One-pot transformation of Ph2P(O)-protected ethynes: Deprotection followed by transition metal-catalyzed coupling

Article abstract of DOI:10.1021/jo402176w

Ph₂P(O)-protected ethynes were successfully transformed to arylethynes in one-pot manner through t-BuOK-catalyzed deprotection followed by Sonogashira coupling with aryl halide. The arylethynes were obtained similarly by Ph₂P(O)-deprotection, stannylation of the resulting terminal ethynes, and Migita-Kosugi-Stille coupling. Deprotection followed by intramolecular Eglinton coupling could be carried out in one-pot to provide cyclic butadiynes.

Full text of DOI:10.1021/jo402176w

Note
pubs.acs.org/joc
One-Pot Transformation of Ph2P(O)-Protected Ethynes: Deprotection
Followed by Transition Metal-Catalyzed Coupling
Lifen Peng, Feng Xu, Yoshinori Suzuma, Akihiro Orita,* and Junzo Otera*
Department of Applied Chemistry, Okayama University of Science, Kita-ku, Okayama 700-0005, Japan
S
* Supporting Information
ABSTRACT: Ph2P(O)-protected ethynes were successfully transformed to arylethynes in one-pot manner through t-BuOK-
catalyzed deprotection followed by Sonogashira coupling with aryl halide. The arylethynes were obtained similarly by Ph2P(O)-
deprotection, stannylation of the resulting terminal ethynes, and Migita-Kosugi-Stille coupling. Deprotection followed by
intramolecular Eglinton coupling could be carried out in one-pot to provide cyclic butadiynes.
Scheme 1. One-Pot Transformation of Ph2P(O)-Protected
Ethyne to Arylethyne and Arylbutadiyne
he protection is one of the fundamental technologies in
organic synthesis.1 Although a number of protecting
T
groups were developed and utilized in synthesis of structurally
complicated compounds, new protecting groups are still being
explored.2 We have been involved in synthesis of acetylenic
compounds having expanded π-systems and explored their
applications to organic materials such as organic light-emitting
diode (OLED),3 organic field-effect transistor (OFET),4 and
dye-sensitized solar cell (DSSC).5 In synthesis of these
arylethynes, Sonogashira coupling of aryl halide with ethynes
protected with trialkylsilyl group such as trimethylsilyl (TMS)
and t-buthyldimethylsilyl (TBDMS) and 2-hydroxy-2-propyl
group is invoked routinely.6 However, this reaction, though
powerful, frequently suffers from a severe drawback upon
isolation of the product: the similar Rf values of starting
compounds and products disturb isolation of the desired
compound. In order to overcome this drawback, we developed
a new protecting group, Ph2P(O), which enabled easy isolation
of the Sonogashira coupling product because of the high
polarity, and exemplified the usefulness of this protection in the
synthesis of phenyleneethynylenes.7 Herein, we have expanded
the applicability of this protecting group to one-pot synthesis of
arylethynes through deprotection followed by transition metal-
catalyzed coupling reactions such as Sonogashira, Migita-
Kosugi-Stille, Hay, and Eglinton couplings (Scheme 1).8 First,
we tried deprotection of 1 followed by Sonogashira coupling of
the resulting terminal ethyne with phenyl bromide in one-pot
(Scheme 2). When a THF solution of 1 was treated with 1.2
equiv of t-BuOK at rt for 2 h, TLC analysis indicated that 1 was
deprotected completely to give phenylethyne. After PhBr,
Pd(PPh3)4, CuI, i-Pr2NH, and toluene had been added to the
THF solution, the mixture was heated at 80 °C for 20 h to give
diphenylethyne in 72% yield.9 In deprotection of this protocol,
t-BuOP(O)Ph2 was formed as a byproduct, but it did not
disturb the following Sonogashira coupling.10 Subjection of 2 to
t-BuOK-catalyzed deprotection followed by Sonogashira
coupling with 3 gave Ph2P(O)-protected ethyne 4 in 72%
yield. In this one-pot reaction, the addition of stoichiometric
amount of t-BuOK enabled selective Ph2P(O)-deprotection of
2 while the Ph2P(O)-protection of 3 remained untouched.11
Similarly, one-pot reaction of 5 with 6 provided 7 in 66% yield,
and no decomposition of cyano group was observed in spite of
the treatment of t-BuOK in the deprotection step. Ph2P(O)-
protected ethyne 7 could be applied to one-pot Ph2P(O)-
deprotection/Sonogashira coupling with 9-bromoanthracene to
afford 8 in 76% yield.
We succeeded in synthesis of phenyleneethynylene having
expanded π-system such as 8 by repeating one-pot depro-
tection/Sonogashira coupling protocol. The synthetic process
Received: October 6, 2013
© XXXX American Chemical Society
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Scheme 2. One-Pot Synthesis of Arylethynes through Ph2P(O)-Deprotection and Sonogashira Coupling
for phenyleneethynylene could be further compacted by
subjection of crude product of the first one-pot protocol to
the second (Scheme 3). When phosphorylethyne 2 was treated
successively with t-BuOK and with aryl bromide 9 and Pd and
Cu catalysts, phosphorylethyne 10 was provided, and
subjection of the crude product 10 to the second
deprotection/coupling with 4-(3,7-dimethyloctyloxy)phenyl
iodide afforded 11 in 54% yield (based on 9). In this synthetic
process, a filtration of the crude product 10 by a thin pad of
silica gel was required. Otherwise, the second one-pot protocol
was disturbed by the remaining oxidized transition metal
catalyst(s) to provide 11 in a low yield. This compacted process
of successive one-pot protocols could be applied to synthesis of
12: subjection of the phosphorylethyne 5 to deprotection/
coupling protocols with 6 and 13 provided 12 in 43% yield.
