An efficient synthesis of substituted meta-halophenols and their methyl ethers: insight into the reaction mechanism

FULL PAPER

DOI: 10.1002/ejoc.201000071

An Efficient Synthesis of Substituted meta-Halophenols and Their Methyl

Ethers: Insight into the Reaction Mechanism

Faiz Ahmed Khan*^[a]and Sumit Choudhury^[a]

Keywords: Oxidation / Ketones / Grob-type fragmentation / meta-Halophenols / Reaction mechanisms

An expeditious synthetic methodology leading to substituted

meta-halophenols and their corresponding methyl ether de-

rivatives through acid-mediated fragmentation of suitably

substituted dihalonorbornyl ketones has been devised. The

reaction sequence consists of TBTH-mediated (TBTH is tri-

n-butyltin hydride) selective bridgehead halogen reduction

of easily accessible Diels–Alder adducts derived from 1,2,3,4-

tetrahalo-5,5-dimethoxycyclopentadiene and β-substituted

vinyl acetates, with subsequent conversion into the requisite

bicyclic ketones by a two-step hydrolysis/oxidation ap-

proach. An extensive mechanistic investigation based on iso-

tope labeling and cross experiments has been carried out and

plausible mechanistic pathways based on these results have

been proposed. The absence of halogen atoms at the bridge-

head positions steers the reaction through a novel pathway

involving the incorporation of proton (or deuterium) followed

by elimination of HX (or DX), so the described methodology

also provides a reliable route to ortho-para dideuterated

phenolic derivatives.

The enormous synthetic importance of substituted phen-

olic derivatives,^[10]together with their biological proper-

ties, make them attractive targets, resulting in a plethora of

synthetic endeavors. Halophenols are commonly synthe-

sized through electrophilic aromatic halogenation reactions

with employment of a variety of halogenating agents.^[11]So

far, a large number of methods for the synthesis of phenol

derivatives have been reported.^[12]Substituted phenols are

conventionally prepared from benzenoid precursors,^[12a–12f]

acyclic precursors,^[12g–12k]or non-benzenoid cyclic sys-

tems.^[12l,12m]Straightforward routes to substituted meta-

halophenols are scarce, however, because these are not ac-

cessible through conventional aromatic electrophilic substi-

tution reactions, by virtue of the ortho-para-directing elec-

tronic effects of hydroxy (or alkoxy) groups, which deter-

mine the regioselectivity in aromatic substitution chemistry.

Traditional approaches to these molecules involve the hy-

drolysis of diazonium salts, necessitating multistep reaction

sequences including aromatic electrophilic substitution,

which generally gives more than one regioisomer, thereby

necessitating a rigorous purification process before proceed-

ing further. Other than this traditional way, only two re-

ports of the synthesis of substituted meta-halophenols are

so far known. Patterson previously reported the synthesis

of highly substituted meta-chlorophenols through Alder–

Rickert reactions from starting chlorocyclohexa-1,3-diene

derivatives.^[13]Subsequently, Maleczka et al. developed an

iridium-catalyzed method for synthesizing meta-halophen-

ols bearing ortho/para-directing groups.^[14]

Introduction

Halophenols are ubiquitous because of their widespread

occurrence in compounds ranging from naturally occurring

bioactive molecules^[1]to industrially important pharmaceu-

ticals,^[2]and serve as synthetic building blocks for the con-

struction of these valuable entities. Chlorophenols are in-

dustrially important because of their broad spectrum of an-

timicrobial properties and their usage as fungicides, herbi-

cides, insecticides, ovicides, and algicides.^[2a]They are of

further industrial significance as a result of their extensive

usage as preservatives for wood, glue, paint, vegetable fi-

bers, and leather.^[2a,2b]On the other hand, differently substi-

tuted bromophenols have been found to exhibit a variety of

bioactivities including enzyme inhibitory activities,^[3]anti-

bacterial activity,^[4]cytotoxic activity,^[5]and free radical

scavenging activity.^[6]Moreover naturally occurring volatile

bromophenols have been found to be widely distributed in

marine fish and seafood and have been recognized as im-

portant contributors to their flavors.^[7]Recent studies have

revealed wide occurrence of bromophenols in marine algae

and this is believed to be a possible source of such com-

pounds in fish that feed predominantly on ocean plants.^[8]

Interestingly a number of brominated phenols have been

detected in the blood of humans, fish, and wild animals,

and their role in living systems has been the subject of in-

tense study.^[9]

[a] Department of Chemistry, Indian Institute of Technology,

Kanpur 208016, India

Fax: +91-512-2597436

E-mail: faiz@iitk.ac.in

As a consequence of our ongoing interest in applications

of the norbornyl moiety as a versatile building block,^[15]we

had earlier reported an efficient synthesis of the trihalo-

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201000071.

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Efficient Synthesis of Substituted meta-Halophenols and Their Methyl Ethers

phenol derivatives 6 (Scheme 1) from inexpensive and easily reorganization of double bonds to give the intermediates

accessible starting materials such as the 1,2,3,4-tetrahalo- 5B, which finally collapse to afford the trihalophenols 6

5,5-dimethoxycyclopentadienes 3 and the β-substituted vi- through enolization of 5C (Scheme 1).^[16]

nyl acetates 2, derived from aldehydes 1.^[16]Diels–Alder re-

In an attempt to extend and exploit this methodology,

actions between 2 and 3 furnished the cycloadducts 4, we wanted to examine the consequences of replacement of

which upon hydrolysis and subsequent oxidation of the re- the bridgehead halogens in compounds 5 by hydrogen

sulting secondary alcohols gave the bicyclic ketones 5.^[16]atoms and exposure of the resulting ketones 7 (Scheme 1)

Extending this concept, we have now achieved an easy route to similar acid treatment. We anticipated that the ketones 7

to substituted meta-halophenols and their methyl ethers, should undergo facile Grob-type fragmentations. However,

which are difficult to prepare by conventional routes. Here because of the lack of a leaving group X at C⁴, elimination

we wish to report an expeditious and flexible synthetic of HX as shown in Scheme 1 for compounds 5 (5A) is not

methodology leading to the title compounds. A detailed dis- possible for compounds 7, so a completely different mech-

cussion of plausible reaction mechanisms with supporting anistic course for the initially formed fragmentation inter-

evidence based on cross experiments and isotope labeling mediates 7A was expected.

experiments is also presented.

With this objective, we first reduced the bridgehead hal-

ogens in the Diels–Alder adducts 4, which had been pre-

pared by our previously reported method (Scheme 1).^[16]

Regioselective bridgehead halogen reductions of com-

pounds 4 were carried out with TBTH at reflux in ben-

zene^[17]to furnish compounds 8 in 72–80% yields (Table 1),

except in the case of 8f, for which the yield was 60%. The

relatively unreactive chloro analogues required 50–60 hours

for the completion of reaction to furnish the reduced prod-

ucts in good yields. The appearance of two doublets of dou-

1

blets (dd) in H NMR spectra of 8 in the δ = 3.0–3.5 ppm

range indicated the replacement of halogens by hydrogen

atoms at the bridgehead positions. The observed dds for the

1

bridgehead protons H¹and H⁴in the H NMR spectra of

8 are due to their coupling with the corresponding vicinal

exo protons H²and H³, respectively, as well as “W” cou-

pling with one another, which falls in the 2.2–2.4 Hz range

(see Figure S1 in the Supporting Information). The appear-

ance of a dd in the δ = 5.3–5.7 ppm range for exo-H²also

Table 1. TBTH-mediated reductions of the bridgehead halogens of

compounds 4.^[a]

Entry

Substrate 4

Time

[h]

Product

Yield

[%]^[b]

X

R

1

2

3

4

5

6

7

8

4a

4b

4c

4d

4e

4f

4g

4h

4i

Br

Cl

n-C₃H₇

n-C₄H₉

n-C₅H₁₁

n-C₆H₁₃

Ph

2.5

3.5

2.5

3

2.5

1

50

60

8a

8b

8c

8d

8e

8f

8g

8h

8i

75

73

74

72

80

60

80

72

77

74

78

Scheme 1. Synthesis and acid-catalyzed fragmentation of com-

pounds 5.

H

n-C₃H₇

n-C₄H₉

n-C₅H₁₁

n-C₆H₁₃

Ph

Results and Discussion

9

10

11

4j

4k

8j

8k

We had earlier proposed a mechanism involving acid-cat-

alyzed Grob-type fragmentation of compounds 5 to afford

the dienols 5A.^[16]The intermediates 5A represent ideal

push-pull systems because X at C⁴, being a good leaving

group, is present in conjugation with the dienol moiety. This

[a] The reactions were carried out in dry benzene (10 mL) with 4

(1 mmol), TBTH^[c](2.4 mmol), and AIBN (0.05 mmol) at reflux

temperature (80–90 °C). [b] Isolated yield after column chromatog-

raphy. [c] TBTH was distilled prior to use and purity was checked

is suitably positioned for HX elimination with simultaneous by GC analysis (ca. 95% purity).

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Table 2. Hydrolysis of acetates 8 to alcohols 9^[a]and their oxidation to the corresponding ketones 7.^[b]

Entry

Substrate 8

Alcohol

Ketone

7/time [h]/yield [%]^[c]

X

R

9/time [h]/yield [%]^[c]

1

2

3

4

5

6

7

8

8a

8b

8c

8d

8e

8f

8g

8h

8i

Br

Cl

n-C₃H₇

n-C₄H₉

n-C₅H₁₁

n-C₆H₁₃

Ph

9a/20/91

9b/20/91

9c/25/95

9d/20/93

9e/30/99

9f/20/90

9g/30/90

9h/50/91

9i/40/92

9j/40/92

9k/50/90

7a/40/90

7b/40/91

7c/30/91

7d/40/90

7e/30/92

7f/40/90

7g/30/91

7h/40/90

7i/50/92

7j/40/94

7k/40/91

H

n-C₃H₇

n-C₄H₉

n-C₅H₁₁

n-C₆H₁₃

Ph

9

10

11

8j

8k

[a] Reactions were carried out in methanol (5 mL) with 8 (1 mmol) and K₂CO₃(1.1 mmol) at room temperature. [b] Reactions were

carried out in dichloromethane (50 mL) with 9 (1 mmol), anhydrous pyridine (13.3 mmol), and CrO₃(6.6 mmol) at room temperature.

