Directed ortho Metalation (D o M)-Linked Corriu-Kumada, Negishi, and Suzuki-Miyaura Cross-Coupling Protocols: A Comparative Study

SYNTHESIS

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C. A. Quesnelle, V. Snieckus

Paper

Synthesis

Directed ortho Metalation (DoM)-Linked Corriu–Kumada, Negishi,

and Suzuki–Miyaura Cross-Coupling Protocols: A Comparative

Study

Claude A. Quesnelle¹

G¹

+

Victor Snieckus*

M

TfO

G²

Queen’s University, Department of Chemistry, Kingston, ON,

K7L 3N6, Canada

M = MgX, ZnX, B(OR)₂

snieckus@chem.queensu.ca

Dedicated to Scott Denmark: By this, we (and KB in absentia)

are celebrating your creativity and stellar achievements.

Published as part of the Special Section dedicated to Scott E. Den-

mark on the occasion of his 65^thbirthday.

Received: 09.07.2018

Accepted after revision: 21.08.2018

Published online: 05.10.2018

gies,¹⁵and the formation of Ar–Ar bonds from the combina-

tion of Ar-LG and Ar-metal partners (Scheme 1) continues

as a sustainable, reliable, and widely practiced method.¹⁶

In our studies on linking the directed ortho metalation

(DoM) reaction to transition-metal-catalyzed cross-cou-

pling strategies,^17–21we have previously disclosed variants

of the Corriu–Kumada,^3,4Negishi,⁵and Suzuki–Miyaura⁷

cross-coupling reactions with aryl triflates,²²O-sulfamates,

^23,24and O-carbamates.^22bWith the various coupling tactics

at the synthetic chemist’s disposal, questions regarding

which choice to make or priorities to set, based on several

factors, are obligatory. To date, a single account of the com-

parison of various coupling reactions has been reported.²⁵

Herein, we report systematic studies on the Corriu–Kuma-

da, Negishi, and Suzuki–Miyaura reactions,²⁶primarily on

DoM reaction-derived substrates (Scheme 1, M = ZnX), with

the aim of assisting and guiding the selection of the cross-

coupling reactions to undertake to prepare the desired biaryls.

DOI: 10.1055/s-0037-1611053; Art ID: ss-2018-c0464-op

Abstract A systematic study of the widely used, titled name reaction

transition-metal-catalyzed cross-coupling reactions with attention to

context with the directed ortho metalation (DoM) is reported. In gener-

al, the Suzuki–Miyaura and Negishi protocols show greater scope and

better yields than the Corriu–Kumada variant, although the latter quali-

tatively proceeds at fastest rate but has low functional group tolerance.

The Negishi process is shown to be useful for substrates with nucleop-

hile and base-sensitive functionality and it is comparable to the Suzuki–

Miyaura reaction in efficiency. The link of these cross-coupling reac-

tions to the DoM strategy lends itself to the regioselective construction

of diversely substituted aromatics and heteroaromatics.

Key words Suzuki–Miyaura coupling, Negishi coupling, Kumada cou-

pling, comparison

Almost half a century has passed since the seminal ob-

servations of transition-metal-catalyzed reactions that

have revolutionised how organic chemists think about C–C,

and later, C–N, C–O, and C–S, bond formation.²The Corriu–

Kumada,^3,4Negishi,⁵Migita–Stille,⁶Suzuki–Miyaura,⁷and,

to a lesser extent, the Hiyama–Denmark,⁸the Sonogashira,⁹

and the mechanistically distinct Mizoroki–Heck¹⁰coupling

reactions have become powerful weapons in the armory of

the synthetic chemist pursuing C–C bond-forming process-

es. More recently, the research of Knochel and co-workers

has introduced an additional dimension in cross-coupling

reactions of Grignard and organozinc reagents.¹¹Especially

significant is the pervasive impact of these reactions on

aryl–aryl and the counterpart heteroaryl molecule con-

struction not only in general adaption in synthesis but in

areas of relevance to the preparation of pharmaceuticals^12,13

and materials.¹⁴While transition-metal-catalyzed C–H acti-

vation reactions are still in an embryonic state, they are

rapidly developing as the next wave of useful methodolo-

LG

+

G²

M

G²

G¹

1

2

3

G¹, G²= various; LG = halogen, OTf, etc.

M = ZnX, B(OR)₂, MgX, SnR₃, SiR₃, etc.

Scheme 1 Aryl–aryl named cross-coupling reactions

A survey of the literature, summarised in Table 1, sug-

gests the various pros and cons of each protocol.²⁷Our ex-

perience on Suzuki–Miyaura coupling reactions of organo-

triflates²⁸dictated this comparative study of name reaction

variants with decision of reaction partners based on ease of

analysis and consistency. The results of direct comparisons

of the Negishi, Corriu–Kumada, and Suzuki–Miyaura reac-

tions with selected aryl triflates are summarised in Table 2.

B

C. A. Quesnelle, V. Snieckus

Paper

Synthesis

Table 1 Comparisons of Named Cross-Coupling Reactions

Reaction

Pro

ready availability of commercial Grignards

stable turbo Grignard,

organozinc reagents

Con

functional group incompatibility

Kumada–Corriu^a

Knochel¹¹

homo coupling

halogen-Mg exchange, direct magnesiation DoM

functional group tolerance

inexpensive, benign Fe catalysis

Negishi^b

inexpensive reagents

overcomes protodeboronation

mild reaction conditions

anhydrous conditions

unconventional solvents

substantial functional group compatibility, including OH, NH

Stille^c

high yields

commercially available

tin reagents

toxic

significantly volatile

anhydrous conditions

connect to DoM

widely used in heteroaromatic coupling

environmental hazard (storage, disposal)

potential tin byproduct impurities

Suzuki–Miyaura^d

boronic acids: nontoxic, stable to moisture, air, heat

ease of operation

protodeboronation

boric acid mutagenicity^e

scale up in industry^12,16

FG compatibility

connect to DoM

nontoxic byproducts

Hiyama–Denmark^f

future promise to rival Stille and Suzuki–Miyaura reactions

single DoM example^27b

^aSee ref.³⁰

^bSee ref.³¹

^cSee ref.³²

^dSee ref.³³

^eSee ref.³⁴

^fSee ref.³⁵

Table 2 summarises the results from varying the metal

on the organometallic component in cross-coupling with

different substituted triflates, some of which were chosen

with the primary intention to evaluate the name reaction

methods linked to DoM chemistry.²⁹

For Corriu–Kumada couplings, preparatively useful yields

were observed for CONEt₂(entries 1–3) but not for

OCONEt₂(entries 4–6) and F (entries 13–15) groups, the

CO₂Me examples being excluded from testing for obvious

reasons. The yields of the products for the OCONEt₂systems

are undoubtedly compromised by competitive Grignard –

O-carbamate coupling reaction,^22bwhile those for F-substi-

tuted substrates may suffer potential S_NAr reaction on the

fluoro substituent.³⁶However, entry 15 indicates that pro-

longed reaction times have no negative effect.

The data for the extensively used Suzuki–Miyaura cou-

pling tactic^17,33shows good to excellent product yields for

the powerful CONEt₂(Table 2, entries 1–3) and OCONEt₂

(entries 10–12) DMG¹⁷systems, and the arguably the less

effective F (entries 13–15) DMG bearing derivative. For all

three ester derivatives (entries 4–6), the mildly basic condi-

tions of the Suzuki–Miyaura reaction caused difficulties

(entries 4–6). Thus, under homogeneous reaction condi-

tions (1,2-dimethoxyethane (DME) as solvent), very low

yields of product were isolated (conditions D). However,

changing the solvent to toluene, hence creating heteroge-

neous conditions,³⁷provided the coupled products in good

yields (entry 5, conditions F and entry 6, conditions F and

G), except for the ortho-substituted ester (entry 4, condi-

tions F). For this case, the use of a weaker base (Cs₂CO₃) at

The following conclusions may be drawn: (1) with a few

exceptions, the organozinc and organoboron cross-coupling

reactions were always better behaved than the Corriu–Ku-

mada processes, irrespective of the catalytic system

(Ni(acac)₂, NiCl₂(dppe)), allowing for higher yields of cou-

pled products (compare, for illustration, respective metal

species in Table 2, entries 2, 10, and 14). Following all of the

reactions (TLC), the consumption of the aryl triflate 4 was

observed, but the Corriu–Kumada reactions proceeded only

in the 50% ranges, always resulting in complex reaction

mixtures that were not as clean as the Negishi and Suzuki–

Miyaura reactions; (2) the location of the substituent G at

ortho-, meta-, and para-positions had marginal effect on

the yields of most of the reasonably high-yielding reactions

that were successful (see below).

The named reactions are now addressed separately. For

the Negishi coupling reactions, consistently good to excel-

lent yields of biaryls were obtained for CONEt₂(Table 2, en-

tries 1–3) and CO₂Me (entries 4–6) (EWGs) and OCONEt₂

(entries 10–12) and F (entries 13–15) (mildly EDGs) groups.

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C. A. Quesnelle, V. Snieckus

Paper

Synthesis

ambient temperatures provided modest amounts of the

product (entry 4, conditions H). That the cause of the de-

crease in the yields was due to ester hydrolysis was shown

by re-esterification of the crude coupling reaction mixture

to afford the product in almost identical yield to that of the

heterogeneous reaction (compare entry 6, conditions D and

G, vs. F).

The NHBoc group is a very valuable and one of the first

heteroarom-DMGs used in the combined DoM–cross-cou-

pling strategy.³⁸However, the NHBoc derivative was intol-

erant of both Negishi and Corriu–Kumada coupling condi-

tions, leading instead to complex, intractable product mix-

tures. In contrast, Suzuki–Miyaura couplings proceeded

cleanly with organoboron reagents to give very good yields

of products (Table 2, entries 7–9). The possibility of compli-

cation caused by the nitrogen anion formed during the re-

action was not pursued, the phenomenon potentially being

tested by N-protection.³⁹

Table 2 Comparative Cross-Coupling Reactions: Effect of Functional Group on Aryl Triflate Partner

O

OTf

O

+

M

G

4

5

6

Entry

4, G

6, Yield (%)^a[conditions,^btime (h)]

5, M = MgBr

M = ZnCl

M = B(OH)₂

66 (D, 16)

1

2

3

4

2-CONEt₂

66 (B, 5)

78 (C, 2.5)

85 (A, 18)

3-CONEt₂

4-CONEt₂

2-CO₂Me

63 (B, 5)

67 (C, 2.5)

95 (A, 20)

86 (A, 20)

96 (A, 24)

80 (D, 25)

67 (D, 16)

78 (B, 3)

65 (C, 3)

–

0 (D, 24)

0 (F, 17)

40 (H, 24)

5

6

3-CO₂Et

4-CO₂Et

–

60 (A, 20)

65 (A, 20)

8 (D, 30)

78 (F, 23)

16 (D, 30)

80 (F, 23)

79 (G, 18)

7

2-NHBoc

3-NHBoc

4-NHBoc

2-OCONEt₂

0^c(C)

0^c(A)

79 (D, 25)

86 (D, 19)

87 (D, 17)

92 (D, 20)

8

0^c(A)

9

0^c(A)

10

23 (B, 4.5)

13 (C, 4)

92 (A, 17)

11

12

13

14

15

3-OCONEt₂

4-OCONEt₂

2-F

41 (B, 4.5)

54 (C, 2)

89 (A, 26)

85 (A, 30)

95 (A, 23)

74 (A, 19)

73 (A, 21)

98 (D, 24)

89 (D, 24)

86 (D, 19)

89 (D, 18)

46 (B, 4)

50 (C, 2)

37 (B, 1.5)

48 (C, 3)

3-F

47 (B, 1.5)

44 (C, 3)

4-F

38 (B, 1)

43 (B, 2)

43 (C, 4)

16

17

3-Py

78 (B, 4.5)

49 (C, 2.5)

87 (A, 18)

81 (D, 18)

61 (D, 21)

4-NO₂

0 (C, 24)

0 (A, 22)

35 (E, 21)

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C. A. Quesnelle, V. Snieckus

Paper

Synthesis

Table 2 (continued)

Entry

4, G

6, Yield (%)^a[conditions,^btime (h)]

5, M = MgBr

M = ZnCl

M = B(OH)₂

OTf

18

NHBoc

58 (B, 4)

Ph

37 (A, 1.5)

82 (C, 16)

OTf

19

N

O

N

O

Bn

52 (B, 5)

67 (A, 4.5)

71 (C, 17)

0 (NC^d)

OTf

Me

MeO

20

MeO

CHO

O

–

74 (A, 2)

95 (C, 14)

O

21

O

OTf

0 (B)

58 (A, 2)

94 (C, 30)

^aConditions A: Ni(acac)₂, PPh₃, MeMgBr, THF, rt. Conditions B: NiCl₂(dppe), THF, rt. Conditions C: Ni(acac)₂, THF, rt. Conditions D: Pd(PPh₃)₄, DME, EtOH, 2 M

Na₂CO₃, reflux. Conditions E: Pd(PPh₃)₄, THF, reflux. Conditions F: Pd(PPh₃)₄, toluene, EtOH, 2 M Na₂CO₃, reflux. Conditions G: i. Pd(PPh₃)₄, DME, EtOH, 2 M Na₂-

CO₃, reflux; ii. H₂SO₄, EtOH, reflux. Conditions H: Pd(PPh₃)₄, DME, 2 M Cs₂CO₃, rt.

^bYield of chromatographically pure material.

^cComplex, inseparable mixture of products.

^dNC = No catalyst.

Two other commercially available boronic acids were

tested. Reactions of the 3-pyridyl triflate⁴⁰in Negishi and

Suzuki–Miyaura reactions proceeded well under all the

cross-coupling variation conditions (Table 2, entry 16),

while the improved coupling conditions (entry 16, compare

Conditions B and C) for the Corriu–Kumada reaction consti-

tutes, with those for 4, G = CONEt₂(entries 1–3), the best

result obtained in our study for these Grignard cross-cou-

pling processes. For the nitro aryl triflate, 4, G = NO₂, the Ni-

catalyzed Negishi and Corriu–Kumada reactions failed, re-

sulting in complete recovery of starting material (entry 17).

This is consistent with previous observations by Kochi that

nitroaromatics inhibit the reaction.^41,42However, when Pd

was used as the catalyst, the reaction proceeded in modest

yields for both Negishi and Suzuki–Miyaura variants, with

the latter providing superior yields.

Outside of the systematic studies above, several miscel-

laneous aryl triflates were studied to provide some struc-

tural variation and functional group tolerance. In Table 2,

entries 18–21 the coupling reactions of four triflates are

compared; these were selected because of their availability

from other ongoing projects in our laboratories. These cases

give additional data on the greater value of the Negishi and

Suzuki–Miyaura reactions. Noteworthy is the attempted

coupling in the absence of catalyst (entry 19), which gave

poor results. As expected, the incompatibility of carbonyl

functional groups in Corriu–Kumada coupling was also

demonstrated (entry 21, conditions B).

In conclusion, in the present study we have systemati-

cally compared the Negishi, Corriu–Kumada and Suzuki–

Miyaura reactions, as three widely used cross-coupling pro-

tocols, using aryl triflate coupling partners. One can make

E

C. A. Quesnelle, V. Snieckus

Paper

Synthesis

the argument that similar trends would be observed with

aryl halides. Pertinent to use of the data for further applica-

tion of aryl–aryl cross-coupling in synthetic practice are the

following general conclusions: (1) Table 2 demonstrates

that the Suzuki–Miyaura and Negishi reactions show great-

er scope and better yields than the Corriu–Kumada variant,

although substrate-for-substrate comparisons suggested

that the latter qualitatively proceeds at the fastest rate; (2)

as a result, if functionality susceptible to nucleophilic at-

tack is absent, the Corriu–Kumada coupling route is the

method of choice within the scope of the classes of com-

pounds studied; (3) if such intolerant functional groups are

present, either the Negishi, Suzuki, or, in our case, the unex-

plored Stille alternative coupling reactions may be used.

The latter, due to the toxicity of the stannane reagents, is a

much less attractive option. The choice of either the Negishi

or Suzuki reactions is a function of the specific system in

question. Even though the Suzuki–Miyaura process is re-

ceiving vast use in synthesis, the mild reaction conditions

of the Negishi variation must not be overlooked and this re-

action should be employed when nucleophile- and aque-

ous-base-sensitive functionality is present in the reactants.

