Functionalized pyrazoles as agents in C-C cross-coupling reactions

(4b(THP)), Me₃Sn (5b(THP)) were obtained by the following syntheses: i) In a ﬁrst step, 4-X-pz

(X = Br (1a), I (2a)) and 4-X-3,5-Ph₂pz (X = Br (1b), I (2b)) were reacted with 3,4-dihydro-2H-

pyran (DHP) to give the related THP-protected bromo- or iodopyrazole derivatives. ii) In a sec-

ond step these THP derivatives were metalated by treatment with nBuLi or iPrMgCl. Subsequent

reactions of the THP-protected metallopyrazoles 4-M-pz(THP) and 4-M-3,5-Ph₂pz(THP) (M = Li,

MgBr) with Bpin(OiPr), Me₃SiCl, and Me₃SnCl yielded the pyrazole derivatives 3a(THP), 3b(THP),

4a(THP), 4b(THP), 5a(THP), and 5b(THP). In contrast to the stannylated pyrazoles 5a(THP) and

5b(THP), the corresponding borylated and silylated derivatives could be easily deprotected: treat-

ment of 3a(THP), 3b(THP), and 4a(THP) with HCl yielded the parent pyrazoles 3a, 3b and 4a.

The microwave-assisted C–C cross-coupling reactions of these pyrazoles with aryl halides were ex-

amined, e. g. Suzuki reactions of 3a with p-pentylphenylbromide, p-hexylphenylbromide, and p-

(2-ethylhexyl)phenylbromide. Similar reactions were also performed with 1a, 1b, 2a, and 2b and

aryl-substituted pinacolatoboranes or boronic acids. Crystals of 5b(THP) suitable for X-ray diffrac-

tion were grown (monoclinic P2₁/c) and their structure determined. The crystal structures of 1a·HBr

¯

(monoclinic P2₁/n), 1b (triclinic P1), (1c)₂·HBr (monoclinic P2/c), 1c·HBr·(Br₂)_0.5(triclinic P1),

¯

(2a)₃·H₂SO₄(triclinic P1), 3a (orthorhombic P2₁2₁2₁), (3a)₃·H₂O (trigonal R3c), 3b (orthorhombic

Pna2₁), and 4a (monoclinic Pc) reveal interesting hydrogen bonding networks.

Key words: Pyrazoles, C–C Cross-Coupling, Luminescence, X-Ray Structure Analysis, Hydrogen

Bonding Networks

Introduction

boron center in the corresponding borane of the pyra-

zolyl borate (Fig. 1). In these cases there is compe-

Multidentate ligand systems have attracted con- tition between the reactions of metal cations and the

siderable interest in the last decades. Prominent ex- pyrazolide anion and the BN adduct formation (Fig. 1).

amples of this class of ligands are₋the (pyrazol-1- Another important factor which inﬂuences the stabil-

yl)borates (scorpionates) [R_nBpz_4−n

] (R = H, alkyl, ity of scorpionates is the degree of steric crowding.

aryl; n = 2, 1, 0; pz = pyrazol-1-yl) [1 – 8]. Scorpi- Several studies have ₋shown that the scorpionates of

onates have found applications in a wide range of the type RB(3-R⁰pz)₃decompose in the presence of

chemistry, from modelling the active site of metalloen- transition metal salts MX_nmuch more easily when R

zymes, through analytical chemistry and organic syn- and R⁰are bulky (Fig. 1) [10]. Especially scorpionates

thesis to catalysis and materials science [9].

with pyrazoles which bear bulky substituents in 3- and

However, degradation reactions of these scorpionate 5-position tend to degradation. Therefore it is unfa-

ligands were often observed in the presence of tran- vorable to tune the properties of scorpionate ligands

sition metal salts MX_n, [10 – 12]. We found that de- by introducing solubility-mediating or functionalized

boronation of scorpionates easily takes place if the groups in their 3- or/and 5-position. Since our group

metal center in MX_nis more Lewis acidic than the has a long-standing interest in the development of new

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M. Pejic et al. · Functionalized Pyrazoles as Agents in C–C Cross-Coupling Reactions

R'

X

R'

R

N

NH

N

NH

Mⁿ⁺

RB

R'

1,2

3,4a

N

R'

(i)

(iii)

N

X

R'

Fig. 1. Metal Scorpionates.

(ii)

R

Br

I

N

N N

THP

R

1(THP)

2(THP)

3(THP)

4(THP)

5(THP)

N

NH

N NH

1a (R = H)

1b (R = Ph)

1c (R = Br)

2a (R = H)

2b (R = Ph)

Scheme 1. Syntheses of the borylated, silylated and stanny-

lated pyrazoles. (i) 1, 2 (R = H, Ph; X = Br, I): toluene,

+DHP; TFA, 95 ^◦C (R = H, Ph; X = Br, I); (ii) 3a, b(THP)

(R⁰= Bpin): nBuLi/iPrMgCl, +Bpin(OiPr); 4a(THP) (R⁰

= SiMe₃): +nBuLi, +Me₃SiCl; 5a, b(THP) (R⁰= SnMe₃):

nBuLi/iPrMgCl +Me₃SnCl; THF, –78 ^◦C, (iii) 3a, b (R⁰

= Bpin), 4a (R⁰= SiMe₃): AcCl in MeOH; subsequent

addition of NEt₃.

Bpin

SiMe₃

SnMe₃

R

N

NH

N

NH

N NH

3a (R = H)

3b (R = Ph)

4a (R = H)

4b (R = Ph)

5a (R = H)

5b (R = Ph)

Fig. 2. The pyrazoles with their different functional groups in

the 4-position.

with nBuLi). Therefore we worked out the following

synthesis strategy for 4-boryl-, 4-silyl-, and 4-stannyl-

ligand systems based on pyrazole, both for use in ho- substituted pyrazoles (Scheme 1): i) At ﬁrst the bromo-

mogeneous catalysis and in the assembly of coordina- and iodopyrazoles 1a, 1b, 2a, and 2b were reacted

tion polymers and networks, we decided to work out with 3,4-dihydro-2H-pyran to give the related THP-

a new strategy to introduce functional groups on pyra- protected bromo- or iodopyrazole derivatives 1a(THP),

zoles. In the course of this study we found that pyra- 1b(THP), 2a(THP), and 2b(THP). ii) In a second step

zole derivatives could conveniently be borylated, sily- these THP derivatives were metalated by treatment

lated or stannylated in the 4-position. Moreover, cou- with nBuLi or iPrMgCl. Subsequent reactions of the

pling protocols allow further functionalization of these THP-protected metallopyrazoles 4-M-pz(THP) and 4-

pyrazoles.

M-3,5-Ph₂pz(THP) (M = Li, MgBr) with Bpin(OiPr),

The purpose of this paper is to describe the synthe- Me₃SiCl, and Me₃SnCl yielded 3a(THP), 3b(THP),

sis and properties of pyrazoles which bear functional 4a(THP), 4b(THP), 5a(THP), and 5b(THP). iii) Fi-

groups in the 4-position (c. f. Fig. 2). In addition we nally the THP derivatives 3a(THP), 3b(THP), and

examined microwave-assisted C–C cross-coupling re- 4a(THP) whose boryl and silyl substituents are inert

actions of these pyrazoles with aryl halides. Finally the against protic agents could be easily transformed into

solid-state structures of the pyrazoles 1b, 3a, 3b, 4a, their parent pyrazoles 3a, 3b, and 4a (Scheme 1). How-

and 5b(THP) and those of the addition products of 1a ever, stannyl group elimination took place when the

with HBr, 1c with HBr, 1c with HBr and Br₂, 2a with THP derivatives 5a(THP) and 5b(THP) were treated

H₂SO₄, and 3a with H₂O are reported herein.

with HCl. Therefore we were not able to synthesize

the deprotected pyrazoles 5a and 5b.

