Insertion of arynes into the carbon-oxygen double bond of amides and its application into the sequential reactions

Article abstract of DOI:10.1016/j.tet.2011.10.072

The reaction of arynes, generated from ortho-(trimethylsilyl)aryl triflates, with the CO bond of formamides gave salicylaldehyde derivatives via the formation of formal [2+2] adducts. The sequential transformation of arynes into ortho-disubstituted arenes, o-aminoalkylphenols or o-hydroxyalkylphenols, was achieved by one-pot procedure using dialkylzincs.

Full text of DOI:10.1016/j.tet.2011.10.072

Tetrahedron 68 (2012) 179e189
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Insertion of arynes into the carboneoxygen double bond of amides and its
application into the sequential reactions
*
Eito Yoshioka, Hideto Miyabe
School of Pharmacy, Hyogo University of Health Sciences, Minatojima, Kobe 650-8530, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 October 2011
Received in revised form 19 October 2011
Accepted 20 October 2011
Available online 28 October 2011
The reaction of arynes, generated from ortho-(trimethylsilyl)aryl triflates, with the C]O bond of form-
amides gave salicylaldehyde derivatives via the formation of formal [2þ2] adducts. The sequential
transformation of arynes into ortho-disubstituted arenes, o-aminoalkylphenols or o-hydrox-
yalkylphenols, was achieved by one-pot procedure using dialkylzincs.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Arynes
N,N-Dimethylformamide
Salicylaldehyde
Dialkylzinc
Insertion
1. Introduction
bond, which gave the benzocyclobutenes D as relatively stable
products.12,13 However, less is known about the insertion into the
Arynes are highly strained and kinetically unstable in-
termediates that have been wildly employed in organic synthesis
since the 1950s.1 In recent years, aryne chemistry has reemerged
and made great advances in synthetic chemistry.2,3 Particularly, the
development of ortho-(trimethylsilyl)aryl triflates as mild aryne
precursors led to a rapid growth of this research area.4 It is note-
worthy that this mild method for generating arynes provides
a highly general solution to the fundamental problems that are
associated with the traditional harsh methods. Initially, the utility
of arynes, derived in this manner, was found in transition metal-
catalyzed reactions involving cross-coupling processes.3f,5e7 More
recently, considerable effort has been directed toward the transi-
tion metal-free reactions.3g,8e11 In most cases, these new aryne-
based reactions comprise the initial addition of nucleophiles to
arynes and the subsequent trapping of intermediates with elec-
trophiles under transition metal-free conditions.
carboneheteroatom double bond (C]X) giving the formal [2þ2]
cycloaddition-type adducts E.14 As a relative study, in 1965,
R
C
C
benzocyclobutenes D
C
C
π-bond
insertion
X
Y
X
C
R
R
R
X
Y
X
C
σ
-bond
insertion
π
-bond
insertion
A
o-substituted
arenes B
formal
[2+2] adducts E
When nucleophile and electrophile belong to the same mole-
cule, most of reactions are classified into the insertion of arynes A
X
Z
into the
the [2þ3] cycloaddition of 1,3-dipolars to arynes giving the [2þ3]
adducts C11 (Fig. 1). As a rare insertion of arynes A into the
-bond,
s
-bond (XeY) giving ortho-disubstituted arenes B10 and
Y
p
R
X
Z
Suzuki’s group has extensively studied the insertion into the C]C
Y
[2+3] adducts C
* Corresponding author. Fax: þ81 78 304 2794; e-mail address: miyabe@huh-
s.ac.jp (H. Miyabe).
Fig. 1. Insertion of arynes giving ortho-disubstituted arenes.
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.072

180
E. Yoshioka, H. Miyabe / Tetrahedron 68 (2012) 179e189
Yaroslavsky reported that the reaction of benzenediazonium chlo-
ride or benzenediazonium-2-carboxylate with N,N-dime-
thylformamide (DMF) gave the low yields of salicylaldehyde.15 The
(Scheme 1). 3-Methoxy-2-(trimethylsilyl)phenyl triflate 1 was
employed as an aryne precursor. All reactions were evaluated at
room temperature in the presence of fluoride ion source for 3 h
(Table 1). Initially, the reaction of triflate 1 with 3 equiv of DMF was
run in CH3CN in the presence of 3 equiv of TBAF$3H2O (entry 1). As
expected, the desired salicylaldehyde derivative 2 was obtained in
31% yield probably via the zwitterion I and the four-membered
intermediate J, accompanied by 31% yield of the recovered start-
ing material 1 (entry 1). The presence of water had an impact on the
chemical efficiency. The isolated yield of 2 increased to 56% yield by
changing TBAF$3H2O into anhydrous TBAF (entry 2). Additionally,
the concentration influenced the chemical efficiency; 0.3 M solu-
tion of triflate 1 gave a better result (entry 3). In these reactions, the
competitive attack of the amide nitrogen atom on aryne H was
suppressed. In regard to the solvent effect, the replacement of
CH3CN with THF, CH2Cl2 or toluene led to a decrease in the chemical
yields (entries 4e6). The protic solvents, such as CH3OH and
CH3CO2H were not suitable for the present reaction (entries 7 and
8). Decreasing the amount of DMF to 1 equiv resulted in a low
chemical yield (entry 9). In contrast, the use of 10 equiv of DMF
improved the chemical yield into 70% (entry 10). It is noteworthy
that the high regioselectivity was achieved due to the electronic
effect by the methoxy group on triflate 1. The reaction of polarized
synthetically useful insertion into the
p-bond of carbonyl com-
pounds was recently achieved by Yoshida and co-workers.16a In
their study, the 2/1 coupling reaction of arynes and aldehydes
proceeds probably through the formation of unstable [2þ2] ad-
ducts E. Our laboratory is interested in developing the sequential
reactions induced by the insertion of arynes into the carbonyl group
of amides. As our successful examples, we recently reported the
sequential transformation involving trapping process of the in-
termediates, such as adducts E with dialkylzincs17a and the multi-
component coupling reaction involving trapping process with the
active methylene compounds.17b More recently, Yoshida’s group
also reported the three-component coupling using arynes and
DMF.16b In this paper, we describe in detail the study on the in-
sertion of arynes, generated from ortho-(trimethylsilyl)aryl tri-
flates, into the carboneoxygen double bond of amides.
Amides are the attractive nucleophiles for researching the re-
activity of aryne, since they have nitrogen and oxygen atoms as
nucleophilic sites. However, in general, the diversity in the reaction
of arynes with amides is limited to the NeC s-bond bond insertion
starting form the addition of amide nitrogen atom to arynes, al-
though the reactions of arynes with various amides including sul-
finamide, enamide, and urea, have been investigated (Fig. 2).18
aryne
H
gave the salicylaldehyde derivative
2
as
a
single
regioisomer.20
Therefore, the development of the C]O p-bond insertion starting
form the addition of amide oxygen atom to arynes is challenging
task. Arynes exhibit extraordinary electrophilicity mainly due to
their low-lying LUMO; thus, we surmised that the enhanced elec-
trophilicity would allow for the attack of the weakly nucleophilic
amide oxygen atom on arynes to give the formal [2þ2] adducts G. In
particular, the substituents R1 and R2 of amides are assumed to play
a pivotal role for directing two competitive attacks between ni-
trogen and oxygen atoms.
OMe
TMS
OMe
CHO
OH
H
NMe2
a) Reagent, rt, 3 h
b) H2O, rt
+
O
OTf
DMF
2
1
OMe
OMe
H
NMe2
F
H
1
O
O
NMe2
H
I
N-C -bond insertion
O
OMe
O
NMe2
H
O
R1
O
R
R
R
R1
NR2
2
R1
NR2
o-substituted
arenes F
H2O
2
NR2
2
2
J
A
Scheme 1. Insertion of aryne into DMF.
This work: C=O -bond insertion
O
R1
R1
NR2
2
R
R
R
R1
NR2
NR2
2
2
O
Table 1
O
Reaction of aryne precursor 1 with DMFa
formal
[2+2] adducts G
A
Entry
Reagent (3.0 equiv)
DMF (equiv)
Solvent
Yieldb (%)
1c
2c
3e
4c
5c
6c
7c
8c
9c
10c
TBAF$3H2O
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
3.0
3.0
3.0
3.0
3.0
3.0
3.0
3.0
1.0
10.0
CH3CN
CH3CN
CH3CN
THF
CH2Cl2
Toluene
CH3OH
CH3CO2H
CH3CN
CH3CN
31d
56
61
46
43
40
No reaction
No reaction
29
Fig. 2. Two reaction paths with amides.
2. Results and discussion
2.1. Insertion of aryne into the carboneoxygen double bond
of DMF
TBAF
70
a
Reactions were carried out at rt for 3 h in the presence of 3.0 equiv of TBAF$3H2O
In organic synthesis, DMF can react as either an electrophilic or
nucleophilic agent.19 At first, we examined the insertion of arynes
or anhydrous TBAF.
b
Isolated yield.
Solution (0.1 M) of 1.
The starting material 1 was recovered in 31% yield.
