Gold versus silver catalyzed intramolecular hydroarylation reactions of [(3-arylprop-2-ynyl)oxy]benzene derivatives

examples of respectively Pt-¹⁹and Pd-catalyzed²⁰cyclization of maintained at room temperature for 48 h (Table 1, entry 1).

[(3-phenylprop-2-yn-1-yl)oxy]benzene into 4-aryl-2H-1-chromene Increasing the reaction temperature to over 60 °C gave 2a in

derivative in moderate yield have been reported so far. The about quantitative yield (Table 1, entries 2, 3). Surprisingly, the

generality, scope and limitations, as well as the product selec- formation of 2a did not occur (Table 1, entry 4) in the presence

tivity in the cyclization of readily available aryl-substituted pro- of Ph₃PAuNTf₂, which was a superior catalyst for the selective

pargylic aryl ethers²¹1 have not been previously investigated. synthesis of 4-unsubstituted-2H-chromenes.^10aThe impor-

Applications of this key reaction can be relevant in natural tance of both the ligand and the non-nucleophilic anion in the

product synthesis of the 2H-chromene moiety which appears gold catalyst is also pointed out by the failure of the formation

in a vast number of naturally occurring and pharmaceutically of 2a in the presence of the chloride B as the catalyst (Table 1,

relevant substrates.^10a

entries 5–7). By contrast with the results observed in the annu-

lation reactions of propargylic anilines,²⁴NaAuCl₄·2H₂O was

not eﬀective in the IMHA of 1a both in ethanol and CH₂Cl₂

(Table 1, entries 8–10). Analogously, under copper catalysis 1a

was recovered unchanged (Table 1, entries 11–12). AgOTf alone

catalyzed the reaction although a little more slowly and less

eﬃciently (Table 1, entry 13). Note that the (2-biphenyl)di-tert-

butylphosphine Buchwald-type ligand hampered the catalytic

activity of AgSbF₆(Table 1, entry 14). We continued to estab-

lish the scope and the generality of gold versus silver catalyzed

IMHA reactions of aryl-substituted propargylic aryl ethers 1 in

terms of rings substitution. To that end a range of readily

accessible derivatives 1 was prepared and then subjected to

the same reaction conditions in the presence of gold catalyst A

or AgOTf.

Hereafter we show the results of our study.

Results and discussion

As part of a program devoted to the chemical valorization of

widespread diﬀused molecules in renewable sources,²²we

became interested in the preparation of 2H-chromene deriva-

tives by using as starting material the 4-(2-hydroxyethyl)phenol

(tyrosol), a naturally occurring bioactive molecule found in

extra virgin olive oil and agricultural wastewater.²³

Its 2-(4-{[3-(4-methoxyphenyl)prop-2-yn-1yl]oxy}phenyl)ethan-

1-ol derivative 1a was used as a model substrate for our initial

studies of the intramolecular hydroarylation (IMHA) of aryl-

substituted propargylic aryl ethers under a spectrum of metal

salts and complexes.²⁴Some of our results of the screening of

the reaction conditions are summarized in Table 1.

The outcomes of such studies are shown in Table 2.

By using the catalyst A (2 mol%) in CH₂Cl₂, the cyclization

of derivatives 1a–o was quite general and proceeded smoothly

at 60 °C to give exclusively the 4-aryl-substituted-2H-chromenes

2a–o in excellent yields. In contrast, the introduction of

In a preliminary experiment, no IMHA of 1a was observed

by using the catalyst A (2 mol%) in a CH₂Cl₂solution^5c

Table 1 Screening optimal conditions

Entry

Catalyst (2 mol%)

Solvent

Temperature (°C)

Time (h)

2a Yield^a,b(%)

CH₂Cl₂

EtOH

r.t.

100

−(100)

>98^c

>99

0.2

Ph₃PAuNTf₂

−(100)

18 (82)

4 (96)

−(100)

83^c

NaAuCl₄·2H₂O

CuCl^d

EtOH

CH₂Cl₂

Dioxane

Toluene

CH₂Cl₂

CuI^d/L-proline^e

AgOTf

4 (96)

^aIf not otherwise stated, yields refer to single run and are for pure isolated products. ^bFigures in brackets refer to the recovered 1a. ^cAverage yield

referred to three runs. ^d5 mol%. ^e10 mol%.

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Paper

Table 2 Scope of gold versus silver catalyzed IMHA reactions of aryl-substi-

tuted propargylic aryl ethers 1

Table 2 (Contd.)

Entry

Catalyst

Time (h)

2 (% yield)^a

Entry

Catalyst

Time (h)

2 (% yield)^a

AgOTf

2j (3)

AgOTf

2b (77)

AgOTf

2k (77)

AgOTf

2c (–)

AgOTf

2l (–)

AgOTf

2d (98)

AgOTf

2m (5)

AgOTf

2e (95)^b

AgOTf

2n (70)

AgOTf

3f (–)

AgOTf

2o (22)

AgOTf

2g (80)^b

^aIf not otherwise stated, yields refer to single run and are for pure

isolated products. ^bAverage yield referred to three runs.

substituents on the aryl groups had a considerable eﬀect on

the yield of the reaction in the presence of the silver catalysis.

