A convenient approach to β-heteroarylated (C-N bond) ketones from Cs2CO3 promoted reaction between propargyl alcohols and nitrogen-heterocycles

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PAPER

A convenient approach to β-heteroarylated (C–N bond) ketones from Cs₂CO₃

promoted reaction between propargyl alcohols and nitrogen-heterocycles†‡

M. Bhanuchandra, Malleswara Rao Kuram and Akhila K. Sahoo*

Received 20th January 2012, Accepted 29th February 2012

DOI: 10.1039/c2ob25165e

An efﬁcient and direct approach to β-heteroarylated (C–N bond) ketones is demonstrated. Base promoted

redox isomerization of propargyl alcohol to α,β-unsaturated ketone followed by conjugate addition to

NH-heteroarenes affords a wide range of β-heteroarylated ketones in good to excellent yields. Aryl,

heteroaryl, alkyl C(sp), and terminal alkynes containing unactivated propargyl alcohols effectively

undergo redox-isomerization conjugate addition (RICA) with NH-heteroarenes. Reaction of 3-substituted

pyrazoles or indazole with propargyl alcohols enables highly regioselective products. A diverse range of

NH-bearing nucleophiles such as: pyrazoles, imidazole, triazoles, pyrrole, indoles and aniline participate

in this reaction and deliver the corresponding β-heteroarylated ketones.

unfortunately, hazardous wastes such as acids and quaternary

Introduction

amines are produced.^5,6The most preferred and atom-efﬁcient

Because of their unique structures, inherent properties and inter-

esting reactivities, nitrogen-containing heteroarenes are often

found in various natural products, materials and biologically

active compounds of pharmaceutical interest.¹Obviously, devel-

opment of simple and efﬁcient processes to N-heteroarenes has

always attracted considerable attention.²The azole-bearing com-

pounds ketoconazole, econazole, miconazole, ﬂuconazole, posa-

conazole are potential antifungal agents and are already in the

market.³Structure–activity relationship (SARs) studies reveal

that the 1-[3-aryloxy-3-aryl)propyl]-1H-imidazoles (A) are lead

structural units, showing potent activity against Candida albi-

cans and dermatophytes.³Compounds of type A can be easily

prepared from β-heteroarylated ketones (3) via the reduction of

the carbonyl group followed by O-arylation (Scheme 1).^5a

strategy is the conjugate addition of NH-bearing nucleophiles to

activated α,β-unsaturated ketones (path IV),⁷however, multiple

steps are invariably required for the preparation of starting

materials.⁸In addition, most of the strategies lack generality and

have a narrow reaction-scope.^4,6Therefore, discovering a practic-

able, and efﬁcient method for the construction of β-heteroary-

lated (C–N bond) ketones (3) from readily available starting

materials is always desirable.⁹

A brief overview of synthetic methods for the preparation of

β-heteroarylated (C–N bond) ketones (3) is shown in Scheme 2.

A multi-component reaction between ketones, formaldehyde and

NH-azoles is a convenient approach, however, this transform-

ation has limited substrate scope (path I).⁴Nucleophilic displace-

ment of β-chloro ketones or β-dialkyl ammonium salt with

nitrogen heterocycles is an alternate route (path II, III),

Scheme 1 Synthetic strategy to azole derivatives A.

School of Chemistry, University of Hyderabad, Hyderabad 500046,

India. E-mail: akssc@uohyd.ernet.in

†Dedicated to Professor Goverdhan Mehta, University of Hyderabad,

India, for his outstanding contribution to organic synthesis and his 70th

birthday.

‡Electronic supplementary information (ESI) available: Detailed optimi-

zation studies and ¹H and ¹³C NMR spectra for all new compounds.

CCDC reference numbers : 863901 and 863903. For ESI and crystallo-

graphic data in CIF or other electronic format see DOI: 10.1039/

c2ob25165e

Scheme 2 Overview of β-heteroarylated ketone synthesis.

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Table 1 Optimization of reaction conditions^a

An elegant method to α,β-unsaturated carbonyl compounds

from propargyl alcohols (1) through Ru-catalyzed redox-isomeri-

zation has been demonstrated by Trost and Livingston.^10f

Exploration of this strategy to O- and N-bearing heterocycles

involving intramolecular conjugate addition of the heteroatom to

α,β-unsaturated carbonyls derived from the propargyl alcohols

has been well-investigated.^10c,dA direct and chemoselective syn-

thesis of β-heteroarylated (C–C) ketones involves the addition of

indoles/furans to propargyl alcohols via a Ru/In catalyzed

tandem redox-isomerization conjugate addition (RICA) sequen-

ce.^10a,eThese results reveal the effective use of the transiently

formed α,β-unsaturated carbonyl compounds from propargyl

alcohols through redox-isomerization.¹⁰Moreover, propargyl

alcohols are highly-stable and easily fabricated by addition of

terminal alkynes into the carbonyl compounds in a single

step.^21e

Recently, we have shown atom-efﬁcient syntheses of aryl-

vinyl ethers and α-acyloxy methyl ketones;¹¹unactivated

alkynes are the key-structural units employed in these useful

transformations and a library of new molecular entities has been

created.¹¹Inspired by the above results and our current interest

in ﬁnding new atom-economical transformations, we envisioned

exploring a direct and efﬁcient approach to β-heteroarylated

ketones. We presume that the conjugate addition of NH-hetero-

arenes to transiently formed α,β-unsaturated carbonyls derived

from propargyl alcohols through redox-isomerization sequence

would create β-heteroarylated ketones directly. Reisch has shown

the addition of aniline to propargyl alcohols in the presence of

K₂CO₃and piperidine, when reﬂuxed in xylene.^12cDBU cata-

lyzed redox isomerization of activated propargyl alcohol fol-

lowed by aza-Michael attack of the nitrogen heterocycle is one

mild method to β-heteroarylated ketone synthesis.^12bTo the best

of our knowledge, intermolecular addition of various NH-hetero-

arenes to aryl, alkyl, TMS substituted and terminal alkynes con-

taining unactivated propargyl alcohols remains elusive.^12a

Herein we report a practical, efﬁcient, and highly-regioselective

single-step reaction strategy to β-heteroarylated ketones via

Cs₂CO₃promoted RICA between propargyl alcohols and NH-

bearing heteroarenes (Scheme 2).

Yield^b

(%)

Entry

2a (equiv)

Base

Solvent

Time (h)

3a

4a

1

2

3

4

5

6

7

8

2.0

1.5

1.2

1.0

K₂CO₃

i-Pr₂NEt

K₃PO₄

Cs₂CO₃

DBU

Cs₂CO₃

Toluene

THF

Dioxane

CH₃CN

DMF

CH₂Cl₂

Toluene

12

01

00

68

95

88

81

74

49

95

92

88

85

17

08

09

05

12

19

26

16

05

08

12

15

9

10

11

12

13

^aReactions were carried out using 1a (0.5 mmol), base (0.5 mmol) in

solvent (1.0 mL). ^bNMR yield.

3a was calculated as 95% by NMR (entry 4). With a selective

base in hand, the effect of solvent on this reaction was then

examined. Polar-aprotic solvents did not affect the progress of

the reaction; however, undesired 4a was detected in a substantial

amount (entries 5–8). For example: use of the solvents such as:

THF, dioxane, CH₃CN and DMF led to the formation of 4a in

12%, 19%, 19% and 26% yields, respectively (entries 5–8).

Among various solvents screened, toluene was found to be the

best (entry 4). Reaction between activated 4-aryl-4-hydroxy-2,3-

alkynyl esters and NH-heterocycles in the presence of DBU in

CH₂Cl₂provides 2-heterocycle-(C–N bond)-substituted-4-oxo-4-

arylbutanoates efﬁciently;^12bhowever, a moderate yield of 3a

was noticed under this reaction condition (entry 9). To our

delight, quantitative formation of 3a and complete consumption

of 1a was observed even within 1 h, when the reaction was per-

formed in Cs₂CO₃in toluene at 70 °C (entry 10). This demon-

strates the efﬁciency of the optimized condition. Next, the

amount of pyrazole required for this RICA transformation was

pursued. Loading of reduced amounts of pyrazole resulted in

producing the more of the redox isomerized product 4a (entries

11–13). Moreover, the use of 2.0 equiv of pyrazole was found to

be optimum.

Results and discussion

To probe the viability of the intermolecular addition of NH-het-

eroarenes to propargyl alcohols, the reaction between 1,3-diphe-

nylprop-2-yn-1-ol (1a) and pyrazole (2a) in the presence of

different bases was investigated at ﬁrst. Table 1 summarizes the

results of the optimization studies.¹³The reaction proceeds slug-

gishly at temperatures below 70 °C. Progress of the reaction was

monitored after stirring overnight (12 h) at 70 °C. Redox isomer-

ization of 1a to α,β-unsaturated ketone (4a) was exclusively

observed albeit in poor yield, when the reaction was performed

in K₂CO₃in toluene (entry 1, Table 1). Organic base i-Pr₂NEt

proved futile, producing only a negligible amount of 4a (entry

2). Gratifyingly, reaction of 1a in the presence of K₃PO₄deliv-

ered the desired 1,3-diphenyl-3-(1H-pyrazol-1-yl)propan-1-one

(3a) and 4a in 68% and 9% yields, respectively (entry 3). To our

delight, Cs₂CO₃base gave the best results and the yield of the

desired redox isomerization conjugate addition (RICA) product

Reaction scope

To explore the generality of the reaction and the synthesis of new

RICA products 3, reactions between a variety of propargyl alco-

hols and pyrazole (2a) were investigated under the optimized

conditions (1 equiv of Cs₂CO₃in toluene at 70 °C). The effect

of substitution on the aryl-moiety at the propargyl position of the

propargyl alcohol, 1-aryl-3-phenylprop-2-yn-1-ol (1), on the

RICA with 2a was examined at ﬁrst (Table 2). As observed in

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Table 2 Effect of arenes at the propargyl position of propargyl

alcohols to the RICAwith 2a^a,b

Table 3 RICA of heteroarenes/arenes and/or C(sp)-alkyls containing

propargyl alcohols with 2a^a,b

^aReactions were carried out using 1 (1.0 mmol), 2a (2.0 mmol),

Cs₂CO₃(1.0 mmol) in toluene (2.0 mL) at 70 °C. ^bIsolated yield. ^cAt

80 °C.

protected hydroxyl groups are sensitive to acidic and basic

reagents.¹⁵To assess the relative stability of the silyl-protecting

groups; the –OTBDMS containing precursor 1j was subjected to

the reaction condition. As anticipated, the TBDMS group was

partial survived and the corresponding silicon protected and de-

protected products 3j and 3i were isolated in 13%, 64% yields,

respectively. The optimized procedure was subsequently applied

to a range of propargyl alcohols having ortho-substituted arenes,

to assess the steric effect in this RICA reaction sequence

(Table 2). The ortho-halo groups on the aryl moiety are inert to

the reaction condition, displaying good reactivity and appreciable

yields (3k–m). Incomplete conversion of 1n was observed to the

synthesis of 3n (77% yield) even with prolonged reaction time.

1-Naphthyl substituted propargyl alcohol underwent RICA with

2a efﬁciently (3o). The more sterically demanding propargyl

alcohol 1p having two ortho-substitutions on aryl group did not

affect the product-formation, although the reaction requires

longer time for completion, producing 3p in slightly lower yield.

These experimental results reveal that the electronic as well as

steric effect on the aryl group at the propargyl position in propar-

gyl alcohol did not inﬂuence much to the reaction outcome.

Next, the RICA reactions of 2a with heteroaryl bearing pro-

pargyl alcohols were surveyed (Table 3). The nucleophilic

β-carbon and the acidic α-hydrogen of furan and thiophene

would lead to C-alkylation product with propargyl alcohols.¹⁷

Fortunately, the furyl- and thienyl-2-substituted propargyl alco-

hols (1q and 1r) reacted efﬁciently with 2a and afforded the cor-

responding β-pyrazolyl ketones 3q and 3r in 70% and 92%

yields, respectively. We then turned our attention to examine the

effect of alkyl-substitution at the C(sp)-center of the propargyl

alcohols on the RICA with 2a. The results are shown in Table 3.

It is obvious that the inductively donating alkyl group enhances

the electron density on the alkynes. As a consequence, slow

^aReactions were carried out using 1 (1.0 mmol), 2a (2.0 mmol),

Cs₂CO₃(1.0 mmol) in toluene (2.0 mL) at 70 °C. ^bIsolated yield.

^cCleavage of O-TBDMS protecting group was observed; the

corresponding –OH bearing product 3i was obtained in 64% yield.

the optimization studies, electronically neutral substrate 1a

reacted efﬁciently with 2a to give 3a in 80% isolated yield.^12d

The Cu-assisted or the base-mediated replacement of aromatic

halo-groups by pyrazole is a well-established phenomenon.¹⁴

Surprisingly ﬂuoro, chloro and bromo groups survived to this

reaction condition and the corresponding products 3b–d were

isolated in good yields. Transition-metal catalyzed functionaliza-

tion of the halo groups would generate new heteroaryl-bearing

valuable substrates. Interestingly, cyano group is survived;

however, trace of moisture in the system hydrolyses the cyano-

group partially, producing 3e in moderate yield.¹⁵Propargyl

alcohols having the electron-donating substitutions methyl,

methoxy or phenoxy groups at the 3- and/or 4-position on aro-

matic ring reacted efﬁciently with 2a and the corresponding pro-

ducts 3f–h are produced in excellent yields. Next, we examined

the RICA of propargyl alcohol containing free phenol-OH

moiety with 2a. A report of Liu group describes the synthesis of

benzofurans from Lewis-acid assisted annulation of phenols with

propargyl alcohols.¹⁶The phenoxide ion generated in situ with

the aid of the base is expected to undergo conjugate addition to

the α,β-unsaturated ketones.^10cGratifyingly, we did not observe

the participation of the free phenol-OH group in the reaction and

3i was exclusively obtained in 77% yield in 3 h. Generally, silyl

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Table 4 Electronic effect of aryl-groups of propargyl alcohols on

the RICAwith 2a^a,b

Table 5 RICA of terminal/TMS substituted propargyl alcohols with

2a^a

Yield^b

(%)

Entry

R¹

Ar

5

Time (h)

6

7

1

2

3

4

5

6

7

H

Me₃Si

C₆H₅

5a

5b

5c

5d

5e

5f

1

2

1

96

93

73

68

87

65

72

—

04

17

07

4-Me-C₆H₅

4-Cl-C₆H₅

1-Naphthyl

4-Me-C₆H₅

4-Cl-C₆H₅

1-Naphthyl

5g

^aReactions were carried out using 5 (1.0 mmol), 2a (2.0 mmol),

Cs₂CO₃(1.0 mmol) in toluene (2.0 mL) at 70 °C. ^bIsolated yield.

^aReactions were carried out using 1 (1.0 mmol), 2a (2.0 mmol),

Cs₂CO₃(1.0 mmol) in toluene (2.0 mL) at 70 °C. ^bIsolated yield.

Next, exploration of terminal and alkynyl-C-TMS protected

propargyl alcohols in the RICA with 2a was pursued and the

results are detailed in Table 5. Generally, base promotes the gen-

eration of the acetylides from terminal alkynes.¹⁸We speculate

that the formation of the corresponding ketones will occur

through the conjugate addition of the C-nucleophile (acetylide)

to α,β-unsaturated ketones, obtained from the base induced

redox isomerization of propargyl alcohol.¹⁹This would inhibit

the formation of the desired β-heteroarylated ketones. To probe

this assumption, the terminal propargyl alcohol 5a and 2a were

exposed to the optimized conditions. To our surprise, the β-pyra-

zolyl ketone 6a was exclusively obtained in 96% yield (entry 1,

Table 5). Similarly, an excellent yield of product 6b was isolated

from the reaction of electron-rich propargyl alcohol 5b with 2a

(entry 2). An electron withdrawing group at the p-position in the

alcohol 5c underwent RICA with 2a efﬁciently (entry 3). Reac-

tion of 2a with naphthalene-containing propargyl alcohol 5d was

performed and 6d was isolated in reasonable yield. Generally,

deprotection of the silyl protecting groups occurs under basic

media at ambient temperature.¹⁵With this fact in mind, we

intend to test the reaction condition for the alkynyl-TMS pro-

tected propargyl alcohols and the results are summarized in

Table 5. Although the reaction between 5e and 2a proceeded

efﬁciently, the corresponding C-TMS containing β-heteroary-

lated ketone 7e was obtained in poor yield (4%) and the silyl-

deprotected product 6b isolated in 87% yield (entry 5). Similar

trends of the product-selectivity were also noticed in case of the

RICA of 4-chlorophenyl and 1-naphthyl substituted alkynyl-

TMS containing propargyl alcohols (entries 6 and 7). We there-

fore conclude that this optimized reaction condition did not toler-

ate the C-TMS group up to our expectations.

redox-iosmerization of the propargyl alcohol to the α,β-conju-

gated ketone is expected. To overcome this problem, we there-

fore performed the reactions at a higher temperature and a

relatively longer time. Gratifyingly, product 3s was isolated in

84% yield, when the reaction between C(sp)-octyl substituted

propargyl alcohol 1s and 2a was conducted at 80 °C for 32 h.