The one-pot deprotection/coupling reaction protocol could
be applied to Migata-Kosugi-Stille coupling12 as well as
Sonogashira coupling. When phosphorylethyne 1 was subjected
to deprotection (t-BuOK), stannylation (Bu3SnOMe), and
Migata-Kosugi-Stille coupling with iodide 14 (Pd2(dba)3 and t-
Bu3P), each step proceeded smoothly to give 15 in 96% yield
(Scheme 4).13 In this process, addition of 0.5 equiv of t-BuOK
enabled the complete deprotection of the Ph2P(O) group and
the formation of stannylethyne 16 because MeOK which was
produced by stannylation of the resulting potassium acetylide
with Bu3SnOMe also served as a deprotection reagent.14 This
deprotection/Migata-Kosugi-Stille coupling protocol proceeded
smoothly in coupling between 1 and 17 to provide 18 in 77%
yield. In this reaction, only stannylethyne 16 reacted with
phenyl iodide moiety of 17, and terminal ethyne moiety of 17
remained untouched.15
We succeeded in synthesis of yne-diynes by taking advantage
of Hay coupling16 followed by one-pot deprotection/
Sonogashira coupling (Scheme 5). When a toluene solution
of monophosphoryl-protected diyne 19 and phenylethyne (20)
was heated in the presence of CuCl, 21 was obtained in 76%
yield. In this Hay coupling, homocoupling products 22 and 23
were produced as byproducts, but the high polarity of Ph2P(O)
group enabled easy purification of the desired heterocoupling
product 21 by column chromatography on silica gel (Rf = 0.55
for 21, 0.24 for 22, and 0.97 for 23 in AcOEt). Subjection of 21
to deprotection and Sonogashira coupling with 4-iodoanisole
furnished yne-diyne 24 in 74% yield. The similar Eglington
coupling between terminal ethynes 25 and 26 followed by
deprotection/Sonogashira coupling of the resulting butadiyne
27 with phenylbromide 28 provided nitro- and trifluoromethyl-
substituted yne-diyne 29 (60% × 62% yield).
By invoking the Ph2P(O)-assisted purification of the
intermediate and copper-catalyzed butadiyne formation, we
succeeded in synthesis of cyclic pentayne 30 (Scheme 6). Hay
B
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Scheme 3. Compacted One-Pot Synthesis of Arylethynes
through Ph2P(O)-Deprotection and Sonogashira Coupling
Scheme 5. Synthesis of Yne-diynes by Invoking Hay
Coupling Followed by Deprotection/Sonogashira Coupling
Scheme 4. One-Pot Deprotection/Stannylation/Migata-
Kosugi-Stille Coupling
Scheme 6. Synthesis of Cyclic Pentaynes by Invoking Hay,
Sonogashira, and Eglinton Couplings
occurred to produce cyclic pentayne 30 in 55% yield. The
final in situ deprotection/Eglington cyclization proceeded
smoothly without isolation of deprotected-terminal ethyne
35. Although Haley has synthesized successfully the cyclic
pentayne 30 by invoking the similar deprotection and
cyclization of TMS-protected pentayne,18 our protocol is
more convenient to some extent than his process, which
coupling between monoprotected diyne 31 and iodoethyne 32
gave iodotriyne 33 in 76% yield, and Sonogashira coupling of
the resulting iodide 33 with 31 provided bis-Ph2P(O)-
protected pentayne 34 in 78% yield. When 34 was subjected
to t-BuOK-catalyzed deprotection followed by Cu(OAc)2-
catalyzed Eglington coupling,17 the expected cyclization
C
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7
1
Five (R = CN): pale yellow powder; mp 163−165 °C; H NMR
(300 MHz, CDCl3): δ 7.48−7.55 (m, 4H), 7.57−7.60 (m, 2H), 7.69
(br, 4H), 7.84−7.92 (m, 4H).
requires transformation of Ar−N3Et2 to Ar−I by heating in a
pressure bottle and in situ desilylation of TMS-proptected
butadiyne/Sonogashira coupling of the terminal butadyne
moiety with aryl iodide under strictly controlled reaction
conditions.
Synthesis of Ph2P(O)-Protected Ethynes 3, 6, and 9
(Representative Procedure for 3). (i). Synthesis of Ethynyldiphe-
nylphosphine Oxide. To a flask were added CuI (190.4 mg, 1.0
mmol), Ph2PCl (1.8 mL, 10.0 mmol), trimethylsilylacetylene (1.7 mL,
12.0 mmol), triethylamine (2.8 mL, 20.0 mmol), and toluene (30.0
mL), and the mixture was stirred under nitrogen at 80 °C for 24 h.
After workup with AcOEt/water, the organic layer was washed with
aqueous NH4Cl and brine, and dried over MgSO4. After filtration, the
solvents were evaporated. To the crude product were added THF
(20.0 mL) and then 30% H2O2aq (30%, 5.0 mL, 40.0 mmol) at 0 °C,
and the mixture was stirred in the air at rt for 13 h. After workup with
CH2Cl2/water, the organic layer was washed with brine, and dried over
MgSO4. After filtration, the solvents were evaporated. To the crude
product were added water (0.5 mL) and THF (50.0 mL), and then
TBAF (1.0 M in THF, 1.0 mL, 1.0 mmol) at 0 °C, and the mixture
was stirred in the air at rt for 5 h. After the solvents were evaporated,
the crude product was subjected to column chromatography on silica
gel (hexane/AcOEt, 1:1) to give ethynyldiphenylphosphine oxide
(1.63 g, 72% yield in 3 steps) in a pure form.
In summary, we have established a new methodology of C−
C bond formation by invoking in situ deprotection of Ph2P(O)
group/transition metal-catalyzed coupling of the resulting
terminal ethyne. In one-pot deprotection/Sonogashira coupling
protocol, unsymmetrically substituted aryleneethynylenes were
obtained easily. When a stoichiometric amount of t-BuOK was
used for deprotection, aryl halide having Ph2P(O)-protected
ethyne could be employed as a coupling counterpart, and the
corresponding aryleneethynylene having Ph2P(O)-protected
ethyne was obtained. By compaction of deprotection,
stannylation and palladium-catalyzed coupling, one-pot depro-
tection/Migata-Kosugi-Stille coupling was realized. In this
coupling protocol, in situ prepared stannylethyne reacted
preferentially with aryl iodide, while unprotected terminal
ethyne moiety of aryl iodide remained intact. Highly polar
Ph2P(O) protecting group enabled easy isolation of unsym-
metrically substituted butadiynes which were obtained by
copper-catalyzed oxidative coupling of teiminal ethynes, and
the following one-pot deprotection/Sonogashira coupling
afforded yne-diynes. In situ deprotection of Ph2P(O) groups/
intramolecular Eglington coupling proceeded smoothly to give
a cyclic pentayne.