AgOTf

2h (84)^b

AgOTf

2i (24)

Substituents were first introduced onto the aromatic ring

attached to the alkyne. Whereas the presence of the electron-

donating group MeO in the para position and the absence of

any substituent (Table 2, entry 2) allowed the formation of the

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Table 3 Investigation on the regioselectivity of the IMHA

Scheme 2

Catalyst/

Entry Substrate 1 time (h)

Product 2 (%

yield)

Product 2′ (%

yield)

corresponding 2H-chromene 2a–b in good yield, the introduc-

tion of the electron-withdrawing carbonyl group resulted in

the failure of the formation of the product 2c (Table 2, entry

4). The introduction of substituents onto the aromatic ring

attached to the oxygen moiety also had a pronounced eﬀect.

The silver-catalyzed formation of the target 4-aryl-2H-chro-

mene derivative 2 occurred only by the introduction of an elec-

tron-donating group on the phenyl ring para to the oxygen

(Table 2, entries 12, 14), while the presence of the acyl or the

phenyl groups on the same position hampered the IMHA reac-

tion (Table 2, entries 18, 24). As expected, the introduction of

an electron-donating group in the para position of both aro-

matic rings of the starting aryl-substituted propargylic aryl

ethers eﬃciently promoted the silver-catalyzed process which

proceeded only in the presence of at least an electron-donating

group on the para position of one of the aromatic rings of the

starting substrate when an electron-withdrawing group was

attached to the para position of the other aromatic moiety

(Table 2, entries 14, 16, 20). It is worth emphasizing that in

A/3

AgOTf/3

A/1.5

2q (40)^b

2q′ (40)^b

AgOTf/4

A/1.5

2r (41)^b,c

2r′ (41)^b,c

AgOTf/4

2s (8)^b

2s′ (8)^b

the presence of the gold catalyst A the IMHA is allowed in ^aYields refer to single run and are for pure isolated products. ^bThe

ratio of the regioisomers was determined by ¹H NMR. ^cAverage yield

almost quantitative yield even in the presence of a withdrawing

carbonyl in the para position of both aryl groups of the reac-

referred to three runs.

tant 1l (Table 2, entry 21).

In absolute agreement with previous considerations of the

positive eﬀect of electronic releasing groups on the silver-cata- exclusively. The undesired formation of a 4-aryl-4H-chromene

lyzed IMHA of the substrates 1, substrate 1p bearing two isomer reported to occur though the Pt(^IV)-catalyzed cyclization

methyl groups on the same benzene nucleus was smoothly of 1d was not observed in our cases.¹⁹Analogously, the for-

converted to the corresponding 4-phenyl-2H-chromene 2p in mation of saturated benzopyran derivatives produced accord-

about quantitative yield either by the gold or silver catalyzed ing to the Pd(OAc)₂/TFA based protocol²⁰is avoided under the

reaction (Scheme 2).

present reaction conditions. Striking improvements over the

In the case of meta-methyl derivatives 1q–s, the gold-cata- previous methodology are due to the suppression of the depro-

lyzed annulation of 1q–s aﬀorded almost only regioisomers pargylation reaction.^10a–dNo dimeric 2H-chromene deriva-

2q–s derived from the IMHA at the para-position to the methyl tives¹⁰as well as benzofuran by-products^5c,10were detected

group (Table 3, entries 1, 3, 5).^10a,c,fBy contrast, under silver during the cycloisomerization reactions. Notably, the draw-

catalysis the formation in a 1 : 1 ratio of both regioisomers backs due to the competing Au-catalyzed hydration of the

derived from the IMHA at the para- and the ortho-position to alkyne moiety²⁵leading to the corresponding ketone derivati-

the methyl group was observed (Table 3, entries 2, 4, 6).

ve^10a,c,dare overcome because of the faster rate of the Au-cata-

Some trends have emerged from the current study regard- lyzed cyclization reaction of substrate 1 promoted by catalyst A.

ing the comparison of gold with silver catalyzed IMHA of sub- The activity of catalyst A and AgOTf was comparable toward

strates 1. Reactions can be carried out in air and rigorous substrates containing arene rings with electron-donating sub-

exclusion of moisture is unnecessary since reactions are com- stituents. From a practical standpoint the AgOTf catalyzed

patible with a small amount of water. Furthermore, products cyclization is more attractive because AgOTf is cheaper than

derived from 6-endo cyclization of substrate 1 are formed catalyst A. Nevertheless it appears that the gold catalyst A

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Paper

Scheme 5

Scheme 3

Scheme 6

Scheme 7

The structure of 2t has been unambiguously assigned by

NMR spectroscopy and chemical evidence. Indeed, the iso-

lation of the alkynyl derivative 2u (80% yield) under Sonoga-

shira modified conditions provided further evidence about the

assignment of the structure of the product of the cyclization of

1t (Scheme 4).

The formation of the benzo[b]furan derivative 3 which

should be generated from the isomer 2t′ under the reaction

conditions above was not observed.³²

Scheme 4

possesses a unique blend of reactivity and selectivity. Our

results revealed that A might be a general catalyst for the cycli-

zation of aryl-substituted-arylpropargyl ethers 1 to the corre-

sponding 4-aryl-2H-chromenes 2 and represent up to now the

only choice to eﬃciently achieve the annulation reaction of

substrates 1 bearing electron deficient arenes.