[c] Isolated yield after column chromatography.

supports the above conjecture, because it also experiences Table 3. Acid-catalyzed fragmentation of 7.^[a]

vicinal couplings with exo-H³and H¹.

The acetates 8 were then hydrolyzed (K₂CO₃in MeOH)

to furnish the corresponding alcohols 9 in good to excellent

yields (Table 2). Subsequently they were oxidized (Py/CrO₃

in dichloromethane) with in situ formation of pyridinium

dichromate (PDC) to afford the corresponding bicyclic

ketones 7 in high yields (Table 2).

Entry Substrate 7

Time

[h]

Product

Yield

[%]^[b]

X

R

The bicyclic ketones 7 were then treated with pTsOH

(PTSA) in toluene at reflux. Unlike in the fragmentation of

the tetrahalo analogues 5, which had furnished the substi-

tuted trihalophenol derivatives 6 (Scheme 1),^[16]two prod-

ucts were formed in this case. From their ¹H and ¹³C NMR

spectra, the structures of the two products were assigned as

the substituted meta-halophenols 10 and the corresponding

methyl ethers 11, the former products being the major ones

in all cases (Table 3). It is rather surprising to note that

products with identical substitution patterns and each con-

taining only one halogen atom were obtained. Unlike in the

case of compounds 5, neither of the two halogens present

in the starting ketones 7 is suitably positioned for HX elimi-

nation, which means that a halogen atom X is lost from a

1

2

3

4

5

6

7

8

7a

7b

7c

7d

7e

7f

7g

7h

7i

Br

Cl

n-C₃H₇

n-C₄H₉

n-C₅H₁₁

n-C₆H₁₃

Ph

H

n-C₃H₇

n-C₄H₉

10

8

12

1

10a, 11a

10b, 11b

10c, 11c

10d, 11d

10e, 11e

10f, 11f

10g, 11g

10h, 11h

10i, 11i

60, 30

49, 36

53, 37

56, 32

51, 32

42, 16

48, 35

44, 37

41, 39

45, 38

44, 39

40

30

9

10

11

n-C₅H₁₁30

n-C₆H₁₃30

7j

7k

10j, 11j

10k, 11k

Ph

30

[a] The reactions were carried out in dry toluene (3 mL) with 7

(0.07 , 0.21 mmol) and PTSA (0.21 mmol) at reflux temperature

(100–110 °C). [b] Isolated yield after column chromatography.

position not well suited for elimination. At this stage, there aromatic protons was now carried out. Because they ap-

were two issues to be settled: i) the mechanism of HX elimi- peared as doublets with coupling constants ranging from

nation, and ii) the origin of the methyl ether formation.

2–2.2 Hz, a typical value for meta-coupling, the products

The NMR spectra of the compounds 10 and 11 showed were assigned the structures 10. Final confirmation of the

similarities, but with compounds 11 each showing one extra structures was provided by acid-catalyzed fragmentation of

1

peak (as a singlet) in the δ = 3.5–3.9 ppm range (corre- 7f. In its H NMR spectrum the thus obtained phenol de-

1

sponding to three protons) in the H spectrum and in the δ rivative 10f showed three doublets in the aromatic region

= 52–57 ppm range in the ¹³C NMR spectrum. The appear- with J values typical for meta-coupling. This is possible

ance in each case of two signals (both as doublets) in only if three protons remain at the 1, 3, and 5 positions of

1

the aromatic region in the H NMR spectra indicated that the aromatic ring. Any other distribution would result in at

compounds 10 were monohalophenols (tetrasubstituted least two hydrogen atoms ortho to each other with a charac-

1

benzenes). To ascertain the substitution patterns of the teristic J value in the 7–10 Hz range in the H NMR spec-

aromatic moieties, analysis of the coupling constants of the trum of 10f, and no such a feature is present.

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Efficient Synthesis of Substituted meta-Halophenols and Their Methyl Ethers

Similar spectral analysis confirmed the structures of the

other compounds 11 as the corresponding methyl ethers.

The phenolic compound 10b, isolated after treatment of 7b

with PTSA, gave 11b on methylation with MeI/K₂CO₃

(Scheme 2). When the crude reaction mixture obtained

from the same reaction (containing both 10b and 11b as

indicated by TLC) was treated with MeI/K₂CO₃in acetone,

exclusive formation of 11b was achieved, which unequivo-

cally confirmed the structure of 11b as the methyl ether

derivative of 10b.

Scheme 3. Plausible mechanism for fragmentation of compounds

7.

in the current case, the earlier mechanism is ruled out, thus

necessitating the postulation of a different route. The inter-

mediates 7A, each containing a dienol moiety as repre-

sented by C⁵–C⁶–C¹–C²–OH, could undergo protonation

Scheme 2. Structural confirmation of the formation of methyl

ethers of the meta-halophenols 10.

Substituted meta-halophenols are valuable intermediates by external acid either at the β-carbon (i.e., C¹) or at the δ-

in organic synthesis, having been found to be useful both in carbon (i.e., C⁵) of the dienol moiety from the less hindered

+

materials science^[18]and in the pharmaceutical industry.^[19]face [opposite to bulky C(OMe)₂group] as shown in

Müller et al. utilized the ethyl ester analogue of 10f as a Scheme 3. Protonation at the β-carbon would generate in-

functionalized building block for the construction of multi- termediates 7B, which could revert back to the original 7A

functional molecular materials such as preorganized oligo- through enolization. On the other hand, protonation at the

functional amphiphiles^[18]and a thrombin inhibitor was δ-carbon would result in the formation of intermediates 7C.

successfully synthesized by Lu et al. through employment These, being cyclohexenone derivatives, can be represented

of the benzyl ester derivative of the chloro analogue of in a half-chair conformation in which H⁴and X⁵occupy

10f.^[19]

axial and pseudoaxial positions, respectively. As a result,

Having confirmed the structures of 10 and 11, our next the acidic proton H⁴and halogen X⁵could then undergo

task was to propose a mechanism to explain the product facile 1,2-elimination to form 7D. The halide X^–could then

formation. A plausible mechanism based on our previous nucleophilically attack the oxocarbenium ions 7D at the

work^[16]and the above experimental results is depicted in methyl carbon to form gaseous MeX and cyclohexadienone

Scheme 3. On exposure to acid, protonation at the carbonyl moieties 7E. Finally, the substituted meta-halophenols 10

group of 7, followed by cleavage of the C¹–C⁷sigma bond could be obtained through enolization of intermediates 7E

in a Grob fragmentation pattern in a similar manner as (Scheme 3).

observed with 5 (Scheme 1), results in the formation of the

Although this mechanism would suffice to explain the

resonance-stabilized intermediate oxocarbenium ion 7A (for formation of the phenols 10 from the cyclohexadienones

convenience, the same numbering sequence as for 7 is re- 7E, further pathways are required in order to explain the

tained for other intermediates).

formation of the corresponding methyl ether derivatives

In the case of cleavage of compounds 5, C⁴was substi- 11.^[20]The fundamental question is: which species is acting

tuted at this stage with halogen (X, 5A, Scheme 1). Its sub- as the methylating agent? In principle, the oxocarbenium

sequent removal from the system as X^–facilitated the gener- species 7D and/or the MeX generated during the reaction

ation of an intermediate 5B capable of triggering extrusion could be responsible for methylation, whereas the nucleo-

of gaseous MeX. Because a hydrogen atom is present at C⁴philic species that undergo methylation could be either the

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phenol derivatives 10 or the intermediate cyclohexadien- of the reaction, with only the normal products (i.e., the phe-

ones 7E. Keeping this in mind, four hypotheses may be en- nol derivative 10b and its methyl ether 11b) being formed;

visaged, as shown in Scheme 4.

no anisole formation was detected (as indicated by GC

analysis). Consequently, a mechanism of this type can prob-

ably be ruled out.

Scheme 5. Fragmentation reaction of 7b in the presence of phenol.

Route (b) (Scheme 4) is incompatible with the in situ gen-

eration of gaseous MeX, the evolution of which during the

course of reaction had been unequivocally corroborated

spectroscopically by the appearance of sharp singlets at δ =

1

2.6 ppm (characteristic of MeBr) in the H NMR spectra

of the crude products obtained from the decomposition

either of 7e or of 7f (Scheme 6).^[21]

Scheme 4. Possible routes for the formation of 11.

If route (a) depicted in Scheme 4 is operative, then ad-

dition of phenol (C₆H₅OH) to the reaction mixture should

furnish anisole (C₆H₅OMe) as one of the products, due to

competition of added phenol with 10. To address this issue,

a known quantity of phenol was added to the reaction mix-

Scheme 6. Decomposition of 7e/7f at room temperature.

To test the feasibility of route (c) as shown in Scheme 4,

ture during the fragmentation reaction of 7b (R = n-C₄H₉) methylation of 10b with MeI was attempted under condi-

in the presence of PTSA in toluene at reflux (Scheme 5). tions similar to those of the fragmentation reaction

Interestingly, we did not observe any change in the outcome (Scheme 7). When the phenol derivative 10b was subjected

Scheme 7. Attempted methylation of 10b under different conditions.