Ethynyldiphenylphosphine oxide:7 white powder; H NMR (500
1
MHz, CDCl3): δ 3.33 (d, J = 9.8 Hz, 1H), 7.48−7.52 (m, 4H), 7.56−
7.59 (m, 2H), 7.83−7.87 (m, 4H); 13C NMR (125 MHz, CDCl3): δ
78.8 (d, J = 159.7 Hz), 94.0 (d, J = 27.4 Hz), 128.7 (d, J = 13.4 Hz),
130.9 (d, J = 11.4 Hz), 131.5, 132.5.
(ii). Sonogashira Coupling of 1-Bromo-3-Iodobenzene with
Ethynyldiphenylphosphine Oxide. A toluene solution (5.0 mL) of
1-bromo-3-iodobenzene (339.5 mg, 1.2 mmol), S1 (226.2 mg, 1.0
mmol), Pd(PPh3)4 (57.8 mg, 0.05 mmol), CuI (9.5 mg, 0.05 mmol),
and diisopropylamine (0.5 mL) was stirred under nitrogen at 80 °C for
15 h. After workup with CH2Cl2/NH4Claq, the combined organic
layer was washed with brine and dried over MgSO4. After filtration, the
solvents were evaporated. The crude product was subjected to column
chromatography on silica gel (hexane/AcOEt, 1:1) to afford 3 in a
pure form (278.3 mg, 73% yield).
EXPERIMENTAL SECTION
■
1
General. H and 13C NMR spectra were recorded at 500 or 300
MHz and at 125 or 75 MHz, respectively, and calibrated with
tetramethysilane (TMS) as an internal reference. High-resolution mass
spectra (FAB) were recorded using p-nitrobenzyl alcohol as a matrix.
Melting points (mp) were measured and uncorrected. All glassware
was flame-dried prior to use, and all reactions were performed under
nitrogen. Anhydrous solvents (THF, CH2Cl2) were purchased and
used without further purification, and toluene and amines (Et3N, i-
Pr2NH) were distilled from sodium and CaH2, respectively, prior to
use. Purification of the products was performed by flash column
chromatography on silica gel (IR-60−63/210). Ethynes 17,19 26,20
and 3221 and 4-(3,7-dimethyloctyloxy)phenyl iodide22 were prepared
according to the reported procedure.
1
3: white powder; mp 98−99 °C; H NMR (500 MHz, CDCl3): δ
7.26 (t, J = 7.9 Hz, 1H), 7.49−7.54 (m, 5H), 7.56−7.60 (m, 3H), 7.74
(s, 1H), 7.86−7.91 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 84.1 (d, J
= 165.7 Hz), 103.1 (d, J = 29.2 Hz), 121.7 (d, J = 3.7 Hz), 122.2, 128.6
(d, J = 13.7 Hz), 130.0, 130.8 (d, J = 11.2 Hz), 132.3 (d, J = 3.1 Hz),
132.4 (d, J = 121.9 Hz), 133.7, 134.8, 134.9; 31P NMR (121 MHz,
CDCl3): δ 9.83; HRMS (FAB) calcd for C20H15BrOP (M+H+):
381.0044, found 381.0049.
7
1
6: 46% yield; pale-yellow powder; mp 94−96 °C; H NMR (500
MHz, CDCl3): δ 7.95 (t, J = 8.0 Hz, 1H), 7.49−7.53 (m, 4H), 7.56−
7.59 (m, 3H), 7.79 (d, J = 7.9 Hz, 1H), 7.86−7.91 (m, 4H), 7.94 (s,
1H); 13C NMR (75 MHz, CDCl3): δ 84.0 (d, J = 165.7 Hz), 93.4,
102.9 (d, J = 29.2 Hz), 121.6 (d, J = 4.0 Hz), 128.5 (d, J = 13.4 Hz),
129.9, 130.7 (d, J = 11.2 Hz), 131.4, 132.2 (d, J = 2.8 Hz), 132.4 (d, J
= 121.9 Hz), 139.5, 140.5; 31P NMR (121 MHz, CDCl3): δ 9.80.
Synthesis of Ph2P(O)-Protected Ethynes 1, 2, and 5
(Representative Procedure for 1). A toluene solution (5.0 mL)
of ethynylbenzene (109.8 μL, 1.0 mmol), CuI (19.0 mg, 0.1 mmol),
Ph2PCl (220.6 μL, 1.2 mmol), and Et3N (277.2 μL, 2.0 mmol) was
stirred under nitrogen at 80 °C for 8 h. After usual workup with
CH2Cl2 and NH4Claq, the combined organic layer was washed with
brine, and dried over MgSO4. After filtration, the solvents were
evaporated. The crude product was used for next step without
purification. To a THF solution (10.0 mL) of the crude diphenyl-
(phenylethynyl)phosphine was added H2O2aq (30%, 2.5 mL, 20.0
mmol) slowly at 0 °C, and the mixture was stirred at rt for 2 h. After
workup with CH2Cl2 and water, the combined organic layer was
washed with brine and dried over MgSO4. After filtration, the solvents
were evaporated. The crude product was subjected to column
chromatography on silica gel (hexane/AcOEt, 1:1) to afford
diphenyl(phenylethynyl)phosphine oxide in a pure form (226.7 mg,
75% yield).
9:7 82% yield; white powder; mp 154−155 °C; H NMR (500
1
MHz, CDCl3): δ 7.46 (d, J = 8.6 Hz, 2H), 7.49−7.59 (m, 8H), 7.86−
7.91 (m, 4H); 13C NMR (75 MHz, CDCl3): δ 83.7 (d, J = 166.3 Hz),
103.6 (d, J = 29.4 Hz), 118.2 (d, J = 4.3 Hz), 125.0, 128.3 (d, J = 13.7
Hz), 130.4 (d, J = 11.2 Hz), 131.5, 132.0 (d, J = 2.8 Hz), 132.2 (d, J =
121.9 Hz), 133.4 (d, J = 1.9 Hz); 31P NMR (121 MHz, CDCl3): δ
9.88.