Transition metal-catalyzed IMHA²⁶approaches have been

reported to involve multiple mechanistic possibilities. These

alternative mechanistic routes include multiple bond acti-

vation–electrophilic substitution,²⁷metal-catalyzed Claisen

rearrangement,^16,28arene metallation–Heck type addition.²⁹

Examples of phenol synthesis in which furan-ynes are used as

substrates have been reported to involve the formation of

metal cyclopropyl carbene intermediates.³⁰Another mechanis-

tic possibility involves hydrometallation of the triple carbon–

carbon bond, generating an alkenyl metal species, followed by

intramolecular substitution of the arene ring.³¹In our pro-

cedure the formation of the only isomer 2t in about quantitat-

ive yield from the substrate 1t in the presence of 2 mol% of

either catalyst A or AgOTf in CH₂Cl₂at 60 °C should rule out

that the cyclization of derivatives 1 proceeds via the Claisen

rearrangement (Scheme 3).

The cyclization of the substrate 1g in the presence of 2

equiv. of D₂O (Scheme 5) revealed that the deuterium atom is

significantly incorporated into product 2g at the C3 position as

judged by ¹H NMR only under silver catalysis.

Interestingly, also the vinyl proton of the 2H-chromene

derivative 2g was deuterated in the presence of AgOTf under

similar conditions (Scheme 6).³³

By contrast the formation of the C3-deuterated 2g did not

occur under the gold catalysis. These results suggest that the

silver catalyzed cyclization of the aryl-substituted arylpro-

pargylic ethers 1 is in accordance with a Friedel–Crafts type

reactivity. Coordination of AgOTf activates the carbon–carbon

triple bond for interception by the benzene ring (Scheme 7).

The following electrophilic attack determines the release of the

proton of the arene into the solvent along the reaction path

and the final hydroarylation product is generated by the

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Organic & Biomolecular Chemistry

intermediacy of the vinyl silver intermediate 4 by some type of

4-(4-M^ETHOXYPHENYL)-6-(2-HYDROXYETHYL)-2H-CHROMENE

(2A).

reversible protonation event.

(0.1117 g, 99% [catalyst A]; 0.0936 g, 83% [AgOTf]). Oil. Found

Diﬀerent C–H activation of arenes has been reported to C, 76.62; H, 6.44. Anal calcd for C₁₈H₁₈O₃, C, 76.57; H, 6.43. IR

occur under gold catalysis via σ-bond metathesis³⁴or electro- (KBr): ν_max/cm⁻¹3431, 2924, 1608, 1512, 1248, 1034, 837, 804.

philic auration,³⁵but in our cases both seem very unlikely. An δ_H(400 MHz; CDCl₃; Me₄Si) 7.29 (d, J = 8.4 Hz, 2H), 7.03 (d, J =

oxidative addition mechanism³⁶for the gold-catalyzed annula- 8.3 Hz, 1H), 6.96 (d, J = 8.4 Hz, 2H), 6.92 (s, 1H), 6.87 (d, J =

tion reaction of substrates 1, where a transient Au(^III) hydride 8.2 Hz, 1H), 5.78 (t, J = 4.0 Hz, 1H), 4.82 (d, J = 4.0 Hz, 2H),

species is formed, would be, also, discarded since 5-exo-dig 3.87 (s, 3H), 3.75 (t, J = 6.7 Hz, 2H), 2.73 (t, J = 6.7 Hz, 2H),

cyclization on the exclusive cis-selectivity can be expected for 1.93 (bs, 1H). δ_C(100.6 MHz; CDCl₃; Me₄Si) 159.3, 153.5,

that intermediate. However, further studies are needed to 136.6, 131.1, 130.6, 129.7, 129.6, 126.3, 124.0, 119.6, 116.3,

unambiguously establish the reaction mechanism for the Au(^I)- 113.9, 65.2, 63.8, 55.3, 38.5. MS (relative intensity): m/z 282

catalyzed process.

(M⁺, 29), 251 (14), 207 (16), 77 (10), 45 (17).

4-P^HENYL-6-(2-HYDROXYETHYL)-2H-CHROMENE (2B). (0.0997 g, 99%

[catalyst A]; 0.0775 g, 77% [AgOTf]). Oil. Found C, 80.98; H,

6.40. Anal calcd for C₁₇H₁₆O₂, C, 80.93; H, 6.39. IR (KBr): ν_max

cm⁻¹3396, 2924, 1630, 1491, 1444, 1228, 1032, 744, 702. δ_H

(400 MHz; CDCl₃; Me₄Si) 7.46–7.37 (m, 5H), 7.05 (d, J = 8.0 Hz,

1H), 6.89 (m, 2H), 5.83 (t, J = 4.0 Hz, 1H), 4.85 (d, J = 4.0 Hz,

2H), 3.74 (t, J = 6.7 Hz, 2H), 2.73 (t, J = 6.7 Hz, 2H), 1.85 (bs,

1H). δ_C(100.6 MHz; CDCl₃; Me₄Si) 153.4, 138.3, 137.1, 131.2,

129.7, 128.6, 128.5, 127.9, 126.3, 123.8, 120.3, 116.3, 65.3, 63.8,

38.5. MS (relative intensity): m/z 252 (M⁺, 45), 221 (39), 207

(21), 175 (22), 77 (32).

