Generation of 3-borylbenzynes, their regioselective Diels-Alder reactions, and theoretical analysis

Article abstract of DOI:10.1016/j.tet.2013.03.016

3-Borylbenzynes were generated in situ from 6-boryl-2-iodophenyl trifluoromethanesulfonates using i-PrMgCl·LiCl and applied to Diels-Alder reactions with substituted furans and pyrroles. The reactions allowed good functional group compatibility and produced the cycloadducts in high yields with high distal selectivities. Effective conversion of the boryl group of the products was achieved. A series of these reactions provides a new method for producing multifunctionalized benzo-fused aromatic compounds. Additionally, the regioselectivities of these Diels-Alder reactions were theoretically analyzed by DFT calculations to find that the reactions were mainly controlled by the electrostatic effect and aryne distortion caused by the boryl group.

Full text of DOI:10.1016/j.tet.2013.03.016

Tetrahedron 69 (2013) 4338e4352
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Generation of 3-borylbenzynes, their regioselective DielseAlder
reactions, and theoretical analysis
Akira Takagi a, Takashi Ikawa a, Yurio Kurita a, Kozumo Saito a, Kenji Azechi a,
,
,
*
Masahiro Egi a, Yuji Itoh b, Hiroaki Tokiwa b, Yasuyuki Kita c y, Shuji Akai a
a School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Suruga-ku, Shizuoka, Shizuoka 422-8526, Japan
b Department of Chemistry, Rikkyo University, 3-34-1, Nishi-Ikebukuro, Toshima, Tokyo 171-8501, Japan
c Graduate School of Pharmaceutical Sciences, Osaka University, 1-6, Yamadaoka, Suita, Osaka 567-0871, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Borylbenzynes were generated in situ from 6-boryl-2-iodophenyl trifluoromethanesulfonates using i-
PrMgCl$LiCl and applied to DielseAlder reactions with substituted furans and pyrroles. The reactions
allowed good functional group compatibility and produced the cycloadducts in high yields with high
distal selectivities. Effective conversion of the boryl group of the products was achieved. A series of these
reactions provides a new method for producing multifunctionalized benzo-fused aromatic compounds.
Additionally, the regioselectivities of these DielseAlder reactions were theoretically analyzed by DFT
calculations to find that the reactions were mainly controlled by the electrostatic effect and aryne dis-
tortion caused by the boryl group.
Received 15 January 2013
Received in revised form 28 February 2013
Accepted 5 March 2013
Available online 13 March 2013
Keywords:
Arylboronate
Aryne
Regioselectivity
DielseAlder reaction
Grignard reagent
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
furans are some of the most intensively studied ones, and they have
found extensive applications in synthesizing multisubstituted naph-
Arylboronic acid derivatives are among the most useful building
blocks in organic synthesis, because they are extensively used in the
CeC, CeN, and CeO bond-forming reactions.1 They have also found
wide applications in saccharide sensing,2 medicinal chemistry,3 and
boron neutron capture therapy.4 Therefore, the development of an
efficient synthesis of boronic acid derivatives is an important re-
search topic these days. The arylboronic acid derivatives have gen-
erally been synthesized by the borylation of boron-free compounds
in the last stage of the synthesis.5 The construction of carbon
frameworks under mild reaction conditions using reactive species
with suitably protected boryl groups has been developed recently,6
which produces different kinds of arylboronic acid derivatives, some
of whose yields are very poor by the existing synthetic methods.
Benzynes are strained and highly reactive intermediates that have
been applied to various bond-forming reactions, such as cycloaddi-
tions, nucleophilic additions, transition metal-catalyzed coupling re-
actions, and noncatalyzed multicomponent coupling reactions.7
Among them, the DielseAlder (DA) reactions of benzynes with
thalene derivatives, for example, in the effective total synthesis of
fused aromatic natural products.7d,8 However, the reactions with un-
symmetrically substituted benzynes with substituted furans generally
produce mixtures of two possible regioisomers. For example, the DA
reactions of benzynes containing an alkyl,9a carbamoyl,9b or nitro9c
group at the C3 position, provided mixtures of the distal and proxi-
mal adducts in varying ratios, some of which were hardly separable,
and their regioselectivities were barely predictable. The steric bulki-
ness of the substituents were less effective, and even the reactions of 3-
phenyl-710 or 3-(tert-butyl)benzyne 8A9d with 2-(tert-butyl)furan 6a
resulted in low regioselectivities (Table 1, entries 1 and 2). On the other
hand, benzynes bearing inductively electron-withdrawing groups,
such as fluoro9e and alkoxy9f groups produced cycloadducts, such as
14a (entry 3), with good-to-excellent proximal selectivities.
We recently reported that 3-silylbenzynes (10A and 10B) un-
derwent DA reactions with a variety of 2-substituted furans to give
distal cycloadducts (15A and 15B) with high selectivities (some
typical examples are shown in entries 4 and 5, Table 1).10 This was
the first example of highly distal selective DA reactions between
substituted benzynes and furans, which are opposite to those of 3-
fluoro- and 3-alkoxybenzynes and were thought to mainly caused
by the inductively electron-donating effect of the silyl group, aris-
ing from the lower electronegativity of silicon relative to carbon.
* Corresponding author. E-mail address: akai@u-shizuoka-ken.ac.jp (S. Akai).
y
Current address: School of Pharmaceutical Sciences, Ritsumeikan University,
1-1-1 Noji-higashi, Kusatsu, Shiga 525-8577, Japan.
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.03.016

A. Takagi et al. / Tetrahedron 69 (2013) 4338e4352
4339
Table 1
Next, we preliminarily examined the generation of bor-
ylbenzyne 11 by the reaction of the precursor 5 with alkyl lithiums.
Due to the high instability of benzynes, the benzyne-generation
reaction was conducted in the presence of 2-(n-butyl)furan 6b to
immediately and effectively trap 11 as a DA adduct. First, according
to the generation of silylbenzynes,10 the reaction of 5A with n-BuLi
was conducted in toluene at ꢀ78 ꢁC to obtain 9% yield of 16Ab
(Table 2, entry 1), which can be improved by conducting the re-
action in THF (entry 2) and further increased by using bulkier and
more reactive alkyl lithiums, such as s-BuLi and t-BuLi (entries 3
and 4). More importantly, the reactions under different conditions
(entries 2e4) produced the distal adduct distal-16Ab, in which the
boryl and n-butyl groups were located away from each other as the
major products with the same distal-to-proximal ratios.17 The use
of 5B also provided a mixture of the corresponding distal- and
proximal-16Bb in similar yield with the same ratio (entry 5). No-
tably, a similar reaction using an alternative precursor 5B0, in which
the positions of the bromo and sulfonyloxy groups were inter-
changed (entry 6), gave a mixture of distal- and proximal-16Bb in
the same ratio and similar yield to that of entry 5. These results
strongly suggested that borylbenzynes (11A and 11B) were cer-
tainly generated under these conditions.
DielseAlder reactions of 3-substituted benzynes 7e11 with 2-(tert-butyl)furan 6a
Entry
R1
R2
Precursor, benzyne
12e16
d:pa
Ref.
1
2
3
4
5
6
Ph
t-Bu
OMe
SiMe3
Si(t-Bu)Me2
Bpinb
H
t-Bu
H
H
H
1, 7
2, 8A
3, 9
4A, 10A
4B, 10B
5A, 11A
12a
13Aa
14a
15Aa
15Ba
16Aa
43:57
63:37
15:85
97:3
>98:2
93:7
10
9d
9f
10
10
12
Me
a
The ratio of distal (d) to proximal (p) adducts.
Bpin¼(pinacol)boryl.
b
Given that boron and silicon have electronegativities similar to
that of carbon (AllredeRochow electronegativities: B, 2.0; Si, 1.7; C,
2.5),11 we expected that the similar DA reactions of 3-
borylbenzynes with furans would selectively produce distal cyclo-
adducts. Furthermore, the CeB bonds of the products were ex-
pected to be convertible into CeC, CeN, and CeO bonds.
Therefore, the DA reaction of 3-borylbenzynes appeared to
undergo regioselective synthesis of not only phenylboronic acid
derivatives but also multisubstituted benzo-fused compounds.
However, there were no reports on the generation and reaction of
benzynes containing boryl groups. Very recently, we have suc-
ceeded in preparing 3-[(pinacol)boryl]benzynes 11 and found that
their DA reactions with furans 6 or pyrroles 41 proceeded with
high distal selectivities and produced highly functionalized aryl-
boronic acid derivatives (for a typical example, see Table 1, entry
6).12,13 We also discovered that the regioselectivities of the DA
reactions of 11 resembled those of 3-silylbenzynes 10, but the
boryl groups exerted effects different from the silyl groups. We
Table 2
Optimization of the reaction conditions for the generation of benzyne 11a
Entry
5
RLi
Solvent
Product
d:pb
Yieldc (%)
1
2
3
4
5
6
5A
5A
5A
5A
5B
5B0
n-BuLi
n-BuLi
s-BuLi
t-BuLie
t-BuLie
t-BuLie
Toluene
THF
THF
THF
THF
16Ab
16Ab
16Ab
16Ab
16Bb
16Bb
NDd
91:9
92:8
92:8
92:8
91:9
9
34
47
67
63
51
describe herein
a full account on the generation of 3-
borylbenzynes 11 and their regioselective DA reactions. We also
analyzed the transition states (TSs) of these reactions by density
functional theory (DFT) calculations to disclose the origin of the
unique regioselectivities of 11.
f
THF
a
Conditions: A mixture of 5 (1.0 equiv), 6b (10 equiv), BuLi (1.2 equiv) in a solvent
(0.10 M) was stirred at ꢀ78 ꢁC for 15 min.
b
The ratio of distal (d) to proximal (p) adducts determined by 500 MHz 1H NMR
2. Results and discussion
analysis of the crude reaction products and also by the yield of the isolated products.
c
Total yield of the isolated distal- and proximal-16.
Not determined.
With 2.2 equiv of t-BuLi.
The precursor 5B0 was used instead of 5B.
d
2.1. The first generation of 3-borylbenzynes and their re-
gioselective DA reactions
e
f
Given that the treatment of 2-bromophenyl trifluoromethane-
sulfonates with BuLi14 has been well known to generate benzynes at
low temperature, 2-bromo-6-[(pinacol)boryl]phenyl trifluorometha-
nesulfonates (5A and 5B) were selected as some of the most prom-
ising precursors of 3-borylbenzynes 11.15 The precursors (5A and 5B)
were synthesized fromthe dibromophenol derivatives 17 in six steps;
viz., MOM protection of the hydroxyl group of 17, halogenelithium
exchange followed by the reaction with trimethyl borate, depro-
tection of the MOM group, esterification of boronic acid with pinacol,
and triflation of the hydroxyl group (Scheme 1). This sequence re-
quired only two chromatographic separations and gave 5A and 5B,
each in 73% overall yield, from 17A and 17B, respectively.16
We then investigated the DA reactions of 11A with selected 2-
substituted furans 6 under the reaction conditions similar to the
entry 4 of Table 2. All reactions gave distal-16 with high selectiv-
ities, and the bulkiness of the furan substituent (R2) was found to
have relatively small effect on the regioselectivities (Table 3, entries
1e4). A similar reaction of 11A with 2-methoxyfuran 6f also pro-
ceeded with exclusive distal selectivity; however, the 1,4-epoxide
moiety of the product 16Af opened immediately to yield 8-boryl-
1-naphthol derivative. Because of its high sorption on silica gel,
silica gel chromatography was performed after the acetylation of
naphthol to give the acetate distal-22Af (Table 3, entry 5).
As already described, we succeeded in generating bor-
ylbenzynes 11 for the first time, and also found that their DA re-
actions with 2-substituted furans 6 preferentially produced distal-
16 with high selectivities. However, the use of very strong bases,
Scheme 1. Preparation of 3-borylbenzyne precursors 5.