Synthesis of Ph2P(O)-Protected Ethynes 19, 25, and 31
(Representative Procedure for 19). A toluene solution (10 mL) of
1,3-diethynylbenzene (126.2 mg, 1.0 mmol), CuI (19.0 mg, 0.1
mmol), Ph2PCl (220.6 μL, 1.2 mmol), and Et3N (277.2 μL, 2.0 mmol)
was stirred under nitrogen at 80 °C for 8 h. After workup with
CH2Cl2/NH4Claq, the combined organic layer was washed with brine,
and dried over MgSO4. After filtration, the solvents were evaporated.
The crude product was used for the next step without purification. To
a THF solution (10.0 mL) of the crude product was added H2O2aq
(30%, 2.5 mL, 20.0 mmol) at 0 °C, and the mixture was stirred at rt for
2 h. After workup with CH2Cl2/water, the combined organic layer was
One (R = H):7 white powder; mp 94−96 °C; 1H NMR (500 MHz,
CDCl3): δ 7.39 (t, J = 7.6 Hz, 2H), 7.46 (d, J = 7.4 Hz, 1H), 7.48−
7.52 (m, 4H), 7.56 (t, J = 7.3 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.89−
7.93 (m, 4H).
7
1
Two (R = 4-MeO): white powder; mp 125−126 °C; H NMR
(500 MHz, CDCl3): δ 3.84 (s, 3H), 6.89 (d, J = 8.8 Hz, 2H), 7.49−
7.56 (m, 8H), 7.88−7.92 (m, 4H).
D
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washed with brine and dried over MgSO4. After filtration, the solvents
were evaporated. The crude product was subjected to column
chromatography on silica gel (hexane/AcOEt, 1:1) to afford 19 in a
pure form (146.8 mg, 45% yield).
mmol) was added t-BuOK (134.6 mg, 1.2 mmol) at 0 °C. After the
mixture had been stirred for 2 h under nitrogen at 0 °C,
bromobenzene (188.4 mg, 1.2 mmol), Pd(PPh3)4 (57.8 mg, 0.05
mmol), CuI (9.5 mg, 0.05 mmol), toluene (16.0 mL), and
diisopropylamine (0.5 mL) were added sequentially. The mixture
was stirred under nitrogen at 80 °C for 15 h. After workup with
CH2Cl2/NH4Claq, the organic layer was washed with brine, and dried
over MgSO4. After filtration, the solvents were evaporated. The crude
product was subjected to column chromatography on silica gel
(hexane) to give diphenylacetylene in a pure form (83.8 mg, 47%
yield).
Compacted One-Pot Synthesis of 11 from 2 through Ph2P(O)-
Deprotection/Sonogashira Coupling (Representative). To a THF
solution (10.0 mL) of 2 (332.3 mg, 1.0 mmol) was added t-BuOK
(134.6 mg, 1.2 mmol). After the mixture had been stirred for 2 h under
nitrogen at rt, 9 (324.0 mg, 0.85 mmol), Pd(PPh3)4 (57.8 mg, 0.05
mmol), CuI (9.5 mg, 0.05 mmol), toluene (16.0 mL), and
diisopropylamine (0.5 mL) were added sequentially. The mixture
was stirred under nitrogen at 80 °C for 15 h. After workup with
CH2Cl2/NH4Claq, the organic layer was washed with brine, and dried
over MgSO4. After filtration, the solvents were evaporated. The crude
product was filtered by a thin pad of silica gel (hexane/AcOEt, 1:1),
and the filtrate was concentrated. To a THF solution (10 mL) of the
crude product 10 was added t-BuOK (134.6 mg, 1.2 mmol) at rt. After
the mixture had been stirred for 2 h under nitrogen at rt, 4-(3,7-
dimethyloctyloxy)-1-iodobenzene (396.3 mg, 1.1 mmol), Pd(PPh3)4
(57.8 mg, 0.05 mmol), CuI (9.5 mg, 0.05 mmol), toluene (16.0 mL),
and diisopropylamine (0.5 mL) were added sequentially. The mixture
was stirred under nitrogen at 80 °C for 15 h. After workup with
CH2Cl2/NH4Claq, the organic layer was washed with brine, and dried
over MgSO4. After filtration, the solvents were evaporated. The crude
product was subjected to column chromatography on silica gel
(hexane/CH2Cl2, 5:1) to afford 11 in a pure form (213.3 mg, 54%
yield, based on bromide).
19:7 white powder; mp 111−113 °C; 1H NMR (500 MHz, CDCl3):
δ 3.12 (s, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.49−7.52 (m, 4H), 7.55−7.58
(m, 4H), 7.71 (s, 1H), 7.87−7.91 (m, 4H).
1
25: 48% yield; white powder; mp 145−147 °C; H NMR (500
MHz, CDCl3): δ 3.24 (s, 1H), 7.48−7.52 (m, 6H), 7.54−7.58 (m,
4H), 7.87−7.91 (m, 4H); 13C NMR (75.45 MHz, CDCl3): δ 80.4,
82.6, 84.6 (d, J = 167.6 Hz), 104.4 (d, J = 29.4 Hz), 120.08, 120.13,
124.5, 128.7 (d, J = 13.7 Hz), 130.9 (d, J = 11.2 Hz), 132.2, 132.4,
132.7 (d, J = 121.9 Hz); 31P NMR (121 MHz, CDCl3): δ 7.11; HRMS
(FAB) calcd for C22H16OP (M+H+): 327.0939, found 327.0946.
1
31: 45%; white powder; mp 121−122 °C; H NMR (500 MHz,
CDCl3): δ 3.27 (s, 1H), 7.36 (t, J = 7.60 Hz, 1H), 7.41 (t, J = 7.65 Hz,
1H), 7.47−7.50 (m, 4H), 7.54−7.56 (m, 3H), 7.60 (d, J = 7.65 Hz,
1H), 7.94−7.99 (m, 4H); 13C NMR (75.45 MHz, CDCl3): δ 81.3,
82.3, 86.4 (d, J = 167.8 Hz), 103.1 (d, J = 29.8 Hz), 123.1 (d, J = 3.7
Hz), 125.8 (d, J = 1.5 Hz), 128.5 (d, J = 13.6 Hz), 128.7, 130.2, 131.1
(d, J = 11.2 Hz), 132.2 (d, J = 3.1 Hz), 132.7, 132.8, 133.0 (d, J =
122.0 Hz); 31P NMR (121 MHz, CDCl3): δ 6.65; HRMS (FAB) calcd
for C22H16OP (M+H+): 327.0939, found 327.0941.