A cursory glance of Table 2 provides ample evidence for

why the Negishi reaction deserves a prominent position in

the regular repertoire of the synthetic chemist. This is evi-

denced in the industrial context.¹⁶Furthermore, the con-

nection to DoM for the preparation of the organometallic

reagents lends itself convincingly to the regiospecific con-

struction of aromatic molecules with highly and diversely

substituted patterns and it has witnessed broad industrial

application. The results from a parallel study of polyaryl

synthesis are reported in the adjoining disclosure.⁴³

All anhydrous solvents used were purified according to Perrin.⁴⁵Tet-

rahydrofuran, dimethoxyethane, and diethyl ether were distilled from

benzophenone ketyl under nitrogen immediately prior to use. t-BuLi

was purchased from Aldrich Chemical Co. as a solution in pentane. n-

BuLi was kindly supplied by FMC, Lithco Division, as a solution in

hexane. The alkyllithium reagents were stored in resealable contain-

ers and titrated periodically against 1,10-phenanthroline/n-BuOH.⁴⁶

N,N,N′,N′-Tetramethylethylenediamine (TMEDA) was dried and dis-

tilled over CaH₂before use. ZnCl₂was purchased from Aldrich Chemi-

cal Co. as a 1.0 M solution in Et₂O. MeMgBr and i-PrMgCl were

purchased as solutions in Et₂O and PhMgBr as a solution in THF.

MgBr₂·OEt₂solution was prepared according to the procedure of

Seebach.⁴⁷All the commercial materials were purchased from Aldrich

Chemical Co. or Lancaster Synthesis Ltd. Pd(PPh₃)₄⁴⁸and NiCl₂(dppe)⁴⁸

were prepared by following the reported methods.

All the reactions were carried out under inert atmosphere (Ar, N₂) un-

less otherwise specified. The transfer via cannula employed addition-

al solvent for quantitative transfer, designated by (amount of sol-

vent+additional amount of solvent). The –78 °C temperature desig-

nated is approximate as achieved by a dry ice-acetone bath. Allowing

a reaction to proceed overnight implies a period of 10–12 h. The

phrase ‘normal workup’ means the addition of saturated aqueous

NH₄Cl solution to the reaction mixture followed by CH₂Cl₂or Et₂O ex-

traction, drying over Na₂SO₄, filtration, and evaporation of the filtrate

in vacuo to afford the crude product.

Standard Methods

Procedure A. Preparation of Aryl Trifluoromethanesulfonates

Prepared by following an adaptation of the published procedure.⁵⁰To

a cooled (0 °C), stirred solution of the phenol (10 mmol) and pyridine

(20 mmol) in CH₂Cl₂(50 mL) under Ar or N₂was added, via syringe,

trifluoromethanesulfonic anhydride (13 mmol). After stirring for 1–3

h, the reaction mixture was treated with aq sat NH₄Cl. The CH₂Cl₂

phase was washed sequentially with aqueous copper sulfate (2×) and

H₂O and dried over MgSO₄. Filtration, concentration in vacuo and pu-

rification afforded the product.

Flash chromatography⁴⁴was carried out using ‘fine’ Merck silica gel

60 (0.04–0.06 mm) purchased from VWR Scientific of Canada Ltd.

with hexane/EtOAc as eluent unless otherwise specified. Melting

points were determined using a Büchi model SMP-20 instrument and

are uncorrected. IR spectra were recorded with either a Perkin–Elmer

983 or a Bomem FTIR infrared spectrophotometer in neat or KBr plate

form. ¹H NMR and ¹³C NMR spectra were recorded with AC-200 or

AM-250 spectrometers in CDCl₃solution using tetramethylsilane as

internal standard unless otherwise specified. ¹H NMR spectra listed

are tabulated in the order: chemical shifts, multiplicity, coupling

constants in Hertz, number of protons and assignment of protons.

¹³C NMR spectra listed are tabulated in the order: chemical shift, type

of carbon [‘o’ designates an odd number of attached protons (i.e., CH₃,

CH), ‘e’ designates an even number (i.e., CH₂, C), as determined by the

JMOD pulse sequence], multiplicity and coupling constants in hertz

where applicable and assignment of carbons. Mass spectra and HRMS

were determined by Dr. R. Smith, McMaster University, Hamilton,

Ontario, Canada, with VG 7070F or Varian spectrometers, Dr. H. S.

McKinnon, Guelph Centre for Mass Spectrometry, University of

Guelph, Guelph, Ontario, Canada with KRATOS MS 890 spectrome-

ters, or Dr. F. Hileman, Monsanto Co., St. Louis, Missouri. Elemental

analyses were performed by Galbraith Laboratories, Knoxville,

Tennessee and MHW Laboratories, Phoenix, Arizona.

Procedure B. Preparation of Aryl Grignard and Zinc Reagents

Method A: To a cold (–78 °C), stirred solution of aryl bromide

(2 mmol) in THF (10 mL) under Ar or N₂was added a solution of ei-

ther n-BuLi (2.2 mmol) or t-BuLi (4.2 mmol). After 15 minutes, the re-

action mixture was allowed to warm to rt. This solution was then

used in subsequent reactions.

Method B (Directed ortho-Metalation Method): To a cold (–78 °C),

stirred solution of the aryl DMG compound (2 mmol) in THF (10 mL)

under Ar or N₂was added a solution of t-BuLi (2.4 mmol). After 1 h,

ZnCl₂(3 mmol) was added and the solution was allowed to warm to

rt. This solution was then subsequently used.

Procedure C. Nickel-Catalyzed Coupling of Grignard Reagents with

Organotriflates

A flask charged with triflate (1 mmol) and nickel catalyst (0.05 mmol)

in either Et₂O or THF (5 mL) under Ar or N₂at 0 °C was treated with a

Grignard reagent (2 mmol). After immediate black coloration, the re-

action flask was removed from the ice bath and stirring was contin-

ued until TLC indicated lack of starting material (ca. 2 h). The reaction

mixture was treated with aq sat. NH₄Cl and extracted with Et₂O. The

combined organics were dried (MgSO₄). Filtration, concentration in

vacuo, and purification by flash chromatography on silica gel yielded

the coupled product.

F

C. A. Quesnelle, V. Snieckus

Paper

Synthesis

Procedure D. Nickel-Catalyzed Coupling of Organozinc Reagents

with Organotriflates

¹H NMR (200 MHz, CDCl₃):  = 1.15 (m, 6 H, NCH₂CH₃), 3.20 (bs, 2 H,

NCH₂CH₃), 3.55 (bm, 2 H, NCH₂CH₃), 7.56–7.31 (m, 4 H).

MS (EI; 70 eV): m/z (%) = 325 (3) [M⁺], 253 (100), 192 (48), 164 (20),

120 (26), 92 (18).

To a stirred solution at rt of nickel catalyst (0.05 mmol) in THF (3 mL)

under Ar or N₂was added sequentially either DIBAL-H or MeMgBr

(0.1 mmol), a freshly prepared aryl organozinc solution (2 mmol) via

cannula, and an organotriflate (1 mmol) in THF (2 mL) with an addi-

tional amount of THF (1 mL) for quantitative transfer. Once all addi-

tions were complete, the reaction mixture was stirred until TLC indi-

cated disappearance of starting material (typically 12–18 h). At this

time, the reaction was treated with aq sat. NH₄Cl and extracted with

Et₂O. The combined extracts were dried (MgSO₄), subjected to filtra-

tion, and the filtrate was concentrated in vacuo to give a residue,

which was subjected to flash chromatography on silica gel to afford

the diaryl product.

HRMS: m/z calcd for C₁₂H₁₅NO₄F₃S: 326.0674; found: 326.0678.

N,N-Diethyl-4-(trifluoromethylsulfonyloxy)benzamide (Table 2,

Entry 3)

According to General Procedure A, a solution of N,N-diethyl-4-hy-

droxybenzamide (1.51 g, 7.79 mmol) and pyridine (1.3 mL,

16.1 mmol) in CH₂Cl₂(35 mL) was treated with Tf₂O (2.0 mL,

11.9 mmol). After 4 h, normal workup followed by bulb-to-bulb dis-

tillation afforded the product.

Yield: 2.53 g (68%); colourless oil that solidified to a colourless solid;

mp 39.5–40.5 °C (pentane); bp 107–108 °C/0.03 mmHg.

Procedure E. Palladium-Catalyzed Coupling of Arylboronic Acids

with Aryl Bromides and Triflates

IR (neat): 1626, 1436, 1223, 1140 cm^–1

.

A mixture of Pd(PPh₃)₄(0.04 mmol) and aryl halide or aryl triflate

(1 mmol) in DME (3 mL) was stirred at rt for 10 min. A 2 M aqueous

Na₂CO₃solution (3 mL) was added, followed by a solution of the aryl-

boronic acid (1.4 mmol) in DME (3 mL), and EtOH (3 mL) if required

for solubility. The resulting mixture was heated at reflux overnight,

cooled to rt to end always with a black color. The crude mixture was

treated with aq sat. NH₄Cl, extracted with Et₂O, the extract was dried

(MgSO₄), subjected to filtration, and the filtrate concentrated in vacuo

and purified by flash chromatography to afford the diaryl product.

¹H NMR (200 MHz, CDCl₃):  = 1.18 (bs, 6 H, NCH₂CH₃), 3.26 (bs, 2 H,

NCH₂CH₃), 3.54 (bs 2 H, NCH₂CH₃), 7.33 (d, J = 8.7, Hz, 2 H), 7.49 (d, J =

8.7 Hz, 2 H).

¹³C NMR (50 MHz, CDCl₃):  = 12.6 (o, NCH₂CH₃), 13.9 (o, NCH₂CH₃),

39.2 (e, NCH₂CH₃), 43.2 (e, NCH₂CH₃), 118.5 (e, q, J = 320.1 Hz, CF₃),

121.3 (o), 128.3 (o), 137.4 (e), 149.5 (e), 169.1 (e).

MS (EI; 70 eV): m/z (%) = 325 (20) [M⁺], 324 (41), 253 (100) [M-NEt₂],

192 (11) [M-Tf], 161 (31), 120 (25).

HRMS: m/z calcd for C₁₂H₁₄F₃NO₄S: 325.0596; found: 325.0577.

Preparation of Aryl Triflates

Methyl 2-(Trifluoromethylsulfonyloxy)benzoate (Table 2, Entry 4)

N,N-Diethyl-2-(trifluoromethylsulfonyloxy)benzamide (Table 2,

Entry 1)

According to General Procedure A, a solution of methyl salicylate

(2.21 g, 14.5 mmol) and pyridine (2.3 mL, 28.4 mmol) in CH₂Cl₂(50

mL) was treated with Tf₂O (3.6 mL, 21.4 mmol). After 2 h, normal

workup followed by bulb-to-bulb distillation afforded the product.

According to General Procedure A, a solution of N,N-diethyl-2-hy-

droxybenzamide (1.95 g, 10.1 mmol) and pyridine (1.4 mL,

17.3 mmol) in CH₂Cl₂(50 mL) was treated with Tf₂O (2.2 mL,

13.1 mmol). After 1.5 h, normal workup followed by bulb-to-bulb dis-

tillation afforded the product.

Yield: 3.93 g (95%); colourless oil; bp 88–90 °C/0.5 mmHg.

IR (neat): 1732, 1429, 1207 cm^–1

.

¹H NMR (200 MHz, CDCl₃):  = 3.95 (s, 3 H, OCH₃), 7.31 (d, J = 8.2 Hz,

1 H), 7.46 (td, J = 7.7, 1.2 Hz, 1 H), 7.62 (td, J = 8.2, 1.9 Hz, 1 H), 8.08

(dd, J = 7.7, 1.9 Hz, 1 H).

¹³C NMR (50 MHz, CDCl₃):  = 52.4 (o, OCH₃), 118.7 (e, q, J = 323.4 Hz,

CF₃), 122.6 (o), 124.2 (e), 128.3 (o), 132.6 (o), 134.2 (o), 148.2 (e),

164.0 (e).

Yield: 2.52 g (77%); colourless oil; bp 95–6 °C/0.01 mmHg.

IR (neat): 1642, 1429, 1215 cm^–1

.

¹H NMR (200 MHz, CDCl₃):  = 1.11 (t, J = 7.1 Hz, 3 H, NCH₂CH₃), 1.26

(t, J = 7.1 Hz, 3 H, NCH₂CH₃), 3.20 (q, J = 7.1 Hz, 2 H, NCH₂CH₃), 3.56

(bs, 2 H, NCH₂CH₃), 7.33–7.50 (m, 4 H).

¹³C NMR (62.9 MHz, CDCl₃):  = 12.1 (o, NCH₂CH₃), 13.6 (o, NCH₂CH₃),

38.9 (e, NCH₂CH₃), 42.8 (e, NCH₂CH₃), 118.3 (e, q, J = 320.3, CF₃), 121.6

(o), 128.2 (o), 128.3 (o), 130.6 (o), 130.9 (e), 145.0 (e), 165.1 (e).

MS (EI; 70 eV): m/z (%) = 284 (86) [M⁺], 253 (57), 189 (100), 135 (14),

120 (37), 95 (40), 69 (31).

MS (EI; 70 eV): m/z (%) = 325 (25) [M⁺], 296 (11), 253 (100), 176 (14),

120 (55), 92 (22), 72 (69).

Ethyl 3-(Trifluoromethylsulfonyloxy)benzoate (Table 2, Entry 5)

According to General Procedure A, a solution of ethyl 3-hydroxyben-

zoate (3.0 g, 18.1 mmol) and pyridine (4.2 mL, 51.9 mmol) in CH₂Cl₂

(50 mL) was treated with Tf₂O (5.6 mL, 33.3 mmol). After 2 h, normal

workup followed by bulb-to-bulb distillation afforded the product.

HRMS: m/z calcd for C₁₂H₁₅NO₄F₃S: 325.0596; found: 325.0601.

N,N-Diethyl-3-(trifluoromethylsulfonyloxy)benzamide (Table 2,

Entry 2)

Yield: 5.04 g (94%); colourless oil; bp 70–72 °C/0.1 mmHg.

According to General Procedure A, a solution of N,N-diethyl-3-hy-

droxybenzamide (1.02 g, 5.28 mmol) and pyridine (1.0 mL,

12.4 mmol) in CH₂Cl₂(50 mL) was treated with Tf₂O (1.3 mL,

7.73 mmol). After 2 h, normal workup followed by bulb-to-bulb dis-

tillation afforded the product.

IR (neat): 1726, 1427, 1225 cm^–1

.

¹H NMR (200 MHz, CDCl₃):  = 1.41 (t, J = 7.1 Hz, 3 H, OCH₂CH₃), 4.42

(q, J = 7.1 Hz, 2 H, OCH₂CH₃), 7.47 (m, 1 H), 7.55 (t, J = 7.3 Hz, 1 H),

7.95 (m, 1 H), 8.09 (dt, J = 7.3, 1.5 Hz, 1 H).

¹³C NMR (50 MHz, CDCl₃):  = 14.1 (o, OCH₂CH₃), 61.7 (e, OCH₂CH₃),

118.7 (e, q, J = 320.9 Hz, CF₃), 122.4 (o), 125.5 (o), 129.4 (o), 130.3 (o),

133.1 (e), 149.4 (e), 164.6 (e).

Yield: 1.15 g (67%); colourless oil; bp 91–3 °C/0.01 mmHg.

IR (neat): 1633, 1436, 1223, 1139 cm^–1

.

G

C. A. Quesnelle, V. Snieckus

Paper

Synthesis

MS (EI; 70 eV): m/z (%) = 298 (40) [M⁺], 270 (54), 253 (100), 206 (14),

189 (57).

Yield: 2.44 g (74%); colourless solid; mp 96.5–97.5 °C (hexane).

IR (KBr): 3381, 1700, 1523, 1422, 1208, 1139 cm^–1

.

¹H NMR (200 MHz, CDCl₃):  = 1.52 (s, 9 H, OC(CH₃)₃), 6.69 (bs, 1 H,

NH), 7.18 (d, J = 9.1 Hz, 2 H), 7.44 (d, J = 9.1 Hz, 2 H).