Even though the reaction took 50 h at 80 °C, an excellent yield

of the desired 3t was isolated with the survival of the chloro

group. The electron-rich propargyl alcohol 1u smoothly partici-

pated in the RICA reaction and furnished the ketone 3u in good

yield. Similarly, the propargyl alcohol having thienyl and C(sp)-

alkyl moieties reacted with 2a and produced 3v in 77% yield.

Importantly, the sterically encumbered C(sp)-t-butyl containing

propargyl alcohol underwent RICA with 2a. Incomplete conver-

sion of 1w was noticed and the corresponding β-pyrazolyl

ketone 3w was isolated in 53% yield, even though the reaction

was continued for 4 days. The more sterically congested product

3x was obtained albeit in poor yield from the RICA between 1x

and 2a under the optimized condition.

Encouraged by the excellent performance of the RICA

between 1 and pyrazole, the effect of electronic groups on both

the arene-moieties attached at the propargyl and C(sp) positions

in propargyl alcohols was next investigated, and the results are

shown in Table 4. The presence of electron donating methoxy

substituents on both arenes did not affect the reaction efﬁciency,

and the desired RICA product 3aa was isolated in 83% yield.

Propargyl alcohol bearing an electron-withdrawing (–F) and

electron donating (–Me) group at para-position on both the aryl

moieties reacted with 2a, affording 3ab in 81% yield. Efﬁcient

reaction and excellent yield of the corresponding β-pyrazolyl

ketone 3ac was obtained from the RICA between the electron-

deﬁcient 1ac and 2a. These results show that the electronic vari-

ation of the propargyl alcohol did not display a pronounced

effect on the reaction efﬁciency.

To broaden the reaction scope, we then investigated the RICA

between various substituted pyrazoles and propargyl alcohols.

Table 6 summarizes the results of this study. The reaction of

3-substituted-pyrazole with the propargyl alcohol usually pro-

vides a mixture of two regioisomers. For example, addition of 3-

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Table 6 RICA between propargyl alcohols and pyrazole derivatives (2)^a

Entry

1

2

8

Time (h)

05

Yield^b(%) 8

1a

2b

83

2

3

4

1a

2c

2d

2e

05

93

79^c

89

Ar¹= 3-Br-C₆H₅

1a

5

6

1a

2f

05

92

1u

2b

32^c

Ar²= 4-Me-C₆H₅

7

2u

2f

60

65^c

^aReactions were carried out using 1 (1.0 mmol), 2 (2.0 mmol), Cs₂CO₃(1.0 mmol) in toluene (2.0 mL) at 70 °C. ^bIsolated yield. ^cAt 80 °C.

substituted pyrazole or indazole to 4-aryl-4-hydroxy-2,3-alkynyl

esters in the presence of DBU in CH₂Cl₂gave two non-separable

regioisomers of the corresponding β-heteroarylated ketones.^12b

To examine the amount of regioselective product formation in

the reaction, RICA between 3-phenyl pyrazole (2b) and 1a was

performed in the presence of Cs₂CO₃(1.0 equiv) in toluene at

70 °C. To our surprise, single regioisomer 8ab was exclusively

produced (entry 1). The structure of 8ab was conﬁrmed based

on X-ray crystallographic analysis.¹³Similarly, reaction of 3-(3-

bromophenyl)-1H-pyrazole (2c) with 1a led to only 8ac in excel-

lent yield. Heteronuclear multiple bond correlation (HMBC)

studies to 8ac reveal a strong correlation between C_aand H_b, H_a

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Table 7 RICA between propargyl alcohols and other NH-heteroarenes^a,c

^aReactions were carried out using 1 (1.0 mmol), 9–16 (2.0 mmol), Cs₂CO₃(1.0 mmol) in toluene (2.0 mL) at 70 °C. ^bReactions were carried out

using toluene (1.5 mL) + DMF (0.5 mL) at 80 °C. ^cIsolated yields. ^dAt 80 °C.

and C_bwhereas the correlation between H_aand C_dare not

seen.¹³Based on this observation, the structure of 8ac is estab-

lished; furthermore, the X-ray crystallographic analysis data sup-

ports its structure (entry 2).¹³We assume that the steric nature of

the substituent and the relatively milder reaction conditions are

detrimental to this high regioselectivity. Electron-poor and rela-

tively small 3-CF₃-substituted pyrazole (2d) reacted efﬁciently

with 1a at 80 °C, affording the desired β-heteroarylated ketone

8ad in 79% yield; a trace of the other regioisomer (ca. ∼3% by

GC) was also noticed (entry 3). Based on the HMBC studies, the

structure of 8ad is conﬁrmed.¹³However, RICA between 3-

methyl pyrazole (2e) and 1a gave a mixture of regioisomers;

both the isomers are separated by ﬂash chromatography resulting

8ae and 8ae′ in 35% and 54% yields, respectively (entry 4).

Once again, the structures of 8ae and 8ae′ are conﬁrmed through

detailed HMBC studies.¹³Divergence in the behaviour of the

observed regioselectivity is interesting; however, the factors

responsible for this effect are unclear. It appears that the steric

and electronic nature of the C-3-substitution in pyrazole contrib-

ute to the regioselectivity. Gratifyingly, a single isomer 8af in

excellent yield was obtained from the RICA between 1a and

indazole (2f) (entry 5). Similarly, 2b and 2f were independently

reacted with 1-p-tolylnon-2-yn-1-ol (1u) and the corresponding

β-heteroarylated ketones 8ub and 8uf are isolated in 32% and

65% yields, respectively; incomplete conversion of 1u was

observed even with the extended reaction time (entries 6 and

7).¹³Poor reactivity and the moderate product yields are the con-

sequences of the alkyl-substitution of the propargyl alcohols.

To widen the synthetic utility of this methodology, various

NH-bearing heterocycles such as triazoles, imidazole, pyrrole,

indole, aniline and its derivatives were tested in the RICA reac-

tion with propargyl alcohols. The results of this survey are

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yield. Relatively poor-reactive C(sp)-alkyl substituted propargyl

alcohols 1s and 1-phenylhept-2-yn-1-ol (1y) successfully under-

went RICA with pyrrole at 80 °C and delivered the correspond-

ing β-pyrrolyl ketones 22 and 23 albeit in moderate yields.

Surprisingly, a fast reaction between 13 and terminal propargyl

alcohol 5a has been observed, the addition product 1-phenyl-3-

(1H-pyrrol-1-yl)propan-1-one (24) was obtained in only 9%

yield. Interestingly, a Michael adduct 24′, obtained through the

conjugate addition of the carbanion (α-to carbonyl) of 24 to the

α,β-unsaturated ketone, was isolated in 24% yield. The products

25, 24, 24′ has been isolated in overall good yield, when 13

reacted with 1-phenyl-3-(trimethylsilyl)prop-2-yn-1-ol (5h).

Because of the nucleophilic character of NH– and the C-3

center of indole, C–C and C–N bond formations with the redox

isomerized product of the propargyl alcohol are possible.^10a,12b

Thus, RICA between indole (14) and 1y was performed; the

β-indolyl-(C–N bond)-ketone (26) and C-3 functionalized

β-indolyl-(C–C bond)-ketone (26′) (5 : 1) are obtained in overall

good yields. However, 2-methyl indole underwent RICA with 1y

and exclusively produced the β-indolyl-(C–N bond)-ketone 27;

the ¹H spectrum of crude reaction mixture did not show any

trace of the corresponding β-indolyl-(C–C bond)-ketone. A

recent report from the Trost group describes the synthesis of

β-indolyl-(C–C bond)-ketones from RICA between substituted

indole derivatives and propargyl alcohols.^10aTherefore, RICA

between propargyl alcohols and indoles under different reaction

conditions can generate two distinct products. Importantly, the

–NH₂group of aniline participated in this RICA to 1a and the

product 28 was generated in only 24% yield. Unfortunately, elec-

tron-rich indole or aniline failed to react with ethyl 4-hydroxy-4-

phenylbut-2-ynoate.^12bTherefore, we believe that our optimized

reaction conditions are better because they show a broader reac-

tion scope.

Scheme 3 RICA of propargyl alcohol (29) with 2a/2f.

Scheme 4 Plausible mechanism.

detailed in Table 7. Conjugate addition of triazole to the propar-

gyl alcohol in the presence of DBU was unsuccessful.^12bUnder

the optimized conditions, addition of triazoles with 1a led to

little conversion of 1a even though the reaction continued for 4

days. This failure inspired us to ﬁnd suitable conditions for this

transformation. In order to improve the product yield and reac-

tion efﬁciency, we at ﬁrst surveyed mixtures of different solvents

for this RICA reaction. Interestingly, complete conversion of 1a

has been observed, when a toluene (1.5 mL) and DMF (0.5 mL)

mixture was employed and the reaction was heated at 80 °C. A

moderate yield of 17 was obtained from the RICA between

1,2,4-triazole (9) and 1a under the modiﬁed reaction conditions.

Although reaction of 1,2,3-triazole (10) with 1a was sluggish,

the corresponding regioisomers 18 and 18′ (6 : 1) were isolated

in satisfactory overall yields.^7d,12bHowever, in case of the ben-

zotriazole, a reverse trend of the regioisomer selectivity 19 and

19′ (1 : 4.5; 55% yield) was noticed.^7cThe reaction between imi-

dazole (12) and 1a was complex, however, the product 20 was

obtained in only 10% yield. The pyrrole-building block has been

widely found in biologically active molecules.^20a,bHowever,

owing to the better reactivity, pyrrole tended to polymerize at

an elevated temperature.^20c,dTherefore, we are interested in

examining the reactivity of pyrrole (13) with various propargyl

alcohols. Interestingly, pyrrole reacted with 1a sluggishly under

the optimized reaction conditions (shown in entry 10, Table 1)

and a moderate amount of product 21 was produced in 53%

To enlarge the molecular diversity by incorporating more het-

eroarenes in the molecule, compound 29 having two propargyl

alcohol units was prepared. The pyrazole (2a) and indazole (2f)

were independently exposed to 29 under the optimized con-

ditions and the desired β-heteroarylated ketone 30 and 31

resulted albeit in reasonable yields (Scheme 3).

Based on the precedence, the reaction is likely to proceed

through the following mechanism, as shown in Scheme 4.²¹The

ﬁrst step is the formation of the carbanion via the abstraction of

the acidic benzylic C–H proton in the presence of base.^21e,f

Stabilization of carbanion through delocalization followed by

protonation with the conjugate acid delivers the corresponding

allenol. Allenol–enone tautomerism gives the reactive α,β-un-

saturated carbonyl compound. Finally, base mediated conjugate

addition of NH-heteroarenes with enones produces the desired

β-heteroarylated ketones.^7b,d,e,g

Conclusion

In conclusion, a direct, practicable and efﬁcient approach to

β-heteroarylated ketones is demonstrated. The reaction proceeds

through the base induced redox-isomerization of easily accessi-

ble propargyl alcohols followed by conjugate addition of NH-

heteroarenes in one-step. This reaction displays broad scope and

tolerates a variety of reactive functional groups. Aryl, heteroaryl,

3544 | Org. Biomol. Chem., 2012, 10, 3538–3555

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alkyl C(sp), and terminal alkynes containing unactivated propar-

gyl alcohols undergo RICA with the pyrazole efﬁciently.

Notably, the RICA of 3-substituted pyrazoles or indazole with

propargyl alcohols delivers the products with a better level of

regioselectivity. RICA between propargyl alcohols and a range

of NH-bearing compounds such as: 1,2,4-triazole, 1,2,3-triazole,

imidazole, pyrrole, indoles and aniline are successfully demon-

strated. Current effort is directed towards exploring the synthetic

application of this methodology.

NMR (400 MHz, CDCl₃) δ 7.52–7.48 (m, 2H), 7.38–7.20 (m,

5H), 7.13 (s, 1H), 6.83 (d, J = 8.0 Hz, 1H), 5.64 (s, 1H), 2.32

(bs, 1H), 1.00 (s, 9H), 0.22 (s, 6H); ¹³C NMR (101 MHz,

CDCl₃) δ 155.9, 142.2, 131.8 (2C), 129.7, 128.6, 128.3 (2C),

122.4, 120.1, 119.6, 118.5, 88.7, 86.6, 64.9, 25.7 (3C), 18.2,

−4.4 (2C); IR (KBr) ν_max3441, 3065, 2932, 2887, 2197, 1643,

1599, 1485, 1439, 1286, 939, 839 cm⁻¹; MS (EI) m/z (%) 339

(M⁺+ 1, 10), 321 (100), 229 (2); Anal. calcd for C₂₁H₂₆O₂Si:

C, 74.51; H, 7.74. Found: C, 74.45; H, 7.71.

1-(4-Chlorophenyl)non-2-yn-1-ol (1t). Following the general

procedure (GP-1), reaction of 4-chlorobenzaldehyde (1′t; 1.40 g,

10.0 mmol), 1-octyne (1.32 g, 12.0 mmol) and n-BuLi (7.5 mL,

1.6 M in THF, 12.0 mmol) gave 1t (2.18 g, 87% yield) as a col-

Experimental section

General procedure for the preparation of 1 from aldehydes (1′)

(GP-1)

1

orless oil. R_f= 0.45 (9 : 1 hexane–EtOAc); H NMR (400 MHz,

CDCl₃) δ 7.48 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.8 Hz, 2H),

5.43 (d, J = 5.6 Hz, 1H), 2.27 (td, J = 1.6, 6.8 Hz, 2H), 2.12 (d,

J = 6.0 Hz, 1H), 1.57–1.50 (m, 2H), 1.43–1.32 (m, 2H),

1.32–1.23 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H); ¹³C NMR

(101 MHz, CDCl₃) δ 139.8, 133.9, 128.6 (2C), 128.0 (2C),

88.1, 79.6, 64.0, 31.2, 28.6, 28.5, 22.5, 18.8, 14.0; IR (Neat)

ν_max3368, 2930, 2858, 1489, 1091, 1014, 779 cm⁻¹; MS (EI)

m/z (%) 203 (M⁺+ 1, 100), 167 (8), 139 (27), 91 (8); Anal.

calcd for C₁₅H₁₉ClO: C, 71.84; H, 7.64. Found: C, 71.94; H,

7.69.

A solution of terminal-alkyne (1.2 equiv) in THF (50 mL) was

stirred in a 100 mL oven-dried two-necked round bottom ﬂask

under an argon atmosphere at −70 °C. n-Butyllithium (1.2 equiv,

1.60 M in THF) was introduced over 30 minutes at −70 °C.

After an additional 1 h stirring, a solution of aldehyde (1′, 1.0

equiv) in THF (5 mL) was added at −70 °C. The resulting

mixture was stirred for 1 h and warmed to room temperature

slowly and stirring continued for 30 minutes. The reaction

mixture was quenched with saturated NH₄Cl aqueous solution

(20 mL) at 0 °C. The organic layer was separated; the aqueous

layer was extracted with Et₂O (2 × 20 mL). The combined

extracts were washed with water (2 × 20 mL), brine (25 mL) and

dried over Na₂SO₄. Solvent was ﬁltered and evaporated under

reduced pressure. The crude residue was puriﬁed using column

chromatography on silica gel. The desired propargyl alcohols are

obtained in good yields. Physical characterization data is exactly

matching with the reported values for the respective compounds

1a–h,²²1k–s,^22,231u–w,²⁴1ab,²⁵1y²⁶and 29,²⁷whereas 1i–j,

1t, 1x, 1aa and 1ac are new.

