Enantioselective Oxy-Heck–Matsuda Arylations: Expeditious Synthesis of Dihydrobenzofuran Systems and Total Synthesis of the Neolignan (?)-Conocarpan

Title: Enantioselective Oxy-Heck-Matsuda Arylations: Expeditious

Synthesis of Dihydrobenzofuran Systems and Total Synthesis of

the Neolignan (-)-Conocarpan

Authors: Carlos Roque Correia, Allan Ribeiro, Ellen Polo, and Nelson

Martins

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10.1002/adsc.201701278

Advanced Synthesis & Catalysis

FULL PAPER

DOI: 10.1002/adsc.201((will be filled in by the editorial staff))

Enantioselective Oxy-Heck-Matsuda Arylations: Expeditious

Synthesis of Dihydrobenzofuran Systems and Total Synthesis of the

Neolignan ()-Conocarpan

Allan R. Silva, Ellen C. Polo, Nelson C. Martins, and Carlos Roque D. Correia*

Institute of Chemistry, University of Campinas, UNICAMP, Campinas, São Paulo, Brazil. roque@iqm.unicamp.br

Received: ((will be filled in by the editorial staff))

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please

delete if not appropriate))

Abstract. This work discloses the first examples of an effec- X-ray diffraction of an advanced brominated intermediate

tive enantioselective oxy-Heck-Matsuda reaction using a in route to -conocarpan has allowed unequivocal as-

variety of styrenic olefins to generate chiral dihydrobenzofu- signment of the absolute stereochemistry of the oxy-Heck-

rans. The reaction proceeds in moderate to good yields, with Matsuda aryl dihydrobenzofuran adducts. A rationale for

high trans diastereoselectivity (up to 20:1) in enantioselec- the mechanism operating in these enantioselective oxy-

tivities up to 90:10 using the N,N-ligand pyrimidine- Heck-Matsuda reactions is also presented.

bisoxazoline (PyriBox). The oxy-Heck-Matsuda reactions

were carried out under mild conditions and rather low cata- Keywords: aryldiazonium salts, oxy-Heck-Matsuda aryla-

lyst loading. The feasibility and practicality of the process is tions, N,N-ligands, dihydrobenzofurans, neolignans

demonstrated by a concise total synthesis of the neolignan

-conocarpan.

structural motifs of several natural products pos-

sessing useful biological activity (Figure 1). Many

Introduction

dihydrobenzofurans derivatives show antioxidant and

The asymmetric Heck reaction is a highly reliable

insecticidal properties, while others display important

and popular method for the construction of C–C

anti-cancer activities.^[5]

bonds in organic synthesis.^[1]Among the many ver-

sions available nowadays, the enantioselective Heck-

Matsuda reaction, relying on arenediazonium salts as

electrophiles, occupies a special position in the syn-

thetic methods arsenal by virtue of its superior reac-

tivity, polar nature (cationic), mild reaction condi-

tions, and its operational simplicity. The Heck-

Matsuda arylation has also been attracting increasing

interest after the development of its enantioselective

versions. In 2012, Correia and co-workers reported

the first examples of the enantioselective Heck-

Matsuda reaction, carrying out the desymmetrization

of unactivated olefins employing chiral bis-

oxazoline^[2]followed by an independent report by

Sigman and co-workers using pyridine-oxazoline

ligands.^[3]These seminal works have significantly

increased the research towards novel developments

and application of the enantioselective Heck-Matsuda

reactions in organic synthesis.

Figure 1. Natural products containing a benzofuranyl-

As part of our strategy to extend the enantioselec-

benzopyran or a dihydrobenzofuran moiety.

tive Heck-Matsuda reactions to more complex sys-

tems, we have envisioned the enantioselective oxy-

Heck-Matsuda as an attractive addition to the synthet-

ic arsenal. Somewhat surprisingly, there is a lack of

Elegant synthesis of racemic trans-2,3-disubstituted

dihydrobenzofurans using an oxy-Heck-Matsuda

effective examples of enantioselective oxy-Heck

reaction was previously reported by Sefkow (Scheme

reactions in the current literature. Oxy-Heck reactions

1) by in situ generation of the aryldiazonium salts.^[6]

date back to the pioneering work of Horino and Inoue

However, the enantioselective version of this reaction

in 1971,^[4]and have been one of the gold standard

still goes unreported. Therefore, our initial aim was to

methods to prepare cis-fused benzofuranyl-

evaluate the feasibility of the oxy-Heck-Matsuda

reaction in a diastereo- and enantioselective manner,

benzopyran and substituted dihydrobenzofuran – the

1

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Advanced Synthesis & Catalysis

and its application in total synthesis of chiral natural

and unnatural dihydrobenzofurans starting from

styrenic olefins.

racemic mixture, plus 52% recovered starting materi-

al. The same reaction using ligand L2 provided dihy-

drobenzofuran 3 in 49% yield as a racemic mixture.

In contrast, arylation of 2-methylstyrene 2b with

aryldiazonium salt 1a employing ligand L2 furnished

the oxy-Heck-Matsuda product 5, containing a qua-

ternary center, in a modest yield of 23% yield, but

with a surprising 70:30 er, along with the acyclic

product 6 (12% yield) in racemic form (Scheme 2).

For comparison purposes, L1 provided the oxy-Heck-

Matsuda product 5 in 30% yield in 60:40 er.

Styrenic systems such as dihydronaphthalenes

have also been well explored in the literature,^[7]but

the enantioselective versions of these reactions have

met with very limited success so far, with the notable

exception of the oxyarylation work of Gaunt and co-

workers in the enantioselective synthesis of diarylox-

azines from allylic amides using electron rich arylio-

donium salts, using copper (II) bisoxazoline as cata-

lyst (Scheme 1).^[8]Apart from styrenic systems, some

efficient enantioselective oxyarylations have also

been reported. For example, Mazet and co-workers

have disclosed the enantioselective oxyarylation of

dihydrofuran, although details regarding the mecha-

nism of such reaction were provided only recently.^[9]

Scheme 2. Initial results in the development of an enanti-

oselective oxy-Heck-Matsuda reaction.

Although modest, these results clearly demonstrated

the feasibility of an enantioselective oxy-Heck-

Matsuda reaction, and so they encouraged us to rein-

vestigate the oxy-Heck-Matsuda arylations previous-

ly reported by Sefkow,^[6]employing chiral N,N-

ligands and anethole (2c) as model substrate (Table

1).

We first established a protocol using styrene 2c,

Pd₂dba₃(5 mol%), N,N-ligand (20 mol%), CaCO₃(1

equiv) in methanol at 60°C (Table 1). Gratifyingly,

arylations with the pyridine-oxazoline (PyOx) L2,

pyrazine-bisoxazoline (PyraBox) L6, and the pyrimi-

dine-bisoxazoline (PyriBox) L7 (Table 1, entries 1, 5

and 6) provided good results regarding yields, dia-

stereoselectivities, and enantioselectivities. PyOx L2

afforded the trans aryl dihydrobenzofuran 7a in an

excellent 83% yield and a good 86:14 er (entry 1),

whereas other ligands with different electronic sub-

stituent effects, such as L3, L4 and L5, afforded

chemical yield up to 74% and er up to 85:15. Consid-

erable erosion in the enantiomeric ratio was observed

when we changed the oxazoline substituent to isopro-

pyl group (L8) or the pyridine moiety to quinoline

(L9) or isoquinoline (L10). Notably, the PyriBox L7

furnished the trans product 7a in 70% yield and

90:10 er. Decreasing L7 loading to 10 mol% led to a

slight decrease in er to 88:12, but a small increase in

the chemical yield to 74% (entries 6 and 19). De-

creasing L7 loading even further led to considerable

Scheme 1. Stereoselective oxy-Heck arylations of styrenic

systems.

Results and Discussion

We commenced our investigation with a few “proof-

of-concept” oxy-Heck-Matsuda arylations. Firstly,

we chose to test the oxyarylation of styrenes 2a and

2b with 2-hydroxybenzene diazonium tetrafluorobo-

rate 1a,^[10]using the chiral N,N-ligands L1 and L2 in

isopropanol as solvent (Scheme 2). 4-Methoxy-

styrene 2a afforded the desired dihydrobenzofuran 3

in only 21% yield in 53:47 er, together with the acy-

clic isopropyl dihydrostilbene 4 in 25% yield as a

2

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Advanced Synthesis & Catalysis

erosion in yields (entries 20 and 21). Bisoxazoline

ligands L11, L12, L13, and L14 furnished the Heck

product in good to low yields (61%, 59%, 23%, and

12% respectively), with L13 providing the Heck

product in only 75:25 er (entry 12). Tridentate ligand

L15 provided the aryl dihydrobenzofuran trans-7a in

only 20% yield in 55:45 er (entry 14).

Arenediazonium salt counter-ions also seem to have

influence in the reaction outcome.^{[10g, 11]}A compari-

son between tetrafluoroborates, tosylates and hex-

afluorophosphates indicated tetrafluoroborates as the

best performing arenediazonium salts in the present

study (entries 1, 15 and 16). Overall, these results

constituted promising results in view of previous

literature precedents for the intermolecular oxy-Heck

arylation of 2H-chromenes compounds, mainly those

provided by ligands L2 and L7.^[12]

Table 1. Optimization of the enantioselective oxy-Heck-

Matsuda reaction.

To find the best reaction conditions, a variety of

Pd sources, bases, and solvents were screened with

the best performing ligands L2 and L7 (Table 2).

Various Pd(II) and Pd(0) sources were evaluated

(entries 1-6) with Pd₂dba₃performing the best.

Among the organic and inorganic bases evaluated

(entries 7-9) only CaCO₃provided the oxy-Heck-

Matsuda adduct in good yield. In the absence of a

base, er decreased significantly (entry 10). Non-

alcoholic solvents afforded the desired oxy-Heck-

Matsuda product in lower yields (entries 16-20). Cu-

riously, acetone as solvent provided the best er but in

very low yield (entry 20).

Entry^a

L

X

trans-7a^b

er^c

dr^c

-

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17^d

18^e

19^e

20^g

21^h

L2

L3

L4

L5

L6

L7

L8

L9

L10

L11

L12

L13

L14

L15

L2

L6

L7

BF₄

83%

74%

48%

46%

62%

70%

31%

39%

35%

61%

59%

23%

12%

20%

44%

62%

78%

60%

74%

55%

48%

86:14

85:15

72:28

80:20

88:12

90:10

70:40

80:20

66:34

62:38

54:46

75:25

56:44

55:45

83:17

85:15

88:12

86:14

80:20

20:1

13:1

16:1

17:1

19:1

20:1

12:1

20:1

10:1

18:1

nd

Table 2. Optimization of the enantioselective oxy-Heck-

Matsuda reaction.

nd

11:1

17:1

11:1

20:1

15:1

20:1

-

PF₆

Deviation from

Yield

OTs^-

Entry

Ligand

standard

conditions^a

none

er^c

(%)^b

-

BF₄

-

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

L2

L2^d

L2

L7

78%

59%

49%

74%

42%

28%

36%

25%

76%

74%

60%

23%

56%

8%

85:15

84:16

83:17

85:15

88:12

77:23

88:12

84:16

74:16

86:14

84:16

86:14

58:42

73:17

90:10

-

Pd(acac)₂

Pd(MeCN)₄(BF₄)

Pd(OPiv)₂

Pd(MeCN)₂Cl₂

Pd(TFA)₂

ZnCO₃

-

L7

-

BF₄

DTBMP

NaOAc

no base

none

EtOH

n-BuOH

i-PrOH

DMC

EtOAc

MeCN

THF

acetone

14%

33%

26%

22%

a)

Conditions: 1a (0.15 mmol), 2c (0.1 mmol), Pd₂dba₃(5

mol%), Ligand (20 mol%), CaCO₃(0.1 mmol), MeOH (0.1

b)

1

c)

e)

g)

M). Determined by H NMR using internal standard.

Determined by chiral HPLC. ^d)using 12 mol% of ligand.

^a)Standard condition: 1a (0.15 mmol), 2c (0.1 mmol), [Pd]

(10 mol%), L7 (10 mol%) or L2 (12 mol%), CaCO₃(0.1

f)

using 10 mol% of the ligand. nd = not determined.

using 7 mol% of ligand. ^h)using 5 mol% of ligand.

b)

1

mmol), MeOH (0.1 M), 60°C, 2 h. Determined by H

NMR using 1 equiv of 1-bromo-3,5-bistrifluoromethyl-

c)

benzene as internal standard.

Determined by chiral

d)

HPLC.

using

20

mol%

of

ligand.

Table 3. Scope of the oxy-Heck-Matsuda reaction.

3

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Advanced Synthesis & Catalysis

a)

Conditions: 1a-h (0.30 mmol), 2c-h (0.2 mmol), Pd₂dba₃(5 mol%), L2 (12 mol%) or L7 (10 mol%), CaCO₃(0.2

mmol), MeOH (0.1 M). ^b)Isolated yields. ^c)Enantiomeric ratio determined by chiral HPLC or SFC.

Based on the results displayed in Tables 1 and 2, we

expanded the scope of the oxy-Heck-Matsuda with

several hydroxy diazonium salts and substituted

styrenic systems, focusing on ligands L2 and L7.

(Table 3).

Aryldiazonium salts 1b-h bearing electron with-

drawing and electron donating groups were checked.

Oxy-arylation was effective regardless of the elec-

tronic nature of the substituents, providing the aryl

dihydrobenzofuran in moderate to good yields, high

diastereoselectivity and moderate enantiomeric ratios.

In general, aryldiazonium salts bearing electron do-

nating groups provided higher yields of the Heck

products (Table 3, compounds 7d, 7f, 7g and 7h).

ty (20:1 dr). Alkyl substituted hydroxy-

benzenediazonium salts provided the corresponding

aryl dihydrobenzofurans 7f, 7g and 7h in yields vary-

ing from 42% (L2) to 76% (L7), in good to excellent

diastereoselectivities (dr from 12:1 up to 19:1) with

moderate to good er ranging from 78:22 to 87:13.