Solution (0.3 M) of 1.
into the C]O
p
-bond of sterically less hindered DMF (R1¼H,
c
R2¼Me in Fig. 2). We were gratified to observe the sufficient nu-
d
e
cleophilicity of carbonyl oxygen atom of DMF toward aryne

E. Yoshioka, H. Miyabe / Tetrahedron 68 (2012) 179e189
181
The best result was obtained, when DMF was employed as
a solvent (Scheme 2, Table 2). In the presence of anhydrous TBAF,
treatment of triflate 1 in DMF gave the desired product 2 in 84%
yield (entry 1). Under the similar reaction conditions, the effect of
fluoride ion sources was studied (entries 2e5). The use of CsF or
tetrabutylammonium bifluoride (TBAHF2) promoted the insertion
to strain energy. Therefore, we anticipated that the quinone
methide E- and Z-forms K and L should be formed from the [2þ2]
adduct J. As expected, the calculation supports that these trans-
formations (Step A2 and Step A3) are thermodynamically favorable
processes (DG<0 kJ/mol). Additionally, the isomerization of the
quinone methide E-form K into Z-form L (Step A4) is supported as
a reasonable pathway. Finally, the hydrolysis of the quinone
methides K and L giving the salicylaldehyde derivative 2 (Step B1
and Step B2) is favorable to proceed in view of thermodynamics.
into the C]O
p-bond to give the product 2 in reasonable yields
(entries 2 and 3). In contrast, the replacement of anhydrous TBAF
with tetrabutylammonium difluorotriphenylsilicate (TBAT) or
TBAF$3H2O led to a decrease in the chemical yields (entries 4 and
5). In these studies, the fluoride ion sources did not affect the
regioselectivity to give the product 2 as a single regioisomer. The
scope of carbonyl compounds was tested by employing ethyl for-
mate and dimethyl carbonate instead of DMF (entries 6 and 7).
However, the corresponding ortho-disubstituted arenes were not
obtained. In the case of ethyl formate, the formation of simple
adduct 3 was observed (entry 6). At the present stage, the carbonyl
oxygen atom of amides was the solitary nucleophile to bring about
OMe
OMe
NMe2
H
O
H
NMe2
Step A1
+
O
H
DMF
J
Step A3
Step A2
p-bond insertion into arynes.
OMe NMe2
OMe
OMe
OMe
OMe
Step A4
a) Reagent, rt
TMS
NMe2
CHO
OH
Solvent, 3 h
O
O
K
b) H2O, rt
OTf
L
OEt
1
2
3
OMe NMe2
OMe
H
NMe2
H
OEt
MeO
OMe
CHO
Step B1
HNMe2
+
+
H2O
O
DMF
O
O
O
OH
Ethyl formate
Dimethyl carbonate
2
K
Scheme 2. Insertion of aryne into C]O bond.
OMe
OMe
CHO
OH
NMe2
Step B2
Table 2
Reaction of aryne precursor 1 with C]O bonda
+
HNMe2
H2O
+
O
2
L
Entry
Reagent
Solvent
Product
(3.0 equiv)
(% yield)b
Scheme 3. Possible reaction pathway.
1
2
3
4
5
6
7
TBAF
CsF
TBAHF2
TBAT
TBAF$3H2O
TBAF
DMF
DMF
DMF
DMF
2 (84)
2 (72)
2 (67)
2 (31)
2 (37)
3 (25)
Table 3
Change in Gibbs free energy, enthalpy, and entropy
DMF
Ethyl formate
Dimethyl carbonate
Step
A1
Change
D
G (kJ/mol)
D
H (kJ/mol)
DS (J/mol K)
TBAF
Complex mixture
Jꢀ(HþDMF)
ꢀ106a
(ꢀ111)b
ꢀ67a
ꢀ177a
(ꢀ177)b
ꢀ63a
ꢀ219a
(ꢀ218)b
13a
a
Reactions were carried out at rt for 3 h in the presence of 3.0 equiv of fluoride
ion source.
A2
A3
A4
B1
B2
KꢀJ
b
Isolated yield.
(ꢀ67)b
ꢀ74a
(ꢀ63)b
ꢀ71a
(12)b
12a
LꢀJ
(ꢀ74)b
ꢀ7.3a
(ꢀ71)b
ꢀ7.6a
(11)b
ꢀ0.9a
(ꢀ1.0)b
19a
The possible reaction pathway is shown in Scheme 3. The
LꢀK
present reaction is assumed to be driven by high reactivity related
to the strain energy of reactants. In other words, this success re-
flects the overall difference in the strain energy of aryne, the four-
membered intermediate, quinone methide, and product. To explore
the validity of the mechanistic hypothesis, the thermodynamic data
were obtained by an ab initio molecular orbital calculation (Table
3). These data indicate that the insertion of aryne H into the C]O
(ꢀ7.4)b
ꢀ93a
(ꢀ7.6)b
ꢀ87a
(2þHNMe2)ꢀ(KþH2O)
(2þHNMe2)ꢀ(LþH2O)
(ꢀ93)b
ꢀ86a
(ꢀ87)b
ꢀ80a
(20)b
20a
(ꢀ85)b
(ꢀ79)b
(21)b
a
At 325.15 K.
b
The numerical values in parentheses are at 298.15 K.
p
-bond (Step A1) is remarkably exothermic (
D
H¼ꢀ177 kJ/mol at
325.15 K and ꢀ177 kJ/mol at 298.15 K) mainly due to the release of
the strain energy of aryne H by reacting with DMF. It is important to
stress that this enthalpy change sufficiently overcomes the entropy
2.2. Reaction of aryne with several amides
loss of the bimolecular coupling process (T
D
S¼ꢀ71 kJ/mol at
We next investigated the effect of two substituents at nitrogen
atom of formamides on the C]O
-bond insertion reaction (see: R2
of amides in Fig. 2). Initially, we allowed triflate 1 to react with
10 equiv of 1-formylpiperidine 4 and 3 equiv of anhydrous TBAF in
CH3CN for 3 h (Scheme 4). As expected, the desired salicylaldehyde
325.15 K and ꢀ65 kJ/mol at 298.15 K). Totally, the changes in Gibbs
p
energy of Step A1 represent that the insertion of aryne H into the
C]O
p-bond of DMF is thermodynamically favorable (DG<0 kJ/
mol). The resulting [2þ2] adduct J is also considerably unstable due

182
E. Yoshioka, H. Miyabe / Tetrahedron 68 (2012) 179e189
derivative 2 was obtained in 60% yield. Interestingly, the simply
aminated product 5 was also formed in 6% yield as a by-product.
When the bulky formamide 6 was employed, the chemical yield
of 2 diminished to 34%; instead, the formation of the simply ami-
nated product 7 increased to 16% yield. In the case of DMF, the
formation of the corresponding aminated product was not ob-
served under the similar reaction conditions (see: entry 10 in Table
1). As one of the possible suppositions, the steric factor of sub-
OMe
Me
NH
a) TBAF, CH3CN
rt, 3 h
H
2 (4%)
1
+
+
b) H2O, rt
O
OH
8 (10 equiv)
9 (52%)
Me
HN
OMe
OMe
H
H
O
protonation
H2O
NMe
H
stituents at nitrogen atom might affect the C]O p-bond insertion
9
O
process from the zwitterion I into the four-membered intermediate
J as shown in Scheme 1. Probably, the aminated products 5 and 7
would be formed by hydrolysis of the ammonium salt M, which was
generated by the attack of the amide nitrogen atom on aryne H
followed by the protonation with the acetonitrile component of the
reaction solvent. The protonation by the acetonitrile was verified by
Greaney’s studies on aryne chemistry.21 However, as an alternative
pathway giving the aminated products 5 and 7, the reaction of
aryne H with N,N-dialkylamines, generated by the hydrolysis of
quinone methide intermediates, would not be rigorously excluded,
although the reactions were carefully conducted under anhydrous
conditions.
H
N
Scheme 5. Reaction of 1 with N-methylformamide 8.
in CH3CN was less effective (entry 1), DMA was employed as a sol-
vent. In the presence of anhydrous TBAF, treatment of 1 with DMA
gave the desired product 10 in 34% yield, accompanied by the
product 11 in 10% yield and the aminated product 12 in 5% yield
(entry 2). The three products 10e12 were also obtained, when CsF
and TBAHF2 were employed (entries 3 and 4). In the light of the fact
that the reported reactions of arynes with amides have concen-
trated on the NeC s s-
-bond insertion,18 the formation of the NeC
OMe
bond insertion product 11 is reasonable.
a) TBAF, CH3CN
TMS
OTf
rt, 3 h
H
N
+
OMe
b) H2O, rt
O
TMS
OTf
Me
NMe2
a) Reagent, rt, 3 h
b) H2O, rt
4 (10 equiv)
1
OMe
OMe
+
CHO
O
DMA
OMe O
+
1
OH
2 (60%)
N
OMe O
OMe
5 (6%)
Me
Me
OMe
+
+
Bn
N
a) TBAF, CH3CN
rt, 3 h
OH
NMe2
NMe2
H
Bn
10
11
12
+
1
2 (34%) +
Bn
b) H2O, rt
O
N
Bn
C=O -bond insertion
6 (10 equiv)
7 (16%)
OMe
Me
OMe
Me
NMe2
OMe
OMe
CH2CN
H2O
NMe2
O
H
O
H
O
protonation
CH3CN
H2O
10
O
5 and 7
NR2
O
N
H
H
R2
H
M
N-C -bond insertion
Scheme 4. Reaction of 1 with formamides 4 and 6.
OMe
Me
OMe
Me
O
11
12
We next studied the reaction using N-monoalkylated formam-
NMe2
ide 8 (Scheme 5). As expected, N-methylformamide 8 worked well
as an oxygen atom nucleophile. However, the undesired product 9
was predominantly formed probably through the intermediate N as
a result of the rapid protonation by protic formamide 8. In a con-
sequence, the sterically less hindered and fully substituted DMF is
N
O
Me2
H
P
Scheme 6. Two competitive insertions into DMA.
a highly efficient oxygen atom nucleophile for the present C]O p-
bond insertion reaction.
Table 4
Reaction of aryne precursor 1 with DMAa
Next, two competitive attacks between nitrogen and oxygen
atoms of amides were investigated by changing amides from
formamide to acetamide (Scheme 6, Table 4). In comparison with
Entry
Reagent
Solvent
Product (% yield)b
10
11
12
1
2
3
4
TBAF, DMA (3 equiv)
TBAF
CsF
CH3CN
DMA
DMA
DMA
3
34
31
19
NDc
10
6
Trace
DMF, the insertion into the C]O p-bond of N,N-dimethylacetamide
5
8
3
(DMA) giving ketone 10 was apparently suppressed, since the steric
factor of DMA gave rise to destabilizing the [2þ2] adduct O. Instead,
TBAHF2
6
the formation of the NeC s-bond bond insertion product 11 and the
a
Reactions were carried out at rt for 3 h in the presence of 3.0 equiv of fluoride
aminated product 12 was observed, except for entry 1. The products
11 and 12 were formed via the intermediate P generated by the
addition of amide nitrogen atom into aryne H. Because the reaction
ion source.
b
c
Isolated yield.
