Phosphinito palladium(ii) complexes as catalysts for the synthesis of 1,3-enynes, aromatic alkynes and ynones

Article abstract of DOI:10.1039/c6ra28855c

An air-stable phosphinito palladium(ii) complex (Ph1-Phoxide) has been found to be an efficient catalyst in the formation of C-C bonds. The coupling of terminal alkynes formed gem-1,3-enynes as the only reaction products. Aromatic alkynes can be synthesized from the coupling of terminal alkynes and haloaromatic compounds (Sonogashira coupling). The phosphinito palladium(ii) complex also catalyses the coupling between acyl chlorides and terminal alkynes (Sonogashira coupling), furnishing ynones in excellent yields.

Full text of DOI:10.1039/c6ra28855c

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Phosphinito palladium(II) complexes as catalysts for
the synthesis of 1,3-enynes, aromatic alkynes and
ynones
Cite this: RSC Adv., 2017, 7, 9780
a
a
R. E. Islas, J. Cardenas, R. Gavino,a E. Garcıa-Rıos,a L. Lomas-Romerob
*
´
˜
´
´
b
*
and J. A. Morales-Serna
An air-stable phosphinito palladium(II) complex (Ph1-Phoxide) has been found to be an efficient catalyst in
the formation of C–C bonds. The coupling of terminal alkynes formed gem-1,3-enynes as the only
reaction products. Aromatic alkynes can be synthesized from the coupling of terminal alkynes and
haloaromatic compounds (Sonogashira coupling). The phosphinito palladium(II) complex also catalyses
the coupling between acyl chlorides and terminal alkynes (Sonogashira coupling), furnishing ynones in
excellent yields.
Received 30th December 2016
Accepted 30th January 2017
DOI: 10.1039/c6ra28855c
rsc.li/rsc-advances
Many phosphinito transition metal complexes have been
synthesized,2 including complexes of palladium,9 platinum,10
1. Introduction
molybdenum,5e nickel,5b gold,3c rhodium5d,6e and ruthenium.11
Applications of SPO Pd complexes in catalysis include Negishi
cross-coupling (POPd1, POPd5 and POPd7),12 conjugate addi-
tion of arylsiloxanes13 to a,b-unsaturated carbonyl compounds
(POPd1),14 Suzuki–Miyaura (POPd1, POP7 and Ph1-Phoxide)15
and Stille and Hiyama-type coupling (POPd1)16 (Fig. 1).
Secondary phosphine oxides (SPOs)1 are a class of pre-
ligands2 that are valued for their stability in air and in
moisture.3 Because of the tautomeric equilibrium between
the pentavalent phosphorus oxide 1 and the trivalent phos-
phinous acid 2 (Scheme 1),4 SPOs form hydrogen bond-
stabilized bidentate ligands.2,5 The shi of this equilibrium
in favour of either species, and therefore the formation of
transition metal complex 4, depends on metal coordination,6
the solvents used in the process7 and the phosphine substit-
uents.8 The formation of 4 can be rationalized as the coor-
dination of phosphinous acid 2 and phosphinito ligand 3,
which in turn, have their origin in two SPOs. A strong
symmetric hydrogen bridge is formed in the presence of
a metal, leading to the formation of mononuclear metal
complex 4 (Scheme 1).
SPO Pd complex 8 exhibits high catalytic activity in Heck-type
reactions as well as high stability towards moisture and air.17
Scheme 1 Tautomerization of SPOs and chelate formation.
Fig. 1 Structures of SPO Pd complexes.
a
´
´
´
Instituto de Quımica, Universidad Nacional Autonoma de Mexico, Circuito Exterior,
´
Ciudad Universitaria, Ciudad de Mexico, 04510, Mexico. E-mail: rjcp@unam.mx;
Fax: +52 55 5616 2217; Tel: +52 55 56224413
b
´
´
Departamento de Quımica, Universidad Autonoma Metropolitana-Iztapalapa, Av. San
´
Rafael Atlixco No. 186, Ciudad de Mexico, C. P. 09340, Mexico. E-mail: joseantonio.
moralesserna@xanum.uam.mx; Fax: +52 55 53189000; Tel: +52 55 5318 9593
Scheme 2 Synthesis of the SPO Pd complex Ph1-Phoxide.
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2. Results and discussion
2.1. Synthesis of 1,3-enynes
Initially, we were interested in evaluating the ligation properties
of the secondary phosphine oxides in complex 8, with the
thought that the sterically demanding groups in that complex
inuence the selectivity of the reaction. The rst reaction
examined was the coupling of two alkynes to obtain 1,3-
enynes.20,21 As shown in Table 1, the dimerization reaction of
alkynes in the presence of 5 mol% complex 8, NaOAc and
ꢀ
toluene as the solvent at 100 C affords 1,3-enynes 12a–12j in
good to excellent yield. In all cases, the use of a microwave
reactor allowed for a signicant reduction in reaction time,
from 18 h to 30 minutes, without affecting yield.
This alkyne dimerization reaction can result in three
different isomers, gem, (Z) and (E), depending on the reaction
conditions and/or the catalyst. In this case, only the gem isomer
was formed, which suggests that the presence of the sterically
bulky group on the SPO has an effect on the regioselectivity of
the reaction. The same reaction in the presence of Pd(OAc)2 and
PPh3 gives a mixture of the three isomers.
The proposed mechanism for the enyne formation is shown
in Scheme 3. The rst step involves the rupture of the Ph1-
Phoxide 8 by sodium acetate to form the catalytic precursor A.
This precursor promotes ligand exchange with the alkyne
substrates B and C–C coupling between them, generating
species C. The enyne is obtained by insertion of another alkyne
substrate molecule, regenerating the proposed catalytic species
B (Scheme 3).20
Table 1 Synthesis of 1,3-enynesa,b
Fig. 2 NMR spectra of complex 8: 1H (blue), 13C (green) and 31P (red).
The SPOs Pd complex 8 was rst synthesized by Dixon18 in 1971
and then later synthesized and crystallized by many groups.19
From a structural view point, 8 can be considered as a dimer of
complex 4. However, our synthesis of 8 was achieved by
hydrolysis of the palladium chlorodiphenylphosphine complex
10 (Scheme 2). Fig. 2 shows the NMR spectra (1H, 13C and 31P) of
complex 8, which is a homogeneous yellow solid.