Substituents on the styrenic system are also well

tolerated. The arylation of styrenes containing an

isopropyl group in the olefin moiety provided dihy-

drobenzofurans 7i and 7j with moderate yield in high

diastereoselectivity (>20:1) with er up to 83:17 using

L7. Styrene bearing an ortho methoxy group on the

aromatic ring provided the oxy-product 7k in 31%

yield, moderate dr (7:1) and enantiomeric ratios of

76:24 for the major product and 72:28 for the minor

one. The 3,4-dimethoxy styrene afforded the desired

trans aryl dihydrobenzofuran 7l in a good 71% yield

With

L2

as

ligand,

the

4-nitro-2-

hydroxybenzenediazonium salt afforded the desired

trans aryl dihydrobenzofuran 7b in a moderate enan-

tiomeric excess of 80:20 er, but in a low yield of 33%. in 88:12 er. The challenging styrene containing a free

Ligand L7 performed better regarding er (86:14) and

diastereoselectivity (trans/cis 20:1), but without im-

provement on yield (33%). Following the same trend,

the diazonium salt containing a 4-carboxymethyl

substituent afforded 7e with similar er and dr, with an

improved yield of 52%. On the other hand, the 5-

nitro-2-hydroxy-benzenediazonium 1c led to com-

plete recovery of the starting olefin. This result is

consistent with the critical nature of the hydroxy-

phenyl diazonium salts as putative phenol/phenolate

intermediate as previously described by Schmidt.^[10g]

Aryl diazonium salt 1d bearing a chlorine substituent

furnished the oxy-Heck-Matsuda product 7d in an

improved yield of 71% (L2) and 66% (L7), with a

moderate er of 75:25 and excellent diastereoselectivi-

phenol provided 7n 53% yield and reasonable enanti-

oselectivity (88:12 er) employing L7, while the pro-

tected styrene containing a labile 4-OTIPS group

furnished the oxy-Heck-Matsuda product 7m in 41%

yield (mmol scale) in a moderate 78:22 er, and excel-

lent diastereoselectivity (18:1).

The influence of the olefin geometry was noticea-

ble when Z-anethole (10:1 Z/E mixture) and isoeuge-

nol (a 1:3 Z/E mixture) were oxyarylated (Table 4).

Z-anethole Z-2c gave the respective trans aryl dihy-

drobenzofuran ent-7a in high dr and a moderate

25:75 er, whereas isoeugenol 2i provided dihydro-

benzofuran 7o in low er probably due the 1:3 diaster-

eoisomeric mixture of the starting material. Notably,

the formation of the trans aryl dihydrobenzofuran

4

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Advanced Synthesis & Catalysis

from Z-anethole with an inverted enantioselectivity

was somewhat intriguing.

Concerning the stereochemistry of the oxy-Heck-

Matsuda products, the relative trans stereochemistry

of the aryl dihydrobenzofurans was secured based on

NMR shifts and coupling constants reported to simi-

lar systems.^[13]

we decided to take an alternative route to conocarpan

starting with the free phenolic styrene 2h (route 2).

Gratifyingly, this styrene underwent a clean oxyaryla-

tion at gram-scale to furnish the corresponding trans-

aryl dihydrobenzofuran 7n in 57% yield as a single

diastereomer (>20:1) in 86:14 er. Moreover, at this

scale it was also possible to isolate previously uni-

dentified minor products of the oxy-Heck-Matsuda

reaction. An interesting regioisomeric adduct 10a was

also obtained in 26% yield, together with a Heck

diarylated product in 6% yield (see Experimental

Section for details).^[17]These results provided a clear-

er picture of inner works of the oxy-Heck-Matsuda

reaction and might pave the way for further develop-

ments of this reaction.

Table 4. Evaluation of stereoisomers in oxy-Heck-

Matsuda reaction.

The phenol moiety was then treated with TIPSCl

to give the TIPS protected aryl dihydrobenzofuran in

83% yield. Bromination as described in Scheme 3

provided aryl bromide 11 in 77% yield in 85:15 er.

The critical Suzuki cross-coupling of 11 occurred

uneventfully this time to provide TIPS-protected

conocarpan, which upon a standard desilylation pro-

cess gave the unnatural (2R,3R)--conocarpan 9 in

a)

Conditions: 1a (0.30 mmol), 2c or 2i (0.2 mmol),

Pd₂dba₃(5 mol%), L7 (10 mol%), CaCO₃(0.2 mmol),

MeOH (0.1 M). Isolated yield. ^c)Enantiomeric ratio de-

b)

termined by chiral HPLC. ^d)Styrene substrate as a 10:1 Z/E

mixture. ^e)Styrene substrate as a 1:3 Z/E mixture.

As mentioned in the introduction, the trans 2,3-

dihydrobenzofuran core is present in a large number

of natural compounds, including neolignan (+)-

conocarpan 9.^[14]We envisioned that an enantioselec-

tive total synthesis of conocarpan 9 should provide

not only the opportunity to demonstrate the synthetic

potential of the method but also to rigorously assign

the absolute stereochemistry of the aryl dihydroben-

zofuran synthesized herein.

Due to structural similarities, aryl dihydrobenzofu-

ran 7a was used as starting material in our initial

synthesis of conocarpan 9 (Scheme 3). Aryl dihydro-

benzofuran 7a was then treated with NBS to provide

the expected aryl bromide in a regioselectively man-

ner, followed by demethylation with BBr₃to give the

brominated aryl dihydrobenzofuran 8 in 56% over

two steps. Suzuki cross-coupling of the brominated

dihydrobenzofuran 8 with trans-propenyl-boronic

acid led to -conocarpan in an overall yield of 32%

67% yield over two steps with a 88:12 er. In summa-

[15]

over four steps in 88:12 er

as a surprising 7:1

a)

b)

NBS, THF/H₂O, rt, overnight. BBr₃, DCM, –78°C to

trans/cis diastereomeric mixture (route 1). As the

precursor bromo dihydrobenzofuran 8 was a 15:1

trans/cis mixture, epimerization was clearly occur-

ring during the Suzuki coupling, due to the basic

condition of the reaction, a feature detected in some

previous synthesis of conocarpan.^[16a]

c)

rt, 2h. trans-propenyl-boronic acid, Pd(dppf)Cl₂·DCM,

K₂CO₃, Toluene/H₂O, 90°C, 5h. ^d)1a (1.1 Equiv), 2h (7.68

mmol), Pd₂dba₃(5 mol%), L7 (10 mol%), CaCO₃(7.68

e)

mmol), MeOH. 60°C, 2h.

TIPSCl, imidazole, DCM,

f)

overnight. Pd(PPh₃)₂Cl₂, K₂CO₃, THF/H₂O, 65°C, over-

night. ^g)TBAF, THF/AcOH.

Comparison of the specific optical rotation of our

synthetic conocarpan ([]_Dobs – 55 (c 1.26, MeOH)

with that reported for the natural (2S,3S)-conocarpan

([]_D^lit+ 103 (c 1.03, MeOH) indicated that we have

synthesized the unnatural (2R,3R)-conocarpan.^[16]

Because of the epimerization of the trans-aryl di-

hydrobenzofuran in the Suzuki cross-coupling step,

Scheme 3. Synthetic routes for the total synthesis of the

neolignan (–)-conocarpan 9.

Figure 2. Rationale for formation of (2R,3R)-2-methyl-3-aryl dihydrobenzofuran-7a.

5

10.1002/adsc.201701278

Advanced Synthesis & Catalysis

rans allowed a rationale for the enantioselective oxy-

Heck-Matsuda reaction.

ry, -conocarpan was prepared in a total of 5 steps

and 24% overall yield from styrene 2h.

A plausible mechanism for this reaction is

shown in Figure 2 starting with styrene trans-2c. It

starts with a ligand exchange involving Pd₂(dba)₃and

the N,N- ligand to form the chiral Pd(0) complex A,

which upon oxidative addition to the aryldiazonium

salt forms the cationic Pd complex B. Coordination

with the styrenic olefin (intermediate C), followed by

the key enantio-determining carbopalladation step

then leads to complex D. At this stage in the catalytic

cycle, it is conceivable that we have two possible

pathways.

As shown in Scheme 3, further evidence for the

absolute stereochemical assignments came from a

single crystal X-ray analysis of the intermediate bro-

mo-aryl dihydrobenzofuran 8, which confirmed the

absolute stereocenters of aryl dihydrobenzofuran 8 as

2R and 3R (see Supporting Information for de-

tails).^[18]Assignment of the absolute stereochemistry

of the trans-aryl dihydrobenzofurans synthesized in

the present study as 2R, 3R was done by analogy. It is

important to point out that assignment of the stereo-

centers in the structure of trans aryl dihydrobenzofu-

Figure

3.

Rationale

for

formation

of

ent-(2S,3S)-2-methyl-3-aryl

dihydrobenzofuran-7a.

C–C bond rotation of the phenol moiety would place

the phenolic hydroxyl group in the appropriate posi-

tion for a S_N2-type displacement of Pd resulting in

the minor cis-7a product and regeneration of Pd(0).

6

10.1002/adsc.201701278

Advanced Synthesis & Catalysis

On the other hand, the major trans-7a Heck

Styrene 12a bearing an electron donating group

was evaluated in comparison to styrene 2b. Oxy-

arylation was very effective, providing the aryl dihy-

drobenzofuran 13a in an excellent 90% yield, but in a

disappointing 50:50 er. 1,2-Dimethyl and 2,2-

dimethyl styrenes 12c and 12b provided the respec-

tive benzofurans in moderate to good yields in mod-

erate enantiomeric ratios of 75:25 and 79:21.

The oxy-Heck-Matsuda arylation of carbocyclic

systems bearing a styrenic double bond were also

evaluated. Styrene 12d afforded the desired aryl di-

hydrobenzofuran in a good 68% yield, in a rather low

er of 58:42. The carbocyclic styrene 12e and dihy-

dronaphthalene 12f performed slightly better regard-

ing er (up to 76:24), but in only moderate yields

(50% and 34%, respectively), probably due to the

sterical hindrance around the double bond. The ben-

zyl cinnamyl alcohol 12g provided the dihydrobenzo-

furan 13g in 41% yield in a reasonable 76:24 er. Fol-

lowing the same trend, the styrene containing the

bulkier phthalimide group 12h afforded a structurally

complex aryl dihydrobenzofuran as a single diastere-

omer with a reasonably good 87:13 er in 23% yield

(see Experimental Section).

product is probably derived from the formation of the

more stable oxypalladium species like complex E.

The literature has precedents for such palladacycle

species,^[19]which upon reductive elimination would

then yield the major trans aryl dihydrobenzofuran-7a.

The formation of the ent-trans aryl dihydrobenzo-

furan product starting from the predominantly cis-

olefinic anethole can be rationalized by a similar

mechanism involving complexes D’, E’ and F’. The

cyclic oxypalladium complex E’ displays an unfavor-

able cis relationship between the aryl and methyl

groups. The equilibrium should then favor complex

F’ which by a S_N2-like displacement forms the ob-

served major ent-trans-7a with 2S,3S configuration.

Table 5. Evaluation of substitution pattern of styrenes in

the enantioselective oxy-Heck-Matsuda reaction.

Conclusion

In conclusion, in this study we present the first

examples of an effective enantioselective oxy-Heck-

Matsuda reaction using a diversity of styrenic sub-

strates. The reaction proceeds in moderate to good

yields, with high diastereoselectivity to the trans aryl

dihydrobenzofurans (up to >20:1) in moderate to

good enantioselectivity of up to 90:10. Application of

this new enantioselective method has allowed the

total synthesis of the unnatural -conocarpan in a

concise manner (5 steps) in 24% overall yield, thus

allowing an unequivocal assignment of the absolute

stereochemistry of the oxy-Heck-Matsuda adducts.

Stereochemical assignments made also possible to

put forward a possible mechanism for these novel

enantioselective oxy-Heck-Matsuda reactions, open-

ing up new synthetic opportunities using aryl diazo-

nium salts. Further developments and applications of

these novel enantioselective oxy-Heck-Matsuda reac-

tions are ongoing, and will be reported in due course.

Experimental Section

1. General Information

a)

All the reactions were carried out in 4 mL vessels under air

(open-vessel), unless stated otherwise. Reaction tempera-

tures are reported as the temperature of the heat transfer

medium surrounding the vessel. Solvents used for chroma-

tography were technical grade and were distilled prior to

use. Commercially available chemicals were purchased

from Sigma-Aldrich Chemical Co. or Strem Chemicals Inc.

and used as received, unless otherwise noted. Analytical

thin layer chromatography (TLC) was performed employ-

ing Merck^®Silica gel 60 F254 plates. Visualization was

accomplished with UV light and phosphomolybdic acid or

ceric ammonium molybdate staining solutions followed by

Conditions: 1a (0.3 mmol), 2 (0.2 mmol), Pd₂dba₃(5

mol%), L7 (10 mol%), CaCO₃(0.2 mmol), MeOH (0.1 M).

b)

c)

Isolated yield. Enantiomeric ratio determined by chiral

HPLC or SFC.

To test the robustness of the method to more complex

benzofurans, we have also investigated the scope of

the oxy-Heck-Matsuda with styrene bearing different

substitution patterns (Table 5).

7

10.1002/adsc.201701278

Advanced Synthesis & Catalysis

heating. Flash column chromatography was performed on

Merck^®Silica gel 60 (230-400 mesh) as stationary phase

and hexanes:EtOAc mixtures as mobile phases, following

raphy (silica, hexanes/EtOAc) to provide the correspond-

ing styrenes.^[24]

[20]

the flash chromatography procedure described by Still.

