Regiocomplementary cycloaddition reactions of boryl- and silylbenzynes with 1,3-dipoles: Selective synthesis of benzo-fused azole derivatives

Article

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Regiocomplementary Cycloaddition Reactions of Boryl- and

Silylbenzynes with 1,3-Dipoles: Selective Synthesis of Benzo-Fused

Azole Derivatives

Takashi Ikawa,^†Akira Takagi,^†Masahiko Goto,^†Yuya Aoyama,^†Yoshinobu Ishikawa,^†Yuji Itoh,^‡

Satoshi Fujii,^†Hiroaki Tokiwa,*^,‡and Shuji Akai*^,†

^†School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan

^‡Department of Chemistry, Faculty of Science, Rikkyo University, 3-34-1, Nishi-ikebukuro, Toshima-ku, Tokyo 171-8501, Japan

S

* Supporting Information

ABSTRACT: Benzo-fused nitrogen-containing heterocycles

are abundant in biologically active compounds. One of the

most important methods for preparing such heterocycles is the

(3 + 2) cycloaddition reaction of benzynes with 1,3-dipolar

compounds. However, the reactions of unsymmetrically

substituted benzynes generally show low selectivity and

hence yield mixtures of two regioisomers. In this paper, we

describe the synthesis of both regioisomers of multisubstituted

benzo-fused azole derivatives such as benzotriazoles, 1H-indazoles, and benzo[d]isoxazoles through the regiocomplementary (3 +

2) cycloaddition reactions of 3-boryl- and 3-silylbenzynes with 1,3-dipoles. The improved generation of 3-borylbenzynes from

new precursors was one of the most important results of this work, which produced the successful (3 + 2) cycloaddition reactions

with exclusive and proximal selectivities. On the other hand, similar reactions of 3-silylbenzynes selectively aﬀorded distal

cycloadducts. Analysis of the reaction pathways of these amazing regioselectivities by density functional theory calculations

revealed that the (3 + 2) cycloadditions of borylbenzynes are controlled by the electrostatic eﬀect of the boryl group, while those

of silylbenzynes are controlled mainly by the steric eﬀect of the bulky silyl groups that produced electrostatically unfavorable

adducts via anomalous transition states.

syntheses of heterocyclic compounds and allow eﬀective

preparation of drug candidate libraries.

INTRODUCTION

■

Benzo-fused azole derivatives are one of the most important

classes of nitrogen-containing heterocycles.¹For example, they

have been reported to have a wide range of biological activities

such as anticancer,²antidepressant,³antidiabetic,⁴antimicro-

bial,⁵antifungal,⁶antitubercular,⁷and antilipolytic activities.⁸

These compounds have traditionally been synthesized using a

linear, stepwise transformation of substituted benzene deriva-

tives.⁹However, these methods usually involve many steps and

are less eﬀective for the preparation of drug candidate libraries

because each compound must be synthesized from a diﬀerent

starting material.

Cycloadditions of benzynes with 4π-components have

attracted much attention recently. Among them, the (3 + 2)

cycloaddition of benzynes with 1,3-dipole compounds has

served as an eﬀective alternative route to benzo-fused azole

derivatives.¹⁰In 2007, Yamamoto et al. reported a synthesis of

1H-indazole^10busing the (3 + 2) cycloaddition of benzynes,

generated from 2-(trimethylsilyl)phenyl triﬂate with a ﬂuoride

source, to diazo compounds. Subsequently, a large number of

benzo-fused azole derivatives such as 1H-indazole,^10d,h,j2H-

indazole,^10kbenzotriazole,^10c,f,gand benzo[d]isoxazole^10a,e,i,l

were synthesized using benzyne reactions. These trans-

formations are valuable for convergent diversity-oriented

However, like most benzyne reactions,¹¹the (3 + 2)

cycloaddition of unsymmetrically substituted benzynes with

1,3-dipoles is not always regioselective. For example, the

reaction of 3-methylbenzyne 1A with 4-methoxyphenyl azide

6a yields a 1:1 mixture of two regioisomers of benzotriazole

(proximal- and distal-7Aa) (Table 1, entry 1),^10gand a similar

reaction of 3-ﬂuorobenzyne 2A also exhibited poor regiose-

lectivity (entry 2).^10gThe reaction of 3-methoxybenzyne 3A is

one of the special cases in which the (3 + 2) cycloaddition with

6a exclusively gave distal-9Aa (entry 3),^10gand similar

regioselective (3 + 2) reactions were also reported using 3-

alkoxybenzynes.^{10b,c,e,g,h,j}In addition, Suzuki et al. discovered

another kind of the regioselective (3 + 2) cycloaddition

reaction using (3-trialkylsilyl)benzyne with nitrone.^10aHow-

ever, since then only a few groups have focused on the

regiocontrol of the (3 + 2) cycloadditions of benzynes

possessing a substituent other than an alkoxy group,^10e,12,13

although so many new 1,3-dipolar cycloadditions have been

reported over the last dacade.¹⁰Moreover, 3-silylbenzynes have

Received: December 25, 2012

A

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cycloadditions of 4 and those of 5, we performed theoretical

analysis of the reaction pathways by density functional theory

(DFT) calculations. Although a part of this work was reported

in our recent brief account,¹⁵this paper describes the full details

of this work. In particular, it provides new information about

the reasons for the improvement of the borylbenzyne precursor

and its development process, the experimental procedures and

spectroscopic data of the benzyne precursors and products, the

preparation of an aza analog of hippadine, and a full discussion

about regioselectivities. Our previously published account only

summarized the results without discussing them in detail, and

in this paper we discuss the details of each reaction, pointing

out many important features of the reactions that were not

mentioned in the previous account.

Table 1. Regioselectivities of (3 + 2) Cycloadditions of 3-

Substituted Benzynes 1A−5A with 4-Methoxyphenyl Azide

6a

a

entry

R

1−5

7−11

proximal:distal

ref

1

2

3

4

5

Me

1A

2A

3A

4A

5A

7Aa

8Aa

9Aa

1:1

10g

F

OMe

1:>50

>50:1

b

Bpin

10Aa

11Aa

this study

SiMe₃

1:5.7

a

b

General rules for the numbering on this paper. Bpin: pinacolboryl

RESULTS

■

Development of Improved Preparation Methods of 3-

Boryl- and 3-Silylbenzynes. The most critical problems

addressed in this project are the development of better

precursors for the boryl- and silylbenzynes (4 and 5) and the

optimization of the conditions for benzyne generation followed

by (3 + 2) cycloaddition, because our preliminary trials, in

which the generation methods for 4 and 5 (developed in our

previous Diels−Alder reactions^14b) were applied to the (3 + 2)

cycloaddition with 4-(tert-butyl)phenyl azide 6b, were not very

successful. For example, i-PrMgCl·LiCl (1.2 equiv) was added

to an Et₂O solution of 6-boryl-2-iodo-4-methylphenyl triﬂate

12B and 6b at −78 °C, and the reaction mixture was stirred at

−78 °C for 30 min to generate 4B and promote the

cycloaddition. We observed the formation of a cycloaddition

product, proximal-10Bb as a single regioisomer; however, its

yield was as low as 15%, and a signiﬁcant amount of byproduct

15 (29%) along with the recovery of 12B (26%) were observed

(Table 2, entry 1). We suspected that 15 was produced by the

competitive hydride reduction¹⁶of 4B by another i-PrMgCl

molecule, which would leave behind a substantial amount of

12B.

been generated under harsh reaction conditions using n-

BuLi.^10a,e,12

We recently reported that 3-boryl- and 3-silylbenzynes

undergo Diels−Alder reactions with substituted furans and

pyrroles to provide cycloadducts with high distal regioselectiv-

ity.¹⁴We applied these benzynes to the (3 + 2) cycloadditions

with various 1,3-dipoles and discovered the following. The

cycloaddition reactions of 3-borylbenzynes 4 selectively gave

proximal benzo-fused azoles 10, whereas similar reactions of 3-

silylbenzynes 5 gave distal products 11. These opposite

regioselectivities were also generally obtained with a range of

1,3-dipoles (typical examples in Table 1, entries 4 and 5; for

more examples, see Table 3). We applied these protocols to the

regioselective synthesis of the biologically interesting triazole

analogue of hippadine, vorozole, and its regioisomer. To reveal

the origin of the opposite regioselectivities of the (3 + 2)

Therefore, to improve the yield of proximal-10Bb, we

attempted to suppress the formation of 15 using two

approaches. First, we used Grignard reagents without β-

Table 2. Eﬃcient Preparation of 3-Borylbenzyne 4B for (3 + 2) Cycloaddition to 4-(tert-Butyl)phenyl Azide 6b

a

entry

R

12B−14B

conditions

−78 °C, 30 min

−78 °C, 30 min then 0 °C, 30 min

yield (%) of proximal-10Bb

b

1

2

3

CF₃

12B

13B

14B

15

C₆H₄-4-Cl

48

c

C₆H₂-2,4,5-Cl₃

67

a

b

1

The yield of proximal-10Bb was determined by H NMR; distal-10Bb was not detected in a crude product of each entry. The formation of 15

c

(29% yield) and the recovery of 12B (26% yield) were also observed. Isolated yield of proximal-10Bb.

B

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nitrone 6r, and nitrile oxide 6s (Figure 1 and Table 3). The (3

+ 2) cycloaddition of 4 generally aﬀorded proximal-10, while

that of 5 selectively aﬀorded distal-11. Many examples of

opposite selectivities are presented in entries 1−9 of Table 3.

On the other hand, nitrone 6r¹³underwent cycloaddition with

both 4 and 5 to give distal 2,3-dihydrobenzo[d]isoxazoles

(10Br and 11Br) with excellent selectivity (entry 10; similar

reactions of 5 with 6r were previously reported by Suzuki^10a

and Danishefsky^10eunder harsh conditions). This is the only

exception in which both 4 and 5 showed the same distal

selectivity.

The (3 + 2) cycloaddition of 4 with Me₃SiCHN₂6n

exclusively gave a desilylated indazole, proximal-10Bn (entry

9), while similar reactions of 5 with diazo compounds (6p and

6q) gave distal 1H-indazoles (11Bp and 11 Bq) (entries 18 and

19). Silylbenzyne 5B and benzonitrile oxide 6s were

simultaneously generated from their precursors (16B and N-

hydroxybenzimidoyl chloride, respectively) using Bu₄NF in a

single ﬂask and exclusively gave distal benzo[d]isoxazole 11Bs

(entry 20).

Figure 1. Structure of 1,3-dipoles 6a−6s.

hydrogen atoms, such as MeMgCl, BnMgCl, and t-

Bu₂CHMgCl, instead of i-PrMgCl; however, there was no

improvement (see Table S1 in Supporting Information). We

next examined leaving groups other than −OSO₂CF₃. Knochel

et al. reported a very important method for preparing

functionalized benzynes from 2-iodophenyl 4-chlorobenzene-

sulfonate using the reaction with i-PrMgCl.¹⁷The use of

corresponding 4-chlorobenzenesulfonate 13B signiﬁcantly

improved the yield of proximal-10Bb by up to 48% (Table 2,

entry 2). After extensive studies on the benzyne precursors (see

Tables S2 and S3 in Supporting Information), we ﬁnally found

that 2,4,5-trichlorobenzenesulfonate 14B^18,19was the best

precursor of 4B and that its (3 + 2) cycloaddition with 6b

aﬀorded proximal-10Bb in 67% yield (Table 2, entry 3). It was

proved that the iodine−magnesium exchange reaction of 14B

proceeded rapidly at −78 °C; however, the subsequent

formation of 4B did not proceed at the same temperature

when 14B was used as a precursor (see Tables S2 and S3 in

Supporting Information). 4B was gradually generated while the

reaction mixture was warmed to 0 °C and immediately reacted

with 6b. Thus, the leaving ability of the sulfonyloxy group of

the benzyne precursor aﬀected the rate of benzyne generation,

and tuning this leaving ability was the key to suppressing the

undesired hydride reduction and allowing the successful

reaction of 4 with 6b. The regioisomer distal-10Bb was not

detected in any of the cases examined (Table 2), indicating the

ﬁrst successful proximal-selective (3 + 2) cycloaddition of 3-

substituted benzynes with azides.

Previously, we prepared silylbenzynes 5 through the reaction

of 2-bromo-6-silylphenyl triﬂates and n-BuLi and applied them

in regioselective Diels−Alder reactions.^14aIn this study, we

found the generation of 5 from 2,6-bis(trimethylsilyl)phenyl

triﬂates 13 using Bu₄NF^14c,20was more suitable for the (3 + 2)

cycloaddition of 5 because of the milder reaction conditions

required. In fact, the reaction of the in situ generated 5-methyl-

3-(trimethylsilyl)benzyne 5B with 6b selectively yielded distal-

11Bb (distal:proximal = 10:1) (Table 3, entry 1).¹²It is worth

noting that the regioselectivity of 5B was opposite to that of the

above-mentioned borylbenzyne 4B. This cannot be explained

by the electrostatic eﬀects of boron and silicon, which are both

less electronegative than carbon (Allred-Rochow electro-

negativities: B, 2.0; Si, 1.7; C, 2.5).²¹

The following features are also worth noting: (i) Functional

groups such as oleﬁn (6i), ester (6g and 6l), bromo (6d), iodo

(6k), and cyano (6m) groups were tolerated under the reaction

conditions when either i-PrMgCl·LiCl (for generating 4) or a

ﬂuoride source (for generating 5) was used. (ii) The reactions

between 4 and most of the azides, including the bulky

diphenylmethyl azide 6h, resulted in complete proximal

selectivity, and the reaction with the extremely bulky adamantyl

azide 6j also exhibited slight proximal preference (proximal-

10Bj:distal-10Bj = 1.1:1) (Table 3, entry 8). (iii) The use of

5B′, which has the more bulky tert-butyldimethylsilyl group,

resulted in better distal selectivity (distal-11Be′:proximal-11Be′

= 10:1) than did the use of 3-(trimethylsilyl)benzyne 5B (entry

4). Similar results were also observed in the reaction with 6n

(entry 9). The distal selectivities also increased with increasing

steric bulk of the alkyl chains in the azides (6e, 6h, and 6j;

compare entries 4, 7, and 8). (iv) The substituent R¹(H, Me, F,

Cl) at the C5 position of 4 and 5 had little eﬀect on the

selectivity of the reaction with 6e (entries 3, 4, 16, and 17).

Synthetic Applications of the (3 + 2) Cycloadducts.

The proximal-selective cycloaddition of 3-borylbenzynes 4 was

applied to the synthesis of triazole analogues (18A and 18B) of

a testicular function inhibitor, hippadine 19²²(Scheme 1a).

When a suitably functionalized azide derivative 6t was used, the

(3 + 2) cycloaddition of borylbenzynes, generated from the

corresponding precursors (14A and 14B), gave benzotriazoles

(proximal-10At and proximal-10Bt) in 69% and 67% isolated

yields, respectively, with exclusive proximal selectivities. Their

intramolecular Suzuki−Miyaura coupling aﬀorded 17A and

17B, which were oxidized by MnO₂to give 18A and 18B in

53% and 61% isolated yields, respectively, in two steps.

The formal synthesis of vorozole 21⁹(Scheme 1b) was

performed using the distal-selective cycloaddition of 3-

silylbenzynes 5.¹⁵First, 3-(tert-butyldimethylsilyl)benzyne,

generated from 16E′²³by Bu₄NF, reacted with trimethylsi-

lylmethyl azide 6u to give distal-11Eu′ (84% isolated yield)

along with proximal-11Eu′ (6% yield). Desilylation of distal-

11Eu′, followed by deacetalization, aﬀorded 20 (90% overall

yield), a key intermediate for the synthesis of biologically active

compounds such as aromatase inhibitor 21⁹and a PI3K

inhibitor.²⁴Moreover, we synthesized a regioisomer 23 of

vorozole 21 via the proximal-selective (3 + 2) cycloaddition of

a 3-borylbenzyne, generated from 14C, with 6u (Scheme 1c).

Scope and Limitation of (3 + 2) Cycloadditions of

Boryl- and Silylbenzynes with Various 1,3-Dipoles.¹⁵We

next investigated the (3 + 2) cycloadditions of 3-borylbenzynes

(4A and 4B) and 3-silylbenzynes 5A−5D with diverse 1,3-

dipoles including azides 6a−6m, diazo compounds 6n−6q,

C

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Table 3. Complementary Regioselective (3 + 2) Cycloaddition of Borylbenzynes 4 and Silylbenzynes 5

a

b

Proximal regioisomer 10 was exclusively observed in ¹H NMR spectra of the crude product. Total isolated yield of distal and proximal isomers 11.

c

d

1

The ratio of distal to proximal products, determined using H NMR spectra of the crude product, is shown in brackets. Results for 3-(tert-

butyldimethylsilyl)benzyne 5B′ [SiR₃= Si(t-Bu)Me₂], which was used instead of 3-(trimethylsilyl)benzyne 5B (SiR₃= SiMe₃) and provided a

mixture of the corresponding distal- and proximal-11B′ [SiR₃= Si(t-Bu)Me₂]. The ratio of distal- to proximal-11B′ [SiR₃= Si(t-Bu)Me₂] is shown in

e

f

brackets. Only the corresponding desilylated product was isolated for proximal-11. Distal regioisomer 10Br was exclusively observed in ¹H NMR

spectra of the crude product. Ad = 1-adamantyl.

D

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a

Scheme 1. Application of [3 + 2] Cycloaddition to the Syntheses of Biologically Active Compounds and Their Aza Analogues

a

(a) Synthesis of hippadine analogues (18A and 18B). (b) Synthesis of vorozole 21. (c) Synthesis of a regioisomer 23 of vorozole 21.

These regiocomplementary syntheses are valuable because the

methylation of norvorozole produced a 1:1:1 mixture of 21 and

its two regioisomers.²⁵Our method involves fewer steps and

allows the convergent synthesis of benzo-fused azoles from

benzyne precursors and 1,3-dipoles. Thus, it should be useful

for the combinatorial synthesis of diverse derivatives of

biologically active compounds.

Table 4. Internal Angle and Natural Charge of 3-

Borylbenzynes 4 and 3-Silylbenzynes 5

internal angle

DISCUSSION

(deg)

natural charge

■

Bpin

R¹

4

C1

C2

C1

C2

Herein, we discuss why the (3 + 2) cycloadditions of

borylbenzynes 4 gave proximal products and those of

silylbenzynes 5 gave distal products using the results of density

functional theory (DFT) calculations.²⁷

H

4A

4B

122

133

132

−0.042

−0.034

0.118

0.111

Me

internal angle

(deg)

natural charge

First, we checked the internal angles of the geometry-

optimized 3-boryl- (4A and 4B) and 3-silylbenzynes (5A−5D,

and 5B′) to evaluate the contribution of distortion energy,¹²

and we also analyzed the charge distributions of these benzynes

by performing natural population analysis in the isolated system

(without solvent eﬀect and coordination of metals) (Table 4).²⁸

Two important features of the benzynes were found: (i) The

internal angles and the charge distribution of all these benzynes

are almost exactly the same, and the substituent R¹at the C5-

position of benzyne has little eﬀect. (ii) C2s are more

electrophilic than C1s because of the electrostatic eﬀect^10a,14,15

of the boryl and silyl groups and also because of the benzyne

distortion.^12,29

SiR₃

R¹

5

C1

C2

C1

C2

SiMe₃

SiH₃

H

5A

121

123

135

134

135

134

132

−0.037

−0.030

−0.027

−0.031

−0.006

0.081

0.076

0.080

0.092

0.072

0.067

Me

F

5B

5C

5D

5B′

5B″

Cl

Me

We next analyzed the experimental regioselectivities of the (3

+ 2) cycloaddition reactions between two benzynes (4B and

5B) and three 1,3-dipoles (6e, 6o, and 6r) (for natural charges

of these 1,3-dipoles, see Figure 2) to ﬁnd whether they were

consistent with their calculated charge distributions and

benzyne distortions. The experimental regioselectivities of the

reactions between borylbenzyne 4B and the 1,3-dipoles (6e, 6o,

and 6r) are consistent with the calculated results, while those

Figure 2. Natural charges of 1,3-dipolar compounds (6e, 6o, and 6r).

between silylbenzyne 5B and the 1,3-dipoles (6e and 6o) are

not (Table 3, entries 4, 9, and 10). These contrasting results

clearly indicate that the regioselectivities are accounted for by

neither the electrostatic eﬀect nor the benzyne distortion.

