 g, 0.03 mmol) and Pd(OAc) (0.006 g, 0.03 mmol) in DMF (3 mL) for 1 h.

2

Column chromatography (hexane:EtOAc; 1:1 to 0:1). The product was obtained as a white solid (0.2

-1

g, 0.52 mmol, 56 %). R = 0.75 (EtOAc); mp = 143 - 144 °C; IR (cm ) 1620, 1519, 1321, 1041, 705;

f

1

H NMR (500 MHz, DMSO-d )  (ppm) 3.22 (s, 1H), 3.95 (s, 1H), 7.44 (t, J = 7.5 Hz, 1H), 7.53 (s,

6

1H), 7.58 (t, J = 7.5 Hz, 1H), 7.91 (d, J = 8.3 Hz, 1H), 7.94 – 8.00 (m, 3H), 8.03 – 8.08 (m, 2H), 8.10

(s, 1H), 12.87 (s, 1H); ¹³C{ H} NMR (126 MHz, DMSO-d )  (ppm) 44.2, 56.4, 89.0, 106.9, 120.5,

1

6

124.9, 126.9, 127.1, 127.4, 127.8, 128.0, 128.3, 128.6, 128.6, 130.6, 135.6, 138.7, 154.7, 169.3;

+

HRMS (APCI-TOF) m/z: [M+H] Calcd for C H NO S 380.0951; Found 380.0956.

21

18

4

3-oxo-2-(pyridin-4-yl)pentanenitrile (2aj).

Prepared according to general procedure B with 3-oxopentanenitrile (0.167 g, 1.72 mmol), 4-

bromopyridine hydrochloride (0.368 g, 1.89 mmol), Cs CO (2.24 g, 6.88 mmol), tBuMePhos (54 mg,

2

3

0

.17 mmol) and Pd(OAc) (10 mg, 0.043 mmol) in DMF (6 mL). Column chromatography

2

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(hexane:EtOAc:MeOH; 1:1:0 to 0:9:1). The product was obtained as a pale orange solid (0.232 g,

.22 mmol, 71 %).

1

or

Prepared according to general procedure B with 3-oxopentanenitrile (0.191 g, 1.97 mmol), 4-

bromopyridine hydrochloride (0.421 g, 2.16 mmol), Cs CO (2.56 g, 7.87 mmol), XPhos (94 mg,

2

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1

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7

8

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1

2

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1

2

3

4

5

6

7

8

9

0

0.197 mmol) and Pd(OAc) (11 mg, 0.049 mmol) in DMF (6 mL). Column chromatography

2

(hexane:EtOAc:MeOH; 1:1:0 to 0:9:1). The product was obtained as a pale orange solid (0.09 g,

0.473 mmol, 24 %).

or

Prepared according to general procedure B with 3-oxopentanenitrile (0.214 g, 1.93 mmol), 4-

bromopyridine hydrochloride (0.393 g, 2.02 mmol), Cs CO (2.51 g, 7.7 mmol), PPh (50 mg, 0.193

2

3

mmol) and Pd(OAc)₂(11 mg, 0.048 mmol) in DMF (6 mL). Column chromatography

(hexane:EtOAc:MeOH; 1:1:0 to 0:9:1). The product was obtained as a pale orange solid (0.237 g,

-1

1

.25 mmol, 65 %). R = 0.53 (EtOAc:MeOH; 20:1); Mp > 175 °C decomp.; IR (cm ) 2175, 1635,

f

1

530, 1465, 1410, 1386, 1365, 1304, 1261, 1233, 1189, 1071, 1051, 885, 851, 815; H NMR (500

MHz, DMSO-d )  (ppm) 1.02 (t, J = 7.5 Hz, 3H), 2.53 (q, J = 7.5 Hz, 2H), 6.49 – 9.44 (br. s, 2H),

6

13

1

7

.98 (d, J = 7.6 Hz, 2H), 12.88 (s, 1H); C{ H} NMR (126 MHz, DMSO-d )  (ppm) 9.5, 33.8, 78.2,

6

+

1

14.4, 123.5, 137.2, 154.4, 193.1; HRMS (APCI-TOF) m/z: [M+H] Calcd for C H N O 175.0866;

10

11

2

Found 175.0868.