(E)-1-(but-2-en-2-yl)-4-methoxybenzene (12c). Follow-

ing the general procedure, a THF solution (20 mL) of 4-

methoxyacetophenone (0.3 g, 2.0 mmol), ethyltri-

phenylphosphonium bromide (0.90 g, 2.4 mmol), and n-

BuLi (2.4 mL, 1 M in hexane) provided styrene 12c as a

pale yellow oil (172 mg, 50% yield) as a 1:1 E/Z diastereo-

isomeric mixture. The isomerization step was performed

NMR analyses were performed on Bruker^®250, 400, 500

or 600 MHz spectrometers in solvents as indicated. 1,3-

Bis(trifluoromethyl)-5-bromobenzene was used as internal

1

standard for the determination of chemical yields by H

1

NMR. Chemical shifts (δ) for H and ¹³C NMR spectra are

given in ppm relative to TMS. The residual solvent signals

1

were used as references for H and ¹³C NMR spectra and

using

a dry DCM solution (20 mL) of styrene,

the chemical shifts converted to the TMS scale (CDCl₃: δH

= 7.26 ppm, δC = 77.16 ppm; CD₃OD: δH = 3.31 ppm, δC

= 49.00 ppm). Data are reported as follows: chemical shift

(δ), multiplicity, coupling constant (J ) in Hertz and inte-

grated intensity. Exact ESI mass spectra were recorded on

a Waters Xevo Q-TOF using electrospray ion source, posi-

tive mode, (ESI) and time-of-flight (TOF) analyzer. Opti-

cal rotations (α) were measured on a Perkin Elmer Model

Pd(MeCN)₂Cl₂(51.5 mg, 20 mol%) for 24 h at room tem-

perature. The purified product was obtained in 80% yield

(136 mg) as a pale yellow oil (7:1 E/Z diastereoisomeric

mixture). ¹H NMR (400 MHz, CDCl₃) δ = 7.31 (maj, d, J

= 8.8, 2H), 7.15 (min, d, J = 8.8, 2H), 6.89 (min, d, J = 8.8,

2H), 6.85 (maj, d, J = 8.8, 2H), 5.53 (min, qq, J = 6.9, 1.4,

1H), 5.79 (maj, qq, J = 6.6, 1.2, 1H), 3.82 (min, s, 4H),

3.81 (maj, s, 3H), 2.04 – 1.98 (maj + min, m, 4H), 1.79

(maj, dq, J = 6.9, 1.2, 3H), 1.62 (min, dq, J = 6.9, 1.5, 3H).

¹³C NMR (101 MHz, CDCl₃) (7:1 E/Z diastereoisomeric

mixture). δ = 158.48, 158.21, 136.82, 136.33, 134.97,

134.31, 129.28, 126.64, 121.25, 120.99, 113.66, 113.54,

55.42, 25.61, 15.66, 15.06, 14.41.

o

341 polarimeter at 20 C using a quartz glass cell (10 mm

path length). Specific rotations are given in

[deg.cm³g⁻¹dm⁻¹] and the concentration of the samples is

expressed in [g.100 mL^–1]. Enantiomeric ratios (er) were

calculated through integration of the enantiomers corre-

sponding signals, set by racemic samples. The products

were analyzed by Supercritical Fluid Chromatography

(SFC) on an Agilent Technologies 1260 SFC Infinity

equipped with an DAD detector using Daicel Chiralpak^®

chiral columns as stationary phase and CO₂:MeOH mix-

tures as mobile phase. Alternatively, it was used High

Performance Liquid Chromatography (HPLC) on an Ag-

ilent Technologies 1260 Infinity equipped with an UV

detector using Daicel Chiralpak^®chiral columns as station-

ary phase and hexanes:ⁱPrOH mixtures as mobile phase.

When applicable, diastereomeric ratios (dr) were deter-

mined by¹H-NMR of the crude reaction mixture.

(E)-2,4-dimethoxy-1-(prop-1-en-1-yl)benzene (2e). Ac-

cording to the general procedure, a THF solution (20 mL)

of 2,4-dimethoxybenzaldehyde (0.35 g, 2.0 mmol), ethyl-

triphenylphosphonium bromide (0.90 g, 2.4 mmol), and n-

BuLi (2.4 mL, 1 M in hexane) provided styrene 2e as a

pale yellow oil (264 mg, 75% yield) with a E/Z diastere-

oselectivity of 2:1. The isomerization step was performed

in a dry DCM solution (15 mL) of the olefin containing

Pd(MeCN)₂Cl₂(76.2 mg, 20 mol%) for 24 h at room tem-

perature. Styrene 2e was obtained as a pale yellow oil in

31% yield (82.8 mg) as a 20:1 E/Z diastereoisomeric mix-

ture.¹H NMR (400 MHz, CDCl₃) δ = 7.29 (d, J = 8.3, 1H),

6.61 (dq, J = 15.8, 1.8, 1H), 6.47 – 6.41 (m, 2H), 6.10 (dq,

J = 15.8, 6.6, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 1.87 (dd, J =

6.6, 1.8, 3H).¹³C NMR (101 MHz, CDCl₃) δ = 159.89,

157.34, 127.17, 125.39, 124.54, 120.33, 104.81, 98.55,

55.56, 55.47, 19.00.

2. Synthesis of Substrates and Ligands

The arenediazonium salts were prepared according to the

literature.^{[11, 21]}Ligands L2, L5, L9, L11, L14, L15 were

purchased from Sigma-Aldrich and used as received. Other

ligands such as L1,^[2b], L3,^[2i]L4,^[2g]L6,^[2b]L7,^[2b]L8,^[29]

L10_,^[30]and L13,^[22]were prepared according to previous

work. Styrenes 2a (4-Methoxystyrene CAS 637-69-4), 2b

(-Methylstyrene CAS 98-83-9) and trans-2c (trans-

anethole CAS 4180-23-8), 2f (1,2-Dimethoxy-4-

propenylbenzene CAS 93-16-3), 2i (Isoeugenol CAS 97-

54-1), 12f (1,2-Dihydronaphthalene CAS 447-53-0) were

purchased from Sigma-Aldrich and used as received. Ole-

fin 12h was prepared according to a previously reported

procedure, followed by recrystallization in chloroform.^[23]

The following protocols were employed without optimiza-

tion of the reaction conditions.

1-methoxy-4-(prop-1-en-2-yl)benzene (12a). According

to the general procedure, a THF solution (15 mL) of 4-

methoxyacetophenone (0.15 g, 1.0 mmol), methyltri-

phenylphosphonium bromide (0.536 g, 1.5 mmol), and n-

BuLi (1.5 mL, 1 M in hexane) provided styrene 12a as a

1

pale yellow oil. H NMR (250 MHz, CDCl₃) δ = 7.44 (d,

J = 8.9, 1H), 6.89 (d, J = 9.0, 1H), 5.34 – 5.28 (m, 1H),

5.03 – 4.98 (m, 1H), 3.83 (s, 2H), 2.15 (dd, J = 1.5, 0.8,

2H). ¹³C NMR (63 MHz, CDCl₃) δ = 159.19, 142.68,

133.87, 126.72, 113.66, 110.82, 110.78, 110.75, 55.39,

22.04.

2.1. General procedure for the synthesis of styrenes 12c,

2e, 12a, and 2h (Wittig olefination followed by palladi-

um isomerization)

(E)-4-(prop-1-en-1-yl)phenol (2h). According to the gen-

eral procedure,

a THF solution (100 mL) of 4-

hydroxybenzaldehyde (1.22 g, 10.0 mmol), ethyltri-

phenylphosphonium bromide (7.42 g, 20 mmol), and n-

BuLi (2.0 M in cyclohexane, 20.0 mmol, 10.0 mL) provid-

ed styrene 2h in 58% yield (5.75 mmol, 0.772 g) as a white

solid. The isomerization step was performed using a dry

DCM solution (15 mL) of olefin containing Pd(MeCN)₂Cl₂

(0.224 g, 0.863 mmol, 15 mol%) for 24 h at room tempera-

ture. Styrene 2h was obtained in 91% yield (0.702 g, 5.23

mmol) with >20:1 E/Z diastereoselectivity as an amor-

phous white solid. ¹H NMR (400 MHz, CDCl₃) δ = 7.25 –

7.17 (m, J = 8.5, 2H), 6.82 – 6.71 (m, 2H), 6.38 – 6.28 (m,

1H), 6.08 (dq, J = 15.7, 6.6, 1H), 4.67 (s, 1H), 1.85 (dd, J

= 6.6, 1.6, 3H). ¹³C NMR (101 MHz, CDCl₃) δ = 154.58,

131.20, 130.41, 127.23, 123.72, 115.49, 18.52.

To a suspension of alkyltriphenylphosphonium bromide

(1.2 equiv) in anhydrous THF (0.1 mmol/mL), at 0°C un-

der nitrogen atmosphere, it was added n-BuLi (1.2 equiv).

After stirring at 0°C for 30 min, a solution of the corre-

sponding aldehyde or ketone (1 equiv) in anhydrous THF

was added. The mixture was allowed to warm to room

temperature and stirred overnight. The reaction was

quenched by the addition of saturated aqueous solution of

NH₄Cl (10 mL). The layers were separated, and the aque-

ous layer was extracted with Et₂O (3 × 20 mL). The com-

bined organic layers were dried over Na₂SO₄, filtered, and

concentrated under reduced pressure. The residue was

purified by flash column chromatography (silica, hex-

anes/EtOAc 98:2) to afford the corresponding styrene.

Next, an E:Z mixture of styrene and Pd(MeCN)₂Cl₂(20

mol%) in anhydrous DCM (1 mmol/mL) was stirred over-

night at room temperature under nitrogen. The mixture was

then diluted with Et₂O and filtered through a short pad of

Celite. The solvent was removed under reduced pressure

and the crude was purified by flash column chromatog-

2.2. General procedure for the synthesis of styrenes 12e,

12d, and 2d (Grignard addition to the aldehydes and

ketones followed by elimination)

To a suspension of the corresponding aldehyde or ketone

(1 equiv) in anhydrous THF (0.1 M), at 8°C under nitro-

8

10.1002/adsc.201701278

Advanced Synthesis & Catalysis

gen, it was added the Grignard reagent solution (1.1 equiv). 12b in 54% yield (878 mg) as a pale yellow oil.^{[25] 1}

H

The mixture was then allowed to warm to room tempera-

ture and stirred for 2h. Next, the reaction was quenched by

the addition of a saturated solution of NH₄Cl (20 mL). The

layers were then separated, and the aqueous layer was

extracted with ethyl acetate (3 × 20 mL). The combined

organic layers were dried over Na₂SO₄, filtered, and con-

centrated under reduced pressure. The residue was then

NMR (400 MHz, CDCl₃) δ = 7.18 (d, J=8.7, 2H), 6.87 (d,

J=8.7, 2H), 6.23 (s, 1H), 3.82 (s, 3H), 1.90 (d, J=1.0, 3H),

1.86 (d, J=0.8, 3H). ¹³C NMR (101 MHz, CDCl₃) δ =

157.67, 133.97, 131.38, 129.81, 124.53, 113.49, 55.24,

26.83, 19.33.

2.4. Preparation of cis-anethole (Z)-1-methoxy-4-(prop-

1-en-1-yl)benzene (cis-2c)

transferred to

a thick walled tube containing 4-

toluenesulfonic acid (20 mol%) in toluene (0.5 M), sealed

under nitrogen, and heated at 110°C (oil bath) for 6 h. The

crude was purified by flash column chromatography (silica,

hexanes/EtOAc 98:2) to afford styrene 12e, 12d and 2d.

1^ststep: To a stirred mixture of 4-anisaldehyde (1.36 g,

1.21 mL, 10 mmol) and carbon tetrabromide (6.6 g, 20

mmol) in dichloromethane (25 mL) at 0 ºC, it was added

triphenyl phosphine (10.5 g, 40 mmol) portionwise over 15

minutes. The resulting solution was then stirred at 0 ºC for

2 h. Next, the reaction mixture was quenched with petrole-

um ether (100 mL), and the resulting precipitate was fil-

tered through a short pad of SiO₂. The filtrate was evapo-

rated in vacuo to obtain a crude mixture, which was further

purified by flash column chromatography (1% EtOAc in

hexane as eluent) to give 2.6 g (quantitative yield) of 1-

(2,2-dibromovinyl)-benzene (2c’) as a yellow oil.^{[26] 1}H

NMR (250 MHz, CDCl₃) δ = 7.52 (d, J = 8.9, 2H), 7.42 (s,

1H), 6.90 (d, J = 8.9, 2H), 3.83 (s, 3H). ¹³C NMR (63

MHz, CDCl₃) δ = 159.78, 136.41, 129.99, 127.90, 113.90,

87.36, 55.39.

4'-methoxy-2,3,4,5-tetrahydro-1,1'-biphenyl (12e). Ac-

cording to the general procedure, a THF solution (50 mL)

of cyclohexanone (0.49 g, 0.52 mL, 5.0 mmol), 4-

methoxyphenylmagnesium bromide solution (12 mL, 0.5

M in THF) was converted into the respective alcohol as a

viscous yellow oil. The elimination step was performed

using a toluene solution (20 mL) of alcohol and 4-

toluenesulfonic acid (0,1722 g, 1 mmol, 20 mol%) for 24 h

under reflux. The styrene 12e was obtained in 60% yield

(606 mg) as a yellow oil. ¹H NMR (600 MHz, CDCl₃) δ =

7.40 – 7.35 (m, 2H), 6.92 – 6.88 (m, 2H), 6.10 (tt, J = 3.9,

1.7, 1H), 3.84 (s, 3H), 2.47 – 2.41 (m, 2H), 2.29 – 2.22 (m,

2H), 1.88 – 1.80 (m, 2H), 1.76 – 1.67 (m, 2H). ¹³C NMR

(151 MHz, CDCl₃) δ = 158.48, 135.94, 135.36, 125.96,

123.13, 113.59, 55.28, 55.24, 27.54, 25.92, 23.21, 22.31.

2^ndstep: the dibromoolefin 2c’ (1.64 g, 5.63 mmol) ob-

tained above was then dissolved in dry THF (50 mL) and

cooled to 8°C under N₂. n-BuLi (35 mmol, 1M in hex-

ane) was added dropwise over 30 min and the solution was

stirred at 8°C for 1h, followed by the addition of iodo-

methane (1.06 g, 0.47 mL, 7.5 mmol,) at 8°C. The mix-

ture was warmed to room temperature and left stirring for

2 h. The reaction was then quenched by the addition of

saturated aqueous solution of NaHCO₃(15 mL). The aque-

ous phase was extracted with hexane (4 × 20 mL), and the

combined organic phases were dried over Na₂SO₄. Column

chromatography (silica, hexanes) afforded 1-methoxy-4-

(prop-1-yn-1-yl)benzene (2c’’) in 83% yield (0.686 g, 4.7

mmol) as a colorless oil. ¹H NMR (250 MHz, CDCl₃) δ =

7.34 (d, J = 8.8, 1H), 6.82 (d, J = 8.8, 1H), 3.79 (s, 2H),

2.04 (s, 2H). ¹³C NMR (63 MHz, CDCl₃) δ = 159.13,

132.90, 116.33, 113.93, 84.18, 79.56, 77.67, 77.16, 76.66,

55.29, 4.34.

1-(cyclohexylidenemethyl)-4-methoxybenzene

(12d).