Results and Discussion

As shown in Scheme 2, Suzuki-type coupling pro-

tocols allow the further functionalization of the

Due to their acidic protons, it is always necessary pyrazoles 1a–3b (Fig. 2). We examined the fol-

to transform parent pyrazoles into their THP deriva- lowing microwave-assisted C–C cross-coupling re-

tives before metalation in 4-position is carried out (e. g. actions in detail: Suzuki reactions of 3a with p-

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M. Pejic et al. · Functionalized Pyrazoles as Agents in C–C Cross-Coupling Reactions

85

R'

Br

(i)

(ii)

(iii)

R

+

N

R

THP

Bpin

R'

N

NH

1a/1b(THP)

R'

I

R

+

N

THP

Bpin

R'

N

NH

2a/2b(THP)

R'

Bpin

R

+

N

THP

Br

N

NH

3a/3b(THP)

Fig. 4. Structure of 1a·HBr in the solid state (ORTEP,

Scheme 2. Substituted pyrazoles 1–3 in C–C cross-coupling

reactions. (i) e. g. 1b(THP) (R = Ph), p-R⁰PhBpin (R⁰=

H) [9]; (ii) e. g. 2b(THP) (R = Ph), p-R⁰PhBpin (R⁰=

Me) [13]; (iii) e. g. 3a(THP) (R = H), p-R⁰PhBpin (R⁰=

pentyl): +Pd(PPh₃)₄, K₃PO₄, H₂O/DMF, 110 ^◦C.

displacement ellipsoids are drawn at the 50% probability

˚

level). Selected bond lengths (A), atom···atom distances

˚

(A), and bond angles (deg): Br(1)–C(1) 1.854(6), C(1)–C(2)

1.381(9), C(1)–C(5) 1.383(9), C(2)–N(3) 1.321(9), N(3)–

N(4) 1.320(10), N(3)–H(3) 0.89(1), N(4)–H(4) 0.89(1),

N(4)–C(5) 1.305(10), N(3)···Br(2) 3.213(6), N(4)···Br(2)

3.258(6); N(3)–H(3)–Br(2) 131(7), N(4)–H(4)–Br(2)

147(7).

The molecular structures of the compounds 1a·HBr,

1b, (1c)₂·HBr, 1c·HBr·(Br₂)_0.5, (2a)₃·H₂SO₄, 3a,

3a·H₂O, 3b, 4a, and 5b are shown in Figs. 4 – 15. Se-

lected bond lengths and angles are listed in the corre-

sponding ﬁgure captions, details of the crystal structure

analyses are summarized in Table 1.

Fig. 3. Cross-coupling products 6(R⁰) (e. g. R⁰= pentyl,

hexyl, 2-ethylhexyl, Ph [13]) and 7(R⁰) (e. g. R⁰= Me,

Ph [13]).

The 1 : 1 addition product of 1a and HBr crys-

pentylphenylbromide, p-hexylphenylbromide, and p- tallizes in the monoclinic space group P2₁/n with

(2-ethylhexyl)phenylbromide. Z = 4 (Fig. 4). The coordinates of the H atoms

In addition we performed Suzuki C–C cross- bonded to N were reﬁned with a bond length re-

˚

coupling reactions with the bromo- and iodo- straint of 0.89(1) A. The packing in the crystal

substituted pyrazoles 1a, 1b, 2a, and 2b and pinaco- shows layers of pyrazolium cations [1aH]⁺paral-

¯

latoboranes Ar-Bpin or aryl-substituted boronic acids lel to the (1 0 4) plane and bromide anions. The

ArB(OH)₂(Fig. 3). In this context it should be noted bromide anion connects three cations by N–H···Br

˚

that most of these C–C cross-coupling products are hydrogen bonds (N(3)–H(3) = 0.89(1) A, N(3)···

◦

˚

ﬂuorophores and emit in the near ultraviolet to blue Br(2) = 3.213(6) A, N(3)–H(3)–Br(2) = 131 (7) ,

˚

regime [13]. Moreover, some of these compounds N(4)–H(4) = 0.89(1) A, N(4)···Br(2) = 3.258(6) A,

◦

˚

show remarkably high solid-state quantum yields [13]. N(4)–H(4)–Br(2) = 147 (7) , N(3)–H(3) = 0.89(1) A,

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M. Pejic et al. · Functionalized Pyrazoles as Agents in C–C Cross-Coupling Reactions

Fig. 5. Molecular structure of 1b in the solid state (ORTEP, displacement ellipsoids are drawn at the 50% probability level).

˚

Selected bond lengths (A), atom···atom distances (A), bond angles (deg), and torsion angles (deg): Br(1)–C(2) 1.878(3),

C(1)–N(5) 1.340(4), C(1)–C(2) 1.395(4), C(1)–C(11) 1.476(4), C(2)–C(3) 1.401(4), C(3)–C(4) 1.346(4), C(3)–N(21)

1.476(4), N(5)–H(5) 0.873(10), N(5A)–H(5A) 0.875(10), N(4)···N(5A) 2.827(4), N(5)···N(4A) 2.814(4); N(5)–H(5)–N(4A)

142(3), N(5A)–H(5A)–N(4) 142(3); pz(N(4))//Ph(C(11)) 35.25(12), pz(N(4))//Ph(C(21)) 31.09(13), pz(N(4A))//Ph(C(11A))

31.90(12), pz(N(4A))//Ph(C(21A)) 27.80(15).

˚

N(3)···Br(2)

=

3.449(7) A, N(3)–H(3)–Br(2)

=

Two different addition products of 3,4,5-

124 (6)^◦; Fig. 4). Thus, one of the H atoms (H(3)) tribromopyrazole (1c) are shown in Figs. 6 and 7.

forms two hydrogen bonds, whereas the other one The ﬁrst one is composed of two molecules of 1c

forms just one.

and one of Br ((1c)₂·HBr) and the second one of one

The molecular structure of the pyrazole derivative molecule each of 1c and HBr, and a half molecule of

¯

1b (triclinic space group P1 with Z = 4) is shown Br₂[1c·HBr·(Br₂)_0.5].

in Fig. 5. The coordinates of the H atoms bonded

The H atoms in (1c)₂·HBr bonded to the N atoms

to N were reﬁned with a bond length restraint of were geometrically positioned and reﬁned using a rid-

˚

0.88(1) A. There are two molecules in the asymmet- ing model. The position of the H atom bonded to the

ric unit differing in the dihedral angles between the N(1) atom is only half-occupied. The asymmetric unit

central pyrazol ring and the attached phenyl rings. In is composed of protonated pyrazole dimers [(1c)₂H]⁺

the ﬁrst molecule, the dihedral angles are 35.25(12)^◦and a bromide anion located on a two-fold axis. In the

and 31.09(13)^◦for the rings containing C(11) and crystal, cations and bromide anions are connected via

C(21), respectively. In the second molecule, the dihe- N–H···N and N–H···Br hydrogen bonds (N(1)–H(1)

dral angles are 31.90(12)^◦and 27.80(15)^◦for the rings = 0.88 A, N(1)···N(1) = 2.610(10) A, N(1)–H(1)–

˚

◦

˚

containing C(11A) and C(21A), respectively. The two N(1) = 175.8 , N(2)–H(2) = 0.88 A, N(2)···Br(1) =

◦

˚

molecules in the asymmetric unit are connected by N– 3.186(6) A, N(2)–H(2)–Br(1) 166.1 ; Fig. 7) forming

H···N hydrogen bonds to form dimers. zigzag chains running along the a axis.

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87

Fig. 6. Unit cell of (1c)₂·HBr.

The H atoms in 1c·HBr·(Br₂)_0.5bonded to the N cations [2aH]⁺, one 4-iodopyrazole molecule, and one

atoms were geometrically positioned and reﬁned using sulfate anion. The neutral iodopyrazole molecule do-

a riding model. The asymmetric unit is composed of nates a hydrogen bond to a sulfate anion (N(1)–H(1)

˚

one cation, one anion and half a Br₂molecule which = 0.97(8) A, N(1)···O(2) = 2.787(5) A, N(1)–H(1)–

is located on a centre of inversion. In the crystal, O(2) = 158 (7)^◦) and accepts one hydrogen bond from

˚

two cations are connected to each other mediated by a iodopyrazolium cation (N(2B)–H(2B) = 0.86(7) A,

˚

two bromide anions forming centrosymmetric dimers N(2B)···N(2) = 2.678(6) A, N(2B)–H(2B)–N(2) =

via N–H···Br hydrogen bonds (N(2)–H(2) = 0.88 A, 166(6)^◦). The other N–H group of this iodopyrazolium

˚

◦

˚

N(2)···Br(1) 3.180(6) A, N(2)–H(2)–Br(1) = 161.8 , cation donates a hydrogen bond to a sulfate anion

˚

N(1)–H(1) = 0.88 A, N(1)···Br(1) = 3.174(6) A, N(1)– (N(1B)–H(1B) = 0.84(6) A, N(1B)···O1 = 2.599(5) A,

H(1)–Br(1) = 167.0^◦; Fig. 7). Anions and cations form N(1B)–H(1B)–O(1) = 172(6)^◦). The second iodopy-

¯

layers in the (1 2 0) plane. The Br₂molecules are lo- razolium cation connects two sulfate anions via N–

˚

cated between the dimers. The shortest contact of a Br₂H···O hydrogen bonds (N(1A)–H(1A) = 0.88(5) A,

˚

molecule is to a bromide anion (3.0906(13) A).