Not detected.

E. Yoshioka, H. Miyabe / Tetrahedron 68 (2012) 179e189
183
Table 5
The reaction of triflate 1 with N,N-dimethylthioformamide 13
was next tested (Scheme 7). However, the insertion of aryne into
the C]S -bond of 13 could not be observed. After being stirred for
Variation of aryne precursorsa
Product (Yield,b ratio)
p
Entry
Precursor
3 h, the reaction mixture was treated with Ac2O, because the S-
incorporated product was difficult to isolate as a pure compound.
We confirmed the formation of product 14 in 14% yield, accompa-
nied with the recovered triflate 1 in 77% yield.
TMS
OTf
CHO
1
OH
21 (68%)
15
OMe
1
MeO
R
H
NMe2
a) TBAF, CH3CN, rt, 3 h
b) Ac2O (10 equiv), rt
O
MeO
TMS
+
1
2
R
S
S
Me
2
22a: R1=CHO, R2=OH
22b: R1=OH, R2=CHO
(81%, 22a:22b = 7:5)
13 (3 equiv)
OTf
14 (14%)
16
Scheme 7. Reaction using N,N-dimethylthioformamide 13.
1
R
2.3. Reaction of several arynes with DMF giving
salicylaldehyde derivatives
2
TMS
R
OTf
3c
With these results in mind, we next examined the effect of
varying the substituents on the aryne precursors (Table 5). The
simple triflate 15 reacted well to afford the salicylaldehyde 21 (entry
1). The reaction of the unsymmetrical aryne, generated from triflate
16 having a methoxy group at 4-position, gave the regioisomers 22a
and 22b in a 7/5 ratio on 1H NMR (entry 2).20 The formation of
regioisomers supports that the present reaction proceeds via aryne
intermediates. The nucleophilicity of DMF toward aryne, generated
from bulky unsymmetrical naphthalene triflate 17, was sufficient to
23a: R1=CHO, R2=OH
23b: R1=OH, R2=CHO
(73%, 23a:23b = 2:1)
17
CHO
TMS
OTf
OH
4d
24 (49%)
bring about the C]O p-bond insertion (entry 3). The adducts 23a
18
and 23b were obtained in 73% combined yield and a 2/1 ratio, ac-
companied by 11% yield of the recovered starting material 17. The
observed regioisomeric ratio revealed the preferential attack of
carbonyl oxygen atom of DMF at the less sterically hindered carbon
atom of aryne. In the case of symmetrical naphthalene triflate 18, the
chemical yield of the desired naphthaldehyde 24 decreased to 49%,
because of the competitive formation of thia-Fries rearrangement
product 25 and the recover of triflate 18 (entry 4).22 In contrast to
triflate 1 having a 3-methoxy group, the use of triflate 19 having a 3-
methyl group led to a decrease in regioselectivity to give the prod-
ucts 26a and 26b in a 7/5 ratio (entry 5). The reaction of triflate 20
resulted in the formation of product 27 in 73% yield (entry 6).
SO CF
2
3
OH
25 (13%)
Me
1
2
R
Me
TMS
OTf
5
R
26a: R1=OH, R2=CHO
26b: R1=CHO, R2=OH
(57%, 26a:26b = 7:5)
19
2.4. Trapping reaction using dialkylzincs
MeO
TMS
OTf
MeO
CHO
OH
We next investigated the trapping reaction of the unstable in-
termediates, the formal[2þ2]adductJ orthe quinonemethideE- and
Z-forms K and L, with organometallic reagents. We found that dia-
lkylzincs have the sufficient reactivity toward these intermediates
and the compatibility of DMFas a solvent (Scheme 8). After a solution
of triflate 1 in freshly distilled DMF was stirred in the presence of CsF
at room temperature for 15 min, dialkylzincs were added to the re-
action mixture, andthen thereaction mixturewas stirred at the same
temperature for 12 h. When a solution of Et2Zn in hexane (1.05 M,
5 equiv) was employed, the desired o-aminoalkylphenol 28 was
obtained in 71% yield by simple one-pot procedure. In this trans-
formation, a small amount of o-hydroxyalkylphenol 32 was also
isolated as a by-product, which was generated by trapping of sali-
cylaldehyde derivative 2 with Et2Zn. Under the similar conditions,
Me2Zn reacted well to give o-aminoalkylphenol 29, accompanied by
o-hydroxyalkylphenol33 in9%yield. Interestingly, Ph2Zntrappedthe
intermediates with high activity to form the aminophenol 30 in 97%
yield without the formation of the corresponding o-hydrox-
yalkylphenol. Similar result was observed when simple triflate 15
was employed as an aryne precursor. As reported in our communi-
cation,17a weassumed that dialkylzincs addedtonot theformal[2þ2]
6
MeO
MeO
27 (73%)
20
a
Reactions were carried out in DMF at rt in the presence of 3.0 equiv of anhydrous
TBAF.
b
c
Isolated yield.
The starting material 17 was recovered in 11% yield.
The starting material 18 was recovered in 26% yield.
d
adduct J but the thermodynamically stable quinone methide E- or Z-
forms K or L based on the calculation study.
We next investigated the one-pot procedure for the sequential
transformation using 1-formylpiperidine 4 (Scheme 9). The re-
action using 10 equiv of 1-formylpiperidine 4 and 3 equiv of CsF in
CH3CN gave the desired adduct 35 in 11% (Table 6, entry 1). Slight
improvement in the chemical yield was observed when the re-
action was carried out in the presence of 30 equiv of 4 (entry 2). The
yield of 35 increased to 40% when anhydrous TBAF was employed

184
E. Yoshioka, H. Miyabe / Tetrahedron 68 (2012) 179e189
OMe Et
OMe Et
OMe Et
a) freshly distilled DMF,
CsF, rt, 15 min
a) CsF, Et2Zn, rt, 1 min
OH
NMe2
NMe2
OH
+
b) triflate 1, rt, 12 h
b) Et2Zn, rt, 12 h
OH
OH
28 (71%)
H
NMe2
32 (9%)
OMe Me
OH
OH
28 (87%)
O
OMe Me
Et
a) freshly distilled DMF,
CsF, rt, 15 min
freshly distilled
DMF
NMe2
a) CsF, Et2Zn, rt, 1 min
1
+
NMe2
OH
b) Me2Zn, rt, 12 h
OH
29 (69%)
b) triflate 18, rt, 12 h
33 (9%)
36 (51%)
OMe Ph
+
27 (16%)
a) freshly distilled DMF,
CsF, rt, 15 min
NMe2
OMe Et
b) Ph2Zn, rt, 12 h
OH
30 (97%)
H
H
N
a) CsF, Et2Zn, rt, 1 min
N
b) triflate 1, rt, 12 h
O
O
OH
Et
Et
a) freshly distilled DMF,
CsF, rt, 15 min
4
35 (84%)
OH
NMe2
15
+
b) Et2Zn, rt, 12 h
OH
34 (12%)
OH
31 (76%)
OMe Et
N
Me
N
Me
a) CsF, Et2Zn, rt, 1 min
Scheme 8. Trapping reaction of the unstable intermediates with R2Zn.
b) triflate 1, rt, 12 h
OH
37
38 (65%)
OMe Et
Scheme 10. The improved one-pot procedure for trapping reaction.
a) Reagent, rt, 15 min
b) Et2Zn, rt, 12 h
H
N
N
1 +
O
OH
35
yield. In these reactions, 1-formylpiperidine 4 and N-allyl-N-meth-
ylformamide 37 were used without the purification by distillation.
4
Scheme 9. Trapping reaction using amide 4.
2.5. Trapping reaction giving o-hydroxyalkylphenols
Table 6
As described above, during the study on the trapping reactions
synthesizing o-aminoalkylphenols, we frequently observed the
Trapping reaction using aryne precursor 1 and 1-formylpiperidine 4a
Entry Reagent
1-Formylpiperidine 4 (equiv) Solvent Yieldb (%)
OMe Et
1
2
3
4
CsF (3.0 equiv)
CsF (3.0 equiv)
TBAF (3.0 equiv) 10
TBAF (3.0 equiv) 10
10
30
CH3CN
CH3CN
CH3CN
11
29
40
a) CsF, DMF, rt, 3 h
b) Et2Zn, rt, 12 h
OH
OH
Toluene 22
a
Reactions were carried out by using 3.0 equiv of Et2Zn (1.0 M in hexane).
Isolated yield.
b
32 (57%)
1
OMe Me
as a fluoride ion source (entry 3). As shown by entry 4, the use of
other solvents led to a decrease in the chemical yield. Under these
reaction conditions, the formation of o-hydroxyalkylphenol 32 and
salicylaldehyde derivative 2 was observed as major by-products
due to hydrolysis of intermediates with contaminated water.
To suppress the formation of o-hydroxyalkylphenols, generated
from salicylaldehyde derivatives, the one-pot procedure was reex-
amined(Scheme 10). BecauseCsF isa moisture-sensitivefluorideion
source, Et2Zn was initially added to a suspension of CsF in freshly
distilled DMF to remove a trace amount of water in the reaction
mixture. Next, triflate 1 was added to the reaction mixture. As ex-
pected, this improved procedure gave the desired o-amino-
alkylphenol 28 in 87% yield without the formation of o-
hydroxyalkylphenol 32, after being stirred at room temperature for
12 h. When the naphthalene triflate 18 was employed, o-amino-
alkylphenol 36 was obtained, accompanied by thia-Fries rear-
rangement product 27. This new procedure was also effective for the
one-pot reactions using 1-formylpiperidine 4. Under the similar
reaction conditions using amide 4, the yield of 35 increased to 84%
(vs 40%, entry 3 in Table 6). Additionally, the one-pot reaction using
N-allyl-N-methylformamide 37 gave the desired product 38 in 65%
a) CsF, DMF, rt, 3 h
b) Me2Zn, rt, 12 h
OH
OH
33 (50%)
MeO
D Et
OH
,
a) CsF, DMF-d rt, 3 h
7
1
b) Et2Zn, rt, 12 h
OH
39 (52%)
D
N(CD3)2
DMF-d
O
7
Et
a) CsF, DMF, rt, 3 h
b) Et2Zn, rt, 12 h
OH
15
OH
34 (53%)
Scheme 11. Trapping reaction giving o-hydroxyalkylphenols.