E

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Table 5. Theoretical and Experimental Ratios in the (3 + 2) Cycloaddition Reactions of Borylbenzynes 4 and Silylbenzyne 5

theoretical results

a

entry

M

4, 5

6

TS1−TS32

ΔΔH^⧧or ΔΔG^⧧(kcal/mol)

ratio of distal to proximal³⁰exptl ratio of distal to proximal from Table 3

1:>50 1:>50

6.5:1 3.3:1

1.3:1

1:43

b

1

Bin

4B

5B

5B′′

4B

5B

6e

6f

TS1, TS2

+2.58

c

2

SiMe₃

SiH₃

TS3, TS4

−1.11

−0.14

+2.22

c

3

TS5, TS6

b

4

Bpin

TS7, TS8

1:>50

1:1.1

b

5

Bpin

6g

6h

6i

TS9, TS10

TS11, TS12

TS13, TS14

TS15, TS16

TS17, TS18

TS19, TS20

TS21, TS22

TS23, TS24

TS25, TS26

TS27, TS28

TS29, TS30

TS31, TS32

+3.94

1:>50

1:28

b

6

Bpin

+1.96

b

7

Bpin

+2.36

1:>50

1:2.9

b

8

Bpin

6j

+0.63

b

9

Bpin

6k

6l

+2.78

1:>50

b

10

11

12

13

14

15

16

Bpin

+3.02

b

Bpin

6m

6c

6j

+3.60

c

SiMe₃

−1.45

−2.40

−1.66

−3.08

11:1

14:1

c

>50:1

20:1

>50:1

c

6p

6q

6s

c

>50:1

c

−2.73

a

Energy diﬀerence between distal-TS and proximal-TS. Positive ΔΔH^⧧or ΔΔG^⧧indicates that distal-TS is higher than proximal-TS, while negative

b

c

ΔΔH^⧧or ΔΔG^⧧represents the opposite. Activation energy diﬀerence is shown as a ΔΔH^⧧value. Activation energy diﬀerence is shown as as a

ΔΔG^⧧value.

Therefore, we performed a theoretical analysis of the reaction

pathways, including the transition states, to quantitatively

rationalize the origin of the selectivities.

As a reference, the transition state TS33 of the reaction of

benzyne 24A and 6e was also calculated, in which the bond

distance (2.40 Å) between the internal nitrogen of 6e and the

benzyne carbon is shorter than that (2.77 Å) between the

terminal nitrogen and the benzyne carbon (Figure 3a). This is

despite the fact that there should be some steric interaction

between the benzylic methylene moiety of 6e and the benzyne

hydrogen. The corresponding bond distances of the TS34,

derived from 5-methylbenzyne 24B, and 6e are close to those

of TS33, which implies that a methyl group at the C5-position

of benzyne hardly aﬀects the structure of the transition state.

The lengths of the two bonds forming in TS2, which is more

stable than TS1 because the electrostatic combination of the

reacting atoms is well matched (Figure 3b), are also very similar

to those of TS34. These facts imply that there is little steric

interaction between the boryl group and the benzyl substituent

and that the exclusive formation of proximal-10Be is dominated

by the electrostatic interactions between the two reactants and

also by the benzyne distortion, both of which are caused by the

boryl group.¹⁵

The transition states (TS1−TS4) of the reactions between

benzyl azide 6e and two benzynes (3-borylbenzyne 4B and 3-

silylbenzyne 5B) were obtained as typical cases (Table 5,

entries 1 and 2). TS2, which leads to proximal-10Be, has an

energy 2.58 kcal/mol lower than that of TS1, which leads to

distal-10Be. This energy diﬀerence corresponds to 1:>50

proximal selectivity, which is in good agreement with our

experimental result (distal-10Be:proximal-10Be = 1:>50; Table

3, entry 4 and Table 5, entry 1). On the other hand, TS3, which

leads to distal-11Be, has an energy 1.1 kcal/mol lower than that

of TS4, which leads to proximal-11Be. This diﬀerence

corresponds to 6.5:1 distal selectivity, which is in reasonable

agreement with our experimental result (distal-11Be:proximal-

11Be = 3.3:1; Table 3, entry 4 and Table 5, entry 2).³⁰

We also performed similar calculations for thirteen other

reactions between 4B (or 5B) and various 1,3-dipolar

compounds 6. All of these results are in good agreement

with the experimental data (Table 5, entries 4−16). These facts

suggest that the calculated transition states are reliable and that

their structures can provide valuable information that can be

used to identify the origin of the regioselectivities.³⁰

In the case of silylbenzyne 5B, the distance between the

internal nitrogen and the benzyne C2 is much longer in TS4

(2.51 Å) than in TS34 (2.41 Å) because of the strong steric

interaction between the trimethylsilyl group and the benzyl

group. This makes the electrostatically and distortionally

F

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Figure 3. Transition states of (3 + 2) cycloaddition reactions of benzynes with 1,3-dipoles.^15,32(a) Transition states of the reactions between

benzyne 24A and 6e (TS33) and between 5-methylbenzyne 24B and 6e (TS34). (b) Most probable transition states (TS1 and TS2) of the reaction

between 3-boryl-5-methylbenzyne 4B and benzyl azide 6e giving distal-10Be and proximal-10Be, respectively. (c) Most probable transition states

(TS3 and TS4) of the reaction between 5-methyl-3-(trimethylsilyl)benzyne 5B and 6e giving distal-11Be and proximal-11Be, respectively. (d) Most

probable transition states (TS5 and TS6) of the reaction between 5-methyl-3-silylbenzyne 5B′′ and 6e.

favorable TS4 less stable than the unfavorable TS3 (Figure 3c)

and results in the preferential formation of distal-11Be. We also

analyzed two transition states (TS5 and TS6) derived from a

virtual benzyne 5B′′ possessing a SiH₃group (Figure 3d). The

distance between the internal nitrogen and the benzyne C2 of

TS6 (2.41 Å) is shorter than that of TS4 (2.51 Å) but similar to

that of TS34 (2.41 Å). Although the benzyne distortion of 5B′′

is quite similar to that of 5B (Table 4), the energy diﬀerence

between TS5 and TS6 is smaller than that between TS3 and

TS4 (Figure 3c and d). These results also prove that the steric

bulkiness of the silyl groups has a signiﬁcant adverse inﬂuence

on the electrostatically favorable proximal transition state. This

steric inﬂuence even overrides the attractive electrostatic

interaction and the benzyne distortion.^15,31

electrostatically controlled, while that of silylbenzynes 5 is more

sterically dominated. Because the boryl and silyl groups of the

cycloaddition products can be converted into carbon, nitrogen,

and oxygen substituents as well as a hydrogen atom,³³the use

of 3-boryl- and 3-silylbenzynes would be the ideal solution to

the longstanding problem of the regioselectivity of substituted

benzynes. Application of this chemistry to the preparation of a

wide range of biologically interesting compounds and further

improvement of the selectivity are in progress in our laboratory.

EXPERIMENTAL SECTION

■

General. All reactions were carried out under an argon or nitrogen

atmosphere in an oven-dried ﬂask containing a stir-bar with a rubber

septum or an inlet adapter with a three-way stopcock. 1-Azido-4-

methoxybenzene 6a,³⁴1-azido-4-(tert-butyl)benzene 6b,³⁵2-azido-1,4-

dimethoxybenzene 6c,^10c2-azido-1,3-dibromobenzene 6d,³⁶1-azido-

decane 6f,³⁷ethyl 2-azidoacetate 6g,^10c(azidomethylene)dibenzene

6h,³⁸(E)-(3-azidoprop-1-en-1-yl)benzene 6i,^10c(1R,3R,5S)-1-azidoa-

damantane 6j,^10c1-(azidomethyl)-2-iodobenzene 6k,^10cmethyl 2-

(azidomethyl)benzoate 6l,³⁹2-(azidomethyl)benzonitrile 6m,⁴⁰

(diazomethylene)dibenzene 6q,⁴¹N-hydroxybenzimidoyl chloride

(for the in situ preparation of benzonitrile N-oxide 6s),⁴²5-

(azidomethyl)-6-iodobenzo[d]1,3-dioxole 6t,⁴³2-iodo-6-(4,4,5,5-tetra-

methyl-1,3-dioxolan-2-yl)phenyl triﬂuoromethanesulfonate 12A,^14b2-

iodo-4-methyl-6-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl triﬂuor-

omethanesulfonate 12B,^14b2,6-bis(trimethylsilyl)phenyl triﬂuorome-

thanesulfonate 16A,^14c4-methyl-2,6-bis(trimethylsilyl)phenyl triﬂuor-

omethanesulfonate 16B,^14c4-ﬂuoro-2,6-bis(trimethylsilyl)phenyl tri-

ﬂuoromethanesulfonate 16C, ^{1 4 c}and 4-chloro-2, 6-

bis(trimethylsilyl)phenyl triﬂuoromethanesulfonate 16D^14cwere

synthesized according to the literature. Flash chromatography⁴⁴was

CONCLUSIONS

■

In conclusion, we have achieved complementary regiocontrol of

the (3 + 2) cycloaddition reaction of benzynes with 1,3-dipoles

by the unique substituent eﬀects of the boryl and silyl groups.

Both regioisomers of benzo-fused azoles such as benzotriazole,

1H-indazole, and benzo[d]isoxazole can be prepared by

choosing a boryl or silyl group as the benzyne substituent. In

particular, the ﬁnding of an improved generation method of 3-

borylbenzynes 4 from new precursors 14 was one of the most

important new results of this work and led to the successful (3

+ 2) cycloaddition reactions to demonstrate the ﬁrst proximal-

selective examples of the cycloaddition reaction of 3-substituted

benzynes with 1,3-dipoles. We have clearly and quantitatively

explained the regioselectivities of these reactions by analyzing

the transition state structures obtained by DFT calculations.

Namely, the (3 + 2) cycloaddition of borylbenzynes 4 is more

1

performed with silica gel 60 N, spherical neutral (40−50 μm). H

NMR and ¹³C NMR spectra were recorded on an instrument (¹H, 500

MHz; ¹³C, 125 MHz) with chemical shifts reported in ppm relative to

G

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the residual deuterated solvent or the internal standard tetramethylsi-

lane. The high-resolution mass spectra were recorded on an ESI or

APCI TOF mass spectrometer. Yield refers to isolated yields of

compounds greater than 95% purity as determined by ¹H NMR

analysis. ¹H NMR and melting points (where applicable) of all known

compounds were taken from references. The regioselectivities were

determined by 500 MHz ¹H NMR spectra of crude reaction mixtures.

Each regiochemistry of representative cycloaddition products (prox-

imal-10Bb, proximal-10Be, proximal-10Bf, proximal-10Bg, proximal-

10Bh, proximal-10 Bi, proximal-10Bj, proximal-10Bn, distal-10Br,

distal-11Bc, distal-11Be, distal-11Bf, distal-11Bh, proximal-11Bh,

distal-11Bj, distal-11Bn, distal-11Bp, and distal-11Bs) was conﬁrmed

by NOESY experiment. The regiochemistries of all other cycloaddition

Table 2, entry 3 and Table 3, entry 1. Following the general

procedure I, a mixture of 14B (21 mg, 34 μmol), 1-azido-4-(tert-

butyl)benzene 6b³⁵(20 mg, 113 μmol), and i-PrMgCl·LiCl (1.3 M in

THF, 40 μL, 52 μmol) in Et₂O (0.40 mL, 0.10 M) was stirred for 30

min at 0 °C. The crude product was puriﬁed by column

chromatography (hexane/EtOAc = 10:1) to provide the titled

compound proximal-10Bb (8.9 mg, 67%) as a colorless solid, the

regiochemistry of which was determined by NOESY spectrum. Mp

160−165 °C. ¹H NMR (500 MHz, CDCl₃) δ: 1.05 (12 H, s), 1.38 (9

H, s), 2.53 (3 H, s), 7.42 (2 H, d, J = 8.5 Hz), 7.53 (2 H, d, J = 8.5

Hz), 7.72 (1 H, d, J = 1.0 Hz), 7.95 (1 H, d, J = 1.0 Hz). ¹³C NMR

(125 MHz, CDCl₃) δ: 21.1, 24.5, 31.3, 31.3, 34.8, 83.8, 121.6, 125.9,

126.0, 133.4, 134.9, 135.8, 137.9, 146.1, 152.2. IR (CHCl₃): 2968

cm⁻¹. HRMS calcd for C₂₃H₃₁BN₃O₂(M + H)⁺m/z: 392.2509, found

392.2507.

1

products were predicted by the similarity of H NMR data.

General Procedure I: Proximal-Selective (3 + 2) Cyclo-

additions of Borylbenzynes 4 (Tables 1−3). An oven-dried ﬂask

was charged with a borylbenzyne precursor 12^14b−14 (1.0 equiv) and

a dipole 6 (3.0 equiv), capped with a rubber septum, then evacuated,

and backﬁlled with argon. Anhydrous Et₂O (0.10 M) was added, and

the mixture was cooled to −78 °C. Then, a 1.0 or 1.3 M solution of i-

PrMgCl·LiCl in THF (1.2 equiv) was slowly added to the reaction

mixture over 5 min. After stirring at −78 °C for 30 min, the reaction

mixture was warmed to 0 °C, stirred for an additional 30 min, and

quenched with a saturated aqueous NH₄Cl solution. Then the reaction

mixture was extracted with EtOAc, and the aqueous layer was

extracted twice with EtOAc. The combined organic layers were

washed with a saturated aqueous NaCl solution and dried over

anhydrous Na₂SO₄. The solution was ﬁltered through a glass ﬁlter and

concentrated under reduced pressure. The crude product was puriﬁed

by silica gel ﬂash column chromatography to give boryl benzazole 10.

1-(4-Methoxyphenyl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxabor-

olan-2-yl)-1H-benzo[d]triazole (proximal-10Aa) (Table 1, entry

4). Following the general procedure I, a mixture of 14A^14b(61 mg,

103 μmol), 1-azido-4-methoxybenzene 6a³⁴(46 mg, 0.31 mmol), and

i-PrMgCl·LiCl (1.0 M in THF, 0.12 mL, 0.12 mmol) in Et₂O (1.1 mL,

0.10 M) was stirred for 30 min at 0 °C. The crude product was

puriﬁed by column chromatography (hexane/EtOAc = 3:1) to provide

the titled compound proximal-10Aa (17 mg, 46%) as a colorless solid.

Mp 142−145 °C. ¹H NMR (500 MHz, CDCl₃) δ: 1.08 (12 H, s), 3.89

(3 H, s), 7.03 (2 H, td, J = 3.0, 9.0 Hz), 7.40 (1 H, dd, J = 7.0, 8.0 Hz),

7.41 (2 H, td, J = 3.0, 9.0 Hz), 7.92 (1 H, dd, J = 1.0, 7.0 Hz), 8.20 (1

H, dd, J = 1.0, 8.0 Hz). ¹³C NMR (125 MHz, CDCl₃) δ: 24.5, 55.6,

83.8, 114.1, 122.7, 123.5, 128.1, 131.3, 136.3, 136.8, 145.3, 160.4. IR

(CHCl₃): 1518 cm⁻¹. HRMS calcd for C₁₉H₂₂BN₃NaO₃(M + Na)⁺

m/z: 374.1652, found 374.1661.

1-(2,5-Dimethoxyphenyl)-5-methyl-7-(4,4,5,5-tetramethyl-

1,3,2-dioxaborolan-2-yl)-1H-benzo[d]triazole (proximal-10Bc)

(Table 3, entry 2). Following the general procedure I, a mixture of

14B (31 mg, 52 μmol), 2-azido-1,4-dimethoxybenzene 6c^10c(50 μL,

166 μmol), and i-PrMgCl·LiCl (1.3 M in THF, 50 μL, 65 μmol) in

Et₂O (0.50 mL, 0.10 M) was stirred for 30 min at 0 °C. The crude

product was puriﬁed by column chromatography (hexane/EtOAc =

10:1) to provide the titled compound proximal-10Bc (13 mg, 65%) as

1

a colorless solid. Mp 116−120 °C. H NMR (500 MHz, CDCl₃) δ:

1.07 (12 H, s), 2.52 (3 H, s), 3.58 (3 H, s), 3.79 (3 H, s), 6.93 (1 H,

dd, J = 1.0, 9.5 Hz), 7.03−7.06 (2 H, m), 7.76 (1 H, d, J = 1.0 Hz),

7.95 (1 H, brs). ¹³C NMR (125 MHz, CDCl₃) δ: 20.6, 24.8, 24.8, 37.3,

83.6, 88.9, 92.5, 114.6, 123.1, 123.7, 128.0, 128.3, 131.4, 134.6, 135.4,

1367.0, 138.4, 145.4. IR (CHCl₃): 1514 cm⁻¹. HRMS calcd for

C₂₁H₂₇BN₃O₄(M + H)⁺m/z: 396.2095, found 396.2086.

1-Benzyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-

1H-benzo[d]triazole (proximal-10Ae) (Table 3, entry 3).

Following the general procedure I, a mixture of 14A (64 mg, 0.11

mmol), (azidomethyl)benzene 6e (41 μL, 0.32 mmol), and i-

PrMgCl·LiCl (1.3 M in THF, 0.10 mL, 0.13 mmol) in Et₂O (1.1

mL) was stirred for 30 min at 0 °C. The crude product was puriﬁed by

column chromatography (hexane/EtOAc = 10:1) to provide the titled

compound proximal-10Ae (32 mg, 89%) as a colorless solid. Mp 89−

92 °C. ¹H NMR (500 MHz, CDCl₃) δ: 1.25 (12 H, s), 6.40 (2 H, s),

7.01 (2 H, d, J = 7.0 Hz), 7.20−7.25 (3 H, m), 7.38 (1 H, dd, J = 7.5

Hz, 8.0 Hz), 8.04 (1 H, dd, J = 1.0 Hz, 7.5 Hz), 8.21 (1 H, dd, J = 1.0

Hz, 8.0 Hz). ¹³C NMR (125 MHz, CDCl₃) δ: 24.6, 52.3, 84.4, 123.3,

123.5, 126.2, 127.3, 128.4, 135.8, 137.1, 137.3, 145.9. IR (CHCl₃):

3010 cm⁻¹. HRMS calcd for C₁₉H₂₃BN₃O₂(M + H)⁺m/z: 336.1883,

found 336.1863.