Driven by our interest in the catalytic properties of SPO Pd
complex 8 in organic reactions and its application in the
synthesis of natural products,17 we report herein the results
obtained in the application of complex 8 as a catalyst for the
synthesis of 1,3-enynes, aromatic-alkynes and ynones (Sono-
gashira coupling). Additionally, we report the utility of
complex 8 in the synthesis of anemarchalconyn, a natural
product isolated from the rhizomes of Anemarrhena aspho-
deloides. To the best of our knowledge, the use of the Pd SPO
a
Reagents: alkyne 11 (1 mmol), Pd complex 8 (5% mmol), NaOAc (2
complex
8 in these reactions has not been reported
b
mmol), toluene (25 mL).
chromatographic purication.
Yield of isolated product aer
previously.
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Table 2 Synthesis of phenyl-alkynesa,b
a
Reagents: alkyne 11 (1 mmol), aryl halide 13 (1 mmol), Pd complex 8
b
(5% mmol), CuI (5% mmol), DIPEA (2 mmol), toluene (25 mL). Yield
of isolated product aer chromatographic purication.
ynones were obtained in excellent yield when the reaction was
performed in the presence of triethylamine in toluene at 100 ꢀC;
the scope of the reaction was then examined using these
optimum reaction conditions. Ynones 16a–16i were obtained in
high yield (Table 3). When the reactions were carried out with
microwave heating, similar yields were obtained in 1 h.
It is noteworthy that when the reaction was carried out with
an alkyl acyl chloride (butyryl chloride 17), the only product
observed was the b-lactone 19. This product could be explained
Scheme 3 Proposed mechanism for 1,3-enynes formation.
2.2. Synthesis of aromatic-alkynes
Following these results, we extended the use of SPO Pd complex
8 towards the coupling of terminal alkynes to aromatic rings
(Sonogashira coupling).22,23 Iodobenzene derivatives were tested
rst, as they are oen used as model substrates for a class of
reactions. The phenyl-alkynes 14a–14f were isolated in excellent
yields (90%, Table 2). The yield decreased to 80% when
substituted bromobenzenes were used. No product was
observed with chlorobenzene derivatives. When the reactions
were carried out in the absence of CuI, only alkyne dimers were
isolated. Again, the use of a microwave reactor allowed for
a signicant reduction in reaction time, from 18 h to 20
minutes, without affecting yield.
Table 3 Synthesis of ynonesa,b
The reaction also works with halogenated heterocycles. For
example, 2- and 3-halopyridines were alkynylated under the
same reaction conditions; both products were obtained in
excellent yield. Notably, alkynylation of the 3-position of pyri-
dine is known to be a difficult reaction, but this reaction
proceeds smoothly in the presence of complex 8 (90% for iodo-
and 80% for bromo-substituted aryls). The reaction also toler-
ates halothiophenes, providing the alkyne-aryl adduct in excel-
lent yield (Table 2).
2.3. Synthesis of ynones
SPO complex 8 was also applied in the synthesis of a,b-acety-
lenic carbonyl compounds (ynones), using highly reactive acyl
chlorides as substrates. Ynones are oen employed as key
intermediates in natural product synthesis.24,25 In this case, the
a
Reagents: alkyne 11 (1 mmol), acyl chloride 15 (1 mmol), Pd complex 8
(5% mmol), CuI (5% mmol), TEA (2 mmol), toluene (25 mL). b Yield of
isolated product aer chromatographic purication.
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Scheme 4 Reaction of alkyl acyl chloride in presence of TEA.
Scheme 6 Synthesis of anemarchalconyn.
intermediate 22 in 80% yield. The silyl group was removed
using basic conditions to give alkyne 14j in 90% yield. Oxidation
of p-anisyl alcohol 23, followed by activation of carbonyl group,
afforded acyl chloride 25. The key step in the synthesis was the
coupling between alkyne 14j and acyl chloride 25 catalysed by
the palladium complex 8, giving ynone 16j in 80% yield. Finally,
removal of the methyl ether protecting group furnished ane-
1
marchalconyn (16k) in 35% yield (Scheme 1). The H and 13C
Scheme 5 Proposed mechanism for aromatic-alkynes and ynones
formation.
NMR spectroscopic data matched those reported for the natural
product.27
as a result of [2 + 2] cycloaddition of ketene 18, which was
formed from alkyl acyl chloride 17 in presence of triethtylamine
(Scheme 4).26
3. Conclusions
In conclusion, we have demonstrated that an air-stable palla-
dium(II) phosphinito complex 8 (Ph1-Phoxide), was able to
catalyse the regioselective dimerization of alkynes to obtain
gem-1,3-enynes, the coupling of haloaromatics and acyl chlo-
rides and the formation of ynones from alkynes and acyl chlo-
rides. Furthermore, the methodology was applied to the
synthesis of anemarchalconyn, an aromatic ynone isolated from
the rhizomes of Anemarrhena asphodeloides.
The mechanism involved in both ynones and phenyl-alkynes
synthesis is proposed as follows: the formation of the catalytic
species D is performed in situ by rupture of the dimeric complex
8. Then species E is formed by oxidative addition of an acyl
chloride or an aryl halide. A trasmetallation reaction between
the complex E and the copper acetylide generates species F.
