Cyclization reactions of 2-alkynylbenzyl alcohol and 2-alkynylbenzylamine derivatives promoted by tetrabutylammonium fluoride

Article abstract of DOI:10.1016/S0040-4020(01)00991-7

The regioselectivity of the cyclization reaction of 2-ethynylbenzyl alcohol and 2-ethynylbenzylamine derivatives promoted by TBAF was investigated. Six-membered ring derivatives were obtained from the compounds, which have a butyl group on the triple bond. Whereas five-membered ring products were afforded from the substrates having hydrogen or aromatic substituents on the acetylene moiety. It was also concluded that both the tetrabutylammonium cation and fluoride anion were essential for the cyclization. Thus, the actual mechanism and catalytic cycle were also suggested.

Full text of DOI:10.1016/S0040-4020(01)00991-7

TETRAHEDRON
Pergamon
Tetrahedron 57 52001) 9697±9710
Cyclization reactions of 2-alkynylbenzyl alcohol
and 2-alkynylbenzylamine derivatives promoted
by tetrabutylammonium ¯uoride
Kou Hiroya,p Rumi Jouka, Mitsuyoshi Kameda, Akito Yasuhara and Takao Sakamotop
Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba-ku, Sendai 980-8578, Japan
Received 20 June 2001; accepted 12 October 2001
AbstractÐThe regioselectivity of the cyclization reaction of 2-ethynylbenzyl alcohol and 2-ethynylbenzylamine derivatives promoted by
TBAF was investigated. Six-membered ring derivatives were obtained from the compounds, which have a butyl group on the triple bond.
Whereas ®ve-membered ring products were afforded from the substrates having hydrogen or aromatic substituents on the acetylene moiety. It
was also concluded that both the tetrabutylammonium cation and ¯uoride anion were essential for the cyclization. Thus, the actual
mechanism and catalytic cycle were also suggested. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
available TBAF usually contains H2Oas crystal water or
ca. 5 wt% in THF solution and the dif®culty in removing
11
H2Owas also reported. Recently, TBAF has sometimes
Intramolecular ring closure reactions, which can be carried
out between the nucleophilic part and carbon±carbon multi-
bond in the same molecules, are one of the useful methods
for constructing cyclic compounds and have been used for
natural product syntheses.1 Sometimes, the ring size of the
products from the ring closure reaction could be predicted
by the famous Baldwin's rule,2 which was an empirically
proposed rule based on stereoelectronic effects. For
example, for the substrates 51) which have a triple bond as
the counterpart, both the `6-endo-dig' mode 5!2) and
`5-exo-dig' mode 5!3) are allowed by Baldwin's rule
5Fig. 1). In fact, both of the cyclized products for the
2-ethynylphenyl derivatives had been shown in the litera-
ture, e.g. indoles,3,4 benzo[b]furans,3,5 isoquinolines,6
3-alkylidenephthalides vs. 3-substituted isocoumarins,3,7
1-alkylideneisobenzofurans vs. 3-substituted 1H-2-benzo-
pyrans,7b,8 and 3-alkylideneisoindolin-1-ones vs. 3-substi-
tuted isoquinolin-1-ones 5Fig. 2).7f,9 Particularly, the
regioselective cyclizations for the latter three cases have
also been reported.8,9 However, in spite of the many reports
about such reactions, there has not been well-documented
the reasons for the regioselectivity.
been used not only as a deprotection reagent, but also as
effective reagents for the aldol-type condensation reac-
tion,12a the Michael-type reaction,11a,12b nucleophilic substi-
tution11a and addition reaction,12c ¯uorination,11c desul-
fonylation,12d,e and promoter for the homocoupling of aryl
halides.12f
In 1992, Jacobi and Rajeswari reported the ®rst TBAF
promoted 5-exo-dig cyclization reaction.13a After this
report, they applied this cyclization reaction to synthesize
various kind of 5-membered cyclic enamide.13b±d However,
in spite of the ef®ciency, the applications of TBAF
promoted cyclization toward the other heterocyclic ring
system syntheses have not been reported.
As part of our program directed toward the development of
new synthetic methods for heterocyclic compounds, we
have already published a mild and ef®cient indole cycli-
zation method mediated by TBAF.4d In this paper, we report
the TBAF-mediated cyclization reaction of 2-ethynylbenzyl
alcohol derivatives and 2-ethynylbenzylamine derivatives
and the mechanistic studies of this cyclization reaction.
Tetrabutylammonium ¯uoride 5TBAF) is a well known
reagent for the cleavage of silyl ethers.10 Commercially
Keywords: TBAF; 5-exo-dig; 6-endo-dig; isobenzofurans; benzopyrans;
cyclization reactions.
p
Corresponding authors. Tel.: 181-22-217-6867; fax: 181-22-217-6864.
Tel.: 181-22-217-6865; fax: 181-22-217-6864;
e-mail: hiroya@mail.cc.tohoku.ac.jp; sakamoto@mail.pharm.tohoku.ac.jp
Figure 1.
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020501)00991-7

9698
K. Hiroya et al. / Tetrahedron 57*2001) 9697±9710
Figure 2.
2. Results and discussion
benzaldehyde and phenylacetylene by the coupling reaction,
followed by NaBH4 reduction. The 4-methoxyphenyl
derivative 510) was synthesized from 2-ethynylbenzyl
alcohol 59), which was obtained from the detrimethylsilyl
reaction of 5, by the coupling reaction with 4-iodoanisole
5Scheme 1).
2.1. Cyclization reactions of 2-ethynylbenzyl alcohol and
2-ethynylbenzylamine derivatives
The trimethylsilyl and alkyl substituted 2-ethynylbenzyl
alcohol derivatives 55, 6, 7) were synthesized from
2-iodobenzyl alcohol 54) and corresponding alkynes using
Sonogashira coupling reaction 5Scheme 1).14 The phenyl-
acetylene derivative 58)8c,d was synthesized from 2-bromo-
When the trimethylsilyl substituted benzyl alcohol 55) was
treated with TBAF in THF at room temperature, only the
detrimethylsilyl reaction proceeded to afford 9 as the sole
Scheme 1. Reagents and conditions: 5i) PdCl25PPh3)2, CuI, trimethylsilylacetylene, Et3N, 08C±rt, 3 h, 83%; 5ii) PdCl25PPh3)2, CuI, 1-hexyne, i-Pr2NH, 08C±rt,
6 h, 90%; 5iii) PdCl25PPh3)2, CuI, 3,3-dimethyl-1-butyne, Et3N, 08C±rt, 3.5 h, 91%; 5iv) PdCl25PPh3)2, CuI, phenylacetylene, Et3N, rt, 6 h; 5v) NaBH4, MeOH,
08C, 80% 5two steps); 5vi) TBAF´3H2O, THF, rt, 1 h; 5vii) PdCl25PPh2)2, CuI, 4-iodoanisole, Et3N, rt, 3.5 h, 64% 5two steps).
Scheme 2. Reagents and conditions: 5i) TBAF, THF, rt, 1.5 h, 62%; 5ii) TBAF, THF, re¯ux; 5iii) H2, Pd±C, toluene, 24 h, 47% 5two steps).

K. Hiroya et al. / Tetrahedron 57*2001) 9697±9710
Table 1. TBAF promoted cyclization reactions of 2-ethynylbenzyl alcohol derivatives
9699
Entry
R
Solvent
Temperature
Time
Yield 5compound number) 5%)
5-exo-dig 6-endo-dig
16
1
2
3
4
5
6
7
TMS 55)
H 59)
Ph 58)
4-Methoxyphenyl 510)
Bu 56)
Bu 56)
THF
THF
THF
THF
THF
Re¯ux
Re¯ux
Re¯ux
Re¯ux
Re¯ux
Re¯ux
1008C
1.5 h
2 h
2 h
Quanta 511)
±
±
Quanta 511)
80 513)
95 514)
±
±
±
±
±
±
±
±
±
4 h
24 h
60 h
6 d
±
±
±
THF-DMF 54:1)
THF
10 515)
t-Bu 57)
±
20b
a
1
Only 11 was detected by H NMR analysis of the crude mixture.
49% of 7 was recovered.
b
product. However, when the reaction mixture was heated
under re¯ux, elimination of trimethylsilyl group was
observed at ®rst by TLC, then the produced 2-ethynylbenzyl
alcohol 59) was cyclized to give the compound 511).
Because of the instability of 11, the structure of 11 was
con®rmed as its reduced form 512) obtained by the H2/
Pd±C reduction 5Scheme 2).15,16 The results with the other
substrates are summarized on Table 1. Brie¯y, the cycli-
zation reactions produced not only RˆH, but also RˆPh
and the 4-methoxyphenyl group in good yields to afford
only the ®ve-membered products 511,15 13,7b,8a,c,d,15,17 14)
5Table 1: entries 1±4). However, for RˆBu, the cyclization
reaction did not proceed in THF, but in THF±DMF 54:1),
the six-membered ring compound 515) was isolated as the
sole product, but yield was poor 5Table 1: entry 5 and 6).
When 7 5Rˆt-Bu) was used as the starting material, the
cyclized compound could not be isolated at all, instead
the oxidized aldehyde 516) was obtained 5Table 1: entry
7). The detail mechanism of this oxidation is not clear yet,
but it can be considered as an air oxidation.
The substituted 2-ethynylbenzylamine derivatives 522±29)
Scheme 3. Reagents and conditions: 5i) 5PhO)2PON3, DBU, toluene, rt, 1 h, 90%;20 5ii) PPh3, THF, 08C±rt, 16 h, then 3N NaOH, rt, 1 h; 5iii) p-TsCl, Et3N,
THF, 08C±rt, 2 h; 5iv) Ac2O, pyridine, rt, 2 h; 5v) Boc2O, THF, rt, 2 h; 5vi) PdCl25PPh3)2, CuI, trimethylsilylacetylene, Et3N±THF, rt, 3 h for 22 and 23, Et3N,
rt, 2 h for 24; 5vii) PdCl25PPh3)2, CuI, phenylacetylene, i-Pr2NH, THF, 08C±rt, 12 h; 5viii) PdCl25PPh3)2, CuI, 1-hexyne, i-Pr2NH, THF, 08C±rt, 12, 5 h for 26,
2.5 h for 27; 5ix) PdCl25PPh3)2, CuI, propargyl alcohol, i-Pr2NH, rt, 6 h; 5x) PdCl25PPh3)2, CuI, 3,3-dimethyl-1-butyne, Et3N±THF, 08C±rt, 2.5 h; 5xi)
5PhO)2PON3, DBU, toluene, rt, 12 h;20 5xii) PPh3, THF, rt±408C, 6 h, then 3N NaOH, rt, 2 h; 5xiii) p-TsCl, Et3N, THF, 08C±rt, 30 h, 46% 5three steps).