N(1A)···O(4) = 2.631(5) A, N(1A)–H(1A)–O(4) =

◦

˚

The H atoms bonded to the N atoms in (2a)₃·H₂SO₄175(5) , N(2A)–H(2A) = 0.88(2) A, N(2A)···O(2) =

◦

˚

were freely reﬁned with a bond length restraint of 2.723(4) A, N(2A)–H(2A)–O2 = 166(5) ). As a result,

˚

0.88(1) A for the bond N(2A)–H(2A). The asymmetric only three of the four sulfate O atoms act as hydrogen

unit is composed of two protonated 4-iodo-pyrazolium bond acceptors, whereas the N atom of the iodopyra-

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M. Pejic et al. · Functionalized Pyrazoles as Agents in C–C Cross-Coupling Reactions

Fig. 8. Unit cell of (2a)₃·H₂SO₄.

order of the water H atoms. Due to the absence

of anomalous scatterers, the absolute structure could

not be determined. The planar ﬁve-membered 1,3,2-

Fig. 7. Unit cell of 1c·HBr·(Br₂)_0.5

.

˚

dioxaborolane ring (r. m. s. deviation = 0.124 A) is

almost coplanar with the pyrazole ring (dihedral an-

zole molecule is involved in a N–H···N hydrogen bond. gle = 8.06(6)^◦). In the crystal, three molecules are

This hydrogen bond pattern leads to a two-dimensional arranged about a threefold rotation axis surrounding

arrangement of double layers in the ab plane (Fig. 8). the water molecule which is located on the threefold

However, there are no hydrogen bonds between these axis. The water molecule donates two hydrogen bonds

layers.

to the N atoms of two pyrazole rings (O(1W)–H(1W)

˚

The molecular structure of the pyrazole 3a (or- = 0.842(14) A, O(1W)···N(4) = 2.885(3) A, O(1W)–

thorhombic, space group P2₁2₁2₁with Z = 4) is H(1W)–N(4) = 160(6)^◦), and the latter two donate

shown in Figs. 9 and 10. The H atom bonded to N an N–H bond to the N atom of the third molecule

˚

was freely reﬁned. The planar ﬁve-membered 1,3,2- (N(3)–H(3) = 0.908(15) A, N(3)···N(3) = 3.140(5) A,

dioxaborolane ring (r. m. s. deviation = 0.118 A) is N(3)–H(3)–N(3) = 142(7)^◦). This molecule donates

˚

almost coplanar with the pyrazole ring (dihedral an- an N–H bond to the water molecule (N(4)–H(4) =

gle 8.98(13)^◦). In the crystal, the molecules are con- 0.909(15) A, N(4)···O(1W) = 2.885(3) A, N(4)–H(4)–

nected via N–H···N hydrogen bonds (N(2)–H(2) = O(1W) = 144(9)^◦) completing a tripodal arrange-

˚

0.81(3) A, N(2)···N(1) = 2.935(3) A, N(2)–H(2)–N(1) ment of three molecules of pyrazole 3a and a water

= 166(3)^◦) to zigzag chains running along the a molecule (Fig. 11). These complexes are not further

axis (Fig. 10). The molecules in this chain are copla- connected via hydrogen bonds to symmetry-equivalent

nar and form ribbons in the (0 1 3) and (0 1 3) complexes.

planes. The borylated pyrazole 3b crystallizes with two

¯

The water O atom in 3a·H₂O is located on a three- molecules in the asymmetric unit in the orthorhombic

fold rotation axis. The water H atoms are thus dis- space group Pna2₁with Z = 8, as shown in Fig. 12.

ordered over three positions with a site occupation In one molecule, the dioxaborolane ring is disordered

factor of 2/3. The H atom bonded to the N atom over two positions with a site occupation factor

is disordered over two positions with site occupa- of 0.695(7) for the site of major occupancy. The

tion factors of 1/3 and 2/3 in accord with the dis- disordered atoms were reﬁned isotropically, while

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89

Fig. 9. Molecular structure of 3a in the solid state (ORTEP, displacement ellipsoids are drawn at the 50% probability level).

˚

Selected bond lengths (A), atom···atom distances (A), bond angles (deg), and torsion angles (deg): B(1)–C(4) 1.542(3),

N(1)–C(5) 1.321(3), N(1)–N(2) 1.351(3), N(2)–C(3) 1.337(3), C(3)–C(4) 1.376(4), C(4)–C(5) 1.407(3), N(2)–H(2) 0.81(3),

B(1)–C(4) 1.542(3), N(2)···N(1) 2.935(3); N(2)–H(2)–N1 166(3), pz(N(1))//Bpin(B(1)) 8.98(13).

Fig. 11. Connectivity of (3a)₃·H₂O in the solid state. Hydro-

gen atoms except those on nitrogen and oxygen atoms have

been omitted for clarity.

pyrazole ring containing N(1) forms dihedral angles of

Fig. 10. Packing of borylated pyrazole molecules in crystals

39.39(10)^◦and 36.64(8)^◦with the phenyl ring contain-

of 3a, viewed in the ab plane. Hydrogen atoms except those

ing C(21) and C(31), respectively. The pyrazole ring

on nitrogen atoms have been omitted for clarity.

containing N(1A) forms dihedral angles of 38.85(11)^◦

the H atoms bonded to N were freely reﬁned. and 41.40(6)^◦with the phenyl rings containing

Due to the absence of anomalous scatterers, the C(21A) and C(31A), respectively. The two molecules

absolute structure could not be determined. The in the asymmetric unit form dimers connected by

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M. Pejic et al. · Functionalized Pyrazoles as Agents in C–C Cross-Coupling Reactions

Fig. 12. Molecular structure of 3b (ORTEP, displacement ellipsoids are drawn at the 50% probability level). Selected

˚

bond lengths (A), atom···atom distances (A), bond angles (deg), and torsion angles (deg): B(1)–C(4) 1.549(5), N(1)–C(5)

1.353(4), N(1)–N(2) 1.364(4), N(2)–C(3) 1.341(4), C(3)–C(4) 1.414(5), C(3)–C(21) 1.477(5), C(4)–C(5) 1.386(5), C(5)–

C(31) 1.480(5), N(1)–H(1) 0.91(4), N(1A)–H(1A) 0.89(5), N(1)···N(2A) 2.926(4), N(2)···N(1A) 2.830(4); N(1)–H(1)–N(2A)

138(3), N(1A)–H(1A)–N(2) 147(4); pz(N(1))//Ph(C(21)) 39.39(10), pz(N(1))//Ph(C(31)) 36.64(8), pz(N(1A))//Ph(C(21A))

38.85(11), pz(N(1A))//Ph(C(31A)) 41.40(6), pz(N(1))//pz(N(1A)) 34.43(10).

˚

N–H···N hydrogen bonds (N(1)–H(1) = 0.91(3) A,

˚

N(1)···N(1)

=

2.926(4) A, N(1)–H(1)–N(2A)

˚

=

◦

138(3) , N(1A)–H(1A) = 0.89(3) A, N(1)···N(1A) =

◦

˚

2.830(4) A, N(1)–H(1)–N(2A) = 147(3) ). The two

hydrogen-bonded pyrazole rings are not coplanar but

inclined at an angle of 34.43(10)^◦.