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Efficient Synthesis of Substituted meta-Halophenols and Their Methyl Ethers

to treatment with MeI in toluene in the absence of any base,

no reaction took place either at room temperature or at

elevated temperature. As expected, addition of PTSA to the

reaction mixture was unable to change the course of the

reaction, whereas the reaction took place only when K₂CO₃

was added (Scheme 7). Because there is no possibility of

any basic species being generated during the acid-catalyzed

fragmentation reaction in toluene at reflux, route (c) in

Scheme 4 can also be eliminated.

Route (d) in Scheme 4 thus appears to be the most likely

pathway for the formation of 11. In order to obtain evi-

dence in support of this, the fragmentation reaction was

carried out with the ketone 7e (R = Ph) under optimized

conditions with the additional presence of a different elec-

trophile, ethyl iodide, in excess (Scheme 8).^[22]It was ob-

served that in addition to the normal products 10e and 11e,

some quantities of the corresponding ethyl ether 12 were 11.

also formed (Scheme 8). This indicates that the cyclohexadi-

enone moiety 7E acts as a nucleophilic species and that H⁺,

MeBr (generated during the reaction) and the added C₂H₅I

Scheme 9. Another possible route for the formation of compounds

To check this, 7b was subjected to optimized conditions

compete as electrophiles. As would be expected on the basis for the fragmentation reaction in the presence of TsOMe

of the steric requirements of the competing electrophiles (Scheme 10). No significant change in the 10b/11b ratio was

(H⁺/MeBr/C₂H₅I), H⁺would win the race to furnish 10e as noticed. Further, in a separate experiment, 10b was also al-

the major product. Factors such as primary vs. secondary lowed to react with TsOMe in toluene at reflux. The methyl

and bromo vs. iodo govern the balance between the electro- ether 11b was not observed, thus ruling out the possibility

philic species MeBr and C₂H₅I, eventually leading to the of direct methylation of the phenols 10 by TsOMe

minor products 11e and 12 in approximately 2:1 ratio (Scheme 10). Additional support in favor of route (d) was

(isolated yields). This supports route (d) as depicted in provided by the gradual decomposition of 7e and 7f on

1

Scheme 4.

storage at room temperature (Scheme 6). H NMR spectral

At this point, if the availability of tosylate anion (TsO^–), analysis of the decomposed 7e showed the presence of 10e

produced from PTSA during the course of the reaction, is and 11e in approximately 1:0.1 ratio whereas the same for

kept in mind, one might conceive that presence of PTSA 7f showed 10f and 11f in a ratio of 1:2.3 along with MeBr

plays a role in the formation of the methyl ether derivatives in both cases (Scheme 10). However, the intensity of the

11, because TsO^–could attack the intermediate oxocarb- peak at δ = 2.6 ppm in the ¹H NMR spectrum (characteris-

enium ions 7D at the methyl carbon thereby generating 7E tic of MeBr) is significantly smaller in the case of 7f than

and TsOMe, which may act as a methylating agent^[23]either in that of 7e because the majority of the MeBr was used up

during enolization of the species 7E and/or through direct as a result of nucleophilic attack during the enolization of

methylation of the phenols 10 already formed in the reac- intermediate cyclohexadienone to form the methyl ether de-

tion, thus affording compounds 11 (Scheme 9).

rivative 11f (see the Supporting Information).

Scheme 8. Fragmentation reaction of 7e in the presence of ethyl iodide.

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Scheme 10. Fragmentation of the bicyclic ketones 7 under different sets of conditions.

Now, to ascertain the fate of the bridgehead hydrogen taken as a model substrate for this purpose and was re-

atoms in the bicyclic ketones 7 during the proposed mech- duced with tri-n-butyltin deuteride (TBTD),^[24]prepared by

anistic course, the ideal solution would therefore be to re- reduction of tri-n-butyltin chloride (TBTCl) with lithium

place them with deuterium and then to carry out the acid- aluminium deuteride (LiAlD₄), to furnish the dideuterated

mediated fragmentation reaction with a non-deuterated compound 13 in 72% yield (Scheme 11).

acid source. Alternatively, the bicyclic ketones 7 (non-deu-

Evidence for the replacement of the bridgehead halogens

terated at bridgehead positions) could be subjected to a of 4b by deuterium was obtained from NMR spectroscopic

deuterated acidic reagent. NMR and mass spectrometry data. The absence of two peaks due to the bridgehead pro-

1

could then be used to identify and locate hydrogen and/or tons in the δ = 3–3.5 ppm range in H NMR spectrum and

deuterium present in the products, thus providing further the appearance of a doublet (d) for exo-2-H, instead of a

insight into the mechanism.

doublet of doublets (dd) as observed in 8b, confirmed the

In order to obtain such labeled bicyclic ketones, the incorporation of deuterium at the bridgehead positions.

bridgehead halogens of the initial acetate adducts 4 would Comparison of ¹³C NMR spectra with 8b also indicated the

need to be replaced by deuterium with subsequent execu- replacement of two intense peaks at δ = 57.9 and 57.7 ppm

tion of the known sequence of reactions. Compound 4b was by weak peaks of multiplet nature arising from C–D cou-

Scheme 11. Synthesis of 15 (with bridgehead deuterium) and its fragmentation reaction in the presence of protonated acid.

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Efficient Synthesis of Substituted meta-Halophenols and Their Methyl Ethers

pling, which further confirmed the structure of 13 (see the During its formation, deuterium initially attached to C¹is

Supporting Information). This was then converted into the probably mostly exchanged for hydrogen from the external

bicyclic ketone 15 by a two-step hydrolysis/oxidation acidic reagent through the process of keto–enol tautomer-

method in high yield. When the ketone 15 was treated with ism. It is presumed that, during this process, electrophilic

PTSA in toluene at reflux both the phenol 16 and its methyl attack at the C¹–C²double bond by the proton supplied by

ether 17 were formed in 48% and 32% yields, respectively.

the acid takes place, predominantly from the less hindered

+

Although PTSA had induced the fragmentation reaction, face [opposite the bulky C(OMe)₂group], forcing the exi-

in order to know the exact roles of the bridgehead hydrogen sting deuterium at C¹to the more hindered face to generate

atoms, it was also necessary to have some other acid, strong the cyclohexenone intermediate 15B in which the deuterium

enough to cause the above reaction and with an easily avail- at C¹occupies a pseudoaxial position. Thus, during enoli-

able deuterated version. In this context, several acidic rea- zation, preferential involvement of pseudoaxially positioned

gents were tested under varying reaction conditions with 7b deuterium, giving rise to 15C, can be anticipated. Subse-

as model substrate (see Table S1 in the Supporting Infor- quent preferential protonation at the C⁵–C⁶vinylic double

mation). It was observed that treatment of 7b with excess bond from the less hindered bottom face by the acid to

trifluoroacetic acid (TFA) in a sealed tube at 110–120 °C generate 15E, 1,2-elimination of DX from this, followed by

resulted in the formation of only one product: the phenol nucleophilic capture of the methyl group of the resulting

derivative 10b. No methyl ether 11b was obtained, perhaps 15F by X^–, and final enolization of the consequent cyclo-

due to the presence of large amount of H⁺.

hexadienone moiety 15G leads to the formation of products

When the ketone 7b (with hydrogen atoms at its bridge- 16 and 17.

head positions) was treated with excess CF₃COOD in tolu-

ene in a sealed tube at 110–120 °C only the phenol deriva-

tive 18 was formed (Scheme 12).

Scheme 12. Fragmentation reaction of 7b (not deuterated at the

bridgehead positions) in the presence of a deuterated acid.

To visualize the presence and extent of deuteration in the

products obtained from these experiments, comparison of

both ¹H and ¹³C NMR spectra of products 16, 18, and

the corresponding normal phenolic compound 10b was now

carried out (see Figure S2 and Figure S3 in the Supporting

Information). Analysis of the integrals of different signals

1

in the H NMR spectrum of 16 in relation to that of 10b

revealed it to be mostly, but not exclusively, protonated,

with the presence of ca. 12% deuterium (as calculated on

the basis of integrals of different signals) being observed in

16. Mass spectral analysis (see the Supporting Information)

also supports the presence of minor quantities of deuterium

in 16. On the other hand, a ¹H and ¹³C NMR spectral study

of 18 found an almost reversed situation with regard to deu-

terium content, as observed in the form of ca. 92% deute-

rium incorporation in 18, which was further supported by

its mass spectrum. Similar ¹H NMR spectral analysis of

17 in relation to that of 11b indicates ca. 16% deuterium

Scheme 13. Plausible mechanism in which the substrate is deuter-

ated and the acidic reagent is not deuterated.

occurrence.

In accordance with these results, the following mechan-

istic proposals have been made to interpret the observed

Of the two deuterium atoms present in 15, the one at C¹

proton/deuterium induction as shown in Scheme 13 and in is lost during exchanges with H⁺supplied by the acidic rea-

Scheme 14 (below). In the cleavage of 15, the intermediate gent and the other at C⁴is removed as DX. On the other

oxocarbenium ion 15A formed by protonation and subse- hand, electrophilic attack at the δ-carbon of the dienol moi-

quent C¹–C⁷sigma bond cleavage can undergo a series of ety in 15C (i.e., at C⁵) is predominantly by H⁺of the acid

deuterium/proton transfer steps to form 15C (Scheme 13). used. As a result, the final phenol derivatives 16 and 17 are

Eur. J. Org. Chem. 2010, 2954–2970

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2961

F. A. Khan, S. Choudhury

FULL PAPER

found to be predominantly protonated at C⁴and C⁶, as of MeX generated in situ in acting as a competing electro-

evidenced by the presence of only ca. 12% and ca. 16% phile, thus ruling out the formation of the methyl ether de-

deuterium in 16 and 17, respectively. The reagent PTSA was rivative.

used as its monohydrate form (pTsOH·H₂O) to effect the

fragmentation reactions of the bicyclic ketones; the water

Conclusions

molecule might thus be acting as an additional proton

source. Minor deuteration can be explained on the basis of

competitive participation by D⁺produced during the course

of the reaction, which is of course outstripped by the al-

ready existing H⁺source.