According to the general procedure, a THF solution (50

mL) of benzaldehyde (0.60 mL, 5.0 mmol), cyclohexyl-

magnesium chloride (6 mL, 1M in diethyl ether) was con-

verted into the respective alcohol as a viscous yellow oil.

The elimination step was performed using a toluene solu-

tion (16 mL) of alcohol and 4-toluenesulfonic acid (0,1722

g, 1 mmol, 20 mol%) for 24 h under reflux. The styrene

12d was obtained in 27% yield (278 mg) as a yellow oil.

¹H NMR (500 MHz, CDCl₃) δ = 7.15 (d, J = 8.4, 2H),

6.87 (d, J = 8.7, 2H), 6.19 (s, 1H), 3.81 (s, 3H), 2.44 – 2.34

(m, 2H), 2.29 – 2.21 (m, J = 5.4, 2H), 1.73 – 1.48 (m,

6H).¹³C NMR (126 MHz, CDCl₃) δ = 157.83, 142.33,

131.09, 130.10, 121.48, 113.57, 55.34, 37.73, 29.53, 28.75,

27.98, 26.86.

3^rdstep: 1-Methoxy-4-(prop-1-yn-1-yl)benzene 2c’’ (73.0

mg, 0.5 mmol), KOH (42.0 mg, 0.75 mmol), Pd(OAc)₂

(4.6 mg, 4 mol%), and DMF (1.0 mL) were placed in a

round bottomed flask (10 mL) under a nitrogen atmosphere,

and heated in an oil bath at 140°C under stirring for 6 h.

Next, the reaction mixture was cooled to room temperature,

dissolved with EtOAc, filtered through a short pad of silica

and the pad was washed again with EtOAc (3 × 10 mL).

After evaporation of the solvent, the crude product was

purified by flash column chromatography (silica, hex-

anes/EtOAc 99:1) to afford the corresponding cis-anethol

(E)-1-methoxy-4-(3-methylbut-1-en-1-yl)benzene (2d).

According to the general procedure, a THF solution (50

mL) of isovaleraldehyde (0.43 g, 0.54 mL, 5.0 mmol), 4-

methoxyphenylmagnesium bromide solution (12 mL, 0.5

M in THF) was converted into the respective alcohol as a

viscous yellow oil. The elimination step was performed

using a toluene solution (20 mL) of alcohol and 4-

toluenesulfonic acid (0.1722 g, 1 mmol, 20 mol%) for 24 h

under reflux. The styrene 2d was obtained in 57% yield

(501 mg) with >20:1 E/Z diastereoselectivity as a pale

1

yellow oil. H NMR (400 MHz, CDCl₃) δ = 7.29 (d, J =

(2c) in 39% yield (10:1 E/Z diastereomeric mixture).^{[27] 1}

H

8.7, 2H), 6.84 (d, J = 8.8, 2H), 6.29 (d, J = 16.0, 1H), 6.06

(dd, J = 15.9, 6.8, 1H), 3.80 (s, 3H), 2.45 (od, J = 6.7, 6.7,

1.2, 1.2, 1H), 1.08 (d, J = 6.8, 6H). ¹³C NMR (101 MHz,

CDCl₃) δ = 158.77, 136.10, 130.94, 127.16, 126.30,

114.05, 55.43, 31.61, 22.71.

NMR (250 MHz, CDCl₃) δ = 7.24 (d, J = 8.6, 2H), 6.87 (d,

J = 8.7, 2H), 6.37 (d, J = 11.6, 1H), 5.69 (dq, J = 11.5, 7.2,

1H), 3.81 (s, 3H), 1.89 (dd, J = 7.2, 1.7, 3H). ¹³C NMR

(63 MHz, CDCl₃) δ = 158.25, 130.48, 130.13, 129.41,

125.23, 113.69, 55.38, 14.72.

2.3. Procedure for the synthesis of styrenes 12b (Ku-

mada cross-coupling)

2.5. Preparation of O-benzyl cinnamyl alcohol (12g)

1-methoxy-4-(2-methylprop-1-en-1-yl)benzene (12b). To

a suspension of 4-bromoanisole (1.87 g, 1.25 mL, 10.0

mmol), Pd₂(dba)₃(228 mg, 2.5 mmol%), PPh₃(262 mg, 10

mol%) in anhydrous THF (100 mL), under nitrogen, it was

added a 2-methyl-1-propenylmagnesium bromide solution

(30 mL, 15.0 mmol, 0.5 M in THF), and the mixture re-

fluxed for 8h. After cooling to rt, the mixture was

quenched with a saturated aqueous solution of NH₄Cl, and

then extracted with ether. The organic layer was dried with

Na₂SO₄and filtered. The filtrate was evaporated under

reduced pressure, and the residue was purified by flash

column chromatography (silica, hexanes) to afford styrene

The starting 4-methoxy cinnamyl acetate was synthesized

according to a reported procedure.^[28]4-Methoxy cinnamyl

acetate (0.989 g, 4.8 mmol) was added into a solution of

KOH (2.8 g, 50 mmol) in EtOH/H₂O (50 mL, 4:1) and

refluxed for 5 h. After cooling to room temperature, the

reaction mixture was washed with DCM (3 × 50 mL) and

the combined organic layers were washed with brine (1 ×

20 mL), and dried over Na₂SO₄. The solvent was removed

under reduced pressure to afford cinnamyl alcohol in 95%

yield (0.747 g) as viscous oil, which was used in the next

step without further purification.

9

10.1002/adsc.201701278

Advanced Synthesis & Catalysis

To a flame-dried round bottomed flask it was added NaH

(60% mineral oil dispersion; 90 mg, 2.2 mmol) followed

by the addition of dry THF (20 mL). The resulting suspen-

sion was cooled to 0°C, and the cinnamyl alcohol (219 mg,

1.5 mmol) was added. The reaction mixture was warmed

up to room temperature and stirred for 30 min. The reac-

tion was cooled again to 0 °C followed by the dropwise

addition of benzyl bromide (0.23 ml, 1.95 mmol), and

stirred for 6 h. Next, the cooling bath was removed and the

reaction was stirred at room temperature for another 18h.

The reaction was quenched with a saturated aqueous solu-

tion of NH₄Cl(10 mL), and extracted with EtOAc (2 × 20

mL). The organic layers were combined, dried over

Na₂SO₄, filtered and concentrated under reduced pressure

to provide the crude product. The crude was purified by

flash chromatography to provide O-benzyl 4-methoxy-

cinnamyl alcohol 12g in 37% overall yield (140 mg) as a

38.25. HRMS (ESI+) calculated to [C₁₅H₁₄O₂+ H⁺]:

227.1072, found: 227.1078.

2-phenyl-2-methyl-2,3-dihydrobenzofuran (5) was ob-

tained in 30% isolated yield (12.6 mg, 0.06 mmol) as a

colorless oil. The enantiomeric ratio of 60:40 was deter-

mined by HPLC analysis using Daicel Chiralpak^®OJ -H

o

column (4.6 mm × 250 mm) at 225 nm, 25 C and 5% i-

PrOH in n-hexane (1.0 mL.min^-1) as a mobile phase: t_R=

13.2 min (major), 16.5 min (minor). H NMR (500 MHz,

CDCl₃) δ = 7.47 (d, J = 7.4, 2H), 7.34 (t, J = 7.7, 2H),

7.28 – 7.21 (m, 1H), 7.18 – 7.10 (m, 2H), 6.89 (d, J = 8.0,

1H), 6.84 (t, J = 7.4, 1H), 3.43 (d, J = 15.4, 1H), 3.37 (d, J

= 15.4, 1H), 1.77 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ

= 158.96, 146.96, 128.49, 128.26, 127.17, 126.60, 125.16,

124.66, 120.55, 109.69, 89.21, 44.88, 29.44.

1

viscous yellow oil. H NMR (500 MHz, CDCl₃) δ = 7.40

4. General procedure for synthesis of aryl dihydroben-

zofurans 7a-7o, 13a-13h

– 7.27 (m, 7H), 6.86 (d, J=8.7, 2H), 6.58 (d, J=15.9, 1H),

6.20 (dt, J=15.9, 6.2, 1H), 4.57 (s, 2H), 4.18 (d, J=6.2, 2H),

3.81 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ = 159.45,

138.51, 132.43, 129.65, 128.56, 127.97, 127.84, 127.76,

123.94, 114.12, 72.20, 71.12, 55.43.

A 4 mL vial containing a magnetic stir bar was charged

with Pd₂(dba)₃(5 mol%, 0.010 mmol, 9.4 mg), ligand

L7(10.0 mol%, 0.020 mmol, 6.6 mg) and MeOH (1.0 mL).

The vial was closed and the reaction mixture was stirred at

2.6. Silylation of phenol 2h

o

60 C for 5 minutes to form the precatalyst. Next, CaCO₃

(1.0 equiv., 0.2 mmol, 20 mg), the substituted styrene 2a-i

or 12a-h (1.0 equiv., 0.2 mmol) and the arenediazonium

salt 1a-h (1.5 equiv., 0.3 mmol) were added, followed by

the addition of another 1.0 mL of MeOH. The vial was

then closed and allowed to stir at 60 °C until total con-

sumption of the styrene (TLC). After 2 hours, heating was

removed and the crude reaction mixture was diluted with

EtOAc, filtered through a short pad of silica, and the pad

was washed again with EtOAc (3 × 10 mL). After evapora-

tion of the solvent under reduced pressure, the crude mix-

ture was purified by flash column chromatography (silica

gel, hexanes/EtOAc as eluent) to afford the corresponding

Heck-Matsuda adducts 7a-7o and 13a-13h.

(E)-triisopropyl(4-(prop-1-en-1-yl)phenoxy)silane (2g).

To a solution of styrene 2h (3.73 mmol, 0.500 g, >20:1

E:Z) in DCM (20 mL) at room temperature, under nitrogen,

it was added TIPSCl (4.48 mmol, 0.96 mL) and imidazole

(4.48 mmol, 0.305 g). The mixture was stirred overnight

and then diluted with Et₂O and H₂O. The layers were sepa-

rated, and the aqueous layer was extracted with Et₂O (3 ×

70 mL). The combined organic layers were dried over

Na₂SO₄, filtered, and concentrated under reduced pressure.

The crude mixture was purified by flash column chroma-

tography (silica, hexanes/EtOAc 90:10) to afford the silyl

1

ether 2g (92%, 3.44 mmol, 1.00 g) as a colorless oil. H

NMR (400 MHz, CDCl₃) δ = 7.24 – 7.12 (m, 2H), 6.85 –

6.75 (m, 2H), 6.39 – 6.27 (m, J = 15.7, 1.5, 1H), 6.08 (dq,

J = 15.7, 6.6, 1H), 1.85 (dd, J = 6.6, 1.6, 3H), 1.33 – 1.17

(m, 3H), 1.10 (d, J = 7.2, 18H). ¹³C NMR (101 MHz,

CDCl₃) δ = 155.22, 131.15, 130.65, 126.92, 123.52,

120.04, 18.54, 18.07, 12.82. HRMS (ESI+) calculated to

[C₁₈H₃₀OSi + H⁺]: 291.2144, found: 291.2155.

(2R,3R)-2-(4-methoxyphenyl)-3-methyl-2,3-

dihydrobenzofuran (7a) was obtained in 74% isolated

yield (35 mg, 0.148 mmol) in 20:1 dr as a colorless oil.

The enantiomeric ratio of 88:12 was determined by HPLC

analysis using Daicel Chiralpak^®OJ -H column (4.6 mm ×

o

250 mm) at 225 nm, 25 C and 10% i-PrOH in n-hexane

(1.0 mL.min^-1) as mobile phase (major diastereomer: t_R=

1

3. Synthesis and characterization of the Oxy-Heck-

Matsuda Products

11.6 min (major), 23.7 min (minor)). H NMR (250 MHz,

CDCl₃) δ = 7.36 (d, J = 8.6, 2H), 7.24 – 7.08 (m, 3H),

6.96 – 6.81 (m, 4H), 5.10 (d, J = 8.9, 1H), 3.81 (s, 3H),

3.53 – 3.33 (m, 1H), 1.40 (d, J = 6.8, 3H). ¹³C NMR (63

MHz, CDCl₃) δ = 159.81, 159.33, 132.90, 132.20, 128.36,

127.78, 123.73, 120.82, 114.18, 109.62, 92.52, 55.47,

45.45, 17.99. HRMS (ESI+) calculated to C₁₆H₁₆O₂+ H⁺]:

241.1223, found: 241.1228. [α]²⁰– 12.0 (c 3.0, CHCl ,

A 4 mL vial containing a magnetic stir bar was charged

with Pd₂(dba)₃(5 mol%, 0.005 mmol, 4.72 mg), ligand L1

or L2 (20 mol%, 0.020 mmol) and 0.5 mL of i-PrOH. The

mixture was stirred at 60^oC for 5 minutes to form the

precatalyst. Next, CaCO₃(1.0 equiv., 0.1 mmol, 10.0 mg),

styrene 2a-b (1.0 equiv., 0.1 mmol, 13.7 µL) and arenedia-

zonium salt 1a (1.5 equiv., 0.15 mmol) were added, fol-

lowed by the addition of another portion of i-PrOH (0.5

mL). The vial was closed and reaction stirred at 60 °C until

total consumption of the aryl diazonium salt (~2 hours).

The crude material was then dissolved in EtOAc, filtered

through a short pad of silica and the cake was washed with

EtOAc (3 × 10 mL). After evaporation of the solvent, the

crude mixture was purified by flash column chromatog-

raphy (silica, hexanes/EtOAc 99:1) to afford the corre-

sponding Heck-Matsuda adducts 3 and 5, respectively.

D

3

88:12 er).

(2S,3S)-2-(4-methoxyphenyl)-3-methyl-2,3-

dihydrobenzofuran (ent-7a) was obtained in 71% isolated

yield (34 mg, 0.14 mmol) in 20:1 dr. The enantiomeric

ratio of 25:75 was determined by HPLC analysis using

Daicel Chiralpak^®OJ -H column (4.6 mm × 250 mm) at

225 nm, 25^oC and 10% i-PrOH in n-hexane (1.0 mL.min^-1)

as mobile phase (major diastereomer: t_R= 22.4 min (major),

11.5 min (minor)).

(2R,3R)-2-(4-methoxyphenyl)-3-methyl-6-nitro-2,3-

dihydrobenzofuran (7b) was obtained in 33% isolated

yield (18.8 mg, 0.066 mmol) in 20:1dr as a pale yellow oil.