1

CAS registry No. [126769-99-1]. H NMR spectrum was consistent with that previously reported in

the literature.³⁰^f

3-ethyl-4-phenyl-1H-pyrazol-5-amine (3a).

Prepared according to general procedure C1 with 3-oxo-2-phenylpentanenitrile (230 mg, 1.34

mmol), N H .H O (0.4 g, 6.6 mmol, 0.4 mL) and HCl (35 %, 1.3 g, 13.4 mmol, 1.2 mL) in absolute

2

4

2

EtOH (3 mL) for 3 hours. Column chromatography (hexane:EtOAc; 4:1 to 0:1). The product was

-1

obtained as a pale white solid (0.2 g, 1.1 mmol, 80 %). R = 0.1 (EtOAc); mp = 169 - 170 °C; IR (cm )

f

1

3371, 1603, 1477, 897, 793, 773, 697; H NMR (300 MHz, DMSO-d )  (ppm) 1.03 – 1.20 (m, 3H),

6

13

1

2

.56 (q, J = 7.6 Hz, 2H), 7.10 – 7.26 (m, 1H), 7.30 – 7.48 (m, 4H); C{ H} NMR (75 MHz, DMSO-d )

6

+



(ppm) 13.3, 18.4, 103.6, 125.0, 128.0, 128.4, 134.1; HRMS (APCI-TOF) m/z: [M+H] Calcd for

C H N 188.1182; Found 188.1182.

11

14

3

1

CAS registry No. [110335-22-3]. H NMR spectrum was consistent with that previously reported in

the literature.³⁰^g

3

-ethyl-4-(4-fluorophenyl)-1H-pyrazol-5-amine (3b).

Prepared according to general procedure C1 with 2-(4-fluorophenyl)-3-oxopentanenitrile (1.89 g,

.88 mmol), N H .H O (0.494 g, 0.48 mL, 9.88 mmol) and CH SO H (0.095 g, 0.064 mL, 0.99 mmol)

9

2

4

2

3

in absolute EtOH (20 mL) for 1 hour. Column chromatography (hexane:EtOAc; 3:1 to 0:1). The

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The Journal of Organic Chemistry

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8

9

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3

4

5

6

product was obtained as a white solid (1.826 g, 8.9 mmol, 90 %). R = 0.28 (EtOAc); mp = 163 - 166

f

-1

1

°

C; IR (cm ) 3374, 1963, 2933, 2853, 1530, 1484, 1225, 1158, 838; H NMR (500 MHz, DMSO-d )

6



(ppm) 1.23 (q, 3H, J = 7.5 Hz), 2.69 (q, 2H, J = 7.5 Hz), 3.48 (s, 2H, J = 77.8 Hz), 7.27 – 7.40 (m,

13

1

2H), 7.42 – 7.52 (m, 2H), 8.51 (s, 1H); C{ H} NMR (126 MHz, DMSO-d )  (ppm) 13.2, 18.4, 102.8,

6

115.2 (d, J = 21.6 Hz), 129.9 (d, J = 7.9 Hz), 130.4 (d, J = 3.1 Hz), 143.1, 160.1 (d, J = 242.2 Hz);

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

1

2

3

4

5

6

7

8

9

0

19

1

-

F{ H} NMR (471 MHz, DMSO-d )  (ppm) – 117.79; HRMS (APCI-TOF) m/z: [M-H] Calcd for

6

C H FN 204.0942; Found 204.0948.

11

3

3-ethyl-4-(4-(trifluoromethyl)phenyl)-1H-pyrazol-5-amine (3c).