In summary, we have developed an efficient route for the

synthesis of substituted meta-halophenol derivatives and

the corresponding methyl ether derivatives through acid-

catalyzed fragmentation of dihalonorbornyl ketones. The

overall transformations are based on a four-step protocol

starting from easily accessible Diels–Alder adducts of

1,2,3,4-tetrahalo-5,5-dimethoxycyclopentadienes and β-

substituted vinyl acetates. TBTH-mediated reduction of the

bridgehead halogens of the initial adducts, followed by hy-

drolysis, oxidation of the resulting secondary alcohols, and

finally acid-mediated fragmentation of the corresponding

bicyclic ketones, led to the title compounds. Detailed mech-

anistic investigation involving isotope labeling and cross ex-

periments was carried out, and plausible mechanistic path-

ways based on the results of these experiments and the

products (or byproducts) formed, as well as on spectro-

scopic data, have been proposed. The experimental results

clearly demonstrate that the external proton (or deuterium)

supplied by the acidic reagent used is being incorporated

predominantly in the final products. The formation of the

methyl ether derivatives has been explained in terms of nu-

cleophilic attack at the methyl halide generated in situ dur-

ing the enolization of the cyclohexadienone moiety presum-

ably produced as an intermediate during the course of the

reaction. Although PTSA in stoichiometric quantities af-

forded both products, trifluoroacetic acid furnished only

the phenolic derivatives, probably because of its usage in

excess, which was found to be an experimental requirement

rather than a matter of choice. The methodology also pro-

vides a reliable route to ortho-para-dideuterated phenolic

derivatives.

On the other hand, the fragmentation reaction of 7b in

the presence of [D]TFA (CF₃COOD) can be mechan-

istically interpreted (Scheme 14) in a similar fashion, the

only difference being hydrogen taking the place of deute-

rium and vice versa. In this case the presence of hydrogen

(ca. 8%) at C⁴and C⁶of 18, which is comparable with the

previous result of ca. 12% deuterium occurrence at C⁴and

C⁶of 16, also supports the discussed mechanistic explana-

tions. The D⁺was present in large excess in the latter case

(1.5 mL for 0.1 mmol of 7b i.e. ca. 200 equivalents), which

was found to be an experimental requirement rather than a

choice to induce the fragmentation reaction of 7b

(Scheme 12) as explained earlier. The large excess of D⁺was

therefore assumed to have almost nullified the effectiveness

Experimental Section

General Methods: All reactions were performed in oven-dried appa-

ratus. All common reagents were obtained from commercial suppli-

ers and were used without further purification. Commercial grade

solvents were distilled by standard methods. Thin layer chromatog-

raphy was performed on microscopic slides coated with silica gel

(300 mesh). Visualization of spots was accomplished by exposure

to iodine vapor and/or UV radiation and/or spraying with ethan-

olic H₂SO₄(4%) followed by charring. Column chromatography

was performed with silica gel (100–200 mesh) and various combi-

nations of ethyl acetate and hexane were used as eluents. AgNO₃-

impregnated silica gel for column chromatography was prepared by

mixing silica gel and AgNO₃(7 wt.-%) in the minimum amount

of water sufficient to generate a homogeneous slurry, followed by

evaporation of water with heating and subsequent drying overnight

in an oven. Melting points reported are uncorrected. IR spectra

were recorded with Perkin–Elmer 1320 and Shimadzu 420 spectro-

photometers as KBr pellets (solids) or thin films (liquids). ¹H

NMR and proton-decoupled ¹³C NMR spectra were recorded with

a JEOL spectrophotometer at 400 and 100 MHz respectively. Sam-

Scheme 14. Plausible mechanism in which the substrate is not deu-

terated and the acid catalyst is deuterated.

2962

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Eur. J. Org. Chem. 2010, 2954–2970

Efficient Synthesis of Substituted meta-Halophenols and Their Methyl Ethers

ples for NMR were dissolved in CDCl₃. The chemical shifts (δ,

ppm) and coupling constants J (Hz) are reported in the standard

fashion with reference either to internal tetramethylsilane (for H)

1720 (C=O), 1580, 1440, 1360, 1220, 1040, 720 cm^–1. C₁₆H₂₄Br₂O₄

(440.17): calcd. C 43.66, H 5.50; found C 43.83, H 5.35.

1

5,6-Dibromo-3-hexyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-yl

Acetate (8d): R_f= 0.6 [EtOAc/hexane 5% (over 7% AgNO₃-im-

pregnated silica gel)]; yield 438 mg, 72% from 4d, viscous liquid.

¹H NMR (400 MHz, CDCl₃): δ = 5.39 (dd, J = 4.2, 7.8 Hz, 1 H,

2-H_exo), 3.41 (dd, J = 2.3, 4.0 Hz, 1 H, 1-H), 3.17 (s, 3 H, OMe),

3.15 (s, 3 H, OMe), 3.09 (br. t, J = 2.8 Hz, 1 H, 4-H), 2.60–2.53

(m, 1 H, 3-H_exo), 2.01 (s, 3 H, OCOCH₃), 1.39–1.17 (series of m,

10 H), 0.86 (t, J = 6.7 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 171.0, 121.7, 118.6, 114.9, 73.5, 57.9, 57.7, 51.9, 49.7,

or to the central line (δ = 77.0 ppm) of CDCl₃(for ¹³C). Data are

reported as follows: s = singlet, d = doublet, t = triplet, q = quartet,

br = broad, m = multiplet. High-resolution mass spectra were re-

corded with a WATERS Q-TOF micro mass spectrometer in the

electron spray ionization (ESI) mode and with a WATERS GCT

micro mass spectrometer in the electron ionization (EI) mode. Ele-

mental analyses were performed with a CE-440 Elemental Analyzer

(Exeter Analytical Inc.).

42.0, 31.7, 29.3, 28.5, 26.2, 22.6, 20.8, 14.1 ppm. IR (neat): ν =

˜

General Procedure for Bridgehead Halogen Reduction of Tetra-

halonorbornyl Acetates 4 to Generate Compounds 8

2900, 1720 (C=O), 1580, 1440, 1360, 1220, 1040, 720 cm^–1.

5,6-Dibromo-7,7-dimethoxy-3-phenylbicyclo[2.2.1]hept-5-en-2-yl

Acetate (8e): R_f= 0.6 [EtOAc/hexane 10% (over 7% AgNO₃-im-

pregnated silica gel)]; yield 502 mg, 80% from 4e; solid, m.p. 110–

5,6-Dibromo-7,7-dimethoxy-3-propylbicyclo[2.2.1]hept-5-en-2-yl

Acetate (8a): Tri-n-butyltin hydride (1.203 gm, 4.13 mmol) and azo-

bis(isobutyronitrile) (AIBN) (13 mg, 0.08 mmol) were added under

argon to a solution of 4a (900 mg, 1.58 mmol) in dry benzene

(15 mL). The reaction mixture was then heated at reflux under ar-

gon for 2.5 h until complete disappearance of starting material by

TLC. The reaction mixture was then concentrated under reduced

pressure to remove the solvent and the resulting crude mass was

used for chromatographic separation. The tin impurities were first

removed by adsorption of the oily crude mass over 7% AgNO₃-

impregnated silica gel, followed by elution with EtOAc/hexane

(5%). The resulting light yellow liquid was further purified by col-

umn chromatography over silica gel with prolonged hexane elution

followed by a controlled increase of polarity with EtOAc/hexane

solvent systems (up to 2% EtOAc/hexane as eluent) to furnish the

doubly reduced product 8a. R_f= 0.6 [EtOAc/hexane 5% (over 7%

AgNO₃-impregnated silica gel)]; yield 488 mg, 75%; viscous liquid.

¹H NMR (400 MHz, CDCl₃): δ = 5.40 (dd, J = 4.1, 7.8 Hz, 1 H,

2-H_exo), 3.41 (dd, J = 2.2, 4.2 Hz, 1 H, 1-H), 3.17 (s, 3 H, OMe),

3.15 (s, 3 H, OMe), 3.08 (dd, J = 2.3, 3.3 Hz, 1 H, 4-H), 2.62–2.57

(m, 1 H, 3-H_exo), 2.01 (s, 3 H, OCOCH₃), 1.42–1.38 (m, 1 H), 1.28–

1.16 (series of m, 3 H), 0.89 (t, J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 171.0, 121.7, 118.6, 114.9, 73.5, 57.9,

1

112 °C. H NMR (400 MHz, CDCl₃): δ = 7.27–7.15 (m, 5 H, Ph),

5.68 (dd, J = 4.0, 7.7 Hz, 1 H, 2-H_exo), 3.88 (dd, J = 3.6, 7.7 Hz, 1

H, 3-H_exo), 3.53 (dd, J = 2.3, 4.0 Hz, 1 H, 1-H), 3.27 (s, 3 H, OMe),

3.22 (s, 3 H, OMe), 3.20 (dd, J = 2.3, 3.5 Hz, 1 H, 4-H), 2.01 (s, 3

H, OCOCH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 170.2,

135.3, 131.1 (2 C), 127.7 (2 C), 127.1, 123.3, 120.1, 115.2, 74.7,

61.0, 58.5, 52.1, 49.9, 48.3, 20.6 ppm. IR (KBr): ν = 2900, 1720

˜

(C=O), 1580, 1480, 1440, 1360, 1220, 1080, 1040, 840, 760,

700 cm^–1. C₁₇H₁₈Br₂O₄(446.13): calcd. C 45.77, H 4.07; found C

46.24, H 3.95.