4,4-Dimethyl-1-o-tolylpent-2-yn-1-ol

(1x). Following

the

general procedure (GP-1), reaction of 2-methylbenzaldehyde

(1′x; 960 mg, 8.0 mmol), 3,3-dimethylbut-1-yne (788 mg,

9.6 mmol) and n-BuLi (6.0 mL, 1.6 M in THF, 9.6 mmol) gave

1x (389 mg, 72% yield) as a colorless oil. R_f= 0.40

(32 : 1 hexane–EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.65 (t, J

= 4.0 Hz, 1H), 7.26–7.20 (m, 2H), 7.20–7.16 (m, 1H), 5.60 (d, J

= 5.6 Hz, 1H), 2.45 (s, 3H), 1.99 (d, J = 5.6 Hz, 1H), 1.26 (s,

9H); ¹³C NMR (101 MHz, CDCl₃) δ 139.1, 136.1, 130.7, 128.2,

126.5, 126.1, 95.1, 78.3, 62.6, 31.0 (3C), 27.5, 19.0; IR (Neat)

ν_max3368, 2968, 1460, 983, 750 cm⁻¹; MS (EI) m/z (%) 203

(M⁺+ 1, 100), 167 (8), 139 (27), 91 (8); Anal. calcd for

C₁₄H₁₈O: C, 83.12; H, 8.97. Found: C, 83.21; H, 8.92.

3-(1-Hydroxy-3-phenylprop-2-ynyl)phenol (1i). Following the

literature procedure,²⁸LiOAc·2H₂O (52 mg, 10 mol%) was

added to a solution of 1-(3-(tert-butyldimethylsilyloxy)phenyl)-

3-phenylprop-2-yn-1-ol (1j, 2.7 g, 8.0 mmol) in DMF–H₂O. The

resulting mixture was heated at 70 °C under an inert atmosphere.

Upon complete consumption of starting material, the reaction

mixture was extracted with ethyl acetate. After usual work up,

the crude material was puriﬁed using silica gel column chrom-

atography. The product 1i was isolated in 1.43 g, 80% yield as a

1-(3-Methoxyphenyl)-3-(4-methoxyphenyl)prop-2-yn-1-ol (1aa).

Following the general procedure (GP-1), reaction of 3-methoxy-

benzaldehyde (1′g; 500 mg, 3.78 mmol), 1-ethynyl-4-methoxy-

benzene (599 mg, 4.53 mmol) and n-BuLi (2.8 mL, 1.6 M in

THF, 4.53 mmol) gave 1aa (730 mg, 72% yield) as a yellow

1

pale yellow thick oil. R_f= 0.28 (4 : 1 hexane–EtOAc); H NMR

1

thick oil. R_f= 0.28 (9 : 1 hexane–EtOAc); H NMR (400 MHz,

(400 MHz, CDCl₃) δ 7.52–7.43 (m, 2H), 7.38–7.23 (m, 4H),

7.19–7.10 (m, 2H), 6.86–6.81 (m, 1H), 5.72 (bs, 1H), 5.64 (s,

1H), 2.34 (bs, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 157.8,

143.9, 131.7 (2C), 129.7, 129.1 (2C), 129.0, 122.8, 117.6,

115.0, 113.8, 91.9, 84.7, 63.3; IR (Neat) ν_max3337, 3155, 2220,

1602, 1466, 1311, 1259, 1163, 1020, 902, 752 cm⁻¹; MS (EI)

m/z (%) 225 (M⁺+ 1, 100), 207 (2), 174 (2); Anal. calcd for

C₁₅H₁₂O₂: C, 80.34; H, 5.39. Found: C, 80.15; H, 5.31.

CDCl₃) δ 7.51–7.26 (m, 3H), 7.25–7.12 (m, 2H), 6.95–6.75 (m,

3H), 5.65 (s, 1H), 3.83 (s, 3H), 3.78 (s, 3H), 2.60 (bs, 1H); ¹³C

NMR (101 MHz, CDCl₃) δ 159.8 (2C), 142.5, 133.3 (2C),

129.7, 119.0, 114.5, 114.0, 113.9 (2C), 112.2, 87.4, 86.6, 65.1,

55.3 (2C); IR (Neat) ν_max3385, 3011, 2968, 2930, 2843, 1606,

1510, 1248, 1170, 1030, 831 cm⁻¹; MS (EI) m/z (%) 269 (M⁺+

1, 100), 186 (13), 137 (23); Anal. calcd for C₁₇H₁₆O₃: C, 76.10;

H, 6.01. Found: C, 76.23; H, 6.10.

1-(3-(tert-Butyldimethylsilyloxy)phenyl)-3-phenylprop-2-yn-1-

ol (1j). Following the general procedure (GP-1), reaction

of 3-(tert-butyldimethylsilyloxy)benzaldehyde (1′j; 1.89 g,

8.00 mmol), phenyl acetylene (980 mg, 9.60 mmol) and n-BuLi

(6.0 mL, 1.6 M in THF, 9.60 mmol) gave 1j (1.63 g, 60% yield)

1-(4-Chlorophenyl)-3-(3-ﬂuorophenyl)prop-2-yn-1-ol

(1ac).

Following the general procedure (GP-1), reaction of 4-chloroben-

zaldehyde (1′c; 1.00 g, 7.14 mmol), 1-ethynyl-3-ﬂuorobenzene

(1.03 g, 8.56 mmol) and n-BuLi (5.0 mL, 1.6 M in THF,

8.56 mmol) gave 1ac (1.40 g, 75% yield) as a colorless solid.

1

as a light yellow thick oil. R_f= 0.42 (4 : 1 hexane–EtOAc); H

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mp 59–60 °C; R_f= 0.45 (6 : 1 hexane–EtOAc); ¹H NMR

(400 MHz, CDCl₃) δ 7.54 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.4

Hz, 2H), 7.33–7.23 (m, 2H), 7.16 (d, J = 9.6 Hz, 1H), 7.06 (t, J

= 8.8 Hz, 1H), 5.67 (d, J = 6.0 Hz, 1H), 2.36 (d, J = 6.0 Hz,

1H); ¹³C NMR (101 MHz, CDCl₃) δ 162.2 (d, J = 248 Hz),

138.7, 134.2, 129.9 (d, J = 8.7 Hz), 128.7 (2C), 128.0 (2C),

127.5 (d, J = 3.2 Hz), 123.8 (d, J = 9.4 Hz), 118.4 (d, J = 23.1

Hz), 116.1(d, J = 21.2 Hz), 89.1, 85.5 (d, J = 3.3 Hz), 64.1; IR

7.37–7.32 (m, 4H), 7.31–7.26 (m, 1H), 6.24 (s, 1H), 6.13 (dd, J

= 5.6, 8.4 Hz, 1H), 4.50 (dd, J = 8.4, 17.6 Hz, 1H), 3.65 (dd, J =

5.2, 17.6 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 196.6, 140.8,

139.3, 136.5, 133.4, 129.8, 128.8 (2C), 128.6 (2C), 128.2 (2C),

128.0, 126.7 (2C), 105.6, 60.8, 44.2; IR (KBr) ν_max3032, 2925,

1682, 758, 563 cm⁻¹; MS (EI) m/z (%) 278 (M⁺+ 2, 54), 241

(27), 209 (100), 105 (8), 69 (8); Anal. calcd for C₁₈H₁₆N₂O: C,

78.24; H, 5.84; N, 10.14. Found: C, 78.09; H, 5.76; N, 10.25.

(KBr) ν_max3341, 2874, 1571, 1487, 1168, 1016, 785, 680 cm⁻¹

;

MS (EI) m/z (%) 203 (M⁺+ 1, 100), 167 (8), 139 (27), 91 (8);

Anal. calcd for C₁₅H₁₀ClFO: C, 69.11; H, 3.87. Found: C,

69.25; H, 3.83.

1-(4-Fluorophenyl)-3-phenyl-3-(1H-pyrazol-1-yl)propan-1-one

(3b). 241 mg, 82% yield; colorless solid; mp 42–43 °C; R_f=

0.38 (9 : 1 hexane–EtOAc); ¹H NMR (400 MHz, CDCl₃) δ

8.04–7.94 (m, 2H), 7.53 (s, 1H), 7.50 (d, J = 1.6 Hz, 1H),

7.37–7.25 (m, 5H), 7.08 (t, J = 8.4 Hz, 2H), 6.24 (t, J = 2.0 Hz,

1H), 6.12 (dd, J = 5.2, 8.4 Hz, 1H), 4.50 (dd, J = 8.8,17.6 Hz,

1H), 3.58 (dd, J = 4.8, 17.6 Hz, 1H); ¹³C NMR (101 MHz,

CDCl₃) δ 194.8, 165.6 (d, J = 255 Hz), 140.5, 139.0, 132.7,

130.7 (d, J = 10.1 Hz, 2C), 129.6, 128.6 (2C), 127.8, 126.4

(2C), 115.5 (d, J = 21.2 Hz, 2C), 105.5, 60.6, 43.8; ¹⁹F NMR

(376 MHz, CDCl₃) δ −104.58 to −104.66 (m); IR (KBr) ν_max

3111, 3034, 2920, 1682, 1599, 1157, 991, 756, 628 cm⁻¹; MS

(EI) m/z (%) 296 (M⁺+ 2, 51), 295 (M⁺+ 1, 100), 259 (24), 227

(70), 123 (11), 101 (11), 69 (14); Anal. calcd for C₁₈H₁₅FN₂O:

C, 73.45; H, 5.14; N, 9.52. Found: C, 73.35; H, 5.21; N, 9.66.

General procedure for the synthesis of 5 from 1′ (GP-2)

A solution of trimethylsilylacetylene (1.2 equiv) in THF

(50 mL) was stirred in a 100 mL oven-dried two-necked round

bottom ﬂask under an argon atmosphere at −70 °C. n-Butyl-

lithium (1.2 equiv, 1.60 M in THF) was introduced over

30 minutes at −70 °C. After an additional 1 h stirring, a solution

of aldehyde (1′, 1.0 equiv) in THF (5 mL) was added at −70 °C.

The resulting mixture was stirred for 1 h and warmed to room

temperature slowly and stirring continued for 30 minutes. The

reaction mixture was quenched with saturated NH₄Cl aqueous

solution (20 mL) at 0 °C. The organic layer was separated; the

aqueous layer was extracted with Et₂O (2 × 20 mL). The com-

bined extracts were washed with water (2 × 20 mL), brine

(25 mL) and dried over Na₂SO₄. Solvent was ﬁltered and evap-

orated under reduced pressure. The crude residue was sub-

sequently used for the desilylation reaction.

Methanol (15 mL) and K₂CO₃(2.5 equiv) was introduced to

the crude residue obtained in the above reaction and the hetero-

geneous mixture was stirred under an argon atmosphere at

ambient temperature overnight. The reaction mixture was diluted

with ethyl acetate (50 mL) and washed with water (2 × 20 mL)

and brine (10 mL). The organic layer was separated, dried over

Na₂SO₄, ﬁltered, and concentrated under vacuum. The crude

residue was puriﬁed using column chromatography on silica gel.

Physical characterization data is exactly matching with the

reported values for the respective compounds 5a–h.^29–34

1-(4-Chlorophenyl)-3-phenyl-3-(1H-pyrazol-1-yl)propan-1-one

(3c). 246 mg, 79% yield; colorless solid; mp 74–75 °C; R_f=

1

0.25 (9 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.90

(d, J = 8.0 Hz, 2H), 7.48 (d, J = 10.8 Hz, 2H), 7.40 (d, J = 8.4

Hz, 2H), 7.39–7.23 (m, 5H), 6.22 (s, 1H), 6.08 (dd, J = 4.8, 8.0

Hz, 1H), 4.49 (dd, J = 8.8, 17.6 Hz, 1H), 3.57 (dd, J = 4.8, 17.2

Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 195.5, 140.6, 139.9,

139.3, 134.9, 129.8, 129.7 (2C), 128.9 (2C), 128.8 (2C), 128.1,

126.6 (2C), 105.7, 60.8, 44.1; IR (KBr) ν_max3042, 2924, 1684,

1087, 750 cm⁻¹; MS (EI) m/z (%) 313 (M⁺+ 2, 54), 312 (M⁺+

1, 54), 311 (M⁺, 100), 139 (19), 107 (3); Anal. calcd for

C₁₈H₁₅ClN₂O: C, 69.57; H, 4.86; N, 9.01. Found: C, 69.37; H,

4.81; N, 9.12.

1-(4-Bromophenyl)-3-phenyl-3-(1H-pyrazol-1-yl)propan-1-one

(3d). 291 mg, 82% yield; pale yellow solid; mp 81–82 °C; R_f=

1

0.40 (9 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.80

(d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.47 (dd, J = 1.6,

12.8 Hz, 2H), 7.36–7.22 (m, 5H), 6.21 (s, 1H), 6.07 (dd, J = 4.8,

8.4 Hz, 1H), 4.45 (dd, J = 8.8, 17.6 Hz, 1H), 3.53 (dd, J = 4.8,

17.6 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 195.4, 140.4,

139.0, 135.0, 131.7 (2C), 129.6, 129.5 (2C), 128.6 (2C), 128.3,

127.9, 126.4 (2C), 105.5, 60.5, 43.9; IR (KBr) ν_max3108, 1684,

1585, 1070, 752, 702 cm⁻¹; MS (EI) m/z (%) 357 (M⁺+ 2, 97),

355 (M⁺, 100), 287 (32), 209 (30), 101 (20), 69 (16); Anal.

calcd for C₁₈H₁₅BrN₂O: C, 60.86; H, 4.26; N, 7.89. Found: C,

60.75; H, 4.31; N, 7.79.

General procedure for the RICA between propargyl alcohols

and NH-heteroarenes (GP-3)

Propargyl alcohol 1 (1.0 mmol), NH-heteroarene (2.0 mmol)

and cesium carbonate (326 mg, 1.0 mmol) were taken in an

oven-dried Schlenk ﬂask under an argon atmosphere. Toluene

(2 mL) was added to this mixture. The resulting solution was

stirred at 70 °C as per the time shown in the representative

tables. Upon complete consumption of 1, the reaction mixture

was diluted with dichloromethane (10 mL), and ﬁltered over a

small pad of Celite. The solvent was evaporated under reduced

pressure and the crude reaction mixture was puriﬁed using

column chromatography on silica gel.

4-(3-Phenyl-3-(1H-pyrazol-1-yl)propanoyl)benzonitrile (3e).

198 mg, 66% yield; yellow solid; mp 117–118 °C; R_f= 0.50

1

(3 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 8.03 (d, J

1,3-Diphenyl-3-(1H-pyrazol-1-yl)propan-1-one (3a). 220 mg,

80% yield; light yellow solid; mp 79–80 °C; R_f= 0.31

(9 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.98 (d, J

= 7.2 Hz, 2H), 7.60–7.50 (m, 3H), 7.45 (t, J = 7.6 Hz, 2H),

3546 | Org. Biomol. Chem., 2012, 10, 3538–3555

= 8.0 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 7.6 Hz,

2H), 7.39–7.22 (m, 5H), 6.22 (s, 1H), 6.07 (dd, J = 4.8, 8.8 Hz,

1H), 4.55 (dd, J = 8.8, 17.6 Hz, 1H), 3.53 (dd, J = 4.8, 17.6 Hz,

1H); ¹³C NMR (101 MHz, CDCl₃) δ 195.5, 140.3, 139.4, 139.1,

1

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132.4 (2C), 129.7, 128.8 (2C), 128.5 (2C), 128.1, 126.5 (2C),

117.8, 116.4, 105.8, 60.6, 44.3; IR (KBr) ν_max3074, 2922,

2227, 1687, 754, 696, 625 cm⁻¹; MS (EI) m/z (%) 303 (M⁺+ 2,

41), 302 (100), 130 (5), 69 (16); Anal. calcd for C₁₉H₁₅N₃O: C,

75.73; H, 5.02; N, 13.94. Found: C, 75.61; H, 5.10; N, 13.86.

NMR (101 MHz, CDCl₃) δ 196.4, 156.7, 140.1, 139.3, 137.5,

130.5, 129.6, 128.8 (2C), 128.1, 126.6 (2C), 120.8, 119.9,

115.1, 105.9, 60.9, 43.8; IR (KBr) ν_max3112, 1684, 1587, 1280,

750, 698, 625 cm⁻¹; MS (EI) m/z (%) 294 (M⁺+ 2, 100), 257

(5), 225 (27), 121 (11), 101 (19), 69 (27); Anal. calcd for

C₁₈H₁₆N₂O₂: C, 73.95; H, 5.52; N, 9.58. Found: C, 73.85; H,

5.48; N, 9.68.