9700
K. Hiroya et al. / Tetrahedron 57*2001) 9697±9710
Scheme 4. Reagents and conditions: 5i) TBAF´3H2O, THF, rt, 9 h, then H2, Pd±C, THF, 18.5 h, 86%; 5ii) TBAF´3H2O, THF, re¯ux, 8 h, then H2, Pd±C, THF,
13 h, 91%; 5iii) TBAF´3H2O, THF, re¯ux, 25 h, then H2, Pd±C, THF, 18 h, 73%.
were synthesized by the coupling reaction with 19, 20, and
21 that could be synthesized from 2-iodobenzyl alcohol 54)
through the azide 517) and the benzylamine 518) 5Scheme
3). The results of the Sonogashira coupling reaction14
between the iodides 519, 20, and 21) and the various acetyl-
enes are summarized in Scheme 3.
CH2OH, and t-Bu groups on the terminal alkyne are
summarized in Table 2.
For R2ˆPh, the compound having both R1ˆTs 532) and Boc
525), only the ®ve-membered products 5399b and 40) were
produced in THF under re¯ux 5Table 2: entries 1 and 2). The
geometry of the double bond of 39 and 40 were determined
by n.O.e. experiments between the ole®nic proton and
aromatic proton shown in the ®gure of Table 2. When the
substrates, which have R2ˆBu 526), were reacted with
TBAF in THF or dioxane±THF, the spontaneous E2 elimi-
nation of the sul®nic acid occurred from almost half of the
product to afford a mixture of 42 and 3-butylisoquinoline
544)18 5Table 2: entries 3 and 4). However, this side reaction
was avoided by changing the solvent to dioxane 5Table 2:
entry 5). Although there is no obvious evidence, presumably
the suppression of the E2 reaction is caused by reducing the
polarity of the solvent by changing from THF to dioxane.
The reaction of 27 5R1ˆBoc, R2ˆBu) did not proceed at all
and only the recovering the starting material was observed
5Table 2: entry 6). In case of 28 5R1ˆTs, R2ˆCH2OH), in
which R2 group is much smaller than 26 5R2ˆBu), two
products 541 and 43) were isolated and the structure of the
former was characterized for ®ve-membered compound and
the latter was six-membered compound by analyzing their
The tosylamide 532) was synthesized from the benzyl
alcohol 58) shown by Scheme 3 in good overall yield.
When 22, 23, and 24 were re¯uxed in THF in the presence
of TBAF, elimination of the trimethylsilyl group on the
terminal alkyne ®rst occurred as the reaction of the benzyl
alcohol 55), and then the cyclization smoothly proceeded
to give the cyclized products 533, 34,9g and 35). As the
products 533, 34, and 35) were also unstable like 11,
determination of the structures was carried out after being
converted to their reduced forms by the catalytic hydro-
genation 5Scheme 4). Among the tested compounds, the
tosylamide 522) had the highest reactivity compared with
the acetamide 523) and the t-butyl carbamate 524) 5rt vs.
THF re¯ux). These results may be ascribed to the difference
in the pKa value of the N±H proton.
The results of the other substrates, which have the Ph, Bu,
Table 2. TBAF promoted cyclization reactions of 2-ethynylbenzylamine derivatives
Entry
Substrate
Reagent
Solvent
Time 5h)
Yield 5compound number) 5%)
5-exo-dig
6-endo-dig
44
1
2
3
4
5
6a
7
32
25
26
26
26
27
28
TBAF´3H2OTHF
28
THF
THF±DMF 510:1)
Dioxane
24
32 5
3
12
12
39)
56 540)
±
±
±
±
TBAF 5THF solution)
TBAF 5THF solution)
TBAF 5THF solution)
TBAF´3H2ODioxane
TBAF 5THF solution)
TBAF´3H2OTHF
±
±
37 542)
54 542)
42)
45
36
±
84 5
±
±
THF
2.5
48
66 5
±
±
41)
30 543)
±
a
100% of 27 was recovered.

K. Hiroya et al. / Tetrahedron 57*2001) 9697±9710
9701
Scheme 5. Reagents and conditions: 5i) TBAF´3H2O, dioxane, re¯ux, 2 d.
1H NMR spectra 5Table 2: entry 7). When 29 5R1ˆTs, R2ˆ
t-Bu) was reacted in dioxane at 1008C, the only isolated
product was the butylated compound on the nitrogen atom
in place of the cyclization 5Scheme 5).
the triple bond.7d,9j On the other hand, substrate independent
6-endo-dig selective cyclization reactions were shown
by Liao 5palladium±zinc chloride catalyze reaction),7e
Sashida7f and Nagarajan9a 5palladium catalyzed reactions;
Sashida reported that benzoic acid derivatives having a
bulky substituent on the acetylne gave a mixture of both
mode products) and almost the same results were also
observed by Bellina et al. for the silver ion catalyzed
cyclization reaction.7g
The following results for this cyclization reaction can be
used for both the benzyl alcohol derivatives and benzyl-
amine derivatives:
1. These cyclization reactions are sensitive to the bulkiness
of the substituents on the terminal alkyne.
2. Generally, the benzylamine derivatives are much more
reactive than the benzyl alcohol derivatives.
3. The reactivity is highly depended on the acidity of the
proton on the nitrogen atom.
4. Five-membered ring products were observed for the
reaction of the substrates having a hydrogen atom or
aromatic ring or smaller alkyl chain on the terminal
alkyne.
In contrast to these results, when the benzyl alcohol deriva-
tives 55±10) were used as the substrates, the regioselectivity
tendency is similar to the reported in the literature.8 Namely,
when a hydrogen or aromatic ring is on the end of the alkyne,
cyclization produced the 5-exo-dig, but the 6-endo-dig
product is produced for the alkyl chain substituent. In our
cases, the observed selectivity not only of the alcohol, but
also the amino derivatives are compatible with the results of
Castro and Padwa.8a,c,d
5. Six-membered ring products were afforded for a rela-
tively bulky alkyl group 5Bu) at the end of the triple bond.
If the resonance effect of the 4-methoxyphenyl group contri-
butes to the reaction, the six-membered ring product might
be produced to some extent 5Fig. 3). However, we could not
detect the six-membered product at all for the reaction of the
phenyl and 4-methoxyphenyl substrates 5Table 1: entries 3
and 4; Table 2: entries 1 and 2). Therefore, at least for
the cyclization of the benzyl alcohol and benzylamine
derivatives, it seems likely that the electronic nature of the
When 2-ethynylbenzoic acid or amide derivatives were used
as the substrates, the observed regioselectivity was highly
dependent on the employed reagents. For example, Kundu
et al. reported that for the triethylammonium salt promoted
cyclization, phthalides and the isoindolin-1-ones are major
products irrespective of the substituted group on the end of
Figure 3.

9702
K. Hiroya et al. / Tetrahedron 57*2001) 9697±9710
Figure 4.
substituted group on the acetylene terminal is not important
for the cyclization mode.
Commercially available TBAF solution in THF is known to
be basic, because it contains a small amount of H2O.11 As
we have already published about the cyclization reaction
mediated by the alkoxide anion,19 we doubted that the
cyclization was caused by the alkaline conditions. However,
under alkaline conditions decomposition of the starting
material 5Table 2: entry 2) or only the detrimethylsilyl
product were observed 5Table 2: entries 1 and 4) and no
cyclized product was detected at all. The reaction with tetra-
butylammonium chloride 5TBACl) did not proceed at all
and only the starting material was recovered even at re¯ux
temperature with or without H2O5Table 2: entries 3 and 4).
These results strongly suggest that the ¯uoride ion is essen-
tial for these cyclization reactions.
On the other hand, the substrate that has butyl group on the
acetylene terminal 526) gave exclusively six-membered
product 542). However, the reaction of the compound
having smaller substituent 528: CH2OH) gave the mixture
of ®ve-membered 541) and six-membered compound 543).
Therefore, it can be concluded that the observed six-
membered ring cyclization selectivity for the alkyl sub-
stituents will be due to the steric repulsion at the transition
state 5Fig. 4).
2.2. Mechanistic study of the cyclization reaction
mediated by TBAF
Next, the effects of the counter cation were investigated.
The reaction with KF in THF or MeCN did not give 11,
even at re¯ux temperature 5Table 2: entries 5 and 6).
However, when CsF was used as the reagent, only the
detrimethylsilyl reaction occurred in THF at rt 5Table 2:
entry 7) or re¯ux temperature 5Table 2: entry 8), in MeCN
at rt 5Table 2: entry 9), but a cyclized product was obtained
To clarify the requirement of this particular cyclization
reactions, we next tested various reaction conditions using
5 as the substrate. The product5s) were analyzed by 1H NMR
spectra of the crude reaction mixture and the results are
shown in Table 3.
Table 3. Cyclization reactions of 5 under various conditions
Entry
Reagents
K2CO3
t-BuOK
TBACl
TBACl10.1N NaOH
KF
KF´2H2OMeCN
CsF
CsF
CsF
CsF
TBACl1KF
TBACl1KF
TBACl1KF´2H2OMeCN
TBACl1AgF
TBACl1AgF
TBAF 550 mol%)
TBAF 510 mol%)
Solvent
Temperature
Time 5h)
Product
1
2
3
4
5
6
7
8
MeOH
THF
THF
THF±H2ORe¯ux
THF±H2ORt
Re¯ux
THF
THF
MeCN
MeCN
THF±H2ORt
THF±H2ORe¯ux
Re¯ux
THF
THF
Rt
Rt
Re¯ux
11.5
0.5
6
9
Decomposed
No reaction
9
2
22.5
No reaction
6
Rt
Re¯ux
Rt
Re¯ux
9
9
9
9
11
9
9
11
25
14
11.5
6
9
10
11
12
13
14
15
16
17
1
2.5
6
Rt
0.5
6
2.5
1.5
9
Re¯ux
Re¯ux
Re¯ux
11 523)a
11 549)a
11 551)a
THF
THF
a
The numbers in the parentheses are isolated yields of 12, which were obtained after hydrogenation.

