2-[(Neopentyl glycolato)boryl]phenyl Triflates and Halides for Fluoride Ion-Mediated Generation of Functionalized Benzynes

Article abstract of DOI:10.1002/adsc.201500315

2-[(Neopentyl glycolato)boryl]phenyl trifluoromethanesulfonates (triflates) and halides have been developed as new benzyne precursors, which generate benzynes at 120°C in the presence of a fluoride ion. There are two major features of these types of precu

Full text of DOI:10.1002/adsc.201500315

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DOI: 10.1002/adsc.201500315
2-[(Neopentyl glycolato)boryl]phenyl Triflates and Halides for
Fluoride Ion-Mediated Generation of Functionalized Benzynes
Takashi Ikawa,a,b,* Rika Yamamoto,a Akira Takagi,a,b Toyohiro Ito,b
Kazunori Shimizu,a Masahiko Goto,b Yoshitaka Hamashima,b and Shuji Akaia,b,*
a
Graduate School of Pharmaceutical Sciences, Osaka University, Yamadaoka, Suita, Osaka, Japan
Fax: (+81)-6-6879-8212 (TI), (+81)-6-6879-8210 (AT); e-mail: ikawa@phs.osaka-u.ac.jp or akai@phs.osaka-u.ac.jp
School of Pharmaceutical Sciences, University of Shizuoka, Yada, Suruga-ku, Shizuoka, Shizuoka, Japan
b
Received: March 29, 2015; Revised: May 21, 2015; Published online: July 14, 2015
Dedicated to Prof. Stephen L. Buchwald on the occasion of his 60th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500315.
Abstract: 2-[(Neopentyl glycolato)boryl]phenyl tri- without using any protecting groups. The in-situ-gen-
fluoromethanesulfonates (triflates) and halides have erated benzynes underwent [4+2], (3+2), and
been developed as new benzyne precursors, which [2+2]cycloadditions to give the benzo-fused multicy-
generate benzynes at 1208C in the presence of a fluo- clic compounds while maintaining such functional
ride ion. There are two major features of these types groups. In particular, 4-aminobenzyne was generated
of precursors. First, they generate benzynes bearing for the first time and underwent the Diels–Alder re-
various reactive functional groups, such as carbonyl, action with the free primary amino group remaining
cyano, bromo, and primary amino groups. Second, intact.
these precursors were directly synthesized through
either the palladium-catalyzed Miyaura borylation of
2-iodophenol derivatives or ortho-selective iodina- Keywords: benzynes; boronic acid esters; borylation;
tion of the corresponding boronic acids as key steps Diels–Alder reaction; microwave heating
Introduction
strongly on the availability of the cycloaddition sub-
strates.[4b,e,f]
Reactions of benzynes are among the oldest and most
Among the reported benzyne precursors, 2-(trime-
potent multi-bond-forming processes for the synthesis thylsilyl)phenyl triflates[5] have gained a high reputa-
of polysubstituted benzenes.[1,2] A wide variety of ben- tion among the most widely used precursors because
zyne precursors has been developed and expanded benzynes can be generated from them under fluoride
the usefulness of benzyne reactions by providing di- ion-mediated mild conditions that have led to the de-
verse arynophiles.[3] However, the generation of velopment of a huge variety of new benzyne reactions
“functionalized benzynes” still remains a challenge.[4] in the past few decades.[1,3b] However, the regioselec-
This is because most of the well-known precursors, tive introduction of functional groups to 2-(trimethyl-
such as 2-halophenyl trifluoromethanesulfonates (tri- silyl)phenyl triflate was not possible,[4f] and the syn-
flates)[3c,4i] and 2-(trimethylsilyl)phenyl triflates,[3b,4g] theses of these compounds from commercially avail-
originally required highly reactive n-BuLi for the gen- able materials required lengthy processes.[4f,g] There-
eration of benzynes from these precursors and/or the fore, for further extension of the synthetic utility of
preparation of the precursors themselves, which re- benzynes, the development of new benzyne precur-
sulted in poor compatibility with reactive functional sors that meet the following three requirements has
groups, such as carbonyl and halo groups. Other syn- been highly desired: (i) generation of benzynes via
thetic methods for the benzyne precursors have in- the treatment of a fluoride ion, (ii) preparation of pre-
volved [4+2]cycloadditions to construct the benzene cursors under milder reaction conditions under which
rings; however, these required many steps, and the many reactive functional groups can be tolerated, and
substituents of the benzenes were limited and relied (iii) ready availability of the precursors in fewer steps.
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Scheme 1. Previously reported generation of benzynes 2 from 2-borylphenyl triflates 1, and this work.
In this context, 2-borylphenyl triflates 1 can be nacolato)boryl]-6-(trimethylsilyl)phenyl
triflate
3
good candidates for such new precursors because using CsF in MeCN at 608C in the presence of furan
1 would be easily synthesized through either stoichio- 4a (Scheme 2)[8a] or amine.[8b] Although we originally
metric[6] or catalytic[7] aromatic C B bond-forming re- intended to generate 3-[(pinacolato)boryl]benzyne,
À
actions in which many functional groups would be tol- the fluoride ion preferentially attacked the boron of
erated. More importantly, our group discovered that 3, rather than the silicon, to generate 5. These results
3-(trimethylsilyl)benzyne was generated from 2-[(pi- encouraged us to develop a new method for benzyne
nacolato)boryl]-6-(trimethylsilyl)phenyl triflate using generation using the combination of 2-borylphenyl
a fluoride ion (vide infra),[8a] which was the first exam- triflates 1 and fluoride ions.
ple of benzyne generation from 2-borylphenyl triflates
We preliminarily examined the feasibility of the
1. Hosoya et al. then reported the generation of ben- generation of benzyne 2a from a simplified precursor,
zynes 2 from 1 via treatment with alkyllithium at 2-[(pinacolato)boryl]phenyl triflate (1a), by trapping
À788C followed by warming to room temperature with furan 4b to afford Diels–Alder adduct 7a. Under
[Scheme 1, Eq. (1)].[9] The thus-generated 2 reacted reaction conditions (2.0 equiv. of CsF, MeCN, 608C)
with various arynophiles; however, the generation of similar to those of Scheme 2, the benzyne generation
benzynes with reactive functional groups was not re- was extremely slow, and gave only a trace amount of
ported, probably due to the need for t-BuLi or s- 7a even after 24 h (Table 1, entry 1). After investiga-
BuLi. Greaney et al. reported the palladium-catalyzed tion of the reaction temperature, we found that the
[2+2+2]cycloaddition of 2, which was generated from benzyne generation was significantly accelerated by
1 using Pd(dba)2, t-BuOK, and DPEPhos in toluene microwave heating at 1208C, giving 7a in 56% yield
at 1008C [Scheme 1, Eq. (2)].[10] The examples were after 2 h (entry 2). Then, we examined other boron
limited to this particular trimerization of benzynes substituents (1b–1i) for more efficient generation of
possessing relatively stable substituents such as me- 2a under the same reaction conditions (entries 3–11)
thoxy, chloro, and fluoro groups.
and found that 2-[(neopentyl glycolato)boryl]phenyl
In this paper, we report the generation of benzynes triflate (1b) provided the best yield of 7a (85%,
2, bearing reactive functional groups, such as bromo,
ester, carbonyl, cyano, and amino groups, from 2-
[(neopentyl glycolato)boryl]phenyl triflates 1 using
a fluoride ion under microwave heating conditions
[Scheme 1, Eq. (3)]. One of the most important
points in this work is the finding that the (neopentyl
glycolato)boryl [B(neop)] group was the best substitu-
ent among the various boryl groups we have exam-
ined for both the generation of benzynes from 1 and
the preparation of 1.
Results and Discussion
As mentioned above, we incidentally discovered the
generation of 3-(trimethylsilyl)benzyne 5 from 2-[(pi-
Scheme 2. Our initial findings on benzyne generation from
2-boryl-6-silylphenyl triflate 3.[8a]
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2-[(Neopentyl glycolato)boryl]phenyl Triflates and Halides
Table 1. Optimization of boryl groups for benzyne generation from 2-borylphenyl
triflates 1a–1i.[a]
[a]
Reaction conditions: 1 (1.0 equiv.), 4b (10 equiv.), CsF (2.0 equiv.) in MeCN
(0.10M) at 1208C using microwaves for 2 h unless otherwise noted.
The yield was determined via analysis of the H NMR spectra of crude products
[b]
1
using 1,4-dimethoxybenzene as an internal standard.
The reaction was performed at 608C for 24 h using an oil bath.
Isolated yield of 7a is shown in parentheses.