3-Phenyl-3-(1H-pyrazol-1-yl)-1-p-tolylpropan-1-one

(3f).

224 mg, 84% yield; colorless solid; mp 41–42 °C; R_f= 0.37

1

(6 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.83 (d, J

1-(3-(tert-Butyldimethylsilyloxy)phenyl)-3-phenyl-3-(1H-pyrazol-

1-yl)propan-1-one (3j). 53 mg, 13% yield; brown color thick

= 8.0 Hz, 2H), 7.47 (d, J = 12.8 Hz, 2H), 7.33–7.24 (m, 4H),

7.24–7.19 (m, 1H), 7.17 (d, J = 8.0 Hz, 2H), 6.18 (s, 1H), 6.10

(dd, J = 5.2, 8.0 Hz, 1H), 4.42 (dd, J = 8.4, 17.2 Hz, 1H), 3.58

(dd, J = 5.2, 17.6 Hz, 1H), 2.32 (s, 3H); ¹³C NMR (101 MHz,

CDCl₃) δ 195.9, 143.9, 140.6, 139.0, 133.8, 129.5, 129.0 (2C),

128.5 (2C), 128.1 (2C), 127.7, 126.5 (2C), 105.3, 60.6, 43.8,

21.4; IR (KBr) ν_max3032, 2920, 1682, 1454, 817, 752,

628 cm⁻¹; MS (EI) m/z (%) 292 (M⁺+ 2, 59), 291 (M⁺+ 1,

100), 255 (14), 223 (59), 119 (14), 91 (8); Anal. calcd for

C₁₉H₁₈N₂O: C, 78.59; H, 6.25; N, 9.65. Found: C, 78.47; H,

6.32; N, 9.55.

1

liquid; R_f= 0.55 (9 : 1 hexane–EtOAc); H NMR (400 MHz,

CDCl₃) δ 7.58 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 10.8 Hz, 2H),

7.42 (s, 1H), 7.38–7.23 (m, 6H), 7.03 (d, J = 8.0 Hz, 1H), 6.24

(bd, J = 1.2 Hz, 1H), 6.10 (t, J = 7.6 Hz, 1H), 4.45 (dd, J = 8.0,

17.6 Hz, 1H), 6.63 (dd, J = 4.8, 17.6 Hz, 1H), 0.99 (s, 9H), 0.21

(s, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 196.4, 160.0, 140.7,

139.3, 138.0, 129.7, 129.6, 128.8 (2C), 128.0, 126.7 (2C),

125.2, 121.3, 119.4, 105.5, 60.8, 44.3, 25.6 (3C), 18.1, −4.4

(2C); IR (Neat) ν_max3065, 2957, 1687, 1581, 1280, 931, 837,

625 cm⁻¹; MS (EI) m/z (%) 408 (M⁺+ 1, 35), 390 (23), 376

(100), 344 (100), 316 (8), 288 (8), 79 (10), 65 (6); Anal. calcd

for C₂₄H₃₀N₂O₂Si: C, 70.90; H, 7.44; N, 6.89. Found: C, 71.21;

H, 7.48; N, 6.75.

1-(3-Methoxyphenyl)-3-phenyl-3-(1H-pyrazol-1-yl)propan-1-one

(3g). 251 mg, 82% yield; light yellow thick liquid; R_f= 0.36

1

(6 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.55 (d, J

= 7.6 Hz, 1H), 7.50 (s, 1H), 7.47 (bd, J = 5.6 Hz, 2H),

7.35–7.21 (m, 6H), 7.07 (dd, J = 2.0, 8.0 Hz, 1H), 6.21 (s, 1H),

6.09 (dd, J = 5.2, 8.0 Hz, 1H), 4.45 (dd, J = 8.8, 18.0 Hz, 1H),

3.78 (s, 3H), 3.64 (dd, J = 5.2, 17.6 Hz, 1H); ¹³C NMR

(101 MHz, CDCl₃) δ 196.0, 159.5, 140.5, 138.9, 137.5, 129.4,

129.3, 128.5 (2C), 127.7, 126.4 (2C), 120.6, 119.7, 111.9,

105.3, 60.5, 55.0, 43.9; IR (Neat) ν_max3065, 2939, 1682, 1454,

1045, 754, 626 cm⁻¹; MS (EI) m/z (%) 308 (M⁺+ 2, 80), 271

(39), 239 (100), 135 (19), 101 (16), 69 (14); Anal. calcd for

C₁₉H₁₈N₂O₂: C, 74.49; H, 5.92; N, 9.14. Found: C, 74.36; H,

5.98; N, 9.25.

1-(2-Bromophenyl)-3-phenyl-3-(1H-pyrazol-1-yl)propan-1-one

(3k). 234 mg, 66% yield; yellow thick liquid; R_f= 0.31

(12 : 1 hexane–EtOAc); ¹H NMR (400 MHz, CDCl₃)

δ

7.60–7.54 (m, 2H), 7.47 (d, J = 2.0 Hz, 1H), 7.39–7.20 (m, 8H),

6.26 (t, J = 2.0 Hz, 1H), 6.08 (dd, J = 5.2, 9.6 Hz, 1H), 4.38

(dd, J = 9.2, 17.2 Hz, 1H), 3.63 (dd, J = 4.8, 17.2 Hz, 1H); ¹³C

NMR (101 MHz, CDCl₃) δ 200.1, 140.7, 140.0, 139.0, 133.4,

131.7, 129.6, 129.0 (2C), 128.7, 128.0, 127.2, 126.5 (2C),

118.5, 105.6, 60.9, 47.9; IR (Neat) ν_max3030, 2918, 1699, 1284,

875 cm⁻¹; MS (EI) m/z (%) 358 (M⁺+ 3, 30), 357 (M⁺+ 2,

100), 356 (M⁺+ 1, 30), 355 (M⁺, 100), 321 (8), 319 (8), 289

(30), 287 (30), 185 (14), 183 (14), 101 (8); Anal. calcd for

C₁₈H₁₅BrN₂O: C, 60.86; H, 4.26; N, 7.89. Found: C, 60.75; H,

4.32; N, 7.68.

1-(3-Phenoxyphenyl)-3-phenyl-3-(1H-pyrazol-1-yl)propan-1-one

(3h). 265 mg, 72% yield; yellow solid; mp 62–63 °C; R_f= 0.68

1

(6 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.67 (d, J

= 7.6 Hz, 1H), 7.58 (s, 1H) 7.49 (s, 1H), 7.46 (s, 1H), 7.41–7.22

(m, 8H), 7.18 (dd, J = 1.6, 8.0 Hz, 1H), 7.11 (t, J = 7.6 Hz, 1H),

6.98 (d, J = 8.4 Hz, 2H), 6.21 (s, 1H), 6.07 (dd, J = 5.2, 8.0 Hz,

1H), 4.44 (dd, J = 8.8, 18.0 Hz, 1H), 3.58 (dd, J = 5.2, 17.6 Hz,

1H); ¹³C NMR (101 MHz, CDCl₃) δ 195.7, 157.5, 156.3, 140.5,

139.0, 138.1, 129.8, 129.7 (2C), 129.5, 128.6 (2C), 127.8, 126.4

(2C), 123.6, 123.3, 122.8, 118.9 (2C), 117.7, 105.4, 60.5, 44.1;

1-(2,3-Dichlorophenyl)-3-phenyl-3-(1H-pyrazol-1-yl)propan-1-

one (3l). 279 mg, 81% yield; pale yellow thick liquid; R_f= 0.30

(9 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.53 (s,

1

1H), 7.48 (dd, J = 1.2, 8.0 Hz, 1H), 7.44 (s, 1H), 7.38–7.22 (m,

6H), 7.17 (t, J = 7.6 Hz, 1H), 6.24 (s, 1H), 6.06 (dd, J = 4.8, 9.2

Hz, 1H), 4.35 (dd, J = 10.0, 17.6 Hz, 1H), 3.57 (dd, J = 4.4,

17.2 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 198.9, 141.0,

139.8, 138.9, 133.6, 132.0, 129.5, 128.6 (2C), 128.5, 127.9,

127.4, 126.8, 126.4 (2C), 105.6, 60.9, 48.2; IR (Neat) ν_max

3065, 2924, 1701, 1410, 736, 625 cm⁻¹; MS (EI) m/z (%) 347

(M⁺+ 2, 84), 346 (M⁺+ 1, 38), 345 (M⁺, 100), 277 (14), 173

(22), 69 (11); Anal. calcd for C₁₈H₁₄Cl₂N₂O: C, 62.62; H, 4.09;

N, 8.11. Found: C, 62.48; H, 4.15; N, 8.25.

IR (KBr) ν_max3032, 2916, 1687, 1581, 1240, 752, 696 cm⁻¹

;

MS (EI) m/z (%) 370 (M⁺+ 2, 51), 369 (M⁺+ 1, 100), 333 (35),

301 (76), 197 (11), 101 (11), 69 (8); Anal. calcd for

C₂₄H₂₀N₂O₂: C, 78.24; H, 5.47; N, 7.60. Found: C, 78.32; H,

5.43; N, 7.52.

1-(3-Hydroxyphenyl)-3-phenyl-3-(1H-pyrazol-1-yl)propan-1-one

(3i). 225 mg, 77% yield; colorless solid; mp 129–130 °C; R_f=

0.53 (2 : 1 hexane–EtOAc); ¹H NMR (400 MHz, CDCl₃) δ

8.70–8.00 (bs, –OH, 1H), 7.55 (dd, J = 2.0, 16.4 Hz, 2H),

7.40–7.36 (m, 1H), 7.35 (bt, J = 2.4 Hz, 1H), 7.31–7.24 (m,

5H), 7.14 (t, J = 8.0 Hz, 1H), 6.91 (dd, J = 2.4, 8.0 Hz, 1H),

6.27 (t, J = 2.4 Hz, 1H), 6.10 (dd, J = 5.2, 8.4 Hz, 1H), 4.42

(dd, J = 8.8, 18.0 Hz, 1H), 3.63 (dd, J = 5.2, 18.0 Hz, 1H); ¹³C

1-(2,4-Dichlorophenyl)-3-phenyl-3-(1H-pyrazol-1-yl)propan-1-

one (3m). 265 mg, 77% yield; yellow thick liquid; R_f= 0.33

(9 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.47 (bd,

J = 1.2 Hz, 1H), 7.38 (dd, J = 2.8, 11.6 Hz, 3H), 7.34–7.19 (m,

6H), 6.21 (t, J = 2.0 Hz, 1H), 6.02 (dd, J = 4.8, 9.6 Hz, 1H),

4.35 (dd, J = 9.6, 17.2 Hz, 1H), 3.53 (dd, J = 4.8, 17.2 Hz, 1H);

¹³C NMR (101 MHz, CDCl₃) δ 198.2, 140.0, 138.9, 137.4,

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136.8, 131.9, 130.6, 130.1, 129.6, 128.7 (2C), 128.0, 127.1,

126.4 (2C), 105.7, 61.0, 48.1; IR (Neat) ν_max3063, 2926, 1697,

1375, 750, 625 cm⁻¹; MS (EI) m/z (%) 347 (M⁺+ 2, 84), 346

(M⁺+ 1, 41), 345 (M⁺, 100), 277 (11), 173 (24), 147 (8), 69 (8);

Anal. calcd for C₁₈H₁₄Cl₂N₂O: C, 62.62; H, 4.09; N, 8.11.

Found: C, 62.71; H, 4.03; N, 8.07.

Anal. calcd for C₁₆H₁₄N₂O₂: C, 72.16; H, 5.30; N, 10.52.

Found: C, 72.28; H, 5.36; N, 10.

3-Phenyl-3-(1H-pyrazol-1-yl)-1-(thiophen-2-yl)propan-1-one

(3r). 259 mg, 92% yield; brown solid; mp 42–43 °C; R_f= 0.18

1

(9 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.76 (bd,

J = 3.6 Hz, 1H), 7.58 (bd, J = 4.8 Hz, 1H), 7.48 (dd, J = 1.2,

17.6 Hz, 2H), 7.35–7.22 (m, 5H), 7.07 (bt, J = 3.6 Hz, 1H), 6.21

(s, 1H), 6.07 (dd, J = 5.6, 8.4 Hz, 1H), 4.38 (dd, J = 8.4, 16.8

Hz, 1H), 3.59 (dd, J = 5.2, 17.2 Hz, 1H); ¹³C NMR (101 MHz,

CDCl₃) δ 189.3, 143.5, 140.3, 139.3, 134.1, 132.4, 129.7, 128.7

(2C), 128.1, 127.9, 126.6 (2C), 105.5, 60.6, 44.6; IR (KBr) ν_max

3103, 2924, 1662, 1053, 750, 625 cm⁻¹; MS (EI) m/z (%) 284

(M⁺+ 2, 35), 283 (100), 247 (5), 215 (35), 111 (3); Anal. calcd

for C₁₆H₁₄N₂OS: C, 68.06; H, 5.00; N, 9.92. Found: C, 68.15;

H, 5.12; N, 9.86.

3-Phenyl-3-(1H-pyrazol-1-yl)-1-o-tolylpropan-1-one

(3n).

223 mg, 77% yield; pale yellow thick liquid; R_f= 0.43

1

(9 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.68 (d, J

= 7.6 Hz, 1H), 7.51 (s, 1H), 7.46 (s, 1H), 7.37–7.16 (m, 8H),

6.22 (s, 1H), 6.06 (dd, J = 5.2, 8.8 Hz, 1H), 4.36 (dd, J = 9.2,

17.6 Hz, 1H), 3.51 (dd, J = 5.2, 17.2 Hz, 1H), 2.34 (s, 3H); ¹³C

NMR (101 MHz, CDCl₃) δ 200.2, 140.4, 139.0, 137.9, 137.5,

131.7, 131.3, 129.5, 128.6 (2C), 128.4, 127.8, 126.5 (2C),

125.5, 105.4, 60.9, 46.8, 20.8; IR (Neat) ν_max3063, 2966, 1689,

1494, 1089, 750, 625 cm⁻¹; MS (EI) m/z (%) 292 (M⁺+ 2, 75),

255 (59), 223 (100), 119 (16), 91 (12), 69 (10); Anal. calcd for

C₁₉H₁₈N₂O: C, 78.59; H, 6.25; N, 9.65. Found: C, 78.66; H,

6.21; N, 9.58.

1-Phenyl-3-(1H-pyrazol-1-yl)undecan-1-one

(3s). Reaction

was performed at 80 °C. 262 mg, 84% yield; colorless solid; mp

43–44 °C; R_f= 0.52 (19 : 1 hexane–EtOAc); ¹H NMR

(400 MHz, CDCl₃) δ 7.91 (d, J = 8.4 Hz, 2H), 7.54 (bt, J = 7.2

Hz, 1H), 7.48 (d, J = 13.6 Hz, 2H), 7.42 (t, J = 7.6 Hz, 2H),

6.15 (bt, J = 2.0 Hz, 1H), 4.91–4.79 (m, 1H), 3.80 (dd, J = 7.2,

17.2 Hz, 1H), 3.32 (dd, J = 5.2, 17.6 Hz, 1H), 2.12–2.01 (m,

1H), 1.87–1.74 (m, 1H), 1.29–1.18 (m, 11 H), 1.12–0.97 (m,

1H), 0.86 (t, J = 6.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ

197.6, 139.5, 136.6, 133.3, 130.0, 128.5 (2C), 128.0 (2C),

104.2, 58.0, 44.0, 35.3, 31.7, 29.3, 29.1, 29.0, 26.1, 22.6, 14.0;

1-(Naphthalen-1-yl)-3-phenyl-3-(1H-pyrazol-1-yl)propan-1-one

(3o). 283 mg, 87% yield; pale yellow solid; mp 77–78 °C; R_f=

1

0.21 (9 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 8.39

(d, J = 8.0 Hz, 1H), 7.87 (d, J = 7.2 Hz, 2H), 7.76 (d, J = 7.2

Hz, 1H), 7.49 (s, 1H), 7.48–7.40 (m, 3H), 7.36 (t, J = 8.0 Hz,

1H), 7.33–7.17 (m, 5H), 6.19 (s, 1H), 6.15 (dd, J = 5.2, 8.8 Hz,

1H), 4.50 (dd, J = 9.2, 17.2 Hz, 1H), 3.61 (dd, J = 4.8, 17.2 Hz,

1H); ¹³C NMR (101 MHz, CDCl₃) δ 200.2, 140.4, 139.1, 135.3,

133.6, 132.7, 129.9, 129.6, 128.6 (2C), 128.2, 127.9, 127.8,

127.7, 126.5 (2C), 126.3, 125.5, 124.2, 105.5, 61.1, 47.3; IR

(KBr) ν_max3036, 1743, 1682, 1396, 752 cm⁻¹; MS (EI) m/z (%)

328 (M⁺+ 2, 100), 291 (27), 259 (95), 155 (49), 144 (11), 69

(3); Anal. calcd for C₂₂H₁₈N₂O: C, 80.96; H, 5.56; N, 8.58.