K. Hiroya et al. / Tetrahedron 57*2001) 9697±9710
9703
for this TBAF promoted cyclization reaction as shown in
Fig. 5.
3. Conclusion
For the cyclization reactions promoted by TBAF, a high
regioselectivity was observed depending on the substituents
on the end of the triple bond. Namely, when the benzyl
alcohol or benzylamine derivatives, which have either a
hydrogen or aromatic ring on the triple bond, were treated
with TBAF, the products always have ®ve-membered ring
55-exo-dig). On the other hand, for a smaller alkyl group
5CH2OH), a mixture of the six-membered ring 56-endo-dig)
and 5-membered ring 55-exo-dig) was produced. Further-
more, the compound having bulky alkyl group only gave
six-membered ring 56-endo-dig). The causes of the observed
regioselectivity were suggested not by the electronic nature
of the functional group on the triple bond, but by the steric
bulkiness. It was also concluded that both the tetrabutyl-
ammonium cation and ¯uoride anion are essential for the
ef®cient cyclization reactions.
4. Experimental
4.1. General
All melting points and boiling points are uncorrected. The
IR spectra were measured using a JASCOIR-810 spectro-
photometer. The 1H NMR spectra were recorded on a
Varian Gemini 2000 5300 MHz) and JEOL GX-500
5500 MHz) in CDCl3 as the solvent, unless otherwise stated.
The chemical shifts are expressed in d 5ppm) values with
tetramethylsilane 5TMS) as the internal reference and
coupling constants 5J) are measured in Hz. The mass spectra
and high-resolution mass spectra were recorded on JEOL
JMS-DX303 and JMS-AX500 instruments, respectively.
Figure 5.
in MeCN at re¯ux, although some side products were
detected 5Table 2: entry 10). These results suggested that
a softer cation would be favorable for the cyclization
reaction of this substrate.
4.2. General procedure for the Sonogashira coupling
reaction between aryliodides and acetylenes using
triethylamine as the solvent
To demonstrate the hypothesis described above, we next
investigated the reaction with TBAF generated in situ. A
mixture of 5, TBACl, and KF in THF at rt or re¯ux tempera-
ture gave only the detrimethylsilyl product 5Table 2: entries
11 and 12), but in MeCN, the cyclized product was obtained
5Table 2: entry 13). Furthermore, for the reaction with
TBACl and AgF in THF, 9 was afforded at rt 5Table 2:
entry 14), but 11 occurred at re¯ux temperature 5Table 2:
entry 15). The evidence described above proves that both
the tetrabutylammonium cation and ¯uoride anion are
essential for the ef®cient cyclization.
Acetylene, PdCl25PPh3)2, and CuI were successively added
to a solution of 2-iodobenzyl alcohol derivatives or 2-iodo-
benzylamine derivatives in triethylamine at 08C, then being
stirred at room temperature. The mixture was ®ltered
through a pad of Celitew, then the ®ltrate was diluted with
Et2O. The organic solution was washed successively with
H2Oand saturated aq. NaCl solution, then dried over
MgSO4 and concentrated. The residue was puri®ed by silica
gel column chromatography to afford the 2-ethynylbenzyl
alcohol derivatives or 2-ethynylbenzylamine derivatives.
Finally, the catalytic reactions were investigated. When
50 mol% 5Table 2: entry 16) or 10 mol% 5Table 2: entry
17) of TBAF was used, only 11 was detected, which means
TBAF worked as a catalyst. Interestingly, the reaction
did not terminate and gave the mixture of 9 and 11, when
4.2.1. 2-2Trimethylsilylethynyl)benzyl alcohol 25). Accor-
ding to the general procedure 5Section 4.2), trimethylsilyl-
acetylene 52.70 g, 27.6 mmol), PdCl25PPh3)2 50.75 g,
1.06 mmol), CuI 50.41 g, 2.14 mmol), and 2-iodobenzyl
alcohol 55.00 g, 21.4 mmol) in triethylamine 540 ml) were
allowed to react for 3 h. The crude products were puri®ed by
silica gel column chromatography eluting with hexane±
AcOEt 54:1) to afford an oil, which was further puri®ed
by bulb to bulb distillation to afford 5 53.63 g, 83%) as a
Ê
TBAF solution in THF pre-treated with 4 A molecular
sieves was used. In this case, the signals of Bu3N were
also detected in the 1H NMR spectrum of the crude
product. Therefore, we deduced the possible mechanism