[c]
[d]
entry 4). Other 2-borylphenyl triflates 1c–1i gave poor functionalized 2-halophenols.[7b,12] The third route em-
yields of 7a (0–32%, entries 5–11). The better reactivi- ployed halogen-metal exchange using i-PrMgCl fol-
ty of 1b than 1a was also proven by heating in an oil lowed by borylation under non-cryogenic conditions
bath at 608C for 24 h (comparison of entries 1 and 3). (route C).[6b,c] This approach was also a good candi-
These results indicated that the (neopentyl glycolato)- date owing to its functional group compatibility and
boryl [B(neop)] group should be one of the best sub- the high reactivity of the intermediate Grignard re-
stituents for the fluoride ion-mediated generation of agents toward B(OR)3.[13] However, this route re-
benzynes from 1.
quired protection of the hydroxy group of 9 and
Next, we planned three synthetic routes to func- therefore required more steps for the synthesis of
tionalized benzyne precursors 1, as shown in 1 than did the others. Accordingly, we decided to syn-
Scheme 3. The first route included the regioselective thesize 1 from 9 through route B.
À
C H borylation of phenol derivatives 8 reported by
The syntheses of several precursors 1 through route
Hartwig et al.[7c] (route A). Although this route was B are shown in Table 2. Notably, the key Pd-catalyzed
the shortest, the compatibility with various functional Miyaura borylation using B2(neop)2 of all 2-iodophe-
groups was unknown, and the installation of B(neop) nol derivatives 9b–9e bearing methoxycarbonyl,
instead of a (pinacolato)boryl [B(pin)] group might acetyl, cyano, and bromo groups provided the corre-
not have been possible under the reported reaction sponding 2-[(neop)boryl]phenols 11b–11e in moderate
conditions.[11] The second route was through Miyaura to good yields under the standard reaction conditions
borylation of 2-halophenols 9 (route B).[7a] This route without loss of the functional groups (entries 2–
was thought to be promising because Wang et al. had 5).[7b,12] The major by-products of this transformation
already achieved similar borylations of hindered and were proto-deiodinated phenols. To our delight, the
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Scheme 3. Synthetic strategies for functionalized benzyne precursors 1.
final triflation reactions of 11b–11e using Tf2O with
pyridine also worked very well, affording functional- creased from 45% (0.25 h) to 79% (1 h) over time, al-
ized benzyne precursors 1b and 1j–1m. though 1j was completely consumed within 0.25 h
It is worth noting that the yield of 7b gradually in-
The reaction conditions for the generation of ben- (Table 3, entries 6–9). These results suggested that
zyne 2b bearing a methoxycarbonyl group were opti- a relatively stable boronate 12 was plausibly generat-
mized as a typical case for the functionalized ben- ed (Figure 1) and gradually produced 2b while being
zynes, which was monitored by the Diels–Alder reac- heated at 1208C.
tion with furan 4b (Table 3). Under the microwave
The most common side reaction of this benzyne
heating conditions, several fluoride sources and sol- generation was the protodeborylation of 1j to produce
vents were tested; it was found that CsF in MeCN triflate 14 in 8–25% yield. The yield of 14 clearly in-
gave the best yield of 7b (79%, entries 1–7). The best creased and that of 7b decreased when hygroscopic
reaction temperature was 1208C among our several CsF was used without drying prior to use. The proto-
studies (entries 6, 10, 11, and 13). A similar 72% yield deborylation probably took place through the forma-
of 7b was obtained under the same reaction condi- tion of boronate intermediate 13, generated by the
tions in a sealed Schlenk flask heated at 1208C in an addition of H2O to the boron atom ahead of a fluoride
oil bath without microwave irradiation (entry 12).
ion, followed by the intramolecular dissociation of 13
to produce 14 (Scheme 4).
Table 2. Syntheses of various 2-[(neop)boryl]phenyl triflates 1.
[a]
[b]
Reaction conditions:
9
(1.0 equiv.), B2(neop)2 (1.2 equiv.), PdCl2(dppf)
(3.0 mol%), AcOK (3.0 equiv.) in DMSO (0.13M) at 808C.
Reaction conditions: 11 (1.0 equiv.), Tf2O (1.5 equiv.), pyridine (3.0 equiv.) in
CH2Cl2 (0.20M) at room temperature.
Isolated yield.
Overall isolated yield from 9e.
[c]
[d]
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2-[(Neopentyl glycolato)boryl]phenyl Triflates and Halides
Table 3. Optimization of reaction conditions for benzyne generation from 2-[(neop)bor-
yl]phenyl triflate 1j.[a]
[a]
Reaction conditions: 1j (1.0 equiv.), 4b (10 equiv.), FÀ source (2.0 equiv.) in solvent
(0.10M) using microwaves.
The yield of 7b was determined via analysis of the H NMR spectra of crude products
[b]
1
using 1,1,2,2-tetrachloroethane as an internal standard.
18-c-6=18-crown-6.
3.0 equiv. of 4b were used.
Isolated yield of 7b is shown in parenthesis.
Oil bath heating.
[c]
[d]
[e]
[f]
Figure 1. Proposed structure of boronate intermediate 12.
Scheme 4. A plausible mechanism for the formation of by-
product 14.
The developed new method for benzyne generation zyne 2c, 4-cyanobenzyne 2d, and 4-bromobenzyne 2e
was found to be similarly effective for other function- were generated with these reactive functional groups
alized precursors 1k–1m, and Diels–Alder adducts 7c– intact.
7e bearing acetyl, cyano, and bromo groups were ob-
Benzyne 2a could also be generated from 2-halo-
tained in 50–69% isolated yields (Table 4, entries 1– phenylboronic acid neopentyl glycol esters 16 and 17a
3). These results clearly indicated that 4-acetylben- under the same reaction conditions (entries 4 and
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Table 4. Diels–Alder reactions of benzynes 2a and 2c–2f, generated from 1k–1m, 16, 17a,
and 17b with 2,5-dimethylfuran (4b).[a]
[a]
Reaction conditions: 1 (1.0 equiv.), 4b (10 equiv.), CsF (2.0 equiv.) in MeCN (0.10M) at
1208C using microwaves for 2 h.
The yield of 7 was determined via analysis of the H NMR spectra of crude products
[b]
1
using 1,1,2,2-tetrachloroethane as an internal standard.
Isolated yield of 7 in parentheses.
Reaction was performed for 1 h.
[c]
[d]
5).[14] This discovery enabled the generation of 4-ami- ple of an experimentally generated benzyne bearing
nobenzyne 2f from 17b, which was effectively pre- a free amino group.[16]
pared via the ortho-selective iodination of boronic
The reaction scope was explored with several ary-
acid[15] followed by esterification. The in-situ-generat- nophiles 18 in Table 5. Functionalized benzynes 2b, 2c
ed 2f underwent the Diels–Alder reaction with 4b to and 2e, generated from 1j, 1k and 1m underwent (3+
afford adduct 7f (entry 6), and this is the first exam- 2) and [2+2]cycloaddition reactions with benzyl azide
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Table 5. Reaction scope of benzynes 2b, 2c, and 2e, generated from 1j, 1k and 1m, with
arynophiles 18a–18c.
[a]
Reaction conditions: 1 (1.0 equiv.), 18 (10 equiv.), CsF (2.0 equiv.) in MeCN (0.10M) at
1208C using microwave for 2 h.
The yield of 19 was determined via analysis of the H NMR spectra of crude products
[b]
1
using 1,1,2,2-tetrachloroethane as an internal standard. Isolated yields are given in pa-
rentheses.
[c]
[d]
[e]
[f]
Ratio of distal-19a and proximal-19a=1.0:1.
Total isolated yield of distal-19 and proximal-19.
Ratio of distal-19b and proximal-19b=1.4:1.
Ratio of distal-19c and proximal-19c=1.0:1.
Ratio of distal-19d and proximal-19d=1.2:1.
[g]
18a (entries 1 and 2), ketene acetal 18b (entry 3) and sponding boronic acids as the key steps. Such func-
nitrone 18c (entry 4) under the same conditions to tionalized precursors generated the benzynes at
produce 19a–d in 52–68% isolated yields, although 1208C (either by microwave irradiation or in an oil
the regioselectivities of these reactions were very low. bath) with the aid of CsF, which immediately under-
went [4+2], (3+2), and [2+2]cycloaddition reactions
with a furan or an azide or a ketene acetal or a nitrone
Conclusions
to give the corresponding benzo-fused multicyclic
compounds while maintaining the functional groups.
This benzyne chemistry should be synthetically val-
In conclusion, we have developed a new method for
benzyne generation using 2-[(neopentyl glycolato)bor- uable because the functionalized benzyne precursors
yl]phenyl triflates and halides as potent precursors. are readily synthesized from commercially available
These precursors, possessing reactive functional materials in a few steps and also because the benzyne
groups such as 4-methoxycarbonyl, 4-acetyl, 4-bromo, generation reactions are easy to perform. Efforts to
and 4-amino groups, can be directly prepared through apply new functionalized benzynes to the syntheses of
either Miyaura borylation of the corresponding 2-io- biologically active compounds are currently under-
dophenols or ortho-selective iodination of the corre- way.