MS (EI; 70 eV): m/z (%) = 341 (5) [M⁺], 285 (14), 152 (12), 108 (15), 57

Ethyl 4-(Trifluoromethylsulfonyloxy)benzoate (Table 2, Entry 6)

According to General Procedure A, a solution of ethyl 4-hydroxyben-

zoate (2.04 g, 12.3 mmol) and pyridine (2.0 mL, 24.7 mmol) in CH₂Cl₂

(50 mL) was treated with Tf₂O (3.1 mL, 18.4 mmol). After 3 h, normal

workup followed by bulb-to-bulb distillation afforded the product.

(100).

2-(Trifluoromethylsulfonyloxy)phenyl Diethylcarbamate (Table 2,

Entry 10)

Yield: 3.46 g (94%); colourless oil; bp 75–78 °C/0.2 mmHg.

IR (neat): 1726, 1280, 1218 cm^–1

.

According to General Procedure A, a solution of 2-hydroxyphenyl di-

ethylcarbamate (1.86 g, 8.89 mmol) and pyridine (1.4 mL, 17.3 mmol)

in CH₂Cl₂(50 mL) was treated with Tf₂O (2.2 mL, 13.1 mmol). After 1.5

h, normal workup followed by bulb-to-bulb distillation afforded the

product.

¹H NMR (250 MHz, CDCl₃):  = 1.40 (t, J = 7.1 Hz, 3 H, OCH₂CH₃), 4.40

(q, J = 7.1 Hz, 2 H, OCH₂CH₃), 7.35 (d, J = 8.7 Hz, 2 H), 8.15 (d, J =

8.7 Hz, 2 H).

¹³C NMR (62.9 MHz, CDCl₃):  = 13.9 (OCH₂CH₃), 61.3 (OCH₂CH₃),

118.6 (q, J = 320.5 Hz, CF₃), 121.2, 130.6, 131.6, 152.3, 164.6.

Yield: 2.96 g (97%); colourless oil; bp 90–91 °C/0.03 mmHg.

MS (EI; 70 eV): m/z (%) = 298 (24) [M⁺], 270 (48) [M-Et], 253 (100),

IR (neat): 1724, 1437, 1236 cm^–1

.

189 (49), 165 (8), 109 (20).

¹H NMR (200 MHz, CDCl₃):  = 1.20 (t, J = 7.1 Hz, 3 H, NCH₂CH₃), 1.26

(t, J = 7.1 Hz, 3 H, NCH₂CH₃), 3.38 (q, J = 7.1 Hz, 2 H, NCH₂CH₃), 3.49 (q,

J = 7.1 Hz, 2 H, NCH₂CH₃), 7.18–7.37 (m, 4 H).

HRMS: m/z calcd for C₁₀H₉F₃O₅S: 298.0123; found: 298.0096.

¹³C NMR (50 MHz, CDCl₃):  = 12.8 (o, NCH₂CH₃), 13.8 (o, NCH₂CH₃),

41.8 (e, NCH₂CH₃), 42.3 (e, NCH₂CH₃), 118.5 (e, q, J = 320.4 Hz, CF₃),

122.1 (o), 124.8 (o), 126.1 (o), 128.8 (o), 141.2 (e), 143.3 (e), 152.3 (e).

N-tert-Butoxycarbonyl-2-(trifluoromethylsulfonyloxy)aniline

(Table 2, Entry 7)

According to General Procedure A, a solution of N-tert-butoxycarbon-

yl-2-hydroxyaniline (2.07 g, 9.89 mmol) and pyridine (1.7 mL,

21.0 mmol) in CH₂Cl₂(50 mL) was treated with Tf₂O (2.4 mL,

14.3 mmol). After 3 h, normal workup followed by bulb-to-bulb dis-

tillation afforded the product.

MS (EI; 70 eV): m/z (%) = 341 (2) [M⁺], 326 (1), 100 (100), 72 (38).

HRMS: m/z calcd for C₁₂H₁₄NO₅SF₃: 341.0545; found: 341.0548.

3-(Trifluoromethylsulfonyloxy)phenyl Diethylcarbamate (Table 2,

Entry 11)

Yield: 3.02 g (89%); pale-yellow oil; bp 90–93 °C/0.2 mmHg.

IR (neat): 3378, 1723, 1520, 1430, 1196 cm^–1

.

According to General Procedure A, a solution of 3-hydroxyphenyl di-

ethylcarbamate (1.71 g, 8.17 mmol) and pyridine (1.3 mL, 16.1 mmol)

in CH₂Cl₂(50 mL) was treated with Tf₂O (1.6 mL, 9.51 mmol). After 2

h, normal workup followed by bulb-to-bulb distillation afforded the

product.

¹H NMR (200 MHz, CDCl₃):  = 1.52 (s, 9 H, OC(CH₃)₃), 6.73 (bs, 1 H,

NH), 7.07 (m, 1 H), 7.24–7.35 (m, 2 H), 8.04 (d, J = 8.22 Hz, 1 H).

MS (EI; 70 eV): m/z (%) = 341 (5) [M⁺], 285 (6), 241 (5), 152 (5), 108

(29), 69 (21), 57 (100).

Yield: 2.57 g (92%); colourless oil; bp 95–96 °C/0.3 mmHg.

IR (neat): 1727, 1421, 1216 cm^–1

.

N-tert-Butoxycarbonyl-3-(trifluoromethylsulfonyloxy)aniline

(Table 2, Entry 8)

¹H NMR (250 MHz, CDCl₃):  = 1.23 (m, 6 H, NCH₂CH₃), 3.41 (m, 4 H,

NCH₂CH₃), 7.16 (m, 3 H), 7.42 (t, J = 8.1 Hz, 1 H).

¹³C NMR (50 MHz, CDCl₃):  = 12.4, 13.3, 41.4, 41.8, 114.9, 117.0,

118.3 (q, J = 320.47 Hz, CF₃), 121.3, 129.6, 148.9, 152.2, 152.4.

According to General Procedure A, a solution of N-tert-butoxycarbon-

yl-3-hydroxyaniline (2.08 g, 9.94 mmol) and pyridine (1.7 mL,

21.0 mmol) in CH₂Cl₂(50 mL) was treated with Tf₂O (2.4 mL,

14.3 mmol). After 1 h, normal workup afforded a solid that was re-

crystallized from hexane to afford the product.

MS (EI; 70 eV): m/z (%) = 341 (1) [M⁺], 100 (100), 72 (38).

HRMS: m/z calcd for C₁₂H₁₄NO₅SF₃: 341.0545; found: 341.0536.

Yield: 2.40 g (71%); colourless solid; mp 75–76 °C (hexane).

IR (KBr): 3330, 1699, 1541, 1440, 1419, 1290, 1246, 1217, 1146 cm^–1

¹H NMR (200 MHz, CDCl₃):  = 1.52 (s, 9 H, OC(CH₃)₃), 6.86 (bs, 1 H,

.

4-(Trifluoromethylsulfonyloxy)phenyl Diethylcarbamate (Table 2,

Entry 12)

NH), 6.92 (m, 1 H), 7.20–7.36 (m, 2 H), 7.55 (m, 1 H).

According to General Procedure A, a solution of 4-hydroxyphenyl di-

ethylcarbamate (2.02 g 9.65 mmol) and pyridine (1.6 mL, 19.8 mmol)

in CH₂Cl₂(50 mL) was treated with Tf₂O (2.4 mL, 14.3 mmol). After 3

h, normal workup followed by bulb-to-bulb distillation afforded the

product.

¹³C NMR (50 MHz, CDCl₃):  = 28.2 (o, OC(CH₃)₃), 81.4 (e, OC(CH₃)₃),

111.3 (o), 115.2 (o), 117.8 (o), 118.7 (e, q, J = 320.4 Hz, CF₃), 130.3 (o),

140.4 (e), 149.9 (e), 152.3 (e).

MS (EI; 70 eV): m/z (%) = 341 (5) [M⁺], 185 (16), 241 (29), 57 (100).

Yield: 2.98 g (91%); colourless oil; bp 103–107 °C/0.2 mmHg.

N-tert-Butoxycarbonyl-4-(trifluoromethylsulfonyloxy)aniline

IR (neat): 1722, 1421, 1213, 1138 cm^–1

.

(Table 2, Entry 9)⁵¹

¹H NMR (200 MHz, CDCl₃):  = 1.23 (m, 6 H), 3.45 (m, 4 H), 7.25 (m,

4 H).

¹³C NMR (62.9 MHz, CDCl₃):  = 12.8 (o, NCH₂CH₃), 13.8 (o, NCH₂CH₃),

41.7 (e, NCH₂CH₃), 42.1 (e, NCH₂CH₃), 118.5 (e, q, J = 320.4 Hz, CF₃),

121.8 (o), 123.2 (o), 145.9 (e), 150.9 (e), 153.2 (e).

According to General Procedure A, a solution of N-tert-butoxycarbon-

yl-4-hydroxyaniline (2.01 g, 9.61 mmol) and pyridine (1.7 mL,

21.0 mmol) in CH₂Cl₂(50 mL) was treated with Tf₂O (2.4 mL,

14.3 mmol). After 2 h, normal workup afforded a solid that was re-

crystallized from hexane to afford the product.

H

C. A. Quesnelle, V. Snieckus

Paper

Synthesis

MS (EI; 70 eV): m/z (%) = 341 (2) [M⁺], 326 (0.5), 100 (100), 72 (40).

HRMS: m/z calcd for C₁₂H₁₄NO₅SF₃: 341.0545; found: 341.0531.

Yield: 3.56 g (87%); colourless platelets; mp 53–54 °C (CH₂Cl₂/hexane)

(Lit.⁵²mp 54–55 °C (EtOH/water)).

N-tert-Butoxycarbonyl-2-[4′-(trifluoromethylsulfonyloxy)phe-

nyl]ethylamine (Table 2, Entry 18)

2-Fluorophenyl Trifluoromethanesulfonate (Table 2, Entry 13)

According to General Procedure A, a solution of 2-fluorophenol

(2.01 g, 17.9 mmol) and pyridine (2.9 mL, 35.9 mmol) in CH₂Cl₂(50

mL) was treated with Tf₂O (4.5 mL, 26.7 mmol). After 7 h, normal

workup followed by bulb-to-bulb distillation afforded the product.

According to General Procedure A, a solution of N-tert-butoxycarbon-

yltyramine⁵⁴(1.74 g, 7.33 mmol) and pyridine (1.2 mL, 14.8 mmol) in

CH₂Cl₂(50 mL) was treated with Tf₂O (1.6 mL, 9.51 mmol). After 2.5 h,

normal workup followed by flash chromatography (4:1, hexane/EtO-

Ac) gave the product.

Yield: 3.70 g (85%); colourless oil; bp 45–50 °C/0.2 mmHg.

IR (neat): 1608, 1427, 1234, 1148, 896 cm^–1

.

Yield: 968 mg (40%); colourless oil which solidified; mp 48–49 °C.

¹H NMR (200 MHz, CDCl₃):  = 7.14–7.39 (m).

¹H NMR (250 MHz, CDCl₃):  = 1.53 (s, 9 H, OC(CH₃)₃), 2.82 (t,

J = 7.0 Hz, 2 H, ArCH₂CH₂N), 3.36 (t, J = 7.0 Hz, 2 H, ArCH₂CH₂N), 4.70

(bs, 1 H, NH), 7.11–7.29 (m, 4 H).

¹³C NMR (50 MHz, CDCl₃):  = 117.6 (o, d, J = 18.2 Hz), 118.8 (e, q, J =

320.4 Hz, CF₃), 123.5 (o), 125.1 (o, d, J = 3.84 Hz), 129.7 (o, d, J =

7.5 Hz), 136.9 (e, d, J = 13.7 Hz), 153.8 (e, d, J = 253.2 Hz, C_Ar-F).

¹³C NMR (62.9 MHz, CDCl₃):

 = 28.2 (o, OC(CH₃)₃), 35.6 (e,

MS (CI; CH₄): m/z (%) = 245 (100) [M⁺].

ArCH₂CH₂N), 41.5 (e, ArCH₂CH₂N), 79.3 (e, OC(CH₃)₃), 118.7 (e, q,

J = 320.9 Hz, CF₃), 121.2 (o), 130.5 (o), 139.7 (e), 148.1 (e), 155.8 (e).

MS (EI; 70 eV): m/z (%) = 369 (3) [M⁺], 313 (11), 251 (13), 239 (12),

3-Fluorophenyl Trifluoromethanesulfonate (Table 2, Entry 14)

According to General Procedure A, a solution of 3-fluorophenol

(1.01 g, 9.01 mmol) and pyridine (1.5 mL, 18.5 mmol) in CH₂Cl₂(50

mL) was treated with Tf₂O (2.3 mL, 13.7 mmol). After 6 h, normal

workup followed by bulb-to-bulb distillation afforded the product.

149 (11), 120 (24), 107 (63), 77 (12), 57 (100).

N-Benzyl-4-(trifluoromethylsulfonyloxy)quinol-2-one (Table 2,

Entry 19)

Yield: 1.74 g (79%); colourless oil; bp 45–50 °C/0.1 mmHg (Lit.⁵²bp

46–47 °C/3.6 mmHg).

According to General Procedure A, a solution of N-benzyl-4-hydroxy-

quinol-2-one⁵⁵(0.675 g, 2.71 mmol) and pyridine (0.50 mL,

6.18 mmol) in CH₂Cl₂(50 mL) was treated with Tf₂O (0.6 mL,

3.57 mmol). After 1.5 h, normal workup followed by flash chromatog-

raphy on silica gel (2:1, hexane/EtOAc) afforded the product.

4-Fluorophenyl Trifluoromethanesulfonate (Table 2, Entry 15)

According to General Procedure A, a solution of 4-fluorophenol

(4.37 g, 39.0 mmol) and pyridine (6.3 mL, 77.9 mmol) in CH₂Cl₂(50

mL) was treated with Tf₂O (7.8 mL, 46.4 mmol). After 3 h, normal

workup followed by bulb-to-bulb distillation afforded the product.

Yield: 921 mg (89%); colourless solid; mp 114–115 °C (hexane).

IR (KBr): 1655, 1433, 1217 cm^–1

.

¹H NMR (250 MHz, CDCl₃):  = 5.50 (s, 2 H, PhCH₂), 6.85 (s, 1 H), 7.4–

7.2 (m, 7 H), 7.49 (t, J = 7.2 Hz, 1 H), 7.78 (d, J = 7.2 Hz, 1 H).

¹³C NMR (62.9 MHz, CDCl₃):  = 46.0 (e, PhCH₂), 111.3 (o), 114.9 (e),

115.3 (o), 118.3 (e, q, J = 320.7 Hz, CF₃), 122.5 (o), 122.9 (o), 126.3 (o),

127.3 (o), 128.6 (o), 132.5 (o), 135.3 (e), 139.4 (e), 153.8 (e), 161.2 (e).

Yield: 6.57 g (90%); colourless oil; bp 45–50 °C/0.1 mmHg.

IR (neat): 3088, 1422, 1189 cm^–1

.

¹H NMR (200 MHz, CDCl₃):  = 7.10 (dd, J = 9.4, 7.7 Hz, 2 H), 7.26 (dd,

J = 9.4, 4.3 Hz, 2 H).

¹³C NMR (50 MHz, CDCl₃):  = 117.0 (o, d, J = 24.3), 118.8 (e, q,

J = 320.5 Hz, CF₃), 123.1 (o, d, J = 9.0 Hz), 145.4 (e, d, J = 2.9 Hz), 161.7

(e, d, J = 248.7 Hz, C_Ar-F).

MS (EI(70 eV)): m/z (%) = 383 (25) [M⁺], 250 (100) [M-Tf], 232 (21),

208 (14), 91 (94).

Anal. Calcd for C₁₇H₁₂F₃NO₄S: C, 53.27; H, 3.16. Found: C, 53.62; H,

3.39.

MS (EI; 70 eV): m/z (%) = 244 (33) [M⁺], 180 (8), 149 (5), 111 (100), 83

(59).

4-Methoxy-3-(trifluoromethylsulfonyloxy)benzaldehyde (Table 2,

Entry 20)

HRMS: m/z calcd for C₇H₄O₃SF₄: 243.9817; found: 243.9798.

According to General Procedure A, a solution of isovanillin (5.38 g,

35.3 mmol) and pyridine (6.0 mL, 74.2 mmol) in CH₂Cl₂(50 mL) was

treated with Tf₂O (7.5 mL, 44.6 mmol). After 1.5 h, normal workup

followed by flash chromatography on silica gel (1:1, hexane/EtOAc)

afforded the product.