Finally, the products are formed by reductive elimination,
which regenerates the palladium catalyst (Scheme 5).22
4. Experimental section
2.4. Synthesis of anemarchalconyn
4.1. General methods
With optimized conditions for ynone formation and aryl alky-
nylation, we decided to apply our methodology to synthesis of All reactions were conducted under a dried argon stream. The
a natural product that would utilize SPO complex 8 in two reagents were purchased from Aldrich Chemical Co, St. Louis
separate steps. Anemarchalconyn (16k, Scheme 6) was isolated Missouri, United States, and used without further purication
from the rhizomes of Anemarrhena asphodeloides and has unless stated otherwise. Yields refer to the chromatographically
inhibitory effects on the adipogenic differentiation of pre- and spectroscopically (1H and 13C) homogeneous materials,
adipocyte 3T3-L1 cells, with an IC50 value of 5.3 mM.27 The unless otherwise stated. All glassware was ame-dried before
synthesis began with the methylation of 4-iodophenol 20, fol- use. The reactions were monitored by TLC carried out on
lowed by the addition of ethynyltrimethylsilane to 4-iodoanisole 0.25 mm E. Merck silica gel plates. The developed TLC plates
21 in the presence of palladium complex 8, generating were visualised under a short-wave UV lamp or by heating aer
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they were dipped in Ce(SO4)2. Flash column chromatography atmosphere. Aer that time, the reaction mixture was allowed to
(FCC) was performed using silica gel (230–400) and employed cool to room temperature, before being quenched with satu-
a solvent polarity correlated with the TLC mobility. NMR rated aqueous ammonium chloride solution (15 mL). The
experiments were conducted on a Varian 300 MHz instrument mixture was extracted with ethyl acetate (2 ꢁ 15 mL). The
in CDCl3 (99.9% D) as the solvent; the chemical shis (d) were combined organic layers were washed successively with 10%
referenced to CDCl3 (7.26 ppm 1H, 77.00 ppm 13C) or Me4Si citric acid solution (2 ꢁ 20 mL), 10% NaHCO3 solution (2 ꢁ 20
(0.00 ppm). The chemical shis are reported with respect to the mL) and brine (3 ꢁ 20 mL), dried over magnesium sulphate,
solvent peak in parts per million (ppm). Microwave irradiation ltered and concentrated under reduced pressure. The result-
experiments were performed on a Monowave 450-Anton Paar, ing residue was puried by ash column chromatography on
using standard sealed microwave glass vials.
silica gel using hexane–EtOAc.
4.2. General procedures
4.3. Characterization data
1
4.2.1. Synthesis of complex Ph1-Phoxide 8. A solution of
4.3.1. 12a28 (92% yield). H NMR (300 MHz, CDCl3): d 5.20
Ph2PCl (0.75 mL 4.04 mmol) in anhydrous THF (5 mL) was (d, J ¼ 1.8 Hz, 1H), 5.12 (d, J ¼ 1.8 Hz, 1H), 2.29 (t, J ¼ 6.9 Hz,
added dropwise whilst stirring to a solution of PdCl2(C6H5CN)2 2H), 2.21 (t, J ¼ 7.2 Hz, 2H), 1.59–1.48 (m, 4H), 1.36–1.29 (m,
(0.76 g, 2 mmol) 9 in anhydrous THF (10 mL) placed in 8H), 0.90 (t, J ¼ 7.2 Hz, 3H), 0.89 (t, J ¼ 7.2 Hz, 3H); 13C NMR (75
a Schlenk ask at room temperature. When the complete MHz, CDCl3): d 132.4, 119.3, 90.1, 81, 37.5, 31.1, 31, 28.5, 27.8,
formation of the dichlorophosphane complex 10 was conrmed 22.5, 22.2, 19.3, 14. Anal. calcd for C14H24: C, 87.42; H, 12.58.
by 31P NMR spectroscopy (d ¼ 87 ppm), 0.5 mL of H2O was Found: C, 87.40; H, 12.50.
added to the reaction mixture, which was stirred at room
4.3.2. 12b28 (91% yield). 1H NMR (300 MHz, CDCl3): d 5.20
temperature during 48 h. Aer that time, the solvent was (d, J ¼ 1.8 Hz, 1H), 5.12 (d, J ¼ 1.8 Hz, 1H), 2.29 (t, J ¼ 6.9 Hz,
removed under reduced pressure to give the complex 8 as 2H), 2.21 (t, J ¼ 7.2 Hz, 2H), 1.59–1.48 (m, 4H), 1.36–1.29 (m,
a yellow crystalline powder (92% yield). 1H NMR (300 MHz, 12H), 0.90 (t, J ¼ 7.2 Hz, 3H), 0.89 (t, J ¼ 7.2 Hz, 3H); 13C NMR
CDCl3): d ¼ 7.7–7.2 (m, 40H); 31P NMR (121.4 MHz, CDCl3): d ¼ (75 MHz, CDCl3): d 132.4, 119.3, 90.1, 81, 37.5, 31.1, 31, 29.1,
78.6.
28.8, 28.1, 27.7, 22.5, 22.3, 19.3, 14. Anal. calcd for C16H28: C,
4.2.2. General procedure for the synthesis of gem-1,3- 87.19; H, 12.81. Found: C, 87.16; H, 12.79.
enynes. A solution of alkyne 11 (1 mmol), NaOAc (2 mmol) and
4.3.3. 12c29 (77% yield). 1H NMR (300 MHz, CDCl3): d 7.75–
catalyst 8 (5% mmol) in anhydrous toluene (25 mL) was heated 7.70 (m, 2H), 7.56–7.53 (m, 2H), 7.42–7.32 (m, 6H), 6.01 (d, J ¼
for 18 h at 100 ꢀC in a silicon oil bath, using a condenser system. 1.0 Hz, 1H), 5.79 (d, J ¼ 1.0 Hz, 1H); 13C NMR (75.5 MHz,
Then, the mixture was cooled to room temperature, diluted with CDCl3): d 137.3, 131.7, 130.6, 128.4, 128.3, 126.1, 123.1, 120.6,
EtOAc (25 mL), washed with brine (3 ꢁ 25 mL), dried over 90.8, 88.6. Anal. calcd for C16H12: C, 94.08; H, 5.92. Found: C,
magnesium sulphate, ltered and concentrated under reduced 94.01; H, 5.88.
pressure. The resulting residue was puried by ash column
chromatography on silica gel using hexane–EtOAc.