4340
A. Takagi et al. / Tetrahedron 69 (2013) 4338e4352
Table 3
Table 4
DielseAlder reactions of borylbenzyne 11A with 2-substituted furans 6a
Optimization of the reaction conditions for generating benzyne 11 using Grignard
reagentsa
Entry
R2
6
Product
d:pb
Yield (%)c
1
2
3
4
5
t-Bu
Me
SiMe3
SnBu3
OMe
6a
6c
6d
6e
6f
16Aa
16Ac
16Ad
16Ae
22Af
93: 7
89:11
94: 6
>98:2
>98:2
63
53
57
Entry R2
Precursor R3MgX
Solvent Product
d:pb Yieldc (%)
Trace
56
66d
1
CF3
5A
i-PrMgCl
i-PrMgCl
i-PrMgCl$LiCl THF
i-PrMgCl$LiCl THF
i-PrMgCl$LiCl THF
THF
THF
16Ab d
2
CF3
28A
28A
29A
16Ab 88:12 82
16Ab 88:12 88
16Ab 87:13 74e
16Ab 89:11 62
16Ab 92: 8 59
16Ab 86:14 59
a
Conditions: A mixture of 5A (1.0 equiv), 6 (10 equiv), and t-BuLi (2.2 equiv) in
THF (0.10 M) was stirred at ꢀ78 ꢁC for 15 min.
3
CF3
C6H4-4-Cl
C6H3-2,5-Cl2 30A
CF3
CF3
CF3
CF3
CF3
CF3
CF3
4d
5d
6
b
The ratio of distal (d) to proximal (p) adducts determined by 500 MHz 1H NMR
analysis of the crude reaction products and also by the yield of the isolated products.
28A
28A
28A
28A
28A
28B
28B0
i-PrMgCl
i-PrMgBr
t-BuMgCl
i-PrMgCl$LiCl Et2O
i-PrMgCl$LiCl Et2O
i-PrMgCl$LiCl Et2O
i-PrMgCl$LiCl Et2O
Et2O
Et2O
Et2O
c
Total yield of the isolated distal- and proximal-16A.
Isolated as 8-boryl-1-naphthyl acetate distal-22Af after the acetylation of the
7f
8f
9f
10
11
12g
d
16Ab
d
Trace
crude reaction products with Ac2O and pyridine.
16Ab 90:10 82
16Ab 92: 8 93
16Bb 90:10 88
16Bb 91:9 24
a
3MgX
Conditions: A mixture of precursor 5 or 28e30 (1.0 equiv), 6b (3.0 equiv), R
such as t-BuLi hampered the application of the method to benzynes
and furans bearing wider range of functional groups.
(1.2 equiv) in a solvent (0.10 M) was stirred at ꢀ78 ꢁ C for 30 min.
b
The ratio of distal (d) to proximal (p) adducts determined by 500 MHz 1H NMR
analysis of the crude products and also by the yield of the isolated products.
c
Total yield of the isolated distal- and proximal-16.
d
Reaction was run at ꢀ78 to 0 ꢁC.
2.2. Generation of borylbenzynes under milder reaction
conditions
e
NMR yield with 1,4-dimethoxybenzene as the internal standard.
f
Reaction was run at 0 ꢁC.
g
The precursor 28B0 was used.
The synthetic utility of 2-(trimethylsilyl)phenyl triflates as another
versatile precursors has been well recognized because they generate
benzynes under mild conditions using a fluoride ion;18 however, BuLi
is still needed in their preparation. Inspired by a report by Knochel, in
which benzynes possessing various functional groups were generated
from the corresponding 2-iodophenyl (4-chlorobenzene)sulfonates
by the use of Grignard reagents at low temperature,19 we suggest that
6-boryl-2-iodophenyl trifluoromethanesulfonates 28 would serve as
new promising precursors for 3-borylbenzynes 11. We prepared
28AeD from the corresponding 2,6-diiodophenols 23AeD in good
overall yields. In particular, the incorporation of Bpin group was suc-
cessfully attained by iodoemagnesium exchange reaction of 24 using
i-PrMgCl at ꢀ78 ꢁC followed by the removal of MOM group and the
esterification of boronic acid moiety with pinacol, while maintaining
the ester and bromo groups intact under these conditions (Scheme 2).
16Ab while maintaining the regioselectivity (entry 3). These results
showed that 28A was highly reactive in generating 11A even at
ꢀ78 ꢁC, whereas (chlorobenzene)sulfonates18 required higher
temperature to generate 11A and produced 16Ab in lower yields
(entries 4 and 5). We also found that Et2O was a slightly better
solvent than THF as far as regioselectivity was concerned, though
the yield reduced (entry 6). Finally, the reaction of 28A with i-
PrMgCl$LiCl in Et2O at ꢀ78 ꢁC was found to be the best reaction
conditions to produce 16Ab in 93% yield with 92:8 regioselectivity
(entry 10),21 whose selectivity was exactly the same as that using t-
BuLi (Table 2, entry 4). In addition, the use of other Grignard re-
agents (Table 4, entries 7 and 8) and/or the reaction at higher
temperature (entry 9) were less effective. The comparison of the
reaction of 28B with that of its regioisomer 28B0 under the same
conditions also proved the generation of benzyne 11B, because
both reactions gave a mixture of distal- and proximal-16Ab in the
same ratio, albeit the yields were different (entries 11 and 12).
Scheme 2. Synthesis of the borylbenzyne precursors 28e30 from 2,6-diiodophenols 23.
2.3. Effect of the boryl group on the generation of bor-
ylbenzyne and its DA reaction
Then, the optimization of the reaction conditions for generating
3-borylbenzyne 11A from 28A was investigated using Grignard
reagents in the presence of 2-butylfuran 6b. A preliminary trial
using i-PrMgCl at ꢀ78 ꢁC for 30 min successfully generated 11A,
which was supported by the formation of 88:12 mixture of distal-
and proximal-16Ab in 82% total yield (Table 4, entry 2). In contrast,
a similar reaction of the corresponding bromide 5A did not proceed
within the range ꢀ78 ꢁC to room temperature, and 5A was re-
covered almost quantitatively (entry 1). The use of more active
Grignard reagent i-PrMgCl$LiCl20 slightly improved the yield of
Next, we examined the effect of the boryl group of benzyne pre-
cursors on the generation of benzynes 11 and their DA reactions with
6b. The borates 31Ae33A were prepared by the esterification of
phenylboronic acid 34A with the corresponding diols (for details, see
SI). Under the same reaction conditions as those of Table 4, entry 10,
the precursor 31A, possessing a (1,3-dimethylpropanediol)boryl
group, reacted with i-PrMgCl$LiCl to directly give a borylnaphthol 39
(49% NMR yield) as a single detectable product (Table 5, entry 2). It was
thought that 39 was generated from the adduct distal-16 via the

A. Takagi et al. / Tetrahedron 69 (2013) 4338e4352
4341
Table 5
Table 6
DielseAlder reaction of 3-borylbenzynes (11A, 35Ae38A), generated from 28A,
Regioselective DielseAlder reactions of 11, generated from 28, with 2-substituted
31Ae34A, with 6ba
furans 6a
Entry R1
28, 11
R2
6
Product
d:pb
6a 16Aa 94:6 (93:7)d
Yield (%)c
Quant (63)d
1
Me
28A, 11A t-Bu
28A, 11A Me
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Me
6c 16Ac 88:12 (89:11)d 85 (53)d
28A, 11A SiMe3 6d 16Ad >98:2 (94:6)d
91 (57)d
28A, 11A SnBu3 6e 16Ae >98:2 (>98:2)d 79 (56)d
Entry
Precursor, benzyne
Product
28A, 11A OMe
28A, 11A Ph
28A, 11A CO2Me 6h 16Ah 93:17
28A, 11A Ac
28A, 11A CN
6f 22Afe >98:2 (>98:2)d 68 (66)d
d:pb
Yieldc (%)
93
6g 22Agf >98:2
40e
57
51
46
68
64
6i 16Ai 87:13
6jg 16Aj >98:2
6bi 16Cb 83:17
6b 16Db 84:16
1d
2
28A, 11A
31A, 35A
16Ab
39
92:8
10h
11
CO2Me 28C, 11C n-Bu
Br 28D, 11D n-Bu
a
de
de
49f
Conditions: A mixture of a precursor 28 (1.0 equiv), 6 (3.0 equiv), and i-
PrMgCl$LiCl (1.2 equiv) in Et2O (0.10 M) was stirred at ꢀ78 ꢁC for 30 min.
b
The ratio of distal (d) to proximal (p) adducts determined by 500 MHz 1H NMR
analysis of the crude products and also by the yield of the isolated products.
3
4
32A, 36A
40
49g
c
Total yield of isolated distal and proximal adducts.
The results of the corresponding reactions of Tables 2 and 3 are shown in the
d
parentheses.
e
Isolated as 8-boryl-1-naphthyl acetate 22Af after the acetylation of the crude
33A, 37A
34A, 38A
16Abh
16Abh
>98:2
>98:2
38
39
reaction products with Ac2O and pyridine.
f
Isolated as 8-boryl-1-naphthyl acetate 22Ag after the acetylation of the crude
reaction products with Ac2O and pyridine.
5i
B(OH)2
g
6j (10 equiv) was used.
i-PrMgBr (2.1 equiv) was applied instead of i-PrMgCl$LiCl.
6b (10 equiv) was used at 0 ꢁC.
h
a
Conditions: A mixture of a precursor 28, 31e34 (1.0 equiv), 6b (3.0 equiv), i-
i
PrMgCl$LiCl (1.2 equiv) in Et2O (0.10 M) was stirred at ꢀ78 ꢁC for 30 min.
b
The ratio of distal (d) to proximal (p) adducts were determined by 500 MHz 1
H
NMR analysis of the crude products and also by the yield of the isolated products.
c
Total yield of the isolated distal and proximal adducts.
d
Cited from Table 4, entry 10.
e
The regioisomer and other cycloadducts were not detected by 500 MHz 1H NMR
analysis of the crude products.
f
Borylnaphtol 39 was obtained, and its yield was determined by NMR analysis
with 1,4-dimethoxybenzene as the internal standard.
g
yields of 16 were significantly improved compared to the results of
Tables 2 and 3, while the selectivities were the same (Table 6, en-
tries 1e5). Various reactive functional groups, such as ester (entries
7 and 10), acetyl (entry 8), nitrile (entry 9), and bromo (entry 11)
groups were tolerant to the reaction conditions. All these reactions
produced distal-16 with high selectivities, although the ester and
bromo group at the C5 position of 11 caused a slight decrease in the
selectivities (entries 10 and 11). Importantly, the reactions with
furans possessing either electron-donating (entry 5) or electron-
withdrawing groups (entries 7e9) at the C2 position produced
similar distal selectivity.
The applicability of 11 to the DA reaction with substituted pyr-
roles 41 was also of interest because the cycloadditions of benzynes
with pyrroles have been extensively studied to synthesize bi-
ologically active compounds.22 We found that the selection of the
N-protective group of 41 was one of the most important factors to
achieve the reaction. Thus, whereas the reactions of 11A with N-
methyl and N-silyl pyrroles (41a and 41b) did not provide any
cycloadducts (Table 7, entries 1 and 2), similar reactions with N-
tosyl (Ts) and N-(tert-butoxy)carbonyl (Boc)-pyrroles (41cee) gave
mixtures of two regioisomers of cycloadducts (distal- and proximal-
42) (entries 3e7). The Boc group was preferred to the Ts group in
producing better regioselectivity (entries 3 and 4), and the regio-
selectivities were higher than those of the DA reactions with furans
6 possessing same or similar substituents (entries 4, 6, and 7).
These results represent the first examples of highly regioselective
DA reactions between the substituted benzynes and pyrroles.23
Borylnaphtol 40 was obtained, and its yield was determined by NMR analysis
with 1,4-dimethoxybenzene as the internal standard.
h
16Ab was obtained after the treatment of the crude products with pinacol.
i-PrMgCl$LiCl (3.1 equiv) was used.
i
spontaneous epoxide ring opening. Similar reaction of (cis-cyclo-
pentane-1,2-diol)boryl precursor 32A also gave naphthol 40 as a
single product (entry 3). In contrast, the benzyne precursor 33A
possessing a small (ethyleneglycol)boryl group exclusively gave a
distal adduct, albeit in lower yield (entry 4). (Because the borate
moiety of the adduct partly hydrolyzed during the aqueous workup
and silica gel chromatography, the product was isolated as pinacol
borate distal-16Ab after transesterification with pinacol.) Similar re-
action of phenylboronic acid 34A also gave distal-16Ab (39% yield)
exclusively after the esterification (entry 5). Thus, the benzyne-gen-
eration and the DA reaction with 6b were generally available for the
precursors possessing a range of boryl groups; the pinacol borate 28A
was found to be the best in terms of the stability and yield of the
cycloadducts.
2.4. Substrate scope of the DA reaction of borylbenzynes 11
generated from triflates 28 using i-PrMgCl$LiCl
The DA reaction of a variety of borylbenzynes 11, generated from
28 using i-PrMgCl$LiCl, with 2-substituted furans 6 gave the cor-
responding products 16 with high distal selectivities (Table 6). The

4342
A. Takagi et al. / Tetrahedron 69 (2013) 4338e4352
Table 7
2.5. Transformation of the boryl group of the DA products
Regioselective DielseAlder reactions of 11, generated from 28, with 2-substituted
pyrroles 41a
The boryl group of the DA product distal-16Ab was converted
into amino group (Table 9, entry 1)24 or cyano group (entry 2)25 by
the treatment with copper reagents, or also into hydroxyl group by
the oxidation with NaBO3 (entry 3).26 The epoxide ring was intact
under these reaction conditions. However, the SuzukieMiyaura
cross-coupling reaction of distal-16Ab gave a complex mixture,
probably because of the reactivity of its 1,4-epoxy-1,4-
dihydronaphthalene frame under the palladium-catalyzed condi-
tions.27 On the other hand, after the TsOH-catalyzed epoxide ring
opening, the corresponding naphthol derivatives (46 and 47) were
subjected to the SuzukieMiyaura cross-coupling reaction with
aryliodides to give biaryl compounds (48e50) in high overall yields
(Table 10).28 Because the boryl group may be easily eliminated by
protodeboronation,29 it additionally serves as a regio-directing
auxiliary. Thus, the regioselective DA reaction of borylbenzynes
11 followed by the transformation of the boryl group provides
a reliable and alternative method for synthesizing multisubstituted
fused aromatic compounds.
Entry R1
28, 11
R2 R3
41
42
d:pb
Yieldc (%)
1
2
3
4
5
6
7
Me
28A, 11A
28A, 11A
28A, 11A Et Ts
28A, 11A Et Boc
28A, 11A Br Boc
H
H
Me
41a 42Aa
d
d
0
0
Me
Me
Me
Me
Si(i-Pr)3 41b 42Ab
41c 42Ac 87:13 63
41d 42Ad >98:2 70
41e 42Ae >98:2 58
41d 42Cd 88:12 61
CO2Me 28C, 11C
Br 28D, 11D Et Boc
Et Boc
41d 42Dd 95:5
72
a
Conditions: A mixture of 28 (1.0 equiv), 41 (3.0 equiv), and i-PrMgCl$LiCl
(1.2 equiv) in Et2O (0.10 M) was stirred at ꢀ78 ꢁC for 30 min.
Table 9
b
The ratio of distal (d) to proximal (p) adducts determined by 500 MHz 1H NMR
Conversion of the boryl group of distal-16Ab
analysis of the crude products and also by the yield of the isolated products.
c
Total yield of the isolated distal- and proximal-42.
In addition, halogen (entries 5 and 7) and ester (entry 6) groups
were tolerant to these reaction conditions.
In this study, we found that the DA reaction of 11A with 3-
methylfuran 6k and with 3-methylpyrroles (41f and 41g) pre-
dominantly gave adducts (16 and 42) with at least 86:14 selectivity,
in which the methyl groups derived from the furan and pyrroles
were located close to the boryl group (Table 8, entries 1e3). In
particular, the N-Boc group again displayed its ability to produce
high regioselectivity, and the reaction with N-Boc-2,4-disubstituted
pyrrole 41h exclusively provided 42Ah (entry 4). These high levels
of regioselectivity are outstanding among the existing DA reactions
of the substituted benzynes and 3-substituted furans. Therefore, it
is worth noting that the boryl group has strong effect in controlling
the orientation in DA reactions even with dienes that have a small
methyl group at the position distant from the reactive site.
Entry
Conditions
R
Product
Yield (%)
1
2
3
a
b
c
NHBu
CN
OH
43
44
45
71
53
85
Table 10
Epoxide ring opening of distal-16Ab and -42Ad and successive SuzukieMiyaura
cross-coupling reactions
Entry
R
X
16, 42
46, 47
Ar
Product
Yield (%)
Table 8
DielseAlder reaction of 11A with 3-methylfuran 6k and with 3-methylpyrroles
1
2
3
n-Bu
n-Bu
Et
O
O
NBoc
16Ab
16Ab
42Ad
46
46
47
Ph
1-Np
Ph
48
49
50
94
99
82
41feha
2.6. Mechanistic consideration of regioselectivity in the DA
reaction of borylbenzynes
Herein, we discuss why the boryl group strongly affected the
regioselective DA reaction of benzynes.
It has been considered that the methoxy group at the C3 posi-
tion of benzyne exhibited electron-withdrawing inductive effect on
Entry
X
R1
Diene
Product
the triple bond of benzyne to make the C1 electron-deficient (
dþ)
b
e).30 Due to the lower electronegativity of
16:160 or 42:420
Yieldc (%)
and C2 electron rich (
d
1
2
3
4
O
H
H
H
6k
16Ak
42Af
42Ag
42Ah
87:13
86:14
92:8
Quant
87
95
boron in respect to carbon, the electron-donating inductive effect of
the boryl group at the C3 position of benzyne was thought to ex-
hibit the opposite trend at these carbons and result in regiose-
lectivities contrasting with those of 3-methoxybenzynes. We also
considered that the possible coordination of anion, such as alkyl
anion and halide ion to the Lewis acidic boron atom might enhance
the electron-donating inductive effect on the triple bond of 11;
however, the fact that the regioselectivities of the DA reactions of 11
NTs
NBoc
NBoc
41f
41g
41h
C2H4Ph
>98:2
81
a
Conditions: A mixture of 28A (1.0 equiv), diene 6 or 41 (3.0 equiv), and i-
PrMgCl$LiCl (1.2 equiv) in Et2O (0.10 M) was stirred ꢀ78 ꢁC for 30 min.
b
The ratio of 16 (or 42) to 160 (or 420) determined by 500 MHz 1H NMR analysis of
the crude products and also by the yield of the isolated products.
c
Total yield of the isolated adducts.