Found: C, 80.75; H, 5.51; N, 8.49.

IR (KBr) ν_max3102, 2918, 1674, 1446, 1095, 760, 625 cm⁻¹

;

MS (EI) m/z (%) 314 (M⁺+ 2, 49), 313 (M⁺+ 1, 100), 277 (11),

245 (19), 101 (3), 69 (6); Anal. calcd for C₂₀H₂₈N₂O: C, 76.88;

H, 9.03; N, 8.97. Found: C, 76.81; H, 9.08; N, 8.85.

1-(4-Chlorophenyl)-3-(1H-pyrazol-1-yl)nonan-1-one

(3t).

Reaction was performed at 80 °C. 290 mg, 91% yield; colorless

1

liquid; R_f= 0.45 (9 : 1 hexane–EtOAc); H NMR (500 MHz,

1-(2,6-Dichlorophenyl)-3-phenyl-3-(1H-pyrazol-1-yl)propan-1-

one (3p). 241 mg, 70% yield; pale yellow liquid; R_f= 0.33

(9 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.55 (d, J

CDCl₃) δ 7.82 (d, J = 8.5 Hz, 2H), 7.46 (dd, J = 1.5, 22 Hz,

2H), 7.37 (d, J = 8.5 Hz, 2H), 6.13 (bt, J = 2.0 Hz, 1H),

4.84–4.80 (m, 1H), 3.78 (dd, J = 7.5, 17.0 Hz, 1H), 3.24 (dd, J

= 5.0, 17.5 Hz, 1H), 2.13–1.99 (m, 1H), 1.87–1.73 (m, 1H),

1.33–1.13 (m, 7H), 1.09–0.98 (m, 1H), 0.84 (t, J = 7.0 Hz, 3H);

¹³C NMR (125 MHz, CDCl₃) δ 196.4, 139.7, 139.5, 134.8,

130.0, 129.4 (2C), 128.8 (2C), 104.3, 58.0, 43.8, 35.3, 31.5,

28.6, 25.9, 22.4, 13.9; IR (Neat) ν_max2926, 1687, 1589, 1091,

831, 750 cm⁻¹; MS (EI) m/z (%) 322 (M⁺+ 3, 11), 321 (M⁺+

2, 51), 320 (M⁺+ 1, 38), 319 (M⁺, 100), 146 (5), 69 (3); Anal.

calcd for C₁₈H₂₃ClN₂O: C, 67.81; H, 7.27; N, 8.79. Found: C,

67.71; H, 7.21; N, 8.68.

1

= 6.8 Hz, 2H), 7.45–7.36 (m, 3H), 7.36–7.19 (m, 5H), 6.25 (s,

1H), 6.11 (t, J = 7.2 Hz, 1H), 4.27 (dd, J = 8.0, 18.8 Hz, 1H),

3.72 (dd, J = 5.2, 18.8 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ

198.4, 139.6, 139.3, 138.5, 130.6, 130.3, 129.5 (2C), 128.5

(2C), 128.1 (2C), 127.9, 126.8 (2C), 105.3, 59.8, 48.9; IR (Neat)

ν_max3067, 2916, 1712, 1431, 779, 625 cm⁻¹; MS (EI) m/z (%)

347 (M⁺+ 2, 86), 345 (M⁺, 100), 309 (49), 277 (22), 173 (22),

69 (16); Anal. calcd for C₁₈H₁₄Cl₂N₂O: C, 62.62; H, 4.09; N,

8.11. Found: C, 62.51; H, 4.15; N, 8.21.

1-(Furan-2-yl)-3-phenyl-3-(1H-pyrazol-1-yl)propan-1-one (3q).

187 mg, 70% yield; light brown solid; mp 98–99 °C; R_f= 0.28

(6 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.58 (s,

3-(1H-Pyrazol-1-yl)-1-p-tolylnonan-1-one (3u). Reaction was

performed at 80 °C. 223 mg, 75% yield; pale yellow thick

1

liquid; R_f= 0.41 (12 : 1 hexane–EtOAc); H NMR (400 MHz,

1H), 7.50 (d, J = 16.8 Hz, 2H), 7.32 (bs, 4H), 7.31–7.25 (m,

1H), 7.22 (bd, J = 3.2 Hz, 1H), 6.52 (bt, J = 1.6 Hz, 1H), 6.22

(s, 1H), 6.07 (dd, J = 5.6, 8.4 Hz, 1H), 4.30 (dd, J = 8.8, 16.8

Hz, 1H), 3.53 (dd, J = 5.2, 17.2 Hz, 1H); ¹³C NMR (101 MHz,

CDCl₃) δ 185.1, 152.0, 146.6, 140.2, 139.1, 129.5, 128.6 (2C),

127.8, 126.5 (2C), 117.7, 112.2, 105.4, 60.2, 43.6; IR (KBr)

ν_max3115, 2922, 1653, 756, 698, 625 cm⁻¹; MS (EI) m/z (%)

268 (M⁺+ 2, 86), 231 (7), 199 (100), 157 (9), 101 (3), 69 (14);

CDCl₃) δ 7.82 (d, J = 8.0 Hz, 2H), 7.50 (dd, J = 1.2, 15.6 Hz,

2H), 7.22 (d, J = 8.0 Hz, 2H), 6.16 (bs, 1H), 4.92–4.78 (m, 1H),

3.77 (dd, J = 7.6, 17.2 Hz, 1H), 3.32 (dd, J = 5.2, 17.2 Hz, 1H),

2.39 (s, 3H), 2.13–2.02 (m, 1H), 1.89–1.78 (m, 1H), 1.35–1.13

(m, 7H), 1.11–0.96 (m, 1H), 0.84 (t, J = 7.2 Hz, 3H); ¹³C NMR

(101 MHz, CDCl₃) δ 197.2, 144.1, 139.5, 134.2, 130.0, 129.2

(2C), 128.2 (2C), 104.2, 58.2, 44.0, 35.4, 31.6, 28.8, 26.1, 22.5,

21.6, 14.0; IR (Neat) ν_max3103, 2928, 1682, 1574, 1043, 812,

3548 | Org. Biomol. Chem., 2012, 10, 3538–3555

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748, 625 cm⁻¹; MS (EI) m/z (%) 300 (M⁺+ 2, 62), 299 (M⁺+

1, 100), 263 (8), 231 (27), 179 (3), 91 (3); Anal. calcd for

C₁₉H₂₆N₂O: C, 76.47; H, 8.78; N, 9.39. Found: C, 76.58; H,

8.68; N, 9.21.

55.2, 44.2; IR (KBr) ν_max3057, 2939, 1682, 1612, 739 cm⁻¹

;

MS (EI) m/z (%) 338 (M⁺+ 2, 57), 337 (M⁺+ 1, 100); Anal.

calcd for C₂₀H₂₀N₂O₃: C, 71.41; H, 5.99; N, 8.33. Found: C,

71.56; H, 6.12; N, 8.21.

3-(1H-Pyrazol-1-yl)-1-(thiophen-2-yl)nonan-1-one (3v). Reac-

tion was performed at 80 °C. 223 mg, 77% yield; pale yellow

thick liquid; R_f= 0.38 (9 : 1 hexane–EtOAc); ¹H NMR

(400 MHz, CDCl₃) δ 7.65 (dt, J = 1.2, 22 Hz, 2H), 7.51 (d, J =

1.2 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H), 7.10–7.06 (m, 1H), 6.14

(dd, J = 1.6, 3.2 Hz, 1H), 4.87–4.73 (m, 1H), 3.71 (dd, J = 7.6,

16.4 Hz, 1H), 3.27 (dd, J = 5.2, 16.4 Hz, 1H), 2.15–2.00 (m,

1H), 1.86–1.74 (m, 1H), 1.35–1.08 (m, 7H), 1.08–0.93 (m, 1H),

0.85 (t, J = 6.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 190.4,

144.0, 139.6, 134.1, 132.5, 130.1, 128.2, 104.3, 58.3, 44.8,

35.3, 31.6, 28.7, 26.0, 22.5, 14.0; IR (Neat) ν_max3103, 2926,

1660, 1516, 1047, 748, 625 cm⁻¹; MS (EI) m/z (%) 292 (M⁺+

2, 51), 291 (M⁺+ 1, 100), 255 (8), 223 (35), 101 (5), 69 (8);

Anal. calcd for C₁₆H₂₂N₂OS: C, 66.17; H, 7.64; N, 9.65. Found:

C, 66.32; H, 7.61; N, 9.59.

1-(4-Fluorophenyl)-3-(1H-pyrazol-1-yl)-3-p-tolylpropan-1-one

(3ab). 249 mg, 81% yield; yellow thick liquid; R_f= 0.52

(6 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.99 (dd,

1

J = 4.8, 10.4 Hz, 2H), 7.47 (dd, J = 1.6, 12.8 Hz, 2H), 7.17 (dd,

J = 8.0, 26 Hz, 4H), 7.08 (t, J = 4.8 Hz, 2H), 6.21 (t, J = 2.0 Hz,

1H), 6.05 (dd, J = 5.2, 8.4 Hz, 1H), 4.40 (dd, J = 8.4, 17.2 Hz,

1H), 3.57 (dd, J = 5.2, 17.6 Hz, 1H), 2.31 (s, 3H); ¹³C NMR

(101 MHz, CDCl₃) δ 195.1, 165.8 (d, J = 256 Hz), 139.2, 137.8,

137.5, 133.0 (d, J = 3.0 Hz), 130.8 (d, J = 9.5 Hz, 2C), 129.6,

129.4 (2C), 126.6 (2C), 115.6 (d, J = 22.0 Hz, 2C), 105.5, 60.6,

44.0, 21.0; ¹⁹F NMR (376 MHz, CDCl₃) δ −104.63 to −104.70

(m); IR (Neat) ν_max3105, 2922, 1684, 1599, 1508, 841,

752 cm⁻¹; MS (EI) m/z (%) 311 (M⁺+ 3, 89), 309 (M⁺+ 1,

100), 299 (57), 277 (73), 243 (5), 209 (14), 173 (3); Anal. calcd

for C₁₉H₁₇FN₂O: C, 74.01; H, 5.56; N, 9.08. Found: C, 74.16;

H, 5.49; N, 9.15.

4,4-Dimethyl-1-phenyl-3-(1H-pyrazol-1-yl)pentan-1-one (3w).

Reaction was performed at 80 °C. 136 mg, 53% yield; colorless

solid; mp 37–38 °C; R_f= 0.43 (9 : 1 hexane–EtOAc); H NMR

1-(4-Chlorophenyl)-3-(3-ﬂuorophenyl)-3-(1H-pyrazol-1-yl)-

propan-1-one (3ac). 296 mg, 90% yield; colorless solid; mp

108–109 °C; R_f= 0.55 (6 : 1 hexane–EtOAc); ¹H NMR

(400 MHz, CDCl₃) δ 7.90 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 7.6

Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.34–7.24 (m, 1H), 7.05 (dd,

J = 8.0, 20 Hz, 2H), 6.97 (t, J = 8.4 Hz, 1H), 6.24 (s, 1H), 6.08

(dd, J = 5.2, 8.8 Hz, 1H), 4.46 (dd, J = 8.8, 17.6 Hz, 1H), 3.55

(dd, J = 5.2, 17.6 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ

195.2, 162.9 (d, J = 247 Hz), 143.1 (d, J = 6.1 Hz), 140.0,

139.5, 134.6, 130.3 (d, J = 8.1 Hz), 129.9, 129.6 (2C), 128.9

(2C), 122.2, 115.0 (d, J = 21.2 Hz), 113.7 (d, J = 22.2 Hz),

105.9, 60.2, 44.0; ¹⁹F NMR (376 MHz, CDCl₃) δ −111.80 to

−111.86 (m); IR (KBr) ν_max3061, 2968, 1680, 1589, 1400, 758,

522 cm⁻¹; MS (EI) m/z (%) 332 (M⁺+ 3, 41), 331 (M⁺+ 2, 76),

330 (M⁺+ 1, 100), 264 (11), 258 (11); Anal. calcd for

C₁₈H₁₄ClFN₂O: C, 65.76; H, 4.29; N, 8.52. Found: C, 65.81; H,

4.23; N, 8.45.

1

(400 MHz, CDCl₃) δ 7.94 (d, J = 6.4 Hz, 2H), 7.59–7.50 (m,

1H), 7.50–7.40 (m, 4H), 6.14 (bt, J = 1.6 Hz, 1H), 4.68 (dd, J =

2.0, 8.0 Hz, 1H), 4.23 (dd, J = 8.0, 14.0 Hz, 1H), 3.20 (dd, J =

2.0, 14.0 Hz, 1H), 1.03 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ

197.9, 138.8, 136.9, 133.1, 131.7, 128.5 (2C), 128.1 (2C),

103.8, 66.0, 38.3, 35.4, 27.2 (3C); IR (KBr) ν_max3109, 2959,

1684, 1402, 754, 626 cm⁻¹; MS (EI) m/z (%) 258 (M⁺+ 2, 43),

257 (M⁺+ 1, 100), 221 (16), 189 (43), 101 (11), 69 (8); Anal.

calcd for C₁₆H₂₀N₂O: C, 74.97; H, 7.86; N, 10.93. Found: C,

74.85; H, 7.95; N, 11.07.

4,4-Dimethyl-3-(1H-pyrazol-1-yl)-1-o-tolylpentan-1-one (3x).

Reaction was performed at 80 °C. 65 mg, 24% yield; colorless

oil; R_f= 0.40 (32 : 1 hexane–EtOAc); ¹H NMR (500 MHz,

CDCl₃) δ 7.62 (d, J = 6.0 Hz, 1H), 7.46 (dd, J = 2.0, 11 Hz,

2H), 7.34 (td, J = 1.0, 7.5 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H),

7.18 (d, J = 7.5 Hz, 1H), 6.16 (bt, J = 2.0 Hz, 1H), 4.36 (dd, J =

8.0, 11 Hz, 1H), 4.10 (dd, J = 11, 17 Hz, 1H), 3.12 (dd, J = 3.0,

17 Hz, 1H), 2.28 (s, 3H), 1.01 (s, 9H); ¹³C NMR (101 MHz,

CDCl₃) δ 202.2, 138.8, 138.3, 137.7, 131.7 (2C), 131.2, 128.3,

125.6, 103.9, 66.5, 41.2, 35.3, 27.1 (3C), 20.7; IR (Neat) ν_max

2962, 1687, 1093, 750, 625 cm⁻¹; MS (EI) m/z (%) 272 (M⁺+

2, 22), 271 (M⁺+ 1, 100), 228 (3), 186 (11), 141 (5), 109 (11);

Anal. calcd for C₁₇H₂₂N₂O: C, 75.52; H, 8.20; N, 10.36. Found:

C, 75.39; H, 8.26; N, 10.45.

1-Phenyl-3-(1H-pyrazol-1-yl)propan-1-one (6a).³⁵192 mg,

96% yield; pale yellow solid; mp 45–46 °C; ¹H NMR

(400 MHz, CDCl₃) δ 7.96 (d, J = 7.6 Hz, 2H), 7.59 (t, J = 7.2

Hz, 1H), 7.52 (s, 2H), 7.48 (t, J = 7.6 Hz, 2H), 6.23 (s, 1H),

4.63 (t, J = 6.4 Hz, 2H), 3.62 (t, J = 6.4 Hz, 2H); ¹³C NMR

(101 MHz, CDCl₃) δ 197.3, 139.5, 136.3, 133.4, 130.0, 128.6

(2C), 128.0 (2C), 105.2, 46.5, 38.8; IR (KBr) ν_max3111, 3063,

2953, 1682, 1448, 1217, 750, 619 cm⁻¹; MS (EI) m/z (%) 202

(M⁺+ 2, 8), 201 (48), 157 (100), 143 (6), 69 (8).