The molecular structure of the silylated pyrazole

4a (monoclinic, space group Pc with Z = 8) is

shown in Figs. 13 and 14. The three methyl groups

in two molecules are disordered over two positions

with site occupation factors of 0.55(6) and 0.78(2)

for the site of major occupancy. Si–C and C–C bond

lengths in the disordered parts were restrained to be

equal to those in a non-disordered SiMe₃group. One

methyl C atom (C(6C)) was restrained to an isotropic

behavior. The H atoms could not be located and

were geometrically positioned. The absolute structure

could not be reliably determined (Flack (x) param-

eter 0.8(5)). There are four molecules in the asym-

metric unit, which are connected by N–H···N hydro-

gen bonds to zigzag chains running along the b axis

Fig. 13. Molecular structure of 4a (ORTEP, displace-

ment ellipsoids are drawn at the 50% probability level).

˚

Selected bond lengths (A), atom···atom distances (A),

˚

and bond angles (deg): C(1)–C(2) 1.395(18) A, C(1)–

C(5) 1.348(18), C(1)–Si(1) 1.860(12), C(2)–N(3) 1.316(18),

N(3)–N(4) 1.379(19), N(4)–C(5) 1.377(16), N(3)–H(3)

0.88, N(3A)–H(3A) 0.88, N(3B)–H(3B) 0.88, N(3C)–H(3C)

0.88, N(3)···N(4A) 2.951(14), N(3A)···N(4B) 2.850(15),

N(3B)···N(4C) 2.932(15), N(3C)···N(4) 2.828(17); N(3)–

H(3)–N(4A) 152, N(3A)–H(3A)–N(4B) 169, N(3B)–H(3B)–

˚

(N(3)–H(3) = 0.88 A, N(3)···N(4A) = 2.951(14) A,

˚

N(3)–H(3)–N(4A) = 152, N(3A)–H(3A) = 0.88 A,

˚

N(3A)···N(4B) = 2.850(15) A, N(3A)–H(3A)–N(4B) N(4C) 148, N(3C)–H(3C)–N(4) 165.

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M. Pejic et al. · Functionalized Pyrazoles as Agents in C–C Cross-Coupling Reactions

91

Fig. 15. Molecular structure of 5b(THP) (ORTEP, dis-

placement ellipsoids are drawn at the 50% probability

˚

level). Selected bond lengths (A) and torsion angles (deg):

Sn(1)–C(4) 2.137(5), Sn(1)–C(6) 2.122(7), Sn(1)–C(7)

2.145(7), Sn(1)–C(8) 2.161(6), N(1)–N(2) 1.358(6), N(1)–

C(5) 1.368(6), N(2)–C(3) 1.335(6), C(3)–C(4) 1.432(7),

C(3)–C(21) 1.478(7), C(4)–C(5) 1.397(7), C(5)–C(31)

1.482(7); pz(N(1))//Ph(C(21)) 40.1(2), pz(N(1))//Ph(C(31))

45.0(2).

Fig. 14. Packing diagram for 4a, viewed along the ab plane.

Hydrogen atoms except those on nitrogen atoms have been

omitted for clarity.

◦

˚

= 169 , N(3B)–H(3B) = 0.88 A, N(3B)···N(4C) =

◦

˚

2.932(15) A, N(3B)–H(3B)–N(4C) = 148 , N(3C)–

Fig. 16. Pyridyl indoles (X = F, Cl).

˚

H(3C) = 0.88 A, N(3C)···N(4) = 2.828(17) A, N(3C)–

H(3C)–N(4) = 165^◦; Fig. 14).

The stannylated pyrazole 5b(THP) crystallizes in

the monoclinic space group P2₁/c with two almost nite hydrogen-bridged zigzag chains of pyrazoles for

identical molecules in the asymmetric unit (Fig. 15). small substituents in the 3- and 5-position (e. g. Fig. 2,

A least-squares ﬁt of all non-H atoms gives an r. m. s. R = H) and hydrogen-bridged dimers for bulky groups

˚

deviation of 0.104 A. Thus, only one molecule is dis- in these positions (e. g. Fig. 2, R = Ph). Also, it was

cussed here. The pyrazole ring forms dihedral angles of found that proton-active compounds could easily be

40.1(2)^◦and 45.0(2)^◦with the phenyl ring containing intercalated in this network. The pyrazole derivatives

C(21) and C(31), respectively. The tetrahydropyranyl which are shown in Fig. 3 are excellent ﬂuorophores

ring adopts a chair conformation. The Sn atom devi- and emit in the near ultraviolet to blue regime [13].

˚

ates by 0.381(9) A from the plane of the pyrazole ring. Moreover most of these compounds feature remark-

The Sn–C bonds adopt typical values (Sn(1)–C(4) = able high solid-state quantum yields [13]. It is our

˚

2.137(5) A, Sn(1)–C(6) = 2.122(7) A, Sn(1)–C(7) = current working hypothesis that the rigid framework

˚

2.146(8) A, Sn(1)–C(8) = 2.161(6) A).

of these pyrazoles, due to the hydrogen bonding net-

In summary, it was found that the crystal structures works in the solid state, prevents self-quenching. In

of herein described pyrazoles reveal two different types contrast to these pyrazoles, despite of their strong ﬂuo-

of hydrogen bonding networks in the solid state: inﬁ- rescence in dilute solutions, many related arenes, e. g.

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M. Pejic et al. · Functionalized Pyrazoles as Agents in C–C Cross-Coupling Reactions

Table 1. Crystal data and

1a·HBr

1b

(2a)₃·H₂SO₄

numbers pertinent to data

collection and structure

reﬁnement of 1a · HBr, 1b,

Formula

M_r

Crystal size, mm³

Crystal system

Space group

C₃H₄Br₂N₂

227.90

C₁₅H₁₁BrN₂

299.17

C₉H₁₁I₃N₆O₄S

680.00

0.60 × 0.06 × 0.03

monoclinic

P2₁/n

4.8444(8)

7.2728(8)

17.666(3)

90

97.711(13)

90

616.79(16)

4

0.20 × 0.20 × 0.10

0.43 × 0.24 × 0.17

(1c)₂·HBr, 1c·HBr·(Br₂)_0.5

,

triclinic

(2a)₃·H₂SO₄, 3a, 3a·H₂O,

3b, 4a, and 5b.

¯

P1

¯

P1

˚

a, A

9.7718(7)

9.8208(8)

13.3022(10)

88.134(6)

78.308(6)

86.384(6)

1247.34(17)

4

8.9930(8)

9.3479(8)

11.1707(9)

77.945(7)

89.325(7)

82.048(7)

909.39(14)

2

˚

b, A

˚

c, A

α, deg

β, deg

γ , deg

3

˚

V, A

Z

D_calcd., g cm⁻³

µ(MoK_α), mm⁻¹

F(000), e

2.45

13.0

424

1.59

3.3

600

2.48

5.3

628

hkl range

((sinθ)/λ)_max, A

±5, ±8, ±21

±12,−10/12, ±16

±10, ±11, ±13

−1

˚

0.603

0.595

Reﬂ. measured

Reﬂ. unique/R_int

Param. reﬁned

7424

1155/0.10

70

0.0520/0.1161

1.166

0.0384/3.3504

–

1.02/−1.19

(1c)₂·HBr

C₆H₃Br₇N₄

690.49

0.26 × 0.09 × 0.09

monoclinic

P2/c

6.7961(8)

8.5362(7)

13.5242(17)

90

97.497(10)

90

777.87(15)

2

2.95

12804

4909/0.08

332

0.0527/0.1196

1.016

0.0873/0

–

0.99/−0.97

1c·HBr·(Br₂)_0.5

C₃H₂Br₅N₂

465.62

13396

3049/0.07

228

0.0320/0.0843

1.264

0.0321/1.9303

–

R(F)/wR(F²)^a(all reﬂs.)