A. Takagi et al. / Tetrahedron 69 (2013) 4338e4352
4343
Table 12
Electron density of
lyzed by the natural bond orbital method
with 2-substituted furans 6 were scarcely influenced by the
benzyne-generation conditions (Tables 2 and 4) probably means
that such coordination to the vacant orbital of the boron of 11 is
very weak or almost negligible.
p
orbital at C2 and C5 positions of 2-substituted furans 6 ana-
We then aimed to quantitatively elucidate the influence of the
boryl group of 3-borylbenzynes on the regioselectivity of their DA
reactions based on DFT calculation. We adopted standard 6-31G(d)
basis sets for C, H, O, N, S, Si, and Br, and the HayeWadt valence
Entry
R
Electron density
double-z (LANL2DZ) basis set, which includes the influence of the
inner-shell electrons on the valence shell using effective core po-
tentials (ECP), for Sn with B3LYP functionals. All calculations were
performed using the Gaussian 09 program package.31 In particular,
we focused our attention to the orbital of the triple bonds of ben-
zynes that deal with the bond formation in the benzyne reactions in
order to evaluate in detail the electrostatic character of the ben-
zynes, whereas the theoretical studies had been reported based on
HOMO and LUMO coefficients of 1 and 2 carbons of benzynes.30
First, the orbitals of the triple bond of benzyne were divided into
C2
C5
C2eC5
1
2
3
4
5
6
t-Bu
Me
OMe
CO2Me
Ac
6a
6c
6f
6h
6i
0.89
0.89
0.84
0.92
0.94
0.98
0.94
0.94
0.98
0.86
0.87
0.89
ꢀ0.05
ꢀ0.05
ꢀ0.14
þ0.06
þ0.07
þ0.09
CN
6j
presence of electron-withdrawing groups, such as methox-
ycarbonyl, acetyl, and cyano groups (6hej) made C5 more electron-
deficient (entries 4e6).35
sp hybrid orbital (ssp) and two
p-bond orbitals (p1 and p2) by
a natural bond orbital (NBO) method32,33 (Fig. 1), and the electron
density of the p1 orbital, which is involved in the bond formation of
benzyne reactions, was analyzed. The electron densities of the p1
orbitals of C1 and C2 of the selected 3-substituted benzynes (7e9,
11A, 11B) and unsubstituted benzyne 51 are summarized in Table 11.
In the cases of 3-phenylbenzyne 7 and 3-(tert-butyl)benzyne 8B, no
extensive differences between the C1 and C2 atoms were observed
(entries 1 and 2). The electron density at the C2 position of 3-
methoxybenzyne 9 was higher than at the corresponding C1 posi-
tion, whereas those of 3-borylbenzynes (11A and 11B) exhibited the
opposite trend, and the substituents (H and Me) at the C5 position
had little influence on the electron densities.
Based on the electron density of each
p orbital and benzyne
distortion, we concluded that the electrostatic interactions be-
tween benzyne 11A and furans (6c and 6f) roughly accounted for
the experimentally favorable orientation of their DA reactions
(Fig. 2). However, similar interactions between 11A and 6hej were
inadequate to explain the preferential formation of distal-16AheAj
(as a typical example, the DA reaction of 11A and 6h is shown in
Fig. 2). The DA reaction of 11A and 6h was theoretically analyzed
based on the frontier orbital theory;29 however, the HOMOeLUMO
interaction of these reactants did not provide an adequate platform
for understanding its anomalous orientation. These results clearly
indicated that the electrostatic and orbital interactions of the re-
actants as well as the benzyne distortion were not always sufficient
for a global and quantitative explanation of the experimental
regioselectivities.36
Fig. 1. Three divided bonding orbitals of the triple bond of benzyne.
Table 11
Electron densities of p1 orbital and internal angles at C1 and C2 positions of 3-
substituted benzynes (7e9, 11A, 11B) and 51 analyzed by the natural bond orbital
method
Fig. 2. Electrostatic interaction between borylbenzyne 11A and furans (6c, 6f, and 6h)
by natural bond orbital (NBO) analysis. The numbers next to the orbital lobes indicate
the electron density of NBO. The distal-to-proximal ratio of each reaction indicates the
experimental result.
Entry
R1
R2
Electron density (p1
)
Internal angle
In order to quantitatively rationalize the origin of the regiose-
lectivities of the DA reactions, reaction pathway analysis, including
a pair of transition states (TSs) leading to distal and proximal ad-
ducts, respectively,37 was subsequently executed. We determined
twelve pairs of TSs of the DA reactions of 11 and furans 6 (Table 13,
entries 1e12) and four pairs of TSs of the DA reactions of 11 and
pyrroles 41 (entries 13e16). For example, TSd2 leading to distal-
16Ab is 1.42 kcal/mol lower than TSp2 leading to proximal-16Ab,
which theoretically indicates a 92:8 distal selectivity and is in ex-
cellent agreement with the experimental result (distal-16Ab/prox-
imal-16Ab¼92:8, Table 13, entry 2). Similarly, the distal-to-
proximal ratios based on the activation energy difference be-
tween two TSs were compared to the experimentally determined
ratios (Table 13). For reference, the TSs of the DA reaction of 3-(tert-
butyl)benzyne 8A and 2-(n-butyl)furan 6b, leading to distal- and
proximal-13b, were also determined, and the theoretical and ex-
perimental ratios were compared with each other (entry 17). Sig-
nificantly, all theoretical ratios were in excellent agreement with
C1
C2
C1eC2
q1
q2
1
2
3
4
5
6
Ph
H
Me
H
Me
H
H
7
8B
9
11A
11B
51
0.95
0.98
0.77
1.03
1.06
0.96
0.98
0.95
1.05
0.85
0.87
0.96
ꢀ0.03
þ0.03
ꢀ0.28
þ0.18
þ0.18
ꢂ0.00
128ꢁ
126ꢁ
135ꢁ
122ꢁ
122ꢁ
127ꢁ
128ꢁ
129ꢁ
119ꢁ
132ꢁ
133ꢁ
127ꢁ
t-Bu
OMe
Bpin
Bpin
H
We also analyzed the internal angles of geometry-optimized 3-
substituted benzynes (7e9, 11A, 11B) and also 51 at C1 and C2 to
evaluate the contribution of distortion energy34 (Table 11) and
found similar tendency. That is, C1 of 9 as well as C2s of 11A and 11B
are more electrophilic.
The electron densities of
p orbital at C2 and C5 of 2-substituted
furans 6 were calculated similarly (Table 12). We found that alkyl
and alkoxy groups at the C2 position of 6 enhanced the electron
density at the C5 position as compared to C2 (entries 1e3), and the

4344
A. Takagi et al. / Tetrahedron 69 (2013) 4338e4352
Table 13
Theoretical and experimental ratios of the DA reactions of borylbenzynes 11 with furans 6 or pyrroles 41.
Entry
R
R1
11
X
R2
R3
Diene
Product
TS
DDEz (kcal/mol)
Theoretical d:p
Experimental d:p
1
2
3
4
5
6
7
8
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
Bpin
t-Bu
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
Me
Br
CO2Me
Me
11A
11A
11A
11A
11A
11A
11A
11A
11A
11A
11A
11B
11A
11A
11C
11D
8B
O
O
O
O
O
O
O
O
O
O
O
O
NTs
NBoc
NBoc
NBoc
O
t-Bu
n-Bu
Me
SiMe3
SnBu3
OMe
Ph
CO2Me
Ac
CN
H
n-Bu
Et
Et
Et
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6b
41c
41d
41d
41d
6b
16Aa
16Ab
16Ac
16Ad
16Ae
16Af
16Ag
16Ah
16Ai
16Aj
16Ak
16Bb
42Ac
42Ad
42Cd
42Dd
13Bb
TSd1, TSp1
TSd2, TSp2
TSd3, TSp3
TSd4, TSp4
TSd5, TSp5
TSd6, TSp6
TSd7, TSp7
TSd8, TSp8
1.63
1.42
1.50
1.58
2.39
1.85
2.48
1.46
1.15
1.81
0.63
1.39
1.42
2.68
2.07
1.38
0.026
94: 6
92: 8
93: 7
93: 7
>98: 2
96: 2
>98: 2
92: 8
88:12
95: 5
74:26
91: 9
92: 8
>98: 2
97: 3
91: 9
51:49
94: 6
92: 8
88:12
>98: 2
>98: 2
>98: 2
>98: 2
93: 7
87:13
>98: 2
87:13
91: 9
87:13
>98: 2
95: 5
88:12
52:48
9
TSd9, TSp9
10
11
12
13
14
15
16
17
TSd10, TSp10
TSd11, TSp11
TSd12, TSp12
TSd13, TSp13
TSd14, TSp14
TSd15, TSp15
TSd16, TSp16
TSd17, TSp17
Et
n-Bu
the experimental ratios. Thus, the reliability of the theoretically
determined TSs was deemed acceptable. These results also sug-
gested that the regioselectivities of DA reactions were critically
controlled by the TSs. To further evaluate the origin of the regio-
selectivities, the structures of these TSs were characterized. They
were also compared with the TSs of the DA reactions of either 11 or
3-(tert-butyl)benzyne 8B with furan itself 6l, that of benzyne itself
51 with 6b, and that of 8B with 6b as standard references. The
following findings are noteworthy:
First, the TS (TS18) of the DA reaction of 11B with 6l showed that
the C2 atom of 11B was closer to the carbon atom of furan than the
C1 atom of 11B (Fig. 3A). The similarity of TS19 to TS18 indicates
that the C5 methyl group had little effect on the TS (Fig. 3B). On the
other hand, the TS (TS20) of the DA reaction of 8B with 6l showed
that the C1 atom of benzyne was closer to the carbon atom of furan
than the C2 atom of benzyne (Fig. 3C). TS (TS21) of the DA reaction
of 51 with 6b showed that the C5 atom of 6b was closer to the
carbon atom of benzyne (Fig. 3D). These results indicate that the
reactions proceeded via non-synchronous concerted mechanism.
Because the electron densities of C1 of 11A and 11B are higher than
those of C2 (Table 11), the electrostatic interaction was found to
have precedence. In addition, the steric hindrance between the
boryl group of 11 and the hydrogen of furan was very small. On the
other hand, the alkyl substituent of either benzyne 8B or furan 6b
had a considerable steric effect to distance its neighboring carbon
from its reaction partner.
Fig. 3. The transition state (TS) structures of the DielseAlder reaction of 3-
borylbenzyne 11B with furan 6l (A), that of 3-boryl-5-methylbenzyne 11A with 6l
(B), that of 3-(tert-butyl)benzyne 8B with 6l (C), and that of benzyne 51 with 2-n-
butylfuran 6b (D).37
Second, we compared twoTS structures (TSd2 and TSp2) of the DA
reaction of 11A with 6b (Fig. 4A). In the case of electrostatically more
favorable TSd2, the distance between the more electron-deficient C2
ꢀ
ꢀ
of11A and the electron-sufficient C5 of6b (2.42 A) is shorter than that
distance of 51 and C2 of 6b (2.78 A, Fig. 3D). These results show that
ꢀ
between C1 of 11A and C2 of 6b (2.90 A). On the other hand, in TSp2,
the TS structures clearly reflect the inherent electrostatic nature of
11A and also that the steric hindrance between the boryl group and
the n-butyl group issmall. The TSstructures of the DA reactionsof 11A
ꢀ
the distance between C2 of 11A and C2 of 6b (2.65 A) is longer than
ꢀ
that between C1 of 11A and C5 of 6b (2.48 A) but is shorter than the