5,6-Dichloro-7,7-dimethoxy-3-propylbicyclo[2.2.1]hept-5-en-2-yl

Acetate (8g): R_f= 0.6 [EtOAc/hexane 4% (over 7% AgNO₃-im-

1

pregnated silica gel)]; yield 1.4 g, 80% from 4g, viscous liquid. H

NMR (400 MHz, CDCl₃): δ = 5.38 (dd, J = 4.0, 7.7 Hz, 1 H, 2-

H_exo), 3.33 (dd, J = 2.4, 4.1 Hz, 1 H, 1-H), 3.17 (s, 3 H, OMe),

3.14 (s, 3 H, OMe), 3.01 (br. t, J = 2.8 Hz, 1 H, 4-H), 2.58–2.53

(m, 1 H, 3-H_exo), 1.99 (s, 3 H, OCOCH₃), 1.40–1.12 (m, 4 H), 0.88

(t, J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

170.9, 128.7, 125.8, 114.2, 73.6, 56.2, 55.9, 51.8, 49.6, 41.6, 28.4,

21.5, 20.7, 14.1 ppm. IR (neat): ν = 2900, 1720 (C=O), 1600, 1440,

˜

1360, 1220, 1020, 720 cm^–1. C₁₄H₂₀Cl₂O₄(323.22): calcd. C 52.02,

H 6.24; found C 51.54, H 6.06.

57.6, 51.9, 49.7, 41.7, 28.3, 21.7, 20.7, 14.1 ppm. IR (neat): ν =

˜

2900, 1720 (C=O), 1580, 1440, 1360, 1220, 1020, 720 cm^–1. HRMS

(EI): m/z: calcd. for C₁₄H₂₀Br₂O₄[M]⁺409.9728; found 409.9729.

3-Butyl-5,6-dichloro-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-yl Acet-

ate (8h): R_f= 0.6 [EtOAc/hexane 4% (over 7% AgNO₃-impreg-

nated silica gel)]; yield 662 mg, 72% from 4h, viscous liquid. ¹H

NMR (400 MHz, CDCl₃): δ = 5.39 (dd, J = 4.0, 7.7 Hz, 1 H, 2-

5,6-Dibromo-3-butyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-yl

Acetate (8b): R_f= 0.6 [EtOAc/hexane 5% (over 7% AgNO₃-im-

pregnated silica gel)]; yield 426 mg, 73% from 4b, viscous liquid.

¹H NMR (400 MHz, CDCl₃): δ = 5.39 (dd, J = 4.2, 7.8 Hz, 1 H,

2-H_exo), 3.42 (dd, J = 2.2, 3.9 Hz, 1 H, 1-H), 3.17 (s, 3 H, OMe),

3.15 (s, 3 H, OMe), 3.08 (br. t, J = 2.3 Hz, 1 H, 4-H), 2.64–2.58

(m, 1 H, 3-H_exo), 2.01 (s, 3 H, OCOCH₃), 1.34–1.19 (series of m,

6 H), 0.88 (t, J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 171.0, 121.7, 118.6, 114.9, 73.5, 57.9, 57.7, 51.9, 49.7,

H_exo), 3.34 (dd, J = 2.3, 4.0 Hz, 1 H, 1-H), 3.17 (s, 3 H, OMe),

3.15 (s, 3 H, OMe), 3.02 (br. t, J = 2.9 Hz, 1 H, 4-H), 2.57–2.51

(m, 1 H, 3-H_exo), 2.00 (s, 3 H, OCOCH₃), 1.35–1.17 (series of m,

6 H), 0.87 ppm (t, J = 7.1 Hz, 3 H, CH₃). ¹³C NMR (100 MHz,

CDCl₃): δ = 170.9, 128.7, 125.8, 114.2, 73.5, 56.1, 55.9, 51.9, 49.6,

41.8, 30.5, 25.9, 22.7, 20.8, 14.0 ppm. IR (neat): ν = 2900, 1720

˜

(C=O), 1600, 1440, 1360, 1220, 1020, 720 cm^–1. C₁₅H₂₂Cl₂O₄

(337.24): calcd. C 53.42, H 6.58; found C 53.32, H 6.35.

41.9, 30.7, 25.8, 22.7, 20.8, 14.1 ppm. IR (neat): ν = 2950, 1740

˜

(C=O), 1580, 1460, 1370, 1210, 1040 cm^–1. EI-HRMS: m/z calcd.

5,6-Dichloro-7,7-dimethoxy-3-pentylbicyclo[2.2.1]hept-5-en-2-yl

for C₁₅H₂₂Br₂O₄[M]⁺423.9885; found 423.9883.

Acetate (8i): R_f= 0.6 [EtOAc/hexane 4% (over 7% AgNO₃-impreg-

5,6-Dibromo-7,7-dimethoxy-3-pentylbicyclo[2.2.1]hept-5-en-2-yl nated silica gel)]; yield 1.05 g, 77 % from 4i, viscous liquid. ¹H

Acetate (8c): R_f= 0.6 [EtOAc/hexane 5% (over 7% AgNO₃-impreg-

NMR (400 MHz, CDCl₃): δ = 5.39 (dd, J = 4.1, 7.8 Hz, 1 H, 2-

H_exo), 3.34 (dd, J = 2.4, 3.9 Hz, 1 H, 1-H), 3.17 (s, 3 H, OMe),

nated silica gel)]; yield 488 mg, 74% from 4c, viscous liquid. ¹H

NMR (400 MHz, CDCl₃): δ = 5.39 (dd, J = 4.0, 7.7 Hz, 1 H, 2- 3.15 (s, 3 H, OMe), 3.02 (br. t, J = 2.8 Hz, 1 H, 4-H), 2.56–2.52

H_exo), 3.41 (dd, J = 2.2, 4.2 Hz, 1 H, 1-H), 3.17 (s, 3 H, OMe),

3.15 (s, 3 H, OMe), 3.09 (br. t, J = 2.8 Hz, 1 H, 4-H), 2.60–2.54

(m, 1 H, 3-H_exo), 2.00 (s, 3 H, OCOCH₃), 1.36–1.14 (series of m,

8 H), 0.86 (t, J = 6.8 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz,

(m, 1 H, 3-H_exo), 2.01 (s, 3 H, OCOCH₃), 1.39–1.23 (series of m, CDCl₃): δ = 170.9, 128.7, 125.8, 114.2, 73.5, 56.2, 55.9, 51.8, 49.6,

8 H), 0.87 (t, J = 6.7 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 170.9, 121.7, 118.6, 114.9, 73.5, 57.9, 57.6, 51.9, 49.7,

41.9, 31.9, 28.0, 26.2, 22.5, 20.7, 14.0 ppm. IR (neat): ν = 2900,

˜

1720 (C=O), 1600, 1440, 1360, 1240, 1040, 720 cm^–1. C₁₆H₂₄Cl₂O₄

(351.27): calcd. C 54.71, H 6.89; found C 54.71, H 6.74.

42.0, 31.9, 28.2, 26.1, 22.5, 20.7, 14.1 ppm. IR (neat): ν = 2900,

˜

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2963

F. A. Khan, S. Choudhury

FULL PAPER

5,6-Dichloro-3-hexyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-yl

Acetate (8j): R_f= 0.6 [EtOAc/hexane 4% (over 7% AgNO₃-impreg-

nated silica gel)]; yield 580 mg, 74% from 4j, viscous liquid. ¹H

3.29 (dd, J = 2.3, 4.0 Hz, 1 H, 1-H), 3.17 (s, 3 H, OMe), 3.13 (s, 3

H, OMe), 3.06 (dd, J = 2.4, 3.4 Hz, 1 H, 4-H), 2.45–2.39 (m, 1 H,

3-H_exo), 1.44–1.09 (m, 9 H, OH peak buried under the peaks of 8

NMR (400 MHz, CDCl₃): δ = 5.39 (dd, J = 4.2, 7.8 Hz, 1 H, 2- H of alkyl chain), 0.87 (t, J = 6.7 Hz, 3 H, CH₃) ppm. ¹³C NMR

H

_exo), 3.34 (dd, J = 2.3, 4.0 Hz, 1 H, 1-H), 3.17 (s, 3 H, OMe),

(100 MHz, CDCl₃): δ = 122.7, 118.1, 115.0, 72.2, 60.5, 58.1, 51.9,

49.6, 42.5, 31.9, 28.4, 25.8, 22.5, 14.1 ppm. IR (neat): ν = 3400

3.15 (s, 3 H, OMe), 3.02 (dd, J = 2.4, 3.4 Hz, 1 H, 4-H), 2.55–2.52

˜

(m, 1 H, 3-H_exo), 2.00 (s, 3 H, OCOCH₃), 1.35–1.16 (series of m, (OH), 2900, 1580, 1440, 1240, 1040 cm^–1. HRMS (EI): m/z: calcd.

10 H), 0.86 (t, J = 6.8 Hz, 3 H) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 170.9, 128.7, 125.8, 114.2, 73.5, 56.2, 55.9, 51.8, 49.6, 41.9,

for C₁₄H₂₂Br₂O₃[M]⁺395.9936; found 395.9936.