3-(Trifluoromethylsulfonyloxy)pyridine (Table 2, Entry 16)

To a cold (–78 °C), stirred solution of 3-hydroxypyridine (6.18 g,

65.0 mmol) and Et₃N (18.0 mL, 129.0 mmol) in CH₂Cl₂(60 mL) under

Ar was added Tf₂O (14.0 mL, 83.2 mmol). After stirring at –78 °C for 3

h, an aqueous, saturated NH₄Cl was added. The organic phase was

washed with H₂O and dried (MgSO₄). Filtration, concentration in vac-

uo, and purified by bulb-to-bulb distillation afforded the product.

Yield: 7.55 g (75%); colourless oil; bp 78–80 °C/0.1 mmHg.

¹H NMR (250 MHz, CDCl₃):  = 3.99 (s, 3 H, OCH₃), 7.42 (d, J = 8.2 Hz,

1 H), 7.52 (dd, J = 8.2, 1.8 Hz, 1 H), 7.57 (d, J = 1.8 Hz, 1 H), 9.97 (s, 1 H,

CHO).

Yield: 7.25 g (49%); colourless oil;⁵³bp 44–45 °C/0.5 mmHg.

¹³C NMR (62.9 MHz, CDCl₃):  = 56.2 (OCH₃), 111.8, 118.5 (q, J =

4-Nitrophenyl Trifluoromethanesulfonate (Table 2, Entry 17)

320.1 Hz, CF₃), 123.0, 123.6, 136.7, 142.4, 152.0, 190.1 (CHO).

According to General Procedure A, a solution of 4-nitrophenol (2.10 g,

15.1 mmol) and pyridine (2.4 mL, 29.7 mmol) in CH₂Cl₂(50 mL) was

treated with Tf₂O (3.8 mL, 22.6 mmol). After 4 h, normal workup af-

forded a solid that was recrystallized from CH₂Cl₂/hexane to afford

the product.

HRMS: m/z calcd for C₉H₈O₅F₃S: 285.0045; found: 285.0042.

I

C. A. Quesnelle, V. Snieckus

Paper

Synthesis

1-(Trifluoromethylsulfonyloxy)fluorenone (Table 2, Entry 21)

reagent via cannula. After 2.5 h, normal workup followed by flash

chromatography (1:1, hexane/EtOAc) gave the product (235 mg, 78%),

which was shown to be identical to that prepared in Procedure 1.

According to General Procedure A, a solution of 1-hydroxyfluorenone

(1.13 g, 5.76 mmol) and pyridine (0.90 mL, 11.1 mmol) in CH₂Cl₂(40

mL) was treated with Tf₂O (1.3 mL, 7.73 mmol). After 3 h, normal

workup gave a solid residue that was recrystallized from CH₂Cl₂/hex-

ane to afford the product.

Procedure 4: According to General Procedure E, N,N-diethyl-2-(triflu-

oromethylsulfonyloxy)benzamide (316 mg, 0.97 mmol) in DME (3

mL) was treated with 3,4-(methylenedioxy)phenylboronic acid

(224 mg, 1.35 mmol) in DME (3 mL) and EtOH (3 mL) in the presence

of Pd(PPh₃)₄(37 mg, 0.032 mmol) and the reaction mixture was heat-

ed to reflux for 16 h and cooled to rt. Normal workup followed by

flash chromatography (1:1, hexane/EtOAc) afforded the product

(190 mg, 66%), which was shown to be identical to that prepared in

Procedure 1.

Yield: 1.62 g (86%); yellow needles; mp 137–138 °C (CH₂Cl₂/hexane).

¹H NMR (200 MHz, CDCl₃):  = 7.09–7.64 (m).

Table 2 Products

N,N-Diethyl-2-[3′,4′-(methylenedioxy)phenyl]benzamide (Table 2,

Entry 1)

N,N-Diethyl-3-[3′,4′-(methylenedioxy)phenyl]benzamide (Table 2,

Procedure 1: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (431 mg, 2.15 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (3.8 mL,

1.24 M, 4.71 mmol) and ZnCl₂(3.0 mL, 1.0 M, 3.00 mmol) and the re-

action mixture was warmed to rt. According to General Procedure D,

to a second flask containing Ni(acac)₂(20 mg, 0.077 mmol) and PPh₃

(88 mg, 0.33 mmol) in THF (3 mL) was added sequentially a solution

of MeMgBr (0.10 mL, 3.0 M, 0.30 mmol), a freshly prepared organoz-

inc solution via cannula and a solution of N,N-diethyl-2-(trifluoro-

methylsulfonyloxy)benzamide (339 mg, 1.04 mmol) in THF (2+1 mL).

After 18 h, normal workup followed by flash chromatography (1:1,

hexane/EtOAc) gave the product.

Entry 2)

Procedure 1: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (400 mg, 1.99 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.6 mL,

1.66 M, 4.32 mmol) and ZnCl₂(3.0 mL, 1.0 M, 3.00 mmol) and the

whole was warmed to rt. According to General Procedure D, to a sec-

ond flask containing Ni(acac)₂(20 mg, 0.077 mmol) and PPh₃(82 mg,

0.31 mmol) in THF (3 mL) was added sequentially a solution of

MeMgBr (0.10 mL, 3.0 M, 0.30 mmol), the freshly prepared organoz-

inc solution via cannula and a solution of N,N-diethyl-3-(trifluoro-

methylsulfonyloxy)benzamide (326 mg, 1.00 mmol) in THF (2+1 mL).

After 20 h, normal workup followed by flash chromatography (1:1,

hexane/EtOAc) gave the product.

Yield: 262 mg (85%); colourless oil.

IR (neat): 1611 cm^–1

.

Yield: 284 mg (95%); colourless solid; mp 78–79 °C (Et₂O/hexane).

¹H NMR (200 MHz, CDCl₃):  = 0.78 (t, J = 7.1 Hz, 3 H, NCH₂CH₃), 0.97

(t, J = 7.1 Hz, 3 H, NCH₂CH₃), 2.72 (m, 1 H, NCH₂CH₃), 2.89–3.07 (m,

2 H, NCH₂CH₃), 3.77 (m, 1 H, NCH₂CH₃), 5.94 (s, 2 H, OCH₂O), 6.81 (d,

J = 7.8 Hz, 1 H), 6.92–6.98 (m, 2 H), 7.32–7.41 (m, 4 H).

IR (KBr): 1618 cm^–1

.

¹H NMR (200 MHz, CDCl₃):  = 1.13–1.24 (bm, 6 H, NCH₂CH₃), 3.29–

3.54 (bm, 4 H, NCH₂CH₃), 5.97 (s, 2 H, OCH₂O), 6.86 (d, J = 8.5 Hz, 1 H),

7.03–7.06 (m, 2 H), 7.25–7.55 (m, 4 H).

¹³C NMR (50 MHz, CDCl₃):  = 11.9 (o, NCH₂CH₃), 13.3 (o, NCH₂CH₃),

38.2 (e, NCH₂CH₃), 42.1 (e, NCH₂CH₃), 100.9 (e, OCH₂O), 108.0 (o),

109.2 (o), 122.3 (o), 128.8 (o), 127.1 (o), 128.7 (o), 129.1 (o), 133.6 (e),

136.1 (e), 137.8 (e), 147.0 (e), 147.6 (e), 170.4 (e).

MS (EI (60 eV)): m/z (%) = 297 (100) [M⁺], 268 (3), 225 (24), 195 (43),

167 (26), 169 (41).

¹³C NMR (50 MHz, CDCl₃):  = 12.7 (o, NCH₂CH₃), 14.0 (o, NCH₂CH₃),

39.1 (e, NCH₂CH₃), 43.1 (e, NCH₂CH₃), 101.0 (e, OCH₂O), 107.3 (o),

108.4 (o), 120.5 (o), 124.5 (o), 127.3 (o), 128.6 (o), 134.5 (e), 137.6 (e),

140.9 (e), 147.2 (e), 148.0 (e), 170.9 (e).

MS (EI (60 eV)): m/z (%) = 297 (100) [M⁺], 268 (2), 225 (53), 197 (6),

167 (3), 139 (23).

HRMS: m/z calcd for C₁₈H₂₀NO₃: 298.1443; found: 298.1443.

Anal. Calcd for C₁₈H₁₉NO₃: C, 72.71; H, 6.44. Found: C, 72.64; H, 6.40.

Procedure 2: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (403 mg, 2.01 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.7 mL,

1.65 M, 4.46 mmol) and MgBr₂·OEt₂(1.0 mL, 2.62 N, 2.62 mmol) and

the whole was warmed to rt. According to General Procedure C, to a

second flask containing N,N-diethyl-2-(trifluoromethylsulfony-

loxy)benzamide (322 mg, 0.99 mmol) and NiCl₂(dppe) (36 mg,

0.067 mmol) in THF (5 mL) was added the freshly prepared Grignard

reagent via cannula. After 5 h, normal workup followed by flash chro-

matography (1:1, hexane/EtOAc) gave the product (195 mg, 66%),

which was shown to be identical to that prepared in Procedure 1.

Procedure 2: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (401 mg, 1.99 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.7 mL,

1.65 M, 4.46 mmol) and MgBr₂·OEt₂(1.0 mL, 2.62 N, 2.62 mmol) and

warmed to rt. According to General Procedure C, to a second flask con-

taining

N,N-diethyl-3-(trifluoromethylsulfonyloxy)benzamide

(325 mg, 1.00 mmol) and NiCl₂(dppe) (37 mg, 0.071 mmol) in THF (5

mL) was added the freshly prepared Grignard reagent via cannula. Af-

ter reaction for 5 h, normal workup followed by flash chromatogra-

phy (1:1, hexane/EtOAc) gave the product (188 mg, 63%), which was

shown to be identical to that prepared in Procedure 1.

Procedure 3: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (416 mg, 2.07 mmol) in

THF (10 mL) was sequentially treated with a solution of t-BuLi (3.0

mL, 1.52 M, 4.56 mmol) and MgBr₂·OEt₂(1.2 mL, 2.62 N, 3.14 mmol)

and the whole was warmed to rt. According to General Procedure C, to

Procedure 3: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (413 mg, 2.06 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (3.0 mL,

1.52 M, 4.56 mmol) and MgBr₂·OEt₂(1.2 mL, 2.62 N, 3.14 mmol) and

the whole was warmed to rt. According to General Procedure C, to a

second flask containing N,N-diethyl-3-(trifluoromethylsulfony-

loxy)benzamide (329 mg, 1.01 mmol) and Ni(acac)₂(18 mg,

0.070 mmol) in THF (5 mL) was added a solution of freshly prepared

Grignard reagent via cannula. After reaction for 2.5 h, normal workup

a

second flask containing N,N-diethyl-2-(trifluoromethylsulfony-

loxy)benzamide (329 mg, 1.01 mmol) and Ni(acac)₂(16 mg,

0.063 mmol) in THF (5 mL) was added the freshly prepared Grignard

J

C. A. Quesnelle, V. Snieckus

Paper

Synthesis

followed by flash chromatography (1:1, hexane/EtOAc) gave the prod-

uct (203 mg, 67%), which was shown to be identical to that prepared

in Procedure 1.

gnard reagent via cannula. After 3 h, normal workup followed by flash

chromatography (1:1, hexane/EtOAc) gave the product (197 mg, 65%),

which was shown to be identical to that prepared in Procedure 1.

Procedure 4: According to General Procedure E, a solution of N,N-di-

ethyl-3-(trifluoromethylsulfonyloxy)benzamide (323 mg, 0.99 mmol)

in DME (3 mL) was treated with a solution of 3,4-(methylenedi-

oxy)phenylboronic acid (220 mg, 1.33 mmol) in DME (3 mL) and

EtOH (3 mL) in the presence of Pd(PPh₃)₄(49 mg, 0.043 mmol). After

25 h, the reaction mixture was cooled to rt. Normal workup followed

by flash chromatography (1:1, hexane/EtOAc) afforded the product

(237 mg, 80%), which was shown to be identical to that prepared in

Procedure 1.

Procedure 4: According to General Procedure E, a solution of N,N-di-

ethyl-4-(trifluoromethylsulfonyloxy)benzamide (331 mg, 1.02 mmol)

in DME (3 mL) was treated with a solution of 3,4-(methylenedi-

oxy)phenylboronic acid (200 mg, 1.21 mmol), DME (3 mL) and EtOH

(3 mL) in the presence of Pd(PPh₃)₄(49 mg, 0.043 mmol). After 6 h,

the reaction was cooled to rt. Normal workup followed by flash chro-

matography (1:1, hexane/EtOAc) afforded the product (203 mg, 67%),

which was shown to be identical to that prepared in Procedure 1.

Methyl 2-[3′,4′-(Methylenedioxy)phenyl]benzoate (Table 2, Entry

N,N-Diethyl-4-[3′,4′-(methylenedioxy)phenyl]benzamide (Table 2,

4)

Entry 3)

Procedure 1: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (413 mg, 2.05 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.6 mL,

1.74 M, 4.52 mmol) and ZnCl₂(3.0 mL, 1.0 M, 3.00 mmol) and the

whole was warmed to rt. According to General Procedure D, to a sec-

ond flask containing Ni(acac)₂(21 mg, 0.081 mmol) and PPh₃(97 mg,

0.37 mmol) in THF (3 mL) was added sequentially solutions of MeMg-

Br (0.10 mL, 3.0 M, 0.30 mmol), the above freshly prepared organoz-

inc solution via cannula, and a solution of methyl 2-(trifluoromethyl-

sulfonyloxy)benzoate (296 mg, 1.04 mmol) in THF (2+1 mL). After

stirring the reaction mixture for 24 h, normal workup followed by

flash chromatography (1:1, hexane/CH₂Cl₂) gave the product.

Procedure 1: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (409 mg, 2.03 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.7 mL,

1.66 M, 4.48 mmol) and ZnCl₂(3.0 mL, 1.0 M, 3.00 mmol) and the re-

action mixture was warmed to rt. According to General Procedure D,

to a second flask containing Ni(acac)₂(18 mg, 0.071 mmol) and PPh₃

(82 mg, 0.31 mmol) in THF (3 mL) was added sequentially a solution

of MeMgBr (0.10 mL, 3.0 M, 0.30 mmol), a freshly prepared solution

of the above organozinc reagent via cannula and a solution of N,N-di-

ethyl-4-(trifluoromethylsulfonyloxy)benzamide (325 mg, 1.00 mmol)

in THF (2+1 mL). After 20 h, normal workup followed by flash chro-

matography (1:1, hexane/EtOAc) afforded the product.

Yield: 257 mg (96%); colourless oil.

Yield: 256 mg (86%); colourless solid; mp 76–77 °C (Et₂O/hexane).

IR (neat): 1724 cm^–1

¹H NMR (200 MHz, CDCl₃):  = 3.68 (s, 3 H, OCH₃), 5.97 (s, 2 H,

.

¹H NMR (200 MHz, CDCl₃):  = 1.20 (bs, 6 H, NCH₂CH₃), 3.45 (bs, 4 H,

NCH₂CH₃), 5.99 (s, 2 H, OCH₂O), 6.87 (d, J = 8.5 Hz, 1 H), 7.03–7.08 (m,

2 H), 7.41 (d, J = 8.2 Hz, 2 H), 7.53 (d, J = 8.2 Hz, 2 H).

¹³C NMR (200 MHz, CDCl₃):  = 101.1 (e, OCH₂O), 107.4 (o), 108.5 (o),

120.6 (o), 126.7 (o), 126.8 (o), 134.6 (e), 135.6 (e), 141.6 (e), 147.3 (e),

148.1 (e), 170.9 (e).

OCH₂O), 6.72–6.85 (m, 3 H), 7.24–7.52 (m, 3 H), 7.76 (m, 1 H).

¹³C NMR (50 MHz, CDCl₃):  = 51.9 (o, OCH₃), 101.6 (e, OCH₂O), 107.9

(o), 108.9 (o), 121.7 (o), 126.9 (o), 129.6 (o), 130.6 (o), 130.9 (e), 131.1

(o), 135.1 (e), 141.9 (e), 146.9 (e), 147.4 (e), 169.0 (e).

MS (EI; 70 eV): m/z (%) = 256 (100) [M⁺], 225 (10), 195 (28), 167 (16),

139 (21).

MS (EI; 70 eV): m/z (%) = 297 (53) [M⁺], 225 (100), 139 (34), 112 (14).