The enantiomeric ratio of 86:14 was determined by HPLC

analysis material using Daicel Chiralpak^®IA-3 column

(4.6 mm × 250 mm) at 225 nm, 25 ^oC and 5% i-PrOH in n-

hexane (1.0 mL.min^-1) as mobile phase (major diastere-

2-(4-methoxyphenyl)-2,3-dihydrobenzofuran (3) was

obtained in 21% isolated yield (9.5 mg, 0.04 mmol) as a

colorless oil. The enantiomeric ratio of 53:47 was deter-

mined by HPLC analysis using Daicel Chiralpak^®IC col-

umn (4.6 mm × 250 mm) at 270 nm, 25^oC and 2% i-PrOH

in n-hexane (1.0 mL.min^-1) as mobile phase: t_R= 14.5 min

(major), 13.9 min (minor). ¹H NMR (400 MHz, CDCl₃) δ

= 7.34 (d, J = 8.6, 2H), 7.16 (dd, J = 7.4, 7.4, 2H), 6.92 –

6.82 (m, 4H), 5.70 (t, J = 8.8, 1H), 3.81 (s, 3H), 3.58 (dd, J

= 15.6, 9.3, 1H), 3.22 (dd, J = 15.6, 8.4, 1H). ¹³C NMR

(101 MHz, CDCl₃) δ = 159.48, 133.88, 128.17, 127.34,

126.69, 124.81, 120.55, 114.02, 109.36, 83.99, 55.33,

1

omer: t_R= 15.6 min (major), 14.2 min (minor)). H NMR

(250 MHz, CDCl₃) δ = 7.83 (dd, J = 8.1, 2.1, 1H), 7.63 (d,

J = 2.1, 1H), 7.33 (d, J = 8.7, 2H), 7.23 (dd, J = 8.3, 1.1,

1H), 6.93 (d, J = 8.7, 2H), 5.24 (d, J = 8.9, 1H), 3.82 (s,

3H), 3.60 – 3.40 (m, 1H), 1.45 (d, J = 6.9, 3H). ¹³C NMR

(63 MHz, CDCl₃) δ = 160.17, 159.89, 148.95, 140.02,

10

10.1002/adsc.201701278

Advanced Synthesis & Catalysis

131.58, 127.71, 123.72, 116.88, 114.37, 105.00, 93.74,

enantiomeric ratio of 85:15 was determined by HPLC

analysis using Daicel Chiralpak^®IB column (4.6 mm ×

55.51, 45.16, 17.72. HRMS (ESI+) calculated to

[C₁₆H₁₅NO₄+ H⁺]: 286.1074, found: 286.1079. [α]²⁰

250 mm) at 225 nm, 25 C and 2% i-PrOH in n-hexane

o

D

+11.6 (c 1.17, CHCl₃, 86:14 er).

(0.5 mL.min^-1) as mobile phase (major diastereomer: t_R=

1

8.8 min (major), 9.9 min (minor)). H NMR (250 MHz,

CDCl₃) δ = 7.36 (d, J = 8.7, 2H), 7.23 – 7.11 (m, 2H),

6.91 (d, J = 8.7, 2H), 6.77 (d, J = 8.2, 1H), 5.08 (d, J = 9.2,

1H), 3.81 (s, 3H), 3.52 – 3.31 (m, 1H), 1.40 (d, J = 6.8,

3H), 1.32 (s, 9H). ¹³C NMR (63 MHz, CDCl₃) δ = 159.57,

156.94, 143.72, 132.80, 131.56, 127.65, 124.93, 120.40,

113.95, 108.59, 92.58, 55.29, 45.52, 34.38, 31.75, 17.56.

HRMS (ESI+) calculated to [C₂₀H₂₄O₂+ H⁺]: 297.1849,

found: 297.1855. [α]²⁰_D–14.8 (c 2.04, CHCl₃, 85:15 er).

(2R,3R)-5-chloro-2-(4-methoxyphenyl)-3-methyl-2,3-

dihydrobenzofuran (7d) was obtained in 66% isolated

yield (36.2 mg, 0.132 mmol) in 20:1 dr, as a pale yellow

oil. The enantiomeric ratio of 77:23 was determined by

HPLC analysis material using Daicel Chiralpak^®IA-3

o

column (4.6 mm × 250 mm) at 225 nm, 25 C and 7% i-

PrOH in n-hexane (1.0 mL.min^-1) as mobile phase (major

1

diastereomer: t_R= 7.0 min (major), 5.4 min (minor)). H

NMR (500 MHz, CDCl₃) δ = 7.33 (d, J = 8.6, 2H), 7.14 –

7.07 (m, 2H), 6.91 (d, J = 8.6, 2H), 6.75 (d, J = 8.4, 1H),

5.12 (d, J = 8.9, 1H), 3.82 (s, 3H), 3.47 – 3.37 (m, 1H),

1.38 (d, J = 6.8, 3H). ¹³C NMR (126 MHz, CDCl₃) δ =

159.93, 157.94, 134.14, 132.28, 128.20, 127.75, 125.52,

124.01, 114.23, 110.56, 93.09, 55.48, 45.44, 17.86. HRMS

(ESI+) calculated to [C₁₆H₁₅ClO₂+ H⁺]: 275.0833, found:

275.0839. [α]²⁰_D–13,5 (c 2.6, MeOH, 77:23 er).

(2R,3R)-3-isopropyl-2-(4-methoxyphenyl)-2,3-

dihydrobenzofuran (7i) was obtained in 28% isolated

yield (15.0 mg, 0.05 mmol) in >20:1 dr as a yellow oil.

The enantiomeric ratio of 80:20 was determined by HPLC

analysis material using Daicel Chiralpak^®OJ -3 column

o

(4.6 mm × 250 mm) at 225 nm, 25 C and 10% i-PrOH in

n-hexane (0.8 mL.min^-1) as mobile phase (major diastere-

1

omer: t_R= 8.3 min (major), 16.1 min (minor)). H NMR

(400 MHz, CDCl₃) δ = 7.25 (d, J = 8.7, 2H), 7.22 – 7.16

(m, J = 7.1, 4.2, 3.1, 2H), 6.90 (dd, J = 7.4, 0.7, 1H), 6.86

(d, J = 8.7, 3H), 5.42 (d, J = 4.8, 1H), 3.79 (s, 3H), 3.32 (t,

J = 4.8, 1H), 2.14 – 2.03 (m, J = 13.6, 6.8, 4.9, 1H), 1.01

(d, J = 6.9, 3H), 0.98 (d, J = 6.9, 3H). ¹³C NMR (101

MHz, CDCl₃) δ = 160.03, 159.44, 135.24, 128.81, 128.51,

127.09, 125.33, 120.41, 114.15, 109.38, 86.41, 57.05,

55.42, 32.25, 19.65, 19.12. HRMS (ESI+) calculated to

[C₁₈H₂₀O₂+ H⁺]: 269.1541, found: 269.1585. [α]²⁰_D–40.5

(c 1.2, MeOH, 80:20 er).

methyl

(2R,3R)-2-(4-methoxyphenyl)-3-methyl-2,3-

dihydrobenzofuran-6-carboxylate (7e) was obtained in

52% isolated yield (31 mg, 0.104 mmol) in 20:1 dr as a

orange oil. The enantiomeric ratio of 83:17 was determined

by HPLC analysis using Daicel Chiralpak^®OJ -3 column

o

(4.6 mm × 250 mm) at 225 nm, 25 C and 15% i-PrOH in

n-hexane (1.0 mL.min^-1) as mobile phase (major diastere-

1

omer: t_R= 21.5 min (major), 49.3 min (minor)). H NMR

(500 MHz, CDCl₃) δ = 7.67 (dd, J = 7.7, 1.2, 1H), 7.50 (d,

J = 0.9, 1H), 7.37 (d, J = 8.6, 2H), 7.20 (d, J = 7.6, 1H),

6.94 (d, J = 8.7, 2H), 5.19 (d, J = 8.9, 1H), 3.93 (s, 3H),

3.84 (s, 3H), 3.52 – 3.44 (m, 1H), 1.44 (d, J = 6.9, 3H).

¹³C NMR (126 MHz, CDCl₃) δ = 167.01, 159.79, 159.34,

137.64, 132.28, 130.61, 127.57, 123.35, 122.81, 114.11,

110.31, 92.71, 55.34, 52.13, 45.31, 17.69. HRMS (ESI+)

calculated to [C₁₈H₁₈O₄+ H⁺]: 299.1278, found: 299.1310.

[α]²⁰_D+29.4 (c 0.95, MeOH, 83:17 er).

(2R,3R)-5-(tert-butyl)-3-isopropyl-2-(4-

methoxyphenyl)-2,3-dihydrobenzofuran (7j) was ob-

tained in 40% isolated yield (26.0 mg, 0.08 mmol) in

>20:1 dr as a pale yellow oil. The enantiomeric ratio of

83:17 was determined by HPLC analysis material using

Daicel Chiralpak^®IA column (4.6 mm × 250 mm) at 280

nm, 25 ^oC and 5% MeOH in supercritical CO₂(3.0

mL.min^-1) as mobile phase (t_R= 3.2 min (major), 2.9 min

(minor)). ¹H NMR (400 MHz, CDCl₃) δ = 7.29 (d, J = 8.7,

2H), 7.25 – 7.21 (m, 2H), 6.89 (d, J = 8.7, 2H), 6.80 (d, J

= 9.1, 1H), 5.43 (d, J = 4.9, 1H), 3.82 (s, 3H), 3.32 (t, J =

4.8, 1H), 2.18 – 2.06 (m, 1H), 1.35 (s, 9H), 1.04 (d, J = 7.0,

3H), 1.02 (d, J = 6.9, 3H). ¹³C NMR (101 MHz, CDCl₃) δ

= 159.24, 157.65, 143.21, 135.33, 128.24, 127.02, 125.03,

122.12, 113.97, 108.21, 86.42, 57.20, 55.28, 34.29, 32.08,

31.80, 19.68, 19.12. HRMS (ESI+) calculated to

[C₂₂H₂₈O₂+ H⁺]: 325.2168, found: 325.2149. [α]²⁰_D–20.2

(c 2.39, MeOH, 83:17 er).

(2R,3R)-2-(4-methoxyphenyl)-3,6-dimethyl-2,3-

dihydrobenzofuran (7f) was obtained in 56% isolated

yield (28.4 mg, 0.112 mmol) in 13:1 dr as a colorless oil.

The enantiomeric ratio of 81:19 was determined by HPLC

analysis using Daicel Chiralpak^®IC column (4.6 mm ×

o

250 mm) at 225 nm, 25 C and 2% i-PrOH in n-hexane

(0.5 mL.min^-1) as mobile phase (major diastereomer: t_R=

1

9.7 min (major), 10.4 min (minor)). H NMR (500 MHz,

CDCl₃) δ = 7.35 (d, J = 8.3, 1H), 7.01 (d, J = 7.4, 1H),

6.91 (d, J = 8.7, 2H), 6.73 (d, J = 7.4, 1H), 6.67 (s, 1H),

5.08 (d, J = 8.8, 1H), 3.81 (s, 3H), 3.43 – 3.34 (m, 2H),

2.33 (s, 3H), 1.38 (d, J = 6.8, 3H). ¹³C NMR (126 MHz,

CDCl₃) δ = 159.61, 159.40, 138.42, 132.90, 129.13,

127.61, 123.19, 121.33, 114.00, 110.21, 92.60, 55.33,

45.11, 21.56, 18.03. HRMS (ESI+) calculated to

[C₁₇H₁₈O₂+ H⁺]: 255.1380, found: 255.1385. [α]²⁰_D–3.7 (c

2.88, CHCl₃, 81:19 er).

(2R,3R)-2-(2,4-dimethoxyphenyl)-3-methyl-2,3-

dihydrobenzofuran (7k) was obtained in 31% isolated

yield (16.7 mg, 0.062 mmol) in 7:1 dr as a colorless oil.

The enantiomeric ratio of 76:24 for the major diastereomer

and 72:28 for the minor diastereomer were determined by

HPLC analysis using Daicel Chiralpak^®IB column (4.6

o

mm × 250 mm) at 290 nm, 25 C and 3% i-PrOH in n-

(2R,3R)-2-(4-methoxyphenyl)-3,5-dimethyl-2,3-

hexane (0.5 mL.min^-1) as mobile phase (major diastere-

dihydrobenzofuran (7g) was obtained in 43% isolated

yield (21.8 mg, 0.086 mmol) in 16:1 dr as a colorless oil.

The enantiomeric ratio of 86:14 was determined by HPLC

analysis using Daicel Chiralpak^®OJ -H column (4.6 mm ×

omer: t_R= 11.4 min (major), 12.0 min (minor), (minor

1

diastereomer: t_R= 12.9 min (major), 9.6 min (minor)). H

NMR (500 MHz, CDCl₃) δ = 7.35 (d, J = 8.3, 1H), 7.01

(d, J = 7.4, 1H), 6.91 (d, J = 8.7, 2H), 6.73 (d, J = 7.4, 1H),

6.67 (s, 1H), 5.08 (d, J = 8.8, 1H), 3.81 (s, 3H), 3.43 –

3.34 (m, 2H), 2.33 (s, 3H), 1.38 (d, J = 6.8, 3H). ¹³C NMR

(151 MHz, CDCl₃) δ = 160.68, 159.43, 158.05, 132.54,

128.12, 127.49, 127.45, 123.99, 122.20, 120.57, 120.55,

109.49, 109.45, 104.38, 104.27, 98.78, 98.68, 87.10, 87.04,

55.61, 55.58, 55.48, 55.46, 44.76, 19.62, 19.54, 17.14.