5,6-Dibromo-7,7-dimethoxy-3-hexylbicyclo[2.2.1]hept-5-en-2-ol (9d):

R_f= 0.4 [EtOAc/hexane 5% (over 7% AgNO₃-impregnated silica

gel)]; yield 328 mg, 93 % from 8d; viscous liquid. ¹H NMR

(400 MHz, CDCl₃): δ = 4.55 (dd, J = 4.2, 7.6 Hz, 1 H, 2-H_exo),

3.24 (dd, J = 2.2, 4.2 Hz, 1 H, 1-H), 3.13 (s, 3 H, OMe), 3.09 (s, 3

H, OMe), 3.02 (br. t, J = 2.8 Hz, 1 H, 4-H), 2.41–2.34 (m, 1 H, 3-

H_exo), 1.38–1.23 (m, 10 H, OH peak buried under the peaks of 9

31.7, 29.3, 28.3, 26.3, 22.6, 20.7, 14.0 ppm. IR (neat): ν = 2900,

˜

1720, 1600, 1440, 1360, 1220, 1040, 720 cm^–1. HRMS (ESI): m/z:

calcd. for C₁₇H₂₇Cl₂O₄[M + H]⁺365.1286; found 365.1284.

5,6-Dichloro-7,7-dimethoxy-3-phenylbicyclo[2.2.1]hept-5-en-2-yl

Acetate (8k): R_f= 0.7 [EtOAc/hexane 10% (over 7% AgNO₃-im-

pregnated silica gel)]; yield 262 mg, 78% from 4k, viscous liquid.

¹H NMR (400 MHz, CDCl₃): δ = 7.29–7.21 (m, 3 H), 7.17–7.14 H of alkyl chain), 1.13–1.08 (m, 1 H), 0.82 (t, J = 6.6 Hz, 3 H,

(m, 2 H), 5.68 (dd, J = 3.9, 7.8 Hz, 1 H, 2-H_exo), 3.88 (dd, J = 3.4,

7.6 Hz, 1 H, 3-H_exo), 3.46 (dd, J = 2.4, 4.2 Hz, 1 H, 1-H), 3.27 (s,

3 H, OMe), 3.24 (s, 3 H, OMe), 3.15 (dd, J = 2.4, 3.4 Hz, 1 H, 4-

H), 1.81 (s, 3 H, OCOCH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 170.1, 135.4, 130.7 (2 C), 129.7, 127.8 (2 C), 127.2, 127.1, 114.5,

CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 122.7, 118.0, 115.0,

72.2, 60.5, 58.1, 51.9, 49.6, 42.5, 31.7, 29.4, 28.7, 25.8, 22.6,

14.1 ppm. IR (neat): ν = 3400 (OH), 2900, 1580, 1440, 1240,

˜

1040 cm^–1. HRMS (EI): m/z: calcd. for C₁₅H₂₄Br₂O₃[M]⁺

410.0092; found 410.0091.

74.6, 59.3, 56.6, 52.0, 49.8, 48.2, 20.6 ppm. IR (neat): ν = 2900,

˜

5,6-Dibromo-7,7-dimethoxy-3-phenylbicyclo[2.2.1]hept-5-en-2-ol

(9e): R_f= 0.4 [EtOAc/hexane 10% (over 7% AgNO₃-impregnated

silica gel)]; yield 402 mg, 99% from 8e; viscous liquid. ¹H NMR

(400 MHz, CDCl₃): δ = 7.27–7.18 (m, 5 H, Ph), 4.83 (dd, J = 4.1,

7.6 Hz, 1 H, 2-H_exo), 3.69 (dd, J = 3.4, 7.6 Hz, 1 H, 3-H_exo), 3.43

(dd, J = 2.3, 4.0 Hz, 1 H, 1-H), 3.19 (br. t, J = 2.9 Hz, 1 H, 4-H),

3.18 (s, 3 H, OMe), 3.17 (s, 3 H, OMe), 1.41 (br. s, 1 H, D₂O

exchangeable, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 135.2,

131.2 (2 C), 128.2 (2 C), 127.2, 122.8, 120.7, 115.4, 73.0, 60.6 (2

1740 (C=O), 1600, 1480, 1440, 1360, 1220, 1120, 1040 cm^–1

.

HRMS (EI): m/z: calcd. for C₁₇H₁₈Cl₂O₄[M]⁺356.0582; found

356.0584.

General Procedure for Hydrolysis of Dihalonorbornyl Acetates 8

5,6-Dibromo-7,7-dimethoxy-3-propylbicyclo[2.2.1]hept-5-en-2-ol

(9a): K₂CO₃(142 mg, 1.03 mmol) was added to a solution of 8a

(400 mg, 0.97 mmol) in MeOH (5 mL) and the mixture was stirred

at room temperature for 20 h. After complete consumption of start-

ing material (TLC monitoring) the solvent was evaporated under

reduced pressure, water (10 mL) was added to the residue, and the

aqueous layer was extracted three times with EtOAc (3ϫ20 mL).

The combined organic layer was then washed with brine and dried

with anhydrous Na₂SO₄. The solvent was evaporated off under vac-

uum to leave a residue which was chromatographed on silica gel to

afford the alcohol 9a. R_f= 0.4 [EtOAc/hexane 5 % (over 7 %

C), 52.1, 49.8, 48.9 ppm. IR (neat): ν = 3300 (OH), 2900, 1580,

˜

1480, 1440, 1260, 1040 cm^–1. HRMS (EI): m/z: calcd. for

C₁₅H₁₆Br₂O₃[M]⁺401.9466; found 401.9465.

5,6-Dibromo-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-ol (9f): R_f= 0.3

[EtOAc/hexane 15 % (over 7 % AgNO₃-impregnated silica gel)];

yield 319 mg, 90% from 8f; viscous liquid. ¹H NMR (400 MHz,

CDCl₃): δ = 4.68 (ddd, J = 2.8, 4.3, 7.1 Hz, 1 H, 2-H_exo), 3.23 (dd,

J = 2.2, 3.9 Hz, 1 H, 1-H), 3.17 (s, 3 H, OMe), 3.11 (s, 3 H, OMe),

AgNO₃-impregnated silica gel)]; yield 328 mg, 91%; solid, m.p. 68–

1

70 °C. H NMR (400 MHz, CDCl₃): δ = 4.60 (dd, J = 4.1, 7.8 Hz, 2.99 (dd, J = 2.1, 3.8 Hz, 1 H, 4-H), 2.30 (ddd, J = 4.1, 7.3, 12.8 Hz,

1 H, 2-H_exo), 3.28 (dd, J = 2.2, 4.1 Hz, 1 H, 1-H), 3.17 (s, 3 H,

1 H, 3-H_exo), 1.71 (br. s, 1 H, D₂O exchangeable, OH), 1.08 (dd, J

OMe), 3.13 (s, 3 H, OMe), 3.05 (dd, J = 2.2, 3.4 Hz, 1 H, 4-H), = 2.2, 12.7 Hz, 1 H, 3-H_endo) ppm. ¹³C NMR (100 MHz, CDCl₃):

2.46–2.42 (m, 1 H, 3-H_exo), 1.46–1.29 (m, 4 H, OH peak buried

under the peaks of 3 H of alkyl chain), 1.16–1.12 (m, 1 H), 0.92 (t,

J = 7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

122.6, 118.1, 115.0, 72.1, 60.5, 58.1, 51.9, 49.6, 42.2, 28.0, 21.9,

δ = 124.1, 117.8, 116.2, 71.6, 59.6, 55.2, 52.1, 49.7, 35.1 ppm. IR

(neat): ν = 3400 (OH), 2900, 1580, 1440, 1240, 1020, 840 cm^–1.

˜

HRMS (EI): m/z: calcd. for C₉H₁₂Br₂O₃[M]⁺325.9153; found

325.9155.

14.2 ppm. IR (KBr): ν = 3400 (OH), 2900, 1580, 1440, 1240, 1020,

˜

5,6-Dichloro-7,7-dimethoxy-3-propylbicyclo[2.2.1]hept-5-en-2-ol

(9g): R_f= 0.4 [EtOAc/hexane 4% (over 7% AgNO₃-impregnated

silica gel)]; yield 802 mg, 90% from 8g; viscous liquid. ¹H NMR

(400 MHz, CDCl₃): δ = 4.57 (dd, J = 4.0, 7.7 Hz, 1 H, 2-H_exo),

840 cm^–1.

5,6-Dibromo-3-butyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-ol (9b):

R_f= 0.4 [EtOAc/hexane 5% (over 7% AgNO₃-impregnated silica

1

gel)]; yield 318 mg, 91% from 8b; solid, m.p. 74–76 °C. H NMR 3.19 (dd, J = 2.4, 3.9 Hz, 1 H, 1-H), 3.17 (s, 3 H, OMe), 3.12 (s, 3

(400 MHz, CDCl₃): δ = 4.59 (dd, J = 4.2, 7.6 Hz, 1 H, 2-H_exo),

3.29 (dd, J = 2.4, 4.2 Hz, 1 H, 1-H), 3.17 (s, 3 H, OMe), 3.13 (s, 3

H, OMe), 2.97 (br. t, J = 2.9 Hz, 1 H, 4-H), 2.42–2.38 (m, 1 H, 3-

H_exo), 1.51 (br. s, 1 H, D₂O exchangeable, OH), 1.42–1.28 (m, 3

H, OMe), 3.06 (dd, J = 2.2, 2.6 Hz, 1 H, 4-H), 2.45–2.39 (m, 1 H, H), 1.13–1.09 (m, 1 H), 0.91 (t, J = 7.2 Hz, 3 H, CH₃) ppm. ¹³C

3-H_exo), 1.43–1.27 (m, 6 H, OH peak buried under the peaks of 5

H of alkyl chain), 1.19–1.11 (m, 1 H), 0.89 (t, J = 7.1 Hz, 3 H,

CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 122.6, 118.1, 115.0,

72.1, 60.5, 58.0, 51.9, 49.6, 42.4, 30.9, 25.5, 22.8, 14.0 ppm. IR

NMR (100 MHz, CDCl₃): δ = 129.2, 125.4, 114.2, 72.0, 58.7, 56.2,

51.7, 49.5, 42.0, 28.1, 21.8, 14.2 ppm. IR (neat): ν = 3400 (OH),

˜

2900, 1600, 1440, 1240, 1080, 1040, 980 cm^–1.