A. Takagi et al. / Tetrahedron 69 (2013) 4338e4352
4345
Fig. 4. Transition state (TS) structures of the DielseAlder reactions of borylbenzyne
11A and 2-(n-butyl)furan 6b (A) and those of 3-(tert-butyl)benzyne 8B and 6b (B).37
with 2-(tert-butyl)furan 6a and those with 2-methylfuran 6c were
also examined to find very close tendencies (for details, see
Supplementary data). Thus, the DA reactions of borylbenzynes 11
seem to be determined mainly by their electrostatic interactions with
furans as well as by a small steric effect.
Third, in the electrostatically more favorable TS (TSd17) of the DA
reaction of 3-(tert-butyl)benzyne 8B with 6b (Fig. 4B), the distance
between C2 of 8B and C5 of 6b was supposed to be shorter than that
between C1 of 8B and C2 of 6b because C2 of 8B is slightly more
electrophilic than C1 (see Table 11, entry 2); however, it is actually
longer. This means that there is much bigger steric hindrance be-
tween the tert-butyl group of 8B and the hydrogen of 6b than that
between the hydrogen of 8B and the n-butyl group of 6b, and such
steric hindrance makes the electrostatically favorable TSd17 con-
siderably unstable. As a result, the energy difference DDEz between
TSd17 and TSp17 is thought to be small (0.026 kcal/mol). The
comparison of Fig. 4A and B also shows that the steric hindrance of
the boryl group of 11A is smaller than that of the tert-butyl group.
Fourth, the origins of regioselectivities of the DA reactions of
borylbenzyne 11A with furans (6hej), possessing an electron-
withdrawing group at the C2 position (Table 6, entries 7e9) were
investigated based on the TS structures, given that the theoretical
distal-to-proximal ratios for the DA reactions with 6hej were in
good agreement with the experimental ratios (Table 13, entries
8e10). For reference, the TS structure (TS22) of the DA reaction of
benzyne itself 51 with 2-methoxyfuran 6f and TS structures (TSd6
and TSp6) of the DA reaction of 11A and 6f were also analyzed to
Fig. 5. Transition state (TS) structures of the DielseAlder reaction of benzyne with 2-
methoxyfuran 6f (A), that of benzyne with methyl furan-2-carboxylate 6h (B), that of
11A with 6f (C), and that of 11A with 6h (D).37
hindrance between the boryl and the methoxycarbonyl groups (the
planer structure of 6h forced these two groups even closer).35
Consequently, the alternative electrostatically less favorable TSd8
became relatively more stable (Fig. 5D).
Thus, it has been revealed that the electrostatic interaction be-
tween the reactants (6 and 11) is a primary factor that determines
the regioselectivities, which makes the distal TSs more stable in
most cases. In some other cases, such as the DA reactions involving
6hej possessing electron-withdrawing groups, the steric hindrance
between the substituents works as the dominant factor and may
override the electrostatic interaction to make the electrostatically
favorable TSs less stable.
ꢀ
show that C5 of 6f was closer (2.22 A) to the carbon of benzyne than
ꢀ
C2 of 6f (2.76 A) (Fig. 5A) and that the corresponding distances of
the electrostatically more favorable TSd6 (Fig. 5C) were similar to
those of TS22. On the other hand, another reference TS (TS23) of the
DA reaction between 51 and methyl furan-2-carboxylate 6h
showed that the more electron-deficient C5 of 6h was closer
ꢀ
(2.41 A) to the carbon of benzyne than the more electron-sufficient
3. Conclusion
ꢀ
C2 of 6h (2.61 A) (Fig. 5B), which might be accounted for by the
steric hindrance between the methoxycarbonyl group of 6h and the
benzyne hydrogen. The favorable electrostatic interaction of C2 of
11A and C2 of 6h in TSp8 probably brought them closer. However,
this made TSp8 extensively unstable because of the large steric
We have developed a new method for the regiocontrol of the DA
reaction of the substituted benzynes by installing a boryl group at C3
position. The generation of the previously unknown borylbenzynes
11 was effectively achieved by reacting the precursors, 6-boryl-2-

4346
A. Takagi et al. / Tetrahedron 69 (2013) 4338e4352
iodophenyl trifluoromethanesulfonates 28, with i-PrMgCl$LiCl,
while 11 immediately reacted with the substituted furans 6 and
pyrroles 41 to produce multisubstituted fused aromatic boronates
(16 and 42) in good-to-excellent yields with high distal regiose-
lectivities. Given that the boryl groups of the DA adducts are con-
vertible into carbon, nitrogen, and oxygen substituents, the
developed method serves as a useful strategy to prepare variously
functionalized naphthalene derivatives. Additionally, the regiose-
lectivities of these reactions were quantitatively interpreted based
on the theoretical analysis of the TS structures obtained from the DFT
calculations, revealing that the boryl group mainly controlled
regioselectivity by electrostatic effects.
was quenched by a saturated aqueous NH4Cl solution. The reaction
mixture was extracted with EtOAc. Aqueous layer was extracted twice
with EtOAc. The combined organic layer was washed with a saturated
aqueous NaCl solution and dried over anhydrous Na2SO4, and the
solvent was removed under reduced pressure. The crude product was
purified by flash column chromatography on silica gel. Most of major
regioisomers (distal-16 and distal-42) were isolated, while minor
regioisomers (proximal-16 and proximal-42) could be hardly isolated
because both distal and proximal adducts were slightly prone to be
adsorbed on silica gel. The structures of the minor regioisomers were
determined by similarity of their characteristic 1H NMR data to those
of proximal-16Ab, whose structure was determined by NOESY spectra.
Thus, this study provides an insight into certain longstanding
problems related to the regioselectivity of the benzyne reactions.
The investigations on the further application of borylbenzynes are
currently underway in our laboratory.
4.2.1. 2-(1-Butyl-7-methyl-1,4-dihydro-1,4-epoxynaphthalen-5-yl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane distal-16Ab. Following the
general procedure, a mixture of 28A (74 mg, 0.15 mmol), 2-n-
butylfuran 6b (64 mL, 0.45 mmol), and i-PrMgCl$LiCl [1.3 M in THF
4. Experimental section
(0.14 mL, 0.18 mmol)] in Et2O (1.5 mL) was stirred for 30 min at
ꢀ78 ꢁC. The crude product (distal/proximal¼92:8, determined by
500 MHz 1H NMR analysis) was purified by column chromatogra-
phy (hexane/EtOAc¼12:1) to provide a mixture of distal- and
proximal-16Ab (47 mg, 93%). Pure distal-16Ab was isolable from the
reaction mixture by the same column chromatography, and its
regiochemistry was determined by NOESY spectra. A colorless
4.1. General considerations
4.1.1. Reagents. Test tubes with ground joint capped with rubber
septa (containing a stir-bar) were used for the copper and palla-
dium-catalyzed reaction. All other reactions were carried out under
an argon or nitrogen atmosphere in a round bottom flask or a pear-
shaped flask containing a stir-bar with an inlet adapter with
a three-way stopcock. 1.6 M n-BuLi in n-hexane and 1.6 M t-BuLi in
n-pentane was purchased from Kanto Chemical Co. 2.0 M i-PrMgCl
in tetrahydrofuran (THF) and 1.3 M i-PrMgCl$LiCl in THF were ob-
tained from Aldrich Chemical Co. and used as they were. Anhydrous
THF, CH2Cl2 and diethyl ether (Et2O) were purchased from Wako
Pure Chemical Industries and used without further purification. 2-
(Trimethylsilyl)furan 6d,38 2-phenylfuran 6g,39 tert-butyl 2-bromo-
1H-pyrrole-1-carboxylate 41e,40 3-methyl-1-tosyl-1H-pyrrole
41f,39 4-methyl-2-phenethyl-1-tosyl-1H-pyrrole 41h,39 2,6-
diiodophenol,41 and 2,6-diiodo-4-methylphenol42 were prepared
according to the literature. All other reagents were purchased from
Tokyo Chemical Industry Co., Aldrich Chemical Co., Kishida Chem-
ical Co. or Nacalai Tesque and used without further purification.
Flash chromatography43 was performed with Silica gel 60N,
solid; mp 118e121 ꢁC. 1H NMR (500 MHz, CDCl3)
d: 0.97 (3H, t,
J¼7.5 Hz), 1.33 (12H, s), 1.45e1.50 (2H, m), 1.56e1.63 (2H, m),
2.23e2.39 (2H, m), 2.28 (3H, s), 6.05 (1H, d, J¼2.0 Hz), 6.73 (1H, d,
J¼5.5 Hz), 7.02 (1H, dd, J¼2.0, 5.5 Hz), 7.04 (1H, s), 7.13 (1H, s); 13C
NMR (125 MHz, CDCl3) d: 14.0, 21.2, 23.2, 24.8, 25.0, 26.8, 29.0, 82.0,
83.6, 92.3, 123.0, 129.9, 133.5, 144.5, 144.7, 150.1, 156.1; IR (CHCl3,
cmꢀ1) 3007; HRMS m/z (FABþ) calcd for C21H3BO3 [(MþH)þ]
341.2292, found. 341.2303.
4.2.2. 2-(4-Butyl-7-methyl-1,4-dihydro-1,4-epoxynaphthalen-5-yl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane proximal-16Ab. Regiochemi-
stry was determined by NOESY spectra of the mixture of distal- and
proximal-16Ab. 1H NMR (500 MHz, CDCl3)
1.38e1.41 (2H, m), 2.19e2.34 (2H, m), 2.27 (3H, s), 2.55e2.63 (2H, m),
5.56 (1H, d, J¼2.0 Hz), 6.82 (1H, d, J¼5.5 Hz), 6.96 (1H, dd, J¼2.0,
5.5 Hz), 7.09 (1H, br s), 7.15 (1H, br s).
d
: 0.92 (3H, t, J¼7.5 Hz),
spherical (40e50 m
m) purchased from Kanto Chemical Co.16
4.2.3. 2-(1-(tert-Butyl)-7-methyl-1,4-dihydro-1,4-epoxynaphthalen-
5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane distal-16Aa. Following
the general procedure, a mixture of 28A (56 mg, 0.12 mmol), 2-tert-
4.1.2. Analytical methods. IR spectra were obtained on a JASCO WS/
IR-8000. 1H NMR and 13C NMR spectra were recorded on a JEOL
JMN-A500 or ECA-500 (1H: 500 MHz, 13C: 125 MHz) instrument
with chemical shifts reported in parts per million relative to the
residual deuterated solvent or the internal standard tetrame-
thylsilane. The mass spectra were measured on a Bruker micrOTOF,
JEOL JMS-700 MStation or JMS-T100TD spectrometer. Elemental
analyzes were performed by YANACO CHN CORDER MT-5 in-
strument. 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 in
references. All new products were further characterized by HRMS.
butylfuran 6a (50 mL, 0.35 mmol), and i-PrMgCl$LiCl [1.3 M in THF
(0.11 mL, 0.14 mmol)] in Et2O (1.2 mL) was stirred for 30 min at
ꢀ78 ꢁC. The crude product (distal/proximal¼94:6, determined by
500 MHz 1H NMR analysis) was purified by column chromatography
(hexane/EtOAc¼15:1) to provide a mixture of distal- and proximal-
16Aa (40 mg, >99%). Pure distal-16Aa was isolable from the reaction
mixture by the same column chromatography (hexane/
EtOAc¼15:1). A colorless oil. 1H NMR (500 MHz, CDCl3)
d: 1.28 (9H,
s), 1.32 (12H, s), 2.29 (3H, s), 6.09 (1H, d, J¼1.5 Hz), 6.90 (1H, d,
J¼5.5 Hz) 7.01 (1H, dd, J¼1.5, 5.5 Hz), 7.13 (1H, br s), 7.28 (1H, br s);
13C NMR (125 MHz, CDCl3)
d: 21.3, 24.8, 25.0, 26.6, 81.7, 83.6, 99.0,
4.2. General procedure for the generation of borylbenzyne 11
followed by its DielseAlder reaction with furan 6 or pyrrol 41
(Tables 4e8)
125.4, 129.7, 142.5, 144.8, 148.7, 157.3; IR (CHCl3, cmꢀ1) 3009; HRMS
m/z (FABþ) calcd for C21H30BO3 [(MþH)þ] 341.2288, found. 341.2292.
4.2.4. 2-(4-(tert-Butyl)-7-methyl-1,4-dihydro-1,4-epoxynaphthalen-
An oven-dried pear-shaped flask was charged with a borylbenzyne
precursor 28 (1.0 equiv) and capped with an inlet adapter with a three-
way stopcock and then evacuated and back-filled with argon. Anhy-
drous Et2O (0.10 M) was added, and the reaction mixture was cooled to
ꢀ78 ꢁC. Furan 6 or pyrrol 41 (3.0 equiv) was added, and then a 1.3 M
solutions of i-PrMgCl$LiCl (1.2 equiv) in THF was slowly added over
5 min. After being stirred at ꢀ78 ꢁC for 30 min, the reaction mixture
5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
NMR (500 MHz, CDCl3) : 1.30 (9H, s), 1.37 (12H, s), 2.25 (3H, s), 5.53
(1H, br s), 6.80 (1H, s), 6.93 (2H, br s), 7.01 (1H, br s).
proximal-16Aa. 1H
d
4.2.5. 2-(1,7-Dimethyl-1,4-dihydro-1,4-epoxynaphthalen-5-yl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane distal-16Ac. Following the
general procedure, a mixture of 28A (57 mg, 0.12 mmol), 2-