9704
K. Hiroya et al. / Tetrahedron 57*2001) 9697±9710
colorless oil, bp 708C/1 mmHg 5Found: C, 70.42; H, 7.75.
C12H16OSi requires C, 70.53; H, 7.89%); nmax 5®lm)/cm21
3400, 2160; dH 5300 MHz, CDCl3) 0.27 59H, s), 2.33 51H, t,
Jˆ6.5 Hz), 4.81 52H, d, Jˆ6.5 Hz), 7.23 51H, dt, Jˆ1.1,
7.4 Hz), 7.33 51H, dt, Jˆ1.1, 7.4 Hz), 7.41 51H, dd,
Jˆ1.1, 7.4 Hz), 7.46 51H, dd, Jˆ1.1, 7.4 Hz); m/z 204
5M1) 5Found: m/z 204.0980, requires C12H16OSi:
204.0971).
7.49 51H, d, Jˆ7.4 Hz), 7.52±7.56 53H, m); m/z 208 5M1)
5Found: m/z 208.0887, requires C15H12O: 208.0888).
4.2.5. 2-Ethynylbenzyl alcohol 29). TBAF´3H2O50.30 g,
1.47 mmol) was added to a solution of 5 50.46 g,
1.47 mmol) in THF 58 ml) at room temperature. After
being stirred for 1 h at the same temperature, Et2Owas
added to the mixture and washed successively with H2O
and saturated aq. NaCl solution. The organic solution was
dried over MgSO4 and concentrated to afford the crude
products, which was puri®ed by silica gel column chroma-
tography [hexane±AcOEt 54:1)] to afford 9 50.176 g, 62%)
as a colorless solid. The analytical sample was recrystallized
from Et2O±hexane to afford 9 as a colorless needle, mp 64±
658C 5Found: C, 81.64; H, 6.19, requires C9H8OC, 81.79;
H, 6.10); nmax 5CHCl3)/cm21 3310, 3050, 2100; dH 5500
MHz, CDCl3) 2.03 51H, t, Jˆ6.1 Hz), 3.33 51H, s), 4.84
52H, d, Jˆ6.1 Hz), 7.26 51H, dt, Jˆ1.2, 7.6 Hz), 7.37 51H,
dt, Jˆ1.2, 7.6 Hz), 7.45 51H, d, Jˆ7.6 Hz), 7.51 51H, d,
Jˆ7.6 Hz); m/z 132 5M1) 5Found: m/z 130.0572, requires
C9H8O: 132.0576).
4.2.2. 2-21-Hexynyl)benzyl alcohol 26). PdCl25PPh3)2
50.350 g, 0.5 mmol) and CuI 50.190 g, 1.0 mmol) were
added to a solution of 2-iodobenzyl alcohol 52.34 g, 10.0
mmol), 1-hexyne 51.23 g, 15.0 mmol), and i-Pr2NH 52.00 g,
20.0 mmol) in THF 550 ml) at 08C. After being stirred for
6 h at room temperature, H2Owas added and the aqueous
solution was extracted with AcOEt 5£3). The organic
solution was dried over MgSO4 and evaporated. The crude
oil was puri®ed by silica gel column chromatography
[hexane±AcOEt 56:1)] to afford 6 51.69 g, 90%) as a viscous
colorless oil, nmax 5®lm)/cm21 3363, 2228; dH 5300 MHz,
CDCl3) 0.96 53H, t, Jˆ7.1 Hz), 1.42±1.67 54H, m), 2.25
51H, t, Jˆ6.3 Hz), 2.46 52H, t, Jˆ6.9 Hz), 4.79 52H, d,
Jˆ6.3 Hz), 7.18±7.31 52H, m), 7.37±7.42 52H, m); m/z
188 5M1) 5Found: m/z 188.1209, requires C13H16O:
188.1201).
4.2.6. 2-[2-24-Methoxyphenyl)ethynyl]benzyl alcohol
210). According to the general procedure 5Section 4.2), the
crude 9 which was obtained from TBAF´3H2O50.30 g,
1.47 mmol) and 5 50.46 g, 1.47 mmol) in THF 58 ml) as
shown in Section 4.2.5, PdCl25PPh3)2 50.29 g, 0.42 mmol),
CuI 50.16 g, 0.83 mmol), and 4-iodoanisole 51.94 g, 8.3
mmol) in triethylamine 520 ml) were stirred for 3.5 h. The
residue was puri®ed by silica gel column chromatography
using hexane±AcOEt 52:1) as an eluent to afford a solid,
which was recrystallized from Et2Oto afford 10 51.27 g,
64%) as a colorless plate, mp 102±1038C 5Found: C,
80.67; H, 5.91, requires C16H14O2 C, 80.65; H, 5.92); nmax
5KBr)/cm21 3350, 1250, 1050; dH 5300 MHz, CDCl3) 2.14
51H, t, Jˆ6.6 Hz), 3.83 53H, s), 4.91 52H, d, Jˆ6.6 Hz), 6.89
52H, d, Jˆ8.8 Hz), 7.25±7.37 52H, m), 7.45±7.54 54H, m);
m/z 238 5M1) 5Found: m/z 238.0969, requires C16H14O2:
238.0994).
4.2.3. 2-23,3-Dimethyl-1-butynyl)benzyl alcohol 27).
According to the general procedure 5Section 4.2), 3,3-
dimethyl-1-butyne 50.82 g, 10 mmol), PdCl25PPh3)2 50.18
g, 0.25 mmol), CuI 595 mg, 0.50 mmol), and 2-iodobenzyl
alcohol 51.23 g, 5.26 mmol) in triethylamine 515 ml) were
stirred for 3.5 h. The residue was puri®ed by silica gel
column chromatography using hexane±AcOEt 56:1) as an
eluent to afford 7 50.99 g, 91%) as a viscous colorless oil,
nmax 5®lm)/cm21 3350, 2230; dH 5300 MHz, CDCl3) 1.34
59H, s), 2.22 51H, t, Jˆ6.6 Hz), 4.79 52H, d, Jˆ6.6 Hz), 7.22
51H, dt, Jˆ1.7, 7.5 Hz), 7.28 51H, dt, Jˆ1.7, 7.5 Hz), 7.37±
7.41 52H, m); m/z 188 5M1) 5Found: m/z 188.1210, requires
C13H16O: 188.1202).
4.2.4.
2-22-Phenylethynyl)benzyl
alcohol
28).8c,d
4.3. General procedure for TBAF promoted cyclization
reaction of 2-ethynylbenzyl alcohol derivatives
PdCl25PPh3)2 50.35 g, 0.5 mmol) and CuI 50.19 g,
1.0 mmol) were added to a solution of 2-bromobenzalde-
hyde 52.00 g, 10.8 mmol) and phenylacetylene 52.20 g,
21.6 mmol) in triethylamine 520 ml) at 08C. After being
stirred for 6 h at room temperature, H2O550 ml) was
added to the mixture, then extracted with AcOEt 5£3).
The combined organic solution was dried over MgSO4
and the ®ltrate was evaporated to afford the crude mixture,
which was used to the next reaction without further
puri®cation.
TBAF 51.0 M solution in THF or TBAF´3H2O) was added to
a solution of the 2-ethynylbenzyl alcohol derivatives in THF
at room temperature, then the mixture was re¯uxed. Et2O
was added to the reaction mixture and washed successively
with H2O, saturated aq. NaCl solution. The organic solution
was dried over MgSO4 and evaporated to afford the crude
product5s), which was puri®ed by silica gel column
chromatography, if necessary.
4.3.1. 1,3-Dihydro-21-methylene)isobenzofuran 211).15
According to the general procedure 5Section 4.3), TBAF
51.0 M solution in THF, 7.34 ml, 7.34 mmol) and 5 51.0 g,
4.89 mmol) in THF 510 ml) was reacted for 1.5 h. The crude
product was used to the next reaction without further
puri®cation, dH 5500 MHz, CDCl3) 4.36 51H, d, Jˆ
2.4 Hz), 4.41 51H, d, Jˆ2.4 Hz), 5.21 52H, s), 7.16±7.25
53H, m), 7.41 51H, m).
NaBH4 50.113 g, 2.7 mmol) was added to a solution of the
crude aldehyde in MeOH 550 ml) at 08C. After the reaction
was terminated, H2Owas added to the reaction mixture and
the aqueous phase was extracted with AcOEt 5£3). The
combined organic solution was dried over MgSO4 and
concentrated to afford the crude oil, which was puri®ed by
silica gel column chromatography [hexane±AcOEt 56:1)] to
afford 8 [1.80 g, 80% 5two steps)] as a colorless solid, mp
67±688C, nmax 5CHCl3)/cm21 3315, 1490, 1454; dH 5300
MHz, CDCl3) 2.10 51H, t, Jˆ6.3 Hz), 4.93 52H, d, Jˆ
6.3 Hz), 7.31 51H, dd, Jˆ1.4, 7.7 Hz), 7.34±7.40 54H, m),
4.3.2. 1,3-Dihydro-1-methylisobenzofuran 212).16 A mix-
ture of the crude 11 and a catalytic amount of Pd±C in

K. Hiroya et al. / Tetrahedron 57*2001) 9697±9710
9705
toluene 520 ml) was stirred under hydrogen gas for 24 h.
Pd±C was ®ltered off, and then toluene was removed at
an atmospheric pressure. The residue was successively puri-
®ed by silica gel column chromatography [hexane±AcOEt
59:1)] and bulb to bulb distillation to afford 12 [0.31 g, 47%
5two steps)] as a colorless oil, bp 258C/15 mmHg 5lit.16
808C/20 mmHg); nmax 5®lm)/cm21 1040; dH 5500 MHz,
CDCl3) 1.50 53H, d, Jˆ6.7 Hz), 5.04 51H, d, Jˆ13.0 Hz),
5.12 51H, dd, Jˆ1.8, 13.0 Hz), 5.31 51H, br q), 7.14±7.33
54H, m); m/z 134 5M1) 5Found: m/z 134.0735, requires
C9H10O: 134.0732).
4.3.7. 2-Iodobenzylazide 217).20 1,8-Diazabicyclo[5.4.0]-
undec-7-ene 5DBU) 51.93 g, 12.7 mmol) was added to a
solution of 2-iodobenzyl alcohol 52.34 g, 10 mmol),
5PhO)2P5O)N3 53.3 g, 12 mmol) in toluene 520 ml) at room
temperature, then being stirred for 1 h. 3N HCl 520 ml) was
added to the mixture and extracted with Et2O . The
combined organic solution was successively washed with
H2Oand saturated aq. NaCl solution, dried over MgSO ,
4
and concentrated. The residue was puri®ed by silica gel
column chromatography [hexane±AcOEt 519:1)] to afford
17 52.34 g, 90%) as a colorless oil; nmax 5KBr)/cm21 2150;
dH 5300 MHz, CDCl3) 4.46 52H, s), 7.04 51H, dt, Jˆ4.4,
8.0 Hz), 7.34±7.43 52H, m), 7.89 51H, d, Jˆ8.0 Hz); m/z
259 5M1) 5Found m/z 258.9606, requires C7H6IN3: 258.9607).
4.3.3. 1-[2Z)-Benzylidene]isobenzofuran 213).7b,8a,c,d,15,17
According to the general procedure 5Section 4.3), 8
559 mg, 0.28 mmol) and TBAF 51.0 M solution in THF,
0.31 ml, 0.31 mmol) was re¯uxed for 2 h. The crude
products were puri®ed by silica gel column chromatography
using hexane±Et2O510:1) as an eluent to afford 13 547 mg,
80%) as a colorless viscous oil, dH 5300 MHz, CDCl3) 5.51
52H, s), 5.95 51H, s), 7.14 51H, t, Jˆ7.4 Hz), 7.30±7.38 55H,
m), 7.55±7.59 51H, m), 7.74 52H, d, Jˆ7.4 Hz); m/z 208
5M1) 5Found m/z 208.0888, requires C15H12O: 208.0926).
4.3.8.
N-22-Iodobenzyl)-24-methylphenyl)sulfonamide
219). Triphenylphosphine 52.62 g, 10 mmol) was added to
a solution of 2-iodobenzylazide 517) 52.34 g, 9.03 mmol) in
THF 540 ml) at 08C and the mixture was stirred at room
temperature. After 16 h, aq. NH3 solution 510 ml) was
added to the mixture and stirred for 3 h, and then 3N aq.
NaOH solution 550 ml) was added. After being stirred for
1 h, the mixture was neutralized with 3N HCl 520 ml) and
the aqueous solution was extracted with Et2O. The organic
solution was washed successively with H2Oand saturated
aq. NaCl solution, dried over MgSO4, and concentrated in
vacuo to afford the crude amine, which was used to the next
reaction without further puri®cation.
4.3.4. 1-[2Z)-4-2Methoxyphenyl)methylidene]isobenzo-
furan 214). According to the general procedure 5Section
4.3), 10 50.11 g, 0.46 mmol) and TBAF´3H2O50.13 g,
0.46 mmol) was re¯uxed for 4 h. The crude products was
puri®ed by silica gel column chromatography using
hexane±AcOEt 510:1) as an eluent to afford 14 50.105 g,
95%) as a colorless solid, the analytical sample was recrys-
tallized from Et2Oto give a colorless plate, mp 98±100 8C
5Found: C, 80.39; H, 5.98, requires C16H14O2, C, 80.65; H,
5.92%); dH 5500 MHz, CDCl3) 3.81 53H, s), 5.49 52H, s),
5.89 51H, s), 6.88 52H, d, Jˆ9.2 Hz), 7.32 53H, m), 7.52
51H, d, Jˆ6.7 Hz), 7.67 52H, d, Jˆ9.2 Hz); m/z 238 5M1)
5Found m/z 238.1011, requires C16H14O2: 238.0993).
p-Toluenesulfonyl chloride 51.33 g, 7.0 mmol) was added to
a solution of the crude 18 52.07 g) and triethylamine 55 ml)
in THF 520 ml) at 08C and being stirred at room temperature
for 2 h. The reaction mixture was extracted with AcOEt.
The combined organic solution was successively washed
with H2Oand saturated aq. NaCl solution, and dried over
MgSO4. The solvent was evaporated to afford the crude
products, which was puri®ed by silica gel column chroma-
tography using hexane±AcOEt 51:2) as the eluent to afford
19 51.46 g, 91%) as a colorless solid. The analytical sample
was recrystallized from Et2O. Colorless needle, mp 101±
1038C 5Found: C, 43.34; H, 3.73; I, 32.75; N, 3.47; S, 8.21,
requires C14H14INO2S: C, 43.42; H, 3.64; I, 32.77; N, 3.62;
S, 8.28); nmax 5®lm)/cm21 3280, 1330, 1155; dH 5300 MHz,
CDCl3) 2.42 53H, s), 4.18 52H, d, Jˆ6.6 Hz), 4.94 51H, t,
Jˆ6.6 Hz), 6.94 51H, dt, Jˆ1.9, 7.4 Hz), 7.23±7.32 54H, m),
7.73 53H, m); m/z: 387 5M1) 5Found: m/z 386.9767, requires
C14H14INO2S: 386.9790).
4.3.5. 3-Butyl-1H-2-benzopyran 215). TBAF 51.0 M solu-
tion in THF, 1.0 ml, 1.0 mmol) was added to a solution of 6
599.8 mg, 0.53 mmol) in THF 52 ml) and DMF 50.5 ml) and
re¯uxed for 60 h. H2O530 ml) was added to the mixture and
extracted with Et2O. The organic solution was dried over
MgSO4 and concentrated in vacuo to afford the crude
products, which was chromatographed on silica gel using
hexane as an eluent to afford 15 510 mg, 10%) as a colorless
viscous oil, dH 5300 MHz, CDCl3) 0.93 53H, t, Jˆ7.4 Hz),
1.38 52H, m), 1.55 52H, m), 2.19 52H, t, Jˆ7.1 Hz), 5.03
52H, s), 5.64 51H, s), 6.91 51H, d, Jˆ7.4 Hz), 6.98 51H, d,
Jˆ7.4 Hz), 7.08 51H, dt, Jˆ1.4, 7.4 Hz), 7.18 51H, dt, Jˆ
1.4, 7.4 Hz); m/z 188 5M1) 5Found m/z 188.1208, requires
C13H16O: 188.1201).
4.3.9. N-22-Iodobenzyl)acetamide 220). Acetic anhydride
50.82 g, 8.0 mmol) was added to a solution of the crude 18 in
pyridine 515 ml) at 08C and being stirred at room tempera-
ture for 2 h. The excess pyridine was removed in vacuo and
the residue was extracted with AcOEt. The combined
organic solution was successively washed with H2Oand
saturated aq. NaCl solution, and dried over MgSO4. The
solvent was evaporated to afford 20 as a colorless solid.
The analytical sample was recrystallized from Et2O±
hexane. Colorless needle, mp 133±1358C; nmax 5CHCl3)/
cm21 3447, 3009, 1670, 1514; dH 5300 MHz, CDCl3) 2.02
53H, s), 4.46 52H, d, Jˆ6.1 Hz), 5.95 51H, br), 6.98 51H, dt,
Jˆ2.0, 7.7 Hz), 7.30±7.40 52H, m), 7.83 51H, d, Jˆ7.7 Hz);
m/z: 276 5M111) 5Found: m/z 275.9874, requires
C9H11INO: 275.9885).
4.3.6.
23,3-Dimethyl-1-butynyl)benzaldehyde
216).
According to the general procedure 5Section 4.3), 7
50.10 g, 0.53 mmol) and TBAF´3H2O50.17 g, 0.53 mmol)
in dioxane 52 ml) was stirred at 1008C for 6 d. The crude
products were puri®ed by silica gel column chromatography
using hexane±AcOEt 550:1) as an eluent to afford 16
518 mg, 20%) as a colorless viscous oil, nmax 5®lm)/cm21
1700; dH 5300 MHz, CDCl3) 1.35 59H, s), 7.35±7.52 53H,
m), 7.89 51H, d, Jˆ7.7 Hz), 10.55 51H, s); m/z 186 5M1)
5Found m/z 186.1052, requires C13H14O: 186.1044). From
the later fraction, 7 549 mg, 49%) was recovered.