3-Butyl-5,6-dichloro-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-ol (9h):

R_f= 0.4 [EtOAc/hexane 4% (over 7% AgNO₃-impregnated silica

(KBr): ν = 3450 (OH), 2950, 1580, 1460, 1260, 1040 cm^–1.

˜

5,6-Dibromo-7,7-dimethoxy-3-pentylbicyclo[2.2.1]hept-5-en-2-ol gel)]; yield 240 mg, 91 % from 8h; viscous liquid. ¹H NMR

(9c): R_f= 0.4 [EtOAc/hexane 5% (over 7% AgNO₃-impregnated

silica gel)]; yield 352 mg, 95% from 8c; viscous liquid. ¹H NMR

(400 MHz, CDCl₃): δ = 4.59 (dd, J = 4.2, 7.6 Hz, 1 H, 2-H_exo),

(400 MHz, CDCl₃): δ = 4.57 (dd, J = 4.2, 7.8 Hz, 1 H, 2-H_exo),

3.20 (dd, J = 2.3, 4.0 Hz, 1 H, 1-H), 3.18 (s, 3 H, OMe), 3.13 (s, 3

H, OMe), 2.98 (br. t, J = 2.9 Hz, 1 H, 4-H), 2.42–2.35 (m, 1 H, 3-

2964

www.eurjoc.org

Eur. J. Org. Chem. 2010, 2954–2970

Efficient Synthesis of Substituted meta-Halophenols and Their Methyl Ethers

H_exo), 1.43 (br. s, 1 H, D₂O exchangeable, OH), 1.39–1.28 (m, 5 5,6-Dibromo-3-butyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-one

H), 1.14–1.11 (m, 1 H), 0.89 (t, J = 6.8 Hz, 3 H, CH₃) ppm. ¹³C (7b): R_f= 0.7 [EtOAc/hexane 5% (over 7% AgNO₃-impregnated

1

NMR (100 MHz, CDCl₃): δ = 129.3, 125.4, 114.3, 72.1, 58.7, 56.2,

silica gel)]; yield 262 mg, 91% from alcohol 9b; viscous liquid. H

NMR (400 MHz, CDCl₃): δ = 3.36–3.33 (m, 2 H, 1-H, 4-H), 3.26

(s, 3 H, OMe), 3.19 (s, 3 H, OMe), 2.46–2.41 (m, 1 H, 3-H_exo),

1.78–1.73 (m, 1 H), 1.43–1.21 (m, 5 H), 0.89 (t, J = 7.3 Hz, 3 H,

CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 206.8, 127.5, 117.3,

114.5, 67.6, 56.7, 52.2, 50.1, 46.3, 30.5, 28.2, 22.3, 13.9 ppm. IR

51.7, 49.5, 42.3, 30.8, 25.6, 22.8, 13.9 ppm. IR (neat): ν = 3400

˜

(OH), 2900, 1600, 1440, 1260, 1040 cm^–1. HRMS (ESI): m/z: calcd.

for C₁₃H₂₁Cl₂O₃[M + H]⁺295.0868; found 295.0864.

5,6-Dichloro-7,7-dimethoxy-3-pentylbicyclo[2.2.1]hept-5-en-2-ol (9i):

R_f= 0.4 [EtOAc/hexane 4% (over 7% AgNO₃-impregnated silica

gel)]; yield 568 mg, 92 % from 8i; viscous liquid. ¹H NMR

(400 MHz, CDCl₃): δ = 4.57 (dd, J = 4.2, 7.8 Hz, 1 H, 2-H_exo),

3.20 (dd, J = 2.2, 3.9 Hz, 1 H, 1-H), 3.18 (s, 3 H, OMe), 3.13 (s, 3

H, OMe), 2.98 (br. t, J = 2.8 Hz, 1 H, 4-H), 2.41–2.37 (m, 1 H, 3-

(neat): ν = 2950, 1750 (C=O), 1580, 1460, 1260, 1100 cm^–1.

˜

5,6-Dibromo-7,7-dimethoxy-3-pentylbicyclo[2.2.1]hept-5-en-2-one

(7c): R_f= 0.7 [EtOAc/hexane 5% (over 7% AgNO₃-impregnated

1

silica gel)]; 224 mg, yield 91% from alcohol 9c; viscous liquid. H

H_exo), 1.42–1.28 (m, 8 H, OH peak buried under the peaks of 7 H

NMR (400 MHz, CDCl₃): δ = 3.35–3.34 (m, 2 H, 1-H, 4-H), 3.26

(s, 3 H, OMe), 3.19 (s, 3 H, OMe), 2.46–2.41 (m, 1 H, 3-H_exo) 1.79–

1.71 (m, 1 H), 1.47–1.20 (m, 7 H), 0.87 (t, J = 6.7 Hz, 3 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 206.8, 127.5, 117.3, 114.5, 67.6,

of alkyl chain), 1.15–1.09 (m, 1 H), 0.87 (t, J = 6.6 Hz, 3 H,

CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 129.3, 125.4, 114.3,

72.1, 58.8, 56.2, 51.8, 49.5, 42.4, 31.9, 28.3, 25.9, 22.5, 14.0 ppm.

IR (neat): ν = 3400 (OH), 2900, 1600, 1440, 1260, 1040 cm^–1

.

˜

56.6, 52.2, 50.1, 46.3, 31.4, 28.5, 27.9, 22.4, 14.0 ppm. IR (neat): ν

˜

HRMS (EI): m/z: calcd. for C₁₄H₂₂Cl₂O₃[M]⁺308.0946; found

= 2900, 1740 (C=O), 1580, 1440, 1240, 1100, 1060, 980 cm^–1.

308.0948.

5,6-Dibromo-3-hexyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-one

5,6-Dichloro-3-hexyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-ol (9j):

R_f= 0.4 [EtOAc/hexane 4% (over 7% AgNO₃-impregnated silica

gel)]; yield 448 mg, 92 % from 8j; viscous liquid. ¹H NMR

(400 MHz, CDCl₃): δ = 4.53 (dd, J = 4.2, 7.6 Hz, 1 H, 2-H_exo),

3.16 (dd, J = 2.4, 3.9 Hz, 1 H, 1-H), 3.13 (s, 3 H, OMe), 3.08 (s, 3

H, OMe), 2.94 (br. t, J = 2.9 Hz, 1 H, 4-H), 2.37–2.31 (m, 1 H, 3-

(7d): R_f= 0.7 [EtOAc/hexane 5% (over 7% AgNO₃-impregnated

silica gel)]; yield 199 mg, 90% from alcohol 9d; viscous liquid. H

1

NMR (400 MHz, CDCl₃): δ = 3.36–3.33 (m, 2 H, 1-H, 4-H), 3.26

(s, 3 H, OMe), 3.19 (s, 3 H, OMe), 2.46–2.41 (m, 1 H, 3-H_exo),

1.79–1.71 (m, 1 H), 1.45–1.18 (m, 9 H), 0.86 (t, J = 6.59 Hz, 3 H,

CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 206.8, 127.5, 117.3,

114.5, 67.7, 56.7, 52.2, 50.1, 46.3, 31.5, 28.9, 28.6, 28.3, 22.6,

H

_exo), 1.37 (br. s, 1 H, D₂O exchangeable, OH), 1.32–1.22 (m, 9

H), 1.11–1.06 (m, 1 H), 0.81 (t, J = 6.6 Hz, 3 H, CH₃) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 129.3, 125.4, 114.3, 72.1, 58.7, 56.2,

51.8, 49.5, 42.4, 31.7, 29.4, 28.6, 25.9, 22.6, 14.0 ppm. IR (neat):

14.0 ppm. IR (neat): ν = 2900, 1740 (C=O), 1580, 1440, 1260,

˜

1060 cm^–1.

5,6-Dibromo-7,7-dimethoxy-3-phenylbicyclo[2.2.1]hept-5-en-2-one

(7e): R_f= 0.7 [EtOAc/hexane 10% (over 7% AgNO₃-impregnated

silica gel)]; yield 410 mg, 92% from alcohol 9e; solid, m.p. 108–

110 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.31–7.24 (m, 3 H), 7.01–

6.98 (m, 2 H), 3.93 (d, J = 3.6 Hz, 1 H, 3-H_exo), 3.57 (d, J = 2.7 Hz,

1 H, 1-H), 3.49 (dd, J = 2.6, 3.5 Hz, 1 H, 4-H), 3.33 (s, 3 H, OMe),

3.31 (s, 3 H, OMe) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 203.5,

135.3, 128.8 (2 C), 128.51 (2 C), 128.48, 127.4, 116.4, 113.9, 68.4,

ν = 3400 (OH), 2900, 1600, 1440, 1260, 1040 cm^–1. C H Cl O

˜

15 24

2

3

(323.26): calcd. C 55.73, H 7.48; found C 55.69, H 7.21.

5,6-Dichloro-7,7-dimethoxy-3-phenylbicyclo[2.2.1]hept-5-en-2-ol

(9k): R_f= 0.5 [EtOAc/hexane 10% (over 7% AgNO₃-impregnated

silica gel)]; yield 158 mg, 90% from cycloadduct 8k; viscous liquid.

¹H NMR (400 MHz, CDCl₃): δ = 7.29–7.20 (m, 5 H, Ph), 4.82 (dd,

J = 4.1, 7.6 Hz, 1 H, 2-H_exo), 3.71 (dd, J = 3.4, 7.6 Hz, 1 H, 3-

H_exo), 3.37 (dd, J = 2.4, 4.2 Hz, 1 H, 1-H), 3.20 (s, 3 H, OMe),

60.2, 52.2, 50.9, 50.4 ppm. IR (KBr): ν = 3500 (OH), 2900, 1600,

˜

3.19 (s, 3 H, OMe), 3.16 (dd, J = 2.5, 3.3 Hz, 1 H, 4-H), 1.41 (br. s,

1 H, D₂O exchangeable, OH) ppm. ¹³C NMR (100 MHz, CDCl₃): δ

= 135.3, 130.8 (2 C), 129.3, 128.2 (2 C), 127.8, 127.2, 114.7, 72.9

1500, 1460, 1260, 1060 cm^–1.