Anal. Calcd for C₁₈H₁₉NO₃: C, 72.71; H, 6.44; N, 4.71. Found: C, 72.80;

H, 6.40; N, 4.81.

Procedure 2: To a solution of methyl 2-(trifluoromethylsulfony-

loxy)benzoate (293 mg, 1.03 mmol) and 3,4-(methylenedioxy)phen-

ylboronic acid (236 mg, 1.42 mmol) in DME (5 mL) was added

Pd(PPh₃)₄(45 mg, 0.039 mmol) and Cs₂CO₃(1.02 g, 3.12 mmol) and

the reaction mixture was stirred at rt. After 25 h, normal workup fol-

lowed by flash chromatography (1:1, hexane/EtOAc) gave the product

(106 mg, 40%), which was shown to be identical to that prepared in

Procedure 1.

Procedure 2: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (404 mg, 2.01 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.9 mL,

1.55 M, 4.50 mmol) and MgBr₂·OEt₂(1.0 mL, 2.62 N, 2.62 mmol) and

the whole was warmed to rt. According to General Procedure C, to a

second flask containing N,N-diethyl-4-(trifluoromethylsulfony-

loxy)benzamide (326 mg, 1.00 mmol) and NiCl₂(dppe) (31 mg,

0.059 mmol) in THF (5 mL) was added the freshly prepared solution

of the above Grignard reagent via cannula. After 3 h, normal workup

followed by flash chromatography (1:1, hexane/EtOAc) gave the prod-

uct (232 mg, 78%), which was shown to be identical to that prepared

in Procedure 1.

Ethyl 3-[3′,4′-(Methylenedioxy)phenyl]benzoate (Table 2, Entry 5)

Procedure 1: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (418 mg, 2.08 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (3.7 mL,

1.24 M, 4.59 mmol) and ZnCl₂(3.0 mL, 1.0 M, 3.00 mmol) and the

whole was warmed to rt. According to General Procedure D, to a sec-

ond flask containing Ni(acac)₂(18 mg, 0.069 mmol) and PPh₃

(103 mg, 0.39 mmol) in THF (3 mL) was added sequentially solutions

of MeMgBr (0.10 mL, 3.0 M, 0.30 mmol), the above freshly prepared

organozinc solution via cannula and a solution of ethyl 3-(trifluoro-

methylsulfonyl)benzoate (339 mg, 1.14 mmol) in THF (2+1 mL). After

stirring the reaction mixture for 20 h, normal workup followed by

flash chromatography (9:1, hexane/Et₂O) gave the product.

Procedure 3: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (411 mg, 2.04 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (3.0 mL,

1.52 M, 4.56 mmol) and MgBr₂·OEt₂(1.2 mL, 2.62 N, 3.14 mmol) and

the whole was warmed to rt. According to General Procedure C, to a

second flask containing N,N-diethyl-4-(trifluoromethylsulfony-

loxy)benzamide (329 mg, 1.01 mmol) and Ni(acac)₂(20 mg,

0.079 mmol) in THF (5 mL) was added the above freshly prepared Gri-

Yield: 185 mg (60%); colourless oil.

IR (neat): 1717 cm^–1

.

K

C. A. Quesnelle, V. Snieckus

Paper

Synthesis

¹H NMR (250 MHz, CDCl₃):  = 1.40 (t, J = 7.1 Hz, 3 H, OCH₂CH₃), 4.39

(q, J = 7.1 Hz, 2 H, OCH₂CH₃), 5.96 (s, 2 H, OCH₂O), 6.86 (d, J = 8.5 Hz,

1 H), 7.04–7.06 (m, 2 H), 7.43 (t, J = 7.7 Hz, 1 H), 7.65 (d, J = 7.9 Hz,

1 H), 7.97 (d, J = 7.7 Hz, 1 H), 8.18 (s, 1 H).

¹³C NMR (62.9 MHz, CDCl₃):  = 14.2 (o, OCH₂CH₃), 60.9 (e, OCH₂CH₃),

101.1 (e, OCH₂O), 107.5 (o), 108.5 (o), 120.6 (o), 127.7 (o), 127.8 (o),

128.6 (o), 131.0 (o), 134.4 (o), 141.0 (e), 147.3 (e), 148.2 (e), 166.4 (e).

chromatography (8:1, hexane/EtOAc) afforded the product (43 mg,

16%), which was shown to be identical to that prepared in Procedure

1.

Procedure 3: To a flask charged with a solution of ethyl 4-(trifluoro-

methylsulfonyloxy)benzoate (318 mg, 1.07 mmol) and 3,4-(methy-

lenedioxy)phenylboronic acid (239 mg, 1.44 mmol) in toluene (6 mL),

EtOH (1.5 mL) and 2N Na₂CO₃(3 mL) was added Pd(PPh₃)₄(53 mg,

0.046 mmol). The reaction vessel was fitted with a reflux condenser

and the contents heated to reflux. After 23 h, the reaction mixture

was cooled to rt. Normal workup followed by flash chromatography

(9:1, hexane/EtOAc) afforded the product (230 mg, 80%), which was

shown to be identical to that prepared in Procedure 1.

MS (EI (60 eV)): m/z (%) = 270 (67) [M⁺], 242 (12), 197 (2), 167 (2), 139

(12), 84 (67), 49 (100).

HRMS: m/z calcd for C₁₆H₁₅O₄: 271.0970; found: 271.0970.

Procedure 2: According to General Procedure E, a solution of ethyl 3-

(trifluoromethylsulfonyl)benzoate (307 mg, 1.03 mmol) in DME (3

mL) was treated with a solution of 3,4-(methylenedioxy)phenylbo-

ronic acid (224 mg, 1.37 mmol) in DME (3 mL) and EtOH (3 mL) in the

presence of Pd(PPh₃)₄(48 mg, 0.042 mmol). After stirring for 30 h, the

reaction mixture was cooled to rt. Normal workup followed by flash

chromatography (9:1, hexane/Et₂O) afforded the product (22 mg, 8%),

which was shown to be identical to that prepared in Procedure 1.

Procedure 4: According to General Procedure E, a solution of ethyl 4-

(trifluoromethylsulfonyloxy)benzoate (313 mg, 1.05 mmol) in DME

(3 mL) was treated with a solution of 3,4-(methylenedioxy)phenylbo-

ronic acid (201 mg, 1.21 mmol) in DME (3 mL) and EtOH (3 mL) in the

presence of Pd(PPh₃)₄(46 mg, 0.040 mmol). After 18 h, the reaction

mixture was cooled to rt, acidified with 10% HCl and extracted with

Et₂O. The combined extracts were concentrated in vacuo. The residue

was dissolved in EtOH (50 mL), concentrated H₂SO₄(1 mL) added and

a reflux condenser fitted and the reaction was heated at reflux for 18

h, cooled to rt and the solvent was removed in vacuo. The residue was

dissolved in Et₂O, the organic layer was washed with H₂O and dried

(MgSO₄). Filtration, concentration and purification by flash chroma-

tography (9:1, hexane/EtOAc) afforded the product (224 mg, 79%),

which was shown to be identical to that prepared in Procedure 1.

Procedure 3: To a flask charged with a solution of ethyl 3-(trifluoro-

methylsulfonyl)benzoate (305 mg, 1.02 mmol) and 3,4-(methylenedi-

oxy)phenylboronic acid (234 mg, 1.41 mmol) in toluene (6 mL), EtOH

(1.5 mL) and 2N Na₂CO₃(3 mL) was added Pd(PPh₃)₄(56 mg,

0.048 mmol). The reaction vessel was fitted with a reflux condenser

and the contents heated to reflux. After 23 h, the reaction was cooled

to rt. Normal workup followed by flash chromatography (4:1, hex-

ane/Et₂O) afforded the product (216 mg, 78%), which was shown to be

identical to that prepared in Procedure 1.

N-tert-Butoxycarbonyl-2-[3′,4′-(methylenedioxy)phenyl]aniline

(Table 2, Entry 7)

Ethyl 4-[3′,4′-(Methylenedioxy)phenyl]benzoate (Table 2, Entry 6)

According to General Procedure E, a solution of N-tert-butoxycarbon-

yl-2-(trifluoromethylsulfonyloxy)aniline (336 mg, 0.98 mmol) in

DME (3 mL) was treated with a solution of 3,4-(methylenedi-

oxy)phenylboronic acid (216 mg, 1.30 mmol) in DME (3 mL) and

EtOH (3 mL) in the presence of Pd(PPh₃)₄(47 mg, 0.041 mmol). After

24 h, the reaction mixture was cooled to rt. Normal workup followed

by flash chromatography (9:1, hexane/EtOAc) afforded the product.

Procedure 1: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (426 mg, 2.12 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (3.7 mL,

1.24 M, 4.59 mmol) and ZnCl₂(3.0 mL, 1.0 M, 3.00 mmol) and the

whole was warmed to rt. According to General Procedure D, to a sec-

ond flask containing Ni(acac)₂(25 mg, 0.095 mmol) and PPh₃

(111 mg, 0.42 mmol) in THF (3 mL) was added sequentially MeMgBr

(0.10 mL, 3.0 M, 0.30 mmol), the above freshly prepared organozinc

solution via cannula and a solution of ethyl 4-(trifluoromethylsulfo-

nyloxy)benzoate (345 mg, 1.16 mmol) in THF (2+1 mL). After stirring

the reaction mixture for 20 h, normal workup followed by flash chro-

matography (8:1, hexane/EtOAc) gave the product.

Yield: 242 mg (79%); colourless solid; mp 136–137 °C (hexane).

IR (KBr): 3426, 1728 cm^–1

.

¹H NMR (200 MHz, CDCl₃):  = 1.47 (s, 9 H, OC(CH₃)₃), 6.00 (s, 2 H,

OCH₂O), 6.54 (b, 1 H, NH), 6.77–6.92 (m, 3 H), 7.01–7.17 (m, 2 H), 7.30

(td, J = 8.6, 1.8 Hz, 1 H), 8.10 (d, J = 8.2 Hz, 1 H).

Yield: 204 mg (65%); colourless solid; mp 92–92.5 °C (Et₂O/hexane).

¹³C NMR (50 MHz, CDCl₃):  = 28.3 (o, OC(CH₃)₃), 80.4 (e, OC(CH₃)₃),

101.2 (e, OCH₂O), 108.7 (o), 109.8 (o), 119.6 (o), 122.6 (o), 122.8 (o),

128.2 (o), 130.1 (o), 130.9 (e), 131.9 (e), 135.4 (e), 147.2 (e), 148.1 (e),

152.8 (e).

MS (EI; 70 eV): m/z (%) = 313 (48) [M⁺], 257 (100), 240 (11), 213 (69),

182 (8), 154 (16), 57 (89).

IR (KBr): 1710 cm^–1

.

¹H NMR (250 MHz, CDCl₃):  = 1.39 (t, J = 7.1 Hz, 3 H, OCH₂CH₃), 4.38

(q, J = 7.1 Hz, 2 H, OCH₂CH₃), 5.96 (s, 2 H, OCH₂O), 6.84 (d, J = 8.5 Hz,

1 H), 7.04–7.07 (m, 2 H), 7.52 (d, J = 8.3 Hz, 2 H), 8.05 (d, J = 8.3 Hz,

2 H).

Anal. Calcd for C₁₈H₁₉NO₄: C, 69.00; H, 6.11; N, 4.47. Found: C, 69.20;

H, 6.21; N, 4.67.

¹³C NMR (62.9 MHz, CDCl₃):  = 14.2 (OCH₂CH₃), 60.7 (OCH₂CH₃),

101.2 (OCH₂O), 107.4, 108.5, 120.8, 126.4, 128.7, 129.9, 134.1, 144.9,

147.6, 148.1, 166.2.

N-tert-Butoxycarbonyl-3-[3′,4′-(methylenedioxy)phenyl]aniline

(Table 2, Entry 8)

MS (EI; 70 eV): m/z (%) = 270 (100) [M⁺], 242 (21), 225 (49), 139 (27),

112 (16).

According to General Procedure E, a solution of N-tert-butoxycarbon-

yl-3-(trifluoromethylsulfonyloxy)aniline (322 mg, 0.94 mmol) in

DME (3 mL) was treated with a solution of 3,4-(methylenedi-

oxy)phenylboronic acid (268 mg, 1.62 mmol) in DME (3 mL) and

EtOH (3 mL) in the presence of Pd(PPh₃)₄(39 mg, 0.034 mmol). After

19 h, the reaction mixture was cooled to rt. Normal workup followed

by flash chromatography (6:1, hexane/EtOAc) afforded the product.

Anal. Calcd for C₁₆H₁₄O₄: C, 71.10; H, 5.22. Found: C, 70.93; H, 5.04.

Procedure 2: According to General Procedure E, a solution of ethyl 4-

(trifluoromethylsulfonyloxy)benzoate (306 mg, 1.03 mmol) in DME

(3 mL) was treated with a solution of 3,4-(methylenedioxy)phenylbo-

ronic acid (240 mg, 1.45 mmol) in DME (3 mL) and EtOH (3 mL) in the

presence of Pd(PPh₃)₄(44 mg, 0.038 mmol). After stirring for 30 h, the

reaction mixture was cooled to rt. Normal workup followed by flash

L

C. A. Quesnelle, V. Snieckus

Paper

Synthesis

Yield: 255 mg (86%); colourless solid; mp 94.5–95 °C (hexane).

IR (KBr): 3378, 1731 cm^–1

¹H NMR (250 MHz, CDCl₃):  = 1.51 (s, 9 H, OC(CH₃)₃), 5.93 (s, 2 H,

OCH₂O), 6.76 (bs, 1 H, NH), 6.81 (d, J = 8.7 Hz, 1 H), 6.99–7.03 (m, 2 H),

7.14 (m, 1 H), 7.25–7.27 (m, 2 H), 7.55 (bs, 1 H).

HRMS: m/z calcd for C₁₈H₂₀NO₄: 314.1392; found: 314.1392.

.

Procedure 2: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (399 mg, 1.99 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.4 mL,

1.84 M, 4.42 mmol) and MgBr₂·OEt₂(0.9 mL, 2.62 N, 2.36 mmol) and

warmed to rt. According to General Procedure C, to a second flask con-

taining a solution of 2-(trifluoromethylsulfonyloxy)phenyl diethyl-

carbamate (340 mg, 1.00 mmol) and NiCl₂(dppe) (33 mg,

0.063 mmol) in THF (5 mL) was added the above freshly prepared Gri-

gnard reagent via cannula. After 4.5 h, normal workup followed by

flash chromatography (3:1, hexane/EtOAc) gave the product (77 mg,

23%), which was shown to be identical to that prepared in Procedure 1.

MS (EI; 70 eV): m/z (%) = 313 (39) [M⁺], 257 (80), 240 (6), 213 (65),

185 (6), 154 (6), 127 (6), 57 (100).

Anal. Calcd for C₁₈H₁₉NO₄: C, 69.00; H, 6.11; N, 4.47. Found: C, 68.74;

H, 6.13; N, 4.46.

N-tert-Butoxycarbonyl-4-[3′,4′-(methylenedioxy)phenyl]aniline

(Table 2, Entry 9)

Procedure 3: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (407 mg, 2.02 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.4 mL,

1.84 M, 4.42 mmol) and MgBr₂·OEt₂(1.0 mL, 2.62 N, 2.62 mmol) and

the whole was warmed to rt. According to General Procedure C, to a

second flask containing a solution of 2-(trifluoromethylsulfony-

loxy)phenyl diethylcarbamate (341 mg, 1.00 mmol) and Ni(acac)₂

(15 mg, 0.058 mmol) in THF (5 mL) was added the above freshly pre-

pared Grignard reagent via cannula. After 4 h, normal workup fol-

lowed by flash chromatography (3:1, hexane/EtOAc) gave the product

(42 mg, 13%), which was shown to be identical to that prepared in

Procedure 1.

According to General Procedure E, a solution of N-tert-butoxycarbon-

yl-4-(trifluoromethylsulfonyl)oxyaniline (361 mg, 1.06 mmol) in

DME (3 mL) was treated with a solution of 3,4-(methylenedi-

oxy)phenylboronic acid (246 mg, 1.48 mmol) in DME (3 mL) and

EtOH (3 mL) in the presence of Pd(PPh₃)₄(48 mg, 0.041 mmol). After

17 h, the reaction mixture was cooled to rt. Normal workup followed

by flash chromatography (4:1, hexane/EtOAc) afforded the product.