GoF (F²)^a

a/b^a

x (Flack)

−3

˚

∆ρ_ﬁn(max/min), e A

1.41/−0.98

3a

Formula

M_r

Crystal size, mm³

Crystal system

Space group

C₉H₁₅BN₂O₂

194.04

0.14 × 0.12 × 0.05

0.47 × 0.07 × 0.06

orthorhombic

P2₁2₁2₁

6.4338(5)

11.6185(11)

14.6384(15)

90

triclinic

¯

P1

˚

a, A

6.2262(7)

9.7680(11)

9.8982(12)

115.824(8)

98.612(7)

90.796(7)

533.64(11)

2

˚

b, A

˚

c, A

α, deg

β, deg

90

γ , deg

3

˚

V, A

1094.24(17)

4

1.18

0.1

416

Z

D_calcd., g cm⁻³

µ(MoK_α), mm⁻¹

F(000), e

2.90

18.8

418

18.0

624

hkl range

((sinθ)/λ)_max, A

±8, ±10, ±16

±7, ±11, ±12

±7,−14/13, ±17

−1

˚

0.607

0.609

0.608

Reﬂ. measured

Reﬂ. unique/R_int

Param. reﬁned

9893

1473/0.09

78

0.0482/0.0757

1.065

0.0245/0

–

11694

2001/0.07

92

0.0568/0.1197

1.066

0.0436/1.6776

–

13084

1213/0.10

131

0.0489/0.1056

1.135

0.0594/0.1273

3(2)

R(F)/wR(F²)^a(all reﬂs.)

GoF (F²)^a

a/b^a

x (Flack)

−3

˚

∆ρ_ﬁn(max/min), e A

0.60/−0.86

1.16/−1.02

0.20/−0.16

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93

Table 1. (Continued.)

(3a)₃·H₂O

3b

4a

5b(THP)

C₂₃H₂₈N₂OSn

467.16

0.45 × 0.44 × 0.42

monoclinic

P2₁/c

Formula

M_r

Crystal size, mm³

Crystal system

Space group

C₉H_15.67BN₂O_2.33

200.04

C₂₁H₂₃BN₂O₂

346.22

0.24 × 0.22 × 0.13

orthorhombic

Pna2₁

C₆H₁₂N₂Si

140.27

0.31 × 0.09 × 0.05

monoclinic

Pc

0.38 × 0.12 × 0.08

trigonal

R3c

˚

a, A

21.9145(13)

12.2459(7)

90

120

5093.1(7)

18

1.17

0.1

1932

14.0983(6)

17.751(11)

15.3822(8)

90

3843.9(4)

8

1.20

0.1

1472

14.738(2)

6.6246(13)

19.942(3)

90

110.334(11)

90

1770.6(5)

8

1.05

13.0408(7)

37.3306(14)

8.9951(5)

90

90.687(4)

90

4378.7(4)

8

1.42

˚

b, A

˚

c, A

α, deg

β, deg

γ , deg

3

˚

V, A

Z

D_calcd., g cm⁻³

µ(MoK_α), mm⁻¹

F(000), e

0.2

608

1.2

1904

hkl range

((sinθ)/λ)_max, A

±26, ±26,−13/15

±17, ±21, ±18

±18, ±7, ±24

±15, ±44, −10/9

−1

˚

0.5905

0.595

Reﬂ. measured

Reﬂ. unique/R_int

Param. reﬁned

21745

2096/0.07

142

0.0520/0.0850

1.102

0.0436/0.4269

−0.8(6)

0.13/−0.13

44335

7400/0.10

474

0.0590/0.1328

1.067

0.0722/0.8198

−0.8(9)

0.51/−0.27

25234

6512/0.18

321

0.1651/0.3216

0.999

0.1952/0

0.5(2)

33450

7739/0.10

487

0.0827/0.1464

1.132

0.0489/9.7047

–

R(F)/wR(F²)^a(all reﬂs.)

GoF (F²)^a

a/b^a

x (Flack)

−3

˚

∆ρ_ﬁn(max/min), e A

1.66/−0.48

0.85/−1.01

a

R(F) = Σ||F_o|−|F ||/Σ|F_o|; wR(F²) = [Σw(F²−F²)²/Σw(F²)²]^1/2; GoF = [Σw(F²−F²)²/(n_obs−n_param)]^1/2; w = [σ²(F_o²)+(aP)²+

c

o

c

o

c

bP]⁻¹, where P = (Max(F_o²,0)+2F²)/3.

c

the pyridyl indols 8(F) and 8(Cl) (Fig. 16) [14], tend to Crystals of 4-bromo-1H-pyrazole and HBr (1a·HBr)

show a poor performance in the solid state, mainly due

to π stacking.

The bromopyrazole 1a was prepared according to the pub-

lished procedure [16]. By slow evaporation of the solvent

water crystals of 1a and HBr were grown from the reaction

mixture at r. t.

Experimental Section

Single crystals of 4-bromo-3,5-diphenyl-1H-pyrazole (1b)

The solvents THF, pentane, toluene, and C₆D₆were

stirred over sodium/benzophenone and distilled prior to

use. 1a [16], 1a(THP) [17], 1b [18], 1c [19], 2a [20],

2a(THP) [21], 2b [20], 3a [22], 3a(THP) [23], and 4a [24]

were prepared according to published procedures. All other

starting materials were purchased from commercial sources

and used without further puriﬁcation. The NMR spectra were

The bromopyrazole 1b was prepared according to the pub-

lished procedure [18]. Single crystals of 1b were grown from

a CH₂Cl₂solution by slow evaporation of the solvent at r. t.

4-Bromo-3,5-diphenyl-1-THP-pyrazole (1b(THP))

3,4-Dihydro-2H-pyran (DHP) (0.62 g, 7.35 mmol) was

recorded on Bruker AM 250, DPX 250, Avance 400, and added dropwise at 85 ^◦C to a mixture of 1b (2.00 g,

Avance 500 spectrometers. NMR chemical shifts are re- 6.69 mmol) and a catalytic amount of triﬂuoroacetic acid

ported in ppm. Abbreviations: s = singlet; d = doublet; dd = (TFA) (0.04 g, 0.33 mmol) in 20 mL toluene. The solution

doublet of doublets; t = triplet; m = multiplet; br = broad; was warmed up to 95 ^◦C and kept stirring for further 1 h.

n. o. = not observed. Mass spectrometry was performed with After removing all volatiles in vacuo, 1b(THP) remained

a Fisons VG Platform II instrument and microwave irradi- as a pale-yellow oil that was suitable for direct conver-

ation was generated with a Biotage Initiator⁺System. El- sion (yield: 2.54 g, 99%). – ¹H NMR (400 MHz, CDCl₃):

emental analyses were carried out by the Microanalytical δ = 7.98 – 7.95 (m, 2H, oPh-H), 7.60 – 7.57 (m, 2H, oPh-

Laboratory of the Goethe University Frankfurt.

H), 7.55 – 7.50 (m, 3H, Ph-H), 7.46 – 7.42 (m, 2H, mPh-H),

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M. Pejic et al. · Functionalized Pyrazoles as Agents in C–C Cross-Coupling Reactions

7.39 – 7.35 (m, 1H, pPh-H), 5.14 (dd, J = 2.5, 10.1 Hz, Crystals of 4-pinacolatoboryl-1H-pyrazole and H₂O

1H, THP-H), 4.14 – 4.10 (m, 1H, THP-H), 3.56 – 3.50 (m, ((3a)₃·H₂O)

1H, THP-H), 2.65 – 2.55 (m, 1H, THP-H), 2.10 – 2.06 (m,

1H, THP-H), 1.87 – 1.83 (m, 1H, THP-H), 1.79 – 1.69 (m,

1H, THP-H), 1.61 – 1.50 (m, 2H, THP-H). – ¹³C NMR

(100 MHz, CDCl₃): δ = 149.0 (pzC-3,5), 143.4 (pzC-3,5),

132.5 (PhC), 130.4 (PhCH), 129.5 (PhCH), 128.7 (PhCH),

128.4 (PhCH), 128.3 (PhCH), 128.3 (PhCH), 93.6 (pzC-

4), 85.2 (THP), 67.9 (THP), 29.5 (THP), 24.9 (THP), 22.9

(THP), n. o. (PhC).

The pyrazole 3a was prepared according to the published

procedure [22]. By slow evaporation of the solvent water

crystals of (3a)₃·H₂O were grown from the reaction solution

at r. t.