Conclusions

In summary, the generality, scope and limitations, as well as

the product selectivity in the cyclization of readily available

aryl-substituted propargylic aryl ethers by means of gold and

silver catalysis have been investigated. Products deriving from

6-endo cyclization of the starting substrate are formed exclu-

sively. The study of the comparison of the gold vs. silver cataly-

sis for the IMHA process showed that the silver-catalyzed

process can be eﬃciently applied only to aryl-substituted aryl-

propargylic ethers containing arene rings bearing electron-

donating substituents in accordance with a Friedel–Crafts type

reactivity. The results observed in the gold-catalyzed IMHA

reaction revealed that gold(^I) catalysis might represent up to

now the only choice possible to eﬃciently achieve the syn-

thesis of 4-aryl-2H-chromenes through the annulation reaction

of starting substrates bearing electron deficient arenes. The

gold-catalyzed IMHA reaction seems to proceed by a diﬀerent

mechanism that determines the unique properties of gold

catalysis in terms of reactivity and product selectivity control.

This unusual mechanistic behaviour should provide new

insight into the burgeoning field of gold catalysis.

4-(4-A^CETYLPHENYL)-6-(2-HYDROXYETHYL)-2H-CHROMENE

(2C).

(0.1129 g, 96% [catalyst A]). Mp: 92–95 °C. Found C, 77.45; H,

6.16. Anal calcd for C₁₉H₁₈O₃, C, 77.53; H, 6.16. IR (KBr): ν_max

cm⁻¹3425, 2864, 1685, 1601, 1489, 1257, 1059, 827, 802. δ_H

(400 MHz; CDCl₃; Me₄Si) 7.99 (d, J = 8.4 Hz, 2H), 7.44 (d, J =

8.4 Hz, 2H), 7.06 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H),

6.82 (s, 1H), 5.86 (t, J = 4.0 Hz, 1H), 4.82 (d, J = 4.0 Hz, 2H),

3.76 (t, J = 6.1 Hz, 2H), 2.73 (t, J = 6.1 Hz, 2H), 2.66 (s, 3H),

1.57 (bs, 1H). δ_C(100.6 MHz; CDCl₃; Me₄Si) 197.8, 153.3,

143.1, 136.5, 136.4, 131.4, 130.0, 128.8, 128.6, 126.1, 123.1,

121.4, 116.4, 65.1, 63.7, 38.5, 26.6. MS (relative intensity): m/z

294 (M⁺, 16), 263 (6), 175 (5), 77 (6), 45 (7), 43 (100).

4-P^HENYL-2H-CHROMENE (2D). (0.0732 g, 88% [catalyst A];

0.0815 g, 98% [AgOTf]). Oil. Found C, 86.45; H, 5.82. Anal

calcd for C₁₅H₁₂O, C, 86.51; H, 5.81. IR (KBr): ν_max/cm⁻¹1603,

1485, 1448, 1225, 758, 700. δ_H(400 MHz; CDCl₃; Me₄Si)

7.47–7.37 (m, 4H), 7.21 (t, J = 7.8 Hz, 1H), 7.08 (d, J = 8.2 Hz,

1H), 6.97 (d, J = 8.2 Hz, 1H), 6.91 (t, J = 7.8 Hz, 1H), 5.85 (t, J =

4.0 Hz, 1H), 4.90 (d, J = 4.0 Hz, 2H). δ_C(100.6 MHz; CDCl₃;

Experimental

TYPICAL PROCEDURES FOR THE GOLD- AND SILVER-CATALYZED SYNTHESIS OF Me₄Si) 154.8, 138.3, 137.2, 129.3, 128.7, 128.4, 127.8, 125.9,

4,6-, OR 4,7- OR 4,8-DISUBSTITUTED-2H-CHROMENES (2): PREPARATION OF 123.7, 121.2, 120.0, 116.3, 65.3. MS (relative intensity): m/z 208

6-METHOXY-4-(4-METHOXYPHENYL)-2H-CHROMENE (2H). A solution of (M⁺, 53).

4-methoxy-O-(4-methoxyphenyl)prop-2-ynylphenol (1h) (0.107 g,

4-(4-M^ETHOXYPHENYL)-2H-CHROMENE (2E). (0.0714 g, 75% [cata-

0.40 mmol, 1 equiv.) in CH₂Cl₂(4 mL) was treated with (aceto- lyst A]; 0.0904 g, 95% [AgOTf]). Mp: 90–91 °C. Found C, 80.72;

nitrile)((2-biphenyl)di-tert-butylphosphine)gold(^I) hexafluoroan- H, 5.90. Anal calcd for C₁₆H₁₄O₂, C, 80.65; H, 5.92. IR (KBr):

timonate (0.0061 g, 0.008 mmol, 0.02 equiv.) or with AgOTf ν_max/cm⁻¹2837, 1606, 1572, 1508, 1456, 1244, 1032, 839, 804.