Yield: 289 mg (87%); colourless solid; mp 161–162 °C (hexane).

IR (KBr): 3357, 1699 cm^–1

.

¹H NMR (200 MHz, CDCl₃):  = 1.53 (s, 9 H, OC(CH₃)₃), 5.98 (s, 2 H,

OCH₂O), 6.49 (bs, 1 H), 6.86 (d, J = 8.6 Hz, 1 H), 6.99–7.04 (m, 2 H),

7.36–7.47 (m, 4 H).

¹³C NMR (62.9 MHz, CDCl₃):  = 28.3 (o, OC(CH₃)₃), 80.6 (e, OC(CH₃)₃),

101.0 (e, OCH₂O), 107.3 (o), 108.5 (o), 118.9 (o), 120.1 (o), 127.2 (o),

135.0 (e), 135.7 (e), 137.3 (e), 146.7 (e), 148.0 (e), 152.8 (e).

Procedure 4: According to General Procedure E, 2-(trifluoromethyl-

sulfonyloxy)phenyl diethylcarbamate (347 mg, 1.02 mmol) in DME (3

mL) was coupled with 3,4-(methylenedioxy)phenylboronic acid

(238 mg, 1.43 mmol) in DME (3 mL) in the presence of Pd(PPh₃)₄

(39 mg, 0.034 mmol). After 20 h, the reaction was cooled to rt. Nor-

mal workup followed by flash chromatography (3:1, hexane/EtOAc)

afforded the product (310 mg, 97%), which was shown to be identical

to that prepared in Procedure 1.

MS (EI; 70 eV): m/z (%) = 313 (24) [M⁺], 257 (100), 213 (36), 154 (7),

127 (7), 57 (52).

Anal. Calcd for C₁₈H₁₉NO₄: C, 69.00; H, 6.11; N, 4.47. Found: C, 68.74;

H, 5.87; N, 4.48.

3-[3,4-(Methylenedioxy)phenyl]phenyl Diethylcarbamate (Table 2,

Entry 11)

2-[3,4-(Methylenedioxy)phenyl]phenyl Diethylcarbamate (Table 2,

Entry 10)

Procedure 1: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (442 mg, 2.20 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (3.3 mL,

1.45 M, 4.79 mmol) and ZnCl₂(3.0 mL, 1.0 M, 3.00 mmol) and the

whole was warmed to rt. According to General Procedure D, to a sec-

ond flask containing a solution of Ni(acac)₂(18 mg, 0.072 mmol) and

PPh₃(89 mg, 0.34 mmol) in THF (3 mL) was added sequentially

MeMgBr (0.10 mL, 3.0 M, 0.30 mmol), the freshly above prepared or-

ganozinc solution via cannula and a solution of 3-(trifluoromethylsul-

fonyloxy)phenyl diethylcarbamate (379 mg, 1.11 mmol) in THF (2+1

mL). After 26 h reaction, normal workup followed by flash chroma-

tography (3:1, hexane/EtOAc) gave the product.

Procedure 1: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (425 mg, 2.12 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (3.8 mL,

1.24 M, 4.71 mmol) and ZnCl₂(3.0 mL, 1.0 M, 3.00 mmol) and the re-

action mixture was warmed to rt. According to General Procedure D,

to

a second flask containing a solution of Ni(acac)₂(19 mg,

0.073 mmol) and PPh₃(76 mg, 0.29 mmol) in THF (3 mL) was added

sequentially solutions of MeMgBr (0.10 mL, 3.0 M, 0.30 mmol), the

above freshly prepared organozinc solution via cannula and a solution

of 2-(trifluoromethylsulfonyloxy)phenyl diethylcarbamate (344 mg,

1.01 mmol) in THF (2+1 mL). After 17 h, normal workup followed by

flash chromatography (3:1, hexane/EtOAc) gave the product.

Yield: 309 mg (89%); colourless oil.

IR (neat): 1713 cm^–1

.

Yield: 291 mg (92%); colourless oil.

¹H NMR (200 MHz, CDCl₃):  = 1.18–1.22 (m, 6 H, NCH₂CH₃), 3.36 (bs,

4 H, NCH₂CH₃), 5.90 (s, 2 H, OCH₂O), 6.81 (d, J = 8.7 Hz, 1 H), 7.00–7.09

(m, 3 H), 7.25–7.4 (m, 3 H).

¹³C NMR (50 MHz, CDCl₃):  = 13.3 (o, NCH₂CH₃), 14.2 (o, NCH₂CH₃),

41.9 (e, NCH₂CH₃), 42.2 (e, NCH₂CH₃), 101.1 (e, OCH₂O), 107.6 (o),

108.4 (o), 120.2 (o), 120.7 (o), 123.5 (o), 129.3 (o), 134.7 (e), 142.2 (e),

147.2 (e), 148.0 (e), 151.8 (e), 154.2 (e).

IR (neat): 2975, 1714 cm^–1

.

¹H NMR (200 MHz, CDCl₃):  = 1.06 (t, J = 7.1 Hz, 6 H, NCH₂CH₃), 3.27

(q, J = 7.1 Hz, 4 H, NCH₂CH₃), 5.93 (s, 2 H, OCH₂O), 6.8–6.9 (m, 3 H),

7.1–7.4 (m, 4 H).

¹³C NMR (62.9 MHz, CDCl₃):  = 13.0 (o, NCH₂CH₃), 13.8 (o, NCH₂CH₃),

41.5 (e, NCH₂CH₃), 41.9 (e, NCH₂CH₃), 100.9 (e, OCH₂O), 107.9 (o),

109.6 (o), 122.5 (o), 123.2 (o), 125.4 (o), 128.0 (o), 130.5 (o), 131.8 (e),

134 (6, e), 146.7 (e), 147 (2, e), 148.4 (e), 153.9 (e).

MS (EI (60 eV)): m/z (%) = 313 (100) [M⁺], 185 (7), 100 (30), 72 (7).

MS (EI (60 eV)): m/z (%) = 313 (100) [M⁺], 183 (15), 155 (12), 127 (9),

HRMS: m/z calcd for C₁₈H₂₀NO₄: 314.1392; found: 314.1392.

100 (94), 87 (31), 72 (31).

M

C. A. Quesnelle, V. Snieckus

Paper

Synthesis

Procedure 2: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (405 mg, 2.02 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.4 mL,

1.84 M, 4.42 mmol) and MgBr₂·OEt₂(0.9 mL, 2.62 N, 2.36 mmol) and

the whole was warmed to rt. According to General Procedure C, to a

second flask containing a solution of 3-(trifluoromethylsulfony-

loxy)phenyl diethylcarbamate (341 mg, 1.00 mmol) and NiCl₂(dppe)

(33 mg, 0.062 mmol) in THF (5 mL) was added the above freshly pre-

pared Grignard reagent via cannula. After 4.5 h reaction, normal

workup followed by flash chromatography (3:1, hexane/EtOAc) gave

the product (134 mg, 41%), which was shown to be identical to that

prepared in Procedure 1.

Procedure 2: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (399 mg, 1.98 mmol) in

THF (10 mL) was sequentially treated with t-BuLi (2.4 mL, 1.84 M,

4.42 mmol) and MgBr₂·OEt₂(1.0 mL, 2.62 N, 2.62 mmol) and warmed

to rt. According to General Procedure C, to a second flask containing 4-

(trifluoromethylsulfonyloxy)phenyl

diethylcarbamate

(341 mg,

1.00 mmol) and NiCl₂(dppe) (34 mg, 0.064 mmol) in THF (5 mL) was

added the freshly prepared Grignard reagent via cannula. After 4 h,

normal workup followed by flash chromatography (4:1, hexane/EtO-

Ac) gave the product (151 mg, 46%), which was shown to be identical

to that prepared in Procedure 1.

Procedure 3: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (417 mg, 2.07 mmol) in

THF (10 mL) was sequentially treated with t-BuLi (3.0 mL, 1.52 M,

4.56 mmol) and MgBr₂·OEt₂(1.4 mL, 2.62 N, 3.67 mmol) and warmed

to rt. According to General Procedure C, to a second flask containing 4-

Procedure 3: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (398 mg, 1.98 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.9 mL,

1.52 M, 4.41 mmol) and MgBr₂·OEt₂(1.3 mL, 2.62 N, 3.41 mmol) and

the whole was warmed to rt. According to General Procedure C, to a

second flask containing a solution of 3-(trifluoromethylsulfony-

loxy)phenyl diethylcarbamate (349 mg, 1.02 mmol) and Ni(acac)₂

(22 mg, 0.087 mmol) in THF (5 mL) was added the above freshly pre-

pared Grignard reagent via cannula. After 2 h reaction, normal work-

up followed by flash chromatography (3:1, hexane/EtOAc) gave the

product (174 mg, 54%), which was shown to be identical to that pre-

pared in Procedure 1.

(trifluoromethylsulfonyloxy)phenyl

diethylcarbamate

(341 mg,

1.00 mmol) and Ni(acac)₂(20 mg, 0.078 mmol) in THF (5 mL) was

added the freshly prepared Grignard reagent via cannula. After 3 h,

normal workup followed by flash chromatography (3:1, hexane/EtO-

Ac) gave the product (157 mg, 50%), which was shown to be identical

to that prepared in Procedure 1.

Procedure 4: According to General Procedure E, 4-(trifluoromethyl-

sulfonyloxy)phenyl diethylcarbamate (338 mg, 0.99 mmol) in DME (3

mL) was coupled with 3,4-(methylenedioxy)phenylboronic acid

(221 mg, 1.33 mmol) in DME (3 mL) and EtOH (3 mL) in the presence

of Pd(PPh₃)₄(40 mg, 0.035 mmol). After 24 h, the reaction was cooled

to rt. Normal workup followed by flash chromatography (3:1, hex-

ane/EtOAc) afforded the product (276 mg, 89%), which was shown to

be identical to that prepared in Procedure 1.

Procedure 4: According to General Procedure E, a solution of 3-(tri-

fluoromethylsulfonyloxy)phenyl

diethylcarbamate

(342 mg,

1.00 mmol) in DME (3 mL) was treated with a solution of 3,4-(methy-

lenedioxy)phenylboronic acid (219 mg, 1.32 mmol) in DME (3 mL)

and EtOH (3 mL) in the presence of Pd(PPh₃)₄(41 mg, 0.036 mmol).

After 24 h, the reaction mixture was cooled to rt. Normal workup fol-

lowed by flash chromatography (3:1, hexane/EtOAc) afforded the

product (307 mg, 98%), which was shown to be identical to that pre-

pared in Procedure 1.

2-Fluoro-3′,4′-(methylenedioxy)biphenyl (Table 2, Entry 13)

Procedure 1: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (396 mg, 1.97 mmol) in

THF (10 mL) was sequentially treated with t-BuLi (2.8 mL, 1.58 M,

4.42 mmol) and ZnCl₂(3.0 mL, 1.0 M, 3.00 mmol) and warmed to rt.

According to General Procedure D, to a second flask containing

Ni(acac)₂(27 mg, 0.10 mmol) and PPh₃(119 mg, 0.45 mmol) in THF

(3 mL) was added sequentially MeMgBr (0.10 mL, 3.0 M, 0.30 mmol),

the freshly prepared organozinc solution via cannula and a solution of

2-fluorophenyl trifluoromethanesulfonate (189 mg, 0.77 mmol) in

THF (2+1 mL). After 24 h, normal workup followed by flash chroma-

tography (9:1 to 4:1, hexane/CH₂Cl₂) gave the product.

4-[3,4-(Methylenedioxy)phenyl]phenyl Diethylcarbamate (Table 2,

Entry 12)

Procedure 1: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (407 mg, 2.03 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (3.6 mL,

1.24 M, 4.46 mmol) and ZnCl₂(3.0 mL, 1.0 M, 3.00 mmol) and the

whole was warmed to rt. According to General Procedure D, to a sec-

ond flask containing a solution of Ni(acac)₂(18 mg, 0.071 mmol) and

PPh₃(87 mg, 0.33 mmol) in THF (3 mL) was added sequentially solu-

tions of MeMgBr (0.10 mL, 3.0 M, 0.30 mmol), the above freshly pre-

pared organozinc solution via cannula and a solution of 4-(trifluoro-

methylsulfonyloxy)phenyl diethylcarbamate (356 mg, 1.04 mmol) in

THF (2+1 mL). After 30 h reaction, normal workup followed by flash

chromatography (4:1, hexane/EtOAc) gave the product.

Yield: 159 mg (95%); colourless oil.

IR (neat): 2895, 1470, 1231, 1040, 757 cm^–1

.

¹H NMR (200 MHz, CDCl₃):  = 5.93 (s, 2 H, OCH₂O), 6.85 (d, J = 7.9 Hz,

1 H), 6.95–7.39 (m, 6 H).

¹³C NMR (50 MHz, CDCl₃):  = 101.1 (e, OCH₂O), 108.3 (o), 109.5 (o, d,

J = 3.6 Hz), 116.0 (o, d, J = 22.9 Hz), 122.6 (o, d, J = 2.5 Hz), 124.2 (o, d,

J = 3.1 Hz), 128.6 (o, J = 7.9 Hz), 129.6 (e), 130.5 (o, d, J = 3.1 Hz), 147.2

(e), 147.7 (e), 159.6 (e, d, J = 247.2 Hz, C_Ar-F).

Yield: 277 mg (85%); colourless solid; mp 66.5–67.5 °C (Et₂O/hexane).

IR (KBr): 1703 cm^–1

.

¹H NMR (250 MHz, CDCl₃):  = 1.23 (bs, 6 H, NCH₂CH₃), 3.41 (bs, 4 H,

NCH₂CH₃), 5.96 (s, 2 H, OCH₂O), 6.85 (d, J = 8.68 Hz, 1 H), 6.99–7.02

(m, 2 H), 7.15 (d, J = 8.6 Hz, 2 H), 7.50 (d, J = 8.6 Hz, 2 H).

MS (EI (60 eV)): m/z (%) = 216 (100) [M⁺], 198 (13), 157 (19), 139 (3).

HRMS: m/z calcd for C₁₃H₁₀FO₂: 217.0665; found: 217.0665.

¹³C NMR (50 MHz, CDCl₃):  = 13.3 (o, NCH₂CH₃), 14.1 (o, NCH₂CH₃),

41.8 (e, NCH₂CH₃), 42.1 (e, NCH₂CH₃), 101.0 (e, OCH₂O), 107.5 (o),

108.4 (o), 120.4 (o), 121.9 (o), 127.6 (o), 134.9 (e), 137.8 (e), 146.9 (e),

148.0 (e), 150.6 (e), 154.1 (e).

MS (EI (60 eV)): m/z (%) = 313 (100) [M⁺], 213 (11), 185 (7), 155 (2),

127 (5), 100 (46), 72 (16).

Procedure 2: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (394 mg, 1.96 mmol) in

THF (10 mL) was sequentially treated with t-BuLi (2.4 mL, 1.84 M,

4.42 mmol) and MgBr₂·OEt₂(1.0 mL, 2.62 N, 2.62 mmol) and warmed

to rt. According to General Procedure C, to a second flask containing 2-

fluorophenyl trifluoromethanesulfonate (229 mg, 1.02 mmol) and

NiCl₂(dppe) (35 mg, 0.067 mmol) in THF (5 mL) was added the freshly

Anal. Calcd for C₁₈H₁₉NO₄: C, 69.00; H, 6.11. Found: C, 68.95; H, 6.13.

N

C. A. Quesnelle, V. Snieckus

Paper

Synthesis

prepared Grignard reagent via cannula. After 1.5 h, normal workup

followed by flash chromatography (9:1, hexane/CH₂Cl₂) gave the

product (82 mg, 37%), which was shown to be identical to that pre-

pared in Procedure 1.

Procedure 3: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (409 mg, 2.03 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (3.0 mL,

1.52 M, 4.56 mmol) and MgBr₂·OEt₂(1.3 mL, 2.62 N, 3.41 mmol) and

the whole was warmed to rt. According to General Procedure C, to a

second flask containing a solution of 3-fluorophenyl trifluorometh-

anesulfonate (249 mg, 1.02 mmol) and Ni(acac)₂(20 mg,

0.078 mmol) in THF (5 mL) was added the above freshly prepared Gri-

gnard reagent via cannula. After 4 h reaction, normal workup fol-

lowed by flash chromatography (9:1, hexane/CH₂Cl₂) gave the prod-

uct (97 mg, 44%), which was shown to be identical to that prepared in

Procedure 1.