E. Yoshioka, H. Miyabe / Tetrahedron 68 (2012) 179e189
185
formation of the small amount of o-hydroxyalkylphenols. There-
fore, we finally tried to establish the one-pot procedure for trapping
of salicylaldehyde derivatives with dialkylzincs to prepare the o-
hydroxyalkylphenols (Scheme 11). For this transformation, we
allowed triflate 1 to react with commercially available DMF in the
presence of moisture-sensitive CsF (5 equiv) for the prolonged
time. After the reaction mixture was stirred at room temperature
for 3 h, a solution of Et2Zn in hexane (1.05 M, 10 equiv) was finally
added. As expected, the desired o-hydroxyalkylphenol 32 was
isolated in 57% by this simple procedure, accompanied with a 10%
yield of o-aminoalkylphenol 28. When Me2Zn was used, the o-
hydroxyalkylphenol 33 was obtained in 50% yield accompanied
with a small amount of o-aminoalkylphenol 29. The DMF-d7 also
acted as a nucleophile to give the deuterated product 39. Under the
similar reaction conditions, the aryne precursor 15 worked well,
allowing facile incorporation of structural variety. Although the
competitive formation of the corresponding o-aminoalkylphenols
was slightly observed, it is noteworthy that o-hydroxyalkylphenols
were prepared as major products by simply changing the experi-
mental procedure.
column chromatography (AcOEt/hexane¼1/20 to 1/8 with 2%
CH2Cl2) afforded the product 2.
3.2.1. 2-Hydroxy-3-methoxybenzaldehyde (2)23. Colorless crystals.
Mp 73.5e74.5 ꢁC (AcOEt/hexane). IR (KBr) 3245, 3084, 2893, 1646,
1618, 1465 cmꢀ1. 1H NMR (CDCl3)
d
11.97 (1H, s), 10.34 (1H, s), 7.41
(1H, dd, J¼8.0, 8.5 Hz), 6.52 (1H, d, J¼8.5 Hz), 6.38 (1H, d, J¼8.0 Hz),
3.89 (3H, s). 13C NMR (CDCl3)
d 194.5, 163.6, 162.5, 138.4, 110.8,
109.9, 101.0, 55.8. MS (EIþ) m/z 84 (100), 153 (MþHþ, 9). HRMS (EIþ)
calcd for C8H9O3 (MþHþ) 153.0546, found 153.0553. Anal. Calcd for
C8H8O3: C, 63.15; H, 5.30%. Found: C, 63.14; H, 5.32%.
3.3. Experimental procedure for the reaction of precursor 1
in DMF (entries 1e5 in Table 2)
To a solution of TBAF, CsF, TBAHF2, TBAT or TBAF$3H2O
(0.60 mmol) in DMF (1.2 mL) was added a solution of 3-methoxy-2-
(trimethylsilyl)phenyl triflate 1 (53 mL, 0.20 mmol) in DMF (0.8 mL)
under argon atmosphere at room temperature. After being stirred
at the same temperature for 3 h, H2O (0.1 mL) was added to the
reaction mixture. The reaction mixture was concentrated under
reduced pressure. Purification of the residue by flash silica gel
column chromatography (AcOEt/hexane¼1/20 to 1/8 with 2%
CH2Cl2) afforded the product 2.
In summary, we have demonstrated that the C]O
p-bond in-
sertion, starting from the addition of amide oxygen atom to arynes,
proceeded effectively by using the sterically less hindered form-
amide. The salicylaldehyde derivatives were formed via a route
involving the transformation of the formal [2þ2] cycloaddition
adducts into quinone methide intermediates. Moreover, the se-
quential transformation of arynes into ortho-disubstituted arenes
was achieved by one-pot procedure using formamides and dia-
lkylzincs. Interestingly, o-aminoalkylphenols and o-hydrox-
yalkylphenols could be selectively prepared by simply changing the
one-pot procedure.
3.4. Experimental procedure for the reaction of precursor 1
in ethyl formate (entry 6 in Table 2)
To a solution of TBAF (157 mg, 0.60 mmol) in ethyl formate
(1.2 mL) was added a solution of 3-methoxy-2-(trimethylsilyl)
phenyl triflate 1 (53 mL, 0.20 mmol) in ethyl formate (0.8 mL) under
3. Experimental
3.1. General
argon atmosphere at room temperature. After being stirred at the
same temperature for 3 h, H2O (0.1 mL) was added to the reaction
mixture. The reaction mixture was concentrated under reduced
pressure. Purification of the residue by flash silica gel column
chromatography (AcOEt/hexane¼1/20 to 1/8 with 2% CH2Cl2)
afforded the product 3 (7.5 mg, 25%).
Melting points were taken on a Yanaco MP-J3 and are un-
corrected. Infrared spectraweremeasured on a JASCO FT/IR-4100.1H
NMR spectra were measured on a JEOL ECX-400 PSK (400 MHz) or
Varian NMRS 600 (600 MHz). 13C NMR spectra were measured on
a JEOL ECX-400 PSK (101 MHz) or Varian NMRS 600 (126 MHz) with
CDCl3 as an internal standard (77.0 ppm). 19F NMR spectrum was
measured on a JEOL ECX-400 PSK (376 MHz) with C6F6 as an internal
standard (-162.2 ppm). Mass spectra (EI-MS and ESI-MS) were ob-
tained by use of a Hitachi M-4100 GC/MS spectrometer or Thermo
Fisher Scientific Exactive LC/MS spectrometer. Elemental analyses
were measured on Yanaco CHN CORDER MT-5. For silica gel column
chromatography, SiliCycle Inc. SiliaFlash F60 was used. The anhy-
drous TBAF was prepared from TBAF$3H2O by heating the hydrate at
40 ꢁC for 6 h, at 60 ꢁC for 12 h, at 80 ꢁC for 6 h, and then at 120 ꢁC for
12 h under reduced pressure. The anhydrous TBAF was used as
a solution in the appropriate solvent, such as DMF, CH3CN, and so on.
Calculation studies were performed on Hartree-Fock 6-311G* by
using Spartan’08 Essential Edition (WAVEFUNCTION, INC).
3.4.1. 3-Ethoxyanisole (3)24. Colorless oil. IR (KBr) 2980, 2936, 1601,
1493 cmꢀ1. 1H NMR (CDCl3)
d
7.17 (1H, t, J¼8.0 Hz), 6.51e6.46 (3H,
m), 4.02 (2H, q, J¼7.0 Hz), 3.79 (3H, s),1.41 (3H, t, J¼7.0 Hz). 13C NMR
(CDCl3)
d 160.8, 160.2, 129.8, 106.6, 106.1, 100.9, 63.3, 55.2, 14.8.
HRMS (ESIþ) calcd for C9H13O2 (MþHþ) 153.0910, found 153.0905.
3.5. Experimental procedure for the reaction of precursor 1
with amides 4, 6, or 8 (Schemes 4 and 5)
To a solution of 3-methoxy-2-(trimethylsilyl)phenyl triflate 1
(53 mL, 0.20 mmol) and 1-formylpiperidine 4, N,N-dibenzylforma-
mide 6, or N-methylformamide 8 (2.0 mmol) in CH3CN (1.4 mL) was
added TBAF (1.0 M solution in CH3CN, 0.60 mL, 0.60 mmol) under
argon atmosphere at room temperature. After being stirred at the
same temperature for 3 h, H2O (0.1 mL) was added to the reaction
mixture. The reaction mixture was concentrated under reduced
pressure. Purification of the residue by flash silica gel column
chromatography (AcOEt/hexane¼1/20 to 1/8 with 2% CH2Cl2)
afforded the products 2, 5, 7, and 9.
3.2. Experimental procedure for the reaction of aryne
precursor 1 with DMF (entries 2 and 4e10 in Table 1)
To a solution of 3-methoxy-2-(trimethylsilyl)phenyl triflate 1
(53 mL, 0.20 mmol) and DMF (0.20 mmol, 0.60 mmol or 2.0 mmol)
in CH3CN, THF, CH2Cl2, CH3OH or CH3CO2H (1.4 mL) was added
TBAF (1.0 M solution in corresponding solvent, 0.60 mL, 0.60 mmol)
under argon atmosphere at room temperature. After being stirred
at the same temperature for 3 h, H2O (0.1 mL) was added to the
reaction mixture. The reaction mixture was concentrated under
reduced pressure. Purification of the residue by flash silica gel
3.5.1. N-(3-Methoxyphenyl)piperidine (5)25. Colorless oil. IR (KBr)
2925, 2853, 1608, 1465 cmꢀ1 1H NMR (CDCl3)
. d 7.14 (1H, br t,
J¼8.0 Hz), 6.55 (1H, br dd, J¼8.0, 2.5 Hz), 6.47 (1H, br t, J¼2.5 Hz),
6.37 (1H. br dd, J¼8.0, 2.5 Hz), 3.78 (3H, s), 3.15 (4H, br t, J¼5.5 Hz),
1.72e1.67 (4H, m), 1.59 (2H, m). 13C NMR (CDCl3)
d 160.5, 153.6,
129.6, 109.3, 103.9, 102.8, 55.1, 50.6, 25.8, 24.4. MS (EIþ) m/z 190

186
E. Yoshioka, H. Miyabe / Tetrahedron 68 (2012) 179e189
(100), 191 (Mþ, 83). HRMS (EIþ) calcd for C12H17NO (Mþ) 191.1305,
found 191.1327.