4.2.3. General procedure for the synthesis of aromatic- 2H), 7.15 (d, J ¼ 8.4 Hz, 2H), 5.91 (d, J ¼ 1.0 Hz, 1H), 5.68 (d, J ¼
alkynes. A solution of aryl halide 13 (1 mmol), DIPEA (2 mmol), 0.9 Hz, 1H), 2.36 (s, 6H); 13C NMR (75 MHz, CDCl3): d 138.4,
CuI (5% mmol) and catalyst 8 (5% mmol) in anhydrous toluene 138.1, 134.5, 131.5, 130.5, 129.1, 129, 125.9, 120, 119.4, 90.7, 88,
(15 mL) was placed in a round bottom ask and evacuated/ 21.4, 21. Anal. calcd for C18H16: C, 93.06; H, 6.94. Found: C,
4.3.4. 12d30 (85% yield). 1H NMR (300 MHz, CDCl3): d 7.61
(d, J ¼ 8.0 Hz, 2H), 7.42 (d, J ¼ 8.0 Hz, 2H), 7.17 (d, J ¼ 8.4 Hz,
backlled with N2 three times. Then, an N2-purged solution of 93.01; H, 6.90.
1
alkyne 11 (1 mmol) in anhydrous toluene (10 mL) was added.
4.3.5. 12e30 (92% yield). H NMR (300 MHz, CDCl3): d 7.39
ꢀ
The reaction mixture was stirred and heated at 80 C for 18 h (dd, J ¼ 7.6, 2.0 Hz, 1H), 7.33 (dd, J ¼ 7.6, 2.0 Hz, 1H), 7.23–7.17
under N2 atmosphere. Aer that time, the reaction mixture was (m, 5H), 7.13–7.09 (m, 1H), 5.86 (d, J ¼ 2.0 Hz, 1H), 5.53 (d, J ¼
allowed to cool to room temperature, diluted with EtOAc (25 2.0 Hz, 1H), 2.49 (s, 3H), 2.41 (s, 3H); 13C NMR (75 MHz, CDCl3):
mL), washed successively with 10% citric acid solution (2 ꢁ 20 d 140.1, 135.5, 132, 131.8, 130.4, 129.4, 128.8, 128.3, 127.9,
mL), 10% NaHCO3 solution (2 ꢁ 20 mL) and brine (3 ꢁ 20 mL), 125.9, 125.5, 125, 123, 93.3, 89.6, 20.7, 20.3. Anal. calcd for
dried over magnesium sulphate, ltered and concentrated
under reduced pressure. The resulting residue was puried by
C
18H16: C, 93.06; H, 6.94. Found: C, 93.02; H, 6.91.
4.3.6. 12f30 (83% yield). 1H NMR (300 MHz, CDCl3): d 7.52–
ash column chromatography on silica gel using hexane– 7.51 (m, 2H), 7.35–7.32 (m, 2H), 7.28–7.21 (m, 2H), 7.15–7.13
EtOAc.
(m, 2H), 5.95 (d, J ¼ 1.0 Hz, 1H), 5.73 (d, J ¼ 1.0 Hz, 1H), 2.38 (s,
4.2.4. General procedure for the synthesis of ynones. A 3H), 2.34 (s, 3H); 13C NMR (75 MHz, CDCl3): d 138, 137.9, 137.3,
solution of acyl chloride 15 (1 mmol), TEA (2 mmol), CuI (5% 132.2, 130.7, 129.3, 129.1, 128.7, 128.3, 128.2, 126.8, 123.3, 123,
mmol) and catalyst 8 (5% mmol) in anhydrous toluene (15 mL) 120.4, 90.8, 88.4, 21.5, 21.2. Anal. calcd for C18H16: C, 93.06; H,
was placed in a round bottom ask and evacuated/backlled 6.94. Found: C, 93.03; H, 6.92.
1
with N2 three times. Then, an N2-purged solution of alkyne 11
4.3.7. 12g30 (81% yield). H NMR (300 MHz, CDCl3): d 7.71
(1 mmol) in anhydrous toluene (10 mL) was added. The reaction (d, J ¼ 7.6 Hz, 1H), 7.43 (d, J ¼ 7.6 Hz, 1H), 7.29–7.25 (m, 2H),
mixture was stirred and heated at 80 ꢀC for 18 h under N2 6.99–6.85 (m, 4H), 6.09 (brs, 1H), 5.95 (brs, 1H), 3.88 (s, 6H); 13
C
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NMR (75 MHz, CDCl3): d 160, 157.2, 133.4, 130.5, 129.5, 129, 125.2, 117, 115.6, 91, 89.7, 56.9; anal. calcd for C15H12O: C,
128, 127.1, 125.4, 120.5, 120.4, 112.7, 111.4, 110.7, 94.1, 85.2, 86.51; H, 5.81. Found: C, 86.48; H, 5.77.
55.8, 55.6. Anal. calcd for C18H16O2: C, 81.79; H, 6.10. Found: C,
81.76; H, 6.08.
4.3.16. 14f34 (80% for bromo- and 91% for iodo-substituted
aryls). 1H NMR (300 MHz, CDCl3): d 7.59–7.55 (m, 2H), 7.43–7.37
4.3.8. 12h30 (85% yield). 1H NMR (300 MHz, CDCl3): d 7.65 (m, 4H), 7.21–7.15 (m, 1H), 6.79–6.75 (m, 2H), 4.29 (brs, 2H); 13
C
(d, J ¼ 8.4 Hz, 2H), 7.46 (d, J ¼ 8.8 Hz, 2H), 6.89 (d, J ¼ 8.4 Hz, NMR (75 MHz, CDCl3): d 148.1, 132.6, 131.9, 130.2, 128.8, 128.6,
2H), 6.86 (d, J ¼ 8.8 Hz, 2H), 5.83 (d, J ¼ 0.7 Hz, 1H), 5.61 (d, J ¼ 123.7, 118.5, 114.8, 108.4, 95.1, 86.3; anal. calcd for C14H11N: C,
0.7 Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H); 13C NMR (75 MHz, CDCl3): 87.01; H, 5.74; N, 7.25. Found: C, 86.99; H, 5.72; N, 7.23.
d 159.7, 159.6, 133.1, 130.1, 127.3, 118.1, 115.3, 114, 113.7, 90.5,
4.3.17. 14g35 (83% for bromo- and 91% for iodo-substituted
1
87.5, 55.3, 55.2. Anal. calcd for C18H16O2: C, 81.79; H, 6.10. aryls). H NMR (300 MHz, CDCl3): d 8.59 (brd, J ¼ 4.1 Hz, 1H);
Found: C, 81.75; H, 6.07.