A. Takagi et al. / Tetrahedron 69 (2013) 4338e4352
4347
methylfuran 6c (31
m
L, 0.34 mmol), and i-PrMgCl$LiCl [1.3 M in THF
and the product was extracted with EtOAc. The combined organic
layer was dried over anhydrous Na2SO4, and the solvent was re-
moved under reduced pressure. The crude product was purified by
column chromatography (hexane/EtOAc¼6:1) to provide distal-22Af
(26 mg, 68%), the regiochemistry of which was determined by
(0.11 mL, 0.14 mmol)] in Et2O (1.2 mL) was stirred for 30 min at
ꢀ78 ꢁC. The crude product (distal/proximal¼88:12, determined by
500 MHz 1H NMR analysis) was purified by column chromatogra-
phy (hexane/EtOAc¼10:1) to provide a mixture of distal- and
proximal-16Ac (29 mg, 85%). Pure distal-16Ac was isolable from the
reaction mixture by the same column chromatography (hexane/
NOESY spectra. A colorless oil; 1H NMR (500 MHz, CDCl3)
d: 1.24
(12H, s), 2.35 (3H, s), 2.50 (3H, s), 3.98 (3H, s), 6.74 (1H, d, J¼8.5 Hz),
EtOAc¼10:1). A colorless oil; 1H NMR (500 MHz, CDCl3)
d: 1.33
6.99 (1H, d, J¼8.5 Hz), 7.60 (1H, d, J¼1.5 Hz), 8.12 (1H, d, J¼1.5 Hz);
(12H, d, J¼2.5 Hz), 1.90 (3H, s), 2.30 (3H, s), 6.02 (1H, d, J¼2.0 Hz),
6.72 (1H, d, J¼5.5 Hz), 7.04 (1H, dd, J¼2.0, 5.5 Hz), 7.06 (1H, s), 7.14
13C NMR (125 MHz, CD3OD)
d: 20.4, 20.9, 24.0, 54.9, 84.0, 103.1, 117.8,
122.7, 126.2, 127.6, 134.3, 135.3, 141.3, 153.2, 171.3; IR (CHCl3, cmꢀ1
)
(1H, s); 13C NMR (125 MHz, CDCl3)
d: 15.2, 21.1, 24.8, 25.0, 82.1, 83.6,
1763, 3017, 3021; HRMS m/z (ESI) calcd for C20H25BNaO5 [(MþNa)þ]
88.8, 122.5, 130.0, 133.6, 144.8, 145.3, 150.8, 155.6; IR (CHCl3, cmꢀ1
)
379.1687, found. 379.1687.
3011; HRMS m/z (FABþ) calcd for C18H24BO3 [(MþH)þ] 299.1819,
found. 299.1818.
4.2.10. 6-Methyl-4-phenyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)naphthalen-1-yl acetate distal-22Ag. Following the general
procedure, a mixture of 28A (56 mg, 0.12 mmol), 2-phenylfuran 6g
(49 mg, 0.34 mmol), and i-PrMgCl$LiCl [1.3 M in THF (0.11 mL,
0.14 mmol)] in Et2O (1.2 mL) was stirred for 30 min at ꢀ78 ꢁC. To the
crude product (distal/proximal¼>98:2, determined by 500 MHz 1H
NMR analysis) were added 1.0 mL of pyridine and 0.10 mL of acetic
anhydride. After 3.0 h, the reaction mixture was quenched by water,
and the product was extracted with EtOAc. The organic layer was
dried over anhydrous Na2SO4, and the solvent was removed under
reduced pressure. The crude product was purified by column chro-
matography (hexane/EtOAc¼8:1) to provide distal-22Ag (18 mg,
40%), the regiochemistry of which was determined by NOESY spectra.
4.2.6. 2-(4,7-Dimethyl-1,4-dihydro-1,4-epoxynaphthalen-5-yl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane proximal-16Ac. 1H NMR
(500 MHz, CDCl3)
d
: 1.25 (12H, d, J¼8.0 Hz), 2.07 (3H, s), 2.27 (3H, s),
5.53 (1H, s, br s), 6.83 (1H, d, J¼5.0 Hz), 6.97 (1H, d, J¼5.0 Hz), 7.08
(1H, br s), 7.14 (1H, br s).
4.2.7. Trimethyl(7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1,4-dihydro-1,4-epoxynaphthalen-1-yl)silane distal-16Ad. Follo-
wing the general procedure, a mixture of 28A (48 mg, 0.10 mmol), 2-
trimethylsilylfuran 6d (46 mL, 0.29 mmol), and i-PrMgCl$LiCl [1.3 M in
THF (0.090 mL, 0.12 mmol)] in Et2O (1.0 mL) was stirred for 30 min at
ꢀ78 ꢁC. The crude product (distal/proximal¼>98:2, determined by
500 MHz 1H NMR analysis) was purified by column chromatography
(hexane/EtOAc¼12:1) to provide a mixture of distal- and proximal-
16Ad (31 mg, 91%). Pure distal-16Ad was isolable from the reaction
mixture by the same column chromatography, and its regiochemistry
was determined by NOESY spectra. A colorless oil; 1H NMR (500 MHz,
A colorless oil; 1H NMR (500 MHz, CDCl3)
2.43 (3H, s), 7.15 (1H, d, J¼8.0 Hz), 7.35 (1H, d, J¼8.0 Hz), 7.41e7.50
(5H, m), 7.60 (1H, br s), 7.67 (1H, br s); 13C NMR (125 MHz, CDCl3)
d: 1.45 (12H, s), 2.40 (3H, s),
d:
21.6, 22.1, 24.9, 83.9,117.6,126.5,127.1,127.2,128.2,130.2,133.2,135.2,
135.4,138.1,140.7,147.1,170.3; IR (CHCl3, cmꢀ1) 1759, 3007; HRMS m/
z (ESI) calcd for C25H27BNaO4 [(MþNa)þ] 425.1895, found. 425.1886.
CDCl3)
6.92 (1H, d, J¼5.5 Hz), 7.03 (1H, dd, J¼1.5, 5.5 Hz) 7.06 (1H, br s), 7.12
(1H, br s); 13C NMR (125 MHz, CDCl3)
: e3.1, 21.2, 24.8, 25.0, 83.5,
d: 0.30 (9H, s), 1.33 (12H, s), 2.28 (3H, s), 6.14 (1H, d, J¼1.5 Hz),
4.2.11. Methyl 7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-1,4-dihydro-1,4-epoxynaphthalene-1-carboxylate distal-16Ah. Fol-
lowing the general procedure, a mixture of 28A (58 mg, 0.12 mmol),
d
85.4, 124.0, 129.6, 133.2, 143.5, 145.4, 151.9, 155.8; IR (CHCl3, cmꢀ1
)
3017; HRMS m/z (FABþ) calcd for C20H30BO3 [(MþH)þ] 357.2057,
methyl furan-2-carboxylate 6h (38 mL, 0.36 mmol), and i-PrMgCl$LiCl
found. 357.2061.
[1.3 M in THF (0.11 mL, 0.14 mmol)] in Et2O (1.2 mL) was stirred for
30 min at ꢀ78 ꢁC. The crude product (distal/proximal¼93:7, de-
termined by 500 MHz 1H NMR analysis) was purified by column
chromatography (hexane/EtOAc¼5:1) to provide a mixture of distal-
and proximal-16Ah (23 mg, 57%). Pure distal-16Ah was isolable from
the reaction mixture by the same column chromatography, and its
regiochemistry was determined by NOESY spectra. A colorless solid;
4.2.8. Tributyl(7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-1,4-dihydro-1,4-epoxynaphthalen-1-yl)stannane distal-16Ae. Follo-
wing the general procedure, a mixture of 28A (49 mg, 0.10 mmol), 2-
tributylstannylfuran 6e (94 mL, 0.30 mmol), and i-PrMgCl$LiCl [1.3 M
in THF (0.090 mL, 0.12 mmol)] in Et2O (1.0 mL) was stirred for 30 min
at ꢀ78 ꢁC. The crude product (distal/proximal¼>98:2, determined by
500 MHz 1H NMR analysis) was purified by column chromatography
(hexane/EtOAc¼18:1) to provide a mixture of distal- and proximal-
16Ae (45 mg, 79%). Pure distal-16Ae was isolable from the reaction
mixture by the same column chromatography, and its regiochemistry
was determined by NOESY spectra. A colorless oil; 1H NMR (500 MHz,
mp 95e97 ꢁC. 1H NMR (500 MHz, CDCl3)
d: 1.34 (12H, s), 2.29 (3H, s),
3.98 (3H, s), 6.02 (1H, d, J¼2.0 Hz), 7.04 (1H, d, J¼5.5 Hz), 7.07 (1H, dd,
J¼2.0, 5.5 Hz), 7.21 (1H, br s), 7.25 (1H, br s); 13C NMR (125 MHz,
CDCl3) d: 21.1, 24.8, 25.0, 52.7, 82.9, 83.8, 90.0, 123.5, 131.1, 134.1, 142.2,
144.0, 146.8, 152.6, 168.6; IR (CHCl3, cmꢀ1): 1742, 3022; HRMS m/z
(ESI) calcd for C19H23BNaO5 [(MþNa)þ] 365.1531, found. 365.1531.
CDCl3)
d
: 0.89 (9H, t, J¼7.0 Hz), 1.11 (6H, t, J¼8.0 Hz), 1.32 (12H, s),
1.33e1.36 (6H, m), 1.53e1.59 (6H, m), 2.27 (3H, s), 6.09 (1H, d,
J¼1.5 Hz), 6.94 (1H, br s), 6.95 (1H, d, J¼6.0 Hz), 7.01 (1H, dd, J¼1.5,
4.2.12. Methyl 6-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-1,4-dihydro-1,4-epoxynaphthalene-1-carboxylate
proximal-
6.0 Hz), 7.09 (1H, br s); 13C NMR (125 MHz, CDCl3)
d: 9.1, 13.6, 21.2,
16Ah. 1H NMR (500 MHz, CDCl3)
d
: 1.33 (12H, s), 2.29 (3H, s), 3.90
24.8, 25.0, 27.4, 29.0, 29.1, 82.8, 83.5, 87.0, 124.0, 129.4, 133.2, 142.2,
148.7, 154.5, 155.4; IR (CHCl3, cmꢀ1) 3005; HRMS m/z (ESI) calcd for
C29H47BNaO3Sn [(MþNa)þ] 597.2532, found. 597.2553.
(3H, s), 5.72 (1H, d, J¼1.5 Hz), 7.00 (1H, dd, J¼1.5, 5.0 Hz), 7.15 (1H,
br s), 7.18 (1H, d, J¼5.0 Hz), 7.21 (1H, br s).
4.2.13. 1-(7-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
4.2.9. 4-Methoxy-6-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)naphthalen-1-yl acetate distal-22Af. Following the general pro-
cedure, a mixture of 28A (51 mg, 0.11 mmol), 2-methoxyfuran 6f
1,4-dihydro-1,4-epoxynaphthalen-1-yl)ethanone
wing the general procedure, a mixture of 28A (64 mg, 0.13 mmol), 2-
acetylfuran 6i (40 L, 0.40 mmol), and i-PrMgCl$LiCl [1.3 M in THF
distal-16Ai. Follo-
m
(30
m
L, 0.33 mmol), and i-PrMgCl$LiCl [1.3 M in THF (0.10 mL,
(0.12 mL, 0.16 mmol)] in Et2O (1.3 mL) was stirred for 30 min at
ꢀ78 ꢁC. The crude product (distal/proximal¼87:13, determined by
500 MHz 1H NMR analysis) was purified by column chromatography
(hexane/EtOAc¼10:1) to provide a mixture of distal- and proximal-
16Ai (22 mg, 51%). Pure distal-16Ai was isolable from the reaction
0.13 mmol)] in Et2O (1.0 mL) was stirred for 30 min at ꢀ78 ꢁC. To the
crude product (distal/proximal¼>98:2, determined by 500 MHz 1H
NMR analysis) were added 1.0 mL of pyridine and 0.10 mL of acetic
anhydride. After 6.5 h, the reaction mixture was quenched by water,