One-Pot Ph2P(O)-Deprotection of 1/Sonogashira Coupling
with Phenyl Bromide (Representative). To a THF solution (10.0
mL) of 1 (302.3 mg, 1.0 mmol) was added t-BuOK (134.6 mg, 1.2
mmol). After the mixture had been stirred for 2 h under nitrogen at rt,
bromobenzene (188.4 mg, 1.2 mmol), Pd(PPh3)4 (57.8 mg, 0.05
mmol), CuI (9.5 mg, 0.05 mmol), toluene (16.0 mL), and
diisopropylamine (0.5 mL) were added sequentially. The mixture
was stirred under nitrogen at 80 °C for 15 h. After workup with
CH2Cl2/NH4Claq, the organic layer was washed with brine, and dried
over MgSO4. After filtration, the solvents were evaporated. The crude
product was subjected to column chromatography on silica gel
(hexane) to give diphenylacetylene in a pure form (128.3 mg, 72%
yield).
11: white powder; mp 151−153 °C; 1H NMR (500 MHz, CDCl3):
δ 0.87 (d, J = 6.75 Hz, 6H), 0.95 (d, J = 6.45 Hz, 3H), 1.15−1.35 (m,
6H), 1.51−1.62 (m, 2H), 1.67−1.68 (m, 1H), 1.80−1.86 (m, 1H),
3.83 (s, 3H), 3.97−4.05 (m, 2H), 6.86−6.89 (m, 4H), 7.45−7.48 (m,
8H); 13C NMR (75 MHz, CDCl3): δ 19.6, 22.59, 22.63, 24.6, 28.0,
29.8, 36.1, 37.2, 39.2, 55.2, 66.4, 87.8, 87.9, 91.1, 91.3, 114.0, 114.6,
114.8, 115.2, 123.0, 123.1, 131.3, 133.0, 133.1, 159.3, 159.7; HRMS
(FAB) calcd for C33H37O2 (M+H+): 465.2794, found 465.2795.
12: white powder; mp 154−155 °C; 1H NMR (500 MHz, CDCl3):
δ 7.28−7.29 (m, 1H), 7.39 (t, J = 7.6 Hz, 1H), 7.54 (dd, J = 1.2 Hz, J =
8.0 Hz, 2H), 7.60−7.62 (m, 3H), 7.66 (d, J = 8.5 Hz, 2H), 7.71 (dt, J =
1.8 Hz, J = 7.9 Hz, 1H), 7.79 (s, 1H), 8.64 (d, J = 4.3 Hz, 1H); 13C
NMR (125 MHz, CDCl3): δ 87.8, 88.3, 89.4, 92.6, 111.6, 118.4, 122.6,
122.8, 123.0, 127.2, 127.8, 128.6, 128.7, 132.0, 132.1, 132.4, 135.1,
136.2, 143.0, 150.1; HRMS (FAB) calcd for C22H13N2 (M+H+):
305.1079, found 305.1086.
Diphenylacetylene:23 white powder; mp 59−61 °C; H NMR (500
1
MHz, CDCl3): δ 7.32−7.37 (m, 6H), 7.52−7.55 (m, 4H); 13C NMR
(125 MHz, CDCl3): δ 89.3, 123.2, 128.2, 128.3, 131.6.
4:7 white powder; mp 151−152 °C; 1H NMR (500 MHz, CDCl3):
δ 3.84 (s, 3H), 6.89 (d, J = 8.8 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.47
(d, J = 8.8 Hz, 2H), 7.49−7.54 (m, 5H), 7.56−7.58 (m, 3H), 7.74 (s,
1H), 7.88−7.93 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 55.3 (d, J =
4.1 Hz), 83.3 (d, J = 167.8 Hz), 86.5, 90.9, 104.4 (d, J = 29.5 Hz),
113.99, 114.04, 114.6, 120.2 (d, J = 4.1 Hz), 124.4, 128.7 (d, J = 13.4
Hz), 130.9 (d, J = 11.3 Hz), 131.6, 132.3, 132.8 (d, J = 122.4 Hz),
133.1 (d, J = 4.2 Hz), 133.4, 135.1, 159.9; 31P NMR (121 MHz,
CDCl3): δ 9.78; HRMS (FAB) calcd for C29H22O2P (M+H+):
433.1357, found 433.1351.
7: white powder; mp 174−176 °C; 1H NMR (500 MHz, CDCl3): δ
7.41 (t, J = 7.8 Hz, 1H), 7.49−7.53 (m, 4H), 7.56−7.61 (m, 6H), 7.65
(d, J = 8.5 Hz, 2H), 7.77 (s, 1H), 7.88−7.92 (m, 4H); 13C NMR (125
MHz, CDCl3): δ 83.9 (d, J = 166.4 Hz), 88.9, 91.8, 103.8 (d, J = 29.4
Hz), 111.9, 118.3, 120.6 (d, J = 3.5 Hz), 123.0, 127.5, 128.7 (d, J =
13.4 Hz), 128.87, 128.94, 130.9 (d, J = 11.3 Hz), 132.1 (d, J = 6.8 Hz),
132.4, 132.7 (d, J = 121.9 Hz), 132.8, 133.7, 135.4; 31P NMR (121
MHz, CDCl3): δ 6.82; HRMS (FAB) calcd for C29H19NOP (M+H+):
428.1204, found 428.1199.