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room temperature, the reaction was quenched with H2O.
The mixture was extracted with EtOAc (this process was re-
peated thrice), and the combined organic phase was washed
with brine and dried over MgSO4. The organic phase was fil-
tered and concentrated under reduced pressure (for calcu-
lating NMR yield, 1,4-dimethoxybenzene or 1,1,2,2-tetra-
chloroethane was added as an internal standard). The resi-
due was purified by flash column chromatography on silica
gel to provide 7 or 19.
Experimental Section
General Experimental Details
All reactions were carried out under an argon or nitrogen
atmosphere. Microwave reactions were conducted using a Bi-
otageꢁ Initiator Classic in a single purpose reaction flask
for the benzyne generation from 1, 16 and 17. Schlenk flasks
were used for benzyne generation from 1 and Miyaura bory-
lation of 9. A round-bottom flask with a 3-way stopcock was
used for other reactions. Anhydrous THF, CH2Cl2 and
MeCN were purchased from Wako Pure Chemical Indus-
tries and used without purification or purified with a Glass
Contour solvent dispensing system (Nikko Hansen, Osaka,
Japan) using two packed columns of activated molecular
sieves. Anhydrous DMSO, anhydrous pyridine, and 2,5-di-
methylfuran (4b) were distilled over CaH2. 2-(5,5-Dimethyl-
1,3,2-dioxaborinan-2-yl)phenol (11a),[17] 1-(4-hydroxy-3-io-
dophenyl)ethan-1-one (9c),[18] 4-hydroxy-3-iodobenzonitrile
(9d),[19] and 4-bromo-2-iodophenol (9e)[20] were prepared ac-
cording to the literature. All other reagents were purchased
from Wako Pure Chemical Industries, Tokyo Chemical In-
dustry, Sigma–Aldrich, Combi-Blocks, Kanto Chemicals and
Kishida Chemical and used without further purification.
Flash chromatography was performed with Silica gel 60,
spherical (40–50 mm) for aryl boronates, and Silica gel 60N,
spherical neutral (40–50 mm) for other chemicals, purchased
from Kanto Chemicals. Melting points were recorded on
a Yanagimoto melting point apparatus and are uncorrected.
IR spectra were obtained on a Shimadzu FT-IR-8400S.
1H NMR, 13C NMR and NOESY spectra were recorded on
a JEOL JMN-ECA-500 (1H: 500 MHz, 13C: 125 MHz) or
a JEOL JMN-ECS-400 (1H: 400 MHz, 13C: 100 MHz) or
a JEOL JMN-AL-300 (1H: 300 MHz, 13C: 75 MHz) instru-
ment with chemical shifts reported in ppm relative to the re-
sidual deuterated solvent. The mass spectra were recorded
on a JEOL JMS-S3000 (MALDI) 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. All new products were further characterized by high
resolution mass spectroscopy (HR-MS). All carbons bearing
boron substituents could not be observed in 13C NMR due
to quadrupolar relaxation.
1,4-Dimethyl-1,4-dihydro-1,4-epoxynaphthalene
(7a)
(Table 1, entry 4):[21] Following General Procedure A, a mix-
ture of CsF (61 mg, 0.40 mmol, dried using oil bath), 1b
(68 mg, 0.20 mmol), 2,5-dimethylfuran 4b (0.21 mL,
2.0 mmol) in MeCN (2.0 mL, 0.10M) was stirred at 1208C
using microwaves for 1 h. The reaction mixture (total NMR
yield: 85%, 1,4-dimethoxybenzene was used as an internal
standard) was purified by flash column chromatography on
silica gel (hexane/EtOAc=10:1) to provide 7a as a pale
1
yellow oil; yield: 29 mg (84%). H NMR (300 MHz, CDCl3):
d=1.90 (6H, s), 6.78 (2H, s), 6.96–6.99 (2H, m), 7.12–7.15
(2H, m); 13C NMR (75 MHz, CDCl3): d=15.2, 88.5, 118.3,
124.7, 146.8, 152.6.
Methyl 1,4-dimethyl-1,4-dihydro-1,4-epoxynaphthalene-6-
carboxylate (7b) (Table 3, entry 6):[22] Following General
Procedure A, a mixture of CsF (39 mg, 0.25 mmol, dried
over a flame), 1j (51 mg, 0.13 mmol), 2,5-dimethylfuran 4b
(0.14 mL, 1.3 mmol) in MeCN (1.3 mL, 0.10M) was stirred
at 1208C using microwaves for 2 h. The reaction mixture
(total NMR yield: 76%, 1,1,2,2-tetrachloroethane was used
as an internal standard) was purified by flash column chro-
matography on silica gel (hexane/EtOAc=5:1) to provide
7b as
a
colorless oil; yield: 20 mg (67%). 1H NMR
(500 MHz, CDCl3): d=1.90 (3H, s), 1.92 (3H, s), 3.89 (3H,
s), 6.75 (1H, d, J=5.0 Hz), 6.78 (1H, d, J=5.0 Hz), 7.17
(1H, d, J=7.5 Hz), 7.74 (1H, s), 7.76 (1H, d, J=7.5 Hz);
13C NMR (125 MHz, CDCl3): d=15.1, 52.0, 88.5, 118.0,
118.8, 127.0, 127.9, 146.2, 147.0, 153.3, 158.1, 167.0.
1-(1,4-Dimethyl-1,4-dihydro-1,4-epoxynaphthalen-6-yl)-
ethan-1-one (7c) (Table 4, entry 1): Following General Pro-
cedure A, a mixture of CsF (44 mg, 0.29 mmol, dried using
oil bath), 1k (51 mg, 0.13 mmol), 2,5-dimethylfuran 4b
(0.15 mL, 1.4 mmol) in MeCN (1.4 mL, 0.10M) was stirred
at 1208C using microwaves for 2 h. The reaction mixture
(total NMR yield: 77%, 1,1,2,2-tetrachloroethane was used
as an internal standard) was purified by flash column chro-
matography on silica gel (hexane/EtOAc=5:1) to provide
7c as a pale yellow oil; yield: 15 mg (50%). 1H NMR
(300 MHz, CDCl3): d=1.91 (3H, s), 1.92 (3H, s), 2.57 (3H,
s), 6.75 (1H, d, J=5.5 Hz), 6.79 (1H, d, J=5.5 Hz), 7.18
(1H, d, J=7.5 Hz), 7.65 (1H, brd, J=7.5 Hz), 7.70 (1H,
brs); 13C NMR (75 MHz, CDCl3): d=15.1, 26.8, 88.5, 88.6,
117.1, 118.0, 127.3, 134.4, 146.0, 147.1, 153.6, 158.2, 197.7; IR
(neat): n=1678 cmÀ1; HR-MS (MALDI): m/z=215.1069,
calcd. for C14H15O2 [M+H+]: 215.1067.
1,4-Dimethyl-1,4-dihydro-1,4-epoxynaphthalene-6-carbo-
nitrile (7d) (Table 4, entry 2): Following General Procedure
A, a mixture of CsF (49 mg, 0.32 mmol, dried using oil
bath), 1l (59 mg, 0.16 mmol), 2,5-dimethylfuran 4b (0.17 mL,
1.6 mmol) in MeCN (1.6 mL, 0.10M) was stirred at 1208C
using microwaves for 2 h. The reaction mixture (total NMR
yield: 70%, 1,1,2,2-tetrachloroethane was used as an internal
standard) was purified by flash column chromatography on
General Procedure for Benzyne Generations
(General Procedure A, Table 1, Table 3, Table 4 and
Table 5)
CsF (2.0 equiv.) was added to a microwave vial and flame-
dried under reduced pressure (or dried at 2008C using an oil
bath under reduced pressure overnight) and back-filled with
argon. Another flask was charged with 2-borylphenyl triflate
1 or halide 16 or 17 (1.0 equiv.) and dried via azeotropic dis-
tillation with toluene and back-filled with argon. To the
flask with 1 (or 16, 17) was added 2,5-dimethylfuran (4b)
(10 equiv.) or benzyl azide (10a) (10 equiv.) or ketene acetal
18b (10 equiv.) via a syringe, [or nitrone 18c (10 equiv.)
under argon flow] and the mixture was added to another
flask containing CsF via cannula with anhydrous MeCN
(0.10M). This mixture was heated to 1208C in a microwave
reactor and stirred for 2 h. After cooling the mixture to
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2-[(Neopentyl glycolato)boryl]phenyl Triflates and Halides
silica gel (hexane/EtOAc=10:1) to provide 7d as a brown
oil; yield: 21 mg (64%). 1H NMR (300 MHz, CDCl3): d=
1.895 (3H, s), 1.900 (3H, s), 6.76 (1H, d, J=5.5 Hz), 6.79
(1H, d, J=5.5 Hz), 7.20 (1H, d, J=7.0 Hz), 7.33 (1H, brs),
7.36 (1H, brd, J=7.0 Hz); 13C NMR (75 MHz, CDCl3): d=
14.96, 14.99, 88.5, 88.6, 108.5, 118.7, 119.2, 120.9, 130.7,
146.3, 146.8, 154.2, 158.2; IR (neat): n=2226 cmÀ1; HR-MS
(MALDI): m/z=198.0905, calcd. for C13H12NO [M+H+]:
198.0913.