(0.0021 g, 0.008 mmol, 0.02 equiv.). The resulting solution was δ_H(400 MHz; CDCl₃; Me₄Si) 7.30 (d, J = 8.8 Hz, 2H), 7.18 (t, J =

stirred at 60 °C for 1 h until determined to be complete by 7.6 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.95 (d, J = 8.8 Hz, 2H),

TLC and then concentrated under reduced pressure. The 6.92 (d, J = 7.5 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 5.79 (t, J =

product was subjected to flash column chromatography (SiO₂4.0 Hz, 1H), 4.86 (d, J = 4.0 Hz, 2H), 3.87 (s, 3H). δ_C

50 g), eluting with n-hexane–ethyl acetate 95 : 5 v/v to aﬀord (100.6 MHz; CDCl₃; Me₄Si) 159.4, 154.9, 136.7, 130.7, 129.8,

the product (2h) as a yellow oil (0.106 g, 99% (catalyst A) or 129.2, 125.9, 124.0, 121.1, 119.2, 116.2, 113.8, 65.3, 55.3. MS

0.0909 g, 85% (AgOTf)).

(relative intensity): m/z 238 (M⁺, 22), 77 (12).

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4-(4-ACETYLPHENYL)-2H-CHROMENE (2F). (0.099 g, 99% [catalyst

4-(4-M^ETHOXYPHENYL)-6-ACETYL-2H-CHROMENE (2K). (0.1109 g,

A]). Mp: 110–112 °C. Found C, 81.43; H, 5.66. Anal calcd for 99% [catalyst A]; 0.0862 g, 77% [AgOTf]). Oil. Found C, 77.18;

C₁₇H₁₄O₂, C, 81.58; H, 5.64. IR (KBr): ν_max/cm⁻¹1682, 1603, H, 5.76. Anal calcd for C₁₈H₁₆O₃, C, 77.12; H, 5.75. IR (KBr):

1487, 1259, 1016, 849, 779. δ_H(400 MHz; CDCl₃; Me₄Si) 8.01 ν_max/cm⁻¹2835, 1676, 1601, 1512, 1250, 1032, 837, 804. δ_H

(d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.19 (t, J = 7.6 Hz, (400 MHz; CDCl₃; Me₄Si) 7.81 (dd, J₁= 8.3 Hz, J₂= 2.0 Hz, 1H),

1H), 6.97 (d, J = 7.6 Hz, 1H), 6.93 (d, J = 7.6 Hz, 1H), 6.88 (t, J = 7.70 (d, J = 2.0 Hz, 1H), 7.28 (d, J = 8.7 Hz, 2H), 6.97 (d, J =

7.6 Hz, 1H), 5.87 (t, J = 4.0 Hz, 1H), 4.87 (d, J = 4.0 Hz, 2H), 8.7 Hz, 2H), 6.92 (d, J = 8.3 Hz, 1H), 5.78 (t, J = 4.0 Hz, 1H),

2.65 (s, 3H). δ_C(100.6 MHz; CDCl₃; Me₄Si) 197.6, 154.7, 143.1, 4.95 (d, J = 4.0 Hz, 2H), 3.87 (s, 3H), 2.47 (s, 3H); δ_C

136.5, 136.4, 129.6, 128.8, 128.5, 125.6, 123.1, 121.3, 121.1, (100.6 MHz; CDCl₃; Me₄Si) 196.7, 159.6, 159.1, 136.0, 130.7,

116.4, 65.1, 26.6. MS (relative intensity): m/z 250 (M⁺, 36), 207 130.1, 129.9, 129.6, 126.4, 123.2, 119.6, 116.2, 114.1, 65.9, 55.3,

(17), 131 (30), 77(5), 43 (100).

6-M^ETHOXY-4-PHENYL-2H-CHROMENE (2G). (0.0714 g, 75% [cata-

26.3. MS (relative intensity): m/z 280 (M⁺, 55), 237 (8), 43 (100).

4-(4-A^CETYLPHENYL)-6-ACETYL-2H-CHROMENE (2L). (0.1156 g, 99%

lyst A]; 0.0762 g, 80% [AgOTf]). Mp: 60–64 °C. Found C, 80.76; [catalyst A]). Mp: 109–112 °C. Found C, 78.12; H, 5.54. Anal

H, 5.95. Anal calcd for C₁₆H₁₄O₂, C, 80.65; H, 5.92. IR (KBr): calcd for C₁₉H₁₆O₃, C, 78.06. IR (KBr): ν_max/cm⁻¹1674, 1603,

ν_max/cm⁻¹2829, 1608, 1491, 1209, 1038, 762, 700. δ_H1568, 1495, 1254, 1080, 829, 806. δ_H(400 MHz; CDCl₃; Me₄Si)

(400 MHz; CDCl₃; Me₄Si) 7.44–7.39 (m, 5H), 6.90 (d, J = 8.8 Hz, 7.99 (d, J = 8.0 Hz, 2H), 7.78 (dd, J₁= 8.4 Hz, J₂= 2.0 Hz, 1H),

1H), 6.77 (dd, J₁= 8.8 Hz, J₂= 2.8 Hz, 1H), 6.65 (d, J = 2.8 Hz, 7.58 (d, J = 2.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 6.91 (d, J =

1H), 5.89 (t, J = 4.0 Hz, 1H), 4.83 (d, J = 4.0 Hz, 2H), 3.71 (s, 8.4 Hz, 1H), 5.86 (t, J = 4 Hz, 1H), 4.95 (d, J = 4 Hz, 2H), 2.62 (s,

3H); δ_C(100.6 MHz; CDCl₃; Me₄Si) 154.0, 148.7, 138.2, 137.3, 3H), 2.43 (s, 3H); δ_C(100.6 MHz; CDCl₃; Me₄Si) 197.5, 196.5,

128.6, 128.4, 127.8, 124.5, 120.9, 116.7, 114.2, 111.7, 65.2, 55.7. 158.9, 142.3, 136.7, 135.7, 130.8, 130.6, 128.7, 128.6, 125.9,

MS (relative intensity): m/z 238 (M⁺, 100), 207 (23), 161 (31), 122.4, 121.5, 116.4, 65.7, 26.7, 26.3. H, 5.52. MS (relative inten-

77 (19).

sity): m/z 292 (M⁺, 10), 206 (3), 173 (6), 43 (100).