Synthesis of 15: One-Pot Ph2P(O)-Deprotection/Stannylation/
Migata-Kosugi-Stille Coupling (Representative). To a THF solution
(5.0 mL) of 1 (302.3 mg, 1.0 mmol) were added Bu3SnOMe (353.2
mg, 316.8 μL, 1.1 mmol) and t-BuOK (56.1 mg, 0.5 mmol) at rt, and
the mixture was refluxed under nitrogen for 5 h. To the reaction
mixture were added 14 (207.1 mg, 0.95 mmol), P(t-Bu)3 (0.1 M in
THF, 330.0 μL, 0.033 mmol), and Pd2(dba)3 (13.7 mg, 0.015 mmol)
at rt, and the mixture was stirred under nitrogen at rt for 4 h. After
workup with diethyl ether (3 × 10.0 mL)/NH4Faq (10%, 10.0 mL),
the organic layer was dried over MgSO4. After filtration, the solvents
were evaporated. The crude product was subjected to column
chromatography on silica gel (hexane) to afford 15 in a pure form
(175.3 mg, 96% yield, based on iodide).
8: yellow powder; mp 215−218 °C; 1H NMR (500 MHz, CDCl3):
δ 7.47 (t, J = 7.65 Hz, 1H), 7.54 (t, J = 7.05 Hz, 2H), 7.58 (d, J = 7.95
Hz, 1H), 7.60−7.64 (m, 2H), 7.64−7.68 (m, 4H), 7.78 (d, J = 7.65
Hz, 1H), 7.96 (s, 1H), 8.04 (d, J = 8.6 Hz, 2H), 8.47 (s, 1H), 8.64 (d, J
= 8.6 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 87.3, 88.4, 92.9, 99.5,
111.7, 116.7, 118.4, 122.8, 124.2, 125.7, 126.57, 126.62, 126.8, 127.9,
128.1, 128.2, 128.8, 131.2, 131.6, 132.08, 132.12, 132.7, 134.6 (d, J =
2.5 Hz); HRMS (FAB) calcd for C31H18N (M+H+): 404.1439, found
404.1430.
15:24 colorless oil; H NMR (500 MHz, CDCl3): δ 2.37 (s, 3H),
1
7.16 (d, J = 7.9 Hz, 2H), 7.30−7.36 (m, 3H), 7.43 (d, J = 7.9 Hz, 2H),
7.52−7.54 (m, 2H); 13C NMR (75 MHz, CDCl3): δ 21.5, 88.7, 89.5,
120.1, 123.4, 128.0, 128.3, 129.1, 131.4, 131.5, 138.3.
One-Pot Me3Si-Deprotection of Trimethyl(Phenylethynyl)-
Silane/Sonogashira Coupling with Phenyl Bromide. To a THF
solution (10.0 mL) of trimethyl(phenylethynyl)silane (174.3 mg, 1.0
18:25 white powder; mp 91−92 °C; H NMR (500 MHz, CDCl3):
1
δ 3.18 (s, 1H), 7.35−7.36 (m, 3H), 7.46−7.50 (m, 4H), 7.52−7.54 (m,
E
dx.doi.org/10.1021/jo402176w | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
2H); 13C NMR (75 MHz, CDCl3): δ 78.9, 83.2, 88.8, 91.3, 121.8,
122.8, 123.7, 128.4, 128.5, 131.4, 131.6, 132.0.
Synthesis of Cyclic Pentayne 30. (i). Synthesis of 33. A mixture
of 31 (326.3 mg, 1.0 mmol), 32 (912.1 mg, 4.0 mmol), CuCl (9.9 mg,
0.1 mmol), piperidine (50.0 μL, 0.5 mmol), and toluene (10.0 mL)
was stirred in the air at 75 °C for 15 h. After workup with CH2Cl2/
NH4Claq, the organic layer was washed with brine, and dried over
MgSO4. After filtration, the solvents were evaporated. The crude
product was subjected to column chromatography on silica gel
(hexane/AcOEt, 1:1) to afford 33 in a pure form (419.8 mg, 76%
yield).
Synthesis of Yne-Diynes 24: Hay Coupling Followed by
Ph2P(O)-Deprotection/Sonogashira Coupling (Representa-
tive). (i). Hay Coupling. A mixture of 19 (326.3 mg, 1.0 mmol), 20
(329.5 μL, 3.0 mmol), CuCl (9.9 mg, 0.1 mmol), piperidine (50.0 μL,
0.5 mmol), and toluene (10 mL) was stirred in the air at 75 °C for 15
h. After workup with CH2Cl2/NH4Claq, the organic layer was washed
with brine, and dried over MgSO4. After filtration, the solvents were
evaporated. The crude product was subjected to column chromatog-
raphy on silica gel (hexane/AcOEt, 1:1) to afford 21 (319.8 mg, 75%
yield), 22 (55.3 mg, 17%), and 23 (215.4 mg, 71% (based on 20)) in
pure forms.
33: yellow powder; mp 129−131 °C; 1H NMR (500 MHz, CDCl3):
δ 7.07 (dt, J = 1.2 Hz, J = 7.6 Hz, 1H) 7.32 (t, J = 7.6 Hz, 1H), 7.36−
7.41 (m, 1H), 7.42−7.44 (m, 2H), 7.48−7.50 (m, 6H), 7.60−7.62 (m,
2H), 7.85 (d, J = 7.9 Hz 1H), 8.00−8.04 (m, 4H); 13C NMR (125
MHz, CDCl3): δ 76.9, 78.5, 80.7, 84.6, 86.9 (d, J = 166.5 Hz), 100.8,
102.6 (d, J = 29.4 Hz), 123.6 (d, J = 4.1 Hz), 125.2 (d, J = 2.1 Hz),
127.7, 128.2, 128.7 (d, J = 12.4 Hz), 129.2, 130.3, 130.4, 130.5, 131.0
(d, J = 11.4 Hz), 132.1, 132.8 (d, J = 122.0 Hz), 133.0 (d, J = 6.6 Hz),
133.9, 138.9; 31P NMR (121 MHz, CDCl3): δ 6.60; HRMS (FAB)
calcd for C30H19IOP (M+H+): 553.0218, found 553.0212.