6-Bromo-1,4-dimethyl-1,4-dihydro-1,4-epoxynaphthalene
(7e) (Table 4, entry 3):[22] Following General Procedure A,
a mixture of CsF (42 mg, 0.28 mmol, dried using oil bath),
1m (58 mg, 0.14 mmol), 2,5-dimethylfuran 3a (0.15 mL,
1.4 mmol) in MeCN (1.4 mL, 0.10M) was stirred at 1208C
using microwaves for 1 h. The reaction mixture (total NMR
yield: 82%, 1,1,2,2-tetrachloroethane was used as an internal
standard) was purified by flash column chromatography on
silica gel (hexane/EtOAc =10:1) to provide 7e as a colorless
oil; yield: 24 mg (69%). 1H NMR (300 MHz, CDCl3): d=
1.87 (6H, s), 6.74 (1H, d, J=5.5 Hz), 6.78 (1H, d, J=
5.5 Hz), 6.98 (1H, d, J=7.5 Hz), 7.11 (1H, dd, J=1.5,
7.5 Hz), 7.25 (1H, d, J=1.5 Hz); 13C NMR (75 MHz,
CDCl3): d=15.1, 88.45, 88.53, 118.6, 119.7, 122.2, 127.2,
146.3, 146.9, 151.9, 155.4.
6-Amino-1,4-dimethyl-1,4-dihydro-1,4-epoxynaphthalene
(7f) (Table 4, entry 6): Following General Procedure A,
a mixture of CsF (37 mg, 0.24 mmol, dried using oil bath),
17b (41 mg, 0.12 mmol), 2,5-dimethylfuran 4b (0.13 mL,
1.2 mmol) in MeCN (1.2 mL, 0.10M) was stirred at 1208C
using microwaves for 2 h. The reaction mixture (total NMR
yield: 65%, 1,1,2,2-tetrachloroethane was used as an internal
standard) was purified by flash column chromatography on
silica gel (hexane/EtOAc =3:1–2:1) to provide 7f as
a brown oil; yield: 8.5 mg (38%). 1H NMR (300 MHz,
CDCl3): d=1.84 (3H, s), 1.85 (3H, s), 6.25 (1H, dd, J=2.0,
7.5 Hz), 6.59 (1H, d, J=2.0 Hz), 6.70 (1H, d, J=5.0 Hz),
6.76 (1H, d, J=5.0 Hz), 6.89 (1H, d, J=7.5 Hz); 13C NMR
(75 MHz, CDCl3): d=15.3, 15.4, 88.38, 88.45, 108.3, 109.2,
118.8, 142.6, 143.3, 145.7, 147.3, 154.6; IR (neat): n=3352,
3456 cmÀ1; HR-MS (MALDI): m/z=188.1066, calcd. for
C12H14NO [M+H+]: 188.1070.
1-Benzyl-5-bromo-1H-benzo[d][1,2,3]triazole[4f] and 1-
benzyl-6-bromo-1H-benzo[d][1,2,3]triazole[4f] (distal- and
proximal-19b) (Table 5, entry 2): Following General Proce-
dure A, a mixture of CsF (49 mg, 0.32 mmol, dried using oil
bath), 1m (67 mg, 0.16 mmol), benzyl azide 18a (0.20 mL,
1.6 mmol) in MeCN (1.6 mL, 0.10M) was stirred at 1208C
using microwaves for 1 h. The reaction mixture (total NMR
yield: 84%, 1,1,2,2-tetrachloroethane was used as an internal
standard) was purified by flash column chromatography on
silica gel (hexane/EtOAc =5:1) to provide distal-19b and
proximal-19b as a colorless solid; yield: 32 mg (68%, distal/
proximal=1.4:1). 1H NMR (500 MHz, CDCl3): d=5.80 (2/
2.4H, s), 5.82 (2.8/2.4H, s), 7.21–7.36 (13.4/2.4H, m), 7.43
(1/2.4H, dd, J=1.5, 9.0 Hz), 7.47 (1.4/2.4H, dd, J=1.5,
9.0 Hz), 7.53 (1/2.4H, brs), 7.92 (1/2.4H, d, J=9.0 Hz), 8.21
(1.4/2.4H, d, J=1.5 Hz); 13C NMR (125 MHz, CDCl3): d=
52.3, 52.5, 111.0, 112.6, 117.2, 121.2, 121.7, 122.6, 127.50,
127.52, 127.7, 128.6, 129.06, 129.10, 130.7, 131.7, 133.8,
134.19, 134.21, 145.1, 147.5.
Methyl 7,7-dimethoxybicyclo[4.2.0]octa-1(6),2,4-triene-3-
carboxylate and methyl 8,8-dimethoxybicyclo[4.2.0]octa-
1(6),2,4-triene-3-carboxylate (distal- and proximal-19c)
(Table 5, entry 3): Following General Procedure A, a mixture
of CsF (36 mg, 0.24 mmol, dried over a flame), 1j (47 mg,
0.12 mmol), 1,1-dimethoxyethene 18b (0.11 mL, 1.2 mmol)
in MeCN (1.2 mL, 0.10M) was stirred at 1208C using micro-
waves for 2 h. The reaction mixture (total NMR yield: 74%,
1,1,2,2-tetrachloroethane was used as an internal standard)
was purified by flash column chromatography on silica gel
(hexane/EtOAc=10:1) to provide a mixture of distal-19c
and proximal-19c as a colorless oil; yield: 13 mg (51%,
1
distal/proximal=1:1). H NMR (400 MHz, CDCl3): d=3.38
(2/2H, s), 3.39 (2/2H, s), 3.449 (6/2H, s), 3.454 (6/2H, s),
3.906 (3/2H, s), 3.909 (3/2H, s), 7.30 (1/2H, d, J=8.0 Hz),
7.34 (1/2H, d, J=8.0 Hz), 7.90 (1/2H, brs), 7.95 (1/2H, brs),
8.00 (1/2H, dd, J=8.0, 1.5 Hz), 8.08 (1/2H, dd, J=8.0,
1.5 Hz); 13C NMR (100 MHz, CDCl3): d=42.7, 43.2, 51.4,
51.5, 52.1, 52.2, 105.0, 120.9, 122.2, 123.9, 125.2, 129.07,
129.10, 131.7, 131.8, 141.4, 145.2, 147.0, 149.8, 167.0, 167.1;
IR (neat): n=1717, 1722, 2937, 2994 cmÀ1
;
HR-MS
(MALDI): m/z=223.0963, calcd. for C12H15O4 [M+H+]:
223.0965.
Methyl 1-benzyl-1H-benzo[d][1,2,3]triazole-5-carboxyla-
te[4f] and methyl 1-benzyl-1H-benzo[d][1,2,3]triazole-6-car-
boxylate[4f] (distal- and proximal-19a) (Table 5, entry 1):
Following General Procedure A, a mixture of CsF (55 mg,
0.36 mmol, dried over a flame), 1j (71 mg, 0.18 mmol),
benzyl azide 18a (0.23 mL, 1.8 mmol) in MeCN (1.8 mL,
0.10M) was stirred at 1208C using microwaves for 1 h. The
reaction mixture (total NMR yield: 80%, 1,1,2,2-tetrachloro-
ethane was used as an internal standard) was purified by
flash column chromatography on silica gel (hexane/
EtOAc=3:1) to provide a mixture of distal-19a and proxi-
mal-19a as a colorless solid; yield: 33 mg (68%, distal/proxi-
1-(2-(tert-Butyl)-3-phenyl-2,3-dihydrobenzo[d]isoxazol-6-
yl)ethan-1-one and 1-(2-(tert-butyl)-3-phenyl-2,3-dihydro-
benzo[d]isoxazol-5-yl)ethan-1-one (distal- and proximal-
19d) (Table 5, entry 4): Following General Procedure A,
a mixture of CsF (31 mg, 0.20 mmol, dried over a flame), 1k
(39 mg, 0.10 mmol), N-tert-butyl-a-phenylnitrone 18c
(0.12 g, 1.0 mmol) in MeCN (1.0 mL, 0.10M) was stirred at
1208C using microwaves for 2 h. The reaction mixture (total
NMR yield: 71%, 1,1,2,2-tetrachloroethane was used as an
internal standard) was purified by flash column chromatog-
raphy on silica gel (hexane/EtOAc=5:1) to provide a mix-
ture of distal-19d and proximal-19d as a colorless oil: yield:
17 mg (54%, distal/proximal=1.2:1).