3.7.1. S-(3-Methoxyphenyl)thioacetate (14). Colorless oil. IR (KBr)
3004, 2938, 1708, 1591, 1479 cmꢀ1. 1H NMR (CDCl3)
7.32 (1H, m),
7.02e6.94 (3H, m), 3.81 (3H, s), 2.42 (3H, s). 13C NMR (CDCl3)
d
3.5.2. 3-Methoxy-N,N-dibenzylaniline (7)26. Colorless oil. IR (KBr)
d
194.0,159.8,130.0,128.8,126.6, 119.5,115.6, 55.3, 30.2. MS (EIþ) m/
3027, 2933, 2834, 1610, 1576, 1499, 1452 cmꢀ1
.
1H NMR (CDCl3)
z 140 (100), 182 (Mþ, 40). HRMS (EIþ) calcd for C9H10O2S (Mþ)
d
7.33e7.29 (4H, m), 7.24e7.21 (6H, m), 7.07 (1H, t, J¼8.0 Hz), 6.36
182.0402, found 182.0419.
(1H, dd, J¼8.0, 2.0 Hz), 6.29e6.26 (2H, m), 4.63 (4H, s), 3.69 (3H, s).
13C NMR (CDCl3)
d
160.7, 150.6, 138.5, 129.9, 128.6, 126.8, 126.6,
3.8. General procedure for the reaction of precursors 15e20
in DMF (Table 5)
105.6, 101.5, 99.0, 55.0, 54.2. MS (EIþ) m/z 303 (Mþ, 100). HRMS
(EIþ) calcd for C21H21NO (Mþ) 303.1618, found 303.1624.
To a solution of TBAF (157 mg, 0.60 mmol) in DMF (1.2 mL) was
added a solution of precursors 15e20 (0.20 mmol) in DMF (0.8 mL)
under argon atmosphere at room temperature. After being stirred
at the same temperature for 3 h, H2O (0.1 mL) was added to the
reaction mixture. The reaction mixture was concentrated under
reduced pressure. Purification of the residue by flash silica gel
column chromatography (AcOEt/hexane¼1/20 to 1/3 with 2%
CH2Cl2) afforded the products 21e27.
3.5.3. 3-Methoxyphenol (9)27. Colorless oil. IR (KBr) 3355, 2959,
2839,1598,1494,1464 cmꢀ1. 1H NMR (CDCl3)
d
7.13 (1H, t, J¼8.0 Hz),
6.51e6.48 (1H, m), 6.44e6.41 (2H, m), 4.95 (1H, br s), 3.78 (3H, s).13C
NMR (CDCl3) 160.9, 156.6, 130.1, 107.7, 106.4, 101.4, 55.3.
d
3.6. Experimental procedure for the reaction of precursor 1
with DMA (entry 2 in Table 4)
To a solution of TBAF (157 mg, 0.60 mmol) in DMA (1.2 mL) was
added a solution of 3-methoxy-2-(trimethylsilyl)phenyl triflate 1
(53 mL, 0.20 mmol) in DMA (0.8 mL) under argon atmosphere at
room temperature. After being stirred at the same temperature for
3 h, H2O (0.1 mL) was added to the reaction mixture. The reaction
mixture was concentrated under reduced pressure. Purification of
the residue by flash silica gel column chromatography (AcOEt/
hexane¼1/20 to 1/8 with 2% CH2Cl2) afforded the products 10
(11.3 mg, 34%), 11 (3.8 mg, 10%), and 12 (1.3 mg, 5%).
3.8.1. 2-Hydroxybenzaldehyde (21)30. Colorless oil. IR (KBr) 3183,
3062, 2845, 1666, 1486 cmꢀ1. 1H NMR (CDCl3)
d
11.02 (1H, s), 9.90
(1H, s), 7.58e7.51 (2H, m), 7.04e6.98 (2H, m). 13C NMR (CDCl3)
196.6, 161.6, 136.9, 133.7, 120.6, 119.8, 117.6.
d
3.8.2. 2-Hydroxy-5-methoxybenzaldehyde (22a)31 and 2-hydroxy-4-
methoxybenzaldehyde (22b)32. A mixture of 22a and 22b (22a/
22b¼7/5). Yellow oil. IR (KBr) 3168, 2944, 2840, 1658, 1629,
1486 cmꢀ1. 1H NMR (CDCl3)
d 11.48 (5/12H, s), 10.63 (7/12H, s), 9.86
(7/12H, s), 9.71 (5/12H, s), 7.42 (5/12H, d, J¼8.5 Hz), 7.14 (7/12H, dd,
J¼9.2, 3.2 Hz), 7.00 (7/12H, d, J¼3.2 Hz), 6.93 (7/12H, d, J¼9.2 Hz),
6.54 (5/12H, dd, J¼8.5, 2.5 Hz), 6.43 (5/12H, d, J¼2.5 Hz), 3.85 (15/
3.6.1. 2-Hydroxy-6-methoxyacetophenone (10)28. Colorless crystals.
Mp 57e57.5 ꢁC (AcOEt/hexane). IR (KBr) 3110, 3009, 2947, 1623,
1594, 1459 cmꢀ1
.
1H NMR (CDCl3)
d
13.23 (1H, s), 7.33 (1H, t,
12H, s), 3.81 (21/12H, s). 13C NMR (CDCl3)
d 196.1, 194.4, 166.8,164.5,
J¼8.0 Hz), 6.56 (1H, dd, J¼8.0, 1.0 Hz), 6.39 (1H, dd, J¼8.0, 1.0 Hz),
156.1, 152.7, 135.2, 125.2, 120.0, 118.7, 115.2, 108.4, 100.6, 55.9, 55.7.
One carbon peak was missing due to overlapping. MS (EIþ) m/z 83
(100), 152 (Mþ, 0.2). HRMS (EIþ) calcd for C8H9O3 (MþHþ)
153.0546, found: 153.0552.
3.90 (3H, s), 2.67 (3H, s). 13C NMR (CDCl3)
d 205.1, 164.6, 161.5, 136.0,
111.3, 110.7, 101.1, 55.6, 33.7. MS (EIþ) m/z 83 (100), 166 (Mþ, 3).
HRMS (EIþ) calcd for C9H10O3 (Mþ) 166.0624, found 166.0646.
3.6.2. 2-(N,N-Dimethyl)amino-6-methoxyacetophenone
3.8.3. 2-Hydroxy-1-naphthaldehyde (23a)33. Pale yellow crystals.
Mp 79e80 ꢁC (CH2Cl2/hexane). IR (KBr) 3249, 3060, 2895, 2807,
(11). Colorless oil. IR (CHCl3) 2942, 1702, 1577, 1468 cmꢀ1. 1H NMR
(CDCl3)
d
7.23 (1H, br t, J¼8.0 Hz), 6.67 (1H, br d, J¼8.0 Hz), 6.56 (1H,
1640, 1584, 1468 cmꢀ1. 1H NMR (CDCl3)
d 13.16 (1H, s), 10.81 (1H, s),
br d, J¼8.0 Hz), 3.78 (3H, s), 2.72 (6H, s), 2.50 (3H, s). 13C NMR
8.34 (1H, br d, J¼8.8 Hz), 7.98 (1H, d, J¼9.3 Hz), 7.80 (1H, br d,
(CDCl3)
d 205.2, 156.2, 151.8, 130.2, 125.3, 111.0, 104.7, 55.8, 44.8,
J¼8.3 Hz), 7.62 (1H, dt, J¼8.3,1.5 Hz), 7.44 (1H, dt, J¼8.3,1.0 Hz), 7.14
31.8. MS (EIþ) m/z 83 (100), 193 (Mþ, 0.4). HRMS (EIþ) calcd for
(1H, d, J¼9.3 Hz). 13C NMR (CDCl3)
d 193.3, 164.9, 139.1, 132.9, 129.5,
C11H15NO2 (Mþ) 193.1097, found 193.1121.
129.1, 127.8, 124.5, 119.2, 118.6, 111.3. MS (EIþ) m/z 172 (Mþ, 100).
HRMS (EIþ) calcd for C11H8O2 (Mþ) 172.0519, found 172.0531.
3.6.3. 3-Methoxy-N,N-dimethylaniline (12)29. Colorless oil. IR (KBr)
2955,1610,1493,1465 cmꢀ1. 1H NMR (CDCl3)
d
7.15 (1H, t, J¼8.0 Hz),
3.8.4. 1-Hydroxy-2-naphthaldehyde (23b)34. Pale yellowcrystals. Mp
6.36 (1H, dd, J¼8.0, 2.5 Hz), 6.31e6.27 (2H, m), 3.80 (3H, s), 2.94
50e51 ꢁC (CH2Cl2/hexane). IR (KBr) 3161, 3057, 2836, 1646, 1629 cmꢀ1
.
(6H, s). 13C NMR (CDCl3)
d
160.6, 151.9, 129.7, 105.7, 101.3, 99.1, 55.1,
1H NMR (CDCl3)
d
12.67 (1H, s), 9.97 (1H, s), 8.45 (1H, br d, J¼8.3 Hz),
40.6. MS (EIþ) m/z 83 (100), 151 (Mþ, 0.4). HRMS (EIþ) calcd for
C9H14NO (MþHþ) 152.1070, found 152.1055.
7.79 (1H, d, J¼8.3 Hz), 7.67 (1H, dd, J¼8.3, 1.5 Hz), 7.56 (1H, dd, J¼8.3,
1.5 Hz), 7.49 (1H, d, J¼8.3 Hz), 7.38 (1H, d, J¼8.3 Hz). 13C NMR (CDCl3)
d
196.3, 161.9, 137.5, 130.6, 127.6, 126.5, 126.1, 124.5, 124.3, 119.4, 114.2.
3.7. Experimental procedure for the reaction of precursor 1
with thioformamide 13 (Scheme 7)
HRMS (ESIꢀ) calcd for C11H7O2 (M-Hꢀ) 171.0452, found 171.0443.