6-M^ETHOXY-4-(4-METHOXYPHENYL)-2H-CHROMENE (2H). (0.1061 g,

4,6-D^IPHENYL-2H-CHROMENE (2M). (0.0943 g, 83% [catalyst A];

99% [catalyst A]; 0.0911 g, 85% [AgOTf]). Oil. Found C, 76.18; 0.0057 g, 5% [AgOTf]). Mp: 133–136 °C. Found C, 88.77; H,

H, 6.03. Anal calcd for C₁₇H₁₆O₃, C, 76.10; H, 6.01. IR (KBr): 5.68. Anal calcd for C₂₁H₁₆O, C, 88.70; H, 5.67. IR (KBr): ν_max

ν_max/cm⁻¹2825, 1608, 1489, 1248, 1034, 837, 806. δ_Hcm⁻¹1599, 1479, 1230, 1061, 766, 698. δ_H(400 MHz; CDCl₃;

(400 MHz; CDCl₃; Me₄Si) 7.32 (d, J = 8.8 Hz, 2H), 6.97 (d, J = Me₄Si) 7.53–7.34 (m, 12H), 7.08 (d, J = 8.4 Hz, 1H), 5.91 (t, J =

8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 1H), 6.76 (dd, J₁= 8.8 Hz, J₂= 4 Hz, 1H), 4.97 (d, J = 4 Hz, 2H). δ_C(100.6 MHz; CDCl₃; Me₄Si)

2.8 Hz, 1H), 6.66 (d, J = 2.8 Hz, 1H), 5.84 (t, J = 4.0 Hz, 1H), 154.5, 146.6, 140.9, 138.2, 137.2, 134.4, 128.8, 128.7, 128.6,

4.80 (d, J = 4.0 Hz, 2H), 3.88 (s, 3H), 3.71 (s, 3H); δ_C128.0, 127.9, 126.8, 124.6, 123.9, 120.4, 116.6, 65.5. MS (relative

(100.6 MHz; CDCl₃; Me₄Si) 159.4, 154.0, 148.8, 136.8, 130.5, intensity): m/z 284 (M⁺, 100), 207 (22), 77 (57).

129.8, 124.8, 120.1, 116.6, 114.1, 113.9, 111.6, 65.2, 55.7, 55.3.

4-(4-M^ETHOXYPHENYL)-6-PHENYL-2H-CHROMENE (2N). (0.1193 g,

95% [catalyst A]; 0.0879 g, 70% [AgOTf]). Mp: 108–110 °C.

MS (relative intensity): m/z 268 (M⁺, 100), 237 (15), 161 (17).

6-M^ETHOXY-4-(4-ACETYLPHENYL)-2H-CHROMENE (2I). (0.1109 g, 99% Found C, 84.12; H, 5.78. Anal calcd for C₂₂H₁₈O₂, C, 84.05; H,

[catalyst A]; 0.0269 g, 24% [AgOTf]). Mp: 95–98 °C. Found C, 5.77. IR (KBr): ν_max/cm⁻¹2924, 2841, 1606, 1508, 1479, 1225,

77.21; H, 5.77. Anal calcd for C₁₈H₁₆O₃, C, 77.12; H, 5.75. IR 1026, 845, 806, 762, 700. δ_H(400 MHz; CDCl₃; Me₄Si) 7.51–7.32

(KBr): ν_max/cm⁻¹2825, 1678, 1601, 1578, 1485, 1427, 1265, (m, 9H), 7.04–6.98 (m, 3H), 5.85 (t, J = 4 Hz, 1H), 4.92 (d, J =

1063, 856, 814. δ_H(400 MHz; CDCl₃; Me₄Si) 8.00 (d, J = 8.4 Hz, 4 Hz, 2H), 3.89 (s, 3H); δ_C(100.6 MHz; CDCl₃; Me₄Si) 159.4,

2H), 7.46 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.7 Hz, 1H), 6.75 (dd, 154.5, 149.7, 140.9, 136.7, 134.3, 130.6, 129.8, 128.7, 127.9,

J₁= 8.8 Hz, J₂= 2.8 Hz, 1H), 6.53 (d, J = 2.8 Hz, 1H), 5.92 (t, J = 126.8, 124.6, 124.1, 119.6, 116.6, 114.0, 65.4, 55.3. MS (relative

4.0 Hz, 1H), 4.80 (d, J = 4.0 Hz, 2H), 3.68 (s, 3H), 2.64 (s, 3H); intensity): m/z 314 (M⁺, 69), 283 (16), 207 (36), 77 (47).