1
21: pale-yellow powder; mp 166−167 °C; H NMR (500 MHz,
CDCl3): δ 7.33−7.41 (m, 4H), 7.49−7.54 (m, 6H), 7.56−7.59 (m,
4H), 7.74 (s, 1H), 7.87−7.92 (m, 4H); 13C NMR (125 MHz, CDCl3):
δ 73.4, 75.3, 79.6, 82.4, 83.8 (d, J = 167.0 Hz), 103.7 (d, J = 29.4 Hz),
120.5 (d, J = 4.1 Hz), 121.4, 122.7, 128.4 (d, J = 5.2 Hz), 128.7 (d, J =
13.4 Hz), 128.9 (d, J = 8.8 Hz), 129.4 (d, J = 3.1 Hz), 130.9 (d, J =
11.3 Hz), 132.4, 132.5, 132.7 (d, J = 121.9 Hz), 132.8, 134.3, 136.1;
31P NMR (121 MHz, CDCl3): δ 6.36; HRMS (FAB) calcd for
C30H20OP (M+H+): 427.1252, found 427.1259.
(ii). Synthesis of 34. A toluene solution (10.0 mL) of 33 (276.2 mg,
0.5 mmol), 31 (195.9 mg, 0.6 mmol), Pd(PPh3)4 (28.9 mg, 0.025
mmol), CuI (4.8 mg, 0.025 mmol), and diisopropylamine (0.25 mL)
was stirred under nitrogen at rt for 28 h. After workup with CH2Cl2/
NH4Claq, the combined organic layer was washed with brine and
dried over MgSO4. After filtration, the solvents were evaporated. The
crude product was subjected to column chromatography on silica gel
(AcOEt) and recrystallization from THF/hexane to afford 34 in a pure
form (292.8 mg, 78% yield).
1
22: pale-yellow powder; mp 198−201 °C; H NMR (300 MHz,
CDCl3): δ 7.38 (t, J = 7.8 Hz, 2H), 7.48−7.61 (m, 16H), 7.75 (s, 2H),
7.86−7.94 (m, 8H); 13C NMR (75 MHz, CDCl3): δ 74.8, 80.4, 83.9
(d, J = 166.0 Hz), 103.6 (d, J = 29.2 Hz), 120.6 (d, J = 4.0 Hz), 122.3,
128.7 (d, J = 13.4 Hz), 128.9, 130.9 (d, J = 11.5 Hz), 132.4 (d, J = 2.8
Hz), 132.6 (d, J = 122.2 Hz), 133.0, 134.4, 136.1; 31P NMR (121
MHz, CDCl3): δ 6.90; HRMS (FAB) calcd for C44H29O2P2 (M+H+):
651.1643, found 651.1641.
1
34: pale-yellow powder; mp 114−116 °C; H NMR (500 MHz,
23:26 white powder; mp 83−84 °C; H NMR (500 MHz, CDCl3):
1
CDCl3): δ 7.21−7.24 (m, 2H), 7.30−7.34 (m, 3H), 7.35−7.39 (m,
5H), 7.40−7.48 (m, 11H), 7.59−7.63 (m, 3H), 7.92−7.98 (m, 8H);
13C NMR (125 MHz, CDCl3): δ 77.6, 78.6, 80.4, 81.8, 86.4 (d, J =
167.9 Hz), 86.9 (d, J = 166.5 Hz), 91.9, 92.4, 102.6 (d, J = 29.4 Hz),
103.5 (d, J = 30.0 Hz), 122.1 (d, J = 3.6 Hz), 123.4 (d, J = 4.1 Hz),
123.9, 125.3 (d, J = 2.0 Hz), 126.2, 126.4 (d, J = 2.0 Hz), 128.4 (d, J =
12.4 Hz), 128.5 (d, J = 11.9 Hz), 128.59, 128.61, 128.7, 129.1, 129.2,
130.3, 130.5, 130.90 (d, J = 11.3 Hz), 130.91 (d, J = 11.4 Hz), 132.1,
132.4, 132.6, 132.7 (d, J = 122.0 Hz), 132.9, 133.0 (d, J = 122.0 Hz),
133.1, 133.2; 31P NMR (121 MHz, CDCl3): δ 7.07; HRMS (FAB)
calcd for C52H33O2P2 (M+H+): 751.1956, found 751.1957.
δ 7.32−7.39 (m, 6H), 7.52−7.54 (m, 4H); 13C NMR (500 MHz,
CDCl3): δ 73.9, 81.5, 121.8, 128.4, 129.2, 132.5.
(ii). Ph2P(O)-Deprotection/Sonogashira Coupling. To a THF
solution (10.0 mL) of 21 (213.2 mg, 0.5 mmol) was added t-BuOK
(67.3 mg, 0.6 mmol) at rt. After the mixture had been stirred under
nitrogen at rt for 2 h, 1-iodo-4-methoxybenzene (128.7 mg, 0.55
mmol), Pd(PPh3)4 (28.9 mg, 0.025 mmol), CuI (4.8 mg, 0.025
mmol), toluene (16.0 mL), and diisopropylamine (0.25 mL) were
added sequentially. The mixture was stirred under nitrogen at 80 °C
for 15 h. After workup with CH2Cl2/NH4Claq, the organic layer was
washed with brine, and dried over MgSO4. After filtration, the solvents
were evaporated. The crude product was subjected to column
chromatography on silica gel (hexane/CH2Cl2, 8:1) to give 24 in a
pure form (123.0 mg, 74% yield).
(iii). Synthesis of 30. To a THF solution (4.0 mL) of 34 (75.1 mg,
0.1 mmol) was added t-BuOK (26.9 mg, 0.24 mmol) at rt, and the
mixture was stirred under nitrogen at rt for 4 h. To the reaction
mixture were added pyridine (20.0 mL) and methanol (20.0 mL), and
the mixture was added to Cu(OAc)2(H2O) (399.3 mg, 2.0 mmol) in a
mixture of pyridine (18.5 mL), methanol (18.5 mL), and Et2O (3.1
mL) at 46 °C by a syringe over 7 h. After the mixture had been stirred
in the air overnight, the mixture was concentrated. After addition of
CH2Cl2 and 10% HCl, the mixture was stirred vigorously for 30 min.
The CH2Cl2 layer was separated, washed with Na2CO3aq solution,
water, and brine, and dried over MgSO4. After filtration, the solvents
were evaporated. The crude product was subjected to column
chromatography on silica gel (hexane/CH2Cl2, 8:1) to afford 30 in
a pure form (19.2 mg, 55% yield).