4-Pinacolatoboryl-3,5-diphenyl-1H-pyrazole (3b)

A 2 M solution of iPrMgCl (0.31 g, 3.03 mmol) was added

dropwise to a cooled (−4 ^◦C) solution of 2b(THP) (0.87 g,

2.02 mmol) in THF (10 mL). After 15 min (Bpin)OiPr

(1.13 g, 6.07 mmol) was added dropwise at −4 ^◦C to the

suspension. The resulting mixture was stirred for further

1.5 h and slowly warmed up to r. t. overnight. After the

addition of saturated aqueous NH₄Cl solution, the slurry

was diluted with toluene (25 mL) and washed with brine

(3 × 20 mL). The organic layer was dried over anhydrous

MgSO₄. After removal of all volatile compounds in vacuo,

a yellow oil was obtained. 3b(THP) was treated with 20 mL

of a methanolic HCl solution (AcCl in MeOH) and stirred for

30 min. After the addition of NEt₃(2 mL), the solution was

stirred for further 30 min, diluted with Et₂O (50 mL), washed

with water (3 × 30 mL), and dried over anhydrous MgSO₄.

Single crystals of (1c)₂·HBr and 1c·HBr·(Br₂)_0.5

The bromopyrazole 1c was prepared according to the pub-

lished procedure [19]. Single crystals of (1c)₂·HBr were

grown from the reaction mixture at r. t. In a second crop crys-

tals containing 1c, HBr, and Br₂in the ratio of 1 : 1 : 0.5 were

obtained from this solution at r. t.

Crystals of 4-iodo-1H-pyrazole and H₂SO₄((2a)₃·H₂SO₄)

The iodopyrazole 2a was prepared according to the pub-

lished procedure [20]. By slow evaporation of the solvent

crystals of (2a)₃·H₂SO₄were grown from a chloroform so-

lution at r. t.

Single crystals of 4-iodo-3,5-diphenyl-1H-pyrazole (2b)

The iodopyrazole 2b was prepared according to the pub- Evaporation of the solvents gave a yellow oil, which was

lished procedure [20]. Single crystals of 2b were grown from puriﬁed by column chromatography (hexane/ethyl acetate

a CHCl₃solution by slow evaporation of the solvent at r. t.

3 : 1). Single crystals were grown by gas-phase diffusion

of cyclohexane into a solution of 3b in benzene. Colorless

solid (yield: 0.52 g, 60%). – H NMR (500 MHz, CDCl₃):

4-Iodo-3,5-diphenyl-1-THP-pyrazole (2b(THP))

1

δ = 7.73 – 7.71 (m, 4H, oPh-H), 7.43 – 7.36 (m, 6H, Ph-H),

1.26 (s, 12H, CH₃), n. o. (N-H). – ¹³C NMR (126 MHz,

CDCl₃): δ = 154.6 (pzC-3,5), 132.5 (PhC), 128.6 (PhCH),

128.5 (PhCH), 128.4 (PhCH), 83.8 (CCH₃), 24.9 (CH₃).

2b(THP) was synthesized following the same procedure

as described for 1b(THP) from DHP (0.13 g, 1.59 mmol),

2b (0.50 g, 1.44 mmol), TFA (0.01 g, 0.07 mmol) and

10 mL toluene. Pale-yellow oil (yield: 0.61 g, 98%). – ¹H

NMR (400 MHz, CDCl₃): δ = 7.92 – 7.90 (m, 2H, oPh-

H), 7.56 – 7.50 (m, 5H, Ph-H), 7.47 – 7.43 (m, 2H, mPh-

H), 7.40 – 7.38 (m, 1H, pPh-H), 5.12 (dd, J = 2.5, 10.1 Hz,

1H, THP-H), 4.12 – 4.08 (m, 1H, THP-H), 3.53 – 3.47 (m,

1H, THP-H), 2.63 – 2.51 (m, 1H, THP-H), 2.08 – 2.04 (m,

–

¹¹B{H} NMR (160 MHz, CDCl₃): δ = 31.3 (h_1/2

=

350 Hz). – MS ((+)-ESI): m/z(%) = 347.6 (100) [M+H]⁺.

– C₂₁H₂₃BN₂O₂(346.2): calcd. C 72.85, H 6.70, N 8.09;

found C 73.41, H 6.68, N 7.47.

1H, THP-H), 1.87 – 1.83 (m, 1H, THP-H), 1.79 – 1.68 (m, 4-Trimethylsilyl-1H-pyrazole (4a)

1H, THP-H), 1.60 – 1.49 (m, 2H, THP-H). – ¹³C NMR

(100 MHz, CDCl₃): δ = 152.3 (pzC-3,5), 146.8 (pzC-3,5),

133.2 (PhC), 130.7 (PhCH), 129.9 (PhC), 129.5 (PhCH),

128.8 (PhCH), 128.7 (PhCH), 128.3 (PhCH), 128.2 (PhCH),

85.4 (THP), 67.9 (THP), 62.3 (pzC-4), 29.6 (THP), 24.9

(THP), 22.9 (THP).

The pyrazole 4a was synthesized from 4a(THP) fol-

lowing the same procedure as described for 3a and 3b.

The THP-protected iodopyrazole 2a(THP) [21] (0.20 g,

0.72 mmol), nBuLi (0.12 g, 1.80 mmol), and Me₃SiCl

(0.23 g, 2.16 mmol) were used as starting materials. – ¹H

NMR (250 MHz, C₆D₆): δ = 7.81 (s, 1H, pzH-3,5), 7.28

(s, 1H, pzH-3,5), 5.68 (dd, J = 3.2, 9.1 Hz, 1H, THP-H),

Single crystals of 4-pinacolatoboryl-1H-pyrazole (3a)

The pyrazole 3a was prepared according to the published 4.10 – 4.04 (m, 1H, THP-H), 3.84 – 3.67 (m, 1H, THP-H),

procedure [22]. Single crystals of 3a were grown from an 2.63 – 2.51 (m, 1H, THP-H), 2.08 – 2.04 (m, 1H, THP-H),

ethyl acetate solution by slow evaporation of the solvent at 1.87 – 1.83 (m, 1H, THP-H), 1.79 – 1.68 (m, 1H, THP-H),

r. t.

1.60 – 1.49 (m, 2H, THP-H), 0.15 (s, 9H, CH₃). After treat-

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95

ment of 4a(THP) with 20 mL of a methanolic HCl solution 4-Trimethylstannyl-1-THP-pyrazole (5a(THP))

(AcCl in MeOH) 4a was obtained. Spectroscopic data see

A 1.52 M nBuLi solution in hexane (0.14 g, 2.20 mmol)

was added dropwise (−78 ^◦C) to a stirred solution of

1a(THP) (0.39 g, 1.70 mmol) in THF (6 mL). After stirring at

−78 ^◦C for 2 h, a solution of Me₃SnCl (0.50 g, 2.53 mmol) in

THF (5 mL) was added dropwise to the cooled reaction mix-

ture (−78 ^◦C). The suspension was warmed to r. t. overnight,

then diluted with Et₂O (60 mL) and treated with water

(60 mL). The organic layer was dried over anhydrous MgSO₄

and evaporated to dryness in vacuo. However, the synthe-

sis of 5a(THP) was not quantitative. Beside the main prod-

uct 5a(THP) we observed two other stannylated and THP-

protected pyrazol derivatives, namely 3-Me₃Sn-pz(THP) and

5-Me₃Sn-pz(THP) (ratio in the ¹H NMR spectrum: ∼65%

for 5a(THP), ∼25% for 3-Me₃Sn-pz(THP), ∼10% for 5-

Me₃Sn-pz(THP)). Spectroscopic data for 5a(THP): – ¹H

NMR (500 MHz, CDCl₃): δ = 7.53 (s, 1H, pzH-3,5), 7.51

(s, 1H, pzH-3,5), 5.42 (dd, J = 2.3, 10.0 Hz, 1H, THP-H),

4.09 – 4.06 (m, 1H, THP-H), 3.73 – 3.68 (m, 1H, THP-H),

2.21 – 2.13 (m, 1H, THP-H), 2.09 – 2.04 (m, 2H, THP-H),

1.74 – 1.66 (m, 3H, THP-H), −0.19 (s, 9H, CH₃). – ¹³C

NMR (125 MHz, CDCl₃): δ = 145.6 (pzC-3,5), 132.8 (pzC-

3,5), 111.7 (pzC-4), 87.5 (THP), 68.1 (THP), 30.8 (THP),

25.2 (THP), 22.8 (THP), −9.1 (CH₃).

ref. [24].