Procedure 3: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (415 mg, 2.06 mmol) in

THF (10 mL) was sequentially treated with t-BuLi (3.0 mL, 1.52 M,

4.56 mmol) and MgBr₂·OEt₂(1.3 mL, 2.62 N, 3.41 mmol) and warmed

to rt. According to General Procedure C, to a second flask containing 2-

fluorophenyl trifluoromethanesulfonate (245 mg, 1.00 mmol) and

Ni(acac)₂(18 mg, 0.071 mmol) in THF (5 mL) was added the freshly

prepared Grignard reagent via cannula. After 3 h, normal workup fol-

lowed by flash chromatography (4:1, hexane/CH₂Cl₂) gave the prod-

uct (104 mg, 48%), which was shown to be identical to that prepared

in Procedure 1.

Procedure 4: According to General Procedure E, a solution of 3-fluo-

rophenyl trifluoromethanesulfonate (256 mg, 1.05 mmol) in DME (3

mL) was treated with a solution of 3,4-(methylenedioxy)phenylbo-

ronic acid (251 mg, 1.51 mmol) in DME (3 mL) and EtOH (3 mL) in the

presence of Pd(PPh₃)₄(45 mg, 0.039 mmol). After 17 h, the reaction

mixture was cooled to rt. Normal workup followed by flash chroma-

tography (9:1, hexane/CH₂Cl₂) afforded the product (194 mg, 86%),

which was shown to be identical to that prepared in Procedure 1.

Procedure 4: According to General Procedure E, 2-fluorophenyl triflu-

oromethanesulfonate (253 mg, 1.13 mmol) in DME (3 mL) was cou-

pled with 3,4-(methylenedioxy)phenylboronic acid (244 mg,

1.47 mmol) DME (3 mL) and EtOH (3 mL) in the presence of Pd(PPh₃)₄

(43 mg, 0.037 mmol). After 19 h, the reaction was cooled to rt. Nor-

mal workup followed by flash chromatography (9:1, hexane/CH₂Cl₂)

afforded the product (194 mg, 80%), which was shown to be identical

to that prepared in Procedure 1.

4-Fluoro-3′,4′-(methylenedioxy)biphenyl (Table 2, Entry 15)

Procedure 1: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (408 mg, 2.03 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.8 mL,

1.58 M, 4.42 mmol) and ZnCl₂(3.0 mL, 1.0 M, 3.00 mmol) and the

whole was warmed to rt. According to General Procedure D, to a sec-

ond flask containing a solution of Ni(acac)₂(16 mg, 0.061 mmol) and

PPh₃(74 mg, 0.28 mmol) in THF (3 mL) was added sequentially solu-

tions of MeMgBr (0.09 mL, 3.0 M, 0.30 mmol), the above freshly pre-

pared organozinc solution via cannula and a solution of 4-fluorophe-

nyl trifluoromethanesulfonate (193 mg, 0.79 mmol) in THF (2+1 mL).

After 24 h reaction, normal workup followed by flash chromatogra-

phy (9:1 to 4:1, hexane/CH₂Cl₂) gave the product.

3-Fluoro-3′,4′-(methylenedioxy)biphenyl (Table 2, Entry 14)

Procedure 1: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (402 mg, 2.00 mmol) in

THF (10 mL) was sequentially treated with t-BuLi (2.8 mL, 1.58 M,

4.42 mmol) and ZnCl₂(3.0 mL, 1.0 M, 3.00 mmol) and warmed to rt.

According to General Procedure D, to a second flask containing

Ni(acac)₂(22 mg, 0.084 mmol) and PPh₃(89 mg, 0.34 mmol) in THF

(3 mL) was added sequentially solutions MeMgBr (0.10 mL, 3.0 M,

0.30 mmol), the above freshly prepared organozinc solution via can-

nula and a solution of 3-fluorophenyl trifluoromethanesulfonate

(188 mg, 1.00 mmol) in THF (2+1 mL). After 19 h reaction, normal

workup followed by flash chromatography (4:1, hexane/CH₂Cl₂) gave

the product.

Yield: 124 mg (73%); colourless solid; mp 56–57 °C (pentane).

IR (KBr): 1487, 1221, 810 cm^–1

.

¹H NMR (250 MHz, CDCl₃):  = 6.00 (s, 2 H, OCH₂O), 6.88 (dd, J = 7.5,

0.9 Hz, 1 H), 6.99–7.05 (m, 2 H), 7.11 (t, J = 8.8 Hz, 2 H), 7.36 (m, 1 H),

7.47 (dd, J = 8.8, 5.3 Hz, 2 H).

Yield: 161 mg (74%); colourless solid; mp 59–60 °C (pentane).

IR (KBr): 2908, 1478, 1233, 1033, 780 cm^–1

.

¹H NMR (200 MHz, CDCl₃):  = 5.96 (s, 2 H, OCH₂O), 6.84 (d, J = 8.5 Hz,

1 H), 6.92–7.03 (m, 3 H), 7.15–7.34 (m, 3 H); ¹³C NMR (50 MHz, CDCl₃):

 = 101.2 (e, OCH₂O), 107.5 (o), 108.6 (o), 113.6 (o, d, J = 21.1 Hz),

113.7 (o, d, J = 21.7 Hz), 120.6 (o), 122.4 (o, d, J = 2.6 Hz), 130.1 (o, d,

J = 8.9 Hz), 134.2 (e), 143.1 (e, d, J = 7.6 Hz), 147.5 (e), 148.2 (e), 163.1

(e, d, J = 245.6 Hz, C_Ar-F).

¹³C NMR (50 MHz, CDCl₃):  = 101.1 (e, OCH₂O), 108.0 (o, d, J =

50.4 Hz), 115.4 (o, d, J = 21.4 Hz), 120.4 (o), 128.2 (o), 128.4 (o), 134.5

(e), 137.0 (e), 147.0 (e), 148.1 (e), 162.1 (e, d, J = 245.7 Hz, C_Ar-F).

MS (EI; 70 eV): m/z (%) = 219 (100) [M⁺], 157 (30), 107 (11).

Anal. Calcd for C₁₃H₉FO₂: C, 72.22; H, 4.20. Found: C, 72.46; H, 4.45.

Procedure 2: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (402 mg, 2.00 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.4 mL,

1.84 M, 4.42 mmol) and MgBr₂·OEt₂(1.0 mL, 2.62 N, 2.62 mmol) and

the whole was warmed to rt. According to General Procedure C, to a

second flask containing a solution of 4-fluorophenyl trifluorometh-

anesulfonate (239 mg, 1.07 mmol) and NiCl₂(dppe) (33 mg,

0.062 mmol) in THF (5 mL) was added the above freshly prepared Gri-

gnard reagent via cannula. After 1 h reaction, normal workup fol-

lowed by flash chromatography (9:1, hexane/CH₂Cl₂) gave the prod-

uct (87 mg, 38%), which was shown to be identical to that prepared in

Procedure 1.

MS (EI (60 eV)): m/z (%) = 216 (100) [M⁺], 157 (13).

Anal. Calcd for C₁₃H₉FO₂: C, 72.22; H, 4.20. Found: C, 72.04; H, 4.42.

Procedure 2: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (396 mg, 1.97 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.4 mL,

1.84 M, 4.42 mmol) and MgBr₂·OEt₂(1.0 mL, 2.62 N, 2.62 mmol) and

the whole was warmed to rt. According to General Procedure C, to a

second flask containing a solution of 3-fluorophenyl trifluorometh-

anesulfonate (231 mg, 1.03 mmol) and NiCl₂(dppe) (34 mg,

0.064 mmol) in THF (5 mL) was added the above freshly prepared Gri-

gnard reagent via cannula. After 1.5 h, normal workup followed by

flash chromatography (9:1, hexane/CH₂Cl₂) gave the product

(105 mg, 47%), which was shown to be identical to that prepared in

Procedure 1.

Procedure 3: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (407 mg, 2.02 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.9 mL,

1.55 M, 4.50 mmol) and MgBr₂·OEt₂(1.0 mL, 2.62 N, 2.62 mmol) and

O

C. A. Quesnelle, V. Snieckus

Paper

Synthesis

the whole was warmed to rt. According to General Procedure C, to a

second flask containing a solution of 4-fluorophenyl trifluorometh-

anesulfonate (223 mg, 1.00 mmol) and NiCl₂(dppe) (32 mg,

0.060 mmol) in THF (5 mL) was added the above freshly prepared Gri-

gnard reagent via cannula. After 2 h reaction, normal workup fol-

lowed by flash chromatography (9:1, hexane/CH₂Cl₂) gave the prod-

uct (93 mg, 43%), which was shown to be identical to that prepared in

Procedure 1.

the whole was warmed to rt. According to General Procedure C, to a

second flask containing a solution of 3-pyridyl trifluoromethanesul-

fonate (249 mg, 1.09 mmol) and NiCl₂(dppe) (37 mg, 0.069 mmol) in

THF (5 mL) was added the above freshly prepared Grignard reagent

via cannula. After 4.5 h reaction, normal workup followed by flash

chromatography (1:2, hexane/EtOAc) gave the product (171 mg, 78%),

which was shown to be identical to that prepared in Procedure 1.

Procedure 3: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (405 mg, 2.01 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.9 mL,

1.52 M, 4.41 mmol) and MgBr₂·OEt₂(1.2 mL, 2.62 N, 3.14 mmol) and

the whole was warmed to rt. According to General Procedure C, to a

second flask containing a solution of 3-pyridyl trifluoromethanesul-

fonate (235 mg, 1.03 mmol) and Ni(acac)₂(19 mg, 0.074 mmol) in

THF (5 mL) was added the above freshly prepared Grignard reagent

via cannula. After 2.5 h reaction, normal workup followed by flash

chromatography (2:1, EtOAc/hexane) gave the product (100 mg, 49%),

which was shown to be identical to that prepared in Procedure 1.

Procedure 4: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (407 mg, 2.02 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (3.0 mL,

1.52 M, 4.56 mmol) and MgBr₂·OEt₂(1.3 mL, 2.62 N, 3.41 mmol) and

the whole was warmed to rt. According to General Procedure C, to a

second flask containing a solution of 4-fluorophenyl trifluorometh-

anesulfonate (258 mg, 1.15 mmol) and Ni(acac)₂(20 mg,

0.079 mmol) in THF (5 mL) was added the above freshly prepared Gri-

gnard reagent via cannula. After 4 h reaction, normal workup fol-

lowed by flash chromatography (9:1, hexane/CH₂Cl₂) gave the prod-

uct (106 mg, 43%), which was shown to be identical to that prepared

in Procedure 1.

Procedure 4: According to General Procedure E, a solution of 3-pyr-

idyl trifluoromethanesulfonate (241 mg, 1.06 mmol) in DME (3 mL)

was treated with a solution of 3,4-(methylenedioxy)phenylboronic

acid (234 mg, 1.41 mmol) in DME (3 mL) and EtOH (3 mL) in the pres-

ence of Pd(PPh₃)₄(41 mg, 0.035 mmol). After 18 h, the reaction mix-

ture was cooled to rt. Normal workup followed by flash chromatogra-

phy (3:2, EtOAc/hexane) afforded the product (171 mg, 81%), which

was shown to be identical to that prepared in Procedure 1.

Procedure 5: According to General Procedure E, a solution of 4-fluo-

rophenyl trifluoromethanesulfonate (250 mg, 1.13 mmol) in DME (3

mL) was treated with a solution of 3,4-(methylenedioxy)phenylbo-

ronic acid (236 mg, 1.42 mmol), DME (3 mL) and EtOH (3 mL) in the

presence of Pd(PPh₃)₄(45 mg, 0.039 mmol). After 18 h reaction, the

reaction mixture was cooled to rt. Normal workup followed by flash

chromatography (9:1, hexane/CH₂Cl₂) afforded the product (198 mg,

89%), which was shown to be identical to that prepared in Procedure

1.

4-[3′,4′-(Methylenedioxy)phenyl]nitrobenzene (Table 2, Entry 17)

Procedure 1: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (412 mg, 2.05 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.7 mL,

1.66 M, 4.48 mmol) and ZnCl₂(3.0 mL, 1.0 M, 3.00 mmol) and the

whole was warmed to rt. According to General Procedure D, to a sec-

ond flask containing Pd(PPh₃)₄(63 mg, 0.054 mmol) in THF (3 mL)

was added sequentially the above freshly prepared organozinc solu-

tion via cannula and a solution of 4-nitrophenyl trifluoromethanesul-

fonate (290 mg, 1.07 mmol) in THF (2+1 mL). The reaction vessel was

then equipped with a reflux condenser and the contents subsequent-

ly heated to reflux. After 21 h, the reaction mixture was cooled to rt.

Normal workup followed by flash chromatography (9:1, hexane/EtO-

Ac) gave the product.

1,2-(Methylenedioxy)-4-(3-pyridyl)benzene (Table 2, Entry 16)

Procedure 1: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (400 mg, 1.99 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.6 mL,

1.66 M, 4.32 mmol) and ZnCl₂(3.0 mL, 1.0 M, 3.00 mmol) and the

whole was warmed to rt. According to General Procedure D, to a sec-

ond flask containing a solution of Ni(acac)₂(18 mg, 0.069 mmol) and

PPh₃(71 mg, 0.27 mmol) in THF (3 mL) was added sequentially solu-

tions of MeMgBr (0.090 mL, 3.0 M, 0.27 mmol), the above freshly pre-

pared organozinc solution via cannula and a solution of 3-pyridyl tri-

fluoromethanesulfonate (239 mg, 1.05 mmol) in THF (2+1 mL). After

18 h reaction, normal workup followed by flash chromatography (2:1,

EtOAc/hexane) gave the product.

Yield: 91 mg (35%); yellow solid; mp 155–160 °C (subl.).

IR (KBr): 2912, 1594, 1509, 1335, 1231, 1032 cm^–1

.

Yield: 182 mg (87%); colourless solid; mp 91–91.5 °C (hexane).

¹H NMR (250 MHz, CDCl₃):  = 6.04 (s, 2 H, OCH₂O), 6.92 (d, J = 7.9 Hz,

1 H), 7.09–7.13 (m, 2 H), 7.64 (d, J = 8.9 Hz, 2 H), 8.25 (d, J = 8.9 Hz,

2 H).

IR (KBr): 2905, 1512, 1477, 1418, 1235, 1033 cm^–1

.

¹H NMR (200 MHz, CDCl₃):  = 6.00 (s, 2 H, OCH₂O), 6.90 (d, J = 8.4 Hz,

1 H), 7.01–7.06 (m, 2 H), 7.31 (dd, J = 7.9, 4.8 Hz, 1 H), 7.78 (dd, J = 7.9,

2.3 Hz, 1 H), 8.54 (d, J = 4.8 Hz, 1 H), 8.78 (d, J = 2.3 Hz, 1 H).

¹³C NMR (50 MHz, CDCl₃):  = 101.3 (e, OCH₂O), 107.4 (o), 108.8 (o),

120.7 (o), 123.4 (o), 131.9 (e), 133.9 (o), 136.3 (e), 147.7 (e), 148.0 (o),

148.4 (e).

MS (EI; 70 eV): m/z (%) = 243 (100) [M⁺], 197 (7), 167 (6), 139 (40).

Anal. Calcd for C₁₃H₉NO₄: C, 64.20; H, 3.73; N, 5.76. Found: C, 64.40;

H, 4.00; N, 5.85.

Procedure 2: According to General Procedure E, a solution of 4-nitro-

phenyl trifluoromethanesulfonate (269 mg, 0.99 mmol) in DME (3

mL) was treated with a solution of 3,4-(methylenedioxy)phenylbo-

ronic acid (215 mg, 1.29 mmol) in DME (3 mL) and EtOH (3 mL) in the

presence of Pd(PPh₃)₄(50 mg, 0.043 mmol). After 15 h, the reaction

mixture was cooled to rt. Normal workup followed by flash chroma-

tography (9:1, hexane/EtOAc) afforded the product (147 mg, 61%),

which was shown to be identical to that prepared in Procedure 1.

MS (EI; 70 eV): m/z (%) = 199 (100) [M⁺], 140 (11), 114 (11), 99 (9).