9706
K. Hiroya et al. / Tetrahedron 57*2001) 9697±9710
4.3.10. t-Butyl N-22-iodobenzyl)carbamate 221). Di-t-
butyl dicarbonate 51.09 g, 5.0 mmol) was added to a solu-
tion of the crude 18 in THF 530 ml) at 08C and being stirred
at room temperature for 2 h. The reaction mixture was
extracted with Et2O. The combined organic solution was
successively washed with H2Oand saturated aq. NaCl solu-
tion, dried over MgSO4, and concentrated. The residue was
chromatographed on silica gel [hexane±AcOEt 56:1)] to
afford 21 as a viscous colorless oil, dH 5300 MHz, CDCl3)
1.46 59H, s), 4.34 52H, br d, Jˆ5.8 Hz), 5.01 51H, br), 6.97
51H, dt, Jˆ2.2, 7.7 Hz), 7.26±7.38 52H, m), 7.82 51H, d,
Jˆ7.7 Hz); m/z: 276 5M1-C4H9) 5Found: m/z 275.9486,
requires C8H7INO2: 275.9522).
3.3 mmol), phenylacetylene 50.408 g, 4.0 mmol), and
i-Pr2NH 50.410 g, 4.0 mmol) in THF 540 ml) at 08C. After
being stirred for 12 h at room temperature, H2O550 ml) was
added and the aqueous solution was extracted with AcOEt
5£3). The organic solution was dried over MgSO4 and
evaporated. The crude oil was puri®ed by silica gel column
chromatography using hexane±AcOEt 510:1) as an eluent to
afford 25 50.582 g, 57%) as a viscous colorless oil, dH
5300 MHz, CDCl3) 1.45 59H, s), 4.55 52H, br d, Jˆ
6.0 Hz), 5.02 51H, br), 7.23±7.41 56H, m), 7.51±7.57 53H,
m); m/z 307 5M1) 5Found: m/z 307.1568, requires
C20H21NO2: 307.1572).
4.3.15.
N-[2-21-Hexynyl)benzyl]-24-methylphenyl)sul-
4.3.11. N-[2-[2-2Trimethylsilyl)ethynyl]benzyl]-24-methyl-
phenyl)sulfonamide 222). According to the general pro-
cedure 5Section 4.2), trimethylsilylacetylene 50.19 g,
3.02 mmol), PdCl25PPh3)2 553 mg, 76 mmol), CuI 529 mg,
0.15 mmol), and 19 50.58 g, 1.51 mmol) in triethylamine
54 ml) and THF 55 ml) were stirred for 3 h. The residue
was puri®ed by silica gel column chromatography eluting
with hexane±AcOEt 53:1) to afford 22 50.47 g, 86%) as a
colorless oil, nmax 5neat)/cm21 3280, 2150, 1330, 1160; dH
5300 MHz, CDCl3) 0.22 59H, s), 2.39 53H, s), 4.30 52H, d,
Jˆ6.6 Hz), 5.06 51H, br t), 7.17±7.24 55H, m), 7.36 51H, m),
7.69 52H, d, Jˆ8.5 Hz); m/z: 357 5M1) 5Found: m/z
357.1202, requires C19H23NO2SSi: 357.1219).
fonamide 226). PdCl25PPh3)2 591 mg, 0.13 mmol) and CuI
551 mg, 0.27 mmol) were added to a solution of 19 51.00 g,
2.68 mmol), 1-hexyne 50.246 g, 3.0 mmol), and i-Pr2NH
50.306 g, 3.0 mmol) in THF 55 ml) at 08C. After being
stirred for 5 h at room temperature, H2O550 ml) was
added and the aqueous solution was extracted with AcOEt
5£3). The organic solution was dried over MgSO4 and
evaporated. The crude oil was puri®ed by silica gel column
chromatography using hexane±AcOEt 52:1) as an eluent to
afford 26 50.807 g, 88%) as a viscous colorless oil, dH
5300 MHz, CDCl3) 0.94 53H, t, Jˆ7.1 Hz), 1.39±1.59
54H, m), 2.36 52H, t, Jˆ6.9 Hz), 2.40 53H, s), 4.27 52H, d,
Jˆ6.3 Hz), 5.02 51H, t, Jˆ6.3 Hz), 7.13±7.19 53H, m), 7.23
52H, d, Jˆ8.2 Hz), 7.28±7.33 51H, m), 7.70 52H, d, Jˆ
8.2 Hz); m/z 341 5M1) 5Found: m/z 341.1445, requires
C20H23NO2S: 341.1450).
4.3.12. N-[2-[2-2Trimethylsilyl)ethynyl]benzyl]acetamide
223). According to the general procedure 5Section 4.2),
trimethylsilylacetylene 50.28 g, 4.50 mmol), PdCl25PPh3)2
579 mg, 0.11 mmol), CuI 543 mg, 0.23 mmol), and 20
50.62 g, 2.25 mmol) in triethylamine 54 ml) and THF
55 ml) were stirred for 3 h. The residue was puri®ed by silica
gel column chromatography eluting with hexane±AcOEt
51:1) to afford 23 50.44 g, 80%) as a colorless solid. The
analytical sample was recrystallized from Et2O±hexane.
Colorless needles, mp 768C 5Found: C, 68.49; H, 7.70; N,
5.67; S, 8.21, requires C14H19NOSi: C, 68.52; H, 7.80; N,
5.71); nmax 5KBr)/cm21 3280, 2160, 1640, 1560; dH
5300 MHz, CDCl3) 0.23 59H, s), 2.00 53H, s), 4.58 52H, br
d, Jˆ6.0 Hz), 5.96 51H, br), 7.25±7.38 53H, m), 7.45 51H,
m); m/z: 245 5M1) 5Found: m/z 245.1248, requires
C14H19NOSi: 245.1209).
4.3.16. t-Butyl N-[2-21-hexynyl)benzyl]carbamate 227).
PdCl25PPh3)2 521 mg, 0.03 mmol) and CuI 511 mg, 0.06
mmol) were added to a solution of 21 51.00 g, 3.0 mmol),
1-hexyne 50.295 g, 3.6 mmol), and i-Pr2NH 50.410 g,
4.0 mmol) in THF 53 ml) at 08C. After being stirred for
2.5 h at room temperature, H2O550 ml) was added and
the aqueous solution was extracted with AcOEt 5£3). The
organic solution was dried over MgSO4 and evaporated. The
crude oil was puri®ed by silica gel column chromatography
using hexane±Et2O520:1) as an eluent to afford 27 50.636 g,
74%) as a viscous colorless oil, dH 5300 MHz, CDCl3) 0.96
53H, t, Jˆ7.4 Hz), 1.45 59H, s), 1.47±1.66 54H, m), 2.45
52H, t, Jˆ6.8 Hz), 4.43 52H, br d, Jˆ5.8 Hz), 5.00 51H, br),
7.16±7.41 54H, m); m/z 287 5M1) 5Found: m/z 287.1899,
requires C18H25NO2: 287.1885).
4.3.13. t-Butyl N-[2-[2-2trimethylsilyl)ethynyl]benzyl]-
carbamate 224). According to the general procedure
5Section 4.2), trimethylsilylacetylene 50.40 g, 6.38 mmol),
PdCl25PPh3)2 5112 mg, 0.16 mmol), CuI 561 mg, 0.32
mmol), and 21 50.95 g, 3.14 mmol) in triethylamine
510 ml) were stirred for 2 h. The residue was puri®ed by
silica gel column chromatography eluting with hexane±
AcOEt 54:1) to afford 24 50.84 g, 89%) as a colorless
viscous oil, nmax 5neat)/cm21 3350, 2150, 1720, 1250,
1165; dH 5300 MHz, CDCl3) 0.27 59H, s), 1.45 59H, s),
4.45 52H, br d, Jˆ6.1 Hz), 5.12 51H, br), 7.21 51H, dt,
Jˆ1.4, 7.1 Hz), 7.30 51H, dd, Jˆ1.4, 7.1 Hz), 7.34 51H, d,
Jˆ7.1 Hz), 7.45 51H, dd, Jˆ1.4, 7.1 Hz); m/z: 303 5M1)
5Found: m/z 303.1635, requires C17H25NO2Si: 303.1654).
4.3.17.
N-[2-23-Hydroxypropynyl)benzyl]-24-methyl-
phenyl)sulfonamide 228). PdCl25PPh3)2 514 mg, 0.02
mmol) and CuI 57.6 mg, 0.04 mmol) were added to a
solution of 19 50.15 g, 0.40 mmol), propargyl alcohol
545 mg, 0.80 mmol) in i-Pr2NH 53.0 ml) at room tempera-
ture and stirring was continued further 6 h at the same
temperature. The mixture was ®ltered through a Celitew
pad eluting with AcOEt. The organic solution was washed
with saturated aq. NaCl solution, dried over MgSO4 and
evaporated. The crude product was puri®ed by silica gel
column chromatography using CHCl3 as an eluent to afford
28 50.120 g, 95%) as a colorless solid. The analytical sample
was recrystallized from Et2O±hexane. Colorless needle, mp
118±1198C, nmax 5CHCl3)/cm21 3510, 3368, 3026, 1329,
1159; dH 5300 MHz, CDCl3) 2.40 53H, s), 2.61 51H, t,
Jˆ6.3 Hz), 4.24 52H, d, Jˆ6.3 Hz), 4.45 52H, d, Jˆ
4.3.14. t-Butyl N-[2-22-phenylethynyl)benzyl]carbamate
225). PdCl25PPh3)2 50.119 g, 0.17 mmol) and CuI 50.063 g,
0.33 mmol) were added to a solution of 21 51.09 g,