7.64 (ddd, J ¼ 7.7, 7.7, 1.8 Hz, 1H), 7.60–7.54 (m, 2H), 7.50 (d, J ¼
1
4.3.9. 12i30 (82% yield). H NMR (300 MHz, CDCl3): d 7.64 7.8 Hz, 1H), 7.37–7.30 (m, 3H), 7.23–7.17 (m, 1H); 13C NMR (75
(d, J ¼ 8.4 Hz, 2H), 7.45 (d, J ¼ 8.4 Hz, 2H), 6.88 (d, J ¼ 8.4 Hz, MHz, CDCl3): d 149.7, 143.1, 135.9, 131.7, 128.7, 128.1, 126.9,
2H), 6.85 (d, J ¼ 8.4 Hz, 2H), 5.82 (brs, 1H), 5.60 (brs, 1H), 4.07– 122.5, 122, 89, 88.4. Anal. calcd for C13H9N: C, 87.12; H, 5.06; N,
4.01 (m, 4H), 1.41 (t, J ¼ 6.4 Hz, 6H); 13C NMR (75 MHz, CDCl3): 7.82. Found: C, 87.08; H, 5.03; N, 7.80.
d 159.1, 159, 133.1, 130.1, 129.9, 127.3, 117.9, 115.1, 114.5,
4.3.18. 14h36 (80% for bromo- and 90% for iodo-
114.2, 90.6, 87.5, 63.5, 63.4, 14.8, 14.7 Anal. calcd for C20H20O2: substituted aryls). 1H NMR (300 MHz, CDCl3): d 8.77 (brs,
C, 82.16; H, 6.89. Found: C, 82.14; H, 6.86.
1H), 8.55 (dd, J ¼ 6.4, 1.4 Hz, 1H), 7.80 (td, J ¼ 8.0, 2.4 Hz, 1H),
4.3.10. 12j30 (76% yield). 1H NMR (300 MHz, CDCl3): d 7.65 7.56–7.54 (m, 2H), 7.38–7.36 (m, 3H), 7.30–7.26 (m, 1H); 13C
(d, J ¼ 8.4 Hz, 2H), 7.46–7.32 (m, 12H), 6.96 (d, J ¼ 8.4 Hz, 2H), NMR (75 MHz, CDCl3): d 152.1, 148.4, 138.3, 131.6, 128.7, 128.3,
6.94 (d, J ¼ 8.8 Hz, 2H), 5.83 (brs, 1H), 5.61 (brs, 1H), 5.08 (brs, 122.9, 122.4, 120.3, 92.5, 85.8, anal. calcd for C13H9N: C, 87.12;
2H), 5.07 (brs, 2H); 13C NMR (75 MHz, CDCl3): d 158.9, 158, H, 5.06; N, 7.82. Found: C, 87.09; H, 5.04; N, 7.80.
136.9, 136.6, 133.1, 130.3, 130, 128.6, 128.6, 128.1, 128, 127.5,
4.3.19. 14i37 (80% for bromo- and 92% for iodo-substituted
127.4, 127.3, 118.2, 115.5, 114.9, 114.6, 90.5, 87.6, 70, 70; Anal. aryls). 1H NMR (300 MHz, CDCl3): d 7.52–7.50 (m, 2H), 7.35–7.32
calcd for C30H24O2: C, 86.51; H, 5.81. Found: C, 86.46; H, 5.77. (m, 3H), 7.29–7.28 (m, 2H), 7.01 (dd, J ¼ 5.0, 3.6 Hz, 1H); 13C
4.3.11. 14a31 (82% for bromo- and 91% for iodo-substituted NMR (75 MHz, CDCl3): d 132.3, 131.8, 128.8, 128.7, 127.6, 127.5,
1
aryls). H NMR (300 MHz, CDCl3): d 7.90 (dd, J ¼ 8.3, 1.2 Hz, 123.7, 123.3, 93.4, 83. Anal. calcd for C12H8S: C, 78.22; H, 4.38; S,
1H), 7.51 (dd, J ¼ 7.8, 1.6 Hz, 1H), 7.46 (ddd, J ¼ 7.8, 7.7, 1.2 Hz, 17.40. Found: C, 78.20; H, 4.35; S, 17.38.
1H), 7.33 (ddd, J ¼ 8.3, 7.7, 1.6 Hz, 1H), 2.42 (t, J ¼ 7.2 Hz, 2H),
4.3.20. 16a38 (93% yield). 1H NMR (300 MHz, CDCl3): d 8.13
(d, J ¼ 8.25 Hz, 2H), 7.59 (td, J ¼ 7.6, 1.1 Hz, 1H), 7.4 (m, 2H),
1.63–1.56 (m, 2H), 1.45–1.28 (m, 4H), 0.89 (t, J ¼ 7.2 Hz, 3H); 13
C
NMR (75 MHz, CDCl3): d 150, 134.6, 132.3, 127.7, 124.2, 119.3, 2.49 (t, J ¼ 7.1 Hz, 2H), 1.68 (m, 2H), 1.34–1.48 (m, 4H), 0.93 (t, J
99.2, 75.9, 30.9, 27.9, 22.1, 19.7, 13.9. Anal. calcd for C13H15NO2: ¼ 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 178.2, 136.9, 133.8,
C, 71.87; H, 6.96; N, 6.45. Found: C, 71.82; H, 6.91; N, 6.39.
129.5, 128.4, 96.8, 79.6, 31, 27.4, 22, 19.1, 13.8. Anal. calcd for
4.3.12. 14b32 (83% for bromo- and 92% for iodo-
C
14H16O: C, 83.96; H, 8.05. Found: C, 83.94; H, 8.02.