Anal. Calcd for C₁₂H₉NO₂: C, 72.35; H, 4.55; N, 7.03. Found: C, 72.45;

H, 4.63; N, 7.14.

Procedure 2: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (410 mg, 2.04 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.7 mL,

1.65 M, 4.46 mmol) and MgBr₂·OEt₂(1.0 mL, 2.62 N, 2.62 mmol) and

P

C. A. Quesnelle, V. Snieckus

Paper

Synthesis

N-tert-Butoxycarbonyl 2-(4-Biphenyl)ethylamine (Table 2, Entry

18)

ter 5 h of reaction time, normal workup followed by flash chromatog-

raphy (2:1, hexane/EtOAc) gave the product (187 mg, 52%), which

was shown to be identical to that prepared in Procedure 1.

Procedure 1: To a flask charged with a solution of ZnCl₂(1.5 mL,

1.0 M, 1.5 mmol) in THF (4 mL) was added at rt a solution of PhLi (1.0

mL, 1.51 M, 1.51 mmol). According to General Procedure D, to a sec-

ond flask containing a solution of Ni(acac)₂(15 mg, 0.059 mmol) in

THF (4 mL) was added sequentially solutions of i-PrMgCl (0.10 mL,

2.0 M, 0.20 mmol), the above freshly prepared organozinc solution via

cannula and a solution of N-tert-butoxycarbonyltyramine trifluoro-

methanesulfonate (119 mg, 0.32 mmol) in THF (2+1 mL) via cannula.

After 4.5 h reaction, normal workup followed by flash chromatogra-

phy (6:1, hexane/EtOAc) gave the product.

Procedure 3: According to General Procedure E, a solution of N-ben-

zyl-4-trifluoromethylsulfonyloxyquinol-2-one (89 mg, 0.23 mmol) in

DME (2 mL) was treated with a solution of phenylboronic acid (99 mg,

0.82 mmol) in DME (2 mL) in the presence of Pd(PPh₃)₄(16 mg,

0.014 mmol) and 2 N Na₂CO₃(1.0 mL). After 17 h, the reaction mix-

ture was cooled to rt. Normal workup followed by flash chromatogra-

phy (2:1, hexane/EtOAc) afforded the product (51 mg, 71%), which

was shown to be identical to that prepared in Procedure 1.

Yield: 35 mg (37%); colourless solid; mp 87.5–88.5 °C (hexane).

4-Methoxy-3-(2′-tolyl)benzaldehyde (Table 2, Entry 20)

¹H NMR (250 MHz, CDCl₃):  = 1.45 (s, 9 H, OC(CH₃)₃), 2.82 (t, J =

6.9 Hz, 2 H, ArCH₂CH₂N), 3.4 (b, 2 H, ArCH₂CH₂N), 4.63 (bs, 1 H, NH),

6.83–6.92 (m, 2 H), 7.18–7.59 (m, 7 H).

MS (EI; 70 eV): m/z (%) = 297 (9) [M⁺], 241 (61), 180 (100), 167 (55),

105 (26), 57 (22).

Procedure 1: According to General Procedure B, Method A, a solution

of 2-bromotoluene (340 mg, 1.99 mmol) in THF (10 mL) was sequen-

tially treated with solutions of t-BuLi (2.6 mL, 1.66 M, 4.32 mmol) and

ZnCl₂(3.0 mL, 1.0 M, 3.00 mmol) and the whole was warmed to rt.

According to General Procedure D, to a second flask containing a solu-

tion of Ni(acac)₂(16 mg, 0.063 mmol) and PPh₃(70 mg, 0.027 mmol)

in THF (3 mL) was added sequentially solutions of MeMgBr (0.090 mL,

3.0 M, 0.27 mmol), the above freshly prepared organozinc solution via

Anal. Calcd for C₁₉H₂₃NO₂: C, 76.74; H, 7.80; N, 4.71. Found: C, 76.61;

H, 7.62; N, 4.78.

Procedure 2: According to General Procedure C, to a flask containing a

solution of N-tert-butoxycarbonyltyramine trifluoromethanesulfon-

ate (342 mg, 1.03 mmol) and NiCl₂(dppe) (27 mg, 0.052 mmol) in THF

(10 mL) was added a solution of PhMgCl (1.5 mL, 2.0 M, 3.00 mmol).

After 4 h reaction time, normal workup followed by flash chromatog-

raphy (4:1, hexane/EtOAc) gave the product (178 mg, 58%), which

was shown to be identical to that prepared in Procedure 1.

cannula and a solution of 4-methoxy-3-(trifluoromethylsulfony-

loxy)benzaldehyde (307 mg, 1.08 mmol) in THF (2+1 mL). After 2 h of

reaction time, normal workup followed by flash chromatography

(4:1, hexane/EtOAc) gave the product.

Yield: 182 mg (74%); colourless oil.

IR (neat): 2729, 1689 cm^–1

.

¹H NMR (250 MHz, CDCl₃):  = 2.11 (s, 3 H, ArCH₃), 3.82 (s, 3 H, OCH₃),

7.06 (d, J = 8.5 Hz, 1 H), 7.1–7.3 (m, 4 H), 7.68 (d, J = 2.2 Hz, 1 H), 7.88

(dd, J = 8.5, 2.2 Hz, 1 H), 9.89 (s, 1 H, CHO).

¹³C NMR (62.9 MHz, CDCl₃):  = 19.7 (o, ArCH₃), 55.7 (o, OCH₃), 110.6

(o), 125.5 (o), 127.7 (o), 129.6 (o), 129.8 (o), 131.3 (o), 131.6 (e), 132.5

(o), 136.5 (e), 137.1 (e), 161.6 (e), 190.7 (o, CHO).

Procedure 3: According to General Procedure E, a solution of N-tert-

butoxycarbonyltyramine

trifluoromethanesulfonate

(337 mg,

1.01 mmol) in DME (3 mL) was treated with a solution of phenylbo-

ronic acid (179 mg, 1.47 mmol) in DME (3 mL) in the presence of

Pd(PPh₃)₄(39 mg, 0.034 mmol). After 16 h, the reaction mixture was

cooled to rt. Normal workup followed by flash chromatography (4:1,

hexane/EtOAc) afforded the product (246 mg, 82%), which was shown

to be identical to that prepared in Procedure 1.

MS (EI (60 eV)): m/z (%) = 226 (100) [M⁺], 211 (5), 197 (7), 182 (9), 165

(17), 152 (10).

HRMS: m/z calcd for C₁₅H₁₅O₂: 227.1072; found: 227.1072.

N-Benzyl-4-phenyl-2-quinolone (Table 2, Entry 19)

Procedure 2: According to General Procedure E, a solution of 4-me-

Procedure 1: To a flask charged with a solution of ZnBr₂(285 mg,

1.26 mmol) in THF (3 mL) was added at r.t. a solution of PhLi (0.56 mL,

1.82 M, 1.02 mmol). According to General Procedure D, to a second

flask containing N-benzyl-4-(trifluoromethylsulfonyloxy)quinol-2-

one (191 mg, 0.50 mmol), Ni(acac)₂(10 mg, 0.039 mmol) and PPh₃

(39 mg, 0.15 mmol) in THF (3 mL) was added sequentially solutions of

DIBAL-H (0.03 mL, 1.5 M, 0.045 mmol) and the above freshly pre-

pared organozinc solution via cannula. After 4.5 h reaction, normal

workup followed by flash chromatography (2:1, hexane/EtOAc) gave

the product.

thoxy-3-(trifluoromethylsulfonyloxy)benzaldehyde

(296 mg,

1.04 mmol) in DME (3 mL) was treated with a solution of 2-tolylbo-

ronic acid (200 mg, 1.47 mmol) in DME (3 mL) and EtOH (3 mL) in the

presence of Pd(PPh₃)₄(39 mg, 0.034 mmol). After 14 h, the reaction

mixture was cooled to rt. Normal workup followed by flash chroma-

tography (4:1, hexane/EtOAc) afforded the product (225 mg, 95%),

which was shown to be identical to that prepared in Procedure 1.

1-(3′,4′-(methylenedioxy)phenyl)fluorenone (Table 2, Entry 21)

Procedure 1: According to General Procedure B, Method A, a solution

of 4-bromo-1,2-(methylenedioxy)benzene (400 mg, 1.99 mmol) in

THF (10 mL) was sequentially treated with solutions of t-BuLi (2.5 mL,

1.73 M, 4.33 mmol) and ZnCl₂(3.0 mL, 1.0 M, 3.0 mmol) and the

whole was warmed to rt. According to General Procedure D, to a sec-

ond flask containing Ni(acac)₂(16 mg, 0.062 mmol) and PPh₃(63 mg,

0.24 mmol) in THF (3 mL) was added sequentially solutions of MeMg-

Br (0.08 mL, 3.0 M, 0.24 mmol), the above freshly prepared organoz-

inc solution via cannula and a solution of 9-(trifluoromethylsulfony-

loxy)fluorenone (336 mg, 0.98 mmol) in THF (4+1 mL) via cannula.

After 2 h of reaction time, normal workup followed by flash chroma-

tography (4:1, hexane/EtOAc) gave the product.

Yield: 104 mg (67%); colourless solid; mp 116–117 °C (CH₂Cl₂/hex-

ane).

¹H NMR (250 MHz, CDCl₃):  = 6.10 (s, 2 H, PhCH₂), 7.53–8.06 (m,

15 H).

¹³C NMR (50 MHz, CDCl₃):  = 45.9 (e), 115.2 (o), 120.6 (e), 121.0 (o),

121.9 (o), 126.6 (o), 127.2 (o), 127.6 (o), 127.8 (o), 128.7 (o), 130.5 (o),

136.3 (e), 137.0 (e), 139.6 (e), 151.4 (e), 162.0 (e).

Procedure 2: According to General Procedure C, to a flask containing a

solution

of

N-benzyl-4-trifluoromethylsulfonyloxyquinol-2-one

(187 mg, 0.49 mmol) and Ni(acac)₂(13 mg, 0.051 mmol) in Et₂O (5

mL) was added a solution of PhMgBr (0.40 mL, 2.0 M, 0.80 mmol). Af-

Yield: 169 mg (58%); yellow solid; mp 132–132.5 °C (Et₂O/hexane).

Q

C. A. Quesnelle, V. Snieckus

Paper

Synthesis

IR (KBr): 1702, 1227, 1034 cm^–1

¹H NMR (200 MHz, CDCl₃):  = 6.00 (s, 2 H, OCH₂O), 6.86 (m, 1 H),

.

(8) (a) Hatanaka, Y.; Hiyama, T. Synlett 1991, 845. (b) Denmark, S.

E.; Regens, C. S. Acc. Chem. Res. 2008, 41, 1486.

(9) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,

4467.

(10) The Mizoroki–Heck Reaction; Oestreich, M., Ed.; Wiley: Wein-

heim, 2009.

(11) Haag, B.; Mosrin, M.; Ila, H.; Malakhov, V.; Knochel, P. Angew.

Chem. Int. Ed. 2011, 50, 9794.

(12) King, A. O.; Yasuda, N. Top. Organomet. Chem. 2004, 6, 205.

(13) (a) For an analysis of cross-coupling reactions in the context of a

medicinal chemist’s toolbox based on limited set of journals,

see: Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.

(b) For the development of nanomole-scale high-throughput

cross-coupling chemistry for the synthesis of complex mole-

cules, see: Santanilla, A. B.; Regalado, E. L.; Pereira, T.; Shevlin,

M.; Bateman, K.; Campeau, L.-C.; Schneeweis, J.; Berritt, S.; Shi,

Z.-C.; Nantermet, P.; Liu, Y.; Helmy, R.; Welch, C. J.; Vachal, P.;

Davies, I. W.; Cernak, T.; Dreher, S. D. Science 2015, 347, 49.

(c) Recently, Buchwald summarized applications of C–N cou-

plings, see: Ruiz-Castillo, P.; Buchwald, S. L. Chem. Rev. 2016, 19,

12564. (d) An analysis of the Suzuki–Miyaura coupling for the

synthesis of pharmaceutically important heterocycles can be

seen here: Almond-Thynne, J.; Blakemore, D. C.; Pryde, D. C.;

Spivey, A. C. Chem. Sci. 2017, 8, 40.

6.97–7.01 (m, 2 H), 7.16 (m, 1 H), 7.26 (m, 1 H), 7.41–7.59 (m, 5 H).

¹³C NMR (50 MHz, CDCl₃):  = 101.1 (e, OCH₂O), 107.9 (o), 109.8 (o),

118.9 (o), 119.9 (o), 122.9 (o), 124.0 (o), 129.1 (o), 129.5 (o), 131.2 (e),

131.5 (o), 134.1 (o), 134.2 (e), 134.4 (o), 141.9 (e), 143.4 (e), 145.5 (e),

147.2 (e), 147.7 (e), 192.9 (e).

MS (EI (60 eV)): m/z (%) = 300 (100) [M⁺], 271 (3), 242 (8), 213 (24),

187 (6), 163 (2), 121 (5).

Anal. Calcd for C₂₀H₁₂O₃: C, 79.99; H, 4.03. Found: C, 79.76; H, 4.23.

Procedure 2: According to General Procedure E, a solution of 9-(tri-

fluoromethylsulfonyloxy)fluorenone (333 mg, 1.02 mmol) in DME (3

mL) was treated with a solution of 3,4-(methylenedioxy)phenylbo-

ronic acid (216 mg, 1.30 mmol) in DME (3 mL) and EtOH (3 mL) in the

presence of Pd(PPh₃)₄(42 mg, 0.036 mmol). After 30 h, the reaction

mixture was cooled to rt. Normal workup followed by flash chroma-

tography (4:1, hexane/EtOAc) afforded the product (286 mg, 94%),

which was shown to be identical to that prepared in Procedure 1.

Funding Information

We are grateful to NSERC Canada, Discovery Grant (DG 05698) for

support of our synthetic programs and CQ thanks NSERC for a gradu-

(14) See, for example: (a) Koch, F. P.; Heeney, M. In Materials Science

and Technology; Cahn, R. W.; Haasen, P.; Kramer, E. J., Ed.;

Wiley-VCH: New York, 2013. (b) Xu, S.; Kim, E. H.; Wei, A.;

Negishi, E.-i. Sci. Technol. Adv. Mater. 2014, 15, 1.

ate fellowship.

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i

e

enri

g

Research

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lc

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of

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a

d

a

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0

5

6

9

8)

(15) (a) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J.

Chem. Soc. Rev. 2016, 45, 2900. (b) For general synthetic and

mechanism aspects of C–H activation, see: Tan, P. W.; Haughey,

M.; Dixon, D. J. Chem. Commun. 2015, 4406; and references to

general synthetic and mechanism aspects of C–H activation.

(16) For application in the pharmaceutical industry, on small- and

large-scale, see for example: (a) Linghu, X.; Wong, N.; Jost, V.;

Fantasia, S.; Sowell, C. G.; Gosselin, F. Org. Process Res. Dev. 2017,

21, 1320. (b) Znidar, D.; Hone, C. A.; Inglesby, P.; Boyd, A.;

Kappe, C. O. Org. Process Res. Dev. 2017, 21, 878. (c) Greshock, T.

J.; Moore, K. P.; McClain, R. T.; Bellomo, A.; Chung, C. K.; Dreher,

S. D.; Kutchukian, P. S.; Peng, Z.; Davies, I. W.; Vachal, P.; Ellwart,

M.; Manolikakes, S. M.; Knochel, P.; Nantermet, P. G. Angew.

Chem. Int. Ed. 2016, 55, 13714. (d) Gontcharov, A.; Dunetz, J. R.

Org. Process Res. Dev. 2014, 18, 1145. See in particular a review

outlining many more: (e) Biajoli, A. F. P.; Schwalm, C. S.;

Limberger, J.; Claudino, T. S.; Monteiro, A. L. J. Braz. Chem. Soc.

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Acknowledgment

We thank Professor Denmark for informing us of ref. 27d.

Supporting Information

Supporting information for this article is available online at

https://doi.org/10.1055/s-0037-1611053.

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Article Doi

Directed ortho Metalation (D o M)-Linked Corriu-Kumada, Negishi, and Suzuki-Miyaura Cross-Coupling Protocols: A Comparative Study

DOI: 10.1055/s-0037-1611053

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Article abstract of DOI:10.1055/s-0037-1611053

Full text of DOI:10.1055/s-0037-1611053

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