K. Hiroya et al. / Tetrahedron 57*2001) 9697±9710
9707
6.3 Hz), 5.16 51H, t, Jˆ6.3 Hz), 7.15±7.26 55H, m), 7.34
51H, m), 7.72 52H, d, Jˆ8.2 Hz); m/z 315 5M1) 5Found: m/z
315.0967, requires C17H17NO3S: 315.0929).
4.4. General procedure for TBAF promoted cyclization
reaction of 2-ethynylbenzylamine derivatives 2Scheme 4)
TBAF´3H2Owas added to a solution of the 2-ethynyl-
benzylamine derivatives in THF at room temperature.
After being stirred at the same temperature, a catalytic
amount of Pd±C was added to the mixture and stirred
under H2. Et2Owas added to the reaction mixture and
washed successively with H2O, saturated aq. NaCl solution.
The organic solution was dried over MgSO4 and concen-
trated in vacuo. The residue was puri®ed by silica gel
column chromatography.
4.3.18. N-[2-23,3-Dimethyl-1-butynyl)benzyl]-24-methyl-
phenyl)sulfonamide 229). According to the general pro-
cedure 5Section 4.2), 3,3-dimethyl-1-butyne 50.82 g, 10.0
mmol), PdCl25PPh3)2 50.18 g, 0.25 mmol), CuI 595 mg,
0.50 mmol), and 19 51.94 g, 5.0 mmol) in triethylamine
515 ml) and THF 55 ml) were stirred for 2.5 h. The residue
was puri®ed by silica gel column chromatography eluting
with hexane±AcOEt 59:1) to afford a colorless solid, which
was recrystallized from Et2O±hexane to afford 29 51.31 g,
77%) as colorless plates, mp 668C 5Found: C, 70.25; H,
6.81; N, 4.18; S, 9.11, requires C20H23NO2S: C, 70.35; H,
6.79; N, 4.10; S, 9.39); nmax 5neat)/cm21 3250, 1330, 1160;
4.4.1. 1,3-Dihydro-1-methyl-2-24-methylphenylsulfonyl)-
isoindole 236). According to the general procedure 5Section
4.4), TBAF´3H2O597 mg, 0.31 mmol) and 22 50.11 g,
0.31 mmol) in THF 52 ml) was stirred for 9 h at room
temperature, followed by being stirred under H2 for
18.5 h. The crude mixture was puri®ed by silica gel column
chromatography using hexane±AcOEt 56:1) as an eluent to
afford 36 576 mg, 86%) as a colorless solid. The analytical
sample was recrystallized from Et2O±hexane to afford
colorless prisms; mp 918C 5Found: C, 52.16; H, 7.65; N,
2.96; S, 11.25, requires C16H17NO2S: C, 52.04; H, 7.64; N,
3.03; S, 11.16); nmax 5neat)/cm21 1340, 1160; dH 5300 MHz,
CDCl3) 1.67 53H, d, Jˆ6.3 Hz), 2.37 53H, s), 4.56 51H, d,
Jˆ14.0 Hz), 4.73 51H, dd, Jˆ2.5, 14.0 Hz), 4.92 51H, dq,
Jˆ2.5, 6.3 Hz), 7.09±7.24 54H, m), 7.27 52H, d, Jˆ8.2 Hz),
7.76 52H, d, Jˆ8.2 Hz); m/z: 287 5M1) 5Found: m/z
287.0994, requires C16H17NO2S: 287.0980).
d
H 5300 MHz, CDCl3) 1.27 59H, s), 2.39 53H, s), 4.26 52H,
br d, Jˆ6.7 Hz), 5.02 51H, br t), 7.14±7.30 56H, m), 7.69
52H, d, Jˆ8.2 Hz); m/z: 341 5M1) 5Found: m/z 341.1431,
requires C20H23NO2S: 341.1450).
4.3.19. N-[2-22-Phenylethynyl)benzyl]-24-methylphenyl)-
sulfonamide 232).20 DBU 50.73 g, 4.56 mmol) was added to
a solution of 8 50.800 g, 3.8 mmol), 5PhO)2P5O)N3 51.25 g,
4.56 mmol) in toluene 510 ml) at room temperature, then
being stirred for 12 h. 3N HCl 510 ml) was added to the
mixture and extracted with Et2O. The combined organic
solution was successively washed with H2Oand saturated
aq. NaCl solution, dried over MgSO4, and concentrated.
The residue used to the next reaction without further
puri®cations.
4.4.2.
2-Acetyl-1,3-dihydro-1-methylisoindole
237).
Triphenylphosphine 51.10 g, 4.2 mmol) was added to a solu-
tion of the crude azide 530) in THF 515 ml) at 08C and the
mixture was stirred for 2 h at room temperature, then for 5 h
at 408C. Aq. NH3 solution 55 ml) was added to the mixture
and stirred for 12 h, then 3N aq. NaOH solution 515 ml) was
added. After been stirred for 2 h, the aqueous solution was
extracted with Et2O. The organic solution was washed
successively with H2Oand saturated aq. NaCl solution,
dried over MgSO4, and concentrated in vacuo to afford the
crude amine, which was used to the next reaction without
further puri®cation.
According to the general procedure 5Section 4.4),
TBAF´3H2O50.13 g, 0.41 mmol) and 23 50.10 g, 0.41
mmol) in THF 52 ml) was re¯uxed for 8 h, followed by
being stirred under H2 for 13 h. The crude mixture was
puri®ed by silica gel column chromatography using
hexane±AcOEt 52:1) as an eluent to afford 37 565 mg,
91%) as a colorless viscous oil, nmax 5neat)/cm21 1650; dH
5300 MHz, CDCl3) 1.52 53H, d, Jˆ6.1 Hz), 2.15 51.8H, s),
2.21 51.2H, s), 4.63 50.4H, d, Jˆ16.0 Hz), 4.75 50.6H, d,
Jˆ14.0 Hz), 4.82 50.6H, d, Jˆ14.0 Hz), 4.95 50.4H, d,
Jˆ16.0 Hz), 5.12 50.4H, q, Jˆ5.7 Hz), 5.31 50.6H, q, Jˆ
6.1 Hz), 7.20±7.34 54H, m); m/z: 175 5M1) 5Found: m/z
175.1000, requires C11H13NO: 175.0997).
p-Toluenesulfonyl chloride 50.72 g, 3.8 mmol) was added to
a solution of the crude amine 531) in pyridine 510 ml) at 08C
and stirred at room temperature for 30 h. The reaction
mixture was extracted with AcOEt, then the combined
organic solution was successively washed with H2O, aq.
CuSO4 solution, 3N HCl, and saturated aq. NaCl solution.
The solution was dried over MgSO4 and the solvent was
evaporated to afford the crude products, which was puri®ed
by silica gel column chromatography using hexane±AcOEt
519:1) as the eluent to afford 32 [0.62 g, 46% 53 steps)] as a
colorless solid. The analytical sample was recrystallized
from Et2O±hexane. Colorless needles, mp 1708C 5Found:
C, 73.05; H, 5.29; N, 3.77; S, 8.89, requires C22H19NO2S: C,
73.10; H, 5.30; N, 3.88; S, 8.87); nmax 5KBr)/cm21 3280,
1325, 1160; dH 5300 MHz, CDCl3) 2.38 53H, s), 4.37 52H,
d, Jˆ6.6 Hz), 4.94 51H, t, Jˆ6.6 Hz), 7.29 52H, d, Jˆ
8.5 Hz), 7.23±7.47 59H, m), 7.71 52H, d, Jˆ8.5 Hz); m/z:
361 5M1) 5Found: m/z 361.1156, requires C22H19NO2S:
361.1137).
4.4.3. 2-t-Butoxycarbonyl-1,3-dihydro-1-methylisoindole
238). According to the general procedure 5Section 4.4),
TBAF´3H2O595 mg, 0.30 mmol) and 24 50.10 g, 0.30
mmol) in THF 52 ml) was re¯uxed for 25 h, followed by
being stirred under H2 for 18 h. The crude mixture was
puri®ed by silica gel column chromatography using
hexane±AcOEt 510:1) as an eluent to afford 38 551 mg,
73%) as a colorless viscous oil, nmax 5neat)/cm21 1700,
1175, 1120; dH 5300 MHz, CDCl3) 1.47 53H, d, Jˆ
6.6 Hz), 1.53 59H, s), 4.59±4.78 52H, m), 5.06 51H, m),
7.10 54H, m); m/z: 233 5M1) 5Found: m/z 233.1411, requires
C14H19NO2: 233.1415).
4.4.4. 2,3-Dihydro-2-[24-methylphenyl)sulfonyl]-1-[2Z)-
phenylmethylidene]isoindole 239)9b 2Table 2: entry 1).
TBAF´3H2O587 mg, 0.28 mmol) was added to a solution of
32 50.10 g, 0.28 mmol) in THF 52 ml) at room temperature,