1
mal=1:1). H NMR (500 MHz, CDCl3): d=3.95 (3/2H, s),
1
3.96 (3/2H, s), 5.87 (2/2H, s), 5.89 (2/2H, s), 7.27–7.38 (11/
2H, m), 8.02 (1/2H, dd, J=1.5, 9.0 Hz), 8.09 (1/2H, dd, J=
1.0, 8.5 Hz), 8.10 (1/2H, d, J=9.0 Hz), 8.16 (1/2H, brs), 8.80
(1/2H, brs); 13C NMR (125 MHz, CDCl3): d=52.5, 52.6,
109.6, 112.3, 120.0, 123.0, 124.7, 126.4, 127.56, 127,59, 128.3,
128.7, 129.1, 129.3, 132.5, 134.26, 134.33, 135.0, 146.1, 148.3,
166.4, 166.5.
For distal-19d: pale yellow solid; mp 84–878C; H NMR
(400 MHz, CDCl3): d=1.18 (9H, s), 2.56 (3H, s), 5.62 (1H,
s), 6.96 (1H, d, J=7.5 Hz), 7.25–7.44 (7H, m); 13C NMR
(125 MHz, CDCl3): d=25.4, 26.8, 61.2, 66.8, 106.4, 121.7,
123.6, 127.3, 127.7, 128.7, 135.3, 138.2, 143.0, 156.6, 197.4; IR
(neat): n=1682, 2973 cmÀ1
;
HR-MS (MALDI): m/z=
296.1644, calcd. for C19H22NO2 [M+H+]: 296.1645. The re-
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Takashi Ikawa et al.
giochemistry of distal-19d was confirmed by NOESY experi-
ments.
entry 1):[9a] An oven-dried round-bottom flask (50 mL) was
charged with 11a[17] (0.66 g, 3.2 mmol) and capped with an
inlet adapter with a 3-way stopcock and then evacuated and
back-filled with argon. Anhydrous CH2Cl2 (16 mL, 0.20M)
was added via a syringe and the mixture was cooled to 08C.
Anhydrous pyridine (0.77 mL, 9.6 mmol) and trifluorome-
thanesulfonic anhydride (0.79 mL, 4.8 mmol) were added
dropwise and the reaction was allowed to warm up to room
temperature and stirred for 30 min. The reaction was
quenched with H2O and the mixture was extracted with
CH2Cl2 (this process was repeated thrice). The combined or-
ganic phase was washed with brine and dried over MgSO4.
The organic phase was filtered and concentrated under re-
duced pressure. The residue was purified by flash column
chromatography on silica gel (hexane/EtOAc =1:1) to pro-
vide the title compound 1b as a pale yellow oil; yield: 1.0 g
For proximal-19d: pale yellow solid; mp 85–888C;
1H NMR (400 MHz, CDCl3): d=1.18 (9H, s), 2.47 (3H, s),
5.60 (1H, s), 6.83 (1H, d, J=8.5 Hz), 7.25–7.41 (5H, m),
7.55 (1H, brs), 7.83 (1H, dd, J=1.5, 8.5 Hz); 13C NMR
(125 MHz, CDCl3): d=25.4, 26.4, 61.4, 66.5, 106.5, 124.5,
127.3, 127.7, 128.8, 130.9, 131.06, 131.11, 143.1, 160.0, 196.2;
IR (neat): n=1672, 2975 cmÀ1; HR-MS (MALDI): m/z=
296.1647, calcd. for C19H22NO2 [M+H+]: 296.1645. The re-
giochemistry of proximal-19d was confirmed by NOESY ex-
periments.
Synthesis of Benzyne Precursor Candidates 1
2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl
tri-
A
1
(95%). H NMR (300 MHz, CDCl3): d=1.05 (6H, s), 3.80
fluoromethanesulfonate (1a) (Table 1, entries 1 and 2):[9a]
(4H, s), 7.17 (1H, brd, J=7.5 Hz), 7.36 (1H, brt, J=7.5 Hz),
7.48 (1H, dt, J=1.5, 7.5 Hz), 7.86 (1H, dd, J=1.5, 7.5 Hz);
13C NMR (75 MHz, CDCl3): d=21.8, 31.8, 72.3, 118.9 (q, J=
320 Hz), 121.0, 127.6, 132.3, 136.5, 154.2.
mixture of 2-hydroxyphenylboronic acid (2.1 g, 15 mmol)
and pinacol (2.7 g, 23 mmol) was stirred in CH2Cl2 (75 mL,
0.20m) at room temperature for 3 h. The reaction was
quenched with H2O and the mixture was extracted with
CH2Cl2 (this process was repeated thrice). The combined or-
ganic phase was washed with brine and dried over Na2SO4.
The organic solvent was removed under reduced pressure to
provide 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phe-
nol (20)[23] as a colorless oil.
2-{(3aR,6aS)-Tetrahydro-4H-cyclopenta[d][1,3,2]dioxa-
borol-2-yl}phenyl trifluoromethanesulfonate (1c) (Table 1,
entry 5): A round-bottom flask (10 mL) was charged with
(1R,2S)-cyclopentane-1,2-diol (18 mg, 0.18 mmol) and 1i
(35 mg, 0.13 mmol) and CH2Cl2 (0.65 mL, 0.20M) was
added. The mixture and stirred overnight at room tempera-
ture. The reaction was quenched with H2O and the mixture
was extracted with CH2Cl2 (this process was repeated
thrice). The combined organic phase was washed with brine
and dried over MgSO4. The organic phase was filtered and
concentrated under reduced pressure to provide the title
compound 1c as a pale yellow oil; yield: 49 mg (quant.).
1H NMR (300 MHz, CDCl3): d=1.60–1.81 (4H, m), 2.08
(2H, dd, J=5.5, 13.0 Hz), 5.05 (2H, brd, J=4.0 Hz), 7.22
(1H, brd, J=7.5 Hz), 7.39 (1H, brt, J=7.5 Hz), 7.53 (1H,
brt, J=7.5 Hz), 7.86 (1H, brd, J=7.5 Hz); 13C NMR
(125 MHz, CDCl3): d=21.4, 34.4, 83.3, 118.8 (q, J=318 Hz),
121.0, 127.8, 133.0, 137.3, 154.2; IR (neat): n=1424,
2967 cmÀ1; HR-MS (MALDI): m/z=359.0348, calcd. for
C12H12BO5F3NaS [M+Na+]: 359.0343.
2-(1,3,2-Dioxaborolan-2-yl)phenyl trifluoromethanesulfo-
nate (1d) (Table 1, entry 6): A flame-dried round-bottom
flask (10 mL) was charged with 1i (35 mg, 0.13 mmol) and
capped with inlet adapter with a 3-way stopcock and then
evacuated and back-filled with argon. Anhydrous CH2Cl2
(0.65 mL, 0.20M) and anhydrous ethylene glycol (7.3 mL,
0.13 mmol) were added via syringes. After the reaction mix-
ture was stirred overnight at room temperature, toluene
(1.0 mL) was added and the mixture was concentrated
under reduced pressure to provide the title compound 1d as
a colorless oil; yield: 36 mg (93%). 1H NMR (300 MHz,
CDCl3): d=4.43 (4H, s), 7.25 (1H, d, J=7.5 Hz), 7.41 (1H,
t, J=7.5 Hz), 7.55 (1H, dt, J=1.5, 7.5 Hz), 7.88 (1H, dd, J=
1.5, 7.5 Hz); 13C NMR (125 MHz, CDCl3): d=66.2, 118.8 (q,
J=320 Hz), 121.1, 127.9, 133.2, 137.3, 154.2; IR (neat): n=
2915, 2996 cmÀ1; HR-MS (MALDI): m/z=319.0028, calcd.
for C9H8BO5F3NaS [M+Na+]: 319.0030.
To a solution of 20 in anhydrous CH2Cl2 (75 mL) were
added anhydrous pyridine (3.6 mL, 45 mmol) and trifluoro-
methanesulfonic anhydride (3.8 mL, 23 mmol) at 08C. The
reaction mixture was stirred for 3 h at 08C. The reaction
was quenched with H2O and the mixture was extracted with
CH2Cl2 (this process was repeated thrice). The combined or-
ganic phase was washed with brine and dried over MgSO4.
The organic solvent was removed under reduced pressure.
The residue was purified by flash column chromatography
on silica gel (hexane/EtOAc =5:1) to provide the title com-
1
pound 1a as a colorless oil; yield: 5.4 g (quant.). H NMR
(300 MHz, CDCl3): d=1.42 (12H, s), 7.22 (1H, brd, J=
7.5 Hz), 7.37 (1H, brt, J=7.5 Hz), 7.51 (1H, dt, J=2.0,
7.5 Hz), 7.88 (1H, dd, J=2.0, 7.5 Hz); 13C NMR (75 MHz,
CDCl3): d=24.7, 84.6, 118.8 (q, J=318 Hz), 121.0, 127.7,
132.9, 137.2, 154.2.