1-Benzyl-5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-

lan-2-yl)-1H-benzo[d]triazole (proximal-10Be) (Table 3, entry

4). Following the general procedure I, a mixture of 14B (61 mg, 101

μmol), (azidomethyl)benzene 6e (40 μL, 0.30 mmol), and i-

PrMgCl·LiCl (1.3 M in THF, 90 μL, 117 μmol) in Et₂O (1.0 mL,

0.10 M) was stirred for 30 min at 0 °C. The crude product was

puriﬁed by column chromatography (hexane/EtOAc = 4:1) to provide

the titled compound proximal-10Be (30 mg, 85%) as a colorless solid,

the regiochemistry of which was determined by NOESY spectrum. Mp

116−118 °C. ¹H NMR (500 MHz, CDCl₃) δ: 1.24 (12 H, s), 2.51 (3

H, s), 6.36 (2 H, s), 6.99 (2 H, d, J = 7.0 Hz), 7.17−7.24 (3 H, m),

7.86 (1 H, d, J = 1.0 Hz), 7.96 (1 H, brs). ¹³C NMR (125 MHz,

CDCl₃) δ: 21.1, 24.7, 52.3, 84.4, 122.5, 126.2, 127.2, 128.4, 133.2,

134.4, 137.2, 139.3, 146.7. IR (CHCl₃): 2982 cm⁻¹. HRMS calcd for

C₂₀H₂₅BN₃O₂(M + H)⁺m/z: 350.2040, found 350.2037.

1-[4-(tert-Butyl)phenyl]-5-methyl-7-(4,4,5,5-tetramethyl-

1,3,2-dioxaborolan-2-yl)-1H-benzo[d]triazole (proximal-10Bb)

(Table 2, entry 1). An oven-dried pear-shaped ﬂask was charged

with 12B^14b(44 mg, 90 μmol), capped with an inlet adapter with a

three-way stopcock, then evacuated, and backﬁlled with argon.

Anhydrous Et₂O (0.90 mL, 0.10 M) and 1-azido-4-(tert-butyl)benzene

6b³¹(62 mg, 0.35 mmol) were added via a syringe, and the mixture

was cooled to −78 °C. i-PrMgCl·LiCl (1.3 M in THF, 0.080 mL, 104

μmol) was slowly added into the reaction mixture over 5 min. After

being stirred at −78 °C for 30 min, the reaction mixture was quenched

with a saturated aqueous NH₄Cl solution. The mixture was extracted

with EtOAc, and the aqueous layer was extracted twice with EtOAc.

The combined organic layers were washed with a saturated aqueous

NaCl solution and dried over anhydrous Na₂SO₄. The solution was

ﬁltered through a glass ﬁlter and concentrated under reduced pressure.

1-Decyl-5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-

lan-2-yl)-1H-benzo[d]triazole (proximal-10Bf) (Table 3, entry

5). Following the general procedure I, a mixture of 14B (56 mg, 93

μmol), 1-azidodecane 6f³⁵(60 mg, 0.33 mmol), and i-PrMgCl·LiCl

(1.3 M in THF, 85 μL, 111 μmol) in Et₂O (0.90 mL, 0.10 M) was

stirred for 30 min at 0 °C. The crude product was puriﬁed by column

chromatography (hexane/EtOAc = 4:1) to provide the titled

compound proximal-10Bf (32 mg, 87%) as a colorless solid, the

regiochemistry of which was determined by NOESY spectrum. Mp

70−72 °C. ¹H NMR (500 MHz, CDCl₃) δ: 0.86 (3 H, t, J = 7.5 Hz),

1

The product yield and ratio were determined by H NMR [proximal-

10Bb (15%), 15⁴⁵(29%), 12B^14b(26%), 1,4-dimethoxybenzene was

used as an internal standard].

Table 2, entry 2. Following the general procedure I, a mixture of

13B (25 mg, 48 μmol), 1-azido-4-(tert-butyl)benzene 6b³⁵(23 mg,

131 μmol), and i-PrMgCl·LiCl (1.3 M in THF, 60 μL, 78 μmol) in

Et₂O (0.50 mL, 0.10 M) was stirred for 30 min at 0 °C. The product

1

yield and ratio were determined by H NMR [proximal-10Bb (48%),

1,4-dimethoxybenzene was used as an internal standard].

H

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1.23−1.37 (14 H, m), 1.40 (12 H, s), 1.87 (2 H, q, J = 7.0 Hz), 2.50 (3

H, s), 5.00 (2 H, t, J = 7.0 Hz), 7.85 (1 H, d, J = 1.5 Hz), 7.90 (1 H,

brs). ¹³C NMR (125 MHz, CDCl₃) δ: 14.1, 21.1, 22.6, 24.9, 26.6, 29.2,

29.3, 29.48, 29.50, 30.9, 31.8, 49.6, 84.3, 122.4, 132.9, 133.9, 139.0,

146.6. IR (CHCl₃): 2927 cm⁻¹. HRMS calcd for C₂₃H₃₉BN₃O₂(M +

H)⁺m/z: 400.3135, found 400.3156.

0.12 mmol) was slowly added to the reaction mixture over 5 min. After

stirring at −78 °C for 30 min, the reaction mixture was quenched with

a saturated aqueous NH₄Cl solution. The reaction mixture was

extracted with EtOAc, and the aqueous layer was extracted twice with

EtOAc. The combined organic layers were washed with a saturated

aqueous NaCl solution and dried over anhydrous Na₂SO₄. The

solution was ﬁltered through a glass ﬁlter and concentrated under

reduced pressure. The crude product was puriﬁed by column

chromatography (hexane/EtOAc = 2:1) to provide the titled

compound proximal-10Bn (12 mg, 54%) as a colorless solid, the

regiochemistry of which was determined by NOESY spectrum. Mp

155−157 °C. ¹H NMR (500 MHz, CDCl₃) δ: 1.40 (12 H, s), 2.48 (3

H, s), 7.37 (1 H, s), 7.52 (1 H, s), 8.42 (1 H, s). ¹³C NMR (125 MHz,

CDCl₃) δ: 21.7, 24.9, 83.9, 112.1, 131.2, 136.3, 136.5, 139.9. IR

(CHCl₃): 3472 cm⁻¹. HRMS calcd for C₁₄H₂₀BN₂O₂(M + H)⁺m/z:

259.1618, found 259.1631.

Ethyl 2-(5-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-

lan-2-yl)-1H-benzo[d]triazol-1-yl)acetate (proximal-10Bg)

(Table 3, entry 6). Following the general procedure I, a mixture of

14B (57 mg, 95 μmol), ethyl 2-azidoacetate 6g^10c(35 μL, 0.30 mmol),

and i-PrMgCl·LiCl (1.3 M in THF, 90 μL, 117 μmol) in Et₂O (1.0

mL, 0.10 M) was stirred for 30 min at 0 °C. The crude product was

puriﬁed by column chromatography (hexane/EtOAc = 3:1) to provide

the titled compound proximal-10Bg (24 mg, 74%) as a colorless solid,

the regiochemistry of which was determined by NOESY spectrum. Mp

1

141−144 °C. H NMR (500 MHz, CDCl₃) δ: 1.21 (3 H, t, J = 7.5

Hz), 1.35 (12 H, s), 2.50 (3 H, s), 4.17 (2 H, q, J = 7.5 Hz), 5.83 (2 H,

s), 7.88 (1 H, d, J = 1.5 Hz), 7.93 (1 H, brs). ¹³C NMR (125 MHz,

CDCl₃) δ: 14.0, 21.1, 24.7, 51.3, 61.5, 84.4, 122.6, 133.2, 134.8, 139.4,

146.6, 167.7. IR (CHCl₃): 1755 cm⁻¹. HRMS calcd for C₁₇H₂₅BN₃O₄

(M + H)⁺m/z: 346.1938, found 346.1933.

2-tert-Butyl-5-methyl-3-phenyl-7-(4,4,5,5-tetramethyl-1,3,2-

dioxaborolan-2-yl)-2,3-dihydrobenzo[d]isoxazole (distal-10Br)

(Table 3, entry 10). An oven-dried ﬂask was charged with 12B^14b(56

mg, 0.11 mmol). The ﬂask was capped with a rubber septum, then

evacuated, and backﬁlled with argon. Anhydrous Et₂O (1.2 mL) and

N-tert-butyl-α-phenylnitrone 6r (61 mg, 0.35 mmol) were added, and

the mixture was cooled to −78 °C. A solution of i-PrMgCl·LiCl (1.3

M in THF, 0.18 mL, 0.23 mmol) was slowly added to the reaction

mixture over 5 min. After stirring at −78 °C for 30 min, the reaction

mixture was quenched with a saturated aqueous NH₄Cl solution. The

reaction mixture was extracted with EtOAc, and the aqueous layer was

extracted twice with EtOAc. The combined organic layers were

washed with a saturated aqueous NaCl solution and dried over

anhydrous Na₂SO₄. The solution was ﬁltered through a glass ﬁlter and

concentrated under reduced pressure. The crude product was puriﬁed

by column chromatography (hexane/EtOAc = 11:1) to provide the

titled compound distal-10Br (29 mg, 64%) as a colorless solid, the

regiochemistry of which was determined by NOESY spectrum. Mp

1-Benzhydryl-5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxa-

borolan-2-yl)-1H-benzo[d]triazole (proximal-10Bh) (Table 3,

entry 7). Following the general procedure I, a mixture of 14B (72

mg, 119 μmol), (azidomethylene)dibenzene 6h³⁹(75 mg, 0.36 mmol),

and i-PrMgCl·LiCl (1.3 M in THF, 0.11 mL, 143 μmol) in Et₂O (1.2

mL, 0.10 M) was stirred for 30 min at 0 °C. The crude product was

puriﬁed by column chromatography (hexane/EtOAc = 5:1) to provide

the titled compound proximal-10Bh (33 mg, 65%) as a colorless solid,

the regiochemistry of which was determined by NOESY spectrum. Mp

130−133 °C. ¹H NMR (500 MHz, CDCl₃) δ: 1.37 (12 H, s), 2.51 (3

H, s), 7.26−7.33 (10 H, m) 7.91 (1 H, d, J = 1.5 Hz), 7.97 (1 H, s),

8.47 (1 H, s). ¹³C NMR (125 MHz, CDCl₃) δ: 21.1, 24.8, 64.9, 84.5,

122.6, 127.6, 128.3, 128.6, 133.1, 135.0, 139.5, 140.0, 146.0. IR

(CHCl₃): 2981 cm⁻¹. HRMS calcd for C₂₆H₂₉BN₃O₂(M + H)⁺m/z:

426.2353, found 426.2347.

1

104−107 °C. H NMR (500 MHz, CDCl₃) δ: 1.07 (6 H, s), 1.13 (6

1-(Adamantan-1-yl)-5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-

dioxaborolan-2-yl)-1H-benzo[d]triazole (proximal-10Bj) (Table

3, entry 8). Following the general procedure I, a mixture of 14B (61

mg, 101 μmol), 1-azidoadamantane 6j^10c(54 mg, 0.30 mmol), and i-

PrMgCl·LiCl (1.3 M in THF, 95 μL, 124 μmol) in Et₂O (1.0 mL, 0.10

M) was stirred for 30 min at 0 °C. The crude product was puriﬁed by

column chromatography (hexane/EtOAc = 5:1) to provide the titled

compound proximal-10Bj (14 mg, 34%) as a colorless solid, the

regiochemistry of which was determined by NOESY spectrum. Mp

H, s), 1.19 (9 H, s), 2.34 (3 H, s), 5.78 (1 H, s), 6.78 (1 H, s), 7.12−

7.13 (4 H, m), 7.19 (2 H, d, J = 7.5 Hz). ¹³C NMR (125 MHz,

CDCl₃) δ: 21.3, 24.5, 24.6, 25.5, 61.3, 66.8, 83.6, 109.8, 126.8, 128.0,

128.27, 128.34, 132.4, 138.3, 144.6, 157.6. IR (CHCl₃): 1582 cm⁻¹.

HRMS calcd for C₂₄H₃₃BNO₃(M + H)⁺m/z: 394.2553, found

394.2546.

1-(2,6-Dibromophenyl)-5-methyl-7-(4,4,5,5-tetramethyl-

1,3,2-dioxaborolan-2-yl)-1H-benzo[d]triazole (proximal-10Bd)

(Table 3, entry 11). Following the general procedure I, a mixture

of 14B (50 mg, 0.080 mmol), 2-azido-1,3-dibromobenzene 6d³⁹(69

mg, 0.25 mmol), and i-PrMgCl·LiCl (1.3 M in THF, 0.080 mL, 0.11

mmol) in Et₂O (0.80 mL) was stirred for 30 min at 0 °C. The crude

product was puriﬁed by column chromatography (hexane/EtOAc =

4:1) to provide the titled compound proximal-10Bd (28 mg, 67%) as a

colorless solid. Mp 181−184 °C. ¹H NMR (500 MHz, CDCl₃) δ: 1.07

(12 H, s), 2.55 (3 H, s), 7.30 (1 H, t, J = 8.0 Hz), 7.68 (2 H, d, J = 8.0

Hz), 7.92 (1 H, d, J = 1.0 Hz), 8.04 (1 H, brs). ¹³C NMR (125 MHz,

CDCl₃) δ: 21.1, 24.4, 83.5, 122.7, 125.2, 131.6, 131.7, 133.7, 134.8,

137.9, 139.7, 145.9. IR (CHCl₃): 1478 cm⁻¹. HRMS calcd for

C₁₉H₂₀BN₃⁷⁹Br⁸¹BrNaO₂(M + Na)⁺m/z: 515.9893, found 515.9882.

1-Cinnamyl-5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxabor-

olan-2-yl)-1H-benzo[d]triazole (proximal-10Bi) (Table 3, entry

12). Following the general procedure I, a mixture of 14B (55 mg, 90

μmol), (E)-(3-azidoprop-1-en-1-yl)benzene 6i^10c(43 mg, 0.27 mmol),

and i-PrMgCl·LiCl (1.3 M in THF, 0.090 mL, 110 μmol) in Et₂O

(0.90 mL, 0.10 M) was stirred for 30 min at 0 °C. The crude product

was puriﬁed by column chromatography (hexane/EtOAc = 40:9) to

provide the titled compound proximal-10Bi (27 mg, 80%) as a

colorless solid, the regiochemistry of which was determined by

NOESY spectrum. Mp 134−136 °C. ¹H NMR (500 MHz, CDCl₃) δ:

1.40 (12 H, s), 2.52 (3 H, s), 5.86 (2 H, dd, J = 1.0, 6.0 Hz), 6.35 (1 H,

d, J = 16 Hz), 6.43 (1 H, dt, J = 6.5, 16 Hz), 7.18−7.27 (5 H, m), 7.88

(1 H, d, J = 1.5 Hz), 7.95 (1 H, brs). ¹³C NMR (125 MHz, CDCl₃) δ:

21.1, 24.9, 50.9, 84.4, 122.5, 124.6, 126.3, 127.7, 128.5, 132.0, 133.1,

1

239−241 °C. H NMR (500 MHz, CDCl₃) δ: 1.41 (12 H, s), 1.80−

1.95 (6 H, m), 2.29 (3 H, brs), 2.48 (3 H, s), 2.57 (6 H, brs), 7.55 (1

H, d, J = 1.0 Hz), 7.88(1 H, brs). ¹³C NMR (125 MHz, CDCl₃) δ:

21.0, 24.7, 29.8, 35.8, 41.6, 62.1, 84.5, 121.6, 131.4, 132.4, 136.0, 147.3.

IR (CHCl₃): 2914 cm⁻¹. HRMS calcd for C₂₃H₃₃BN₃O₂(M + H)⁺m/

z: 394.2660, found 394.2680.

1-(Adamantan-1-yl)-6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-

dioxaborolan-2-yl)-1H-benzo[d]triazole (distal-10Bj) (Table 3,

entry 8). This product, the regiochemistry of which was determined

by NOESY spectrum, was obtained by the column chromatography

(EtOAc) of the above-mentioned crude product and the following

treatment with pinacol in CH₂Cl₂to give a mixture of distal-10Bj

(34%), Et₂O, and pinacol (1:0.072:0.065) as a colorless solid. Mp

174−180 °C.¹H NMR (500 MHz, CDCl₃) δ: 1.42 (12 H, s), 1.84 (6

H, brs), 2.29 (3 H, brs), 2.46 (6 H, brs), 2.51 (3 H, s), 7.62 (1 H, s),

7.64 (1 H, s). ¹³C NMR (125 MHz, CDCl₃) δ: 21.8, 24.8, 29.5, 36.1,

42.1, 61.1, 84.1, 114.3, 131.4, 133.4, 135.4, 148.6. IR (CHCl₃): 2918

cm⁻¹. HRMS calcd for C₂₃H₃₂BN₃NaO₂(M + Na)⁺m/z: 416.2485,

found 416.2485.

6-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-

1H-indazole (proximal-10Bn) (Table 3, entry 9). An oven-dried

ﬂask was charged with 12B (43 mg, 88 μmol). The ﬂask was capped

with a rubber septum, then evacuated, and backﬁlled with argon.

Anhydrous Et₂O (0.90 mL) and (diazomethyl)trimethylsilane 6n (2.0

M in Et₂O 0.14 mL, 0.28 mmol) were added, and the mixture was

cooled to −78 °C. A solution of i-PrMgCl (2.0 M in THF, 0.060 mL,

I

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The Journal of Organic Chemistry

Article

134.0, 136.2, 139.2, 146.6. IR (CHCl₃): 3421 cm⁻¹. HRMS calcd for

C₂₂H₂₇BN₃O₂(M + H)⁺m/z: 376.2196, found 376.2193.

(1 H, dd, J = 7.0, 8.0 Hz), 7.65 (1 H, dd, J = 1.0, 8.0 Hz), 7.66 (2 H,

dd, J = 2.0, 8.5 Hz). ¹³C NMR (125 MHz, CDCl₃) δ: −0.77, 55.6,

110.7, 114.9, 124.5, 127.3, 129.6, 130.2, 131.4, 133.9, 150.2, 159.6. IR

(CHCl₃): 1520 cm⁻¹. HRMS calcd for C₁₆H₁₉N₃NaOSi (M + Na)⁺

m/z: 320.1195, found 320.1192.

1-(2-Iodobenzyl)-5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-di-

oxaborolan-2-yl)-1H-benzo[d]triazole (proximal-10Bk) (Table

3, entry 13). Following the general procedure I, a mixture of 14B (58

mg, 97 μmol), 1-(azidomethyl)-2-iodobenzene 6k^10c(76 mg, 0.29

mmol), and i-PrMgCl·LiCl (1.3 M in THF, 0.090 mL, 117 μmol) in

Et₂O (1.0 mL, 0.10 M) was stirred for 30 min at 0 °C. The crude

product was puriﬁed by column chromatography (hexane/EtOAc =

5:1) to provide the titled compound proximal-10Bk (33 mg, 71%) as a

colorless solid. Mp 185−187 °C. ¹H NMR (500 MHz, CDCl₃) δ: 1.13

(12 H, s), 2.54 (3 H, s), 5.93 (1 H, dd, J = 1.0, 7.5 Hz), 6.22 (2 H, s),

6.91 (1 H, dt, J = 1.0, 7.5 Hz), 7.05 (1 H, t, J = 7.5 Hz), 7.88 (1 H, d, J

= 7.5 Hz), 7.90 (1 H, d, J = 1.0 Hz), 8.0 (1 H, brs). ¹³C NMR (125

MHz, CDCl₃) δ: 21.1, 24.4, 58.4, 84.3, 95.9, 122.7, 125.7, 128.4, 128.6,

133.4, 134.8, 139.1, 139.7, 146.7. IR (CHCl₃): 2982 cm⁻¹. HRMS

calcd for C₂₀H₂₄BIN₃O₂(M + H)⁺m/z: 476.1006, found 476.1017.