1-(3-Methoxyphenyl)-3-(4-methoxyphenyl)-3-(1H-pyrazol-1-yl)-

propan-1-one (3aa). 278 mg, 83% yield; pale yellow solid; mp

62–63 °C; R_f= 0.42 (3 : 1 hexane–EtOAc); ¹H NMR (400 MHz,

CDCl₃) δ 7.56 (d, J = 7.6 Hz, 1H), 7.50 (s, 1H), 7.46 (s, 2H),

7.33 (t, J = 8.0 Hz, 1H), 7.30–7.23 (m, 2H), 7.09 (dd, J = 1.6,

8.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 2H), 6.21 (s, 1H), 6.04 (bt, J =

7.2 Hz. 1H), 4.40 (dd, J = 8.0, 17.6 Hz, 1H), 3.81 (s, 3H), 3.76

(s, 3H), 3.64 (dd, J = 5.6, 17.6 Hz, 1H); ¹³C NMR (101 MHz,

CDCl₃) δ 196.5, 159.7, 159.2, 139.2, 137.8, 132.5, 129.5, 129.4,

128.0 (2C), 120.8, 120.0, 114.0 (2C), 112.1, 105.4, 60.3, 59.3,

3-(1H-Pyrazol-1-yl)-1-p-tolylpropan-1-one (6b). 199 mg, 93%

yield; pale yellow thick liquid; R_f= 0.23 (4 : 1 hexane–EtOAc);

¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 8.0 Hz, 2H), 7.50 (d,

J = 2.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 6.20 (bt, J = 2.0 Hz,

1H), 4.58 (t, J = 6.4 Hz, 2H), 3.56 (t, J = 6.4 Hz, 2H), 2.39 (s,

3H); ¹³C NMR (101 MHz, CDCl₃) δ 196.9, 144.3, 139.4, 133.8,

130.0, 129.2 (2C), 128.0 (2C), 105.1, 46.6, 38.6, 21.6; IR (Neat)

ν_max3032, 2951, 1682, 1398, 1089, 978, 752 cm⁻¹; MS (EI)

m/z (%) 216 (M⁺+ 2, 35), 215 (M⁺+ 1, 100), 147 (8), 101 (3),

This journal is © The Royal Society of Chemistry 2012

Org. Biomol. Chem., 2012, 10, 3538–3555 | 3549

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91 (3), 69 (6); Anal. calcd for C₁₃H₁₄N₂O: C, 72.87; H, 6.59; N,

13.07. Found: C, 72.91; H, 6.51; N, 13.15.

1H), 7.73 (d, J = 7.2 Hz, 1H), 7.59–7.42 (m, 4H), 7.40 (bd, J =

1.6 Hz, 1H), 6.13 (bt, J = 1.6 Hz, 1H), 4.60 (dd, J = 3.2, 11.2

Hz, 1H), 4.06 (dd, J = 10.8, 16.8 Hz, 1H), 3.14 (dd, J = 3.2,

16.8 Hz, 1H), 0.13 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ

202.8, 139.0, 136.0, 133.8, 132.6, 130.6, 129.9, 128.3, 127.8,

127.6, 126.4, 125.5, 124.3, 104.3, 50.1, 42.9, −3.0 (3C); IR

(Neat) ν_max3051, 2955, 1682, 1249, 844, 750, 623 cm⁻¹; MS

(EI) m/z (%) 325 (M⁺+ 2, 32), 324 (100), 288 (5), 255 (27), 165

(27), 101 (5), 69 (14); Anal. calcd for C₁₉H₂₂N₂OSi: C, 70.77;

H, 6.88; N, 8.69. Found: C, 70.65; H, 6.91; N, 8.61.

1-(4-Chlorophenyl)-3-(1H-pyrazol-1-yl)propan-1-one

(6c).

171 mg, 73% yield; colorless solid; mp 76–77 °C; R_f= 0.14

1

(6 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.87 (d, J

= 8.4 Hz, 2H), 7.50 (s, 2H), 7.42 (d, J = 8.4 Hz, 2H), 6.21 (s,

1H), 4.59 (t, J = 6.8 Hz, 2H), 3.56 (t, J = 6.4 Hz, 2H); ¹³C NMR

(101 MHz, CDCl₃) δ 196.2, 139.9, 139.6, 134.6, 130.0, 129.4

(2C), 128.9 (2C), 105.2, 46.4, 38.7; IR (KBr) ν_max3103, 2924,

1689, 1589, 1400, 754, 617 cm⁻¹; MS (EI) m/z (%) 238 (M⁺+

3, 11), 237 (M⁺+ 2, 65), 236 (M⁺+ 1, 30), 235 (M⁺, 100), 167

(3), 101 (12), 69 (19); Anal. calcd for C₁₂H₁₁ClN₂O: C, 61.41;

H, 4.72; N, 11.94. Found: C, 61.52; H, 4.66; N, 11.85.

1,3-Diphenyl-3-(3-phenyl-1H-pyrazol-1-yl)propan-1-one (8ab).

293 mg, 83% yield; colorless solid; mp 110–111 °C; R_f= 0.51

1

(6 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 8.02 (d, J

1-(Naphthalen-1-yl)-3-(1H-pyrazol-1-yl)propan-1-one

(6d).

= 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H),

7.49–7.42 (m, 3H), 7.42–7.37 (m, 2H), 7.34 (td, J = 1.6, 6.4 Hz,

4H), 7.29–7.22 (m, 2H), 6.52 (bd, J = 2.0 Hz, 1H), 6.11 (dd, J =

5.2, 8.8 Hz, 1H), 4.61 (dd, J = 8.4, 17.2 Hz, 1H), 3.56 (dd, J =

5.2, 17.6 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 196.7, 150.8,

140.7, 136.6, 133.7, 133.2, 130.9, 128.7 (2C), 128.5 (2C), 128.3

(2C), 128.1 (2C), 127.9, 127.3, 126.7 (2C), 125.5 (2C), 102.9,

61.2, 44.2; IR (KBr) ν_max3063, 2920, 1684, 1454, 750,

694 cm⁻¹; MS (EI) m/z (%) 354 (M⁺+ 2, 51), 353 (M⁺+ 1,

100), 263 (5); Anal. calcd for C₂₄H₂₀N₂O: C, 81.79; H, 5.72; N,

7.59. Found: C, 81.65; H, 5.76; N, 7.88. X-Ray crystallographic

analysis conﬁrms the structure of 8ab.¹³

171 mg, 68% yield; pale yellow thick liquid; R_f= 0.14

(6 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 8.62 (d, J

1

= 8.8 Hz, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.86 (dd, J = 7.6, 12.8

Hz, 2H), 7.60 (dtd, J = 1.6, 1.2, 8.2 Hz, 1H), 7.57–7.52 (m, 3H),

7.47 (t, J = 7.2 Hz, 1H), 6.24 (t, J = 2.0 Hz, 1H), 4.68 (t, J = 6.4

Hz, 2H), 3.68 (t, J = 6.4 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃)

δ 201.1, 139.6, 134.8, 133.8, 133.1, 130.0, 129.9, 128.4, 128.1,

128.0, 126.4, 125.6, 124.3, 105.2, 46.9, 41.8; IR (Neat) ν_max

3049, 2951, 1678, 1510, 777, 619 cm⁻¹; MS (EI) m/z (%) 252

(M⁺+ 2, 38), 251 (M⁺+ 1, 100), 215 (19), 183 (19), 165 (16),

101 (11), 69 (11); Anal. calcd for C₁₆H₁₄N₂O: C, 76.78; H,

5.64; N, 11.19. Found: C, 76.62; H, 5.58; N, 11.25.

3-(1H-Pyrazol-1-yl)-1-p-tolyl-3-(trimethylsilyl)propan-1-one (7e).

11 mg, 4% yield; pale yellow liquid; R_f= 0.74 (6 : 1 hexane–

EtOAc); H NMR (400 MHz, CDCl₃) δ 7.80 (d, J = 8.4 Hz,

3-(3-(3-Bromophenyl)-1H-pyrazol-1-yl)-1,3-diphenylpropan-1-

one (8ac). 401 mg, 93% yield; colorless solid; mp 105–106 °C;

R_f= 0.42 (6 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ

1

2H), 7.40 (d, J = 12.8 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 6.09 (t,

J = 2.0 Hz, 1H), 4.51 (dd, J = 3.2, 10.0 Hz, 1H), 3.92 (dd, J =

10.0, 17.6 Hz, 1H), 3.10 (dd, J = 3.2, 17.6 Hz, 1H), 2.39 (s,

3H), 0.10 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 198.1, 144.1,

138.9, 134.3, 130.5, 129.2 (2C), 128.2 (2C), 104.2, 49.4, 39.2,

21.6, −2.9 (3C); IR (Neat) ν_max2951, 1684, 1506, 1182, 844,

748 cm⁻¹; MS (EI) m/z (%) 288 (M⁺+ 2, 51), 287 (M⁺+ 1,

100), 251 (19), 219 (32), 101 (5), 69 (5); Anal. calcd for

C₁₆H₂₂N₂OSi: C, 67.09; H, 7.74; N, 9.78. Found: C, 67.22; H,

7.69; N, 9.71.

8.01 (d, J = 7.6 Hz, 2H), 7.87 (d, J = 1.2 Hz, 1H), 1.57 (dd, J =

8.0, 17.2 Hz, 2H), 7.51–7.41 (m, 3H), 7.41–7.25 (m, 6H), 7.17

(t, J = 8.0 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 6.10 (dd, J = 4.8,

8.8 Hz, 1H), 4.58 (dd, J = 8.8, 17.6 Hz, 1H), 3.52 (dd, J = 4.8,

17.2 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 196.7, 149.3,

140.4, 136.5, 135.7, 133.2, 131.1, 130.1, 129.9, 128.7 (2C),

128.5 (2C), 128.3, 128.1 (2C), 128.0, 126.6 (2C), 124.0, 122.5,

103.1, 61.3, 44.1; IR (KBr) ν_max3063, 2918, 1684, 1452, 995,

752, 688 cm⁻¹; MS (EI) m/z (%) 434 (M⁺+ 2, 30), 433 (M⁺+

1, 100), 431 (M⁺, 100), 257 (8), 255 (8), 209 (67), 145 (16);

Anal. calcd for C₂₄H₁₉BrN₂O: C, 66.83; H, 4.44; N, 6.49.

Found: C, 66.75; H, 4.51; N, 6.41.

1-(4-Chlorophenyl)-3-(1H-pyrazol-1-yl)-3-(trimethylsilyl)propan-

1-one (7f). 52 mg, 17% yield; colorless liquid; R_f= 0.66

1

(6 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.81 (d, J

= 8.4 Hz, 2H), 7.41 (bd, J = 1.6 Hz, 1H), 7.39–7.33 (m, 3H),

6.08 (bt, J = 2.2 Hz, 1H), 4.47 (dd, J = 2.8, 10.4 Hz, 1H), 3.93

(dd, J = 10.4, 17.2 Hz, 1H), 3.04 (dd, J = 2.8, 17.2 Hz, 1H),

0.09 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 197.5, 139.6,

139.0, 135.0, 130.5, 129.5 (2C), 128.8 (2C), 104.3, 49.5, 39.2,

−3.0 (3C); IR (Neat) ν_max3103, 2955, 1689, 1589, 1091, 845,

696 cm⁻¹; MS (EI) m/z (%) 310 (M⁺+ 3, 24), 309 (M⁺+ 2, 76),

308 (M⁺+ 2, 59), 307 (M⁺, 100), 239 (5), 223 (110, 101 (3), 69

(11); Anal. calcd for C₁₅H₁₉ClN₂OSi: C, 58.71; H, 6.24; N,

9.13. Found: C, 58.62; H, 6.21; N, 9.21.

The structure of 8ac is established based on the heteronuclear

multiple bond correlation (HMBC) studies; correlations between

C_a(61.3 ppm) and H_b(7.43 ppm), H_a(6.20 ppm) and C_b

(131.1 ppm) are quite signiﬁcant whereas the correlation

between H_aand C_d(149.3 ppm) is not seen. Furthermore, the X-

ray crystallographic analysis data supports the structure of 8ac.¹³

1-(Naphthalen-1-yl)-3-(1H-pyrazol-1-yl)-3-(trimethylsilyl)propan-

1-one (7g). 23 mg, 7% yield; pale yellow liquid; R_f= 0.62

1

(6 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 8.34 (d, J

= 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 7.2 Hz,

3550 | Org. Biomol. Chem., 2012, 10, 3538–3555

View Article Online

1,3-Diphenyl-3-(3-(triﬂuoromethyl)-1H-pyrazol-1-yl)propan-1-

one (8ad). Reaction was performed at 80 °C. 272 mg, 79%

yield; colorless solid; mp 80–81 °C; R_f= 0.38 (6 : 1 hexane–

9.2, 17.6 Hz, 1H), 3.57 (dd, J = 4.4, 17.6 Hz, 1H), 2.35 (s, 3H);

¹³C NMR (101 MHz, CDCl₃) δ 196.9, 141.0, 138.8, 138.1,

136.6, 133.2, 128.7 (2C), 128.5 (2C), 128.2 (2C), 127.6, 126.5

(2C), 105.5, 57.0, 44.7, 11.0; IR (Neat) ν_max3030, 2922, 1685,

1448, 752, 698 cm⁻¹; MS (EI) m/z (%) 292 (M⁺+ 2, 35), 291

(M⁺+ 1, 100), 241 (22), 209 (81), 115 (22), 83 (22); Anal. calcd

for C₁₉H₁₈N₂O: C, 78.59; H, 6.25; N, 9.65. Found: C, 78.49; H,

6.21; N, 9.76.

1

EtOAc); H NMR (400 MHz, CDCl₃) δ 7.96 (dd, J = 0.8, 6.4

Hz, 2H), 7.56 (tt, J = 1.2, 6.8 Hz, 1H), 7.50 (bd, J = 1.6 Hz,

1H), 7.45 (bt, J = 8.0 Hz, 2H), 7.36–7.27 (m, 5H), 6.47 (bd, J =

2.0, 1H), 6.11 (dd, J = 5.2, 8.4 Hz, 1H), 4.49 (dd, J = 8.4, 17.6

Hz, 1H), 3.61 (dd, J = 4.8, 17.6 Hz, 1H); ¹³C NMR (101 MHz,

CDCl₃) δ 196.3, 142.2 (q, J = 58.3 Hz), 139.5, 136.3, 133.5,

131.1, 128.9 (2C), 128.6 (2C), 128.4, 128.1 (2C), 126.7 (2C),

121.3 (d, J = 270 Hz), 104.4, 61.8, 44.0; ¹⁹F NMR (376 MHz,

CDCl₃) δ −66.54; IR (KBr) ν_max3151, 2947, 1693, 1242, 773,

688 cm⁻¹; MS (EI) m/z (%) 346 (M⁺+ 2, 41), 345 (M⁺+ 1,

100), 195 (11), 165 (5), 91 (3); Anal. calcd for C₁₉H₁₅F₃N₂O:

C, 66.27; H, 4.39; N, 8.14. Found: C, 66.15; H, 4.46; N, 8.21.

The structure of 8ae′ is established based on the HMBC studies;

correlation between C_d(138.8 ppm) and H_a(6.08 ppm) is quite

signiﬁcant whereas correlations between C_a(57.0 ppm) and H_b

(7.42 ppm), H_aand C_b(138.1 ppm) are not seen.¹³

3-(1H-Indazol-1-yl)-1,3-diphenylpropan-1-one (8af). 301 mg,

92% yield; colorless solid; mp 92–93 °C; R_f

= 0.42

1

(6 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 8.00 (s,

1H), 7.98 (s, 2H), 7.68 (d, J = 8.0 Hz, 1H), 7.52 (t, J = 7.6 Hz,

2H), 7.43 (t, J = 8.0 Hz, 2H), 7.37–7.20 (m, 6H), 7.10 (t, J = 8.0

Hz, 1H), 6.46 (dd, J = 5.2, 8.8 Hz, 1H), 4.67 (dd, J = 8.8, 18.0

Hz, 1H), 3.74 (dd, J = 4.8, 17.6 Hz, 1H); ¹³C NMR (101 MHz,

CDCl₃) δ 196.4, 140.7, 139.5, 136.4, 133.1, 132.9, 128.6 (2C),

128.4 (2C), 128.0 (2C), 127.6, 126.5 (2C), 126.2, 124.1, 120.8,

120.7, 109.4, 57.3, 44.2; IR (KBr) ν_max3061, 2916, 1682, 1018,

750, 696 cm⁻¹; MS (EI) m/z (%) 328 (M⁺+ 2, 41), 327 (M⁺+

1, 100), 241 (5), 209 (67), 151 (3), 119 (14); Anal. calcd for

C₂₂H₁₈N₂O: C, 80.96; H, 5.56; N, 8.58. Found: C, 80.85; H,

5.51; N, 8.65. X-Ray crystallographic analysis elucidates the

structure of 8af.¹³

The structure of 8ad is established based on the HMBC studies;

correlations between C_a(61.8 ppm) and H_b(7.50 ppm), H_a

(6.11 ppm) and C_b(131.1 ppm) are quite signiﬁcant whereas the

correlation between H_aand C_d(142.3 ppm) is not seen.¹³

3-(3-Methyl-1H-pyrazol-1-yl)-1,3-diphenylpropan-1-one (8ae).