Prepared according to general procedure C1 with 3-oxo-2-(4-(trifluoromethyl)phenyl)pentanenitrile

(

0.27 g, 1.12 mmol), N H .H O (67 mg, 65 L, 1.34 mmol) and CH SO H (33 mg, 21 L, 0.34 mmol)

2

4

2

3

in absolute EtOH (5 mL) for 3 hours. Column chromatography (EtOAc:MeOH; 1:0 to 10:1). The

product was obtained as as a pale yellow solid (29 mg, 0.114 mmol, 10 %).

or

Prepared according to general procedure C3 with 3-oxo-2-(4-(trifluoromethyl)phenyl)pentanenitrile

(

90 mg, 0.37 mmol), N H .H O (120 mg, 120 L, 1.86 mmol) and HCl (35 %, 337 mg, 290 L, 3.37

2

4

2

mmol) in absolute EtOH (5 mL) for 3 hours. Column chromatography (Hexane:EtOAc; 1:1 to 0:1 to

EtOAc:MeOH; 1:0 to 10:1). The product was obtained as a pale yellow solid (80 mg, 0.31 mmol, 85

-1

1

%

). R = 0.16 (EtOAc); mp = 144 - 146 °C; IR (cm ) 3374, 1618, 1322, 1117, 1050, 846; H NMR

f

(

500 MHz, DMSO-d )  (ppm) 1.11 (td, J = 7.5, 1.4 Hz, 3H), 2.60 (qd, J = 7.6, 1.4 Hz, 2H), 4.60 (s,

6

13

1

2

H), 7.54 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 7.9 Hz, 2H), 11.56 (s, 1H); C{ H} NMR (126 MHz, DMSO-

d₆)  (ppm) 13.6, 19.2, 125.7 (q, J = 3.6 Hz), 128.7, 139.3; ¹⁹F{ H} NMR (282 MHz, DMSO-d ) 

1

6

+

(

ppm) -55.9; HRMS (APCI-TOF) m/z: [M+H] Calcd for C H F N 256.1056; Found 256.1056.

12 13

3

3-ethyl-4-(4-nitrophenyl)-1H-pyrazol-5-amine (3d).

Prepared according to general procedure C2 with 2-(4-nitrophenyl)-3-oxopentanenitrile (50 mg, 0.23

mmol), N H .H O (15 mg, 0.23 mmol) in AcOH (1 mL) for 4 hours. Column chromatography

2

4

2

(hexane:EtOAc; 1:1 to 1:1 to EtOAc:MeOH; 10:1). The product was obtained as a pale orange wax

-1

(

40 mg, 0.17 mmol, 75 %). R = 0.1 (EtOAc); IR (cm ) 3112, 2944, 2911, 1599, 1510, 1341, 1107,

f

1

923, 858, 830, 732; H NMR (500 MHz, DMSO-d )  (ppm) 1.13 (t, J = 7.6 Hz, 3H), 2.64 (q, J = 7.6

6

Hz, 2H), 4.84 (s, 2H), 7.57 – 7.62 (m, 2H), 8.18 – 8.24 (m, 2H), 11.84 (s, 1H); ¹³C{ H} NMR (126

1

MHz, DMSO-d )  (ppm) 12.9, 19.1, 101.7, 123.7, 127.8, 142.2, 143.9, 145.2; HRMS (APCI-TOF)

6

+

m/z: [M+H] Calcd for C H N O 233.1033; Found 233.1033.

11

13

4

2

4-(5-amino-3-ethyl-1H-pyrazol-4-yl)benzonitrile (3e).

Prepared according to general procedure C1 with 4-(1-cyano-2-oxobutyl)benzonitrile (80 mg, 0.4

mmol), N H .H O (28 mg, 27 L, 0.44 mmol) and CH SO H (3 mg, 2 L, 0.03 mmol) in absolute

2

4

2

3

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Article Doi

Preparation of 3,4-Substituted-5-Aminopyrazoles and 4-Substituted-2-Aminothiazoles

DOI: 10.1021/acs.joc.8b02655

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Authors:

Article abstract of DOI:10.1021/acs.joc.8b02655

Full text of DOI:10.1021/acs.joc.8b02655

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