Methyl 2-[(5-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-

lan-2-yl)-1H-benzo[d]triazol-1-yl)methyl]benzoate (proximal-

10Bl) (Table 3, entry 14). Following the general procedure I, a

mixture of 14B (57 mg, 95 μmol), ethyl methyl 2-(azidomethyl)-

benzoate 6l⁴⁰(56 mg, 0.29 mmol), and i-PrMgCl·LiCl (1.3 M in THF,

0.090 mL, 117 μmol) in Et₂O (1.0 mL, 0.10 M) was stirred for 30 min

at 0 °C. The crude product was puriﬁed by column chromatography

(hexane/EtOAc = 4:1) to provide the titled compound proximal-10Bl

1-(4-Methoxyphenyl)-7-(trimethylsilyl)-1H-benzo[d]triazole

(proximal-11Aa) (Table 1, entry 5). Product (7.9 mg, 10%) was

obtained by column chromatography of the above-mentioned crude

1

product as a colorless solid. Mp 106−109 °C. H NMR (500 MHz,

CDCl₃) δ: 0.02 (9 H, s), 3.92 (3 H, s), 7.08 (2 H, dd, J = 2.0, 7.0 Hz),

7.39 (1 H, dd, J = 7.0, 7.5 Hz), 7.44 (2 H, dd, J = 2.0, 7.0 Hz), 7.70 (1

H, d, J = 7.0 Hz), 8.14 (1 H, d, J = 7.0 Hz). ¹³C NMR (125 MHz,

CDCl₃) δ: 0.51, 55.7, 114.5, 121.3, 122.6, 123.6, 129.3, 130.9, 136.1,

138.3, 145.0, 160.9. IR (CHCl₃): 1518 cm⁻¹. HRMS calcd for

C₁₆H₁₉N₃NaOSi (M + Na)⁺m/z: 320.1195, found 320.1197.

1-(4-(tert-Butyl)phenyl)-6-methyl-4-(trimethylsilyl)-1H-

benzo[d]triazole (distal-11Bb) (Table 3, entry 1). Following the

general procedure II, a mixture of 16B^14a(70 mg, 0.20 mmol), 1-

azido-4-(tert-butyl)benzene 6b³⁵(105 mg, 0.60 mmol), and Bu₄NF

(1.0 M in THF, 0.40 mL, 0.40 mmol) in THF (2.0 mL) was stirred for

1.0 h. The ratio of distal- to proximal-11Bb (10:1) was determined

1

using H NMR spectra of the crude product. The crude product was

puriﬁed by column chromatography (hexane/EtOAc = 30:1) to

provide the titled compound distal-11Bb (42 mg, 61%) as a yellow

1

solid. Mp 92−94 °C. H NMR (500 MHz, CDCl₃) δ: 0.52 (9 H, s),

(29 mg, 74%) as a colorless solid. Mp 127−129 °C. H NMR (500

1.40 (9 H, s), 2.53 (3 H, s), 7.32 (1 H, s), 7.49 (1 H,s), 7.61 (2 H, d, J

= 8.0 Hz), 7.68 (2 H, d, J = 8.0 Hz). ¹³C NMR (125 MHz, CDCl₃) δ:

−0.7, 22.0, 31.3, 34.8, 110.2, 122.6, 126.6, 131.7, 131.9, 133.2, 134.7,

137.7, 149.0, 151.5. IR (CHCl₃): 2964, 1600, 1519, 1411 cm⁻¹. HRMS

calcd for C₂₀H₂₈N₃Si (M + H)⁺m/z: 338.2053, found 338.2055.

1-(4-(tert-Butyl)phenyl)-5-methyl-7-(trimethylsilyl)-1H-

benzo[d]triazole (proxiaml-11Bb) (Table 3, entry 1). Product (12

mg, 18%) was obtained by column chromatography of the above-

mentioned crude product as a colorless oil. ¹H NMR (500 MHz,

CDCl₃) δ: −0.02 (9 H, s), 1.40 (9 H, s), 2.53 (3 H, s), 7.43 (2 H, d, J

= 8.0 Hz), 7.51 (1 H, s), 7.58 (2 H, d, J = 8.0 Hz), 7.89 (1 H, s). ¹³C

NMR (125 MHz, CD₃OD) δ: 0.4, 21.4, 31.3, 34.9, 120.1, 122.2, 126.3,

127.4, 133.3, 135.5, 136.7, 138.4, 145.8, 153.7. IR (CHCl₃): 1602,

1514, 1261, 1236 cm⁻¹. HRMS calcd for C₂₀H₂₈N₃Si (M + H)⁺m/z:

338/.2053, found 338.2059.

MHz, CDCl₃) δ: 1.05 (12 H, s), 2.53 (3 H, s), 3.97 (3 H, s), 6.01 (1

H, d, J = 7.5 Hz), 6.73 (2 H, s), 7.21 (1 H, dt, J = 1.0, 7.5 Hz), 7.27 (1

H, dt, J = 1.0, 7.5 Hz), 7.86 (1 H, d, J = 1.0 Hz) 8.0 (1 H, brs) 8.11 (1

H, dd, J = 1.0, 7.5 Hz). ¹³C NMR (125 MHz, CDCl₃) δ: 21.1, 24.3,

52.0, 52.7, 84.1, 122.6, 125.4, 126.7, 126.8, 131.1, 132.9, 133.3, 134.9,

139.3, 140.5, 146.7, 167.1. IR (CHCl₃): 1717 cm⁻¹. HRMS calcd for

C₂₂H₂₇BN₃O₄(M + H)⁺m/z: 408.2095, found 408.2100.

2-[(5-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-

yl)-1H-benzo[d]triazol-1-yl)methyl]benzonitrile (proximal-

10Bm) (Table 3, entry 15). Following the general procedure I, a

mixture of 14B (62 mg, 102 μmol), 2-(azidomethyl)benzonitrile 6m⁴¹

(49 mg, 0.31 mmol), and i-PrMgCl·LiCl (1.3 M in THF, 0.10 mL, 124

μmol) in Et₂O (1.0 mL, 0.10 M) was stirred for 30 min at 0 °C. The

crude product was puriﬁed by column chromatography (hexane/

EtOAc = 3:1) to provide the titled compound proximal-10Bm (30 mg,

1

78%) as a colorless solid. Mp 174−176 °C. H NMR (500 MHz,

1-(2,5-Dimethoxyphenyl)-6-methyl-4-(trimethylsilyl)-1H-

benzo[d]triazole (distal-11Bc) (Table 3, entry 2). Following the

general procedure II, a mixture of 16B^14a(50 mg, 0.13 mmol), 2-

azido-1,4-dimethoxybenzene 6c^10c(69 mg, 0.39 mmol), and Bu₄NF

(1.0 M in THF, 0.26 mL, 0.26 mmol) in THF (1.3 mL) was stirred for

0.5 h. The ratio of distal- to proximal-11Bc (14:1) was determined

CDCl₃) δ: 1.16 (12 H, s), 2.54 (3 H, s), 6.19−6.22 (1 H, m), 6.58 (2

H, s), 7.30−7.34 (2 H, m), 7.71−7.74 (1 H, m), 7.92 (1 H, d, J = 1.5

Hz), 8.01 (1 H, brs). ¹³C NMR (125 MHz, CDCl₃) δ: 21.1, 24.4, 51.3,

84.4, 109.8, 117.1, 122.9, 125.5, 127.5, 132.7, 133.2, 133.7, 134.7,

140.0, 141.7, 146.7. IR (CHCl₃): 2226 cm⁻¹. HRMS calcd for

C₂₁H₂₄BN₄O₂(M + H)⁺m/z: 375.1992, found 375.1984.

1

using H NMR spectra of the crude product. The crude product was

General Procedure II: Distal-Selective (3 + 2) Cycloadditions

of Silylbenzynes 5 (Tables 1 and 3). An oven-dried ﬂask was

charged with a silylbenzyne precursor 16 (1.0 equiv), capped with a

rubber septum, and evacuated, and backﬁlled with argon. Anhydrous

THF (0.10 M) was added via a syringe, and the reaction mixture was

cooled to 0 °C. After 5 min, a dipole 6 (3.0 equiv) and Bu₄NF (1.0 M

THF solution, 2.0 equiv) were added in that order, and the reaction

mixture was stirred at 0 °C for 30 min. The mixture was ﬁltered

through a short pad of silica gel (hexane/EtOAc = 10:1 as the eluent).

The eﬄuent mixture was concentrated under reduced pressure and

further puriﬁed by silica gel ﬂash column chromatography to give silyl

benzazole 11.

1-(4-Methoxyphenyl)-4-(trimethylsilyl)-1H-benzo[d]triazole

(distal-11Aa) (Table 1, entry 5). Following the general procedure II,

a mixture of 16A¹⁷(100 mg, 0.27 mmol), 1-azido-4-methoxybenzene

6a³⁴(124 mg, 0.83 mmol), and Bu₄NF (1.0 M in THF, 0.54 mL, 0.54

mmol) in THF (2.7 mL, 0.10 M) was stirred for 30 min at 0 °C. The

ratio of distal- to proximal-11Aa (5.7:1) was determined using ¹H

NMR spectra of the crude product. The crude product was puriﬁed by

column chromatography (hexane/EtOAc = 10:1 to 5:1) to provide the

titled compound distal-11Aa (39 mg, 49%) as a colorless solid. Mp

97−100 °C. ¹H NMR (500 MHz, CDCl₃) δ: 0.53 (9 H, s), 3.90 (3 H,

s), 7.11 (2 H, dd, J = 2.0, 8.5 Hz), 7.47 (1 H, dd, J = 1.0, 7.0 Hz), 7.51

puriﬁed by column chromatography (hexane/EtOAc = 15:1) to

provide the titled compound distal-11Bc (30 mg, 68%) as a colorless

solid, the regiochemistry of which was determined by NOESY

1

spectrum. Mp 140−142 °C. H NMR (500 MHz, CDCl₃) δ: 0.52 (9

H, s), 2.50 (3 H, s), 3.74 (3 H, s), 3.81 (3 H, s), 7.04 (1 H, d, J = 2.0

Hz), 7.07 (1 H, dd, J = 2.0, 8.0 Hz), 7.09 (1 H, d, J = 8.0 Hz), 7.13 (1

H, brs), 7.30 (1 H, d, J = 2.0 Hz). ¹³C NMR (125 MHz, CDCl₃) δ:

−0.7, 22.0, 55.9, 56.5, 111.0, 113.4, 113.8, 116.2, 126.0, 131.65, 132.8,

133.3, 137.2, 147.7, 148.2, 153.8. IR (CHCl₃): 2959, 1595, 1514 cm⁻¹.

HRMS calcd for C₁₈H₂₄N₃O₂Si (M + H)⁺m/z: 342.1638, found

342.1622.

1-(2,5-Dimethoxyphenyl)-5-methyl-7-(trimethylsilyl)-1H-

benzo[d]triazole (proximal-11Bc) (Table 3, entry 2). Product (2.7

mg, 6.0%) was obtained by column chromatography of the above-

1

mentioned crude product as a colorless solid. Mp 99−100 °C. H

NMR (500 MHz, CDCl₃) δ: 0.01 (9 H, s), 2.53 (3 H, s), 3.64 (3 H, s),

3.81 (3 H, s), 6.99 (1 H, d, J = 8.0 Hz), 7.02 (1 H, d, J = 2.0 Hz), 7.11

(1 H, dd, J = 2.0, 8.0 Hz), 7.49 (1 H, s), 7.90 (1 H, s). ¹³C NMR (125

MHz, CD₃OD) δ: 1.2, 22.1, 57.2, 57.3, 115.2, 118.4, 119.3, 121.1,

124.6, 128.5, 136.1, 139.5, 140.4, 147.1, 152.6, 155.6. IR (CHCl₃):

2960, 1620, 1514 cm⁻¹. HRMS calcd for C₁₈H₂₄N₃O₂Si (M + H)⁺m/

z: 342.1638, found 342.1615.

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1-Benzyl-4-(trimethylsilyl)-1H-benzo[d]triazole (distal-11Ae)

(Table 3, entry 3). Following the general procedure II, a mixture of

16A^14a(50 mg, 0.14 mmol), (azidomethyl)benzene 6e (54 μL, 0.42

mmol), and Bu₄NF (1.0 M in THF, 0.28 mL, 0.28 mmol) in THF (1.4

mL) was stirred for 0.5 h. The ratio of distal- to proximal-11Ae (3.6:1)

21.4, 27.0, 52.4, 110.4, 118.6, 120.6, 126.1, 127.6, 128.7, 132.8, 136.6,

139.6, 146.0. IR (CHCl₃): 2929, 1606, 1566, 1497 cm⁻¹. HRMS calcd

for C₂₀H₂₈N₃Si (M + H)⁺m/z: 338.2053, found 338.2038.

1-Decyl-6-methyl-4-(trimethylsilyl)-1H-benzo[d]triazole (dis-

tal-11Bf) (Table 3, entry 5). Following the general procedure II, a

mixture of 16B^14a(50 mg, 0.13 mmol), 1-azidodecane 6f³⁵(71 mg,

0.39 mmol), and Bu₄NF (1.0 M in THF, 0.26 mL, 0.26 mmol) in THF

(1.3 mL) was stirred for 0.5 h. The ratio of distal- to proximal-11Bf

1

was determined using H NMR spectra of the crude product. The

crude product was puriﬁed by column chromatography (hexane/

EtOAc = 10:1) to provide the titled compound distal-11Ae (14.9 mg,

38%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ: 0.49 (9 H, s),

5.83 (2 H, s), 7.29−7.36 (7 H, m), 7.43 (1 H, dd, J = 2.0, 8.0 Hz). ¹³C

NMR (125 MHz, CDCl₃) δ: −0.8, 52.1, 110.2, 126.6, 127.6, 128.3,

128.9, 129.3, 131.5, 133.8, 134.9, 150.4. IR (CHCl₃): 1724, 1597, 1497

cm⁻¹. HRMS calcd for C₁₆H₂₀N₃Si (M + H)⁺m/z: 282.1427, found

282.1454.

1-Benzyl-7-(trimethylsilyl)-1H-benzo[d]triazole (proximal-

11Ae) (Table 3, entry 3). Product (5.3 mg, 14%) was obtained by

column chromatography of the above-mentioned crude product as a

colorless oil. ¹H NMR (500 MHz, CDCl₃) δ: 0.35 (9 H, s), 6.05 (2 H,

s), 6.89 (2 H, d, J = 8.0 Hz), 7.27−7.30 (3 H, m), 7.38 (1 H, t, J = 8.0

Hz), 7.68 (1 H, d, J = 8.0 Hz), 8.15 (1 H, dd, J = 2.0, 8.0 Hz). ¹³C

NMR (125 MHz, CD₃OD) δ: 1.5, 50.1, 122.6, 124.3, 126.2, 127.9,

129.7, 130.7, 137.8, 138.8, 139.6, 146.8. IR (CHCl₃): 2396, 1778,

1620, 1527, 1497 cm⁻¹. HRMS calcd for C₁₆H₂₀N₃Si (M + H)⁺m/z:

282.1427, found 282.1446.

1

(4.0:1) was determined using H NMR spectra of the crude product.

The crude product was puriﬁed by column chromatography (hexane/

EtOAc = 20:1) to provide the titled compound distal-11Bf (24 mg,

53%) as a colorless solid, the regiochemistry of which was determined

1

by NOESY spectrum. Mp 58−59 °C. H NMR (500 MHz, CD₃OD)

δ: 0.44 (9 H, s), 0.88 (3 H, t, J = 7.5 Hz), 1.24−1.33 (14 H, m), 1.98

(2 H, quint, J = 7.5 Hz), 2.54 (3 H, s), 4.65 (2 H, t, J = 7.5 Hz), 7.33

(1 H, d, J = 2.0 Hz), 7.51 (1 H, d, J = 2.0 Hz). ¹³C NMR (125 MHz,

CD₃OD) δ: −0.8, 14.1, 22.0, 22.6, 26.8, 29.1, 29.2, 29.3, 29.5, 29.7,

31.8, 47.9, 109.1, 131.5, 132.2, 133.0, 136.6, 148.6. IR (CHCl₃): 2928,

2857, 2099, 1605, 1466 cm⁻¹. HRMS calcd for C₂₀H₃₆N₃Si (M + H)⁺

m/z: 346.2679, found 346.2684.

1-Decyl-5-methyl-7-(trimethylsilyl)-1H-benzo[d]triazole

(proximal-11Bf) (Table 3, entry 5). Product (9.0 mg, 20%) was

obtained by column chromatography of the above-mentioned crude

product as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 0.46 (9 H, s),

0.87 (3 H, t, J = 7.5 Hz), 1.25−1.43 (14 H, m), 2.06 (2 H, quint, J =

7.5 Hz), 2.49 (3 H, s), 4.65 (2 H, t, J = 7.5 Hz), 7.43 (1 H, d, J = 2.0

Hz), 7.82 (1 H, brs). ¹³C NMR (125 MHz, CD₃OD) δ: 0.8, 14.1, 21.3,

22.7, 26.8, 29.3, 29.4, 29.5, 30.8, 31.6, 31.8, 49.6, 120.3, 121.0, 132.8,

135.4, 137.0, 145.7. IR (CHCl₃): 2928, 2857, 1717, 1601, 1466 cm⁻¹.

HRMS calcd for C₂₀H₃₆N₃Si (M + H)⁺m/z: 346.2679, found

346.2649.

1-Benzyl-6-methyl-4-(trimethylsilyl)-1H-benzo[d]triazole

(distal-11Be) (Table 3, entry 4). Following the general procedure II,

a mixture of 16B^14a(50 mg, 0.13 mmol), (azidomethyl)benzene 6e

(50 μL, 0.39 mmol), and Bu₄NF (1.0 M in THF, 0.26 mL, 0.26 mmol)

in THF (1.3 mL) was stirred for 0.5 h. The ratio of distal- to proximal-

1

11Be (3.3:1) was determined using H NMR spectra of the crude

product. The crude product was puriﬁed by column chromatography

(hexane/EtOAc = 10:1) to provide the titled compound distal-11Be

(22 mg, 57%) as a colorless oil, the regiochemistry of which was

Ethyl 2-(6-Methyl-4-(trimethylsilyl)-1H-benzo[d]triazol-1-yl)-

acetate (distal-11Bg) (Table 3, entry 6). Following the general

procedure II, a mixture of 16B^14a(50 mg, 0.13 mmol), ethyl 2-

azidoacetate 6g^10c(50 mg, 0.39 mmol) and Bu₄NF (1.0 M in THF,

0.26 mL, 0.26 mmol) in THF (1.3 mL) was stirred for 0.5 h. The ratio

1

determined by NOESY spectrum. H NMR (500 MHz, CDCl₃) δ:

0.64 (9 H, s), 2.60 (3 H, s), 5.92 (2 H, s), 7.40−7.49 (7 H, m). ¹³C

NMR (125 MHz, CDCl₃) δ: −0.8, 21.9, 51.8, 109.3, 127.4, 128.1,

128.8, 131.6, 132.0, 133.0, 135.1, 136.9, 148.9. IR (CHCl₃): 2277,

1605 cm⁻¹. HRMS calcd for C₁₇H₂₂N₃Si (M + H)⁺m/z: 296.1583,

found 296.1554.

1

of distal- to proximal-11Bg (3.3:1) was determined using H NMR

spectra of the crude product. The crude product was puriﬁed by

column chromatography (hexane/EtOAc = 20:1) to provide the titled

compound distal-11Bg (22 mg, 58%) as a yellow solid. Mp 58−60 °C.

¹H NMR (500 MHz, CDCl₃) δ: 0.48 (9 H, s), 1.29 (3 H, t, J = 7.5

Hz), 2.52 (3 H, s), 4.26 (2 H, q, J = 7.5 Hz), 5.35 (2 H, s), 7.20 (1 H,

brs), 7.28 (1 H, d, J = 2.0 Hz). ¹³C NMR (125 MHz, CDCl₃) δ: −0.8,

14.1, 22.0, 48.9, 62.2, 108.9, 131.8, 132.7, 133.3, 137.5, 148.7, 166.7. IR

(CHCl₃): 1755, 1605 cm⁻¹. HRMS calcd for C₁₄H₂₂N₃O₂Si (M + H)⁺

m/z: 292.1481, found 292.1507.