(2-{[(Trifluoromethyl)sulfonyl]oxy}phenyl)boronic
acid
(1i) (Table 1, entry 11):[9a] To a solution of 2-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)phenyl trifluoromethanesul-
fonate 1a (5.4 g, 15 mmol) and NaIO4 (9.6 g, 45 mmol) in
THF (24 mL) and H2O (6.0 mL) was added 1.0N HCl
(45 mL, 45 mmol) at room temperature and stirred for 2 h.
The reaction was quenched with saturated Na2S2O3 solution
and the mixture was extracted with EtOAc (this process was
repeated thrice). The combined organic phase was washed
with brine and dried over Na2SO4. The organic solvent was
removed under reduced pressure. The residue was purified
by recrystallization using cyclohexane to provide the title
compound 1i as a colorless solid; yield: 3.0 g (75%); mp
1
100–1048C. H NMR (300 MHz, CDCl3): d=4.96 (2 OH, s),
7.30 (1H, brd, J=7.5 Hz), 7.44 (1H, brt, J=7.5 Hz), 7.56
(1H, brt, J=7.5 Hz), 7.88 (1H, brd, J=7.5 Hz); 13C NMR
(125 MHz, CDCl3): d=118.6 (q, J=318 Hz), 121.1, 128.3,
132.9, 136.7, 153.3.
2-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)phenyl trifluoro-
methanesulfonate (1b) (Table 1, entries 3 and 4, Table 2,
2-{1H-Naphtho[1,8-de][1,3,2]diazaborinin-2(3H)-yl}phenyl
trifluoromethanesulfonate (1e) (Table 1, entry 7): A mixture
of 1i (50 mg, 0.19 mmol) and 1,8-diaminonaphthalene
(29 mg, 0.19 mmol) was stirred in CH2Cl2 (0.93 mL, 0.20M)
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2-[(Neopentyl glycolato)boryl]phenyl Triflates and Halides
at room temperature for 2 h. The reaction was quenched
with H2O and the mixture was extracted with CH2Cl2 (this
process was repeated thrice). The combined organic phase
was washed with brine and dried over MgSO4. The organic
phase was filtered and concentrated under reduced pressure.
The residue was purified by flash column chromatography
on silica gel (hexane/Et2O=5:1) to provide the title com-
pound 1e as a pale yellow solid; yield: 72 mg (99%) mp 71–
0.74 mmol), KHF2 (0.14 g, 1.8 mmol), MeOH (1.7 mL,
0.44M), and H2O (0.42 mL, 1.8M) was stirred for 59 h at
room temperature. The precipitate in the mixture was fil-
tered and washed with MeCN to provide the title compound
1h as a colorless solid; yield: 0.27 g (quant.); mp 240–2448C.
1H NMR (500 MHz, DMSO-d6): d=7.07 (1H, d, J=7.5 Hz),
7.24 (1H, t, J=7.5 Hz), 7.28 (1H, dt, J=2.0, 7.5 Hz), 7.53
(1H, dd, J=2.0, 7.5 Hz); 13C NMR (125 MHz, DMSO-d6):
d=118.6 (q, J=318 Hz), 119.4, 127.2, 128.0, 135.0, 153.9; IR
(KBr): n=3038 cmÀ1; HR-MS (MALDI): m/z=354.9404,
calcd. for C7H4BO3F6NaSK [M+Na+]: 354.9408.
1
758C. H NMR (500 MHz, CDCl3): d=6.08 (2NH, brs), 6.41
(2H, d, J=8.0 Hz), 7.08 (2H, d, J=8.0 Hz), 7.14 (2H, t, J=
8.0 Hz), 7.35 (1H, d, J=8.0 Hz), 7.46 (1H, t, J=8.0 Hz),
7.54 (1H, dt, J=2.0, 8.0 Hz), 7.67 (1H, dd, J=2.0, 8.0 Hz);
13C NMR (125 MHz, CDCl3): d=106.3, 118.3, 118.6 (q, J=
318 Hz), 119.9, 121.6, 127.6, 128.4, 131.8, 134.3, 136.2, 140.4,
152.4; IR (neat): n=3053, 3424 cmÀ1; HR-MS (MALDI):
m/z=392.0611, calcd. for C17H12BN2O3F3S [M+]: 392.0608.
2-(6-Methyl-4,8-dioxo-1,3,6,2-dioxazaborocan-2-yl)phenyl
trifluoromethanesulfonate (1f) (Table 1, entry 8): A round-
bottom flask with a stir bar was charged with 1i (0.30 g,
1.1 mmol), N-methyliminodiacetic acid (0.16 g, 1.1 mmol)
and evacuated and back-filled with argon. Anhydrous tolu-
ene (10 mL) and anhydrous DMSO (0.61 mL) were added
to the mixture. The flask was equipped with a Dean–Stark
trap, a Dimroth condenser with a 3-way stopcock and the
reaction was stirred at 1308C under argon. Anhydrous tolu-
ene was added to the reaction mixture at the indicated
times (5 mL at 2 h 40 min, 10 mL at 13 h, 10 mL at 21 h).
After stirring for 22 h, MeCN (6.0 mL) was added at room
temperature and the mixture was concentrated under re-
duced pressure. The crude product was filtered through
a pad of silica gel (MeCN/Et2O=1:1) and the filtrate was
concentrated under reduced pressure. The residue was fil-
tered again through a pad of silica gel (Et2O, and MeCN/
Et2O=1:1) and the filtrate was concentrated under reduced
pressure to provide the title compound 1f as a colorless
solid; yield: 0.39 g (93%); mp 157–1638C. 1H NMR
(500 MHz, DMSO-d6): d=2.62 (3H, s), 4.21 (2H, d, J=
17.0 Hz), 4.44 (2H, d, J=17.0 Hz), 7.41 (1H, brd, J=
7.5 Hz), 7.54 (1H, dt, J=1.5, 7.5 Hz), 7.60 (1H, dd, J=1.5,
7.5 Hz), 7.66 (1H, dt, J=1.5, 7.5 Hz); 13C NMR (125 MHz,
DMSO-d6): d=47.5, 62.4, 118.4 (q, J=319 Hz), 120.7, 128.5,
General Procedure of Miyaura Borylation for the
Synthesis of Boronate 11 (General Procedure B,
Table 2)
An oven-dried Schlenk flask was charged with 9, bis(neo-
pentyl glycolato)diboron (1.2 equiv.), [1,1’-bis(diphenylphos-
phino)ferrocene]dichloropalladium(II) (0.03 equiv.), and
AcOK (3.0 equiv.). After the Schlenk flask was evacuated
and back-filled with argon, anhydrous DMSO (0.13M) was
added via a syringe, and the reaction was allowed to warm
up to 808C and stirred for several hours. The reaction was
quenched with H2O and the mixture was extracted with
Et2O (this process was repeated thrice). The combined or-
ganic phase was washed with brine and dried over MgSO4.
The organic phase was filtered and concentrated under re-
duced pressure. Then, the residue was purified by flash
column chromatography on silica gel to provide 11.
General Procedure for Triflation in the Synthesis of
Triflate 1 (General Procedure C, Table 2)
A flame-dried round-bottom flask was charged with 11,
capped with an inlet adapter with a 3-way stopcock, and
then evacuated and back-filled with argon. Anhydrous
CH2Cl2 (0.20M) was added via a syringe and the mixture
was cooled to 08C. Anhydrous pyridine (3.0 equiv.) and tri-
fluoromethanesulfonic anhydride (1.5 equiv.) were added via
syringes. The reaction was allowed to warm to room temper-
ature and stirred for several hours. The reaction was
quenched with H2O and the mixture was extracted with
CH2Cl2 (this process was repeated thrice). The combined or-
ganic phase was washed with brine and dried over MgSO4.
The organic phase was filtered and concentrated under re-
duced pressure. Then, the residue was purified by flash
column chromatography on silica gel to provide 1.
Methyl 3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-hydroxy-
benzoate (11b) (Table 2, Entry 2): Following General Proce-
dure B, a mixture of 9b[23] (1.0 g, 3.6 mmol), bis(neopentyl
glycolato)diboron (0.98 g, 4.3 mmol), 1,1’-bis(diphenylphos-
phino)ferrocene]dichloropalladium(II) (80 mg, 0.11 mmol)
and AcOK (1.1 g, 11 mmol) in anhydrous DMSO (29 mL,
0.13M) was stirred at 808C for 10 h. The reaction mixture
was purified by flash column chromatography (hexane/
EtOAc/AcOH=2:1:0.1) to provide 11b as a colorless solid;
yield: 0.65 g (68%); mp 66–738C. 1H NMR (300 MHz,
CDCl3): d=1.05 (6H, s), 3.83 (4H, s), 3.87 (3H, s), 6.86
(1H, d, J=8.5 Hz), 8.01 (1H, dd, J=2.5, 8.5 Hz), 8.34 (1H,
d, J=2.5 Hz), 8.72 (OH, s). 13C NMR (75 MHz, CDCl3) d:
21.8, 32.0, 51.7, 72.4, 115.7, 121.3, 134.8, 137.7, 167.0, 167.6;
132.3, 136.4, 153.6, 168.8; IR (neat): n=1424, 1767 cmÀ1
HR-MS (MALDI): m/z=404.0198, calcd. for
C12H11BNO7F3NaS [M+Na+]: 404.0194.