4348
A. Takagi et al. / Tetrahedron 69 (2013) 4338e4352
mixture by the same column chromatography, and its regiochemistry
PrMgCl$LiCl [1.3 M in THF (0.060 mL, 0.080 mmol)] in Et2O
(0.70 mL) was stirred for 30 min at ꢀ78 ꢁC. The crude product
(distal/proximal¼91:9, determined by 500 MHz 1H NMR analysis)
was purified by column chromatography (hexane/EtOAc¼13:1) to
provide a mixture of distal- and proximal-16Bb (5.1 mg, 24%). Pure
distal-16Bb was isolable from the reaction mixture by the same
column chromatography (hexane/EtOAc¼13:1). A colorless oil; 1H
was determined by NOESY spectra. A colorless solid; mp 104e106 ꢁC.
1H NMR (500 MHz, CDCl3)
d
: 1.34 (6H, s), 1.35 (6H, s), 2.28 (3H, s), 2.40
(3H, s), 6.21 (1H, d, J¼1.0 Hz), 7.02e7.04 (2H, m), 7.14 (1H, br s), 7.20
(1H, br s); 13C NMR (125 MHz, CDCl3)
: 21.1, 24.8, 25.0, 26.8, 82.7,
d
83.8, 95.4, 123.1, 130.9, 134.1, 141.9, 143.8, 147.1, 153.0, 205.8; IR (CHCl3,
cmꢀ1) 1717, 3017; HRMS m/z (ESI) calcd for C19H23BNaO4 [(MþNa)þ]
349.1582, found. 349.1601.
NMR (500 MHz, CDCl3)
d
: 0.97 (3H, t, J¼7.5 Hz), 1.33 (12H, s),
1.43e1.51 (2H, m), 1.53e1.64 (2H, m), 2.22e2.36 (2H, m), 6.09 (1H,
d, J¼2.0 Hz), 6.75 (1H, d, J¼5.5 Hz), 6.96 (1H, t, J¼7.5 Hz), 7.04 (1H,
dd, J¼2.0, 5.5 Hz), 7.21 (1H, d, J¼7.5 Hz), 7.33 (1H, d, J¼7.5 Hz); 13C
4.2.14. 1-(6-Methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
1,4-dihydro-1,4-epoxynaphthalen-1-yl)ethanone proximal-16Ai. Char-
acteristic 1H NMR (500 MHz, CDCl3)
d: 2.30 (3H, s), 2.37 (3H, s), 5.73
NMR (125 MHz, CDCl3) d: 14.0, 23.2, 24.75, 24.80, 25.0, 26.9, 28.9,
(1H, d, J¼2.0 Hz), 6.98 (1H, dd, J¼2.0, 5.0 Hz).
82.1, 83.7, 92.3, 121.5, 123.9, 130.1, 144.5, 144.7, 149.6, 158.9; IR
(CHCl3, cmꢀ1) 3007; HRMS m/z (FABþ) calcd for C20H28BO3
[(MþH)þ] 327.2132, found. 327.2118.
4.2.15. 7-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-
dihydro-1,4-epoxynaphthalene-1-carbonitrile distal-16Aj. Following
the general procedure, a mixture of 28A (53 mg, 0.11 mmol), 2-
4.2.18. 2-(4-Butyl-1,4-dihydro-1,4-epoxynaphthalen-5-yl)-4,4,5,5-
furancarbonitrile 6j (95
mL, 1.1 mmol), and i-PrMgCl$LiCl [1.3 M in
tetramethyl-1,3,2-dioxaborolane proximal-16Bb. 1H NMR (500 MHz,
THF (0.10 mL, 0.13 mmol)] in Et2O (1.1 mL) was stirred for 30 min at
ꢀ78 ꢁC. The crude product (distal/proximal¼>98:2, determined by
500 MHz 1H NMR analysis) was purified by column chromatography
(hexane/EtOAc¼12:1) to provide a mixture of distal- and proximal-
16Aj (16 mg, 46%). Pure distal-16Aj was isolable from the reaction
mixture by the same column chromatography, and its regiochem-
istry was determined by NOESY spectra. A colorless solid; mp
CDCl3)
d
: 0.94 (3H, t, J¼7.5 Hz), 1.37 (12H, s), 1.41e1.49 (2H, m),
1.54e1.64 (2H, m), 2.53e2.64 (2H, m), 5.61 (1H, d, J¼2.0 Hz), 6.83
(1H, d, J¼5.0 Hz), 6.93 (1H, t, J¼7.5 Hz), 6.99 (1H, dd, J¼2.0, 5.0 Hz),
7.25 (1H, d, J¼7.5 Hz), 7.34 (1H, d, J¼7.5 Hz).
4.2.19. Methyl 4-butyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-1,4-dihydro-1,4-epoxynaphthalene-6-carboxylate distal-16Cb. Fol-
lowing the general procedure, a mixture of 28C (59 mg, 0.11 mmol),
2-n-butylfuran 6b (0.15 mL, 1.1 mmol), and i-PrMgBr [0.77 M in THF
(0.30 mL, 0.23 mmol)] in Et2O (1.1 mL) was stirred for 30 min at
ꢀ78 ꢁC. The crude product (distal/proximal¼83:17, determined by
500 MHz 1H NMR analysis) was purified by column chromatography
(hexane/EtOAc¼12:1) to provide a mixture of distal- and proximal-
16Cb (29 mg, 68%). Pure distal-16Cb was isolable from the reaction
mixture by the same column chromatography, and its regiochem-
istry was determined by NOESY spectra. A colorless oil; 1H NMR
111e112 ꢁC. 1H NMR (500 MHz, CDCl3)
d: 1.34 (6H, s), 1.35 (6H, s),
2.34 (3H, s), 6.18 (1H, d, J¼2.0 Hz), 6.97 (1H, d, J¼5.5 Hz), 7.14 (1H, dd,
J¼2.0, 5.5 Hz), 7.25 (1H, s), 7.34 (1H, s); 13C NMR (125 MHz, CDCl3)
d:
21.1, 24.9, 25.0, 79.0, 83.5, 84.0, 115.5, 123.2, 131.9, 134.9, 141.1, 144.5,
145.8, 151.1; IR (CHCl3, cmꢀ1) 1599, 3019; HRMS m/z (ESI) calcd for
C18H20BNNaO3 [(MþNa)þ] 332.1428, found. 332.1442.
4.2.16. 2-(3,7-Dimethyl-1,4-dihydro-1,4-epoxynaphthalen-5-yl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane distal-16Ak and its re-
gioisomer proximal-16Ak. Following the general procedure, a mix-
(500 MHz, CDCl3)
d: 0.97 (3H, t, J¼7.0 Hz),1.34 (12H, s),1.47 (2H, sext,
ture of 28A (54 mg, 0.11 mmol), 3-methylfuran 6k (30
mL,
J¼7.0 Hz), 1.51e1.62 (2H, m), 2.24e2.39 (2H, m), 3.89 (3H, s), 6.10
(1H, d, J¼1.5 Hz), 6.76 (1H, d, J¼5.0 Hz), 7.00 (1H, dd, J¼1.5, 5.0 Hz),
7.80 (1H, d, J¼1.5 Hz), 8.09 (1H, d, J¼1.5 Hz); 13C NMR (125 MHz,
0.34 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 ꢀ78 ꢁC. The crude product
(distal/proximal¼87:13, determined by 500 MHz 1H NMR analysis)
was purified by column chromatography (hexane/EtOAc¼10:1) to
provide a hardly separable mixture of proximal- and distal-16Ak
(33 mg, quant), the regiochemistries of which were determined by
CDCl3) d: 14.0, 23.1, 24.7, 24.8, 25.0, 26.8, 28.8, 52.0, 82.0, 84.0, 92.3,
121.7, 126.2, 133.2, 143.8, 145.0, 150.4, 164.1, 167.2; IR (CHCl3, cmꢀ1
)
1715, 3026; HRMS m/z (ESI) calcd for C22H29BNaO5 [(MþNa)þ]
407.2000, found. 407.2022.
NOESY spectra. A colorless oil; 1H NMR (500 MHz, CDCl3)
d: 1.33 (6/
6H, s), 1.34 (36/6H, s), 1.36 (30/6H, s), 1.89 (3/6H, d, J¼1.5 Hz), 1.91
(15/6H, J¼1.5 Hz, d), 2.30 (18/6H, br s), 5.28 (1/6H, br s), 5.61 (5/6H,
br s), 5.80 (5/6H, br s), 6.06 (1/6H, br s), 6.38e6.39 (5/6H, m),
6.44e6.46 (1/6H, m), 7.12 (5/6H, br s), 7.16 (5/6H, br s), 7.19 (2/6H, br
4.2.20. Methyl 1-butyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-1,4-dihydro-1,4-epoxynaphthalene-6-carboxylate
proximal-
: 0.94 (3H, t, J¼7.5 Hz), 1.38 (12H,
16Cb. 1H NMR (500 MHz, CDCl3)
d
s), 1.43e1.62 (4H, m), 2.52e2.64 (2H, m), 3.88 (3H, s), 5.64 (1H, d,
J¼1.5 Hz), 6.80 (1H, d, J¼5.5 Hz), 6.99e7.02 (1H, m), 7.83 (1H, d,
J¼1.5 Hz), 8.09 (1H, d, J¼1.5 Hz).
s); 13C NMR (125 MHz, CDCl3)
d: 14.0, 14.1, 15.3, 23.1, 23.3, 24.6, 24.7,
24.78, 24.83, 25.0, 26.7, 27.2, 28.8, 29.7, 65.8, 80.7, 81.8, 84.0, 84.2,
85.0, 92.3, 94.9, 118.1, 118.4, 121.8, 122.8, 125.0, 125.1, 132.3, 133.4,
135.7, 139.8, 143.9, 144.3, 144.6, 145.3, 152.7, 152.9, 153.4, 155.7,
4.2.21. 2-(7-Bromo-1-butyl-1,4-dihydro-1,4-epoxynaphthalen-5-yl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane distal-16Db and its re-
gioisomer proximal-16Db. Following the general procedure, a mix-
157.7; IR (CHCl3, cmꢀ1
) 3009; HRMS m/z (ESI) calcd for
C18H23BNaO3 [(MþNa)þ] 321.1632, found. 321.1638.
ture of 28D (56 mg, 0.10 mmol), 2-n-butylfuran 6b (50
mL,
4.2.17. 2-(1-Butyl-1,4-dihydro-1,4-epoxynaphthalen-5-yl)-4,4,5,5-
tetramethyl-1,3,2-dioxaborolane distal-16Bb. From 28B: Following
the general procedure, a mixture of 28B (52 mg, 0.11 mmol), 2-n-
0.35 mmol), and i-PrMgCl$LiCl [1.3 M in THF (0.10 mL, 0.12 mmol)]
in Et2O (1.0 mL) was stirred for 30 min at ꢀ78 ꢁC. The crude product
(distal/proximal¼84:16, determined by 500 MHz 1H NMR analysis)
was purified by column chromatography (hexane/EtOAc¼12:1) to
provide a hardly separable mixture of distal- and proximal-16Db
(29 mg, 64%), the regiochemistries of which were determined by
butylfuran 6b (47 mL, 0.33 mmol), and i-PrMgCl$LiCl [1.3 M in THF
(0.10 mL, 0.13 mmol)] inEt2O (1.1 mL)wasstirredfor30minatꢀ78ꢁC.
The crude product (distal/proximal¼90:10, determined by 500 MHz
1H NMR analysis) was purified by column chromatography (hexane/
EtOAc¼13:1) to provide a mixture of distal- and proximal-16Bb
(31 mg, 88%). Pure distal-16Bb was isolable from the reaction mixture
by the same column chromatography (hexane/EtOAc¼13:1).
NOESY spectra. A colorless oil; 1H NMR (500 MHz, CDCl3)
d: 0.93 (3/
5H, t, J¼7.5 Hz), 0.97 (12/5H, t, J¼7.5 Hz), 1.33 (48/5H, s), 13.6 (12/
5H, s), 1.41e1.50 (8/5H, m), 1.51e1.61 (8/5H, m), 2.18e2.32 (8/5H,
m), 2.32e2.35 (2/5H, m), 2.50e2.59 (2/5H, m), 3.48 (1/5H, q,
J¼7.5 Hz), 5.56 (1/5H, d, J¼1.5 Hz), 6.03 (4/5H, d, J¼1.5 Hz), 6.73 (4/
5H, d, J¼7.5 Hz), 6.82 (1/5H, d, J¼7.5 Hz), 6.96 (1/5H, dd, J¼1.5,
From 28B0: Following the general procedure, a mixture of 28B0
(31 mg, 64
mmol), 2-n-butylfuran 6b (30 mL, 0.21 mmol), i-