3.8.5. 3-Hydroxy-2-naphthaldehyde (24)35. Pale yellow crystals. Mp
94e95 ꢁC (CH2Cl2/hexane). IR (KBr) 3303, 3052, 2873, 1674, 1503,
To a solution of TBAF (157 mg, 0.60 mmol) in CH3CN (1.2 mL)
were added a solution of 3-methoxy-2-(trimethylsilyl)phenyl tri-
1459 cmꢀ1. 1H NMR (CDCl3)
d 10.32 (1H, br s), 10.10 (1H, br s), 8.16
flate 1 (53
(51 L, 0.60 mmol) in CH3CN (0.8 mL) under argon atmosphere at
room temperature. After being stirred at the same temperature for
3 h, Ac2O (189 L, 2.0 mmol) was added to the reaction mixture.
After being stirred for 12 h, the reaction mixture was concentrated
under reduced pressure. Purification of the residue by flash silica gel
column chromatography (AcOEt/hexane¼1/20 to 1/3 with 2%
CH2Cl2) afforded the product 14 (5.1 mg, 14%) and the recovered
triflate 1 (50.5 mg, 77%).
m
L, 0.20 mmol) and N,N-dimethylthioformamide 13
(1H, br s), 7.88 (1H, br d, J¼8.0 Hz), 7.72 (1H, br d, J¼8.0 Hz), 7.57
m
(1H, dt, J¼7.0, 1.5 Hz), 7.38 (1H, dt, J¼7.0, 1.5 Hz), 7.29 (1H, s). 13C
NMR (CDCl3)
d 197.3, 156.4, 138.8, 138.5, 130.9, 130.0, 128.0, 127.3,
m
125.0, 122.9, 112.5. MS (EIþ) m/z 83 (100), 172 (Mþ, 0.7). HRMS (EIþ)
calcd for C11H8O2 (Mþ) 172.0519, found 172.0531.
3.8.6. 3-Trifluoromethanesulfonyl-2-naphthol (25)22. Yellow crys-
tals. Mp 120e121 ꢁC (benzene/hexane). Sublimation (ca. 102 ꢁC). IR
(KBr) 3296, 2873,1687,1504,1459 cmꢀ1. 1H NMR (CDCl3)
d 8.46 (1H,

E. Yoshioka, H. Miyabe / Tetrahedron 68 (2012) 179e189
187
s), 7.98 (1H, s, offset by D2O), 7.91 (1H, d, J¼8.0 Hz), 7.78 (1H, d,
3121, 3060, 2962, 2838, 1609, 1593, 1466 cmꢀ1
.
1H NMR (CDCl3)
J¼8.0 Hz), 7.66 (1H, ddd, J¼1.5, 1.5, 7.5 Hz), 7.48 (2H, m). 13C NMR
d
7.48 (2H, br d, J¼7.0 Hz), 7.27e7.17 (3H, m), 7.03 (1H, t, J¼8.0 Hz),
(CDCl3)
d
151.8, 139.5, 135.7, 131.5, 129.6, 127.3, 126.7, 125.8, 119.8 (q,
6.49 (1H, dd, J¼8.0, 1.0 Hz), 6.26 (1H, dd, J¼8.0, 1.0 Hz), 4.69 (1H, s),
J¼327 Hz), 115.1, 114.6. 19F NMR (CDCl3)
d
ꢀ79.3. MS (EIþ) m/z 115
3.70 (3H, s), 2.27 (6H, br s). The exchangeable proton peak of OH
(100), 276 (Mþ, 87). HRMS (EIþ) calcd for C11H7F3O3S (Mþ)
276.0063, found 276.0068. Anal. Calcd for C11H7F3O3S: C, 47.83; H,
2.55%. Found: C, 48.07; H, 2.78%.
group was not clearly detected. 13C NMR (CDCl3)
d 157.9, 157.4,
141.2, 128.4 (2C), 127.4, 114.8, 109.9, 101.5, 70.2, 55.5, 44.2 (br s). One
carbon peak was missing due to overlapping. MS (EIþ) m/z 211
(100), 257 (Mþ, 37). HRMS (EIþ) calcd for C16H19NO2 (Mþ) 257.1416,
found 257.1431; Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44; N,
5.44%. Found: C, 74.69; H, 7.46; N, 5.41%.
3.8.7. 2-Hydroxy-3-methylbenzaldehyde (26a)36. Colorless oil. IR
(KBr) 3413, 2923, 1729, 1464 cmꢀ1. 1H NMR (CDCl3)
d 11.27 (1H, s),
9.88 (1H, s), 7.41e7.39 (2H, m), 6.93 (1H, t, J¼7.5 Hz), 2.27 (3H, s). 13C
NMR (CDCl3)
d
196.7, 160.0, 137.8, 131.3, 126.8, 120.0, 119.3, 15.0. MS
3.9.4. 2-[1-(Dimethylamino)propyl]phenol (31). Colorless oil. IR
(EIþ) m/z 136 (Mþ, 0.1), 83 (100). HRMS (EIþ) calcd for C8H9O2
(MþHþ) 137.0597, found: 137.0577.
(KBr) 3303, 2975, 1608, 1461 cmꢀ1. 1H NMR (CDCl3)
d 7.18 (1H, dt,
J¼8.0, 2.0 Hz), 6.96 (1H, dd, J¼7.5, 2.0 Hz), 6.87 (1H, dd, J¼8.0,
1.0 Hz), 6.81 (1H, dt, J¼7.5, 1.0 Hz), 3.43 (1H, br dd, J¼9.5, 4.0 Hz),
2.47 (6H, s), 2.09e1.83 (2H, m), 0.79 (3H, t, J¼7.5 Hz). The ex-
changeable proton peak of OH group was not clearly detected. 13C
3.8.8. 2-Hydroxy-6-methylbenzaldehyde (26b)37. Colorless oil. IR
(KBr) 3240, 3046, 2927, 1642, 1458 cmꢀ1 1H NMR (CDCl3)
. d 11.91
(1H, s), 10.33 (1H, s), 7.38 (1H, t, J¼8.0 Hz), 6.82 (1H, t, J¼8.0 Hz),
NMR (CDCl3) d 156.5, 129.2, 129.1, 123.3, 119.1, 116.7, 71.7, 42.6, 23.5,
6.72 (1H, d, J¼8.0 Hz), 2.61 (3H, s). 13C NMR (CDCl3)
d
195.3, 163.2,
10.8. MS (EIþ) m/z 84 (100), 179 (Mþ, 0.1). HRMS (EIþ) calcd for
142.1, 137.4, 121.8, 118.5, 116.1, 18.1. HRMS (ESIꢀ) calcd for C8H7O2
C11H17NO (Mþ) 179.1310, found 179.1329.
(MꢀHꢀ) 135.0452, found 135.0442.
3.10. Experimental procedure for the trapping reaction using
amide 4 (entry 3 in Table 6)
3.8.9. 2-Hydroxy-4,5-dimethoxybenzaldehyde (27)38. Pale yellow
crystals. Mp 104e105 ꢁC (CH2Cl2/hexane). IR (KBr) 3249, 2959, 2923,
2842, 1628, 1593, 1507 cmꢀ1. 1H NMR (CDCl3)
d
11.39 (1H, s), 9.69
To a solutionofTBAF(157 mg, 0.60 mmol)and 1-formylpiperidine
(1H, s), 6.89 (1H, s), 6.47 (1H, s), 3.93 (3H, s), 3.87 (3H, s). 13C NMR
4 (222
mL, 2.0 mmol) in CH3CN (1.2 mL) was added a solution of 3-
(CDCl3)
d
194.0, 159.3, 157.2, 142.9, 113.2, 112.8, 100.1, 56.4, 56.3.
methoxy-2-(trimethylsilyl)phenyl triflate 1 (53 m
L, 0.20 mmol) in
HRMS (ESIþ) calcd for C9H11O4 (MþHþ) 183.0652, found 183.0650.
CH3CN (0.8 mL) under argon atmosphere at room temperature. After
being stirred at the same temperature for 15 min, Et2Zn (1.05 M in
hexane, 0.95 mL, 1.0 mmol) was added to the reaction mixture. After
being stirred at the same temperature for 12 h, H2O (0.1 mL) was
added to the reaction mixture. The reaction mixture was concen-
trated under reduced pressure. Purification of the residue by flash
silica gel column chromatography (AcOEt/hexane¼1/20 to 1/0 with
2% CH2Cl2) afforded the product 35 (20.1 mg, 40%).
3.9. General procedure for the trapping reaction giving o-
aminoalkylphenols 28e31 (Scheme 8)
To a suspension of CsF (91 mg, 0.60 mmol) in freshly distilled
DMF (1.2 mL) was added a solution of aryne precursor 1 or 15
(0.20 mmol) in freshly distilled DMF (0.8 mL) under argon atmo-
sphere at room temperature. After being stirred at the same tem-
perature for 15 min, Et2Zn (1.05 M in hexane, 0.95 mL, 1.0 mmol),
Me2Zn (1.0 M in hexane, 1.0 mL, 1.0 mmol), or Ph2Zn (220 mg,
1.0 mmol) were added to the reaction mixture at room tempera-
ture. After being stirred at the same temperature for 12 h, H2O
(0.1 mL) was added to the reaction mixture. The reaction mixture
was concentrated under reduced pressure. Purification of the res-
idue by flash silica gel column chromatography (AcOEt/hexane¼1/
20 to 1/0 with 2% CH2Cl2) afforded the products 28e31, accompa-
nied by the products 32e34.