;
2-(6-Methyl-1,3,6,2-dioxazaborocan-2-yl)phenyl trifluoro-
methanesulfonate (1g) (Table 1, entry 9): A flame-dried
round-bottom flask (10 mL) was charged with 1i (35 mg,
0.13 mmol) and CH2Cl2 (0.65 mL, 0.20M). N-Methyldietha-
nolamine (15 mL, 0.13 mmol) was added via a syringe and
stirred overnight at room temperature. Toluene (1.0 mL)
was added to the crude mixture and the solvent was re-
moved under reduced pressure to provide the title com-
pound 1g as a colorless solid; yield: 53 mg (quant.); mp 70–
1
738C. H NMR (500 MHz, CDCl3); d=2.47 (3H, s), 3.09–
3.21 (4H, m), 4.09–4.20 (4H, m), 7.14 (1H, brd, J=8.0 Hz),
7.30–7.36 (2H, m), 7.79 (1H, brd, J=6.5 Hz); 13C NMR
(125 MHz, CDCl3): d=46.6, 61.5, 62.2, 118.7 (q, J=318 Hz),
120.4, 127.6, 130.0, 136.5, 155.0; IR (neat): n=2866 cmÀ1
;
HR-MS
(MALDI):
m/z=354.0792,
calcd.
for
C12H16BNO5F3S [M+H+]: 354.0789.
Potassium trifluoro(2-{[(trifluoromethyl)sulfonyl]oxy}phe-
nyl)borate (1h) (Table 1, entry 10): A mixture of 1i (0.20 g,
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Takashi Ikawa et al.
IR (neat): n=1717, 2961, 3376 cmÀ1; HR-MS (MALDI): m/
z=265.1248, calcd. for C13H18BO5 [M+H+]: 265.1242.
yield: 0.28 g (30%); mp 99–1028C. 1H NMR (300 MHz,
CDCl3): d=1.06 (6H, s), 3.84 (4H, s), 6.88 (1H, d, J=
8.5 Hz), 7.57 (1H, dd, J=2.0, 8.5 Hz), 7.94 (1H, d, J=
2.0 Hz), 8.78 (OH, s); 13C NMR (75 MHz, CDCl3): d=21.7,
32.1, 72.5, 102.8, 116.7, 119.5, 136.5, 140.3, 166.9; IR (neat):
n=2222, 3370 cmÀ1; HR-MS: (MALDI): m/z=254.0969,
calcd. for C12H14BNO3Na [M+Na+]: 254.0959.
Methyl 3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-4-{[(tri-
fluoromethyl)sulfonyl]oxy}benzoate (1j) (Table 2, entry 2):
Following General Procedure C, a mixture of 11b (0.38 g,
1.4 mmol), anhydrous pyridine (0.35 mL, 4.3 mmol) and tri-
fluoromethanesulfonic anhydride (0.35 mL, 2.1 mmol) in
CH2Cl2 (7.1 mL, 0.20M) was stirred for 19 h at room tem-
perature. The reaction mixture was purified by flash column
chromatography on silica gel (hexane/EtOAc=5:1) to pro-
vide 1j as a pale yellow solid; yield: 0.52 g (93%); mp 70–
748C. 1H NMR (300 MHz, CDCl3): d=1.05 (6H, s), 3.82
(4H, s), 3.94 (3H, s), 7.25 (1H, d, J=9.0 Hz), 8.14 (1H, dd,
J=2.5, 9.0 Hz), 8.53 (1H, d, J=2.5 Hz); 13C NMR (75 MHz,
CDCl3): d=21.8, 31.8, 52.4, 72.3, 118.8 (q, J=318 Hz), 121.3,
4-Cyano-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl
trifluoromethanesulfonate (1l) (Table 2, entry 4): Following
General Procedure C, a mixture of 11d (0.22 mg, 1.0 mmol),
trifluoromethanesulfonic anhydride (0.24 mL, 1.5 mmol) and
anhydrous pyridine (0.23 mL, 2.9 mmol) in anhydrous
CH2Cl2 (4.8 mL, 0.20M) was stirred for 2 h at room temper-
ature. The reaction mixture was purified by flash column
chromatography on silica gel (hexane/EtOAc=20:1 to 10:1)
to provide 1l as a pale yellow oil; yield: 0.31 g (90%).
1H NMR (300 MHz, CDCl3): d=1.23 (6H, s), 3.81 (4H, s),
7.29 (1H, d, J=8.5 Hz), 7.77 (1H, dd, J=2.0, 8.5 Hz), 8.19
(1H, d, J=2.0 Hz); 13C NMR (125 MHz, CDCl3): d=21.7,
31.8, 72.4, 112.2, 117.4, 118.7 (q, J=319 Hz), 122.3, 135.8,
129.5, 133.7, 138.1, 156.9, 165.8; IR (neat): n=1732 cmÀ1
HR-MS (MALDI): m/z=419.0545, calcd. for
C14H16BO7F3NaS [M+Na+]: 419.0554.
;
1-[3-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-4-hydroxyphe-
nyl]ethan-1-one (11c) (Table 2, entry 3): Following General
Procedure B, a mixture of 9c (1.0 g, 3.8 mmol), bis(neopen-
tyl glycolato)diboron (1.0 g, 4.6 mmol), [1,1’-bis(diphenyl-
140.8, 156.2; IR (neat): n=1427, 2236 cmÀ1
; HR-MS
(MALDI): m/z=386.0448, calcd. for C13H13BNO5F3NaS
phosphino)ferrocene]dichloropalladium(II)
(94 mg,
[M+Na+]: 386.0452.
0.11 mmol) and AcOK (1.1 g, 11 mmol) in anhydrous
DMSO (31 mL, 0.13M) was stirred at 808C for 18.5 h. The
reaction mixture was purified by flash column chromatogra-
phy on silica gel (hexane/EtOAc=1:1) and the residue was
recrystallized by cyclohexane to provide 11c as a pale
yellow solid; yield: 0.40 g (41%, contaminated with 2% of
4-Bromo-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenol
(11e) (Table 2, entry 5): Following General Procedure B,
a mixture of 9e (1.0 g, 3.4 mmol), bis(neopentyl glycolato)di-
boron (0.76 g, 3.4 mmol), [1,1’-bis(diphenylphosphino)ferro-
cene]dichloropalladium(II) (82 mg, 0.10 mmol) and AcOK
(0.99 g, 10 mmol) in anhydrous DMSO (23 mL, 0.13M) was
stirred at 808C for 15 h. The reaction mixture was purified
by flash column chromatography on silica gel (hexane/
EtOAc=1:1) to provide 11e; yield: 0.52 g (54%).
4’-hydroxyacetophenone);
mp
105–1118C.
1H NMR
(300 MHz, CDCl3): d=1.06 (6H, s), 2.56 (3H, s), 3.84 (4H,
s), 6.88 (1H, d, J=8.5 Hz), 7.99 (1H, dd, J=2.5, 8.5 Hz),
8.26 (1H, d, J=2.5 Hz), 8.77 (OH, s); 13C NMR (75 MHz,
CDCl3): d=21.7, 26.3, 32.0, 72.3, 115.9, 129.1, 133.5, 137.0,
The mixture of 11e contaminated with by-product was pu-
rified by flash column chromatography on silica gel (hexane/
EtOAc=5:1) to provide 11e as a colorless solid; yield:
167.8, 197.0; IR (neat): n=1674, 3374 cmÀ1
; HR-MS
1
(MALDI): m/z=271.1129, calcd. for C13H17BO4Na [M+
76 mg (8%); mp 85–888C. H NMR (300 MHz, CDCl3): d=
Na+]: 271.1112.
1.04 (6H, s), 3.81 (4H, s), 6.73 (1H, d, J=9.0 Hz), 7.39 (1H,
dd, J=2.5, 9.0 Hz), 7.70 (1H, d, J=2.5 Hz), 8.27 (OH, s);
13C NMR (125 MHz, CDCl3): d=21.7, 32.0, 72.4, 111.6,
4-Acetyl-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl
trifluoromethanesulfonate (1k) (Table 2, entry 3): Following
General Procedure C, a mixture of 11c (0.35 g, 1.4 mmol),
trifluoromethanesulfonic anhydride (0.35 mL, 2.1 mmol), an-
hydrous pyridine (0.34 mL, 4.2 mmol) in anhydrous CH2Cl2
(7.0 mL, 0.20M) was stirred for 1.5 h at room temperature.