24: white powder; mp 126−128 °C; 1H NMR (500 MHz, CDCl3):
δ 3.84 (s, 3H), 6.89 (d, J = 8.8 Hz, 2H), 7.29−7.40 (m, 4H), 7.45−
7.50 (m, 4H), 7.54 (d, J = 6.7 Hz, 2H), 7.67 (s, 1H); 13C NMR (125
MHz, CDCl3): δ 55.3 (d, J = 4.1 Hz), 73.8, 74.4, 80.7, 81.8, 86.9, 90.4,
114.0, 114.1, 114.9, 121.7, 122.1, 124.2, 128.5, 129.3, 131.7, 132.0,
132.5, 133.2 (d, J = 8.3 Hz), 135.2 (d, J = 3.1 Hz), 159.8; HRMS
(FAB) calcd for C25H17O (M+H+): 333.1279, found 333.1285.
27: white powder; mp 253−255 °C; 1H NMR (500 MHz, CDCl3):
δ 7.49−7.54 (m, 6H), 7.56−7.59 (m, 4H), 7.60−7.64 (m, 4H), 7.87−
7.91 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 75.7, 76.4, 81.38,
81.44, 85.4 (d, JC−P = 166.4 Hz), 104.1 (d, JC−P = 29.4 Hz), 120.7,
120.8, 123.6 (q, JC−F = 272.0 Hz), 123.8, 125.2 (d, JC−F = 1.5 Hz),
30:18 pale-yellow powder; mp 159 °C (decomp); H NMR (500
1
125.4 (d, JC−F = 3.1 Hz), 128.7 (d, JC−P = 13.4 Hz), 130.95 (d, JC−P
=
10.8 Hz), 130.98 (q, JC−F = 32.5 Hz), 132.4, 132.5 (d, JC−P = 8.9 Hz),
132.6 (d, JC−P = 122.0 Hz), 132.8; 19F NMR (282 MHz, CDCl3): δ
−94.03; 31P NMR (121 MHz, CDCl3): δ 6.51; HRMS (FAB) calcd for
C31H19F3OP (M+H+): 495.1126, found 495.1122.
MHz, CDCl3): δ 7.21−7.29 (m, 6H), 7.32−7.35 (m, 2H), 7.40 (d, J =
7.0 Hz, 2H), 7.47 (d, J = 7.6 Hz, 2H); 13C NMR (125 MHz, CDCl3):
δ 77.7, 80.8, 81.6, 82.2, 93.0, 123.2, 126.9, 128.1, 128.5, 129.0, 129.1,
130.5, 133.7, 134.5.
29: white powder; mp 159−161 °C; 1H NMR (500 MHz, CDCl3):
δ 7.52−7.57 (m, 5H), 7.62 (q, J = 8.6 Hz, 4H), 7.83 (d, J = 7.9 Hz,
1H), 8.19−8.21 (m, 1H), 8.38 (s, 1H); 13C NMR (125 MHz, CDCl3):
ASSOCIATED CONTENT
■
δ 75.6, 76.0, 80.9, 82.0, 89.5, 91.1, 121.9, 123.2, 123.3, 123.7 (q, JC−F
=
S
* Supporting Information
272.1 Hz), 124.6, 125.4 (q, JC−F = 2.9 Hz), 126.4, 126.5, 129.4, 130.9
(q, JC−F = 32.8 Hz), 131.8, 132.6, 132.7, 137.2, 148.2; 19F NMR (282
MHz, CDCl3): δ −63.49; HRMS (FAB) calcd for C25H13F3NO2 (M
+H+): 416.0898, found 416.0902.
1H, 13C, 19F, and 31P NMR spectra for all products. This
material is available free of charge via the Internet at http://
pubs.acs.org.
F
dx.doi.org/10.1021/jo402176w | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
oxide by a yttrium complex: Lu, E.; Chen, Y.; Zhou, J.; Leng, X.
Organometallics 2012, 31, 4574.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: orita@high.ous.ac.jp.
*E-mail: otera@high.ous.ac.jp.
(11) For complete deprotection of 2, 1.2 equiv of t-BuOK were used,
although 3 would undergo also deprotection by an excess amount of t-
BuOK. In order to consume phosphoryl bromide 3 completely in the
coupling stage, 0.85 equiv of 3 was used for the Sonogashira coupling.
Otherwise the remaining phosphoryl-ethyne 2 and -bromide 3 would
prevent easy isolation of 4 because of similar Rf values of 2, 3, and 4
(Rf = 0.30 for 2, 0.32 for 3, and 0.29 for 4, hexane/AcOEt (1:1)).
(12) (a) Kosugi, M.; Fugami, K. Handbook of Organopalladium
Chemistry for Organic Synthesis, Negishi, E., Ed.; Wiley: New York,
2002. (b) Tsuji, J. Palladium Reagents and Catalysts; Wiley: Chichester,
U.K., 2004. (c) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(d) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100, 363.
(13) It was reported that Me3Si-CCR was transformed successfully to
Bu3Sn-CCR by treatment with (Bu3Sn)2O in the presence of a
catalytic amount of tetrabutylammonium fluoride (TBAF). Warner, B.
P.; Buchwald, S. L. J. Org. Chem. 1994, 59, 5822.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Organic Synthesis based on
Reaction Integration. Development of New Methods and
Creation of New Substances” (No. 2105), matching fund
subsidy for private universities from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, the Japan
Society for the Promotion of Science (JSPS) through its
“Funding Program for World-Leading Innovative R&D on
Science and Technology (FIRST Program)” and Okayama
Prefecture Industrial Promotion Foundation.
(14) When 0.3 equiv of t-BuOK and 1.1 equiv of Bu3SnOMe were
added for dephosphorylation/stannylation, TLC analysis indicated a
poor yield (<50%) of 16 after reflux for 12 h. In contrast to this, when
0.5 or 1.0 equiv of t-BuOK was used, complete transformation of 1 to
16 was observed on TLC analysis.
(15) Kiyokawa, K.; Tachikake, N.; Yasuda, M.; Baba, A. Angew.
Chem., Int. Ed. 2011, 50, 10393.
(16) For high polarity-assisted syntheses of diynes, see: (a) For (3-
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G
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