9708
K. Hiroya et al. / Tetrahedron 57*2001) 9697±9710
and then the mixture was re¯uxed for 28 h. Et2Owas added
to the reaction mixture and washed successively with H2O,
saturated aq. NaCl solution. The organic solution was dried
over MgSO4 and evaporated to afford the residue, which
was puri®ed by silica gel column chromatography using
hexane±AcOEt 59:1) as an eluent to afford 39 532 mg,
32%) as a colorless viscous oil, dH 5300 MHz, CDCl3)
2.15 53H, s), 4.70 52H, s), 6.66 51H, s), 6.90±7.19 57H,
m), 7.30 52H, d, Jˆ8.4 Hz), 7.45 52H, d, Jˆ8.2 Hz), 7.80
52H, d, Jˆ8.4 Hz); m/z: 361 5M1).
methylmethylidene)isoindole 241) and 3-hydroxymetnyl-
2-[24-methylphenyl)sulfonyl]-1,2-dihydroisoquinoline 243)
2Table 2: entry 7). TBAF´3H2O5107 mg, 0.29 mmol) was
added to a solution of 28 590 mg, 0.29 mmol) in THF 52 ml)
at room temperature, and then the mixture was re¯uxed for
2.5 h. AcOEt was added to the reaction mixture and the
organic solution was washed successively with H2Oand
saturated aq. NaCl solution. The organic solution was
dried over MgSO4 and evaporated to afford the residue,
which was puri®ed by silica gel column chromatography
using hexane±AcOEt 52:1) as an eluent to afford 43
527 mg, 30%) as a colorless viscous oil, nmax 5CHCl3)/
cm21 3394, 1344, 1161; dH 5500 MHz, CDCl3) 2.17 53H,
s), 2.72 51H, br), 4.50 52H, s), 4.74 52H, s), 6.38 51H, s), 6.73
51H, d, Jˆ7.3 Hz), 6.87 52H, d, Jˆ8.3 Hz), 6.94 51H, d,
Jˆ7.3 Hz), 6.99 51H, dt, Jˆ1.2, 7.3 Hz), 7.05 51H, dt,
Jˆ1.2, 7.3 Hz), 7.34 52H, d, Jˆ 8.3 Hz); dC 5125 MHz,
CDCl3) 21.3, 50.5, 64.2, 120.2, 124.6, 125.0, 127.0, 127.5,
127.9, 128.8, 129.3, 130.3, 134.6, 139.8, 143.6; m/z: 315
5M1) 5Found: m/z 315.0928, requires C17H17NO3S
315.0929). From the later fractions, 41 560 mg, 66%) was
afforded as colorless viscous oil, nmax 5CHCl3)/cm21 3387,
1352, 1165; dH 5300 MHz, CDCl3) 2.21 51H, br), 2.25 53H,
s), 4.57 52H, t, Jˆ7.7 Hz), 4.69 52H, s), 6.10 52H, t,
Jˆ7.7 Hz), 6.99 51H, d, Jˆ6.6 Hz), 7.05 52H, d,
Jˆ8.5 Hz), 7.08±7.17 52H, m), 7.31 51H, d, Jˆ6.6 Hz),
7.55 52H, d, Jˆ8.5 Hz); m/z: 315 5M1) 5Found: m/z
315.0912, requires C17H17NO3S 315.0929).
4.4.5.
2-t-Butoxycarbonyl-2,3-dihydro-1-[2Z)-phenyl-
methylidene]isoindole 240) 2Table 2: entry 2). TBAF
51.0 M THF solution, 0.11 ml, 0.11 mmol) was added to a
solution of 25 532 mg, 0.104 mmol) in THF 51 ml) at room
temperature, and then the mixture was re¯uxed for 3 h. H2O
was added to the reaction mixture and extracted with Et2O.
The organic solution was dried over MgSO4 and evaporated
to afford the residue, which was puri®ed by silica gel
column chromatography using hexane±AcOEt 510:1) as
an eluent to afford 40 517.8 mg, 56%) as a colorless viscous
oil, dH 5300 MHz, CDCl3) 1.19 59H, s), 4.95 52H, s), 6.48
51H, s), 7.15 51H, t, Jˆ7.1 Hz), 7.24±7.34 55H, m), 7.38
52H, d, Jˆ7.4 Hz), 7.57±7.61 51H, m); m/z:307 5M1)
5Found: m/z 307.1579, requires C20H21NO2: 307.1573).
4.4.6. 3-Butyl-2-[24-methylphenyl)sulfonyl]-1,2-dihydro-
isoquinoline 242) and 3-butylisoquinoline 244)18 2Table 2
entry 4). TBAF 51.0 M THF solution, 1.1 ml, 1.1 mmol)
was added to a solution of 26 50.12 g, 0.35 mmol) in
dioxane 51 ml) at room temperature, then the mixture was
re¯uxed for 12 h. H2Owas added to the reaction mixture
and extracted with AcOEt. The organic solution was dried
over MgSO4 and evaporated to afford the residue, which
was puri®ed by silica gel column chromatography using
hexane±AcOEt 54:1) as an eluent to afford 42 565 mg,
54%) as colorless a viscous oil, dH 5300 MHz, CDCl3)
0.95 53H, t, Jˆ7.4 Hz), 1.36±1.44 52H, m), 1.60±1.70
52H, m), 2.18 53H, s), 2.68 52H, t, Jˆ6.9 Hz), 4.70 52H,
s), 6.15 51H, s), 6.63 51H, d, Jˆ8.0 Hz), 6.85 52H, d, Jˆ
8.2 Hz), 6.92±7.02 53H, m), 7.31 52H, dt, Jˆ1.9, 8.2 Hz);
m/z: 341 5M1). From the later fractions, 44 524 mg, 36%)
was afforded as colorless viscous oil, dH 5300 MHz, CDCl3)
0.96 53H, t, Jˆ7.4 Hz), 1.43 52H, sextet, Jˆ7.6 Hz), 1.80
52H, quintet, Jˆ7.6 Hz), 2.94 52H, t, Jˆ7.6 Hz), 7.47 51H,
s), 7.52 51H, t, Jˆ8.0 Hz), 7.64 51H, t, Jˆ8.2 Hz), 7.74 51H,
d, Jˆ8.2 Hz), 7.93 51H, d, Jˆ8.0 Hz), 9.20 51H, s); m/z:185
5M1) 5Found: m/z 185.1211, requires C13H15N: 185.1204).
4.4.9. N-Butyl-N-[2-23,3-dimethyl-1-butynyl)benzyl]-24-
methylphenyl)sulfonamide 245). TBAF´3H2O590 mg,
0.29 mmol) was added to a solution of 29 50.10 g,
0.289 mmol) in dioxane 52 ml) at room temperature, then
the mixture was re¯uxed for 8 d. Et2Owas added to the
reaction mixture and washed successively with H2Oand
saturated aq. NaCl solution. The organic solution was
dried over MgSO4 and evaporated to afford the residue,
which was puri®ed by silica gel column chromatography
using hexane±AcOEt 510:1) as an eluent to afford 45
542 mg, 35%) as a colorless viscous oil, nmax 5neat)/cm21
1340, 1160; dH 5300 MHz, CDCl3) 0.74 53H, t, Jˆ7.3 Hz),
1.14 52H, m), 1.25 59H, s), 1.30 52H, m), 2.44 53H, s), 3.07
52H, t, Jˆ7.7 Hz), 4.51 52H, s), 7.18 51H, dt, Jˆ1.4, 7.4 Hz),
7.24 51H, dt, Jˆ1.6, 7.4 Hz), 7.30 53H, m), 7.45 51H, d,
Jˆ7.7 Hz), 7.76 52H, d, Jˆ8.5 Hz); m/z5FAB):398
5M111). From the later fractions, 29 563 mg, 63%) was
recovered.
4.4.10. Cyclization reaction of 2-2trimethylsilylethynyl)-
benzyl alcohol 25) by TBACl and AgF 2Table 3: entry
15). TBACl 51.36 g, 4.89 mmol) was added to a solution of
2-5trimethylsilylethynyl)benzyl alcohol 55) 51.0 g, 4.89
mmol) and AgF 50.62 g, 4.89 mmol) in THF 510 ml) at
room temperature, then the mixture was re¯uxed for 6 h.
Et2Owas added to the reaction mixture and the organic
solution was washed successively with H2Oand saturated
aq. NaCl solution. The organic solution was dried over
MgSO4 and evaporated to afford the crude product, which
was used to the next reaction without further puri®cation.
4.4.7. 3-Butyl-2-[24-methylphenyl)sulfonyl]-1,2-dihydro-
isoquinoline 242) 2Table 2 entry 5). TBAF´3H2O595 mg,
0.30 mmol) was added to a solution of 26 583 mg, 0.25
mmol) in dioxane 52 ml) at room temperature, and then
the mixture was re¯uxed for 12 h. TBAF´3H2O525 mg,
0.08 mmol) was added to a solution, and then the mixture
was further re¯uxed for 12 h. H2Owas added to the reaction
mixture and extracted with AcOEt. The organic solution
was dried over MgSO4 and evaporated to afford the residue,
which was puri®ed by silica gel column chromatography
using hexane±AcOEt 54:1) as an eluent to afford 42
569 mg, 84%) as a colorless viscous oil.
1
The H NMR spectrum of the crude product showed only
the presence of 11.
4.4.8. 3-Dihydro-2-[24-methylphenyl)sulfonyl]-1-2hydroxy-
A mixture of the crude 11 and a catalytic amount of Pd±C in