HRMS (ESI+) calculated to [C₁₇H₁₈O₂+ H⁺]: 271.1329,

found: 271.1324. [α]²⁰+1.82 (c 4.11, CHCl₃, 7:1 dr,

76:24 er (major), 72:28 ^Der (minor)).

o

250 mm) at 225 nm, 25 C and 10% i-PrOH in n-hexane

(1.0 mL.min^-1) as mobile phase (major diastereomer: t_R=

1

12.1 min (major), 23.3 min (minor)). H NMR (500 MHz,

CDCl₃) δ = 7.35 (d, J = 8.6, 2H), 6.99 – 6.93 (m, 2H),

6.90 (d, J = 8.7, 2H), 6.73 (d, J = 8.0, 1H), 5.07 (d, J = 9.0,

1H), 3.81 (s, 3H), 3.44 – 3.34 (m, 1H), 2.31 (s, 3H), 1.38

(d, J = 6.8, 3H). ¹³C NMR (126 MHz, CDCl₃) δ = 159.74,

157.21, 132.99, 132.17, 130.11, 128.64, 127.76, 124.33,

114.13, 109.13, 92.58, 55.45, 45.51, 21.01, 17.93. HRMS

(ESI+) calculated to [C₁₇H₁₈O₂+ H⁺]: 255.1380, found:

255.1385. [α]²⁰_D–18.5 (c 1.2, CHCl₃, 86:14 er).

(2R,3R)-2-(3,4-dimethoxyphenyl)-3-methyl-2,3-

dihydrobenzofuran (7l) was obtained in 71% isolated

yield (38.2 mg, 0.14 mmol) in >20:1 dr as a colorless oil.

The enantiomeric ratio of 88:12 was determined by HPLC

analysis material using Daicel Chiralpak^®OJ -H column

(2R,3R)-5-(tert-butyl)-2-(4-methoxyphenyl)-3-methyl-

2,3-dihydrobenzofuran (7h) was obtained in 76% isolated

yield (45 mg, 0.15 mmol) in 14:1 dr as a colorless oil. The

11

10.1002/adsc.201701278

Advanced Synthesis & Catalysis

(4.6 mm × 250 mm) at 225 nm, 25 ^oC and 5% i-PrOH in n-

yield (26.0 mg, 0.103 mmol) in 6:4 dr as a colorless oil.

The enantiomeric ratio of 79:21 for the major diastereomer

and 78:22 for the minor diastereomer were determined by

HPLC analysis using Daicel Chiralpak^®IB column (4.6

hexane (1.0 mL.min^-1) as mobile phase (major diastere-

1

omer: t_R= 4.4 min (major), 14.0 min (minor)). H NMR

(500 MHz, CDCl₃) δ = 7.21 (t, J = 7.7, 1H), 7.18 (d, J =

7.4, 1H), 7.03 – 6.98 (m, 2H), 6.96 (td, J = 7.5, 0.7, 1H),

6.90 (d, J = 8.0, 2H), 5.12 (d, J = 9.2, 1H), 3.92 (s, 3H),

3.91 (s, 3H), 3.53 – 3.44 (m, 1H), 1.44 (d, J = 6.8, 3H).

¹³C NMR (126 MHz, CDCl₃) δ = 159.16, 149.31, 149.16,

133.05, 132.06, 128.26, 123.60, 120.77, 118.94, 111.03,

o

mm × 250 mm) at 225 nm, 25 C and 1% i-PrOH in n-

hexane (0.3 mL.min^-1) as mobile phase (major diastere-

omer: t_R= 17.9 min (major), 19.9 min (minor) (minor dia-

1

stereomer: t_R= 18.8 min (major), 17.1 min (minor)). H

NMR (400 MHz, CDCl₃) Mixture of diastereoisomer δ =

7.42 (maj , d, J = 8.8, 2H), 7.30 (min, d, J = 8.8, 1H), 7.21

– 7.10 (maj + min, m, 2H), 7.11 – 7.04 (min, m, 1H), 6.93

– 6.84 (maj + min, m, 6H), 3.81 (min, s, 1H), 3.80 (maj , s,

3H), 3.53 (maj , q, J = 7.1, 1H), 3.35 (min, q, J = 7.1, 1H),

1.76 (min, s, 1H), 1.59 (maj , s, 3H), 1.38 (maj , d, J = 7.2,

3H), 0.79 (min, d, J = 7.2, 1H). ¹³C NMR (101 MHz,

CDCl₃) δ = 158.77, 158.63, 158.22, 158.09, 139.45,

134.74, 132.98, 132.47, 128.30, 128.25, 126.99, 125.88,

124.67, 124.03, 120.60, 113.79, 113.42, 109.70, 109.69,

92.08, 55.41, 55.35, 47.81, 47.78, 28.42, 22.45, 18.57,

15.01. HRMS (ESI+) calculated to [C₁₇H₁₈O₂+ H⁺]:

109.55, 109.22, 92.68, 55.98, 55.95, 45.30, 17.66. [α]²⁰

1.3 (c 0.9, MeOH, 88:12 er).

–

D

4-((2R,3R)-3-methyl-2,3-dihydrobenzofuran-2-

yl)phenol (7n) was obtained in 40% isolated yield (9 mg,

0.04 mmol) in 11:1 dr as a colorless oil. The enantiomeric

ratios of 88:12 for the major diastereomer and 88:12 for

the minor diastereomer of aryl dihydrobenzofuran 7n were

determined by SFC analysis using Daicel Chiralpak^®IA

o

column (4.6 mm × 250 mm) at 25 C and 5% MeOH in

supercritical CO₂(3.0 mL.min^-1) as mobile phase (major

diastereoisomer: t_R= 17.8 min (major), 11.2 min (minor);

minor diastereoisomer: t_R= 12.3 min (major), 13.7 min

(minor)). (c 0.61, CHCl₃, 11:1 dr, 88:12 er (major), 88:12

er (minor)).

255.1379, found: 255.1382. [α]²⁰– 9.5 (c 3.81, MeOH,

D

6:4 dr, 79:21 er (major), 78:22 er (minor)).

(S)-2-(4-methoxyphenyl)-2H-spiro[benzofuran-3,1'-

cyclohexane] (13d) was obtained in 68% isolated yield

(40.0 mg, 0.13 mmol) as a colorless oil. The enantiomeric

ratio of 58:42 was determined by HPLC analysis using

Daicel Chiralpak^®IA-3 column (4.6 mm × 250 mm) at 225

nm, 25^oC and 5% i-PrOH in n-hexane (1.0 mL.min^-1) as

mobile phase (major diastereomer: t_R= 6.5 min (major),

7.3 min (minor)). ¹H NMR (600 MHz, CDCl₃) δ = 7.35 (d,

J = 7.2, 1H), 7.23 (d, J = 8.7, 2H), 7.18 (td, J = 7.7, 1.3,

1H), 6.91 (td, J = 7.5, 0.9, 1H), 6.88 (d, J = 8.1, 1H), 6.87

(d, J = 8.7, 2H), 5.31 (s, 1H), 3.81 (s, 3H), 1.90 – 1.82 (m,

1H), 1.78 (t, J = 5.8, 2H), 1.73 – 1.66 (m, 1H), 1.55 – 1.42

(m, 3H), 1.42 – 1.33 (m, 1H), 1.22 – 1.10 (m, 2H). ¹³C

NMR (151 MHz, CDCl₃) δ = 159.42, 159.06, 136.33,

130.18, 128.47, 127.98, 124.60, 120.31, 113.45, 113.43,

109.55, 93.80, 93.77, 55.26, 55.22, 48.77, 37.84, 32.80,

29.72, 25.45, 22.79, 21.73. HRMS (ESI+) calculated to

[C₂₀H₂₂O₂+ H⁺]: 295.1693, found: 295.1692. [α]²⁰_D–44.9

(c 3.67, MeOH, 75:25 er).

2-methoxy-4-((2R,3R)-3-methyl-2,3-

dihydrobenzofuran-2-yl)phenol (7o) was obtained in

70% isolated yield (36.0 mg, 0.14 mmol) in 10:1 dr as a

colorless oil. The enantiomeric ratio of 61:39 was deter-

mined by HPLC analysis using Daicel Chiralpak^®IB-3

o

column (4.6 mm × 250 mm) at 225 nm, 25 C and 5% i-

PrOH in n-hexane (1.0 mL.min^-1) as mobile phase (major

1

diastereomer: t_R= 11.7 min (major), 14.4 min (minor)). H

NMR (250 MHz, CDCl₃) δ = 7.23 – 7.13 (m, 2H), 7.00 –

6.96 (m, 1H), 6.95 – 6.85 (m, 4H), 5.68 (s, 1H), 5.09 (d, J

= 9.2, 1H), 3.89 (s, 3H), 3.53 – 3.37 (m, J = 13.7, 6.7, 1H),

1.42 (d, J = 6.8, 3H). ¹³C NMR (63 MHz, CDCl₃) δ =

159.12, 146.78, 145.79, 132.43, 132.05, 128.22, 123.57,

120.74, 119.67, 114.25, 109.50, 108.59, 92.77, 55.96,

45.31, 17.61. HRMS (ESI+) calculated to [C₁₆H₁₆O₃+ H⁺]:

257.1172, found: 257.1178. [α]²⁰–4.3 (c 1.26, CHCl₃,

D

61:39 er).

(4aR,9bR)-4a-(4-methoxyphenyl)-1,2,3,4,4a,9b-

(R)-2-(4-methoxyphenyl)-2-methyl-2,3-

hexahydrodibenzo[b,d]furan (13e) was obtained in 50%

isolated yield (28.0 mg, 0.1 mmol) as a colorless oil. The

enantiomeric ratio of 73:27 was determined by HPLC

analysis using Daicel Chiralpak^®OJ -H column (4.6 mm ×

dihydrobenzofuran (13a) was obtained in 90% isolated

yield (43.2 mg, 0.18 mmol) as a yellow oil. The enantio-

meric ratio of 50:50 was determined by HPLC analysis

material using Daicel Chiralpak^®OJ -3 column (4.6 mm ×

o

250 mm) at 225 nm, 25 C and 10% i-PrOH in n-hexane

(1.0 mL.min^-1) as mobile phase (major diastereomer: t_R=

(1.0 mL.min^-1) as mobile phase (t_R= 16.4 min, 21.1 min).

¹H NMR (400 MHz, CDCl₃) δ = 7.42 (d, J = 8.9, 2H),

7.20 – 7.13 (m, 2H), 6.90 (d, J = 8.9, 3H), 6.86 (dd, J =

7.4, 0.8, 1H), 3.81 (s, 3H), 3.44 (d, J = 15.4, 1H), 3.36 (d,

J = 15.4, 1H), 1.78 (s, 3H). ¹³C NMR (101 MHz, CDCl₃)

δ = 158.94, 158.69, 138.99, 128.18, 126.69, 125.86, 125.11,

120.44, 113.75, 109.61, 88.99, 55.35, 44.85, 29.24. HRMS

(ESI+) calculated to [C₁₆H₁₆O₂+ H⁺]: 241.1223, found:

241.1221.

1

19.0 min (major), 21.8 min (minor)). H NMR (500 MHz,

CDCl₃) δ = 7.47 (d, J = 8.8, 2H), 7.12 (t, J = 7.7, 1H),

7.08 (d, J = 7.2, 1H), 6.89 – 6.82 (m, 4H), 3.79 (s, 3H),

3.59 (t, J = 5.6, 1H), 2.07 – 1.98 (m, J = 14.4, 11.3, 5.8,

3H), 1.93 – 1.86 (m, 1H), 1.66 – 1.58 (m, J = 11.6, 6.3,

1H), 1.52 – 1.43 (m, 3H). ¹³C NMR (126 MHz, CDCl₃) δ

= 158.79, 158.61, 138.02, 132.42, 128.07, 126.87, 123.64,

120.60, 113.65, 110.12, 90.80, 55.40, 47.05, 35.32, 27.62,

21.15, 20.72. HRMS (ESI+) calculated to [C₁₉H₂₀O₂+ H⁺]:

281.1536, found: 281.1542. [α]²⁰_D+10.35 (c 0.86, CHCl₃,

73:27er).

(S)-2-(4-methoxyphenyl)-3,3-dimethyl-2,3-

dihydrobenzofuran (13b) was obtained in 72% isolated

yield (36.5 mg, 0.14 mmol) as a colorless oil. The enanti-

omeric ratio of 75:25 was determined by HPLC analysis

material using Daicel Chiralpak^®IA-3 column (4.6 mm ×

(6aS,11aR)-5,6,6a,11a-tetrahydronaphtho[1,2-

b]benzofuran (13f) was obtained in 34% isolated yield

(15.0 mg, 0.07 mmol) in >20:1 dr as a colorless oil. The

enantiomeric ratio of 76:24 was determined by HPLC

analysis using Daicel Chiralpak^®OJ -3 column (4.6 mm ×

250 mm) at 225 nm, 25^oC and 10% i-PrOH in n-hexane

(1.0 mL.min^-1) as mobile phase (major diastereomer: t_R=

o

250 mm) at 225 nm, 25 C and 5% i-PrOH in n-hexane

(1.0 mL.min^-1) as mobile phase (major diastereomer: t_R=

1

5.9 min (major), 6.2 min (minor)). H NMR (500 MHz,

CDCl₃) δ = 7.31 (d, J = 8.7, 2H), 7.18 (td, J = 7.7, 1.4,

1H), 7.12 (d, J = 7.3, 1H), 6.93 (dd, J = 6.7, 4.6, 4H), 5.29

(s, 1H), 3.83 (s, 3H), 1.47 (s, 3H), 0.79 (s, 3H). ¹³C NMR

(126 MHz, CDCl₃) δ = 159.33, 158.36, 137.20, 129.73,

127.95, 127.47, 122.76, 120.89, 113.58, 109.75, 94.21,

55.28, 45.52, 26.74, 25.43 HRMS (ESI+) calculated to

[C₁₇H₁₈O₂+ H⁺]: 255.1393, found: 255.1381. [α]²⁰_D–44,9

(c 3.67, MeOH, 75:25 er).

1

22.1 min (major), 13.6 min (minor)). H NMR (400 MHz,

CDCl₃) δ = 7.58 (dd, J = 7.3, 1.8, 1H), 7.37 – 7.28 (m,

1H), 7.27 (s, 1H), 7.22 – 7.11 (m, 3H), 6.92 (td, J = 7.4,

1.0, 1H), 6.82 (d, J = 8.0, 1H), 5.71 (d, J = 8.5, 1H), 3.73

(td, J = 8.2, 5.9, 2H), 2.75 (ddd, J = 15.5, 7.5, 4.1, 1H),

2.67 (ddd, J = 15.5, 8.3, 4.0, 1H), 2.10 (dddd, J = 13.1, 7.5,

5.6, 4.1, 1H), 1.86 (dtd, J = 12.7, 8.2, 4.1, 1H). ¹³C NMR

(101 MHz, CDCl₃) δ = 159.39, 138.90, 133.43, 131.33,

130.20, 128.43, 128.26, 126.67, 124.35, 120.57, 109.56,

(2R,3R)-2-(4-methoxyphenyl)-2,3-dimethyl-2,3-

dihydrobenzofuran (13c) was obtained in 52% isolated

12

10.1002/adsc.201701278

Advanced Synthesis & Catalysis

99.98, 81.81, 41.11, 28.07, 27.58. [α]²⁰–250 (c 0.60,

0.41 mmol, 18:1 dr) as a colorless oil. The enantiomeric

ratio of 78:22 for the major diastereomer and 78:22 for the

minor diastereomer were determined by SFC analysis

using Daicel Chiralpak^®IA column (4.6 mm × 250 mm) at

D

MeOH, 76:24 er).