101 mg, 35% yield; pale yellow thick liquid; R_f= 0.35

1

(12 : 1 hexane–EtOAc); H NMR (500 MHz, CDCl₃) δ 7.98 (d,

J = 8.0 Hz, 2H), 7.55 (t, J = 7.5 Hz, 1H), 7.44 (t, J = 5.5 Hz,

2H), 7.35 (d, J = 2.5 Hz, 1H), 7.31 (d, J = 4.5 Hz, 4H),

7.28–7.24 (m, 1H), 6.02 (dd, J = 5.5, 8.0 Hz, 1H), 5.98 (d, J =

2.0 Hz, 1H), 4.41 (dd, J = 8.0, 17.5 Hz, 1H), 3.65 (dd, J = 5.5,

17.5 Hz, 1H), 2.24 (s, 3H); ¹³C NMR (125 MHz, CDCl₃) δ

196.8, 148.5, 140.9, 136.7, 133.3, 130.4, 128.7 (2C), 128.6

(2C), 128.3 (2C), 127.9, 126.7 (2C), 105.1, 60.7, 44.3, 13.8; IR

(Neat) ν_max2926, 1685, 1450, 1203, 752 cm⁻¹; MS (EI) m/z (%)

292 (M⁺+ 2, 20), 291 (M⁺+ 1, 100), 219 (3), 97 (3); Anal.

calcd for C₁₉H₁₈N₂O: C, 78.59; H, 6.25; N, 9.65. Found: C,

78.45; H, 6.31; N, 9.58.

3-(3-Phenyl-1H-pyrazol-1-yl)-1-p-tolylnonan-1-one

(8ub).

Reaction was performed at 80 °C. 120 mg, 32% yield; pale

1

yellow thick liquid; R_f= 0.63 (9 : 1 hexane–EtOAc); H NMR

(400 MHz, CDCl₃) δ 7.82 (d, J = 8.0 Hz, 2H), 7.76 (dd, J = 1.2,

8.4 Hz, 2H), 7.46 (d, J = 2.0 Hz, 1H), 7.35 (t, J = 7.2 Hz, 2H),

7.24 (tt, J = 1.2, 7.2 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 6.42 (d,

J = 2.0 Hz, 1H), 4.86–4.80 (m, 1H), 3.83 (dd, J = 7.2, 17.2 Hz,

1H), 3.30 (dd, J = 5.2, 17.2 Hz, 1H), 2.34 (s, 3H), 2.18–2.07 (m,

1H), 1.88–1.78 (m, 1H), 1.37–1.18 (m, 7H), 1.17–1.07 (m, 1H),

0.84 (t, J = 6.8 Hz, 3H); ¹³C NMR (101 MHz, CDCl₃) δ 197.4,

151.4, 144.0, 134.3, 134.0, 131.1, 129.2 (2C), 128.4 (2C), 128.2

(2C), 127.2, 125.6 (2C), 101.6, 58.5, 43.9, 35.2, 31.6, 28.7,

26.1, 22.5, 21.5, 14.0; IR (Neat) ν_max3034, 2928, 1682, 1606,

1458, 750, 694 cm⁻¹; MS (EI) m/z (%) 376 (M⁺+ 2, 54), 375

(M⁺+ 1, 100), 263 (3), 231 (19), 177 (11), 145 (19), 91 (3);

Anal. calcd for C₂₅H₃₀N₂O: C, 80.17; H, 8.07; N, 7.48. Found:

C, 80.06; H, 8.12; N, 7.56.

The structure of 8ae is established based on the HMBC studies;

correlations between C_a(60.7 ppm) and H_b(7.38 ppm), H_a

(6.05 ppm) and C_b(130.4 ppm) are quite signiﬁcant whereas the

correlation between H_aand C_d(148.5 ppm) is not seen.¹³

3-(5-Methyl-1H-pyrazol-1-yl)-1,3-diphenylpropan-1-one (8ae′).

157 mg, 54% yield; pale yellow thick liquid; R_f= 0.35

1

(12 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 8.01 (d,

J = 7.2 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.46 (t, J = 8.0 Hz,

2H), 7.42 (d, J = 1.6 Hz, 1H), 7.37–7.31 (m, 2H), 7.31–7.25 (m,

3H), 6.08 (dd, J = 4.4, 8.8 Hz, 1H), 6.03 (s, 1H), 4.66 (dd, J =

Org. Biomol. Chem., 2012, 10, 3538–3555 | 3551

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1,3-Diphenyl-3-(1H-1,2,3-triazol-1-yl)propan-1-one

(18′).^7d

Reaction was performed in toluene (1.5 mL) + DMF (0.5 mL)

mixture at 80 °C. 31mg, 11% yield; colorless solid; mp

147–148 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J = 8.0 Hz,

2H), 7.68 (s, 1H), 7.61 (s, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.45 (t,

J = 7.6 Hz, 2H), 7.39–7.29 (m, 5H), 6.32 (dd, J = 4.8, 8.4 Hz,

1H), 4.65 (dd, J = 8.4, 17.6 Hz, 1H), 3.74 (dd, J = 5.2, 18.0 Hz,

1H); ¹³C NMR (101 MHz, CDCl₃) δ 195.7, 139.0, 136.1, 133.8,

133.6, 129.0 (2C), 128.7 (2C), 128.1 (2C), 127.1, 126.8 (2C),

124.2, 60.3, 44.2; IR (KBr) ν_max3097, 1682, 1213, 752, 690,

549 cm⁻¹; MS (EI) m/z (%) 280 (M⁺+ 3, 14), 279 (M⁺+ 2, 35),

278 (M⁺+ 1, 100), 156 (3), 123 (5).

The structure of 8ub is established based on the NMBC studies;

correlations between C_a(58.5 ppm) and H_b(7.51 ppm), H_a

(4.83 ppm) and C_b(131.1 ppm) are quite signiﬁcant whereas the

correlation between H_aand C_d(151.4 ppm) is not seen.¹³

3-(1H-Indazol-1-yl)-1-p-tolylnonan-1-one (8uf). Reaction was

performed at 80 °C. 226 mg, 65% yield; pale yellow thick

1

liquid; R_f= 0.47 (9 : 1 hexane–EtOAc); H NMR (400 MHz,

CDCl₃) δ 8.01 (s, 1H), 7.81 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.0

Hz, 1H), 7.61 (d, J = 8.8 Hz, 1H), 7.39 (td, J = 0.8, 6.8 Hz, 1H),

7.20 (d, J = 8.0 Hz, 2H), 7.12 (t, J = 7.6 Hz, 1H), 5.23–5.32 (m,

1H), 3.85 (dd, J = 7.2, 17.6 Hz, 1H), 3.46 (dd, J = 5.6, 17.2 Hz,

1H), 2.38 (s, 3H), 2.24–2.13 (m, 1H), 2.00–1.87 (m, 1H),

1.30–1.13 (m, 7H), 1.05–0.93 (m, 1H), 0.82 (t, J = 6.8 Hz, 3H);

¹³C NMR (101 MHz, CDCl₃) δ 197.3, 144.1, 140.2, 134.2,

133.3, 129.2 (2C), 128.2 (2C), 126.1, 123.4, 120.8, 120.4,

109.4, 54.1, 43.8, 35.5, 31.5, 28.8, 26.1, 22.5, 21.6, 13.9; IR

(Neat) ν_max3059, 2928, 1682, 1608, 1014, 740 cm⁻¹; MS (EI)

m/z (%) 350 (M⁺+ 2, 62), 349 (M⁺+ 1, 100), 263 (14), 231

(57), 151 (11), 119 (19); Anal. calcd for C₂₃H₂₈N₂O: C, 79.27;

H, 8.10; N, 8.04. Found: C, 79.45; H, 8.06; N, 8.12.

3-(1H-Benzo[d][1,2,3]triazol-1-yl)-1,3-diphenylpropan-1-one

(19).^7cReaction was performed in toluene (1.5 mL) + DMF

(0.5 mL) mixture at 80 °C. 147 mg, 45% yield; light yellow

solid; mp 85–86 °C; ¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, J =

8.4 Hz, 1H), 7.97 (d, J = 7.2 Hz, 2H), 7.53 (s, 1H), 7.51 (t, J =

3.6 Hz, 1H), 7.45–7.35 (m, 5H), 7.35–7.22 (m, 4H), 6.60 (dd, J

= 4.8, 8.8 Hz, 1H), 4.86 (dd, J = 8.8, 18 Hz, 1H), 3.89 (dd, J =

4.8, 17.6 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 195.7, 145.9,

138.9, 135.9, 133.4, 132.8, 128.8 (2C), 128.5 (2C), 128.3, 128.0

(2C), 127.1, 126.5 (2C), 123.9, 119.6, 109.8, 58.1, 44.2; IR

(KBr) ν_max3061, 2924, 1687, 1267, 920, 746 cm⁻¹; MS (EI)

m/z (%) 228 (M⁺+ 1, 100), 196 (46), 183 (14), 100 (6).

3-(2H-Benzo[d][1,2,3]triazol-2-yl)-1,3-diphenylpropan-1-one

(19′).^7cReaction was performed in toluene (1.5 mL) + DMF

(0.5 mL) mixture at 80 °C. 33 mg, 10% yield; yellow thick

liquid; ¹H NMR (400 MHz, CDCl₃) δ 8.02–7.30 (m, 14 H), 6.78

(dd, J = 5.0, 9.0 Hz, 1H), 4.73 (dd, J = 9.0, 18.0 Hz, 1H), 3.89

(dd, J = 5.0, 18.0 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ

195.5, 144.1 (2C), 138.8, 136.2, 133.5, 130.9, 128.9 (2C), 128.7

(2C), 128.2 (2C), 126.8 (2C), 126.2 (2C), 118.2 (2C), 65.7,

44.1; IR (KBr) ν_max3063, 2930, 1582, 1332, 960, 700,

687 cm⁻¹; MS (EI) m/z (%) 328 (M⁺+ 1, 100), 277 (14), 191

(22), 108 (6), 67 (6).

The structure of 8uf is established based on the HMBC studies;

correlation between C_b(140.2 ppm) and H_a(5.31 ppm) is quite

signiﬁcant whereas correlations between C_a(54.1 ppm) and H_d

(8.01 ppm), H_aand C_d(133.3 ppm) are not seen.¹³

1,3-Diphenyl-3-(1H-1,2,4-triazol-1-yl)propan-1-one

(17).³⁶

Reaction was performed in toluene (1.5 mL) + DMF (0.5 mL)

mixture at 80 °C. 162 mg, 58% yield; pale yellow solid; mp

1

77–78 °C; H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.96 (d,

3-(1H-Imidazol-1-yl)-1,3-diphenylpropan-1-one (20).³⁷Reac-

tion was performed in toluene (1.5 mL) + DMF (0.5 mL)

mixture at 80 °C. 28 mg, 10% yield; pale yellow solid; mp

147–148 °C; ¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, J = 7.2 Hz,

2H), 7.52 (t, J = 7.2 Hz, 1H), 7.39 (t, J = 8.0 Hz, 3H), 7.35–7.23

(m, 4H), 7.23–7.16 (m, 1H), 6.90 (s, 2H), 4.84 (t, J = 6.8 Hz,

1H), 4.22 (dd, J = 7.6, 18.0 Hz, 1H), 3.58 (dd, J = 6.0, 18.0 Hz,

1H); ¹³C NMR (101 MHz, CDCl₃) δ 198.2, 149.4, 141.6, 136.6,

133.2 (2C), 128.8 (2C), 128.5 (2C), 128.1 (2C), 128.0 (2C),

127.1 (2C), 44.1, 40.0; IR (KBr) ν_max3040, 1682, 1462, 752,

688, 553 cm⁻¹; MS (EI) m/z (%) 278 (M⁺+ 2, 46), 277 (M⁺+

1, 100), 209 (3), 157 (5), 69 (2).

J = 8.0 Hz, 2H), 7.92 (s, 1H), 7.56 (t, J = 7.6 Hz, 1H),

7.50–7.32 (m, 7H), 6.20 (dd, J = 4.8, 9.2 Hz, 1H), 4.44 (dd, J =

8.8, 17.6 Hz, 1H), 3.63 (dd, J = 4.4, 17.6 Hz, 1H); ¹³C NMR

(101 MHz, CDCl₃) δ 195.8, 151.6, 143.5, 138.7, 136.0, 133.7,

129.0 (2C), 128.7 (2C), 128.6, 128.1 (2C), 126.9 (2C), 58.9,

43.7; IR (KBr) ν_max2922, 1685, 1502, 1006, 754, 690 cm⁻¹

;

MS (EI) m/z (%) 279 (M⁺+ 2, 30), 278 (M⁺+ 1, 100), 241 (16),

209 (57), 105 (8), 70 (8).

1,3-Diphenyl-3-(2H-1,2,3-triazol-2-yl)propan-1-one

(18).^7d

Reaction was performed in toluene (1.5 mL) + DMF (0.5 mL)

mixture at 80 °C. 166 mg, 60% yield; colorless solid; mp

1

90–91 °C; H NMR (400 MHz, CDCl₃) δ 7.95 (d, J = 7.6 Hz,

1,3-Diphenyl-3-(1H-pyrrol-1-yl)propan-1-one (21). 146 mg,

53% yield; pale yellow solid; mp 89–90 °C; R_f= 0.57

2H), 7.59–7.49 (m, 3H), 7.41 (t, J = 8.0 Hz, 2H), 7.35–7.22 (m,

5H), 6.51 (dd, J = 5.2, 9.2 Hz, 1H), 4.51 (dd, J = 9.2, 18.0 Hz,

1H), 3.69 (dd, J = 5.2, 18.0 Hz, 1H); ¹³C NMR (101 MHz,

CDCl₃) δ 195.6, 139.3, 136.2, 134.0 (2C), 133.3, 128.7 (2C),

128.5 (2C), 128.1, 128.0 (2C), 126.5 (2C), 63.8, 43.8; IR (KBr)

ν_max3063, 2908, 1682, 1332, 960, 750, 687 cm⁻¹; MS (EI) m/z

(%) 279 (M⁺+ 2, 15), 278 (M⁺+ 1, 52), 241 (6), 209 (100), 79

(5), 68 (5).

1

(6 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃) δ 7.95 (d, J

= 7.6 Hz, 2H), 7.59 (t, J = 8.2 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H),

7.37–7.25 (m, 3H), 7.22 (d, J = 7.2 Hz, 2H), 6.79 (s, 2H), 6.17

(s, 2H), 5.99 (t, J = 6.8 Hz, 1H), 3.96 (dd, J = 7.2, 17.2 Hz, 1H),

3.80 (dd, J = 6.4, 17.2 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ

196.2, 141.1, 136.5, 133.5, 128.8 (2C), 128.7 (2C), 128.0 (2C),

127.8, 126.4 (2C), 119.7 (2C), 108.4 (2C), 58.2, 44.6; IR (KBr)

3552 | Org. Biomol. Chem., 2012, 10, 3538–3555

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ν_max3059, 2924, 1680, 1269, 723, 634 cm⁻¹; MS (EI) m/z (%)

277 (M⁺+ 2, 5), 276 (M⁺+ 1, 24), 156 (100), 129 (13), 105

(15), 97 (33); Anal. calcd for C₁₉H₁₇NO: C, 82.88; H, 6.22; N,

5.09. Found: C, 82.75; H, 6.28; N, 5.15.

1-Phenyl-3-(1H-pyrrol-1-yl)-3-(trimethylsilyl)propan-1-one (25).