1-Benzyl-5-methyl-7-(trimethylsilyl)-1H-benzo[d]triazole

(proximal-11Be) (Table 3, entry 4). Product (6.5 mg, 18%) was

obtained by column chromatography of the above-mentioned crude

product as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ: 0.34 (9 H, s),

2.52 (3 H, s), 6.02 (2 H, s), 6.87 (2 H, d, J = 8.0 Hz), 7.26−7.28 (3 H,

m), 7.48 (1 H, brs), 7.90 (1 H, brs). ¹³C NMR (125 MHz, CDCl₃) δ:

0.7, 21.4, 52.4, 120.5, 121.1, 126.1, 127.8, 128.8, 133.1, 136.1, 136.3,

137.6, 145.9. IR (CHCl₃): 2463, 1620, cm⁻¹. HRMS calcd for

C₁₇H₂₂N₃Si (M + H)⁺m/z: 296.1583, found 296.1605.

Ethyl 2-(5-Methyl-1H-benzo[d]triazol-1-yl)acetate (Desily-

lated Product of proximal-11Bg) (Table 3, entry 6). Product

(5.3 mg, 20%) was obtained by column chromatography of the above-

1-Benzyl-4-(tert-butyldimethylsilyl)-6-methyl-1H-benzo[d]-

triazole (distal-11Be′) (Table 3, entry 4). Following the general

procedure II, a mixture of 16B′ (50 mg, 0.12 mmol), (azidomethyl)-

benzene 6e (46 μL, 0.36 mmol) and Bu₄NF (1.0 M in THF, 0.24 mL,

0.24 mmol) in THF (1.2 mL) was stirred for 0.5 h. The ratio of distal-

1

mentioned crude product as a colorless solid. Mp 104−105 °C. H

NMR (500 MHz, CDCl₃) δ: 1.26 (3 H, t, J = 7.5 Hz), 2.53 (3 H, s),

4.25 (2 H, q, J = 7.5 Hz), 5.39 (2 H, s), 7.35 (2 H, brs), 7.84 (1 H,

brs). ¹³C NMR (125 MHz, CDCl₃) δ: 14.1, 21.5, 49.1, 62.3, 108.7,

119.1, 130.1, 131.9, 134.2, 146.6, 166.4. IR (CHCl₃): 1755, 1591 cm⁻¹.

HRMS calcd for C₁₁H₁₄N₃O₂(M + H)⁺m/z: 220.1086, found

220.1084.

1

to proximal-11Be′ (10:1) was determined using H NMR spectra of

the crude product. The crude product was puriﬁed by column

chromatography (hexane/EtOAc = 10:1) to provide the titled

1

compound distal-11Be′ (27 mg, 69%) as a colorless oil. H NMR

1-Benzhydryl-6-methyl-4-(trimethylsilyl)-1H-benzo[d]-

triazole (distal-11Bh) (Table 3, entry 7). Following the general

procedure II, a mixture of 16B^14c(50 mg, 0.13 mmol),

(azidomethylene)dibenzene 6h³⁹(82 mg, 0.39 mmol), and Bu₄NF

(1.0 M in THF, 0.26 mL, 0.26 mmol) in THF (1.3 mL) was stirred for

1.0 h. The ratio of distal- to proximal-11Bh (5.0:1) was determined

(500 MHz, CDCl₃) δ: 0.52 (6 H, s), 0.95 (9 H, s), 2.46 (3 H, s), 5.77

(2 H, s), 7.12 (1 H, brs), 7.24 (1 H, d, J = 2.0 Hz), 7.28−7.34 (5 H,

m). ¹³C NMR (125 MHz, CDCl₃) δ: −4.9, 17.2, 22.0, 26.9, 51.8,

109.3, 127.5, 128.2, 128.9, 130.9, 132.1, 133.2, 135.2, 136.7, 149.5. IR

(CHCl₃): 2927, 1605, 1406 cm⁻¹. HRMS calcd for C₂₀H₂₈N₃Si (M +

H)⁺m/z: 338.2053, found 338.2066.

1

using H NMR spectra of the crude product. The crude product was

puriﬁed by column chromatography (hexane/EtOAc = 15:1) to

provide the titled compound distal-11Bh (27 mg, 55%) as a colorless

solid, the regiochemistry of which was determined by NOESY

1-Benzyl-7-(tert-butyldimethylsilyl)-5-methyl-1H-benzo[d]-

triazole (proximal-11Be′) (Table 3, entry 4). Product (3.1 mg,

8.0%) was obtained by column chromatography of the above-

mentioned crude product as a colorless oil. ¹H NMR (500 MHz,

CDCl₃) δ: 0.37 (6 H, s), 0.88 (9 H, s), 2.53 (3 H, s), 6.00 (2 H, s),

6.83 (2 H, dd, J = 2.0, 8.0 Hz), 7.24−7.27 (3 H, m), 7.52 (1 H, d, J =

2.0 Hz), 7.91 (1 H, brs). ¹³C NMR (125 MHz, CDCl₃) δ: −2.3, 17.9,

1

spectrum. Mp 138−139 °C. H NMR (500 MHz, CDCl₃) δ: 0.47 (9

H, s), 2.40 (3 H, s), 6.92 (1 H, s), 7.23−7.26 (7 H, m), 7.31−7.36 (5

H, m). ¹³C NMR (125 MHz, CDCl₃) δ: −0.7, 22.0, 66.7, 110.1, 128.2,

128.4, 128.7, 131.7, 132.3, 133.1, 136.8, 138.1, 148.8. IR (CHCl₃):

K

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The Journal of Organic Chemistry

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1601, 1497, 1454 cm⁻¹. HRMS calcd for C₂₃H₂₆N₃Si (M + H)⁺m/z:

372.1896, found 372.1909.

colorless solid. Mp 145−147 °C. ¹H NMR (500 MHz, CDCl₃) δ: 0.43

(9 H, s), 0.92 (9 H, s), 2.50 (3 H, s), 7.13 (1 H,s), 7.28 (1 H, s), 8.09

(1 H, s). ¹³C NMR (125 MHz, CDCl₃) δ: −4.8, 17.3, 22.0, 26.7, 109.9,

125.8, 130.9, 131.1, 135.9, 136.5, 139.7. IR (CHCl₃): 3469, 1602, 1251

cm⁻¹. HRMS calcd for C₁₄H₂₃N₂Si (M + H)⁺m/z: 247.1631, found

247.1652.

2-(tert-Butyl)-5-methyl-3-phenyl-7-(trimethylsilyl)-2,3-

dihydrobenzo[d]isoxazole (distal-11Br) (Table 3, entry 10).^10a

Following the general procedure II, a mixture of 16B^14c(50 mg, 0.13

mmol), N-tert-butyl-α-phenylnitrone 6r (69 mg, 0.39 mmol), and

Bu₄NF (1.0 M in THF, 0.26 mL, 0.26 mmol) in THF (1.3 mL) was

stirred for 3.0 h. The crude product was puriﬁed by column

chromatography (hexane/EtOAc = 10:1) to provide the titled

compound distal-11Br (41 mg, 94%) as a colorless oil. ¹H NMR

(500 MHz, CDCl₃) δ: 0.32 (9 H, s), 1.17 (9 H, s), 2.20 (3 H, s), 5.51

(1 H, s), 6.70 (1 H, s), 7.00 (1 H, s), 7.24 (1 H, t, J = 8.0 Hz), 7.32 (2

H, t, J = 8.0 Hz), 7.36 (2 H, d, J = 8.0 Hz) ¹³C NMR (125 MHz,

CDCl₃) δ: −1.2, 20.7, 25.4, 60.9, 66.7, 116.7, 125.1, 127.2, 127.4,

128.2, 128.5, 129.4, 134.2, 144.1, 159.2. IR (CHCl₃): 2976, 1602,

1454, 1393 cm⁻¹. HRMS calcd for C₂₁H₃₀NOSi (M + H)⁺m/z:

340.2097, found 340.2090.

1-Benzhydryl-5-methyl-7-(trimethylsilyl)-1H-benzo[d]-

triazole (proximal-11Bh) (Table 3, entry 7). Product (5.1 mg,

10%) was obtained by column chromatography of the above-

mentioned crude product as a colorless oil, the regiochemistry of

1

which was determined by NOESY spectrum. H NMR (500 MHz,

CDCl₃) δ: 0.39 (9 H, s), 2.51 (3 H, s), 4.11−4.25 (1 H, m), 7.15 (4 H,

dd, J = 2.0, 8.0 Hz), 7.31 (5 H, m), 7.39 (1 H, s), 7.49 (1 H, s), 7.90 (1

H, s). ¹³C NMR (125 MHz, CDCl₃) δ: 1.0, 21.3, 65.8, 120.6, 121.0,

128.0, 128.4, 128.5, 128.8, 133.1, 136.4, 137.7, 139.5. IR (CHCl₃):

1719, 1568, 1495, 1450 cm⁻¹. HRMS calcd for C₂₃H₂₆N₃Si (M + H)⁺

m/z: 372.1896, found 372.1903.

1-(3,5,7-Adamantan-1-yl)-6-methyl-4-(trimethylsilyl)-1H-

benzo[d]triazole (distal-11Bj) (Table 3, entry 8). Following the

general procedure II, a mixture of 16B^14c(50 mg, 0.13 mmol), 1-

azidoadamantane 6j^10c(69 mg, 0.39 mmol), and Bu₄NF (1.0 M in

THF, 0.26 mL, 0.26 mmol) in THF (1.3 mL) was stirred for 0.5 h.

The crude product was puriﬁed by column chromatography (hexane/

EtOAc = 30:1) to provide the titled compound distal-11Bj (25 mg,

57%) as a colorless solid, the regiochemistry of which was determined

by NOESY spectrum. Mp 198−199 °C. ¹H NMR (500 MHz, CDCl₃)

δ: 0.47 (9 H, s), 1.86 (6 H, brs), 2.32 (3 H, s), 2.50 (6 H, d, J = 2.0

Hz), 2.53 (3 H, s), 7.23 (1 H, brs), 7.53 (1 H, brs). ¹³C NMR (125

MHz, CDCl₃) δ: −0.8, 22.1, 29.6, 36.2, 41.9, 61.0, 112.3, 130.8, 131.0,

133.0, 135.5, 149.6. IR (CHCl₃): 2855, 1730, 1597, 1456 cm⁻¹. HRMS

calcd for C₂₀H₃₀N₃Si (M + H)⁺m/z: 340.2209, found 340.2210.

5-Methyl-7-(trimethylsilyl)-1H-indazole (distal-11Bn) (Table

3, entry 9). Following the general procedure II, a mixture of 16B^14c

(50 mg, 0.13 mmol), (diazomethyl)trimethylsilane 6n (2.0 M in Et₂O,

0.20 mL, 0.39 mmol), and Bu₄NF (1.0 M in THF, 0.26 mL, 0.26

mmol) in THF (1.3 mL) was stirred for 1.0 h. The ratio of distal- to

1-Benzyl-6-ﬂuoro-4-(trimethylsilyl)-1H-benzo[d]triazole (dis-

tal-11Ce) (Table 3, entry 16). Following the general procedure II, a

mixture of 16C^14c(50 mg, 0.13 mmol), (azidomethyl)benzene 6e (50

μL, 0.39 mmol), and Bu₄NF (1.0 M in THF, 0.26 mL, 0.26 mmol) in

THF (1.3 mL) was stirred for 0.5 h. The ratio of distal- to proximal-

1

11Ce (2.8:1) was determined using H NMR spectra of the crude

product. The crude product was puriﬁed by column chromatography

(hexane/EtOAc = 10:1) to provide the titled compound distal-11Ce

1

(27 mg, 56%) as a colorless oil. H NMR (500 MHz, CDCl₃) δ: 0.48

(9 H, s), 5.77 (2 H, s), 6.91 (1 H, dd, J = 2.0, 8.0 Hz), 7.16 (1 H. dd, J

= 2.0, 8.0 Hz), 7.28−7.36 (5 H, m). ¹³C NMR (125 MHz, CDCl₃) δ:

−0.9, 52.3, 95.6 (J = 25 Hz), 118.7 (J = 25 Hz), 127.7, 128.5, 129.0,

132.2 (J = 10 Hz), 134.5, 136.8 (J = 10 Hz), 147.1, 161.7 (J = 240 Hz).

IR (CHCl₃): 1724, 1604, 1501 cm⁻¹. HRMS calcd for C₁₆H₁₉FN₃Si

(M + H)⁺m/z: 300.1332, found 300.1336.

1

proximal-11Bn (1.4:1) was determined using H NMR spectra of the

crude product. The crude product was puriﬁed by column

chromatography (hexane/EtOAc = 5:1) to provide the titled

compound distal-11Bn (16 mg, 59%) as a colorless solid, the

regiochemistry of which was determined by NOESY spectrum after

1-Benzyl-5-ﬂuoro-1H-benzo[d]triazole (Desilylated Product

of proximal-11Ce) (Table 3, entry 16). Product (8.2 mg, 28%) was

obtained by column chromatography of the above-mentioned crude

1

N¹-methylation using MeI and t-BuOK. Mp 137−139 °C. H NMR

(500 MHz, CDCl₃) δ: 0.43 (9 H, s), 2.46 (3 H, s), 7.34 (1 H, d, J = 2.0

Hz), 7.54 (1 H, brs), 8.01 (1 H, s), 10.6 (NH, brs). ¹³C NMR (125

MHz, CDCl₃) δ: −0.7, 21.3, 120.2, 120.9, 122.3, 130.0, 134.4, 135.0,

142.5. IR (CHCl₃): 3479, 1776, 1578, 1530 cm⁻¹. HRMS calcd for

C₁₁H₁₇N₂Si (M + H)⁺m/z: 205.1161, found 205.1140.

1

product as a colorless solid. Mp 101−103 °C. H NMR (500 MHz,

CDCl₃) δ: 5.84 (2 H, s), 7.18 (1 H, dt, J = 2.0, 8.0 Hz), 7.27−7.37 (6

H, m), 7.68 (1 H, dd, J = 2.0, 8.0 Hz). ¹³C NMR (125 MHz, CDCl₃)

δ: 52.6, 104.6 (J = 26 Hz), 110.7 (J = 10 HZ), 117.4 (J = 26 Hz),

127.6, 128.7, 129.1, 129.8, 134.3, 146.6 (J = 10 Hz), 159.7 (J = 240

Hz). IR (CHCl₃): 2396, 1778, 1627, 1595, 1499 cm⁻¹. HRMS calcd

for C₁₃H₁₁FN₃(M + H)⁺m/z: 228.0937, found 228.0916.

6-Methyl-4-(trimethylsilyl)-1H-indazole (proximal-11Bn)

(Table 3, entry 9). Product (10 mg, 39%) was obtained by column

chromatography of the above-mentioned crude product as a colorless

1

solid. Mp 57−58 °C. H NMR (500 MHz, CDCl₃) δ: 0.41 (9 H, s),

1-Benzyl-6-chloro-4-(trimethylsilyl)-1H-benzo[d]triazole

(distal-11De) (Table 3, entry 17). Following the general procedure

II, a mixture of 16D^14c(50 mg, 0.12 mmol), (azidomethyl)benzene 6e

(46 μL, 0.36 mmol), and Bu₄NF (1.0 M in THF, 0.24 mL, 0.24 mmol)

in THF (1.2 mL) was stirred for 1.0 h. The ratio of distal- to proximal-

2.49 (3 H, s), 7.14 (1 H, brs), 7.28 (1 H, brs), 8.11 (1 H, brs), 10.0

(NH, brs). ¹³C NMR (125 MHz, CDCl₃) δ: −0.6, 21.9, 109.9, 124.9,

129.3, 133.4, 135.5, 136.2, 139.8. IR (CHCl₃): 3469, 1782, 1531 cm⁻¹.

HRMS calcd for C₁₁H₁₇N₂Si (M + H)⁺m/z: 205.1161, found

205.1149.

1

11De (3.0:1) was determined using H NMR spectra of the crude

5-Methyl-7-(tert-butyldimethylsilyl)-1H-indazole (distal-

11Bn′) (Table 3, entry 9). Following the general procedure II, a

mixture of 16B′ (85 mg, 0.20 mmol), (diazomethyl)trimethylsilane 6n

(2.0 M in Et₂O, 0.30 mL, 0.60 mmol) and Bu₄NF (1.0 M in THF, 0.40

mL, 0.40 mmol) in THF (2.0 mL) was stirred for 1 h. The ratio of

distal- to proximal-11Bn′ (3.3:1) was determined using ¹H NMR

spectra of the crude product. The crude product was puriﬁed by

column chromatography (hexane/EtOAc = 5:1) to provide the titled

compound distal-11Bn′ (38 mg, 76%) as a colorless solid. Mp 199−

201 °C. ¹H NMR (500 MHz, CDCl₃) δ: 0.45 (6 H, s), 0.93 (9 H, s),

2.47 (3 H, s), 7.30 (1 H, s), 7.54 (1 H, s), 7.99 (1 H, s). ¹³C NMR

(125 MHz, CDCl₃) δ: −5.2, 17.6, 21.3, 26.5, 117.9, 120.9, 122.4,

129.6, 134.0, 136.5, 143.1. IR (CHCl₃): 3483, 1722, 1600, 1463, 1257

cm⁻¹. HRMS calcd for C₁₄H₂₃N₂Si (M + H)⁺m/z: 247.1631, found

247.1645.

product. The crude product was puriﬁed by column chromatography

(hexane/EtOAc = 20:1) to provide the titled compound distal-11De

(12 mg, 31%) as a colorless oil. H NMR (500 MHz, CDCl₃) δ: 0.48

1

(9 H, s), 5.78 (2 H, s), 7.29−7.36 (7 H, m). ¹³C NMR (125 MHz,

CDCl₃) δ: −0.9, 52.2, 109.7, 127.6, 128.6, 129.1, 130.0, 132.3, 133.5,

134.4, 136.0, 148.8. IR (CHCl₃): 2959, 1750, 1593, 1497 cm⁻¹. HRMS

calcd for C₁₆H₁₉ClN₃Si (M + H)⁺m/z: 316.1037, found 316.1048.

1-Benzyl-5-chloro-1H-benzo[d]triazole (Desilylated Product

of proximal-11De) (Table 3, entry 17). Product (3.0 mg, 12%) was

obtained by column chromatography of the above-mentioned crude

1

product as a colorless solid. Mp 148−149 °C. H NMR (500 MHz,

CDCl₃) δ: 5.84 (2 H, s), 7.25−7.27 (4 H, m), 7.33−7.37 (3 H, m),

8.05 (1 H, d, J = 2.0 Hz). ¹³C NMR (125 MHz, CDCl₃) δ: 52.6, 110.7,

119.5, 127.69, 128.4, 128.7, 129.1, 129.9, 131.5, 134.3, 147.0. IR

(CHCl₃): 1732, 1583, 1497, 1479 cm⁻¹. HRMS calcd for C₁₃H₁₁ClN₃

(M + H)⁺m/z: 244.0642, found 244.0624.