((2R,3S)-3-((benzyloxy)methyl)-2-(4-methoxyphenyl)-

2,3-dihydrobenzofuran (13g) was obtained in 41% isolat-

ed yield (40.0 mg, 0.08 mmol) in >20:1 dr as a pale yellow

oil. The enantiomeric ratio of 70:30 was determined by

HPLC analysis using Daicel Chiralpak^®IA column (4.6

mm × 250 mm) at 225nm, 25^oC and 5% MeOH in super-

critical CO₂(3.0 mL.min^-1) as mobile phase (t_R= 10.7 min

o

25 C and 5% MeOH in supercritical CO₂(2.0 mL.min^-1)

as mobile phase (major diastereoisomer: t_R= 6.5 min (ma-

jor), 5.0 min (minor); minor diastereoisomer: t_R= 6.0 min

1

(major), 6.3 min (minor)). H NMR (500 MHz, CDCl₃) δ

= 7.31 – 7.27 (m, J = 6.4, 4.7, 2H), 7.21 – 7.12 (m, 2H),

6.94 – 6.83 (m, 4H), 5.09 (d, J = 9.0, 1H), 3.48 – 3.39 (m,

1H), 1.40 (d, J = 6.8, 3H), 1.34 – 1.21 (m, 3H), 1.11 (d, J =

7.4, 18H). ¹³C NMR (126 MHz, CDCl₃) δ = 159.34,

156.32, 133.12, 132.27, 128.33, 127.66, 123.73, 120.79,

120.09, 109.61, 92.63, 45.45, 18.07, 17.97, 12.83. HRMS

(ESI+) calculated to [C₂₄H₃₄O₂Si+ H⁺]: 383.2406, found:

383.2437. [α]²⁰_D– 9.1 (c 1.23, CHCl₃, 78:22 er).

1

(major), 9.1 min (minor)). H NMR (500 MHz, CDCl₃) δ

= 7.37 – 7.27 (m, 7H), 7.22 – 7.16 (m, J = 10.1, 7.6, 2H),

6.91 – 6.84 (m, J = 11.9, 5.5, 4H), 5.51 (d, J = 5.3, 1H),

4.62 – 4.51 (m, 2H), 3.80 (s, 3H), 3.79 – 3.75 (m, J = 7.7,

5.2, 1H), 3.72 – 3.67 (m, J = 9.2, 4.5, 2H). ¹³C NMR (126

MHz, CDCl₃) δ = 159.85, 159.52, 138.21, 134.01, 128.99,

128.58, 127.85, 127.80, 127.39, 127.34, 124.97, 120.72,

114.11, 109.68, 87.39, 73.39, 72.60, 55.46, 51.34. HRMS

(ESI+) calculated to [C₂₃H₂₂O₃+ H⁺]: 347.1642, found:

347.1633. [α]²⁰_D+13.40 (c 1.59, CHCl₃, 70:30 er).

5. Total synthesis of (–)-conocarpan

5.1. Route 1

2-(((2R,3S)-2-(4-methoxyphenyl)-2,3-

Bromination

of

2-(4-methoxyphenyl)-3-methyl-2,3-

dihydrobenzofuran-3-yl)methyl)isoindoline-1,3-dione

dihydrobenzofuran (7a). To a 50 mL round bottom flask

containing a magnetic stir bar, it was added dihydrobenzo-

furan 7a (0.73 mmol, 0.175 g), freshly recrystallized N-

Bromosuccinimide (1.095mmol, 0.195g), THF (6 mL) and

H₂O (1.5 mL). The mixture was stirred at room tempera-

ture for 24 h. The crude material was then rotaevaporated

to eliminate the volatiles and the aqueous layer was

washed with DCM (3 × 15 mL). The organic phase was

separated, dried over Na₂SO₄, filtered and concentrated

under reduced pressure. The crude product was purified by

flash column chromatography (silica, hexanes/EtOAc 98:2

as eluent) to afford the bromo aryl dihydrofuran 7a’ in

(13h)

and

(E)-2-(3-(2-hydroxyphenyl)-3-(4-

methoxyphenyl) allyl)isoindoline-1,3-dione (13h‘). The

reaction of styrene 12h afforded two arylation isomer. The

dihydrobenzofuran 13h in 23% yield (17 mg, 0.046 mmol,

20:1 dr) as a colorless oil and diarylstyrene 13h‘ in 64%

yield (49.3 mg, 0.13 mmol, 2:1 dr ) as a white solid. (13h)

The enantiomeric ratio of 87:13 of 13h was determined by

HPLC analysis using Daicel Chiralpak^®IA column (4.6

o

mm × 250 mm) at 225nm, 25 C and 8% MeOH in super-

critical CO₂(3.0 mL.min^-1) as mobile phase (t_R= 15.0 min

(major), 21.9 min (minor)). ¹H NMR (400 MHz, CDCl₃) δ

= 7.79 (dd, J = 5.5, 3.0, 2H), 7.69 (dd, J = 5.4, 3.1, 2H),

7.25 (d, J = 7.4, 1H), 7.21 (d, J = 8.1, 1H), 7.18 (d, J = 8.7,

2H), 6.91 (t, J = 7.5, 1H), 6.85 (d, J = 8.0, 1H), 6.68 (d, J

= 8.7, 2H), 5.52 (d, J = 7.0, 1H), 4.20 – 3.97 (m, 4H), 3.68

(s, 3H). ¹³C NMR (101 MHz, CDCl₃) δ = 168.34, 159.56,

159.51, 134.04, 132.30, 131.74, 129.20, 127.69, 126.88,

124.53, 123.33, 120.83, 113.92, 109.80, 88.34, 55.21,

49.34, 40.92. HRMS (ESI+) calculated to [C₂₄H₁₉O₄+ H⁺]:

386.1387, found: 386.1385. [α]²⁰_D–108.9 (c 1.02, CHCl₃,

1

76% yield (0.56 mmol, 0.178 g) in 24:1 dr (trans/cis). H

NMR (500 MHz, CDCl₃) δ = 7.25 (d, J = 8.6, 2H), 7.23 –

7.16 (m, 1H), 7.15 (s, 1H), 6.84 (d, J = 8.7, 2H), 6.64 (d, J

= 8.4, 1H), 5.04 (d, J = 8.9, 1H), 3.74 (s, 3H), 3.44 – 3.28

(m, 1H), 1.31 (d, J = 6.8, 3H). ¹³C NMR (126 MHz,

CDCl₃) δ = 159.94, 158.45, 134.69, 132.23, 131.12,

127.75, 126.88, 114.24, 112.61, 111.21, 93.04, 55.47,

45.38, 17.88.

1

87:13 er); (13h‘) H NMR (500 MHz, CDCl₃) δ = 7.82

Demethylation 5-bromo-2-(4-methoxyphenyl)-3-methyl-

2,3-dihydrobenzofuran (8) To a 25 mL round bottom flask

containing a magnetic stir bar it was added the bromo

dihydrobenzofuran 7a’ (0.56 mmol, 0.175 g), and DCM (6

mL) under nitrogen. The mixture was cooled to 8°C

followed by addition of a BBr₃solution in DCM (0.9

mol/L, 2.8 mmol, 3.11 mL). Next, the mixture was warmed

up to room temperature and stirred for 3 hours. The reac-

tion was quenched by the addition of water and the mixture

was washed with DCM (3 × 15 mL). The organic phase

was separated, dried over Na₂SO₄, filtered and concentrat-

ed under reduced pressure. The crude mixture was then

purified by flash column chromatography (silica, hex-

anes/EtOAc 90:10) to afford bromophenol 8 in 72% yield

(0.40 mmol, 0.123 g) and 15:1 dr (trans/cis). An analytical

sample was obtained by recrystallization of bromophenol 8

in hexane/EtOAc (6:1) and sent to X-Ray diffractometry

analysis. ¹H NMR (250 MHz, CDCl₃) δ = 7.32 – 7.18 (m,

4H), 6.82 (d, J = 8.6, 2H), 6.71 (d, J = 8.3, 1H), 5.10 (d, J

= 8.8, 1H), 5.08 (s, 1H, ArOH, 3.51 – 3.32 (m, 1H), 1.37

(d, J = 6.8, 3H). ¹³C NMR (63 MHz, CDCl₃) δ = 158.36,

155.92, 134.64, 132.43, 131.14, 127.98, 126.90, 115.69,

112.69, 111.21, 93.02, 45.38, 17.91.

(dd, J = 5.4, 3.1, 2H), 7.70 (dd, J = 5.5, 3.0, 2H), 7.32 –

7.27 (m, 1H), 7.19 (d, J = 8.8, 2H), 7.09 (dd, J = 7.5, 1.7,

1H), 7.06 (dd, J = 8.2, 1.2, 1H), 6.98 (td, J = 7.4, 1.2, 1H),

6.78 (d, J = 8.9, 2H), 6.13 (t, J = 6.7, 1H), 4.31 (s, 1H),

3.76 (s, 3H). ¹³C NMR (126 MHz, CDCl₃) δ = 168.40,

159.76, 152.96, 139.52, 134.24, 132.23, 132.11, 130.88,

129.70, 128.01, 125.33, 123.50, 122.93, 120.97, 117.11,

113.97, 55.39, 38.23.

Synthesis

of

triisopropyl(4-((2R,3R)-3-methyl-2,3-

dihydrobenzofuran-2-yl)phenoxy)silane (7m) at 1 mmol

scale. A 4 mL vial containing a magnetic stir bar was

charged with Pd₂(dba)₃(5 mol%, 0.050 mmol, 45.8 mg),

ligand L7 (10 mol%, 0.100 mmol, 33.0 mg) and MeOH

(3.0 mL). The vial was then closed and the mixture was

stirred at 60^oC for 15 minutes to form the precatalyst. In a

separate round-bottom flask, it was added CaCO₃(1.0

equiv., 1.0 mmol, 100.1 mg), styrene 2g (1.0 equiv., 1.00

mmol, 290.5 mg, >20:1 E:Z) and the arenediazonium salt

1a (1.5 equiv., 1.5 mmol, 312 mg), followed by the addi-

tion of MeOH (5.0 mL) and the solution of the precatalyst

formed previously. Another portion of MeOH (2 mL) was

used to transfer the totality of the precatalyst to the round-

bottom flask. The reaction flask was closed, warmed up to

60°C and stirred until total consumption of the aryl diazo-

nium salt. After 2 hours, another portion of aryldiazonium

salt 1a (0.5 equiv., 0.5 mmol, 104 mg) was added and the

reaction stirred for another 2 hours. The mixture was con-

centrated under reduced pressure and the crude material

was diluted with EtOAc, filtered through a short pad of

silica gel, which was further washed with EtOAc (3 × 20

mL). After evaporation of the solvent in vacuum, the crude

mixture was purified by flash column chromatography

(silica gel, hexanes/EtOAc as eluent) to afford the corre-

sponding Heck-Matsuda adduct 7m in 41% yield (156 mg,

Procedure for the preparation of (–)-conocarpan 9 from

bromophenol 8, and determination of its absolute config-

uration. A Schlenk flask containing a magnetic stir bar

was charged with bromophenol 8 (0.22 mmol, 68.2 mg),

Pd(dppf)Cl₂.CH₂Cl₂(5 mol%, 0.011 mmol, 9.1 mg), trans-

1-propen-1-ylboronic acid (0.44 mmol, 38.4 mg), K₂CO₃

(0.66 mmol, 92.7 mg), toluene (0.8 mL) and distilled water

(0.3 mL). The mixture was degassed by a freeze-pump-

thaw procedure followed by heating at 95^oC for 3 hours.

Next, the crude mixture was cooled to room temperature,

diluted with water (2 mL) and washed with EtOAc (3 × 10

13

10.1002/adsc.201701278

Advanced Synthesis & Catalysis

mL). The organic phase was separated, dried over Na₂SO₄,

filtered and concentrated under reduced pressure. After

evaporation of the solvent, the crude mixture was purified

by flash column chromatography (silica, hexanes/EtOAc

90:10 as eluent) to afford (–)-conocarpan in 78% yield

(0.17 mmol, 38.8 mg). Comparison of the optical rotation

reported by the Clive’s and Hashimoto’s group^[16]with the

one obtained herein for the final product 9 indicated the

stereogenic centres as R,R (see Supporting Information for

details).

119.96, 117.74, 115.14, 111.08, 98.21, 44.81, 19.54.

HRMS (ESI+) calculated to [C₂₁H₁₈O₃+ H⁺]: 319.1334,

found: 319.1345.

Triisopropyl(4-((2R,3R)-3-methyl-2,3-

dihydrobenzofuran-2-yl)phenoxy)silane (7m‘) To a solu-

tion of the aryl dihydrobenzofuran 7n (985 mg, 4.35

mmol) in DCM (20 mL), at room temperature, under nitro-

gen, it was added TIPSCl (1.12 mL, 5.22 mmol) and imid-

azole (0.355 g, 5.52 mmol). The reaction flask was capped

with a rubber septum and the mixture stirred overnight.