1
substituted aryls). H NMR (300 MHz, CDCl3): d 7.43–7.41 (m,
4.3.21. 16b39 (81% yield). 1H NMR (300 MHz, CDCl3): d 8.08
2H), 7.30–7.29 (m, 3H), 2.43 (t, J ¼ 7.2 Hz, 2H), 1.67–1.60 (m, (d, J ¼ 8.6 Hz, 2H), 7.45 (d, J ¼ 8.6 Hz, 2H), 2.50 (t, J ¼ 7.1 Hz,
2H), 1.48–1.37 (m, 4H), 0.95 (t, J ¼ 7.2 Hz, 3H); 13C NMR (75 2H), 1.68 (m, 2H), 1.34–1.47 (m, 4H), 0.93 (t, J ¼ 7.2 Hz, 3H); 13
C
MHz, CDCl3): d ppm 133.1, 129.8, 129.1, 125.6, 92.1, 82.1, 32.7, NMR (75 MHz, CDCl3): d 177, 140.5, 135.5, 131, 128.9, 97.6, 79.5,
30.1, 23.9, 21, 15.7; anal. calcd for C13H16: C, 90.64; H, 9.36. 31.2, 27.6, 22.2, 19.3, 14. Anal. calcd for C14H15ClO: C, 71.4; H,
Found: C, 90.61; H, 9.32.
6.44. Found: C, 71.3; H, 6.42.
4.3.13. 14c33 (81% for bromo- and 90% for iodo-substituted
4.3.22. 16c39 (82% yield). 1H NMR (300 MHz, CDCl3): d 8.10
1
aryls). H NMR (300 MHz, CDCl3): d 7.99 (dd, J ¼ 8.2, 1.4 Hz, (d, J ¼ 8.9 Hz, 2H), 6.94 (d, J ¼ 8.9 Hz, 2H), 3.88 (s, 3H), 2.48 (t, J
1H), 7.64 (dd, J ¼ 7.8, 1.4 Hz, 1H), 7.54 (ddd, J ¼ 7.8, 7.8, 1.4 Hz, ¼ 7.1 Hz, 2H), 1.67 (m, 2H), 1.34–1.47 (m, 4H), 0.93 (t, J ¼
1H), 7.46–7.41 (m, 1H), 0.27 (s, 9H); 13C NMR (75 MHz, CDCl3): 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d 177, 164.4, 132, 130.4,
d ppm 150.3, 135.2, 132.7, 128.9, 124.5, 118.5, 103.8, 99.4, ꢂ0.3; 113.8, 95.1, 79.7, 55.6, 31.2, 27.6, 22.2, 19.2, 14. Anal. calcd for
anal. calcd for C11H13NO2Si: C, 60.24; H, 5.97; N, 6.39. Found: C,
60.21; H, 5.95; N, 6.37.
C
15H18O2: C, 78.23; H, 7.88. Found: C, 78.21; H, 7.87.
4.3.23. 16d38 (85% yield). 1H NMR (300 MHz, CDCl3): d 8.19
4.3.14. 14d32 (80% for bromo- and 92% for iodo- (dd, J ¼ 8.0, 1.6 Hz, 2H), 7.63 (d, J ¼ 8.0 Hz, 2H), 7.57 (t, J ¼
substituted aryls). 1H NMR (300 MHz, CDCl3): d 7.53 (d, J ¼ 8.0 Hz, 1H), 7.48–7.34 (m, 5H); 13C NMR (75 MHz, CDCl3):
7.6, 2H), 7.46 (d, J ¼ 8.4 Hz, 2H), 7.36–7.32 (m, 5H); 13C NMR (75 d 178.2, 137, 134.4, 133.3, 131.1, 129.8, 129, 128.9, 120.2, 93.4,
MHz, CDCl3): d 135.9, 134.5, 133.3, 130.3, 130.1, 130, 124.6, 87.2. Anal. calcd for C15H10O: C, 87.36; H, 4.84. Found: C, 87.35;
123.4, 91.9, 89.9; anal. calcd for C14H9Cl: C, 79.06; H, 4.27. H, 4.83.
Found: C, 79.02; H, 4.23.
4.3.24. 16e38 (82% yield). 1H NMR (300 MHz, CDCl3): d 8.09
4.3.15. 14e32 (81% for bromo- and 90% for iodo-substituted (d, J ¼ 8.8 Hz, 2H), 7.56 (d, J ¼ 7.6 Hz, 2H), 7.32–7.28 (m, 3H),
aryls). 1H NMR (300 MHz, CDCl3): d 7.52–7.50 (m, 2H), 7.47 (d, J 6.87 (d, J ¼ 8.8 Hz, 2H), 3.76 (s, 3H); 13C NMR (75 MHz, CDCl3):
¼ 8.8 Hz, 2H), 7.36–7.32 (m, 3H), 6.88 (d, J ¼ 8.8 Hz, 2H), 3.83 (s, d 176.6, 164.5, 132.9, 131.9, 130.6, 130.2, 128.6, 120.2, 113.8,
3H); 13C NMR (75 MHz, CDCl3): d 161.2, 134.7, 133.1, 130, 129.6,
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92.3, 86.9, 55.5. Anal. calcd for C16H12O2: C, 81.34; H, 5.12. Aer that time, the reaction mixture was allowed to cool to room
Found: C, 81.32; H, 5.11. temperature, diluted with EtOAc (25 mL), washed successively
4.3.25. 16f38 (80% yield). 1H NMR (300 MHz, CDCl3): d 8.07 with 10% citric acid solution (2 ꢁ 20 mL), 10% NaHCO3 solu-
(ddd, J ¼ 7.8, 1.8, 0.3 Hz, 1H), 7.65–7.61 (m, 2H), 7.57–7.51 (m, tion (2 ꢁ 20 mL) and brine (3 ꢁ 20 mL), dried over magnesium
1H), 7.48–7.36 (m, 3H), 7.08–7.00 (m, 2H), 3.04 (s, 3H); 13C NMR sulphate, ltered and concentrated under reduced pressure.
(75 MHz, CDCl3): d 176.7, 159.8, 134.9, 132.9, 132.5, 130.4, The resulting residue was puried by ash column chroma-
128.5, 126.7, 120.6, 120.2, 112.1, 91.5, 89.1, 55.9. Anal. calcd for tography on silica gel using hexane–EtOAc, to give 592 mg of 22
1
C
16H12O2: C, 81.34; H, 5.12. Found: C, 81.31; H, 5.09.