6-Methyl-4-(tert-butyldimethylsilyl)-1H-indazole (proximal-

11Bn′) (Table 3, entry 9). Product (12 mg, 24%) was obtained by

column chromatography of the above-mentioned crude product as a

Ethyl 5-Methyl-7-(trimethylsilyl)-1H-indazole-3-carboxylate

(distal-11Bp) (Table 3, entry 18). Following the general procedure

L

dx.doi.org/10.1021/jo302802b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

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II, a mixture of 16B^14c(50 mg, 0.13 mmol), ethyl 2-diazoacetate 6p

(40 μL, 0.39 mmol), and Bu₄NF (1.0 M in THF, 0.26 mL, 0.26 mmol)

in THF (1.3 mL) was stirred for 0.5 h. The ratio of distal- to proximal-

1-((6-Iodobenzo[d][1,3]dioxol-5-yl)methyl)-5-methyl-7-

(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]-

triazole (proximal-10Bt). Following the general procedure I, a

mixture of 14B (0.20 g, 0.33 mmol), 5-(azidomethyl)-6-iodobenzo-

[d]1,3-dioxole 6t⁴³(0.30 g, 0.99 mmol), and i-PrMgCl·LiCl (1.3 M in

THF, 0.31 mL, 0.39 mmol) in THF (1.0 mL) was stirred for 30 min at

0 °C. The crude product was puriﬁed by column chromatography

(hexane/EtOAc = 7:1) to provide the titled compound proximal-10Bt

1

11Bp (12:1) was determined using H NMR spectra of the crude

product. The crude product was puriﬁed by column chromatography

(hexane/EtOAc = 10:1) to provide the titled compound distal-11Bp

(30 mg, 83%) as a colorless solid, the regiochemistry of which was

1

determined by NOESY spectrum. Mp 165−166 °C. H NMR (500

1

(115 mg, 67%) as a colorless solid. Mp 163−165 °C. H NMR (500

MHz, CDCl₃) δ: 0.44 (9 H, s), 1.48 (3 H, t, J = 8.0 Hz), 2.50 (3 H, s),

4.51 (2 H, q, J = 8.0 Hz), 7.36 (1 H, s), 8.03 (1 H, s), 10.35 (NH, brs).

¹³C NMR (125 MHz, CDCl₃) δ: −0.8, 14.4, 21.5, 60.9, 121.3, 121.9,

MHz, CDCl₃) δ: 1.21 (12 H, s), 2.53 (3 H, s), 5.49 (1 H, s), 5.85 (2

H, s), 6.13 (2 H, s), 7.30 (1 H, s), 7.90 (1 H, s), 7.99 (1 H, s). ¹³C

NMR (125 MHz, CDCl₃) δ: 21.1, 24.5, 58.0, 83.7, 84.4, 101.6, 106.9,

118.5, 122.8, 133.3, 133.5, 134.7, 139.8, 146.6, 147.4, 148.6. IR

(CHCl₃): 2982, 1042 cm⁻¹. HRMS calcd for C₂₁H₂₃BIN₃NaO₄(M +

Na)⁺m/z: 542.0724, found 542.0724.

122.0, 132.6, 135.6, 136.1, 143.8, 162.7. IR (CHCl₃): 3466, 1715,

1601, 1452 cm⁻¹. HRMS calcd for C₁₄H₂₁N₂O₂Si (M + H)⁺m/z:

277.1372, found 277.1351.

Ethyl 6-Methyl-4-(trimethylsilyl)-1H-indazole-3-carboxylate

(proximal-11Bp) (Table 3, entry 18). Product (3.6 mg, 10%) was

obtained by column chromatography of the above-mentioned crude

7H-[1,3]Dioxolo[4,5-j]triazolo[4,5,1-de]phenanthridine

(17A). An oven-dried round-bottom ﬂask was charged with proximal-

10At (50 mg, 0.096 mmol), PdCl₂(dppf)·CH₂Cl₂(24 mg, 0.029

mmol), and Ba(OH)₂·8H₂O (91 mg, 0.29 mmol). The ﬂask was

capped with a rubber septum, then evacuated, and backﬁlled with

argon. Anhydrous dioxane (0.50 mL) was added via a syringe, and the

mixture was stirred at 100 °C for 16 h. After the reaction, the mixture

was ﬁltered through a short pad of Celite, washed with CH₂Cl₂, and

evaporated under reduced pressure. The residue was washed with

acetone to provide the titled compound 17A (10 mg, 40%) as a

colorless solid. Mp >350 °C. ¹H NMR (500 MHz, (CD₃)₂SO, 80 °C)

δ: 6.02 (2 H, s), 6.12 (2 H, s), 7.05 (1 H, s), 7.34 (1 H, t, J = 7.5 Hz),

7.68 (1 H, s), 7.76 (2 H, d, J = 7.5 Hz). ¹³C NMR (125 MHz,

(CD₃)₂SO, 80 °C) δ: 50.5, 103.3, 104.8, 109.5, 118.4, 118.7, 121.3,

123.1, 126.8, 126.9, 132.3, 144.6, 149.4, 150.0. IR (CHCl₃): 3008,

1039 cm⁻¹. HRMS calcd for C₁₄H₁₀N₃O₂(M + H)⁺m/z: 252.0773,

found 252.0796.

1

product as a colorless oil. H NMR (500 MHz, CDCl₃) δ: 0.41 (9 H,

s), 1.46 (3 H, t, J = 7.5 Hz), 2.49 (3 H, s), 4.48 (2 H, q, J = 7.5 Hz),

7.34 (1 H, s), 7.39 (1 H, s). ¹³C NMR (125 MHz, CDCl₃) δ: 1.1, 14.5,

21.8, 61.2, 110.5, 128.8, 130.1, 133.8, 134.4, 136.6, 141.6, 163.1. IR

(CHCl₃): 3451, 1724, 1609, 1443 cm⁻¹. HRMS calcd for

C₁₄H₂₁N₂O₂Si (M + H)⁺m/z: 277.1372, found 277.1356.

5-Methyl-3,3-diphenyl-7-(trimethylsilyl)-3H-indazole (distal-

11Bq) (Table 3, entry 19). Following the general procedure II, a

mixture of 16B^14c(50 mg, 0.13 mmol), (diazomethylene)dibenzene

6q⁴²(76 μL, 0.39 mmol), and Bu₄NF (1.0 M in THF, 0.26 mL, 0.26

mmol) in THF (1.3 mL) was stirred for 1.0 h. The ratio of distal- to

proximal-11 Bq (3.0:1) was determined using ¹H NMR spectra of the

crude product. The crude product was puriﬁed by column

chromatography (hexane/EtOAc = 50:1) to provide the titled

compound distal-11 Bq (37 mg, 80%) as a colorless solid. Mp 122−

123 °C. ¹H NMR (500 MHz, CDCl₃) δ: 0.49 (9 H, s), 2.45 (3 H, s),

7.27−7.30 (10 H, m), 7.37 (1 H, s), 7.40 (1 H, s). ¹³C NMR (125

MHz, CD₃OD) δ: 0.6, 22.5, 102.3, 127.6, 129.6, 130.0, 130.5, 137.3,

137.9, 140.3, 142.3, 145.7, 161.7. IR (CHCl₃): 2959, 1591, 1493, 1466

cm⁻¹. HRMS calcd for C₂₃H₂₅N₂Si (M + H)⁺m/z: 357.1787, found

357.1766 .

2-Methyl-7H-[1,3]dioxolo[4,5-j]triazolo[4,5,1-de]-

phenanthridine (17B). An oven-dried round-bottom ﬂask was

charged with proximal-10Bt (50 mg, 0.096 mmol),

PdCl₂(dppf)·CH₂Cl₂(24 mg, 0.029 mmol), and Ba(OH)₂·8H₂O (91

mg, 0.29 mmol). The ﬂask was capped with a rubber septum, then

evacuated, and backﬁlled with argon. Anhydrous dioxane (0.50 mL)

was added via a syringe, and the mixture was stirred at 100 °C for 16 h.

After the reaction, the mixture was ﬁltered through a short pad of

Celite, washed with CH₂Cl₂, and evaporated under reduced pressure.

The residue was washed with acetone to provide the titled compound

5-Methyl-3-phenyl-7-(trimethylsilyl)benzo[d]isoxazole (dis-

tal-11Bs) (Table 3, entry 20). Following the general procedure II,

a mixture of 16B^14c(50 mg, 0.13 mmol), N-hydroxybenzimidoyl

chloride⁴³(61 mg, 0.39 mmol), and Bu₄NF (1.0 M in THF, 0.65 mL,

0.65 mmol) in THF (1.3 mL) was stirred for 24 h. The crude product

was puriﬁed by column chromatography (hexane/EtOAc = 20:1) to

provide the titled compound distal-11Bs (27 mg, 73%) as a colorless

solid, the regiochemistry of which was determined by NOESY

1

17B (15 mg, 59%) as a colorless solid. Mp 267−269 °C. H NMR

(500 MHz, CDCl₃) δ: 2.53 (3 H, s), 5.92 (2 H, s), 6.07 (2 H, s), 6.79

(1 H, s), 7.32 (1 H, s), 7.35 (1 H, s), 7.55 (1 H, s). ¹³C NMR (125

MHz, CDCl₃) δ: 22.2, 49.4, 101.9, 103.1, 107.7, 116.6, 118.9, 119.1,

122.2, 124.5, 129.9, 135.6, 144.2, 148.3, 148.7. IR (CHCl₃): 3008,

1039 cm⁻¹. HRMS calcd for C₁₅H₁₂N₃O₂(M + H)⁺m/z: 266.0930,

found 266.0921.

1

spectrum. Mp 159−160 °C. H NMR (500 MHz, CDCl₃) δ: 0.45 (9

H, s), 2.51 (3 H, s), 7.45 (1 H, d, J = 2.0 Hz), 7.51−7.58 (3 H, m),

7.68 (1 H, brs), 7.95 (2 H, dd, J = 2.0, 8.0 Hz). ¹³C NMR (125 MHz,

CDCl₃) δ: −1.2, 21.3, 119.1, 121.8, 122.2, 128.0, 129.0, 129.4, 129.9,

133.1, 136.8, 156.8, 167.1. IR (CHCl₃): 3059, 2361, 1595 cm⁻¹.

HRMS calcd for C₁₇H₂₀NOSi (M + H)⁺m/z: 282.1314, found

282.1323.

Preparation of 7H-[1,3]Dioxolo[4,5-j]triazolo[4,5,1-de]-

phenanthridin-7-one (18A) from proximal-10At. An oven-dried

round-bottom ﬂask was charged with proximal-10At (50 mg, 0.099

mmol), PdCl₂(dppf)·CH₂Cl₂(24 mg, 0.030 mmol), and Ba-

(OH)₂·8H₂O (94 mg, 0.30 mmol). The ﬂask was capped with a

rubber septum, then evacuated, and backﬁlled with argon. Anhydrous

dioxane (0.50 mL) was added via a syringe and the mixture was stirred

for 18 h at 100 °C. After the reaction, the mixture was ﬁltered through

a short pad of Celite, washed with CH₂Cl₂, and evaporated under

reduced pressure to give crude 17A. Then, activated MnO₂(85 mg,

0.99 mmol) was added into the crude 17A. The ﬂask was capped with

a rubber septum, then evacuated, and backﬁlled with argon. Anhydrous

CH₂Cl₂(3.3 mL) was added via a syringe, and the mixture was stirred

for 24 h at room temperature. After the reaction, the mixture was

ﬁltered through a short pad of Celite, washed with CH₂Cl₂, and

evaporated under reduced pressure. The crude product was washed

with ethanol to provide the titled compound 18A (10 mg, 53% from

Synthesis of Hippadine Analogue 18 (Scheme 1a). 1-[(6-

Iodobenzo[d][1,3]dioxol-5-yl)methyl]-7-(4,4,5,5-tetramethyl-

1,3,2-dioxaborolan-2-yl)-1H-benzo[d]triazole (proximal-10At).

Following the general procedure I, a mixture of 14A (0.30 g, 0.51

mmol), 5-(azidomethyl)-6-iodobenzo[d]1,3-dioxole 6t⁴³(0.46 g, 1.5

mmol), and i-PrMgCl·LiCl (1.3 M in THF, 0.47 mL, 0.61 mmol) in

Et₂O (5.1 mL) was stirred for 30 min at 0 °C. The crude product was

puriﬁed by column chromatography (hexane/EtOAc = 10:1) to

provide the titled compound proximal-10At (178 mg, 69%) as a

colorless solid. Mp 166−168 °C. ¹H NMR (500 MHz, CDCl₃) δ: 1.21

(12 H, s), 5.51 (1 H, s), 5.85 (2 H, s), 6.16 (2 H, s), 7.30 (1 H, s), 7.41

(1 H, t, J = 7.5 Hz), 8.08 (1 H, d, J = 7.5 Hz), 8.24 (1 H, d, J = 7.5

Hz). ¹³C NMR (125 MHz, CDCl₃) δ: 24.5, 58.0, 83.7, 84.4, 101.6,

106.9, 118.5, 123.6, 123.7, 133.2, 136.2, 137.8, 145.9, 147.4, 148.6. IR

(CHCl₃): 2982, 1042 cm⁻¹. HRMS calcd for C₂₀H₂₁BIN₃NaO₄(M +

Na)⁺m/z: 528.0567, found 528.0568.

1

proximal-10At) as a pale yellow solid. Mp >350 °C. H NMR (500

MHz, (CD₃)₂SO, 80 °C) δ: 6.32 (2 H, s), 7.77 (1 H, t, J = 7.5 Hz),

7.90 (1 H, s), 8.13 (1 H, s), 8.33 (1 H, d, J = 7.5 Hz), 8.54 (1 H, d, J =

7.5 Hz). ¹³C NMR (125 MHz, (CD₃)₂SO, 80 °C) δ: 103.8, 108.5,

M

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The Journal of Organic Chemistry

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117.7, 121.3, 123.2, 124.9, 127.8, 129.2, 131.4, 144.2, 149.9, 154.2,

155.4. IR (CHCl₃): 3008, 1715, 1039 cm⁻¹. HRMS calcd for

C₁₄H₈N₃O₃(M + H)⁺m/z: 266.0566, found 266.0583.

(125 MHz, CDCl₃) δ: 34.7, 112.4, 120.9, 124.0, 133.5, 135.1, 148.6,

191.3. IR (CHCl₃): 1703, 1616, 1602, 1236 cm⁻¹. HRMS calcd for

C₈H₈N₃O (M + H)⁺m/z: 162.0667, found 162.0692.

Preparation of 2-Methyl-7H-[1,3]dioxolo[4,5-j]triazolo[4,5,1-

de]phenanthridin-7-one (18B) from proximal-10Bt. An oven-

dried round-bottom ﬂask was charged with proximal-10Bt (50 mg,

0.096 mmol), PdCl₂(dppf)·CH₂Cl₂(24 mg, 0.030 mmol), and

Ba(OH)₂·8H₂O (91 mg, 0.30 mmol). The ﬂask was capped with a

rubber septum, then evacuated, and backﬁlled with argon. Anhydrous

dioxane (0.50 mL) was added, and the mixture was stirred at 100 °C

for 18 h. After the reaction, the mixture was ﬁltered through a short

pad of Celite, washed with CH₂Cl₂, and evaporated under reduced

pressure to give crude 17B. Then, activated MnO₂(80 mg, 0.96

mmol) was added into the crude 17B. The ﬂask was capped with a

rubber septum, then evacuated, and backﬁlled with argon. Anhydrous

CH₂Cl₂(3.3 mL) was added, and the mixture was stirred for 24 h at

room temperature. After the reaction, the mixture was ﬁltered through

a short pad of Celite, washed with CH₂Cl₂, and evaporated under

reduced pressure. The residue was washed with acetone to provide the

titled compound 18B (16 mg, 61% from proximal-10Bt) as a pale

Synthesis of iso-Vorozole 23 (Scheme 1c). 5-(1,3-Dioxolan-

2-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-

((trimethylsilyl)methyl)-1H-benzo[d]triazole (proximal-10Cu).

Following the general procedure I, a mixture of 14C (94 mg, 0.14

mmol), (azidomethyl)trimethylsilane 6u (0.21 mL, 1.41 mmol), and i-

PrMgCl·LiCl (1.3 M in THF, 0.21 mL, 0.27 mmol) in Et₂O (1.4 mL)

was stirred for 30 min at 0 °C. The crude product was puriﬁed by

column chromatography (hexane/EtOAc = 5:2) to provide the titled

1

compound proximal-10Cu (33 mg, 57%) as a colorless oil. H NMR

(500 MHz, CDCl₃) δ: 0.15 (9 H, s), 1.40 (12 H, s), 4.07−4.09 (2 H,

m), 4.17−4.20 (2 H, m), 4.57 (2 H, s), 5.98 (1 H, s), 8.10 (1 H, d, J =

1.5 Hz), 8.24 (1 H, d, J = 1.5 Hz). ¹³C NMR (125 MHz, CDCl₃) δ:

−2.1, 24.9, 40.7, 65.3, 84.5, 103.5, 121.3, 132.9, 135.2, 136.9, 145.3. IR

(CHCl₃): 1587 cm⁻¹. HRMS calcd for C₁₉H₃₀BN₃NaO₄Si (M + Na)⁺

m/z: 426.1996, found 426.1991.

5-(1,3-Dioxolan-2-yl)-1-methyl-1H-benzo[d]triazole (25). The

mixture of proximal-10Cu (27 mg, 67 μmol), 10% Pd/C (3.4 mg), and

KF (12 mg, 0.20 mmol) was evacuated and backﬁlled with argon.

MeOH (0.70 mL) was added into the reaction tube, and the mixture

was heated using microwave for 3 h at 150 °C.²⁶The reaction mixture

was ﬁltered through a short pad of Celite and evaporated under

reduced pressure. CH₂Cl₂was added into the mixture, ﬁltered through

a short pad of Celite, concentrated under reduced pressure to provide

25 as a colorless solid (13.5 mg), and used without further puriﬁcation

for the next reaction.

1

yellow solid. Mp 256−258 °C. H NMR (500 MHz, CDCl₃) δ: 2.69

(3 H, s), 6.22 (2 H, s), 7.60 (1 H, s), 7.93 (2 H, s), 7.98 (1 H, s), 8.06

(1 H, s). ¹³C NMR (125 MHz, CDCl₃) δ: 22.1, 102.2, 102.9, 109.5,

116.7, 120.7, 123.6, 124.4, 127.7, 130.9, 137.4, 144.9, 149.6, 153.8,

155.2. IR (CHCl₃): 3008, 1703, 1039 cm⁻¹. HRMS calcd for

C₁₅H₁₀N₃O₃(M + H)⁺m/z: 280.0722, found 280.0727.

Formal Synthesis of Vorozole 21 (Scheme 1b). 4-(tert-

Butyldimethylsilyl)-6-(1,3-dioxolan-2-yl)-1-methyl-1H-benzo-

[d]triazole (distal-11Eu′). Following the general procedure II, a

mixture of 16E′ (100 mg, 0.158 mmol), (azidomethyl)trimethylsilane

6u (62 mg, 0.48 mmol) (for safety reasons, commercially available 6u

was used as an equivalent of the highly explosive methyl azide), and

Bu₄NF (1.0 M in THF, 0.32 mL, 0.32 mmol) in THF (1.6 mL) was

stirred for 30 min at 0 °C. The ratio of distal- to proximal-11Eu′

1-Methyl-1H-benzo[d]triazole-5-carbaldehyde (22). TsOH·-

H₂O (3.8 mg, 20 μmol) was added into an acetone solution (0.70 mL)

of 25 (13.5 mg). The mixture was stirred at room temperature for 9 h.

After the reaction, a saturated aqueous NaHCO₃was added into the

reaction mixture and extracted with EtOAc. The aqueous layer was

extracted twice with EtOAc. The combined organic layers were

washed with a saturated aqueous NaCl solution. The organic layer was

dried over anhydrous Na₂SO₄and evaporated under reduced pressure.