A. Takagi et al. / Tetrahedron 69 (2013) 4338e4352
4349
7.5 Hz), 7.02 (4/5H, dd, J¼1.5, 7.5 Hz), 7.30 (4/5H, d, J¼1.5 Hz), 7.35
(1/5H, d, J¼1.5 Hz), 7.46 (4/5H, d, J¼1.5 Hz), 7.47 (1/5H, d, J¼1.5 Hz);
determined by NOESY spectra. A colorless oil; 1H NMR (500 MHz,
CDCl3)
: 1.34 (15H, s), 1.35 (6H, s), 2.31 (3H, s), 5.93 (1H, d, J¼3.0 Hz),
6.80 (1H, d, J¼6.0 Hz), 6.96 (1H, dd, J¼3.0, 6.0 Hz), 7.20 (1H, br s), 7.33
(1H, br s); 13C NMR (125 MHz, CDCl3)
: 21.1, 24.9, 25.0, 28.0, 67.4,
76.5, 81.3, 83.8, 125.1, 131.5, 134.5, 142.9, 147.4, 148.4, 151.2, 155.4; IR
(CHCl3, cmꢀ1) 1724, 3007; HRMS m/z (ESI) calcd for C22H29BBrNNaO4
[(MþNa)þ] 484.1265, found. 484.1268.
d
13C NMR (125 MHz, CDCl3)
d: 14.0, 14.1, 21.0, 21.1, 24.8, 24.9, 25.0,
82.5, 83.3, 83.58, 83.62, 85.2, 85.8, 123.2, 123.6, 129.8, 130.3, 133.2,
133.8, 134.5, 135.1, 148.2, 149.4, 153.6, 154.1, 154.6, 154.9; IR (CHCl3,
cmꢀ1) 3019; HRMS m/z (ESI) calcd for C20H26BBrNaO3 [(MþNa)þ]
427.1051, found. 427.1057.
d
4.2.22. 1-Ethyl-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)-9-tosyl-1,4-dihydro-1,4-epiminonaphthalene distal-42Ac. Follo-
wing the general procedure, a mixture of 28A (52 mg, 0.11 mmol), 2-
ethyl-1-tosyl-1H-pyrrole 41c (77 mg, 0.31 mmol), and i-PrMgCl$LiCl
[1.3 M in THF (0.10 mL, 0.13 mmol)] in Et2O (1.1 mL) was stirred for
30 min at ꢀ78 ꢁC. The crude product (distal/proximal¼87:13, de-
termined by 500 MHz 1H NMR analysis) was purified by column
chromatography (hexane/EtOAc¼9:1) to provide a mixture of distal-
and proximal-42Ac (31 mg, 63%). Pure distal-42Ac was isolable from
the reaction mixture by the same column chromatography, and its
regiochemistry was determined by NOESY spectra. A colorless oil;
4.2.26. 9-tert-Butyl 6-methyl 4-ethyl-8-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1,4-dihydro-1,4-epiminonaphthalene-6,9-
dicarboxylate distal-42Cd. Following the general procedure, a mix-
ture of 28C (53 mg, 0.10 mmol), tert-butyl 2-ethyl-1H-pyrrole-1-
carboxylate 41d (58 mg, 0.30 mmol), and i-PrMgCl$LiCl [1.3 M in
THF (0.090 mL, 0.12 mmol)] in Et2O (1.0 mL) was stirred for 30 min
at ꢀ78 ꢁC. The crude product (distal/proximal¼88:12, determined
by 500 MHz 1H NMR analysis) was purified by column chroma-
tography (hexane/EtOAc¼7:1) to provide a mixture of distal- and
proximal-42Cd (29 mg, 61%). Pure distal-42Cd was isolable from the
reaction mixture by the same column chromatography. A colorless
1H NMR (500 MHz, CDCl3)
d
: 1.349 (3H, t, J¼7.0 Hz), 1.354 (6H, s),
oil; 1H NMR (500 MHz, CDCl3)
d
: 1.23 (3H, t, J¼7.0 Hz), 1.32 (9H, s),
1.37 (6H, s), 2.09 (3H, s), 2.27 (3H, s), 2.40 (1H, qd, J¼7.0, 15.0 Hz),
2.58 (1H, qd, J¼7.0, 15.0 Hz), 5.85 (1H, d, J¼3.0 Hz), 6.70 (1H, s), 6.72
(1H, d, J¼6.0 Hz), 6.78 (1H, s), 6.89 (2H, d, J¼8.0 Hz), 7.02 (1H, dd,
1.35 (12H, s), 2.52 (1H, qd, J¼7.0, 14.0 Hz), 2.64e2.78 (1H, m), 3.88
(3H, s), 5.99 (1H, d, J¼1.5 Hz), 6.65 (1H, d, J¼6.0 Hz), 6.95 (1H, br s),
7.82 (1H, br s), 8.09 (1H, br s); 13C NMR (125 MHz, CDCl3)
d: 9.6, 21.0,
J¼3.0, 6.0 Hz), 7.26 (2H, d, J¼8.0 Hz); 13C NMR (125 MHz, CDCl3)
d:
24.9, 25.0, 28.1, 28.2, 52.0, 67.4, 77.9, 84.0, 122.2, 126.1, 133.2, 146.4,
150.7, 154.9, 163.2, 167.2; IR (CHCl3, cmꢀ1) 1708, 3019; HRMS m/z
(ESI) calcd for C25H34BNNaO6 [(MþNa)þ] 478.2371, found.
478.2373.
9.6, 20.4, 20.8, 21.3, 24.8, 25.0, 68.2, 79.6, 83.7, 123.7, 128.5, 129.9,
133.5, 134.8, 142.5, 143.7, 146.1, 147.9, 154.2; IR (CHCl3, cmꢀ1) 1597,
3015; HRMS m/z (ESI) calcd for C26H32BNNaO4S [(MþNa)þ]
488.2037, found. 488.2037.
4.2.27. 9-tert-Butyl 6-methyl 1-ethyl-8-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1,4-dihydro-1,4-epiminonaphthalene-6,9-
dicarboxylate proximal-42Cd. Characteristic 1H NMR (500 MHz,
4.2.23. 1-Ethyl-6-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-9-tosyl-1,4-dihydro-1,4-epiminonaphthalene proximal-42Ac. 1H -
NMR (500 MHz, CDCl3)
d
: 1.27 (3H, t, J¼7.5 Hz), 1.35 (12H, d,
CDCl3)
d
: 5.43 (1H, d, J¼3.0 Hz).
J¼7.5 Hz), 2.06 (3H, s), 2.29 (3H, s), 2.65e2.72 (1H, m), 2.83e2.90 (1H,
m), 5.26 (1H, d, J¼3.0 Hz), 6.67 (1H, br s), 6.70 (1H, d, J¼5.5 Hz), 6.75
(1H, br s), 6.91 (1H, dd, J¼3.0, 5.5 Hz), 6.95 (2H, d, J¼8.0 Hz), 7.30 (2H,
d, J¼8.0 Hz).
4.2.28. tert-Butyl 7-bromo-1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1,4-dihydro-1,4-epiminonaphthalene-9-
carboxylate distal-42Dd. Following the general procedure, a mix-
ture of 28D (54 mg, 0.10 mmol), tert-butyl 2-ethyl-1H-pyrrole-1-
carboxylate 41d (60 mg, 0.31 mmol), and i-PrMgCl$LiCl [1.3 M in
THF (0.090 mL, 0.12 mmol)] in Et2O (1.0 mL) was stirred for 30 min
at ꢀ78 ꢁC. The crude product (distal/proximal¼95:5, determined by
500 MHz 1H NMR analysis) was purified by column chromatogra-
phy (hexane/EtOAc¼13:1) to provide a mixture of distal- and
proximal-42Dd (33 mg, 72%). Pure distal-42Dd was isolable from
the reaction mixture by the same column chromatography. A col-
4.2.24. tert-Butyl 1-ethyl-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1,4-dihydro-1,4-epiminonaphthalene-9-
carboxylate distal-42Ad. Following the general procedure, a mix-
ture of 28A (52 mg, 0.11 mmol), tert-butyl 2-ethyl-1H-pyrrole-1-
carboxylate 41d (0.54 g, 1.1 mmol), and i-PrMgCl$LiCl [1.3 M in
THF (1.0 mL, 1.3 mmol)] in Et2O (11 mL) was stirred for 30 min at
ꢀ78 ꢁC. The crude product (distal/proximal¼>98:2, determined by
500 MHz 1H NMR analysis) was purified by column chromatogra-
phy (hexane/EtOAc¼13:1) to provide distal-42Ad (0.32 g, 70%). A
orless oil; 1H NMR (500 MHz, CDCl3)
d: 1.21 (3H, t, J¼7.5 Hz), 1.33
(15H, s), 1.34 (6H, s), 2.44 (1H, qd, J¼7.5, 14.0 Hz), 2.54e2.70 (1H,
m), 5.91 (1H, d, J¼2.0 Hz), 6.62 (1H, d, J¼5.0 Hz), 6.96 (1H, dd, J¼2.0,
5.0 Hz), 7.31 (1H, d, J¼2.0 Hz), 7.46 (1H, d, J¼2.0 Hz); 13C NMR
colorless oil; 1H NMR (500 MHz, CDCl3)
d
: 1.22 (3H, t, J¼7.5 Hz),
1.336 (12H, s), 1.344 (9H, s), 2.28 (3H, s), 2.49 (1H, qd, J¼7.5,
14.0 Hz), 2.59e2.72 (1H, br m), 5.93 (1H, br s), 6.62 (2H, d,
J¼6.0 Hz), 6.97 (1H, br s), 7.05 (1H, br s), 7.13 (1H, br s); 13C NMR
(125 MHz, CDCl3) d: 9.5, 21.0, 24.9, 25.0, 28.1, 67.1, 77.9, 80.3, 84.0,
118.3, 125.6, 132.4, 145.8, 152.9, 154.8, 156.7; IR (CHCl3, cmꢀ1) 1703,
3019; HRMS m/z (ESI) calcd for C23H31BBrNNaO4 [(MþNa)þ]
498.1422, found. 498.1440.
(125 MHz, CDCl3) d: 9.6, 21.1, 21.2, 24.9, 25.0, 28.2, 67.3, 77.9, 83.6,
123.6, 130.1, 133.4, 145.9, 150.4, 155.1; IR (CHCl3, cmꢀ1) 1701, 3021;
HRMS m/z (ESI) calcd for C24H34BNNaO4 [(MþNa)þ] 434.2473,
found. 434.2473.
4.2.29. tert-Butyl 6-bromo-1-ethyl-8-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1,4-dihydro-1,4-epiminonaphthalene-9-
carboxylate proximal-42Dd. Characteristic 1H NMR (500 MHz,
CDCl3)
J¼3.0, 5.5 Hz).
4.2.25. tert-Butyl 1-bromo-7-methyl-5-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1,4-dihydro-1,4-epiminonaphthalene-9-carboxylate
distal-42Ae. Following the general procedure, a mixture of 28A
(50 mg, 0.10 mmol), tert-butyl 2-bromo-1H-pyrrole-1-carboxylate
41e (86 mg, 0.35 mmol), and i-PrMgCl$LiCl [1.3 M in THF (0.10 mL,
0.13 mmol)] in Et2O (1.0 mL) was stirred for 30 min at ꢀ78 ꢁC. The
crude product (distal/proximal¼>98:2, determined by 500 MHz 1H
NMR analysis) was purified by column chromatography (hexane/
EtOAc¼11:1) to provide a mixture of distal- and proximal-42Ae
(27 mg, 58%). Pure distal-42Ae was isolable from the reaction mixture
by the same column chromatography, and its regiochemistry was
d: 5.35 (1H, d, J¼3.0 Hz), 6.69 (1H, d, J¼5.5 Hz), 6.88 (1H, dd,
4.2.30. 2,6-Dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-9-tosyl-1,4-dihydro-1,4-epiminonaphthalene distal-42Af and its
regioisomer proximal-42Af. Following the general procedure,
a mixture of 28A (50 mg, 0.10 mmol), 3-methyl-1-tosyl-1H-pyrrole
41f (72 mg, 0.31 mmol), and i-PrMgCl$LiCl [1.3 M in THF (0.10 mL,
0.12 mmol)] in Et2O (1.0 mL) was stirred for 30 min at ꢀ78 ꢁC. The
crude product (distal/proximal¼86:14, determined by 500 MHz 1H

4350
A. Takagi et al. / Tetrahedron 69 (2013) 4338e4352
NMR analysis) was purified by column chromatography (hexane/
EtOAc¼5:1) to provide a hardly separable mixture of distal- and
proximal-42Af (40 mg, 87%), the regiochemistries of which were
determined by NOESY spectra. A colorless oil; 1H NMR (500 MHz,
pressure. The crude product was purified by silica gel column
chromatography (hexane/EtOAc¼10:1) to provide 43 (8.7 mg, 71%).
A colorless oil; 1H NMR (500 MHz, CDCl3)
d: 0.95e0.98 (6H, m),
1.39e1.51 (4H, m), 1.51e1.65 (4H, m), 2.16e2.31 (2H, m), 2.25 (3H,
s), 3.08e3.19 (2H, m), 3.37 (1H, br s), 5.72 (1H, d, J¼1.5 Hz), 6.15 (1H,
s), 6.48 (1H, s), 6.75 (1H, d, J¼5.5 Hz), 7.02 (1H, dd, J¼1.5, 5.5 Hz);
CDCl3) d: 1.34 (42/7H, s), 1.35 (6/7H, s), 1.36 (36/7H, s), 1.76 (3/7H, d,
J¼1.5 Hz), 1.77 (18/7H, d, J¼1.5 Hz), 2.13 (21/7H, br s), 2.30 (21/7H,
br s), 4.94 (1/7H, br s), 5.29e5.32 (6/7H, m), 5.57 (6/7H, br s), 5.82
(1/7H, br s), 6.23e6.27 (6/7H, m), 6.31e6.34 (1/7H, m), 6.82 (6/7H,
br s), 6.86 (6/7H, br s), 6.88 (1/7H, br s), 6.89 (1/7H, br s), 6.98 (14/
7H, d, J¼8.0 Hz), 7.35 (14/7H, d, J¼8.0 Hz); 13C NMR (125 MHz,
13C NMR (125 MHz, CDCl3)
d: 13.9, 14.0, 20.2, 21.5, 23.2, 26.8, 29.1,
32.0, 44.5, 79.3, 93.0, 111.4, 130.7, 136.3, 141.3, 144.0, 144.3, 152.1; IR
(CHCl3, cmꢀ1) 3005, 3422; HRMS m/z (ESI) calcd for C19H28NO
[(MþH)þ] 286.2165, found. 286.2179.
CDCl3) d: 14.9, 15.0, 20.75, 20.84, 21.4, 24.7, 24.8, 24.9, 25.1, 68.0,
68.2, 70.8, 70.9, 83.6, 83.7, 124.2, 124.7, 127.1, 128.3, 128.8, 129.8,
130.3, 133.3, 133.8, 134.7, 134.9, 135.3, 142.7, 147.1, 152.0, 153.7,
154.5; IR (CHCl3, cmꢀ1) 1597, 3026; HRMS m/z (ESI) calcd for
C25H30BNNaO4S [(MþNa)þ] 474.1881, found. 474.1875.
4.4. Cyanidation of the boryl group of distal-16Ab (Table 9,
entry 2)
4.4.1. 1-Butyl-7-methyl-1,4-dihydro-1,4-epoxynaphthalene-5-
carbonitrile 44. A suspension of distal-16Ab (24 mg, 69
mmol),
4.2.31. tert-Butyl 2,6-dimethyl-8-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)-1,4-dihydro-1,4-epiminonaphthalene-9-
carboxylate distal-42Ag and its regioisomer proximal-42Ag. Following
the general procedure, a mixture of 28A (50 mg, 0.10 mmol), tert-
butyl 3-methyl-1H-pyrrole-1-carboxylate 41g (54 mg, 0.30 mmol),
and i-PrMgCl$LiCl [1.3 M in THF (0.10 mL, 0.12 mmol)] in Et2O
(1.0 mL) was stirred for 30 min at ꢀ78 ꢁC. The crude product (distal/
proximal¼92:8, determined by 500 MHz 1H NMR analysis) was pu-
rified by column chromatography (hexane/EtOAc¼11:1) to provide
a hardly separable mixture of distal-42Ag and its regioisomer prox-
imal-42Ag (38 mg, 95%), the regiochemistries of which were de-
termined by NOESY spectra. A colorless oil; 1H NMR (500 MHz,
copper(I) cyanide (9.3 mg, 0.10 mmol), and potassium carbonate
(29 mg, 0.21 mmol) in DMF (1.4 mL) was stirred at 60 ꢁC for 12 h.
The reaction mixture was filtered through a pad of Celite, and the
filtrate was concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography (hexane/
EtOAc¼15:1) to provide 44 (8.7 mg, 53%). A colorless oil; 1H NMR
(500 MHz, CDCl3)
d
: 0.97 (3H, t, J¼7.5 Hz), 1.45e1.60 (4H, m),
2.20e2.34 (2H, m), 2.32 (3H, s), 5.83 (1H, d, J¼1.5 Hz), 6.79 (1H, d,
J¼5.5 Hz), 6.95 (1H, br s), 7.05 (1H, dd, J¼1.5, 5.5 Hz), 7.13 (1H, br s);
13C NMR (125 MHz, CDCl3)
d: 13.9, 21.1, 23.1, 26.7, 28.7, 80.6, 93.3,
104.2, 117.0, 124.3, 126.3, 136.2, 143.7, 145.0, 152.6, 153.4; IR (CHCl3,
cmꢀ1) 1548, 2232, 3009; HRMS m/z (ESI) calcd for C16H17NNaO
[(MþNa)þ] 262.1202, found. 262.1191.
CDCl3) d: 1.34 (60/10H, s), 1.36 (150/10H, s), 1.89 (30/10H, br s), 2.27
(30/10H, br s), 5.05 (1/10H, br s), 5.35 (9/10H, br s), 5.60 (10/10H, br
s), 6.34 (10/10H, br s), 7.13 (20/10H, br s); 13C NMR (125 MHz, CDCl3)
4.5. Oxidation of the boryl group of distal-16Ab (Table 9, en-
d: 15.1, 15.2, 21.0, 21.1, 24.8, 24.9, 28.1, 66.1, 66.7, 69.6, 70.4, 80.0, 83.6,
try 3)
123.4, 124.3, 129.8, 133.1, 133.4, 134.2, 148.7, 149.3, 153.0, 153.3, 154.1,
155.0, 155.7, 155.9; IR (CHCl3, cmꢀ1) 1701, 3007; HRMS m/z (ESI)
calcd for C23H32BNNaO4 [(MþNa)þ] 420.2317, found. 420.2304.
4.5.1. 1-Butyl-7-methyl-1,4-dihydro-1,4-epoxynaphthalen-5-ol 45. A
round bottom flask was charged with distal-16Ab (27 mg, 80 mmol)
and sodium perborate tetrahydrate (62 mg, 0.40 mmol). THF/H2O
(1:1, 1.0 mL) was added. The reaction mixture was stirred for 3.0 h
at room temperature. H2O was added to the reaction mixture. The
reaction mixture was extracted with EtOAc. Aqueous layer was
extracted twice with EtOAc. The combined organic layer was
washed with saturated aqueous NaCl and dried over anhydrous
Na2SO4, and the solvent was removed under reduced pressure. The
crude product was purified by silica gel column chromatography
(hexane/EtOAc¼3:1) to provide 45 (16 mg, 85%). A colorless oil; 1H
4.2.32. tert-Butyl 3,7-dimethyl-1-phenethyl-5-(4,4,5,5-tetramethyl-
1,3,2-dioxaborolan-2-yl)-1,4-dihydro-1,4-epiminonaphthalene-9-
carboxylate distal-42Ah. Following the general procedure, a mix-
ture of 28A (60 mg, 0.12 mmol), tert-butyl 4-methyl-2-phenethyl-
1H-pyrrole-1-carboxylate 41h (0.10 g, 0.36 mmol), and i-
PrMgCl$LiCl [1.3 M in THF (0.11 mL, 0.14 mmol)] in Et2O (1.2 mL)
was stirred for 30 min at ꢀ78 ꢁC. The crude product (distal/
proximal¼>98:2, determined by 500 MHz 1H NMR analysis) was
purified by column chromatography (hexane/EtOAc¼13:1) to pro-
vide distal-42Ah (49 mg, 81%). A colorless oil; 1H NMR (500 MHz,
NMR (500 MHz, CDCl3)
d
: 0.97 (3H, t, J¼7.5 Hz), 1.42e1.50 (2H, m),
1.62e1.52 (2H, m), 2.25 (3H, s), 2.17e2.33 (2H, m), 4.71 (1H, s), 5.83
(1H, d, J¼2.0 Hz), 6.23 (1H, s), 6.63 (1H, s), 6.75 (1H, d, J¼5.5 Hz),
CDCl3) d: 1.34 (9H, s), 1.37 (6H, s), 1.38 (6H, s), 1.91 (3H, br s), 2.29
(3H, s), 2.62e2.69 (1H, m), 2.88e3.05 (2H, m), 3.05e3.12 (1H, m),
5.68 (1H, br s), 6.11 (1H, br s), 7.04 (1H, br s), 7.15 (1H, br s), 7.22 (1H,
7.03 (1H, dd, J¼2.0, 5.5 Hz); 13C NMR (125 MHz, CDCl3)
d: 14.0, 21.2,
23.2, 26.8, 29.0, 78.8, 93.2, 114.1, 114.5, 131.8, 137.1, 144.0, 144.1,
148.0, 153.3; IR (CHCl3, cmꢀ1) 1616, 3017; HRMS (FABþ) calcd for
C15H18O2 (Mþ): 230.1307, found: 230.1318.
t, J¼7.5 Hz), 7.31e7.37 (4H, m); 13C NMR (125 MHz, CDCl3)
d: 15.2,
21.2, 24.8, 25.0, 28.2, 30.0, 31.4, 71.1, 77.4, 79.8, 83.5, 84.2, 122.8,
125.7, 128.3, 128.4, 129.7, 133.6, 137.6, 142.7, 151.2, 155.0, 155.4; IR
(CHCl3, cmꢀ1) 1699, 3020; HRMS m/z (ESI) calcd for C31H40BNNaO4
[(MþNa)þ] 524.2943, found. 524.2945.
4.6. General procedure for the ring opening of 1,4-epoxy ring
and SuzukieMiyaura cross-coupling reactions of cycloadducts
(16Ab and 42Ad) (Table 10)
4.3. Copper catalyzed amination of the boryl group of distal-
16Ab (Table 9, entry 1)
A round bottom flask was charged with 16Ab [or 42Ad
(1.1 equiv)] and p-TsOH$H2O (1.0 equiv) and then evacuated and
back-filled with nitrogen. Anhydrous THF (0.05 M) was added via
syringe, and the reaction mixture was stirred at room tempera-
ture. After 12 h, the second portion of p-TsOH$H2O (1.0 equiv) was
added, and the reaction mixture was stirred for another 12 h. The
reaction mixture was separated, and the aqueous layer was
extracted twice with EtOAc. The combined organic layer was
washed with saturated aqueous NaCl, dried over Na2SO4, and
concentrated under reduced pressure. A suspension of crude
4.3.1. N,1-Dibutyl-7-methyl-1,4-dihydro-1,4-epoxynaphthalen-5-
amine 43. A suspension of distal-16Ab (21 mg, 60
acetate (0.60 mg, 3.3 mol), and cesium fluoride (4.6 mg, 30
in acetonitrile (1.0 mL) was stirred at room temperature for
5e10 min. n-Butylamine (3.0 L, 30 mol) was added, and the re-
m
mol), copper(II)
m
m
mol)
m
m
action mixture was stirred at room temperature under an oxygen
atmosphere for 12 h. The reaction mixture was filtered through
a pad of Celite, and the filtrate was concentrated under reduced