(80% yield). H NMR (300 MHz, CDCl3): d 7.41 (d, J ¼ 8.4 Hz,
4.3.26. 16g38 (83% yield). 1H NMR (300 MHz, CDCl3): d 8.16 2H), 6.82 (d, J ¼ 8.4 Hz, 2H), 3.81 (s, 3H), 0.25 (s, 9H); 13C NMR
(d, J ¼ 8.8 Hz, 2H), 7.70 (d, J ¼ 7.9 Hz, 2H), 7.51–7.40 (m, 5H); (75 MHz, CDCl3): d 159.7, 133.4, 115.2, 113.7, 105.1, 92.4, 55.2,
13C NMR (75 MHz, CDCl3): d 176.4, 140.6, 135.3, 132.9, 130.8, 0.06. Anal. calcd for C12H16OSi: C, 70.53; H, 7.89. Found: C,
130.7, 128.8, 128.6, 119.8, 93.5, 86.5. Anal. calcd for C15H9ClO: 70.51; H, 7.87.
C, 74.85; H, 3.77. Found: C, 74.86; H, 3.78.
4.4.3. 1-Ethynyl-4-methoxybenzene 14j. K2CO3 (45 mg, 0.33
4.3.27. 16h40 (80% yield). 1H NMR (CDCl3, 300 MHz): mmol) and the mixture MeOH–CHCl3 (10 mL, 1 : 1) were added
d 7.71–7.64 (m, 3H), 7.48–7.39 (m, 4H), 6.62 (dd, J ¼ 3.8, 1.8 Hz, to ((4-methoxyphenyl)ethynyl)trimethylsilane 22 (200 mg, 0.98
1H); 13C NMR (CDCl3, 75.5 MHz): d 164.7, 153.2, 147.9, 132.9, mmol) in a 50 mL recovery ask. The suspension was stirred at
130.8, 128.6, 120.8, 119.9, 112.6, 91.8, 86.2. Anal. calcd for room temperature for 18 h. Aer that time, the reaction mixture
C
13H8O2: C, 79.58; H, 4.11. Found: C, 79.55; H, 4.8.
was diluted with EtOAc (25 mL), washed successively with 10%
4.3.28. 16i39 (80% yield). 1H NMR (300 MHz, CDCl3): d 7.88 citric acid solution (2 ꢁ 20 mL) and brine (3 ꢁ 20 mL), dried
(dd, J ¼ 3.8, 1.0 Hz, 1H), 7.67 (dd, J ¼ 4.9, 1.0 Hz, 1H), 7.14 (t, J ¼ over magnesium sulphate, ltered and concentrated under
3.9 Hz, 1H), 2.46 (t, J ¼ 7.1 Hz, 2H), 1.66 (m, 2H), 1.46–1.33 (m, reduced pressure. The resulting residue was puried by ash
4H), 0.92 (t, J ¼ 7.2 Hz, 3H); 13C NMR (75.5 MHz, CDCl3): column chromatography on silica gel using hexane–EtOAc, to
d 170.2, 145.2, 135, 128.3, 95.6, 79.4, 31.2, 27.5, 22.2, 19.2, 14. give 116 mg of 14j (90% yield). 1H NMR (300 MHz, CDCl3): d 7.46
Anal. calcd for C12H14OS: C, 69.86; H, 6.84; S, 15.54. Found: C, (d, J ¼ 8.4 Hz, 2H), 6.87 (d, J ¼ 8.4 Hz, 2H), 3.84 (s, 3H), 3.02 (s,
69.83; H, 6.81; S, 15.52.
1H); 13C NMR (75.5 MHz, CDCl3): d 159.9, 133.5, 114.2, 113.9,
93.9, 83.6, 55.3. Anal. calcd for C9H8O: C, 81.79; H, 6.10. Found:
C, 81.76; H, 6.08.
4.4. Synthesis of anemarchalconyn
4.4.4. 4-Methoxybenzoic acid 24. A solution of (4-methox-
4.4.1. 1-Iodo-4-methoxybenzene 21. p-Iodophenol 20 (1 g, yphenyl)methanol 23 (600 mg, 4.41 mmol) in 10 mL of acetone
4.5 mmol) and NaOH (800 mg, 20 mmol) were mixed and was added to a 100 mL three-necked ask tted with a long-
ground in a mortar to have a ne powder. Then, the mixture was stem dropping funnel and a thermometer. The agitated solu-
placed in a three-necked round-bottomed ask (100 mL) tted tion was cooled in a water bath to about 20ꢀ. The Jones reagent
with an efficient stirrer, separatory funnel and reux condenser. (CrO3/H2SO4) was added from the dropping funnel. The rate of
The mixture was cooled at 0 ꢀC. There was then added through addition was adjusted so that the temperature of the reaction
the separatory funnel, with stirring, dimethyl sulfate (252 mg, mixture does not rise above 25ꢀ. Aer the complete conversion
4.5 mmol). This addition at 0 ꢀC requires one hour. The mixture of starting material, monitored by thin layer chromatographic,
ꢀ
was then heated for 18 h at 60 C. Aer that time, the reaction the reaction mixture was allowed to cool to room temperature,
mixture was allowed to cool to room temperature, before being before being quenched with isopropanol (10 mL). Then, the
quenched with H2O (25 mL). The mixture was extracted with reaction mixture was ltrated to eliminate chromium salts. The
ethyl acetate (2 ꢁ 20 mL). The combined organic layers were resulting residue was puried by ash column chromatography
washed successively with 10% citric acid solution (2 ꢁ 20 mL) on silica gel using hexane–EtOAc, to give 603 mg of 24 (90%
and brine (3 ꢁ 20 mL), dried over magnesium sulphate, ltered yield). 1H NMR (300 MHz, DMSO-d6): d 7.90 (d, J ¼ 8.4 Hz, 2H),
and concentrated under reduced pressure. A with solid was 7.00 (d, J ¼ 8.4 Hz, 2H), 3.81 (s, 3H); 13C NMR (75 MHz, DMSO-
obtained aer the recrystallization of the residue with hexane– d6): d 169.3, 165.8, 131.3, 122.5, 114.2, 55.8. Anal. calcd for
EtOAc (947 mg, 90% yield). 1H NMR (300 MHz, CDCl3): d 7.55 (d, C8H8O3: C, 63.15; H, 5.30. Found: C, 63.13; H, 5.28.