The crude product was puriﬁed by ﬂash column chromatography

(hexane/EtOAc = 2:1) to provide the titled compound 22 (9.5 mg,

1

(15:1) was determined using H NMR spectra of the crude product.

The crude product was puriﬁed by column chromatography (hexane/

EtOAc = 3:1) to provide the titled compound distal-11Eu′ (43 mg,

84%) as a colorless solid. Mp 92−94 °C. ¹H NMR (500 MHz, CDCl₃)

δ: 0.52 (6 H, s), 0.93 (9 H, s), 4.09−4.20 (4 H, m), 4.28 (3 H, s), 6.00

(1 H, s), 7.54 (1 H, d, J = 8.0 Hz), 7.68 (1 H, d, J = 8.0 Hz). ¹³C NMR

(125 MHz, CDCl₃) δ: −5.0, 17.2, 26.9, 34.1, 65.4, 103.5, 107.5, 129.5,

131.8, 133.2, 136.2, 151.0. IR (CHCl₃): 1602, 1408, 1328, 1236, 1120

cm⁻¹. HRMS calcd for C₁₆H₂₆N₃O₂Si (M + H)⁺m/z: 320.1794, found

320.1801.

1

88% 2 steps) as a colorless solid. Mp 165−167 °C. H NMR (500

MHz, CDCl₃) δ: 4.36 (3 H, s), 7.63 (1 H, d, J = 8.5 Hz), 8.09 (1 H,

dd, J = 1.0, 8.5 Hz), 8.55 (1 H, brs), 10.13 (1 H, s). ¹³C NMR (125

MHz, CDCl₃) δ: 34.5, 110.1, 125.6, 126.1, 133.1, 136.5, 145.7, 191.1.

IR (CHCl₃): 1701 cm⁻¹. HRMS calcd for C₈H₇N₃NaO (M + Na)⁺m/

z: 184.0487, found 184.0481.

6-(1,3-Dioxolan-2-yl)-1-methyl-1H-benzo[d]triazole (24).

Bu₄NF (1.0 M in THF, 0.35 mL, 350 μmol) was added into the

THF solution (0.70 mL, 0.10 M) of distal-11E′ (23 mg, 71 μmol) and

stirred for 48 h at 70 °C. The reaction mixture was cooled to room

temperature and evaporated under reduced pressure. The crude

product was puriﬁed by column chromatography (hexane/EtOAc =

3:1) to provide the titled compound 24 (14 mg, 94%) as a colorless

solid. Mp 97−98 °C. ¹H NMR (500 MHz, CDCl₃) δ: 4.08−4.18 (4 H,

m), 4.31 (3 H, s), 5.98 (1 H, s), 7.49 (1 H, d, J = 8.0 Hz), 7.69 (1 H,

s), 8.05 (1 H, d, J = 8.0 Hz). ¹³C NMR (125 MHz, CDCl₃) δ: 34.3,

65.4, 103.2, 107.1, 120.0, 122.6, 133.3, 137.7, 146.4. IR (CHCl₃):

1600, 1193 cm⁻¹. HRMS calcd for C₁₀H₁₂N₃O₂(M + H)⁺m/z:

206.0930, found 206.0910.

1-Methyl-1H-benzo[d]triazole-6-carbaldehyde (20). TsOH·-

H₂O (3.4 mg, 20 μmol) was added into the acetone solution (0.70

mL) of 24 (14 mg), and the mixture was stirred at room temperature

for 3 h. After the reaction, a saturated aqueous NaHCO₃was added

into the reaction mixture, and the mixture was extracted with Et₂O.

The aqueous layer was extracted twice with Et₂O. The combined

organic layers were washed with a saturated aqueous NaCl solution.

The organic layer was dried over anhydrous Na₂SO₄and evaporated

under reduced pressure. The crude product was puriﬁed by column

chromatography (hexane/EtOAc = 3:1) to provide the titled

compound 20 (10 mg, 96%) as a colorless solid. Mp 119−122 °C.

¹H NMR (500 MHz, CDCl₃) δ: 4.41 (3 H, s), 7.91 (1 H, d, J = 8.0

Hz), 8.11 (1 H, s), 8.19 (1 H, d, J = 8.0 Hz), 10.19 (1 H, s). ¹³C NMR

(4-Chlorophenyl)(1-methyl-1H-benzo[d]triazol-5-yl)-

methanol (26). An oven-dried ﬂask was charged with 22 (46 mg,

0.29 mmol), capped with an inlet adapter with a three-way stopcock,

then evacuated, and backﬁlled with argon. Et₂O (2.8 mL, 0.10 M) was

added via a syringe into the reaction mixture and cooled to −78 °C. 4-

Chlorophenylmagnesiumbromide (1.0 M in Et₂O, 0.57 mL, 0.57

mmol) was added into the solution and stirred at −78 °C for 1 h. The

reaction mixture was quenched with a saturated aqueous NH₄Cl and

extracted with EtOAc. The aqueous layer was extracted twice with

EtOAc. The combined organic layers were washed with a saturated

aqueous NaCl solution. The organic layer was dried over anhydrous

Na₂SO₄and evaporated under reduced pressure. The crude product

was puriﬁed by column chromatography (hexane/EtOAc = 2:1) to

1

provide the titled compound 26 (65 mg, 83%) as a colorless oil. H

NMR (500 MHz, CDCl₃) δ: 4.28 (3 H, s), 6.00 (1 H, s), 7.32 (4 H,

m), 7.46 (2 H, s), 8.08 (1 H, s). ¹³C NMR (125 MHz, CDCl₃) δ: 34.3,

75.3, 109.5, 117.3, 126.6, 127.9, 128.7, 133.1, 133.5, 139.9, 142.0,

145.9. IR (CHCl₃): 3603, 1600, 1491, 1281, 1236 cm⁻¹. HRMS calcd

for C₁₄H₁₃ClON₃(M + H)⁺m/z: 274.0747, found 274.0726.

5-((4-Chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl)-1-methyl-

1H-benzo[d]triazole (23). A mixture of 26 (65 mg, 0.23 mmol),

1,2,4-triazole (33 mg, 0.47 mmol), and TsOH·H₂O (13 mg, 71 μmol)

in a pear-shaped ﬂask was dissolved in toluene (5.0 mL). The ﬂask was

connected with a Dean−Stark apparatus and stirred at 150 °C for 24 h.

The reaction mixture was cooled to room temperature and quenched

with a saturated aqueous NaHCO₃. The reaction mixture was

N

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extracted with EtOAc, and the aqueous layer was extracted twice with

EtOAc. The combined organic layers were washed with a saturated

aqueous NaCl solution and dried over anhydrous Na₂SO₄. The

solution was ﬁltered through a glass ﬁlter and concentrated under

reduced pressure. The crude product was puriﬁed by column

chromatography (hexane/EtOAc = 1:2) to provide the titled

2-Iodo-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-

2-yl)phenyl 2,3-Dichlorobenzenesulfonate (34). Following the

general procedure SIII, a mixture of a mixture of 32B^14b(crude

product from 29B) (101 mg, 0.28 mmol), Et₃N (0.12 mL, 0.84

mmol), and 2,3-dichlrobenzenesulfonyl chloride (103 mg, 0.42 mmol)

in CH₂Cl₂(1.0 mL, 0.30 M) was stirred for 3 h at room temperature.

The crude product was puriﬁed by column chromatography (hexane/

EtOAc = 10:1) to provide the titled compound 34 (126 mg, 79% from

1

compound 23 (60 mg, 79%) as a colorless oil. H NMR (500 MHz,

CDCl₃) δ: 4.31 (3 H, s), 6.90 (1 H, s), 7.10 (2 H, d, J = 8.0 Hz), 7.36

(1 H, d, J = 8.0 Hz), 7.37 (2 H, d, J = 8.0 Hz), 7.55 (1 H, d, J = 8.0

Hz), 7.78 (1H, s), 8.00 (1 H, s), 8.05 (1 H, s). ¹³C NMR (125 MHz,

CDCl₃) δ: 34.4, 66.9, 110.14, 119.8, 127.6, 129.3, 129.4, 133.4, 133.8,

135.0, 143.5, 145.9, 152.5. IR (CHCl₃): 1732, 1597, 1492, 1274, 1238

cm⁻¹. HRMS calcd for C₁₆H₁₄ClN₆(M + H)⁺m/z: 325.0968, found

325.0984.

1

29B) as a colorless solid. Mp 135−140 °C. H NMR (500 MHz,

CDCl₃) δ: 1.40 (12 H, s), 2.28 (3 H, s), 7.29 (1 H, t, J = 8.0 Hz), 7.56

(1 H, s), 7.58 (1 H, s), 7.74 (1 H, d, J = 8.0 Hz), 7.78 (1 H, d, J = 8.0

Hz). ¹³C NMR (125 MHz, CDCl₃) δ: 20.1, 24.8, 84.6, 88.5, 127.1,

130.2, 133.4, 135.6, 136.2, 136.6, 138.2, 138.3, 143.0, 151.7. IR

(CHCl₃): 2982 cm⁻¹. HRMS calcd for C₁₉H₂₀BCl₂INaO₅S (M + Na)⁺

m/z: 590.9444, found 590.9451.

General Procedure SIII: Synthesis of Benzyne Precursor

Candidate (13B, 14A, 14B, and 33−37).

2-Iodo-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-

2-yl)phenyl 2,4-Dichlorobenzenesulfonate (35). Following the

general procedure SIII, a mixture of a mixture of 32B^14b(crude

product from 29B) (101 mg, 0.30 mmol), Et₃N (0.12 mL, 0.84

mmol), and 2,4-dichlrobenzenesulfonyl chloride (103 mg, 0.42 mmol)

in CH₂Cl₂(1.0 mL, 0.30 M) was stirred for 20 h at room temperature.

The crude product was puriﬁed by column chromatography (hexane/

EtOAc = 10:1) to provide the titled compound 35 (116 mg, 73% from

1

29B) as a colorless solid. Mp 100−105 °C. H NMR (500 MHz,

CDCl₃) δ: 1.40 (12 H, s), 2.28 (3 H, s), 7.33 (1 H, dd, J = 2.5, 8.5

Hz), 7.55 (1 H, d, J = 1.5 Hz), 7.57 (1 H, d, J = 2.5 Hz), 7.59 (1 H, d, J

= 1.5 Hz), 7.78 (1 H, d, J = 8.5 Hz). ¹³C NMR (125 MHz, CDCl₃) δ:

20.1, 24.9, 84.6, 88.7, 127.3, 132.2, 132.9, 134.7, 135.9, 136.6, 138.4,

141.0, 142.9, 151.5. IR (CHCl₃): 2982 cm⁻¹. HRMS calcd for

C₁₉H₂₀BCl₂INaO₅S (M + Na)⁺m/z: 590.9444, found 590.9471.

2-Iodo-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-

2-yl)phenyl 2,6-Dichlorobenzenesulfonate (36). Following the

general procedure SIII, a mixture of a mixture of 32B^14b(crude

product from 29B) (101 mg, 0.28 mmol), Et₃N (0.12 mL, 0.84

mmol), and 2,6-dichlrobenzenesulfonyl chloride (103 mg, 0.42 mmol)

in CH₂Cl₂(1.0 mL, 0.30 M) was stirred for 5 h at room temperature.

The crude product was puriﬁed by column chromatography (hexane/

EtOAc = 10:1) to provide the titled compound 36 (142 mg, 89% from

An oven-dried round-bottom ﬂask was charged with 32^14b(crude

product from 29) (1.0 equiv), capped with an inlet adapter with a

three-way stopcock, then evacuated, and backﬁlled with nitrogen.

Anhydrous CH₂Cl₂(0.30 M) was added via a syringe, and the mixture

was cooled to 0 °C. Et₃N (3.0 equiv) and chlorinated benzene sulfonyl

chloride (1.5 equiv) were added and stirred for several hours at room

temperature. After the completion of the reaction, water was added to

the reaction mixture. The mixture was extracted with CH₂Cl₂, and the

aqueous layer was extracted twice with CH₂Cl₂. The combined organic

layers were washed with a saturated aqueous NaCl. The organic layer

was dried over anhydrous Na₂SO₄, ﬁltered through a glass ﬁlter, and

concentrated under reduced pressure. The crude product was puriﬁed

by ﬂash column chromatography on silica gel to provide 13B, 14A,

14B, and 33−37.

1

29B) as a colorless solid. Mp 197−202 °C. H NMR (500 MHz,

CDCl₃) δ: 1.39 (12 H, s), 2.29 (3 H, s), 7.38 (1 H, t, J = 8.0 Hz), 7.46

(2 H, d, J = 8.0 Hz), 7.56 (1 H, d, J = 2.0 Hz), 7.61 (1 H, d, J = 2.0

Hz). ¹³C NMR (125 MHz, CDCl₃) δ: 20.1, 24.8, 84.6, 88.2, 131.5,

133.6, 135.1, 136.7, 137.2, 138.3, 142.9, 151.9. IR (CHCl₃): 3011

cm⁻¹. HRMS calcd for C₁₉H₂₀BCl₂INaO₅S (M + Na)⁺m/z: 590.9444,

found 590.9468.

2-Iodo-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-

2-yl)phenyl 4-Chlorobenzenesulfonate (13B). Following the

general procedure SIII, a mixture of 2-iodo-4-methyl-6-(4,4,5,5-

tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 32B^14b(crude product

from 29B) (1.0 g, 2.8 mmol), Et₃N (0.80 mL, 5.6 mmol), and 4-

chlorobenzenesulfonyl chloride (0.89 g, 4.2 mmol) in CH₂Cl₂(5.0

mL, 0.30 M) was stirred for 5 h at room temperature. The crude

product was puriﬁed by column chromatography (hexane/EtOAc =

11:1) to provide the titled compound 13B (0.85 g, 59% from 29B) as

2-Iodo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-

phenyl 2,4,5-Trichlorobenzenesulfonate (14A). Following the

general procedure SIII, a mixture of a mixture of 2-iodo-6-(4,4,5,5-

tetramethyl-1,3,2-dioxaborolan-2-yl)phenol 32A^14b(crude product

from 29A) (2.9 mmol of 29A), Et₃N (0.87 mL, 6.2 mmol), and

2,4,5-trichlrobenzenesulfonyl chloride (0.87 g, 3.1 mmol) in CH₂Cl₂

(7.0 mL) was stirred for 4 h at room temperature. The crude product

was puriﬁed by column chromatography (hexane/EtOAc = 10:1) to

provide the titled compound 14A (1.0 g, 75% from 29A) as a colorless

1

a colorless solid. Mp 165−170 °C. H NMR (500 MHz, CDCl₃) δ:

1.41 (12 H, s), 2.29 (3 H, s), 7.48 (2 H, d, J = 8.5 Hz), 7.55 (1 H, s)

7.57 (1 H, s), 7.74 (2 H, d, J = 8.5 Hz). ¹³C NMR (125 MHz, CDCl₃)

δ: 20.2, 24.9, 84.6, 89.6, 129.5, 130.5, 135.3, 136.5, 138.3, 141.1, 142.7,

150.8. IR (CHCl₃): 3036 cm⁻¹. HRMS calcd for C₁₉H₂₁BClINaO₅S

(M + Na)⁺m/z: 556.9834, found 556.9860.

1

solid. Mp 106−108 °C. H NMR (500 MHz, CDCl₃) δ: 1.39 (12 H,

s), 7.02 (1 H, t, J = 7.5 Hz), 7.67 (1 H, s), 7.79 (1 H, dd, J = 1.5, 7.5

Hz), 7.81 (1 H, dd, J = 1.5, 7.5 Hz), 7.97 (1 H, s). ¹³C NMR (125

MHz, CDCl₃) δ: 20.1, 24.8, 84.7, 88.7, 131.6, 133.0, 133.4, 133.5,

135.6, 136.8, 138.6, 139.3, 143.0, 151.4. IR (CHCl₃): 3009 cm⁻¹.

HRMS calcd for C₁₈H₁₇BCl₃INaO₅S (M + Na)⁺m/z: 610.8898, found

610.8871.

2-Iodo-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-

2-yl)phenyl 2,4,5-Trichlorobenzenesulfonate (14B). Following

the general procedure SIII, a mixture of a mixture of 32B^14b(crude

product from 29B) (1.1 g, 3.0 mmol), Et₃N (1.2 mL, 8.9 mmol), and

2,4,5-trichlrobenzenesulfonyl chloride (1.2 g, 4.4 mmol) in CH₂Cl₂

(10 mL, 0.30 M) was stirred for 12 h at room temperature. The crude

product was puriﬁed by column chromatography (hexane/EtOAc =

10:1) to provide the titled compound 14B (1.3 g, 75% from 29B) as a

colorless solid. Mp 134−138 °C. ¹H NMR (500 MHz, CDCl₃) δ: 1.39

2-Iodo-4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-

2-yl)phenyl 2,5-Dichlorobenzenesulfonate (33). Following the

general procedure SIII, a mixture of a mixture of 32B^14b(crude

product from 29B) (2.0 g, 5.6 mmol), Et₃N (1.6 mL, 11 mmol), and

2,5-dichlrobenzenesulfonyl chloride (1.6 mg, 6.7 mmol) in CH₂Cl₂

(19 mL, 0.30 M) was stirred for 5 h at room temperature. The crude

product was puriﬁed by column chromatography (hexane/EtOAc =

20:1) to provide the titled compound 33 (2.5 g, 78% from 29B) as a

colorless solid. Mp 115−117 °C. ¹H NMR (500 MHz, CDCl₃) δ: 1.40

(12 H, s), 2.29 (3 H, s), 7.46−7.54 (2 H, m), 7.56 (1 H, d, J = 1.5 Hz),

7.61 (1 H, d, J = 1.5 Hz), 7.88 (1 H, d, J = 2.5 Hz). ¹³C NMR (125

MHz, CDCl₃) δ: 20.1, 24.8, 84.6, 88.7, 131.7, 133.0, 133.1, 133.4,

134.8, 136.7, 137.3, 138.4, 143.0, 151.5. IR (CHCl₃): 3036 cm⁻¹.

HRMS calcd for C₁₉H₂₀BCl₂INaO₅S (M + Na)⁺m/z: 590.9444, found

590.9447.

O

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(12 H, s), 2.30 (3 H, s), 7.57 (1 H, d, J = 1.5 Hz), 7.62 (1 H, d, J = 1.5

Hz), 7.67 (1 H, s), 7.97 (1 H, s). ¹³C NMR (125 MHz, CDCl₃) δ:

20.1, 24.8, 84.7, 88.7, 131.6, 133.0, 133.4, 133.5, 135.6, 136.8, 138.6,

139.3, 143.0, 151.4. IR (CHCl₃): 3034 cm⁻¹. HRMS calcd for

C₁₉H₁₉BCl₃INaO₅S (M + Na)⁺m/z: 624.9054, found 624.9068.

Methyl 3-Iodo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-

yl)-4-(((2,4,5-trichlorophenyl)sulfonyl)oxy)benzoate (37). Fol-

lowing the general procedure SIII, a mixture of methyl 4-hydroxy-3-

iodo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 32D^14b

(1.06 g, crude product from 29D), Et₃N (1.1 mL, 7.9 mmol), and

2,4,5-trichlrobenzenesulfonyl chloride (1.1 g, 3.9 mmol) in CH₂Cl₂

(26 mL, 0.10 M) was stirred for 12 h at room temperature. The crude

product was puriﬁed by column chromatography (hexane/EtOAc =

5:1) to provide the titled compound 37 (1.46 g, 53% from 29D) as a

colorless solid. Mp 174−176 °C. ¹H NMR (500 MHz, CDCl₃) δ: 1.40

(12 H, s), 3.92 (3 H, s), 7.68 (1 H, brs), 7.98 (1 H, brs), 8.42 (1 H, d,

J = 2.0 Hz), 8.47 (1 H, d, J = 2.0 Hz). ¹³C NMR (125 MHz, CDCl₃) δ:

24.8, 52.5, 85.0, 88.9, 129.9, 131.8, 132.9, 133.3, 133.6, 135.4, 137.4,

139.7, 143.8, 156.5, 164.6. IR (CHCl₃): 1705 cm⁻¹. HRMS calcd for

C₂₀H₁₉BCl₃INaO₇S (M + Na)⁺m/z: 668.8952, found 668.8944.