An alternative and more convenient synthesis of 4a: 4-

Bromo-1H-pyrazole (6.69 g, 45.52 mmol) was dissolved in

50 mL THF and the solution was cooled to −78 ^◦C. This

solution was treated dropwise with a 1.6 M nBuLi solu-

tion in hexane (5.83 g, 91.04 mmol). The reaction mixture

was subsequently stirred for 1 h at 0 ^◦C. Me₃SiCl (14.02 g,

129.05 mmol) was added dropwise at −78 ^◦C. The reac-

tion mixture was warmed up to r. t. overnight. Then it was

quenched with an aqueous NaOH solution, diluted with ethyl

acetate (150 mL) and washed with a saturated NaHCO₃solu-

tion (3 × 50 mL). The crude product was puriﬁed by column

chromatography (hexane/ethyl acetate 2 : 1) to yield col-

orless crystals (yield: 2.19 g, 60%). Spectroscopic data see

ref. [24].

4-Trimethylsilyl-3,5-diphenyl-1-THP-pyrazole (4b(THP))

The pyrazole 4b(THP) was synthesized following the

same procedure as described for 3a(THP), 3a(THP), and

4a(THP). The THP-protected iodopyrazole 2b(THP) [21]

(0.20 g, 0.52 mmol), nBuLi (0.08 g, 1.30 mmol), and

Me₃SiCl (0.17 g, 1.57 mmol) were used as starting materi-

1

4-Trimethylstannyl-3,5-diphenyl-1-THP-pyrazole (5b)

als. – H NMR (250 MHz, C₆D₆): δ = 7.86 – 7.82 (m, 2H,

oPh-H), 7.30 – 7.10 (m, 8H, Ph-H), 5.04 (dd, J = 3.2, 9.6 Hz,

1H, THP-H), 3.88 – 3.84 (m, 1H, THP-H), 3.16 – 3.06 (m,

1H, THP-H), 2.87 – 2.68 (m, 1H, THP-H), 1.74 – 1.61 (m,

2H, THP-H), 1.37 – 1.26 (m, 1H, THP-H), 1.07 – 0.88 (m,

2H, THP-H), −0.01 (s, 9H, CH₃).

1b(THP) (1.09 g, 2.84 mmol) in THF (15 mL) was treated

dropwise with a 1.35 M nBuLi solution in hexane (0.24 g,

3.70 mmol) at −78 ^◦C and stirred for 2 h. A solution of

Me₃SnCl (0.85 g, 4.27 mmol) in THF (10 mL) was added

dropwise to the cooled reaction mixture (−78 ^◦C). After

warming up to r. t. overnight, the suspension was diluted

with Et₂O (100 mL) and treated with water (150 mL). The

organic layer was dried over anhydrous MgSO₄and con-

4-Trimethylsilyl-3,5-diphenyl-1-TMS-pyrazole (4b(TMS))

4-Bromo-3,5-diphenyl-1H-pyrazole (0.40 g, 1.34 mmol) centrated to a volume of 2 mL. The product precipitated af-

was dissolved in 10 mL THF, and the solution was cooled ter 12 h. Analytically pure 5 was obtained from the crude

to −78 ^◦C. This solution was treated dropwise with a 1.52 M product by washing with hexane. Single crystals were grown

nBuLi solution in hexane (0.21 g, 3.34 mmol). The reaction by slow evaporation of a CDCl₃solution. Colorless solid

mixture was subsequently stirred for 1 h at 0 ^◦C. Me₃SiCl (yield: 0.95 g, 72%). – ¹H NMR (250 MHz, CDCl₃): δ =

(0.43 g, 4.01 mmol) was added dropwise at −78 ^◦C. The 7.64 – 7.59 (m, 2H, oPh-H), 7.47 (s, 5H, Ph-H), 7.42 – 7.33

reaction mixture was warmed up to r. t. overnight. NMR (m, 3H, Ph-H), 5.10 (dd, J = 2.4, 10.3 Hz, 1H, THP-H),

data were collected without further puriﬁcation. Colorless 4.14 – 4.08 (m, 1H, THP-H), 3.55 – 3.45 (m, 1H, THP-H),

solid (yield: 0.95 g, 72%). – ¹H NMR (500 MHz, C₆D₆): 2.69 – 2.53 (m, 1H, THP-H), 2.07 – 2.01 (m, 1H, THP-H),

δ = 7.85 – 7.83 (m, 2H, oPh-H), 7.29 – 7.27 (m, 2H, oPh- 1.90 – 1.85 (m, 1H, THP-H), 1.79 – 1.46 (m, 3H, THP-H),

H), 7.24 – 7.21 (m, 2H, mPh-H), 7.18 – 7.14 (m, 1H, pPh- −0.19 (s, 9H, CH₃). – ¹³C NMR (63 MHz, CDCl₃): δ =

H), 7.10 – 7.03 (m, 3H, Ph-H), 0.19 (s, 9H, NSiCH₃), 0.00 158.7 (pzC-3,5), 151.0 (pzC-3,5), 136.2 (PhC), 132.5 (PhC),

(s, 9H, CSiCH₃). – ¹³C NMR (125 MHz, C₆D₆): δ = 130.4 (PhCH), 128.9 (PhCH), 128.8 (PhCH), 128.5 (PhCH),

161.3 (pzC-3,5), 156.9 (pzC-3,5), 137.7 (PhC), 135.3 (PhC), 128.2 (PhCH), 127.7 (PhCH), 112.1 (pzC-4), 84.6 (THP),

131.2 (PhCH), 130.1 (PhCH), 128.9 (PhCH), 128.4 (PhCH), 67.9 (THP), 30.0 (THP), 25.0 (THP), 23.1 (THP), −8.0

128.2 (PhCH), 128.0 (PhCH), 113.8 (pzC-4), 1.2 (CSiCH₃), (CH₃). – MS ((+)-ESI): m/z(%) = 469.2 (100) [M+H]⁺.

0.9 (NSiCH₃). – ²⁹Si NMR (99 MHz, C₆D₆): δ = 15.4, – C₂₃H₂₈N₂OSn (467.2): calcd. C 59.13, H 6.04, N 6.00;

−10.9.

found C 58.98, H 6.12, N 5.98.

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M. Pejic et al. · Functionalized Pyrazoles as Agents in C–C Cross-Coupling Reactions

4-(p-Pentylphenyl)-1H-pyrazole (6(pentyl)) [13]

3.86 mmol), Pd(PPh₃)₄(0.15 g, 0.12 mmol), 3a(THP)

(0.36 g, 1.29 mmol), and 4-(2-ethylhexyl)bromobenzene

(0.35 g, 1.29 mmol). Colorless solid (yield: 0.29 g, 65%). –

¹H NMR (250 MHz, CD₃OD): δ = 7.90 (s, 2H, pzH-3,5),

7.47 (d, 2H, J = 8.3 Hz, Ph-H), 7.14 (d, 2H, J = 8.3 Hz, Ph-

H), 2.53 (d, 2H, J= 7.0 Hz, CH₂), 1.62 – 1.52 (m, 1H, CH),

1.35 – 1.24 (m, 8H, 4 × CH₂), 0.93 – 0.87 (m, 6H, 2 × CH₃),

n. o. (N-H). – ¹³C NMR (63 MHz, CD₃OD): δ = 141.1

(PhC), 131.4 (PhC), 130.7 (PhCH), 126.4 (PhCH), 123.8

(pzC-4), 42.5 (CH), 40.8 (CH₂), 33.5 (CH₂), 30.0 (CH₂),

26.6 (CH₂), 24.0 (CH₂), 14.4 (CH₃), 11.2 (CH₃), n. o. (pzC-

3,5). – MS ((+)-ESI): m/z(%) = 258.3 (100) [M+H]⁺. –

C₁₇H₂₄N₂(256.4): calcd. C 79.64, H 9.44, N 10.33; found

C 79.28, H 9.29, N 9.81.