47 mg, 17% yield; light brown liquid; R_f= 0.66 (12 : 1 hexane–

EtOAc); along with 24 (39 mg, 19% yield), and 24′ (49 mg,

1

29% yield). H NMR (400 MHz, CDCl₃) δ 7.89 (d, J = 3.6 Hz,

2H), 7.56 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 6.63 (s,

2H), 6.08 (s, 2H), 4.34 (dd, J = 4.4, 9.6 Hz, 1H), 3.63 (dd, J =

9.6, 17.2 Hz, 1H), 3.21 (dd, J = 4.4, 17.2 Hz, 1H), 0.10 (s, 9H);

¹³C NMR (101 MHz, CDCl₃) δ 197.9, 136.7, 133.1, 128.6 (2C),

128.0 (2C), 120.4 (2C), 107.5 (2C), 46.9, 40.4, −3.0 (3C); IR

(Neat) ν_max2957, 1687, 1251, 979, 842, 721, 628 cm⁻¹; MS

(EI) m/z (%) 274 (M⁺+ 3, 16), 273 (M⁺+ 2, 51), 272 (M⁺+ 1,

100), 254 (11), 237 (110, 205 (14), 152 (110, 93 (3); Anal. calcd

for C₁₆H₂₁NOSi: C, 70.80; H, 7.80; N, 5.16. Found: C, 70.58;

H, 7.76; N, 5.21.

1-Phenyl-3-(1H-pyrrol-1-yl)undecan-1-one (22). Reaction was

performed at 80 °C. 180 mg, 58% yield; brown color solid; mp

41–42 °C; R_f= 0.52 (19 : 1 hexane–EtOAc); ¹H NMR

(400 MHz, CDCl₃) δ 7.88 (d, J = 7.2 Hz, 2H), 7.56 (bt, J = 7.6

Hz, 1H), 7.44 (bt, J = 7.6 Hz, 2H), 6.72 (s, 2H), 6.11 (s, 2H),

4.63 (bt, J = 7.2 Hz, 1H), 3.46 (dd, J = 6.4, 17.2 Hz, 1H), 3.32

(dd, J = 6.8, 17.2 Hz, 1H), 1.81 (bd, J = 6.4 Hz, 2H), 1.35–1.15

(m, 12 H), 0.86 (t, J = 6.4 Hz, 3H); ¹³C NMR (101 MHz,

CDCl₃) δ 197.4, 136.7, 133.2, 128.6 (2C), 128.0 (2C), 118.9

(2C), 107.8 (2C), 55.7, 45.7, 36.2, 31.8, 29.3, 29.2 (2C), 26.1,

22.6, 14.1; IR (KBr) ν_max3130, 2922, 1680, 758 cm⁻¹; MS (EI)

m/z (%) 312 (M⁺+ 1, 49), 311 (100), 269 (8), 210 (3); Anal.

calcd for C₂₁H₂₉NO: C, 80.98; H, 9.38; N, 4.50. Found: C,

80.78; H, 9.41; N, 4.61.

3-(1H-Indol-1-yl)-1-phenylheptan-1-one (26). Reaction was

performed at 80 °C. 177 mg, 58% yield; pale yellow thick

1

liquid; R_f= 0.43 (19 : 1 hexane–EtOAc); H NMR (400 MHz,

CDCl₃) δ 7.85 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 8.0 Hz, 1H),

7.54–7.44 (m, 2H), 7.39 (bt, J = 7.6 Hz, 2H), 7.23–7.16 (m,

2H), 7.08 (t, J = 7.2 Hz, 1H), 6.52 (d, J = 2.4 Hz, 1H),

5.15–5.05 (m, 1H), 3.55–3.40 (m, 2H), 2.04–1.90 (m, 2H),

1.36–1.18 (m, 3H), 1.13–1.01 (m, 1H), 0.80 (t, J = 6.4 Hz, 3H);

¹³C NMR (101 MHz, CDCl₃) δ 197.3, 136.5, 135.9, 133.3,

128.6 (2C), 128.5, 127.9 (2C), 124.7, 121.4, 120.9, 119.3,

109.8, 101.9, 52.2, 44.7, 34.9, 28.3, 22.3, 13.8; IR (Neat) ν_max

3055, 2957, 1658, 1460, 1307, 740, 690 cm⁻¹; MS (EI) m/z (%)

307 (M⁺+ 2, 46), 306 (M⁺+ 1, 100), 236 (5), 209 (8), 91 (10);

Anal. calcd for C₂₁H₂₃NO: C, 82.58; H, 7.59; N, 4.59. Found:

C, 82.45; H, 7.65; N, 4.51.

1-Phenyl-3-(1H-pyrrol-1-yl)heptan-1-one (23). Reaction was

performed at 80 °C. 99 mg, 39% yield; brown color solid; mp

47–48 °C; R_f= 0.47 (19 : 1 hexane–EtOAc); ¹H NMR

(400 MHz, CDCl₃) δ 7.90 (d, J = 7.2 Hz, 2H), 7.57 (t, J = 7.2

Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 6.75 (t, J = 2.4 Hz, 2H), 6.14

(t, J = 2.0 Hz, 2H), 4.72–4.59 (m, 1H), 3.49 (dd, J = 6.4, 17.2

Hz, 1H), 3.34 (dd, J = 6.8, 17.2 Hz, 1H), 1.93–1.76 (m, 2H),

1.43–1.19 (m, 3H), 1.19–1.05 (m, 1H), 0.87 (t, J = 6.8 Hz, 3H);

¹³C NMR (101 MHz, CDCl₃) δ 197.4, 136.7, 133.3, 128.6 (2C),

127.9 (2C), 118.9 (2C), 107.8 (2C), 55.7, 45.7, 35.9, 28.3, 22.2,

13.9; IR (KBr) ν_max3059, 2957, 1682, 1448, 725, 690 cm⁻¹

;

3-(1H-Indol-3-yl)-1-phenylheptan-1-one (26′). Reaction was

MS (EI) m/z (%) 257 (M⁺+ 2, 35), 256 (100), 238 (51), 189 (5),

136 (11), 80 (8); Anal. calcd for C₁₇H₂₁NO: C, 79.96; H, 8.29;

N, 5.49. Found: C, 79.85; H, 8.32; N, 5.41.

performed at 80 °C. 36 mg, 12% yield; brown color thick liquid;

1

R_f= 0.13 (19 : 1 hexane–EtOAc); H NMR (400 MHz, CDCl₃)

δ 7.99–7.93 (bs, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.0

Hz, 1H), 7.51 (t, J = 7.6 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.33

(t, J = 8.0 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 7.10 (t, J = 7.6 Hz,

1H), 7.01 (s, 1H), 3.72–3.61 (m, 1H), 3.42 (dd, J = 6.4, 16.0 Hz,

1H), 3.34 (dd, J = 7.2, 16.4 Hz, 1H), 1.91–1.77 (m, 2H),

1.33–1.23 (m, 4H), 0.82 (t, J = 6.8 Hz, 3H); ¹³C NMR

(101 MHz, CDCl₃) δ 199.9, 137.3, 136.5, 132.8, 128.4 (2C),

128.0 (2C), 126.6, 121.8, 121.2, 119.5, 119.4, 119.1, 111.2,

45.3, 35.2, 32.9, 29.9, 22.7, 14.0; IR (Neat) ν_max3416, 3057,

2928, 1682, 1454, 740 cm⁻¹; MS (EI) m/z (%) 307 (M⁺+ 2,

46), 306 (100), 236 (5), 209 (8), 91 (10); Anal. calcd for

C₂₁H₂₃NO: C, 82.58; H, 7.59; N, 4.59. Found: C, 82.71; H,

7.52; N, 4.65.

1-Phenyl-3-(1H-pyrrol-1-yl)propan-1-one (24).³⁸18 mg, 9%

yield; brown color semi-solid; H NMR (400 MHz, CDCl₃) δ

1

7.93 (d, J = 8.0 Hz, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.47 (t, J =

8.0 Hz, 2H), 6.73 (s, 2H), 6.16 (s, 2H), 4.39 (t, J = 6.8 Hz, 2H),

3.46 (t, J = 6.8 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 197.4,

136.4, 133.4, 128.7 (2C), 127.9 (2C), 120.7 (2C), 108.3 (2C),

44.2, 40.5; IR (Neat) ν_max3057, 2935, 1678, 1498, 1284, 1089,

748, 621 cm⁻¹; MS (EI) m/z (%) 201 (M⁺+ 2, 24), 200 (M⁺+

1, 100), 182 (5), 156 (3), 80 (8).

2-((1H-Pyrrol-1-yl)methyl)-1,5-diphenylpentane-1,5-dione (24′).

39 mg, 24% yield; brown thick liquid; R_f= 0.34 (12 : 1 hexane–

EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 7.91–7.82 (m, 4H), 7.54

(t, J = 7.2 Hz, 2H), 7.42 (t, J = 7.6 Hz, 4H), 6.63 (t, J = 1.6 Hz,

2H), 6.06 (t, J = 2.0 Hz, 2H), 4.38 (q, J = 9.6 Hz, 1H),

4.15–4.04 (m, 2H), 3.01–2.89 (m, 1H), 2.89–2.76 (m, 1H),

2.29–2.18 (m, 1H), 2.10–2.00 (m, 1H); ¹³C NMR (101 MHz,

CDCl₃) δ 202.2, 199.1, 136.7, 136.5, 133.5, 133.1, 128.7 (2C),

128.5 (2C), 128.1 (2C), 127.9 (2C), 120.9 (2C), 108.5 (2C),

51.2, 47.3, 35.0, 25.1; IR (Neat) ν_max3061, 2928, 1680, 1448,

1089, 727, 690 cm⁻¹; MS (EI) m/z (%) 332 (M⁺+ 1, 50), 314

(100), 265 (40), 212 (16), 200 (20), 194 (25); Anal. calcd for

C₂₂H₂₁NO₂: C, 79.73; H, 6.39; N, 4.23. Found: C, 79.65; H,

6.31; N, 4.35.

3-(2-Methyl-1H-indol-1-yl)-1-phenylheptan-1-one (27). Reac-

tion was performed at 80 °C. 132 mg, 41% yield; brown color

thick liquid; R_f= 0.27 (12 : 1 hexane–EtOAc); ¹H NMR

(400 MHz, CDCl₃) δ 7.99 (bs, 1H), 7.93 (d, J = 7.6 Hz, 2H),

7.81–7.73 (m, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.41 (t, J = 8.0 Hz,

2H), 7.31–7.23 (m, 1H), 7.21–7.13 (m, 2H), 3.73–3.60 (m, 2H),

3.46 (dd, J = 8.8, 18.4 Hz, 1H), 2.37 (s, 3H), 2.15–2.02 (m, 1H),

1.98–1.85 (m, 1H), 1.45–1.20 (m, 4H), 0.89 (t, J = 6.4 Hz, 3H);

¹³C NMR (101 MHz, CDCl₃) δ 200.4, 137.2, 135.5, 132.6,

131.4, 128.3 (2C), 127.9 (2C), 127.0, 120.3, 118.8, 118.6,

113.4, 110.5, 44.6, 34.7, 32.8, 30.2, 22.5, 13.9, 11.8; IR (Neat)

ν_max3055, 2928, 1680, 1462, 742, 690 cm⁻¹; MS (EI) m/z (%)

Org. Biomol. Chem., 2012, 10, 3538–3555 | 3553

View Article Online

320 (M⁺+ 1, 100), 232 (38), 199 (65), 200 (100), 144 (65), 132

(5); Anal. calcd for C₂₂H₂₅NO: C, 82.72; H, 7.89; N, 4.38.

Found: C, 82.59; H, 7.81; N, 4.43.

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1,3-Diphenyl-3-(phenylamino)propan-1-one (28).³⁹72 mg,

24% yield; colorless solid; mp 165–166 °C; ¹H NMR

(400 MHz, CDCl₃) δ 7.96–7.87 (m, 2H), 7.57 (tt, J = 1.2, 7.2

Hz, 1H), 7.51–7.41 (m, 4H), 7.34 (t, J = 8.0 Hz, 2H), 7.29–7.22

(m, 1H), 7.15–7.05 (m, 2H), 6.68 (t, J = 7.2 Hz, 1H), 6.57 (dd, J

= 0.8, 8.4 Hz, 2H), 5.02 (dd, J = 5.2, 7.6 Hz, 1H), 4.57 (bs, 1H),

3.52 (dd, J = 5.2, 16.0 Hz, 1H), 3.43 (dd, J = 7.6, 16.0 Hz, 1H);

¹³C NMR (101 MHz, CDCl₃) δ 198.2, 147.0, 142.9, 136.7,

133.4, 129.1 (2C), 128.8 (2C), 128.7 (2C), 128.2 (2C), 127.3,

126.3 (2C), 117.7, 113.8 (2C), 54.8, 46.3; IR (KBr) ν_max3385,

3024, 2918, 1670, 1599, 1290, 744, 686 cm⁻¹; MS (EI) m/z (%)

300 (M⁺− 1, 100), 284 (5).

1,1′-(1,4-Phenylene)bis(3-phenyl-3-(1H-pyrazol-1-yl)propan-1-

one) (30). 265 mg, 56% yield; light brown solid; mp

173–174 °C; R_f= 0.28 (3 : 1 hexane–EtOAc); ¹H NMR

(400 MHz, CDCl₃) δ 8.01 (s, 4H), 7.47 (dd, J = 1.6, 10.0 Hz,

4H), 7.42–7.30 (m, 10H), 6.22 (t, J = 2.0 Hz, 2H), 6.08 (dd, J =

4.8, 8.4 Hz, 2H), 4.52 (dd, J = 8.8, 17.6 Hz, 2H), 3.58 (dd, J =

5.2, 17.6 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 196.2 (2C),

140.4 (2C), 139.8 (2C), 139.2 (2C), 129.7 (2C), 128.8 (4C),

128.4 (4C), 128.1 (2C), 126.6 (4C), 105.7 (2C), 60.7 (2C), 44.5

(2C); IR (KBr) ν_max3063, 2918, 1687, 1398, 754, 626 cm⁻¹

;

MS (EI) m/z (%) 476 (M⁺+ 2, 16), 474 (M⁺, 61), 473 (41), 406

(51), 353 (51), 338 (100), 238 (3), 96 (3); Anal. calcd for

C₃₀H₂₆N₄O₂: C, 75.93; H, 5.52; N, 11.81. Found: C, 75.86; H,

5.49; N, 11.68.

1,1′-(1,4-Phenylene)bis(3-(1H-indazol-1-yl)-3-phenylpropan-1-

one) (31). 276 mg, 48% yield; yellow thick liquid; R_f= 0.50

(3 : 1 hexane–EtOAc); ¹H NMR (400 MHz, CDCl₃) δ 8.07–8.02

(m, 6H), 7.72 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H),

7.41–7.25 (m, 12 H), 7.15 (t, J = 7.6 Hz, 2H), 6.49 (dd, J = 4.4,

8.8 Hz, 2H), 4.75 (dd, J = 8.8, 17.6 Hz, 2H), 3.74 (dd, J = 4.4,

17.6 Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 196.2 (2C), 140.5

(2C), 139.7 (2C), 139.5 (2C), 133.0 (2C), 128.7 (4C), 128.3

(4C), 127.8 (2C), 126.5 (4C), 126.3 (2C), 124.2 (2C), 120.9

(2C), 120.8 (2C), 109.4 (2C), 57.4 (2C), 44.6 (2C); IR (Neat)

ν_max3061, 2924, 1687, 1498, 1024, 740 cm⁻¹; MS (EI) m/z (%)

576 (M⁺+ 1, 14), 575 (M⁺, 35), 457 (20), 339 (100), 151 (51),

119 (82); Anal. calcd for C₃₈H₃₀N₄O₂: C, 79.42; H, 5.26; N,

9.75. Found: C, 79.52; H, 5.21; N, 9.68.

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Acknowledgements

We gratefully acknowledge the University of Hyderabad,

ACRHEM and the DST (Grant No. SR/S1/OC-34/2009) for

support. M.B and Kuram thank CSIR, India for graduate fellow-

ship. We are grateful to Mr Krishna Chary and Mr Sudalai

Kumar for solving the X-ray crystallographic data.

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A convenient approach to β-heteroarylated (C-N bond) ketones from Cs2CO3 promoted reaction between propargyl alcohols and nitrogen-heterocycles

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