3.10.1. 3-Methoxy-2-[1-(1-piperidinyl)propyl]phenol (35). Colorless
oil. IR (KBr) 3141, 2934, 1606, 1592, 1466 cmꢀ1 1H NMR (CD3OD)
.
d
7.02 (1H, t, J¼8.0 Hz), 6.40 (1H, br dd, J¼8.0, 1.0 Hz), 6.32 (1H, br
dd, J¼8.0, 1.0 Hz), 3.92 (1H, dd, J¼8.0, 4.0 Hz), 3.74 (3H, s),
2.65e2.45 (4H, br m), 1.89e1.52 (8H, m), 0.74 (3H, t, J¼7.5 Hz). The
exchangeable proton peak of OH group was not clearly detected. 13C
NMR (CD3OD)
d 160.0, 159.7, 129.4, 114.5, 110.5, 102.4, 64.6, 55.8,
52.8, 27.1, 25.2, 24.9, 9.8. MS (EIþ) m/z 83 (100), 249 (Mþ, 0.1). HRMS
(EIþ) calcd for C15H23NO2 (Mþ) 249.1729, found 249.1738.
3.9.1. 2-[1-(Dimethylamino)propyl]-3-methoxyphenol
3.11. Improved experimental procedure for the trapping
reaction (Scheme 10)
(28). Colorless oil. IR (KBr) 3311, 2937, 1593, 1468 cmꢀ1 1H NMR
.
(CDCl3)
d
7.06 (1H, t, J¼8.0 Hz), 6.44 (1H, dd, J¼8.0,1.0 Hz), 6.35 (1H, dd,
J¼8.0,1.0 Hz), 3.76 (3H, s), 3.74 (1H, m), 2.33 (6H, s),1.88e1.72 (2H, m),
0.76 (3H, t, J¼7.5 Hz). The exchangeable proton peak of OH group was
To a suspension of CsF (152 mg, 1.0 mmol) in freshly distilled
DMF, 1-formylpiperidine 4, or N-allyl-N-methylformamide 37
(2.0 mL) was added Et2Zn (1.05 M in hexane, 0.95 mL, 1.0 mmol)
under argon atmosphere at room temperature. After being stirred
at the same temperature for 1 min, aryne precursor 1 or 18
(0.20 mmol) was added to the reaction mixture at room tempera-
ture. After being stirred at the same temperature for 12 h, the re-
action mixture was diluted with water and then extracted with
CH2Cl2. The organic phase was washed with saturated NaCl, dried
over Na2SO4, and concentrated under reduced pressure. Purifica-
tion of the residue by flash silica gel column chromatography
(AcOEt/hexane¼1/10 to 1/0 with 2% CH2Cl2) afforded the products
28, 35, 36, or 38.
not clearly detected. 13C NMR (CDCl3)
d 158.7, 157.9, 128.1, 113.7, 109.6,
101.1, 64.4, 55.3, 43.3 (br s), 24.9, 9.5. MS (EIþ) m/z 153 (100), 209 (Mþ,
13). HRMS (EIþ) calcd for C12H19NO2 (Mþ) 209.1416, found 209.1421.
3.9.2. 2-[1-(Dimethylamino)ethyl]-3-methoxyphenol (29). Colorless
oil. IR (KBr) 3428, 2957,1566,1461 cmꢀ1. 1H NMR (CDCl3)
d 7.04 (1H,
t, J¼8.0 Hz), 6.44 (1H, dd, J¼8.0, 1.0 Hz), 6.34 (1H, dd, J¼8.0, 1.0 Hz),
3.84 (1H, t, J¼6.5 Hz), 3.78 (3H, s), 2.33 (6H, br s), 1.33 (3H, d,
J¼6.5 Hz). The exchangeable proton peak of OH group was not
clearly detected. 13C NMR (CDCl3)
d 158.3, 157.0, 128.0, 116.1, 109.7,
101.2, 59.4, 55.5, 43.4 (br s), 18.7. MS (EIþ) m/z 180 (100), 195 (Mþ,
51). HRMS (EIþ) calcd for C11H17NO2 (Mþ) 195.1259, found 195.1275.
3.11.1. 3-[1-(Dimethylamino)propyl]-2-naphthalenol
solid. Mp 85e86 ꢁC (CH2Cl2/hexane). Sublimation (ca. 80 ꢁC). IR
(KBr) 3138, 3052, 2965,1633,1462 cmꢀ1. 1H NMR (CDCl3)
7.67 (2H,
(36). Yellow
3.9.3. 2-[1-(Dimethylamino)phenylmethyl]-3-methoxyphenol
(30). Colorless crystals. Mp 150e151 ꢁC (AcOEt/hexane). IR (KBr)
d

188
E. Yoshioka, H. Miyabe / Tetrahedron 68 (2012) 179e189
br d, J¼8.5 Hz), 7.39e7.34 (2H, m), 7.26 (1H, m), 7.16 (1H, br s), 3.28
(1H, dd, J¼10.0, 4.0 Hz), 2.38 (6H, s), 2.05e1.95 (1H, m), 1.87e1.76
(1H, m), 0.77 (3H, t, J¼7.5 Hz). The exchangeable proton peak of OH
(EIþ) m/z 84 (100), 183 (Mþ, 0.6). HRMS (EIþ) calcd for C10H13DO3
(Mþ) 183.1005, found 183.1017.
group was not clearly detected. 13C NMR (CDCl3)
d 155.4, 134.2,
Acknowledgements
128.2, 128.0, 127.6, 127.3, 126.0, 125.8, 122.9, 110.5, 73.2, 43.2, 24.3,
11.2. MS (EIþ) m/z 200 (100), 229 (Mþ, 21). HRMS (EIþ) calcd for
C15H19NO (Mþ) 229.1467, found 229.1454.
This work was supported in part by Grant-in-Aid for Scientific
Research (C) (H.M.) and for Young Scientists (B) (E.Y.) from Japan
Society for the Promotion of Science.
3.11.2. 2-[1-(Allylmethylamino)propyl]-3-methoxyphenol
(38). Colorless oil. IR (KBr) 3308, 3078, 2971, 1594, 1467 cmꢀ1. 1H
References and notes
NMR (CD3OD)
d
7.07 (1H, t, J¼8.0 Hz), 6.45 (1H, br dd, J¼8.0, 1.0 Hz),
1. Roberts, J. D.; Simmons, H. E., Jr.; Carlsmith, L. A.; Vaughan, C. W. J. Am. Chem.
Soc. 1953, 75, 3290.
2. For reviews, see: (a) Kessar, S. V. In Comprehensive Organic Synthesis; Trost, B. M.
, Flemming, I., Eds.; Pergamon: Oxford, 1991; Vol. 4, pp 483e515; (b) Saito, S.;
Yamamoto, Y. Chem. Rev. 2000, 100, 2901; (c) Pellissier, H.; Santelli, M. Tetra-
hedron 2003, 59, 701; (d) Wenk, H. H.; Winkler, M.; Sander, W. Angew. Chem.,
Int. Ed. 2003, 42, 502; (e) Pena, D.; Perez, D.; Guitian, E. Angew. Chem., Int. Ed.
2006, 45, 3579; (f) Yoshida, H.; Ohshita, J.; Kunai, A. Bull. Chem. Soc. Jpn. 2010,
83, 199.
6.36 (1H, dd, J¼8.0, 1.0 Hz), 5.91e5.81 (1H, m), 5.19e5.14 (2H, m),
3.95 (1H, dd, J¼8.5, 4.0 Hz), 3.76 (3H, s), 3.29e2.95 (2H, br m), 2.31
(3H, br s), 1.93e1.72 (2H, m), 0.76 (3H, t, J¼7.5 Hz). The exchange-
able proton peak of OH group was not clearly detected. 13C NMR
(CD3OD)
d 158.8, 158.1, 134.0, 128.2, 118.7, 113.6, 109.7, 101.2, 62.4,
~
ꢀ
ꢀ
57.8, 55.3, 38.5, 24.6, 9.7. HRMS (ESI) calcd for C14H22NO2 (MþHþ)
236.1651, found 236.1647.
3. For some recent studies, see: (a) Dockendorff, C.; Sahli, S.; Olsen, M.; Mihau, L.;
Lautens, M. J. Am. Chem. Soc. 2005, 127, 15028; (b) Asao, N.; Sato, K. Org. Lett.
2006, 8, 5361; (c) Soorukram, D.; Qu, T.; Barrett, A. G. M. Org. Lett. 2008, 10,
3833; (d) Ganta, A.; Snowden, T. S. Org. Lett. 2008, 10, 5103; (e) Akai, S.; Ikawa,
T.; Takayanagi, S.; Morikawa, Y.; Mohri, S.; Tsubakiyama, M.; Egi, M.; Wada, Y.;
Kita, Y. Angew. Chem., Int. Ed. 2008, 47, 7673; (f) Gerfaud, T.; Neuville, L.; Zhu, J.
Angew. Chem., Int. Ed. 2009, 48, 572; (g) Sha, F.; Huang, X. Angew. Chem., Int. Ed.
2009, 48, 3458; (h) Ikawa, T.; Takagi, A.; Kurita, Y.; Saito, K.; Azechi, K.; Egi, M.;
Kakiguchi, K.; Kita, Y.; Akai, S. Angew. Chem., Int. Ed. 2010, 49, 5563; (i) Biju, A.
T.; Glorius, F. Angew. Chem., Int. Ed. 2010, 49, 9761; (j) Bronner, S. M.; Goetz, A.
E.; Garg, N. K. J. Am. Chem. Soc. 2011, 133, 3832.
3.12. General procedure for the trapping reaction giving o-
hydroxyalkylphenols 32e34 and 39 (Scheme 11)
To a suspension of CsF (152 mg, 1.0 mmol) in undistilled DMF
(2.0 mL) was added aryne precursor 1 or 15 (0.20 mmol) under
argon atmosphere at room temperature. After being stirred at the
same temperature for 3 h, Et2Zn (1.05 M in hexane, 1.9 mL,
2.0 mmol) or Me2Zn (1.0 M in hexane, 2.0 mL, 2.0 mmol) was added
to the reaction mixture at room temperature. After being stirred at
the same temperature for 12 h, the reaction mixture was concen-
trated under reduced pressure. Purification of the residue by flash
silica gel column chromatography (AcOEt/hexane¼1/20 to 1/0 with
2% CH2Cl2) afforded the products 32e34 and 39.
4. Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211.
~
5. For selected examples of [2þ2þ2] cycloaddition, see: (a) Pena, D.; Escudero, S.;
ꢀ
ꢀ
~
Perez, D.; Guitian, E.; Castedo, L. Angew. Chem., Int. Ed. 1998, 37, 2659; (b) Pena,
ꢀ
ꢀ
D.; Perez, D.; Guitian, E.; Castedo, L. J. Am. Chem. Soc. 1999, 121, 5827; (c) Sato, Y.;
Tamura, T.; Mori, M. Angew. Chem., Int. Ed. 2004, 43, 2436; (d) Qiu, Z.; Xie, Z.
Angew. Chem., Int. Ed. 2009, 48, 5729; (e) Saito, N.; Shiotani, K.; Kinbara, A.; Sato,
Y. Chem. Commun. 2009, 4284; (f) Iwayama, T.; Sato, Y. Chem. Commun. 2009,
~
ꢀ
ꢀ
5245; (g) Rodríguez-Lojo, D.; Pena, D.; Perez, D.; Guitian, E. Chem. Commun.
2010, 3386.
3.12.1.
(32). Colorless oil. IR (KBr) 3292, 2933, 1593, 1469 cmꢀ1
(CDCl3)
a
-Ethyl-2-hydroxy-6-methoxybenzenemethanol
6. For selected examples of coupling reactions, see: (a) Yoshikawa, E.; Yamamoto,
Y. Angew. Chem., Int. Ed. 2000, 39, 173; (b) Jeganmohan, M.; Cheng, C.-H. Org.
Lett. 2004, 6, 2821; (c) Henderson, J. L.; Edwards, A. S.; Greaney, M. F. J. Am.
Chem. Soc. 2006, 128, 7426; (d) Liu, Z.; Larock, R. C. Angew. Chem., Int. Ed. 2007,
46, 2535; (e) Jayanth, T. T.; Cheng, C.-H. Angew. Chem., Int. Ed. 2007, 46, 5921; (f)
Xie, C.; Zhang, Y.; Yang, Y. Chem. Commun. 2008, 4810; (g) Jeganmohan, M.;
Bhuvaneswari, S.; Cheng, C.-H. Angew. Chem., Int. Ed. 2009, 48, 391; (h) Mor-
ishita, T.; Yoshida, H.; Ohshita, J. Chem. Commun. 2010, 640; (i) Li, R.-J.; Pi, S.-F.;
Liang, Y.; Wang, Z.-Q.; Song, R.-J.; Chen, G.-X.; Li, J.-H. Chem. Commun. 2010,
8183.
.
1H NMR
d
8.59 (1H, br s), 7.09 (1H, t, J¼8.0 Hz), 6.51 (1H, d, J¼8.0 Hz),
6.39 (1H, d, J¼8.0 Hz), 5.32 (1H, t, J¼6.5 Hz), 3.77 (3H, s), 2.49 (1H,
br s), 1.92e1.75 (2H, m), 0.99 (3H, t, J¼7.5 Hz). 13C NMR (CDCl3)
d
157.1, 156.6, 128.7, 115.4, 110.2, 101.9, 71.8, 55.5, 29.3, 10.0. MS (EIþ)
m/z 153 (100), 182 (Mþ, 54). HRMS (EIþ) calcd for C10H14O3 (Mþ)
182.0943, found 182.0962.
7. For transition metal-catalyzed insertion into
s-bond, see: (a) Yoshida, H.;
Honda, Y.; Shirakawa, E.; Hiyama, T. Chem. Commun. 2001, 1880; (b) Yoshida, H.;
Ikadai, J.; Shudo, M.; Ohshita, J.; Kunai, A. J. Am. Chem. Soc. 2003, 125, 6638; (c)
Yoshida, H.; Tanino, K.; Ohshita, J.; Kunai, A. Angew. Chem., Int. Ed. 2004, 43,
5052; (d) Yoshida, H.; Okada, K.; Kawashima, S.; Tanino, K.; Ohshita, J. Chem.
Commun. 2010, 1763.
8. For some reactions of arynes with nucleophile followed by electrophile, see: (a)
Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. Angew. Chem., Int. Ed. 2004, 43,
3935; (b) Zhao, J.; Larock, R. C. Org. Lett. 2005, 7, 4273; (c) Raminelli, C.; Liu, Z.;
Larock, R. C. J. Org. Chem. 2006, 71, 4689; (d) Yoshida, H.; Fukushima, H.; Oh-
shita, J.; Kunai, A. J. Am. Chem. Soc. 2006, 128, 11040; (e) Yoshida, H.; Morishita,
T.; Fukushima, H.; Ohshita, J.; Kunai, A. Org. Lett. 2007, 9, 3367; (f) Okuma, K.;
Nojima, A.; Matsunaga, N.; Shioji, K. Org. Lett. 2009, 11, 169; (g) Liu, Z.; Larock,
R. C. J. Org. Chem. 2007, 72, 583; (h) Okano, K.; Fujiwara, H.; Noji, T.; Fukuyama,
T.; Takuyama, H. Angew. Chem., Int. Ed. 2010, 49, 5925.
3.12.2. 2-Hydroxy-6-methoxy-
(33). Colorless oil. IR (KBr) 3288, 2965, 1594, 1469 cmꢀ1
(CDCl3)
8.65 (1H, br s), 7.08 (1H, t, J¼8.0 Hz), 6.50 (1H, d, J¼8.0 Hz),
a
-methylbenzenemethanol
.
1H NMR
d
6.38 (1H, br d, J¼8.0 Hz), 5.55 (1H, q, J¼6.5 Hz), 3.78 (3H, s), 2.55
(1H, br s), 1.52 (3H, t, J¼6.5 Hz). 13C NMR (CDCl3)
d 156.8, 156.2,
128.6, 116.4, 110.3, 101.9, 66.9, 55.5, 22.6. MS (EIþ) m/z 83 (100), 168
(Mþ, 0.9). HRMS (EIþ) calcd for C9H12O3 (Mþ) 168.0786, found
168.0785.
3.12.3.
a
-Ethyl-2-hydroxybenzenemethanol (34)39. Colorless oil. IR
7.94 (1H, br s),
(KBr) 3312, 2927, 1587, 1456 cmꢀ1. 1H NMR (CDCl3)
d
9. For some reactions involving the nucleophilic addition and subsequent pro-
tonation, see: (a) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 99; (b) Jeganmohan, M.;
Cheng, C.-H. Chem. Commun. 2006, 2454; (c) Ramtohul, Y. K.; Chartrand, A. Org.
Lett. 2007, 9, 1029; (d) Jones, E. P.; Jones, P.; Barrett, A. G. M. Org. Lett. 2011, 13,
1012.
7.16 (1H, br dt, J¼8.0, 2.0 Hz), 6.94 (1H, br dd, J¼7.5, 2.0 Hz), 6.87
(1H, br d, J¼8.0 Hz), 6.82 (1H, br dt, J¼7.5, 1.5 Hz), 4.76 (1H, t,
J¼7.0 Hz), 2.56 (1H, br s), 1.99e1.80 (2H, m), 0.97 (3H, t, J¼7.5 Hz).
13C NMR (CDCl3)
d 155.6, 128.9, 127.3, 127.0, 119.6, 117.2, 77.8, 30.2,
10. For selected examples of the insertion into
s-bond, see: (a) Yoshida, H.; Ter-
ayama, T.; Ohshita, J.; Kunai, A. Chem. Commun. 2004, 1980; (b) Yoshida, H.;
Minabe, T.; Ohshita, J.; Kunai, A. Chem. Commun. 2005, 3454; (c) Tambar, U. K.;
Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 5340; (d) Yoshida, H.; Watanabe, M.;
Ohshita, J.; Kunai, A. Tetrahedron Lett. 2005, 46, 6729; (e) Tambar, U. K.; Ebner,
D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11752; (f) Huang, X.; Xue, J. J. Org.
Chem. 2007, 72, 3965; (g) Yoshida, H.; Watanabe, M.; Morishita, T.; Ohshita, J.;
Kunai, A. Chem. Commun. 2007, 1505; (h) Yoshida, H.; Mimura, Y.; Ohshita, J.;
Kunai, A. Chem. Commun. 2007, 2405; (i) Yang, Y.-Y.; Shou, W.-G.; Wang, Y.-G.
10.2. MS (EIþ) m/z 83 (100), 152 (Mþ, 8.4). HRMS (EIþ) calcd for
C9H12O2 (Mþ) 152.0837, found 152.0830.
3.12.4.
(39). Colorless oil. IR (KBr) 3260, 2926, 1593, 1468 cmꢀ1
(CDCl3)
8.56 (1H, br s), 7.09 (1H, t, J¼8.0 Hz), 6.50 (1H, dd, J¼8.0,
a
-Deuterium-
a
-ethyl-2-hydroxy-6-methoxybenzenemethanol
.
1H NMR
d
ꢀ
~
ꢀ
Tetrahedron Lett. 2007, 48, 8163; (j) Beltran-Rodil, S.; Pena, D.; Guitian, E. Synlett
2007, 1308; (k) Yoshida, H.; Kishida, T.; Watanabe, M.; Ohshita, J. Chem. Com-
mun. 2008, 5963; (l) Liu, Y.-L.; Liang, Y.; Pi, S.-F.; Li, J.-H. J. Org. Chem. 2009, 74,
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1.0 Hz), 6.39 (1H, dd, J¼8.0, 1.0 Hz), 3.77 (3H, s), 2.45 (1H, br s),
1.92e1.74 (2H, m), 0.99 (3H, t, J¼7.5 Hz). 13C NMR (CDCl3)
d 157.1,
156.6, 128.7, 115.4, 110.2, 101.9, 71.4 (t, J¼91 Hz), 55.5, 29.3, 10.0. MS

E. Yoshioka, H. Miyabe / Tetrahedron 68 (2012) 179e189
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