A. Takagi et al. / Tetrahedron 69 (2013) 4338e4352
4351
product 46 [or 47 (1.1 equiv)], Pd2(dba)3 (0.05 equiv), SPhos
1721, 3009, 3428; HRMS m/z (ESI) calcd for
[(MþNa)þ] 384.1934, found. 384.1953.
C
24H27NNaO2
(0.10 equiv), and K3PO4 (3.0 equiv) in toluene (0.20 M) was stirred
under ambient conditions for 5e10 min. Aryl iodide (1.0 equiv)
was added, and the reaction mixture was heated at 100 ꢁC under
an argon atmosphere for 12 h. The reaction mixture was diluted
with Et2O (1.0 mL) and filtered through a pad of Celite, and the
filtrated was concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography to
provide the product.
Acknowledgements
This work was supported by KAKENHI (No. 19890182) and
a Grant-in-Aid for the Global COE Program from MEXT. T.I. is also
gratefulforreceivingtheDaicelChemicalIndustryAward inSynthetic
Organic Chemistry (Japan). The Japan Society for the Promotion of
Science is gratefully acknowledged for predoctoral fellowship to A.T.
4.6.1. 4-Butyl-6-methyl-8-phenylnaphthalen-1-ol 48. Following the
general procedure, a mixture of distal-16Ab (0.33 g, 0.97 mmol), p-
TsOH$H2O (0.19 g, 0.98 mmol) in THF (10 mL) was stirred at room
temperature for 12 h. p-TsOH$H2O (0.19 g, 0.98 mmol) was added,
and the reaction mixture was stirred for another 12 h. A solution of
Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.03.016.
the crude product 46 (34 mg), Pd2(dba)3 (3.9 mg, 4.6
(3.5 mg, 8.5 mol), K3PO4 (54 mg, 0.25 mmol), and iodobenzene
(9.4 L, 84
mol) in toluene was stirred at 100 ꢁC for 7.0 h. The crude
mmol), SPhos
m
References and notes
m
m
product was purified by column chromatography (hexane/
1. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457e2483; (b) Monnier, F.;
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EtOAc¼10:1) to give 48 (22 mg, 94% 2 steps). A colorless oil; 1H
NMR (500 MHz, CDCl3)
d
: 0.99 (3H, t, J¼7.5 Hz), 1.47 (2H, sext,
J¼7.5 Hz), 1.74 (2H, q, J¼7.5 Hz), 2.54 (3H, s), 3.01 (2H, t, J¼7.5 Hz),
5.22 (1H, s), 6.76 (1H, d, J¼7.5 Hz), 7.06 (1H, br s), 7.22 (1H, d,
J¼7.5 Hz), 7.46e7.55 (5H, br s), 7.83 (1H, br s); 13C NMR (125 MHz,
3. (a) Baker, S. J.; Zhang, Y.-K.; Akama, T.; Lau, A.; Zhou, H.; Hernandez, V.; Mao, W.;
Alley, M. R. K.; Sanders, V.; Plattner, J. J. J. Med. Chem. 2006, 49, 4447e4450; (b)
Dorsey, B. D.; Iqbal, M.; Chatterjee, S.; Menta, E.; Bernardini, R.; Bernareggi, A.;
CDCl3) d: 14.1, 21.7, 22.9, 33.00, 33.04,110.4,119.9, 123.7,127.1, 128.4,
ꢁ
Cassara, P. G.; D’Arasmo, G.; Ferretti, E.; De Munari, S.; Oliva, A.; Pezzoni, G.;
128.9, 129.4, 130.4, 130.5, 133.8, 134.0, 136.6, 141.7, 151.4; IR (CHCl3,
cmꢀ1) 3019, 3514; HRMS m/z (FABþ) calcd for C21H23O [(MþH)þ]
291.1743, found. 291.1767.
Allievi, C.; Strepponi, I.; Ruggeri, B.; Ator, M. A.; Willliams, M.; Mallamo, J. P. J.
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4.6.2. 5-Butyl-3-methyl-[1,10-binaphthalen]-8-ol 49. Similarly to the
preparation of 48, a mixture of distal-16Ab (82 mg, 0.24 mmol), p-
TsOH$H2O (46 mg, 0.24 mmol) in THF (2.4 mL) was stirred at room
temperature for 12 h. p-TsOH$H2O (46 mg, 0.24 mmol) was added,
and the reaction mixture was stirred for 3.0 h. A solution of 46
(42 mg), Pd2(dba)3 (3.7 mg, 4.0
m
mol), SPhos (3.3 mg, 8.0
mmol),
K3PO4 (52 mg, 0.24 mmol), and 1-iodonaphthalene (12 mL, 82 mmol)
in toluene was stirred at 100 ꢁC for 2.0 h. The crude product was
purified by column chromatography (hexane/EtOAc¼10:1) to give
49 (30 mg, 99%). A colorless oil; 1H NMR (500 MHz, CDCl3)
d: 1.04
(3H, t, J¼7.5 Hz), 1.53 (2H, sext, J¼7.5 Hz), 1.80 (2H quint, J¼7.5 Hz),
2.57 (3H, s), 3.02e3.12 (2H, m), 5.19 (1H, s), 6.69 (1H, d, J¼8.0 Hz),
7.13 (1H, d, J¼1.5 Hz), 7.23 (1H, d, J¼7.5 Hz), 7.36e7.39 (1H, m), 7.45
(1H, d, J¼7.5 Hz), 7.51e7.54 (1H, m), 7.59 (1H, d, J¼2.5 Hz), 7.60 (1H,
br s), 7.93 (1H, d, J¼2.5 Hz), 7.95 (1H, br s), 7.98e8.01 (1H, m); 13C
NMR (125 MHz, CDCl3) d: 14.1, 21.7, 22.9, 33.0, 33.1, 110.2, 121.2,
123.9, 125.2, 126.4, 126.6, 126.9, 127.0, 127.3, 128.2, 129.0, 130.5,
130.8, 132.6, 133.5, 133.8, 134.2, 134.4, 139.0, 151.5; IR (CHCl3, cmꢀ1
)
3006, 3510; HRMS m/z (ESI) calcd for C25H24NaO [(MþNa)þ]
363.1719, found. 363.1712.
10. Akai, S.; Ikawa, T.; Takayanagi, S.; Morikawa, Y.; Mohri, S.; Tsuabkiyama, M.;
Egi, M.; Wada, Y.; Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 7673e7676.
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13. A part of this work was also briefly reported in our very recent review article,
see: Ikawa, T.; Tokiwa, H.; Akai, S. J. Synth. Org. Chem., Jpn. 2012, 70, 1123e1133.
14. Matsumoto, T.; Hosoya, T.; Katsuki, M.; Suzuki, K. Tetrahedron Lett. 1991, 32,
6735e6736.
4.6.3. tert-Butyl (4-ethyl-6-methyl-8-phenylnaphthalen-1-yl)carba-
mate 50. Similarly to the preparation of 48, a mixture of distal-
42Ad (24 mg, 59
(1.0 mL) was stirred at room temperature for 3.0 h. p-TsOH$H2O
(12 mg, 59 mol) was added, and the reaction mixture was stirred
for 3.0 h to give a crude product 47. A solution of 47 (21 mg),
Pd2(dba)3 (2.0 mg, 2.2 mol), SPhos (2.1 mg, 5.1 mol), K3PO4
L, 43 mol) in toluene
mmol), p-TsOH$H2O (12 mg, 59 mmol) in THF
m
15. The generation of borylbenzyne 11 from the substrates (IeIII) was also ex-
amined using LDA. Only I gave DielseAlder adduct 16Ab in low yield (for detail,
see Supplementary data).
m
m
(33 mg, 0.15 mmol), and iodobenzene (4.8
m
m
was stirred at 100 ꢁC for 12 h. The crude product was purified by
column chromatography (hexane/EtOAc¼12:1) to give 50 (13 mg,
82%). A colorless oil; 1H NMR (500 MHz, CDCl3)
d: 1.32 (9H, s), 1.38
(3H, t, J¼7.5 Hz), 2.53 (3H, s), 3.09 (2H, q, J¼7.5 Hz), 6.10 (1H, br s),
7.12 (1H, d, J¼1.5 Hz), 7.32 (1H, d, J¼7.5 Hz), 7.37e7.48 (5H, m), 7.65
(1H, d, J¼7.5 Hz), 7.86 (1H, br s); 13C NMR (125 MHz, CDCl3)
d: 15.1,
16. Because phenylboronic acids were prone to the adsorption on the silica gel, the
flash SiO2-chromatography purification was conducted after converting the
acids into their corresponding pinacol esters, which were in general relatively
21.6, 26.4, 28.1, 28.4, 79.3, 119.8, 123.0, 123.4, 125.4, 127.3, 128.6,
131.3, 131.8, 133.4, 133.8, 136.0, 137.6, 143.8, 152.9; IR (CHCl3, cmꢀ1
)

4352
A. Takagi et al. / Tetrahedron 69 (2013) 4338e4352
stable during the flash chromatography. However, it would be better if it is
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conducted under slightly acidic conditions (pH 6.5e6.8).
17. The regiochemistries of the products, distal-16Ab and proximal-16Ab, were
determined by NOESY NMR experiment.
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action conditions, with 6b gave 52:48 mixture of distal- and proximal-13Bb,
which reaffirmed the powerful effect of the boryl group on the regiocontrol of
the DA reaction.
35. The conventional analysis of the charge distribution based on the Mulliken and
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possessing an electron-withdrawing methoxycarbonyl, acetyl, and cyano
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Entry
R
Natural charge
C2
C5
1
2
3
4
5
6
t-Bu
Me
OMe
CO2Me
Ac
6a
6c
6f
6h
6i
0.31
0.30
0.63
0.17
0.19
0.17
0.09
0.09
0.06
0.13
0.13
0.13
CN
6j
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ꢂ
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