The reaction mixture was purified by flash column chroma-
tography on silica gel (hexane/EtOAc=1:1) to provide 1k as
117.6, 135.7, 137.3, 162.6; IR (neat): n=2963, 3408 cmÀ1
;
HR-MS (MALDI): m/z=284.0210, calcd. for C11H14BO3Br
[M+]: 284.0214.
4-Bromo-2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl
trifluoromethanesulfonate (1m) (Table 2, entry 5): Following
General Procedure B, a mixture of 9e (1.0 g, 3.4 mmol), bis-
(neopentyl glycolato)diboron (0.76 g, 3.4 mmol), [1,1’-bis(di-
a
colorless solid; yield: 0.54 g (quant.); mp 42–488C.
1H NMR (500 MHz, CDCl3): d=1.05 (6H, s), 2.64 (3H, s),
3.82 (4H, s), 7.26 (1H, d, J=9.0 Hz), 8.07 (1H, dd, J=2.5,
9.0 Hz), 8.43 (1H, d, J=2.5 Hz); 13C NMR (75 MHz,
CDCl3): d=21.8, 26.7, 31.8, 72.3, 118.8 (q, J=318 Hz), 121.6,
132.2, 136.0, 137.0, 156.9, 196.7; IR (neat): n=1427, 1694,
2965 cmÀ1; HR-MS (MALDI): m/z=403.0595, calcd. for
C14H16BO6F3NaS [M+Na+]: 403.0605.
3-(5,5-Dimethyl-1,3,2-dioxaborinan-2-yl)-4-hydroxybenzo-
nitrile (11d) (Table 2, entry 4): Following General Procedure
B, a mixture of 9d (1.0 g, 4.1 mmol), bis(neopentyl glycola-
to)diboron (1.1 g, 4.9 mmol), [1,1’-bis(diphenylphosphino)-
ferrocene]dichloropalladium(II) (0.10 g, 0.12 mmol) and
AcOK (1.2 g, 12 mmol) in anhydrous DMSO (33 mL,
0.13M) was stirred at 808C for 13.5 h. The reaction mixture
was purified by flash column chromatography on silica gel
(hexane/EtOAc=1:1) to provide 11d as a colorless solid;
phenylphosphino)ferrocene]dichloropalladium(II)
(82 mg,
0.10 mmol) and AcOK (0.99 g, 10 mmol) in anhydrous
DMSO (23 mL, 0.13M) was stirred at 808C and stirred for
15 h. The crude product was used for next reaction without
further purification.
Following General Procedure C, a mixture of the above
obtained crude 11e, trifluoromethanesulfonic anhydride
(3.4 mL, 21 mmol) and anhydrous pyridine (2.5 mL,
31 mmol) in anhydrous CH2Cl2 (52 mL, 0.065M) was stirred
for 4 h at room temperature. The reaction mixture was puri-
fied by flash column chromatography on silica gel (hexane/
CH2Cl2 =5:1) to provide 1m as a colorless solid; yield: 1.3 g
1
(30% from 9e); mp 30–318C. H NMR (300 MHz, CDCl3):
d=1.04 (6H, s), 3.80 (4H, s), 7.05 (1H, d, J=8.5 Hz), 7.58
(1H, dd, J=2.5, 8.5 Hz), 7.97 (1H, d, J=2.5 Hz); 13C NMR
(75 MHz, CDCl3): d=21.8, 31.8, 72.4, 118.8 (q, J=318 Hz),
2298
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FULL PAPERS
2-[(Neopentyl glycolato)boryl]phenyl Triflates and Halides
121.7, 122.9, 135.1, 139.3, 153.0; IR (neat): n=2965 cmÀ1
HR-MS (MALDI): m/z=438.9590, calcd. for
C12H13BO5F3NaSBr [M+Na+]: 438.9604.
;
8.5 Hz), 6.88 (1H, d, J=2.5 Hz), 7.54 (1H, d, J=8.5 Hz);
13C NMR (125 MHz, CDCl3): d=21.9, 31.7, 72.3, 85.1, 118.4,
122.1, 139.8, 145.3; IR (neat): n=2960, 3372, 3458 cmÀ1
;
HR-MS (MALDI): m/z=332.0317, calcd. for C11H16BNO2I
[M+H+]: 332.0313.
Synthesis of Other Benzyne Precursors, 2-Haloaryl
Boronates 16, 17a and 17b
2-(2-Bromophenyl)-5,5-dimethyl-1,3,2-dioxaborinane
(16)
Acknowledgements
(Table 4, entry 4): 2,2-Dimethyl-1,3-propanediol (0.62 g,
6.0 mmol) was added to a solution of 2-bromophenylboronic
acid (1.0 g, 5.0 mmol) in CH2Cl2 (10 mL, 0.50M) and the
mixture was stirred for 3.5 h at room temperature. The reac-
tion was quenched with H2O and the mixture was extracted
with CH2Cl2 (this process was repeated thrice). The com-
bined organic phase was washed with brine and dried over
MgSO4. The organic phase was filtered and concentrated
under reduced pressure to provide 16 as a colorless solid;
This work was financially supported by the JSPS KAKENHI
(grant numbers 23790017 and 25460018) and the Platform
for Drug Discovery, Informatics, and Structural Life Science
from the MEXT foundation. TI also expresses thanks for the
grant from the University of Shizuoka.
yield: 1.3 g (quant.); mp 28–308C. 1H NMR (300 MHz, References
CDCl3): d=1.07 (6H, s), 3.81 (4H, s), 7.20 (1H, dt, J=2.0,
7.5 Hz), 7.27 (1H, dt, J=1.0, 7.5 Hz), 7.52 (1H, dd, J=1.0,
7.5 Hz), 7.56 (1H, dd, J=2.0, 7.5 Hz); 13C NMR (75 MHz,
CDCl3): d=21.8, 31.6, 72.4, 126.2, 126.9, 131.0, 132.5, 135.3;
IR (neat): n=2961, 3063 cmÀ1; HR-MS (MALDI): m/z=
291.0163, calcd. for C11H14BO2NaBr [M+Na+]: 291.0162.
2-(2-Iodophenyl)-5,5-dimethyl-1,3,2-dioxaborinane (17a)
(Table 4, entry 5): 2,2-Dimethyl-1,3-propanediol (0.47 g,
4.5 mmol) was added to a solution of 2-iodophenylboronic
acid (0.74 g, 3.0 mmol) in CH2Cl2 (20 mL, 0.15M) and the
mixture was stirred for 18 h at room temperature. The reac-
tion was quenched with H2O and the mixture was extracted
with CH2Cl2 (this process was repeated thrice). The com-
bined organic phase was washed with brine and dried over
MgSO4. The organic phase was filtered and concentrated
under reduced pressure to provide 17a as a pale yellow oil;
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yield: 0.95 g (quant.). H NMR (300 MHz, CDCl3): d=1.08
(6H, s), 3.80 (4H, s), 7.03 (1H, dt, J=2.0, 7.5 Hz), 7.31 (1H,
dt, J=1.0, 7.5 Hz), 7.50 (1H, dd, J=2.0, 7.5 Hz), 7.83 (1H,
dd, J=1.0, 7.5 Hz); 13C NMR (75 MHz, CDCl3): d=21.9,
31.7, 72.3, 99.7, 126.8, 131.1, 135.1, 139.3; IR (neat): n=
2962 cmÀ1; HR-MS (MALDI): m/z=339.0050, calcd. for
C11H14BO2NaI [M+Na+]: 339.0024.
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(17b) (Table 4, entry 6): To a solution of 3-aminophenylbor-
onic acid (0.50 g, 3.7 mmol) and silver sulfate (0.63 g,
2.0 mmol)[15] in EtOH (12 mL) was added dropwise a solu-
tion of iodine (0.93 g, 3.7 mmol) in EtOH (12 mL). The re-
action mixture was stirred for 6 h at room temperature. The
mixture was filtered through a short pad of Celite using
CH2Cl2. The filtrate was washed with brine and dried over
Na2SO4. The organic solvent was removed under reduced
pressure. The crude product (0.81 g) was dissolved in
CH2Cl2 (10 mL, 0.37M) then 2,2-dimethylpropanediol
(0.38 g, 3.7 mmol) was added to the mixture. The reaction
mixture was stirred at room temperature for 9 h. The reac-
tion was quenched with H2O and the mixture was extracted
with CH2Cl2 (this process was repeated twice). The com-
bined organic phase was dried over Na2SO4 and the solvent
was removed under reduced pressure. The residue was puri-
fied by flash column chromatography (hexane/EtOAc =2:1)
to provide the titled compound 17b as a dark blown solid;
yield: 0.73 g (60%); mp 84–878C. 1H NMR (300 MHz,
CDCl3): d=1.06 (6H, s), 3.78 (4H, s), 6.43 (1H, dd, J=2.5,
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