K₃PO₄(0.33 g, 1.54 mmol) was dissolved in 5 mL dmf

and 5 mL water, and the solution was saturated with ar-

gon. A mixture of Pd(PPh₃)₄(0.06 g, 0.05 mmol), 3a(THP)

(0.14 g, 0.51 mmol), and 4-pentylbromobenzene (0.12 g,

92 µL, 0.51 mmol) was added to the K₃PO₄solution. The

resulting suspension was saturated with argon. After mi-

crowave irradiation at 120 ^◦C for 20 min, the reaction mix-

ture was treated with a saturated aqueous NaHCO₃solu-

tion (30 mL). The product was extracted into ethyl acetate

(3 × 30 mL). The combined organic layers were washed

three times with 30 mL of a saturated aqueous NaCl solu-

tion and dried over anhydrous MgSO₄. After removal of the

solvent in vacuo, the THP-protected product remained as

a pale-yellow oil (0.12 g, 82%). Treatment with a solution Crystal structure determinations

of HCl in MeOH (10 mL, AcCl in MeOH) and stirring for

Data for (1c)₂·HBr and 1c·HBr·(Br₂)_0.5were collected

30 min yielded the hydrochloride of 6(pentyl) [13]. When

the hydrochloride was treated with NEt₃(1 mL), the pyra-

zole 6(pentyl) [13] was obtained quantitatively. After evapo-

ration of the solvent, the crude product was puriﬁed by col-

umn chromatography (hexane/ethyl acetate 2 : 1). Colorless

solid (yield: 0.07 g, 68%). – ¹H NMR (500 MHz, CD₃OD):

δ = 7.90 (br, 2H, pzH-3,5), 7.46 (d, 2H, J = 8.0 Hz, Ph-

H), 7.17 (d, 2H, J = 8.0 Hz, Ph-H), 2.60 (t, 2H, J = 7.6 Hz,

CH₂), 1.66 – 1.60 (m, 2H, CH₂), 1.38 – 1.29 (m, 4H, 2 ×

CH₂), 0.91 (t, 3H, J = 7.0 Hz, CH₃), n. o. (N-H). – ¹³C

NMR (126 MHz, CD₃OD): δ = 142.2 (PhC), 137.3 (pzC-

3,5), 131.4 (PhC), 129.9 (PhCH), 126.5 (PhCH), 123.7 (pzC-

4), 36.5 (CH₂), 32.6 (CH₂), 32.4 (CH₂), 23.6 (CH₂), 14.4

(CH₃). – MS ((+)-ESI): m/z(%) = 215.9 (13) [M+H]⁺.

on a Stoe IPDS II two-circle diffractometer with graphite-

˚

monochromated MoK_αradiation (λ = 0.71073 A) and cor-

rected for absorption with an empirical absorption correc-

tion using the program PLATON [25]. Data for 1a·HBr, 1b,

(2a)₃·H₂SO₄, 3a, (3a)₃·H₂O, 3b, 4a, and 5b(THP) were

collected on a Stoe IPDS II two-circle diffractometer with

a Genix Microfocus tube with mirror optics using MoK_α

˚

radiation (λ = 0.71073 A) and were scaled using the frame

scaling procedure in the X-AREA program system [26]. The

structures were solved by Direct Methods using the program

SHELXS [27] and reﬁned against F²with full-matrix least-

squares techniques using the program SHELXL-97 [27].

The H atoms bonded to the N atoms in 1c·HBr·(Br₂)_0.5

and (1c)₂·HBr were geometrically positioned and reﬁned us-

ing a riding model. The H atom bonded to the N(1) atom has

an occupation factor of 0.5.

4-(p-Hexylphenyl)-1H-pyrazole (6(hexyl)) [13]

6(hexyl) [13] was synthesized following the same proce-

dure as for 6 from K₃PO₄(0.34 g, 1.62 mmol), Pd(PPh₃)₄

(0.06 g, 0.05 mmol), 3a(THP) (0.15 g, 0.54 mmol), and 4-

hexylbromobenzene (0.13 g, 0.54 mmol). Colorless solid

The coordinates of the H atoms bonded to N in 1a·HBr

˚

were reﬁned restraining the N–H bond lengths to 0.89(1) A.

The H atoms bonded to B in 3a were isotropically reﬁned.

Due to the absence of anomalous scatterers, the absolute

structure of 3a could not be determined. The coordinates of

the H atoms bonded to N and O in (3a)₃·H₂O were reﬁned

1

(yield: 0.11 g, 65%). – H NMR (500 MHz, CD₃OD): δ =

7.90 (s, 2H, pzH-3,5), 7.45 (d, 2H, J = 8.0 Hz, Ph-H),

7.15 (d, 2H, J = 8.0 Hz, Ph-H), 2.60 (t, 2H, J = 7.5 Hz,

CH₂), 1.66 – 1.58 (m, 2H, CH₂), 1.38 – 1.29 (m, 6H, 3x

CH₂), 0.91 – 0.88 (m, 3H, CH₃), n. o. (N-H). – ¹³C NMR

(126 MHz, CD₃OD): δ = 142.2 (PhC), 133.1 (pzC-3,5),

131.4 (PhC), 129.9 (PhCH), 126.5 (PhCH), 123.7 (pzC-

4), 36.5 (CH₂), 32.6 (CH₂), 32.4 (CH₂), 25.0 (CH₂), 23.6

(CH₂), 14.4 (CH₃). – MS ((+)-ESI): m/z(%) = 229.8 (100)

[M+H]⁺.

˚

restraining the O–H bond lengths to 0.84(1) A and the N–

˚

H bond lengths to 0.91(1) A. The H atoms bonded to O and

N(3) have a site occupation factor of 2/3 and the H atom

bonded to N(4) has a site occupation factor of 1/3. Due to

the absence of anomalous scatterers, the absolute structure

of (3a)₃·H₂O could not be determined.

In 4a the three methyl groups of two molecules are dis-

ordered over two positions with site occupation factors of

0.55(6) and 0.78(2) for the site with the major occupancy.

Si–C and C–C bond lengths in the disordered parts were

restrained to be equal to those in a non-disordered SiMe₃

4-(p-(2-Ethylhexyl)phenyl)-1H-pyrazole (6(2-ethylhexyl))

[13]

6(2-ethylhexyl) [13] was synthesized following the same group. The disordered atoms were reﬁned isotropically. One

procedure as for 6(pentyl) [13] from K₃PO₄(0.82 g, methyl C atom (C(6C)) was restrained to an isotropic behav-

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M. Pejic et al. · Functionalized Pyrazoles as Agents in C–C Cross-Coupling Reactions

97

ior. The H atoms could not be located and were geometrically solute structure could not be determined. The coordinates of

positioned. The absolute structure could not be reliably de- the H atoms bonded to the N atoms in 1b were reﬁned re-

˚

termined, Flack (x) parameter 0.8(5). Attempts to reﬁne the straining the N–H bond lengths to 0.88(1) A.

structure in the space group P2₁/c failed.

CCDC 954167 (1a·HBr), CCDC 954174 (1b), CCDC

The H atoms bonded to N in (1a)₃·H₂SO₄were isotrop- 954166 ((1c)₂·HBr), CCDC 954165 (1c·HBr·(Br₂)_0.5),

ically reﬁned restraining the N(2A)–H(2A) bond length to CCDC 954171 ((2a)₃·H₂SO₄), CCDC 954168 (3a),

˚

0.88(1) A.

CCDC 954169 ((3a)₃·H₂O), CCDC 954172 (3b),

In one molecule of 3b, the dioxaborolane ring is disor- CCDC 954170 (4a), and CCDC 954173 (5b(THP))

dered over two positions with a factor of 0.695(7) for the contain the supplementary crystallographic data for

site with the major occupancy. The disordered atoms were this paper. These data can be obtained free of charge

reﬁned isotropically. The H atoms bonded to N were freely from The Cambridge Crystallographic Data Centre via

reﬁned. Due to the absence of anomalous scatterers, the ab- www.ccdc.cam.ac.uk/data request/cif.

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Functionalized pyrazoles as agents in C-C cross-coupling reactions

DOI: 10.5560/ZNB.2014-3224

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