J ¼ 8.4 Hz, 2H), 6.68 (d, J ¼ 8.4 Hz, 2H), 3.78 (s, 3H); 13C NMR (75
4.4.5. 4-Methoxybenzoyl chloride 25. To stirred solution of
MHz, CDCl3): d 159.7, 138.4, 116.6, 82.9, 55.5. Anal. calcd for carboxylic acid 24 (200 mg, 1.36 mmol) in toluene (10 mL),
C7H7IO: C, 35.92; H, 3.01. Found: C, 35.91; H, 3.00.
SOCl2 (810 mg, 6.8 mmol) was added at room temperature.
4.4.2. ((4-Methoxyphenyl)ethynyl)trimethylsilane 22.
A
Then, the reaction mixture was stirred and heated at reux
solution of 1-iodo-4-methoxybenzene 21 (850 mg, 3.63 mmol), temperature for 6 h under N2 atmosphere. Aer that time, the
DIPEA (480 mg, 3.72 mmol), CuI (34 mg, 0.18 mmol, 5% mmol) reaction mixture was cooled to room temperature and concen-
and catalyst 8 (196 mg, 0.18 mmol, 5% mmol) in anhydrous trated under reduced pressure. The resulting residue was used
toluene (20 mL) was placed in a round bottom ask and in next reaction without further purication.
evacuated/backlled with N2 three times. Then, an N2-purged
4.4.6. 1,3-Bis(4-methoxyphenyl)prop-2-yn-1one 16j. A solu-
solution of ethynyltrimethylsilane (365 mg, 3.72 mmol) in tion of acyl chloride 25 (150 mg, 0.87 mmol), CuI (8 mg,
anhydrous toluene (10 mL) was added. The reaction mixture 0.043 mmol, 5% mmol) and catalyst 8 (47 mg, 0.043 mmol, 5%
ꢀ
was stirred and heated at 80 C for 18 h under N2 atmosphere. mmol) in anhydrous TEA (15 mL) was placed in a round bottom
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ask and evacuated/backlled with N2 three times. Then, an N2-
purged solution of alkyne 14j (92 mg, 0.7 mmol) in anhydrous
TEA (10 mL) was added. The reaction mixture was stirred and
A. M. Chapman, G. Buntkowsky, T. Gutmann,
P. B. Groszewicz and P. W. N. M. van Leeuwen, J. Am.
Chem. Soc., 2015, 137, 7718; (d) E. Raer, T. Gutmann,
ꢀ
¨
heated at 80 C for 18 h under N2 atmosphere. Aer that time,
F. Low, G. Buntkowsky, K. Philippot, B. Chaudret and
the reaction mixture was allowed to cool to room temperature,
before being quenched with saturated aqueous ammonium
chloride solution (15 mL). The mixture was extracted with ethyl
acetate (2 ꢁ 15 mL). The combined organic layers were washed
successively with 10% citric acid solution (2 ꢁ 20 mL), 10%
NaHCO3 solution (2 ꢁ 20 mL) and brine (3 ꢁ 20 mL), dried over
magnesium sulphate, ltered and concentrated under reduced
pressure. The resulting residue was puried by ash column
chromatography on silica gel using hexane–EtOAc. To give
149 mg of 16j (80% yield). 1H NMR (300 MHz, CDCl3): d 8.19 (d, J
¼ 8.7 Hz, 2H), 7.63 (d, J ¼ 8.7 Hz, 2H), 6.99 (d, J ¼ 8.7 Hz, 2H),
6.93 (d, J ¼ 8.7 Hz, 2H), 3.90 (s, 3H), 3.86 (s, 3H); 13C NMR (75
MHz, CDCl3): d 176.7, 164.3, 161.6, 134.9, 131.9, 130.5, 114.4,
113.8, 112.2, 93.4, 86.8, 55.6, 55.4. Anal. calcd for C17H14O3: C,
76.68; H, 5.30. Found: C, 76.66; H, 5.28.
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4.4.7. Anemarchalconyn 16k.27 A solution of 16j (145 mg,
0.54 mmol) in 5 mL of DMF was placed in a round bottom.
Then, iodocyclohexane (1.3 mL, 10.0 mmol) was added.41 The
reaction system was equipped with reux condenser under
argon. The reaction mixture was stirred and heated at 90 ꢀC for
18 h under N2 atmosphere. Aer that time, the reaction mixture
was allowed to cool to room temperature, before being
quenched with saturated aqueous ammonium chloride solu-
tion (10 mL). The mixture was extracted with ethyl acetate (2 ꢁ
10 mL). The combined organic layers were washed successively
with 10% NaHCO3 solution (2 ꢁ 10 mL) and brine (2 ꢁ 10 mL),
dried over magnesium sulphate, ltered and concentrated
under reduced pressure. The resulting residue was puried by
ash column chromatography on silica gel using hexane–
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1
EtOAc. To give 45 mg of anemarchalconyn 16k (35% yield). H
NMR (300 MHz, CD3OD): d 8.07 (d, J ¼ 8.7 Hz, 2H), 7.55 (d, J ¼
8.7 Hz, 2H), 6.90 (d, J ¼ 8.7 Hz, 2H), 6.85 (d, J ¼ 8.7 Hz, 2H); 13
C
NMR (75 MHz, CD3OD): d 178.5, 165.2, 161.8, 136.3, 133.2,
130.3, 117.1, 116.6, 111.5, 95.7, 87.2. Anal. calcd for C15H10O3:
C, 75.62; H, 4.23. Found: C, 75.58; H, 4.20.
Acknowledgements
The authors are very grateful for economic support acquired
from CONACyT (Project-255819) and PRODEP-SEP (Project-
DSA/103.5/16/10288). JAMS is grateful to the Royal Society
(UK) for the International Alumni Grant.
Notes and references
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´
2 T. Achard, Chimia, 2016, 70, 8.
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