K. Hiroya et al. / Tetrahedron 57*2001) 9697±9710
9709
Commum. 1976, 738±741. 5d) Baldwin, J. E.; Thomas, R. C.;
Kruse, L. I.; Silberman, L. J. Org. Chem. 1977, 42, 3846±
3852. 5e) Johnson, C. D. Acc. Chem. Res. 1993, 26, 476±482.
3. Castro, C. E.; Gaughan, E. J.; Owsley, D. C. J. Org. Chem.
1966, 31, 4071±4078.
toluene 510 ml) was stirred under H2 for 2 d. Pd±C was
®ltered off, and then toluene was removed at an atmospheric
pressure. The residue was successively puri®ed by silica gel
column chromatography [hexane±AcOEt 59:1)] and bulb to
bulb distillation to afford 12 [0.151 g, 23% 5two steps)] as a
colorless oil.
4. 5a) Sundberg, R. J. Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996; Vol. 2, p. 119. 5b) Cacchi, S.;
Fabrizi, G.; Marinelli, F.; Moro, L.; Pace, P. Synlett 1997,
1363±1366. 5c) Larock, R. C.; Yum, E. K.; Refvik, M. D.
J. Org. Chem. 1998, 63, 7652±7662. 5d) Yasuhara, A.;
Kanamori, Y.; Kaneko, M.; Numata, A.; Kondo, Y.;
Sakamoto, T. J. Chem. Soc., Perkin Trans. 1 1999, 529±
534. 5e) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1
2000, 1045±1075, and references cited therein.
4.5. General procedure for the cyclization reaction of
2-2trimethylsilylethynyl)benzyl alcohol 25) by catalytic
amount of TBAF
TBAF´3H2Owas added to a solution of 2-5trimethylsilyl-
ethynyl)benzyl alcohol 55) in THF at room temperature,
then the mixture was re¯uxed. Et2Owas added to the
reaction mixture and the organic solution was washed
successively with H2Oand saturated aq. NaCl solution.
The organic solution was dried over MgSO4 and evaporated
to afford the crude product, which was used to the next
reaction without further puri®cation.
5. 5a) Friedrichsen, W. Comprehensive Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996; Vol. 2, p. 351. 5b) Arcadi, A.;
Cacchi, S.; Rosario, M. D.; Fabrizi, G.; Marinelli, F. J. Org.
Chem. 1996, 61, 9280±9288. 5c) Arcadi, A.; Cacchi, S.;
Fabrizi, G.; Marinelli, F.; Moro, L. Synlett 1999, 1432±
1434, and references cited therein.
A mixture of the crude 11 and a catalytic amount of Pd-C in
toluene was stirred under H2. Pd±C was ®ltered off, and then
toluene was removed at an atmospheric pressure. The
residue was successively puri®ed by silica gel column
chromatography [hexane±AcOEt 59:1)] and bulb to bulb
distillation to afford 12 as a colorless oil.
6. 5a) Roesch, K. R.; Larock, R. C. J. Org. Chem. 1998, 63,
5306±5307. 5b) Roesch, K. R.; Larock, R. C. Org. Lett.
1999, 1, 553±556. 5c) Tovar, J. D.; Swager, T. M. J. Org.
Chem. 1999, 64, 6499±6504. 5d) Sakamoto, T.; Numata, A.;
Kondo, Y. Chem. Pharm. Bull. 2000, 48, 669±672.
7. 5a) Sakamoto, T.; An-naka, M.; Kondo, Y.; Yamanaka, H.
Chem. Pharm. Bull. 1986, 34, 2754±2759. 5b) Villemin, D.;
Goussu, D. Heterocycles 1989, 29, 1255±1261. 5c) Ogawa,
Y.; Maruno, M.; Wakamatsu, T. Heterocycles 1995, 41,
2587±2599. 5d) Kundu, N. G.; Pal, M.; Nandi, B. J. Chem.
Soc., Perkin Trans. 1 1998, 561±568. 5e) Liao, H.-Y.; Cheng,
C.-H. J. Org. Chem. 1995, 60, 3711±3716. 5f) Sashida, H.;
Kawamukai, A. Synthesis 1999, 1145±1148. 5g) Bellina, F.;
Ciucci, D.; Vergamini, P.; Rossi, R. Tetrahedron 2000, 56,
2533±2545. 5h) Rossi, R.; Bellina, F.; Biagetti, M.; Catanese,
A.; Mannina, L. Tethraherdon. Lett. 2000, 41, 5281±5286,
and references cited therein.
4.5.1. Cyclization reaction of 2-2trimethylsilylethynyl)-
benzyl alcohol 25) by 50 mol% of TBAF 2Table 3:
entry 16). According to the general procedure 5Section
4.5), TBAF´3H2O50.77 g, 2.45 mmol), 2-5trimethylsilyl-
ethynyl)benzyl alcohol 55) 51.00 g, 4.89 mmol) in THF
510 ml) was re¯uxed for 2.5 h, and then worked up. The
1H NMR spectrum of the crude product showed only the
presence of 11.
After hydrogenation and puri®cation as described in Section
4.5, 12 [0.323 g, 49% 5two steps)] was obtained as a color-
less oil.
Â
8. 5a) Castro, C. E.; Havlin, R.; Honwad, V. K.; Malte, A.; Moje,
S. J. Am. Chem. Soc. 1969, 91, 6464±6470. 5b) Swenton, J. S.;
Callinan, A.; Wang, S. J. Org. Chem. 1992, 57, 78±85.
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36, 4717±4720. 5d) Padwa, A.; Krumpe, K. E.; Weingarten,
M. D. J. Org. Chem. 1995, 60, 5595±5603.
4.5.2. Cyclization reaction of 2-2trimethylsilylethynyl)-
benzyl alcohol 25) by 50 mol% of TBAF 2Table 3:
entry 16). According to the general procedure 5Section
4.5), TBAF´3H2O5147 mg, 0.47 mmol), 2-5trimethylsilyl-
ethynyl)benzyl alcohol 55) 50.95 g, 4.65 mmol) in THF
510 ml) was re¯uxed for 1.5 h, and then worked up. The
1H NMR spectrum of the crude product showed only the
presence of 11.
9. 5a) Nagarajan, A.; Balasubramanian, T. R. Indian J. Chem.,
Sect. B 1989, 67±68. 5b) Luo, F.-T.; Wang, R.-T. Tetrahedron
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N.; Sakamoto, T.; Yamanaka, H. Tetrahedron 1994, 50,
11803±11812. 5d) Koseki, Y.; Nagasaka, T. Chem. Pharm.
Bull. 1995, 43, 1604±1606. 5e) Khan, M. W.; Kundu, N. G.
Synlett 1997, 1435±1437. 5f) Koseki, Y.; Kusano, S.; Sakata,
H.; Nagasaka, T. Tetrahedron Lett. 1999, 40, 2169±2172.
After hydrogenation and puri®cation as described in Section
4.5, 12 [0.321 g, 51% 5two steps)] was obtained as a color-
less oil.
 Â
5g) Cid, M. M.; Domõnguez, D.; Castedo, L.; Vazquez-
Â
Lopez, E. M. Tetrahedron 1999, 55, 5599±5610. 5h) Kundu,
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