4-Formyl-2-iodo-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-

2-yl)phenyl 2,4,5-Trichlorobenzenesulfonate (38). An oven-

dried round-bottom ﬂask was charged with 37 (1.34 g, 2.1 mmol),

capped with an inlet adapter with a three-way stopcock, then

evacuated, and backﬁlled with nitrogen. CH₂Cl₂(11 mL) was added

into the ﬂask via a syringe and cooled to −78 °C. A 1.0 M diisobutyl

aluminum hydride solution in CH₂Cl₂(2.1 mL, 2.1 mmol) was added

to the mixture and stirred over 1 h. MeOH (0.50 mL) and a saturated

aqueous Rochell’s salt (2.0 mL) were added to the reaction mixture

and stirred over 1 h at room temperature. The mixture was ﬁltered

through a pad of Celite and constructed twice by CH₂Cl₂. The

combined organic layer was dried over anhydrous Na₂SO₄, and solvent

was removed under reduced pressure. Compound 38 was obtained as

a colorless solid (1.26 g) and used as such without further puriﬁcation

for the next reaction.

organic layers were washed with a saturated aqueous NaCl solution.

The organic layer was dried over anhydrous MgSO₄, and solvent was

removed under reduced pressure. The crude product was puriﬁed by

column chromatography (hexane) to provide the titled compound 39

(3.2 g, 92%) as a colorless solid. Mp 54−56 °C. ¹H NMR (500 MHz,

CDCl₃) δ: 0.31 (9 H, s), 0.36 (6 H, s), 0.91 (9 H, s), 2.27 (3 H, s),

4.90 (1 H, s), 7.12 (1 H, d, J = 2.0 Hz), 7.17 (1 H, d, J = 2.0 Hz). ¹³C

NMR (125 MHz, CDCl₃) δ: −4.6, −0.8, 17.6, 20.6, 26.6, 120.5, 124.6,

128.5, 137.2, 138.2, 163.5 . IR (CHCl₃): 3612, 1570, 1464, 1402, 1253,

1167 cm⁻¹. HRMS calcd for C₁₆H₂₉OSi₂(M−H⁺) m/z: 293.1733,

found 293.1757.

2-(tert-Butyldimethylsilyl)-4-(1,3-dioxolan-2-yl)-6-

(trimethylsilyl)phenyl Triﬂuoromethanesulfonate (16B′). An

oven-dried round-bottom ﬂask was charged with 39 (1.0 g, 3.4

mmol), capped with an inlet adapter with a three-way stopcock, then

evacuated, and backﬁlled with nitrogen. Et₂O (14 mL, 0.25 M) was

added into the ﬂask via a syringe, cooled to −78 °C, and stirred for 10

min. n-BuLi (1.62 M in hexane, 2.3 mL, 3.7 mmol) was added and

stirred at −78 °C for 10 min. Then, triﬂuoromethanesulfonic

anhydride (0.62 mL, 3.7 mmol) was added into the mixture at −78

°C. The mixture was warmed to room temperature and stirred at room

temperature for 3 h. The reaction mixture was quenched with a

saturated aqueous NH₄Cl and extracted with EtOAc. The aqueous

layer was extracted twice by EtOAc. The combined organic layers were

washed with a saturated aqueous NaCl solution. The organic layer was

dried over anhydrous Na₂SO₄and concentrated under reduced

pressure (this reaction did not complete). Et₂O (13 mL, 0.25 M) was

added into the ﬂask via a syringe, cooled to −78 °C, and stirred for 10

min. n-BuLi (1.62 M in hexane, 0.23 mmol) was added and stirred at

−78 °C for 10 min. Then, triﬂuoromethanesulfonic anhydride (63 μL,

0.38 mmol) was added into the mixture at −78 °C. The mixture was

warmed to room temperature and stirred at room temperature for 3 h.

The reaction mixture was quenched with a saturated aqueous NH₄Cl

and extracted with EtOAc. The aqueous layer was extracted twice by

EtOAc. The combined organic layers were washed with a saturated

aqueous NaCl solution. The organic layer was dried over anhydrous

Na₂SO₄and concentrated under reduced pressure. The crude product

was puriﬁed by column chromatography (hexane/EtOAc = 20:1) to

provide the titled compound 16B′ (1.31 g, 90%) as a colorless oil. ¹H

NMR (500 MHz, CD₃OD) δ: 0.33 (9 H, s), 0.39 (6 H, s), 0.78 (9 H,

s), 2.39 (3 H, s), 7.43 (1 H, d, J = 2.0 Hz), 7.47 (1 H, d, J = 2.0 Hz).

¹³C NMR (125 MHz, CDCl₃) δ: −4.0, −0.56, 18.1, 20.8, 26.9, 118.5

4-(1,3-Dioxolan-2-yl)-2-iodo-6-(4,4,5,5-tetramethyl-1,3,2-di-

oxaborolan-2-yl)phenyl 2,4,5-Trichlorobenzenesulfonate

(14C). A mixture of 38 (196 mg) and ethylene glycol (40 μL, 0.72

mmol) in CH₂Cl₂(3.0 mL) was cooled to 0 °C and stirred under

argon. Trimethylsilyl chloride (80 μL, 0.63 mmol) was added to the

solution and slowly warmed to room temperature. After 9 h, solvent

was removed under reduced pressure. The crude product was puriﬁed

by column chromatography (hexane/EtOAc = 6:1) to provide the

titled compound 14C (104 mg, 49%) as a colorless solid. Mp 73−75

(q, J = 318 Hz), 131.6, 134.8, 136.1, 138.7, 139.2, 152.7. IR (CHCl₃):

1566, 1463, 1392, 1367, 1253 cm⁻¹. HRMS calcd for C₁₇H₃₀F₃O₃SSi₂

(M + H)⁺m/z: 427.1406, found 427.1419.

1

°C. H NMR (500 MHz, CDCl₃) δ: 1.39 (12 H, s), 4.03−4.11 (4 H,

m), 5.76 (1 H, s), 7.67 (1 H, brs), 7.86 (1 H, d, J = 2.0 Hz), 7.92 (1 H,

d, J = 2.0 Hz), 7.96 (1 H, brs). ¹³C NMR (125 MHz, CDCl₃) δ: 24.8,

65.4, 84.8, 88.8, 101.8, 131.7, 133.0, 133.4, 133.5, 134.5, 135.6, 138.3,

139.4, 140.6, 153.9. IR (CHCl₃): 1394 cm⁻¹. HRMS calcd for

C₂₁H₂₁BCl₃INaO₇S (M + Na)⁺m/z: 682.9109, found 682.9110.

Synthesis of Silylbenzyne Precursors (16B′ and 16E′)^14c2-

(tert-Butyldimethylsilyl)-4-methyl-6-(trimethylsilyl)phenol

(39). An oven-dried round-bottom ﬂask was charged with 2-bromo-6-

(tert-butyldimethylsilyl)-4-methylphenol^14a(3.6 g, 12 mmol), capped

with an inlet adapter with a three-way stopcock, then evacuated, and

backﬁlled with nitrogen. CH₂Cl₂(30 mL, 0.40 M) was added into the

ﬂask via a syringe, cooled to 0 °C, and stirred for 10 min.

Triethylamine (2.0 mL, 14 mmol) and trimethylsilyl chloride (1.9

mL, 14 mmol) were added into the ﬂask, and the mixture was stirred

at room temperature for 3 h. The reaction mixture was evaporated

under reduced pressure. Hexane was added to the residue, ﬁltered

through a pad of short pad of Celite, and concentrated under reduced

pressure to aﬀord (3-bromo-5-methyl-2-[(trimethylsilyl)oxy]phenyl)-

(tert-butyl)dimethylsilane. THF (24 mL, 0.50 M) was added to the

crude product, and the mixture was stirred at −78 °C for 10 min. n-

BuLi (1.6 M in hexane, 7.4 mL, 12 mmol) was added to the mixture

and stirred at room temperature for 1 h. The reaction mixture was

quenched with a saturated aqueous NH₄Cl and evaporated under

reduced pressure. The residue was extracted with hexane and water.

The aqueous layer was extracted twice with hexane. The combined

4-(1,3-Dioxolan-2-yl)-2,6-diiodophenol (40). A mixture of 4-

hydroxy-3,5-diiodobenzaldehyde (3.0 g, 8.0 mmol), ethylene glycol

(0.90 mL, 16 mmol) and TsOH·H₂O (69 mg, 0.40 mmol) was

dissolved in toluene. The reaction ﬂask was connected with Dean−

Stark apparatus and stirred at 150 °C for 10 h. After the reaction was

completed, K₂CO₃(0.20 g, 1.4 mmol) was added to the mixture,

ﬁltered, and concentrated under reduced pressure. The crude product

was puriﬁed by column chromatography (hexane/EtOAc = 1:1) to

provide the titled compound 40 (3.0 g, 89%) as a colorless solid. Mp

120−122 °C. ¹H NMR (500 MHz, CDCl₃) δ: 4.04 (4 H, m), 5.66 (1

H, s), 5.88 (1 H, s), 7.77 (2 H, s). ¹³C NMR (125 MHz, CDCl₃) δ:

65.2, 82.0, 101.4, 133.9, 137.5, 154.1. IR (CHCl₃): 3479, 2891, 1600,

1460, 1363, 1238 cm⁻¹. HRMS calcd for C₉H₉I₂O₃(M + H)⁺m/z:

418.8670, found 418.8641.

(4-(1,3-Dioxolan-2-yl)-2,6-diiodophenoxy)(tert-butyl)-

dimethylsilane (41). A mixture of 40 (1.0 g, 2.4 mmol) and

imidazole (0.24 g, 3.6 mmol) was dissolved in THF (10 mL, 0.25 M).

tert-Butyldimethylsilyl chloride was added to the mixture and stirred at

room temperature for 1 h. The reaction mixture was quenched with a

saturated aqueous NH₄Cl and extracted with EtOAc. The aqueous

layer was extracted twice with EtOAc. The combined organic layers

were washed with a saturated aqueous NaCl solution. The organic

layer was dried over anhydrous Na₂SO₄and concentrated under

reduced pressure. The crude product was puriﬁed by column

chromatography (hexane/EtOAc = 10:1) to provide the titled

P

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compound 41 (1.20 g, 95%) as a colorless solid. Mp 103−104 °C. ¹H

NMR (500 MHz, CDCl₃) δ: 0.46 (6 H, s), 1.07 (9 H, s), 4.05 (4 H,

m), 5.65 (1 H, s), 7.86 (2 H, s). ¹³C NMR (125 MHz, CDCl₃) δ: 0.0,

18.9, 26.5, 65.3, 88.5, 101.5, 134.4, 138.5, 155.9. IR (CHCl₃): 2958,

2931, 2887, 2858, 1600, 1448, 1276, 1255 cm⁻¹. HRMS calcd for

C₁₅H₂₃I₂O₃Si (M + H)⁺m/z: 532.9528, found 532.9506.

not complete). THF (125 mL, 0.10 M), NaH (0.25 g, 6.2 mmol) and

nonaﬂuorobutanesulfonyl ﬂuoride (1.2 mL, 7.1 mmol) were added

again to obtain a full conversion. The mixture was stirred at 80 °C for

20 h. The reaction mixture was quenched with water and evaporated

under reduced pressure. The residue was extracted with EtOAc and

water, and the aqueous layer was extracted twice with hexane. The

combined organic layers were washed with a saturated aqueous NaCl

solution. The organic layer was dried over anhydrous Na₂SO₄, ﬁltered

with a glass ﬁlter and evaporated under reduced pressure. The crude

product was puriﬁed by column chromatography (hexane/EtOAc =

5:1) to provide the titled compound 16E′ (6.1 g, 77%) as a colorless

2-(tert-Butyldimethylsilyl)-4-(1,3-dioxolan-2-yl)-6-iodophe-

nol (42). An oven-dried round-bottom ﬂask was charged with 41

(0.80 g, 1.51 mmol), capped with an inlet adapter with a three-way

stopcock, then evacuated, and backﬁlled with nitrogen. THF (15 mL,

0.10 M) was added into the ﬂask via a syringe, cooled to −78 °C, and

stirred for 10 min. n-BuLi (1.65 M in hexane, 1.2 mL, 2.0 mmol) was

added to the solution at −78 °C, warmed to room temperature, and

stirred for 2 h. The reaction mixture was quenched with a saturated

aqueous NH₄Cl and extracted with EtOAc. The aqueous layer was

extracted twice with EtOAc. The combined organic layers were

washed with a saturated aqueous NaCl solution. The organic layer was

dried over anhydrous Na₂SO₄and concentrated under reduced

pressure. The crude product was puriﬁed by column chromatography

(hexane/EtOAc = 10:1) to provide the titled compound 42 as a

1

solid. Mp 67−69 °C. H NMR (500 MHz, CDCl₃) δ: 0.35 (9 H, s),

0.40 (6 H, s), 0.79 (9 H, s), 4.05−4.12 (4 H, m), 5.84 (1 H, s), 7.67 (2

H, s). ¹³C NMR (125 MHz, CDCl₃) δ: −4.0, 0.5, 18.1, 26.9, 65.3,

102.9, 108.6−120.8 (4 C, m), 132.4, 135.5, 135.9, 136.1, 136.3, 136.7,

155.2. IR (CHCl₃): 1603, 1396, 1352, 1238, 1194, 1146 cm⁻¹. HRMS

calcd for C₂₅H₂₈F₉O₃SSi₂(M + H)⁺m/z: 635.1154, found 635.1149.

ASSOCIATED CONTENT

* Supporting Information

■

S

1

colorless solid (0.53 g, 88%). Mp 112−113 °C. H NMR (500 MHz,

Optimization of 3-borylbenzyne precursors (Tables S1−S3),

interaction of ions with silyl- and borylbenzynes 4 and 5

(Tables S4−S6), ¹H and ¹³C NMR spectra for all new

compounds, and Cartesian Coordinates for ground and

transition state structures. This material is available free of

charge via the Internet at http://pubs.acs.org.

CDCl₃) δ: 0.30 (6 H, s), 0.89 (9 H, s), 0.78 (9 H, s), 4.06 (4 H, m),

5.53 (1 H, s), 5.70 (1 H, s), 7.36 (1 H, d, J = 2.0 Hz), 7.80 (1 H, d, J =

2.0 Hz). ¹³C NMR (125 MHz, CDCl₃) δ: −4.8, 17.6, 27.0, 65.2, 87.2,

102.8, 123.5, 131.2, 135.7, 137.4, 159.4. IR (CHCl₃): 3489, 2955,

2928, 2886, 2856, 1589, 1560, 1413, 1359, 1248 cm⁻¹. HRMS calcd

for C₁₅H₂₄IO₃Si (M + H⁺) m/z: 407.0539, found 407.0551.

2-(tert-Butyldimethylsilyl)-4-(1,3-dioxolan-2-yl)-6-

(trimethylsilyl)phenol (43). An oven-dried round-bottom ﬂask was

charged with 42 (63 mg, 0.15 mmol), capped with an inlet adapter

with a three-way stopcock, then evacuated, and backﬁlled with

nitrogen. CH₂Cl₂(1.0 mL, 0.25 M) was added into the ﬂask via a

syringe, cooled to 0 °C, and stirred for 10 min. Triethylamine (26 μL,

0.19 mmol) and trimethylsilyl chloride (25 μL, 0.19 mmol) were

added into the ﬂask, and the mixture was stirred at room temperature

for 1 h. The reaction mixture was evaporated under reduced pressure.

Hexane was added to the residue, ﬁltered through a pad of short pad of

Celite and concentrated under reduced pressure to aﬀord (5-(1,3-

dioxolan-2-yl)-3-iodo-2-((trimethylsilyl)oxy)phenyl)(tert-butyl)-

dimethylsilane. The crude product was dissolved in THF (1.0 mL, 0.25

M) and stirred at −78 °C for 10 min. n-BuLi (1.5 M in hexane, 0.12

mL, 0.19 mmol) was added to the mixture and stirred at room

temperature for 1 h. The reaction mixture was quenched with a

saturated aqueous NH₄Cl and evaporated under reduced pressure.

The residue was extracted with hexane and water. The aqueous layer

was extracted twice with hexane. The combined organic layers were

washed with a saturated aqueous NaCl solution. The organic layer was

dried over anhydrous Na₂SO₄and solvent was removed under reduced

pressure. The crude product was puriﬁed by column chromatography

(hexane/EtOAc = 20:1) to provide the titled compound 43 (23 mg,

42%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ: 0.32 (9 H, s),

0.39 (6 H, s), 0.92 (9 H, s), 4.08 (4 H, m), 5.16 (1 H, s), 5.74 (1 H, s),

7.41 (1 H, d, J = 2.0 Hz), 7.50 (1 H, d, J = 2.0 Hz). ¹³C NMR (125

MHz, CDCl₃) δ: −4.6, −0.9, 17.6, 26.5, 65.2, 104.2, 120.3, 125.0,

128.6, 134.9, 136.3, 166.5. IR (CHCl₃): 3609, 2955, 1587, 1576, 1409,

1364, 1238 cm⁻¹. HRMS calcd for C₁₈H₃₃O₃Si₂(M + H⁺) m/z:

353.1968, found 353.1982.

2-(tert-Butyldimethylsilyl)-4-methyl-6-(trimethylsilyl)phenyl

1,1,2,2,3,3,4,4,4-Nonaﬂuorobutane-1-sulfonate (16E′). Com-

pound 43 (4.4 g, 12.5 mmol) and 18-crown-6 (3.3 g, 12.5 mmol)

were dissolved in THF (125 mL, 0.10 M) and stirred at 0 °C for 10

min. NaH (0.75 g, 18.7 mmol) was added to the mixture and stirred at

0 °C for 30 min. Then, nonaﬂuorobutanesulfonyl ﬂuoride²³(0.62 mL,

3.7 mmol) was added to the solution and stirred at 80 °C for 20 h. The

reaction mixture was quenched with water and evaporated under

reduced pressure. The residue was extracted with EtOAc and water,

and the aqueous layer was extracted twice with hexane. The combined

organic layers were washed with a saturated aqueous NaCl solution.

The organic layer was dried over anhydrous Na₂SO₄, ﬁltered with a

glass ﬁlter, and concentrated under reduced pressure (this reaction did

AUTHOR INFORMATION

Corresponding Author

*E-mail: akai@u-shizuoka-ken.ac.jp; tokiwa@rikkyo.ac.jp.

Notes

■

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This research was supported by Grant-in-Aid for Scientiﬁc

Research (no. 19890182) and the global COE program from

the Ministry of Education, Culture, Sports, Science and

Technology (Japan). We thank the Uehara Memorial

Foundation and Hoansha foundation for the ﬁnancial support

extended to this study. The Japan Society for the Promotion of

Science is gratefully acknowledged for predoctoral fellowship to

A.T.

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dx.doi.org/10.1021/jo302802b | J. Org. Chem. XXXX, XXX, XXX−XXX

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Regiocomplementary cycloaddition reactions of boryl- and silylbenzynes with 1,3-dipoles: Selective synthesis of benzo-fused azole derivatives

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