δ_C(100.6 MHz; CDCl₃; Me₄Si) 197.5, 154.1, 148.6, 143.0, 136.6,

4-(4-A^CETYLPHENYL)-6-PHENYL-2H-CHROMENE (2O). (0.1291 g, 99%

136.5, 128.8, 128.5, 123.8, 122.0, 116.9, 114.5, 111.4, 65.0, 55.7, [catalyst A]; 0.0287 g, 22% [AgOTf]). Mp: 146–148 °C. Found C,

26.6. MS (relative intensity): m/z 280 (M⁺, 46), 237 (12), 161 84.71; H, 5.54. IR (KBr): ν_max/cm⁻¹2922, 1678, 1603, 1481,

(14), 77 (3), 43 (100).

1259, 1016, 824, 804, 762, 700. δ_H(400 MHz; CDCl₃; Me₄Si)

4-P^HENYL-6-ACETYL-2H-CHROMENE (2J). (0.0990 g, 99% [catalyst 8.03 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.48–7.43 (m,

A]; 0.0031 g, 3% [AgOTf]). Oil. Found C, 81.43; H, 5.66. Anal 3H), 7.39 (t, J = 7.4 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 7.22 (d, J =

calcd for C₁₇H₁₄O₂, C, 81.58; H, 5.64. IR (KBr): ν_max/cm⁻¹2835, 2.0 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 5.93 (t, J = 4.0 Hz, 1H),

1676, 1601, 1491, 1246, 1014, 766, 702. δ_H(400 MHz; CDCl₃; 4.93 (d, J = 4.0 Hz, 2H), 2.67 (s, 3H). δ_C(100.6 MHz; CDCl₃;

Me₄Si) 7.81 (dd, J₁= 8.4 Hz, J₂= 2.0 Hz, 1H), 7.68 (d, J = 2.0 Hz, Me₄Si) 197.6, 154.4, 143.0, 140.7, 136.7, 136.5, 134.5, 128.8,

1H), 7.44–7.34 (m, 5H), 6.93 (d, J = 8.4 Hz, 1H), 5.82 (t, J = 128.7, 128.6, 128.3, 126.9, 126.7, 124.3, 123.3, 121.5, 116.8,

4.0 Hz, 1H), 4.97 (d, J = 4.0 Hz, 2H), 2.45 (s, 3H); δ_C65.3, 26.6. Anal calcd for C₂₃H₁₈O₂, C, 84.64; H, 5.56. MS (rela-

(100.6 MHz; CDCl₃; Me₄Si) 196.7, 159.0, 137.6, 136.4, 130.8, tive intensity): m/z 326 (M⁺, 26), 283 (5), 207 (8), 77 (10), 43

130.2, 128.7, 128.4, 128.2, 126.3, 123.0, 120.4, 116.2, 65.9, 26.3. (100).

MS (relative intensity): m/z 250 (M⁺, 17), 207 (5), 173 (5), 77 (5),

43 (100).

5,7-D^IMETHYL-4-(4-METHOXYPHENYL)-2H-CHROMENE (2P). (0.1053 g,

99% [catalyst A]; 0.1053 g, 99% [AgOTf]). Oil. Found C, 81.24;

9706 | Org. Biomol. Chem., 2012, 10, 9700–9708

Organic & Biomolecular Chemistry

H, 6.80. Anal calcd for C₁₈H₁₈O₂, C, 81.17; H, 6.81. IR (KBr): 1H), 4.78 (d, J = 3.6 Hz, 2H), 3.93 (bs, 1H), 3.79 (s, 3H); δ_C

ν_max/cm⁻¹2833, 1608, 1518, 1458, 1246, 1034, 837, 806. δ_H(100.6 MHz; CDCl₃; Me₄Si) 160.1, 157.5, 153.9, 148.0, 133.9,

(400 MHz; CDCl₃; Me₄Si) 7.20 (d, J = 8.4 Hz, 2H), 6.92 (d, J = 133.8, 131.6, 129.7, 129.1, 128.2, 127.8, 123.9, 121.0, 114.6,

8.4 Hz, 2H), 6.75 (s, 1H), 6.63 (s, 1H), 5.86 (t, J = 4.8 Hz, 1H), 111.3, 110.7, 103.1, 91.9, 85.6, 65.1, 55.4. MS (relative inten-

4.59 (d, J = 4.8 Hz, 2H), 3.87 (s, 3H), 2.34 (s, 3H), 1.81 (s, 3H). sity): m/z 354 (M⁺, 100).

δ_C(100.6 MHz; CDCl₃; Me₄Si) 159.0, 156.6, 138.8, 138.0, 135.7,

134.0, 128.7, 125.9, 121.2, 120.6, 114.5, 113.8, 64.4, 55.3, 22.4,

21.2. MS (relative intensity): m/z 266 (M⁺, 100), 235 (13), 159

(10), 108 (8), 77 (16).

Acknowledgements

7-M^ETHYL-4-PHENYL-2H-CHROMENE (2Q). (0.0879 g, 99% [catalyst The authors are grateful for financial support from the Consor-

A]). oil. Found C, 86.52; H, 6.36. Anal calcd for C₁₆H₁₄O, C, zio di Ricerca per l’Innovazione Tecnologica, la Qualità e la

86.45; H, 6.35. Found C, 86.52; H, 6.36. IR (KBr): ν_max/cm⁻¹Sicurezza degli Alimenti S.C.R.L. (grant number 28497/2006)

2922, 1618, 1491, 1446, 1255, 1039, 764, 702. δ_H(400 MHz; and from Sapienza, Università di Roma.