After this period, the reaction mixture was diluted with

Et₂O and H₂O. The layers were separated, and the aqueous

layer was extracted with Et₂O (3 × 70 mL). The combined

organic layers were dried over Na₂SO₄, filtered, and con-

centrated under reduced pressure. The crude mixture was

purified by flash column chromatography (silica, hex-

anes/EtOAc 99:1 as eluent) to afford the corresponding

silyl ether 7m‘ as a colorless oil in 83% yield (1.38 g, 3.61

mmol, 17:1 dr). The enantiomeric ratios of 86:14 for the

major diastereomer and 88:12 for minor diastereomer were

determined by SFC analysis using Daicel Chiralpak^®IA

5.2. Route 2 – Gram Scale Enantioselectivity Heck-

Matsuda Reaction

A 10 mL vial containing a magnetic stir bar was charged

with Pd₂(dba)₃(0.3508 g, 5 mol%, 0.384 mmol), ligand L7

(0.2545 g, 10 mol%, 0.768 mmol) and MeOH (5 mL). The

mixture was stirred at 60^oC for 15 minutes to form the

precatalyst. Next, in a separate round-bottom flask, it was

added CaCO₃(0.768 g, 7.68 mmol), styrene 2h (1.032 g,

7.68 mmol, >20:1 E:Z), and MeOH (60.0 mL), followed by

the addition of the precatalyst. Another portion of MeOH

(5 mL) was used to transfer the precatalyst to the round-

bottom flask completely. Then, arenediazonium salt 1a

was added portionwise (seven portions of 1.2 mmol, 250

mg) every 25 min. The development of the reaction was

followed by the rate of N₂bubbling and by the disappear-

ance of the yellow color of the reaction. At the end of the

reaction, the mixture was concentrated under reduced pres-

sure and the crude material was diluted with EtOAc, fil-

tered through a pad of silica and the cake washed with

EtOAc (6 × 50 mL). After evaporation of the solvent, the

crude mixture was purified by flash column chromatog-

raphy (silica, hexanes/EtOAc as eluent) to afford the corre-

sponding Heck-Matsuda aryl dihydrobenzofuran 7n (major

product, pale yellow oil) in 57% yield (985 mg, 4.35

mmol) in 24:1 dr, the unstable olefin 10a as a orange solid

in 26% yield in 10:1 dr, and small amounts of a diarylated

dihydrobenzofuran (10b in 6% yield; see SI for details).

The enantiomeric ratios of 86:14 for the major trans dia-

stereomer and 85:14 for the minor cis diastereomer of aryl

dihydrobenzofuran 7n were determined by SFC analysis

using Daicel Chiralpak^®IA column (4.6 mm × 250 mm) at

o

column (4.6 mm × 250 mm) at 25 C and 5% MeOH in

supercritical CO₂(2.0 mL.min^-1) as mobile phase (major

diastereoisomer: t_R= 6.8 min (major enantiomer), 5.2 min

(minor enantiomer); minor diastereoisomer: t_R= 6.2 min

(major enantiomer), 6.5 min (minor enantiomer).

(4-((2R,3R)-5-bromo-3-methyl-2,3-dihydrobenzofuran-2-

yl)phenoxy)triisopropylsilane (11). To a 50 mL round-

bottom flask containing a magnetic stir bar it was added

the aryl dihydrobenzofuran 7m‘ (3.61 mmol, 1.38 g),

freshly

recrystallized

N-bromosuccinimide

(5.42

mmol,0.965 g), THF (120 mL) and H₂O (30 mL). The

mixture was stirred at room temperature overnight. Next,

the crude reaction mixture was rotaevaporated to eliminate

the volatiles and the aqueous residue was washed with

DCM (3 × 80 mL). The organic phases were separated,

dried over Na₂SO₄, filtered and concentrated under reduced

pressure. The crude mixture was purified by flash column

chromatography (silica gel, hexanes/EtOAc 98:2 as eluent)

to afford the bromo aryl dihydrobenzofuran 11 in 77%

yield (1.28 g, 2.77 mmol, 43:1 dr ) as a light yellow oil.

The enantiomeric ratio of 85:15 for the compound 11 was

determined by SFC analysis using Daicel Chiralpak^®IA-3

o

25 C and 5% MeOH in supercritical CO₂(3.0 mL.min^-1)

as mobile phase (major diastereoisomer: t_R= 17.4 min

(major enantiomer), 11.3 min (minor enantiomer); minor

diastereoisomer: t_R= 12.4 min (major enantiomer), 13.8

min (minor enantiomer)).

o

column (4.6 mm × 250 mm) at 25 C and 3% MeOH in

supercritical CO₂(2.0 mL.min^-1) as mobile phase: t_R= 18.6

min (major), 10.3 min (minor)). ¹H NMR (400 MHz,

CDCl₃) δ = 7.30 – 7.20 (m, 4H), 6.91 – 6.85 (m, 2H), 6.72

(d, J = 8.4, 1H), 5.10 (d, J = 8.9, 1H), 3.50 – 3.36 (m, 1H),

1.38 (d, J = 6.8, 3H), 1.31 – 1.20 (m, 3H), 1.10 (d, J = 7.2,

18H). ¹³C NMR (101 MHz, CDCl₃) δ = 158.49, 156.51,

134.76, 132.49, 131.10, 127.62, 126.89, 120.16, 112.60,

111.20, 93.16, 45.41, 18.06, 17.92, 12.82. HRMS (ESI+)

calculated to [C₂₄H₃₃BrO₂Si+ H⁺]: 461.1512, found:

461.1505. [α]²⁰_D–33.64 (c 1.21, CHCl₃, 43:1 dr, 85:15 er).

4-((2R,3R)-3-methyl-2,3-dihydrobenzofuran-2-

1

yl)phenol (7n). H NMR (500 MHz, CDCl₃) δ = 7.41 –

7.28 (m, J = 8.5, 2H), 7.23 – 7.10 (m, 2H), 6.97 – 6.90 (m,

1H), 6.88 – 6.81 (m, 3H), 5.10 (d, J = 8.9, 1H), 4.97 (s,

1H), 3.50 – 3.38 (m, 1H), 1.41 (d, J = 6.8, 3H). ¹³C NMR

(126 MHz, CDCl₃) δ = 159.22, 155.77, 133.05, 132.16,

128.38, 128.02, 123.75, 120.89, 115.61, 109.62, 92.48,

45.42, 17.98. HRMS (ESI+) calculated to [C₁₅H₁₄O₂+ H⁺]:

227.1072, found: 227.1098.

Triisopropyl(4-((2R,3R)-3-methyl-5-((E)-prop-1-en-1-yl)-

2,3-dihydrobenzofuran-2-yl)phenoxy)silane (TIPS-9). A

Schlenk flask containing a magnetic stir bar was charged

with bromophenol 11 (0.65 mmol, 0.300 g, 43:1 dr),

Pd(PPh₃)₂Cl₂(5 mol%, 0.0325 mmol, 22.8 mg), trans-1-

propen-1-ylboronic acid (1.30 mmol,0.112 g), K₂CO₃(2.60

mmol,0.359 g), THF (6.7 mL) and distilled water (1.7 mL).

This mixture was degassed by a freeze-pump-thaw proce-

(E)-2-(1-(4-hydroxyphenyl)prop-1-en-1-yl)phenol (10a).

¹H NMR (400 MHz, CDCl₃) δ = 7.26 (td, J = 7.5, 1.8, 1H),

7.14 (d, J = 8.7, 2H), 7.02 (dd, J = 7.5, 1.8, 1H), 7.01 –

6.92 (m, 2H), 6.74 (d, J = 8.7, 2H), 6.36 (q, J = 7.0, 1H),

5.07 (s, 1H), 4.91 (s, 1H), 1.70 (d, J = 7.0, 3H). ¹³C NMR

(126 MHz, CDCl₃) δ = 155.33, 153.01, 136.10, 133.46,

130.74, 129.27, 127.99, 125.72, 125.64, 120.72, 115.51,

115.41, 15.65.

o

dure followed by heating at 65 C (oil bath temperature)

for 20 hours. Next, the crude material was cooled to room

temperature, diluted with water (5 mL) and washed with

EtOAc (3 × 30 mL). The organic phases were combined,

dried over Na₂SO₄, filtered and concentrated under reduced

pressure. After evaporation of solvent, the crude mixture

was purified by flash column chromatography (silica gel,

hexanes/EtOAc 99:1 as eluent) to give the product TIPS-9

in 78% yield (0.51 mmol, 214 mg, >20:1 dr) as a light

yellow oil. The enantiomeric ratio of 86:14 was determined

by SFC analysis using Daicel Chiralpak^®IA-3 column (4.6

2-(2-(4-hydroxyphenyl)-3-methyl-2,3-

dihydrobenzofuran-2-yl)phenol (10b). ¹H NMR (500

MHz, CDCl₃) δ = 7.87 (s, 1H), 7.37 (d, J = 8.8, 2H), 7.27

(d, J = 7.1, 1H), 7.22 – 7.15 (m, 1H), 7.13 (td, J = 8.0, 1.3,

1H), 6.99 (dd, J = 7.9, 1.6, 1H), 6.94 (td, J = 7.4, 0.9, 1H),

6.89 (dd, J = 8.2, 1.0, 1H), 6.87 – 6.85 (m, 1H), 6.85 –

6.81 (m, 1H), 6.70 (d, J = 8.8, 2H), 5.14 (s, 1H), 4.16 (q, J

= 6.9, 1H), 1.02 (d, J = 7.1, 4H). ¹³C NMR (126 MHz,

CDCl₃) δ = 155.56, 155.11, 154.81, 136.24, 134.27,

129.23, 128.98, 128.70, 128.56, 125.75, 124.16, 122.16,

o

mm × 250 mm) at 25 C and 3% MeOH in supercritical

CO₂(2.0 mL.min^-1) as mobile phase: t_R= 15.6 min (major),

1

11.3 min (minor)). H NMR (400 MHz, CDCl₃) δ = 7.46

14

10.1002/adsc.201701278

Advanced Synthesis & Catalysis

– 7.35 (m, 2H), 7.30 – 7.20 (m, 2H), 7.06 – 6.97 (m, 2H),

6.89 (d, J = 8.1, 1H), 6.49 (dd, J = 15.7, 1.2, 1H), 6.21 (dq,

J = 15.6, 6.6, 1H), 5.20 (d, J = 8.9, 1H), 3.58 – 3.47 (m,

1H), 1.99 (dd, J = 6.6, 1.3, 3H), 1.51 (d, J = 6.8, 3H), 1.46

– 1.32 (m, 3H), 1.23 (d, J = 7.4, 18H). ¹³C NMR (101

MHz, CDCl₃) δ = 158.51, 156.32, 133.07, 132.59, 131.34,

130.94, 127.64, 123.07, 120.85, 120.07, 109.40, 92.90,

45.36, 18.54, 18.06, 17.94, 12.81. HRMS (ESI+) calculat-

Oliveira, N. C. Martins, C. R. D. Correia, Chem. Eur. J.

2014, 20, 13117–13121; e) I. U. Khan, S. Kattela, A.

Hassan, C. R. D. Correia Org. Biomol. Chem. 2016, 14

1091, 9476–9480; f) F. de Azambuja, R. C. Carmona,

T. H. D. Chorro, G. Heerdt, C. R. D. Correia, Chem.

Eur. J. 2016, 22, 11205–11209; g) J. de Oliveira Silva,

R. A. Angnes, V. H. Menezes da Silva, B. M. Servilha,

M. Adeel, A. A. C. Braga, A. Aponick, C. R. D.

Correia, J. Org. Chem. 2016, 81, 2010–2018; h) R. C.

Carmona, C. R. D. Correia, Adv. Synth Catal. 2015,

357, 2639-2643; i) S. Kattela, G. Heerdt, C. R. D. Cor-

reia, Adv. Synth. Catal. 2017, 359, 260-267.

ed to [C₂₇H₂₈OSi+ H⁺]: 423.2719, found: 423.2741. [α]²⁰

D

–63.63 (c 0.91, CHCl₃, >20:1 dr, 86:14 er).

4-((2R,3R)-3-methyl-5-((E)-prop-1-en-1-yl)-2,3-

dihydrobenzofuran-2-yl)phenol, conocarpan (9). To a

solution of silyl ether TIPS-9 (0.218 mmol, 92 mg) in

THF/AcOH glacial (6:1, 2.3 mL) at 0 °C it was added

TBAF (1 M in THF, 0.33 mmol, 0.33 mL). The mixture

was allowed to warm to room temperature and stirred

overnight. The reaction was then diluted with H₂O (10 mL)

and EtOAc (10 mL). The layers were separated, and the

aqueous layer was extracted with EtOAc (3 × 50 mL). The

combined organic layers were dried over Na₂SO₄, filtered,

and concentrated under reduced pressure. After evapora-

tion of the solvent, the crude mixture was purified by flash

column chromatography (silica, hexanes/EtOAc 90:10 as

eluent) to afford (–)-conocarpan 9 in 86% yield (0.188

mmol, 50 mg) as a white solid. The enantiomeric ratio of

88:12 was determined by HPLC analysis using Daicel

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o

Chiralpak^®OJ -3 column (4.6 mm × 250 mm) at 25 C and

20% i-PrOH in n-hexane (1.0 mL.min^-1) as mobile phase:

1

t_R= 16.7 min (major), 46.4 min (minor)). H NMR (400

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2H), 6.84 – 6.79 (m, 2H), 6.79 – 6.75 (m, 1H), 6.38 (dd, J

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5.09 (d, J = 8.9, 1H), 3.47 – 3.36 (m, 1H), 1.87 (dd, J = 6.6,

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92.81, 45.28, 18.53, 17.92. [α]²⁰–97.6 (c 1.26, MeOH,

D

20:1 dr, 88:12 er). (see Supporting Information for details).

Acknowledgements

We thank the São Paulo Research Foundation (FAPESP, grants:

2014/25770-6 and 2013/07600-3[CRDC]; 2013/25886-1 [ARS]);

2013/17083-6 [NCM], the Brazilian National Research Council

(CNPq, grants: 157522/2015-6 [ECP] and 457027/2014-

2[CRDC]), and the Coordination for the Improvement of Higher

Education Personnel (PNPD-CAPES [ECP]) for financial sup-

port and fellowships. We also thank Dr. D Simoni (UNICAMP)

for the X-ray crystallographic analyse.

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16

10.1002/adsc.201701278

Advanced Synthesis & Catalysis

FULL PAPER

Enantioselective Oxy-Heck-Matsuda Arylations:

Expeditious Synthesis of Dihydrobenzofuran

Systems and Total Synthesis of the Neolignan

(–)-Conocarpan

Adv. Synth. Catal. Year, Volume, Page – Page

Allan R. Silva, Ellen C. Polo, Nelson C. Martins,

and Carlos Roque D. Correia*

17

Article Doi

Enantioselective Oxy-Heck–Matsuda Arylations: Expeditious Synthesis of Dihydrobenzofuran Systems and Total Synthesis of the Neolignan (?)-Conocarpan

DOI: 10.1002/adsc.201701278

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