CDCl₃; Me₄Si) 7.46–7.41 (m, 5H), 6.98 (d, J = 7.5 Hz, 1H), 6.82

(s, 1H), 6.74 (d, J = 7.5 Hz, 1H), 5.80 (t, J = 4.0 Hz, 1H), 4.89 (d,

J = 4.0 Hz, 2H), 2.38 (s, 3H).). δ_C(100.6 MHz; CDCl₃; Me₄Si)

154.8, 139.6, 138.5, 137.2, 128.7, 128.4, 127.8, 125.7, 121.9,

Notes and references

121.1, 118.9, 116.8, 65.3, 21.4 MS (relative intensity): m/z 222

(M⁺, 100).

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7-M^ETHYL-4-(4-METHOXYPHENYL)-2H-CHROMENE (2R). (0.0958 g,

95% [catalyst A]). Oil. Found C, 80.99; H, 6.37. Anal calcd for

C₁₇H₁₆O₂, C, 80.93; H, 6.39. IR (KBr): ν_max/cm⁻¹2924, 1610,

1450, 1263, 1022, 873. δ_H(400 MHz; CDCl₃; Me₄Si) 7.32 (d, J =

8.4 Hz, 2H), 6.98–6.82 (m, 3H), 6.78 (s, 1H), 6.72 (d, J = 7.6 Hz,

1H), 5.74 (t, J = 4.0 Hz, 1H), 4.85 (d, J = 4.0 Hz, 2H), 3.89 (s,

3H), 2.36 (s, 3H). δ_C(100.6 MHz; CDCl₃; Me₄Si) 159.3, 154.8,

139.5, 136.7, 130.9, 129.7, 125.7, 121.9, 121.3, 118.1, 116.8,

113.8, 65.3, 55.3, 21.3. MS (relative intensity): m/z 252 (M⁺, 92),

205 (81), 145 (87).

7-M^ETHYL-4-(4-ACETYLPHENYL)-2H-CHROMENE (2S). (0.0993 g, 94%

[catalyst A]; 0.008 g, 8% [AgOTf]). Mp: 91–93 °C. Found C,

81.85; H, 6.11. Anal calcd for C₁₈H₁₆O₂, C, 81.79; H, 6.10. IR

(KBr): ν_max/cm⁻¹2841, 1684, 1604, 1560, 1502, 1462, 1261,

1016, 841, 806. δ_H(400 MHz; CDCl₃; Me₄Si) 8.00 (d, J = 8.4 Hz,

2H), 7.45 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 7.6 Hz, 1H), 6.76 (s,

1H), 6.70 (d, J = 7.5 Hz, 1H), 5.81 (t, J = 4.0 Hz, 1H), 4.84 (d, J =

4.0 Hz, 2H), 2.64 (s, 3H), 2.32 (s, 3H). δ_C(100.6 MHz; CDCl₃;

Me₄Si) 197.6, 154.7, 143.3, 140.0, 136.4, 128.8, 128.5, 125.4,

122.1, 120.4, 120.0, 117.0, 65.2, 26.6, 21.4. MS (relative inten-

sity): m/z 264 (M⁺, 65), 145 (50), 43 (100).

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8-B^ROMO-5-HYDROXY-4-(4-METHOXYPHENYL)-2H-CHROMENE

(2T).

(0.1265 g, 95%; [catalyst A]; 0.1066 g, 80% [AgOTf]). Oil. Found

C, 57.73; H, 3.92. Anal calcd for C₁₆H₁₃BrO₃, C, 57.78; H, 3.93;

Br, 23.98. IR (KBr): ν_max/cm⁻¹3483, 2841, 1604, 1558, 1508,

1464, 1248, 1030, 839, 802, 557. δ_H(400 MHz; CDCl₃; Me₄Si)

7.33–7.30 (m, 3H), 6.99 (d, J = 8.8 Hz, 2H), 6.42 (d, J = 8.8 Hz,

1H), 5.82 (t, J = 4.0 Hz, 1H), 4.77 (d, J = 4.0 Hz, 2H), 3.87 (s,

3H); δ_C(100.6 MHz; CDCl₃; Me₄Si) 160.4, 152.7, 152.4, 133.8,

133.2, 129.2, 128.8, 121.6, 114.9, 112.5, 111.9, 101.1, 65.2, 55.4.

MS (relative intensity): m/z 333 (M⁺, 72), 286 (46), 223 (53).

8-P^HENYLETHYNYL-5-HYDROXY-4-(4-METHOXYPHENYL)-2H-CHROMENE

(2U). (0.0685 g, 80%; Oil. Found C, 81.27; H, 5.11, Br, 23.92.

Anal calcd for C₂₄H₁₈O₃, C, 81.34; H, 5.12. IR (KBr): ν_max/cm⁻¹

3487, 2927, 2150, 1510, 1243, 1033, 1248, 835. δ_H(400 MHz;

CDCl₃; Me₄Si) 7.57 (d, J = 6.8 Hz, 2H), 7.36–7.30 (m, 6H), 6.96

(d, J = 8.4 Hz, 2H), 6.45 (d, J = 8.4 Hz, 1H), 5.81 (t, J = 3.6 Hz,

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