5,6-Dibromo-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-one (7f): R_f=

0.6 [EtOAc/hexane 15% (over 7% AgNO₃-impregnated silica gel)];

(2 C), 51.9, 58.7, 49.7, 48.8 ppm. IR (neat): ν = 3500 (OH), 2900,

˜

1

1600, 1500, 1460, 1260, 1060 cm^–1.

yield 259 mg, 90% from alcohol 9f; white solid, m.p. 64–66 °C. H

NMR (400 MHz, CDCl₃): δ = 3.33 (d, J = 2.7 Hz, 1 H, 1-H), 3.31

(d, J = 2.7 Hz, 1 H, 4-H), 3.27 (s, 3 H, OMe), 3.21 (s, 3 H, OMe),

2.29 (dd, J = 3.0, 19.9 Hz, 1 H, 3-H_exo), 2.06 (d, J = 16.8 Hz, 1 H,

3-H_endo) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 203.7, 129.5,

General Procedure for Oxidation of Alcohols 9

5,6-Dibromo-7,7-dimethoxy-3-propylbicyclo[2.2.1]hept-5-en-2-one

(7a): CrO₃(504 mg, 5.04 mmol) was added to a solution of pyridine

(798 mg, 10.1 mmol) in CH₂Cl₂(20 mL) and the mixture was

stirred at room temperature for 30 min. A solution of the alcohol

9a (280 mg, 0.76 mmol) in CH₂Cl₂(20 mL) was added to this deep-

brown-colored mixture, which was stirred at room temperature for

40 h. The reaction mixture was then filtered through a small silica

gel pad to remove the inorganic impurities and the filtrate was con-

centrated in vacuo. The residue was purified by silica gel column

chromatography to furnish the corresponding bicyclic keto com-

pound 7a. R_f= 0.7 [EtOAc/hexane 5% (over 7% AgNO₃-impreg-

nated silica gel)]; yield 250 mg, 90%; white solid, m.p. 56–58 °C.

¹H NMR (400 MHz, CDCl₃): δ = 3.31–3.29 (m, 2 H, 1-H, 4-H),

3.22 (s, 3 H, OMe), 3.16 (s, 3 H, OMe), 2.43–2.39 (m, 1 H, 3-H_exo),

1.71–1.63 (m, 1 H), 1.45–1.31 (m, 2 H), 1.24–1.17 (m, 1 H), 0.86

(t, J = 7.3 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

206.8, 127.5, 117.3, 114.5, 67.6, 56.7, 52.2, 50.1, 46.0, 30.6, 21.5,

117.2, 114.8, 67.2, 54.1, 52.4, 50.3, 34.8 ppm. IR (KBr): ν = 2900,

˜

1740 (C=O), 1580, 1440, 1400, 1240, 1200, 1160, 1120, 1040, 1020,

980, 820 cm^–1.

5,6-Dichloro-7,7-dimethoxy-3-propylbicyclo[2.2.1]hept-5-en-2-one

(7g): R_f= 0.7 [EtOAc/hexane 4% (over 7% AgNO₃-impregnated

1

silica gel)]; yield 652 mg, 91% from alcohol 9g; viscous liquid. H

NMR (400 MHz, CDCl₃): δ = 3.28–3.25 (m, 2 H, 1-H, 4-H) over-

lapping with 3.27 (s, 3 H, OMe), 3.19 (s, 3 H, OMe), 2.47–2.43 (m,

1 H, 3-H_exo), 1.74–1.69 (m, 1 H), 1.48–1.37 (m, 2 H), 1.26–1.19 (m,

1 H), 0.89 (t, J = 7.3 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 206.9, 134.2, 122.4, 116.5, 65.5, 54.8, 52.1, 50.0, 45.9,

30.6, 21.4, 13.7 ppm. IR (neat): ν = 2900, 1740 (C=O), 1600, 1440,

˜

1260, 1040, 980 cm^–1. HRMS (ESI): m/z: calcd. for C₁₂H₁₇Cl₂O₃

[M + H]⁺279.0555; found 279.0558.

13.6 ppm. IR (KBr): ν = 2900, 1750 (C=O), 1550, 1440, 1160, 1100, 3-Butyl-5,6-dichloro-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-one

˜

960 cm^–1.

(7h): R_f= 0.7 [EtOAc/hexane 4% (over 7% AgNO₃-impregnated

Eur. J. Org. Chem. 2010, 2954–2970

www.eurjoc.org

2965

F. A. Khan, S. Choudhury

FULL PAPER

silica gel)]; yield 180 mg, 90% from alcohol 9h; viscous liquid. H

NMR (400 MHz, CDCl₃): δ = 3.24–3.23 (m, 2 H, 1-H, 4-H) over-

lapping with 3.23 (s, 3 H, OMe), 3.15 (s, 3 H, OMe), 2.41–2.36 (m,

1

= 167.8, 155.3, 132.9, 129.9, 125.4, 121.7, 119.0, 52.6, 28.5, 23.3,

14.4 ppm. IR (KBr): ν = 3200 (OH), 2900, 1680 (C=O), 1560, 1440,

˜

1400, 1340, 1260, 1200, 1060, 1000, 940, 840 cm^–1. C₁₁H₁₃BrO₃

1 H, 3-H_exo), 1.76–1.68 (m, 1 H), 1.39–1.14 (m, 5 H), 0.84 (t, J = (273.13): calcd. C 48.37, H 4.80; found C 48.35, H 4.67.

7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 206.8,

Compound 11a: R_f= 0.8 [EtOAc/hexane 5% (over 7% AgNO₃-

134.2, 122.4, 116.5, 65.6, 54.9, 52.2, 50.0, 46.3, 30.4, 28.3, 22.3,

impregnated silica gel)]; yield 38 mg, 30% from ketone 7a; viscous

13.9 ppm. IR (neat): ν = 2900, 1740 (C=O), 1600, 1440, 1240, 1040,

˜

1

liquid. H NMR (400 MHz, CDCl₃): δ = 7.43 (d, J = 2.0 Hz, 1 H,

980 cm^–1. HRMS (ESI): m/z: calcd. for C₁₃H₁₉Cl₂O₃[M + H]⁺

Ar-H), 7.01 (d, J = 1.7 Hz, 1 H, Ar-H), 3.81 (s, 3 H, OMe), 3.76

(s, 3 H, OMe), 2.75 (t, J = 7.8 Hz, 2 H, ArCH₂), 1.49–1.42 (m, 2

293.0711; found 293.0711.

5,6-Dichloro-7,7-dimethoxy-3-pentylbicyclo[2.2.1]hept-5-en-2-one H), 0.88 (t, J = 7.4 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz,

(7i): R_f= 0.7 [EtOAc/hexane 4% (over 7% AgNO₃-impregnated

silica gel)]; yield 458 mg, 92% from alcohol 9i; viscous liquid. ¹H

NMR (400 MHz, CDCl₃): δ = 3.27 (broad peak, 2 H, 1-H, 4-H)

CDCl₃): δ = 167.2, 158.6, 132.6, 132.3, 124.5, 119.2, 116.6, 55.9,

52.2, 28.4, 23.2, 14.3 ppm. IR (neat): ν = 2900, 1700 (C=O), 1560,

˜

1440, 1380, 1240, 1220, 1180, 1060, 1040, 880, 820 cm^–1

.

overlapping with 3.27 (s, 3 H, OMe), 3.19 (s, 3 H, OMe), 2.45–2.42 C₁₂H₁₅BrO₃(287.15): calcd. C 50.19, H 5.27; found C 50.48, H

(m, 1 H, 3-H_exo), 1.78–1.72 (m, 1 H), 1.45–1.19 (m, 7 H), 0.86 (t, 5.22.

J = 6.7 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

Methyl 5-Bromo-2-butyl-3-hydroxybenzoate (10b): R_f= 0.5 [EtOAc/

206.9, 134.2, 122.4, 116.5, 65.5, 54.7, 52.1, 49.9, 46.2, 31.4, 28.5,

hexane 5% (over 7% AgNO₃-impregnated silica gel)]; yield 55 mg,

27.9, 22.3, 13.9 ppm. IR (neat): ν = 2900, 1740 (C=O), 1600, 1440,

˜

49 % from ketone 7b; white solid, m.p. 96–98 °C. ¹H NMR

(400 MHz, CDCl₃): δ = 7.49 (d, J = 2.0 Hz, 1 H, Ar-H), 7.06 (d,

J = 2.2 Hz, 1 H, Ar-H), 3.87 (s, 3 H, OMe), 2.83 (t, J = 7.9 Hz, 2

H, ArCH₂), 1.54–1.46 (m, 2 H), 1.42–1.35 (m, 2 H), 0.90 (t, J =

7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 167.4,

155.0, 132.7, 129.8, 125.3, 121.5, 118.8, 52.4, 31.9, 26.2, 22.9,

1240, 1040, 980 cm^–1.

5,6-Dichloro-3-hexyl-7,7-dimethoxybicyclo[2.2.1]hept-5-en-2-one

(7j): R_f= 0.7 [EtOAc/hexane 4% (over 7% AgNO₃-impregnated

silica gel)]; yield 355 mg, 94% from alcohol 9j; viscous liquid. ¹H

NMR (400 MHz, CDCl₃): δ = 3.27 (broad peak, 2 H, 1-H, 4-H)

overlapping with 3.27 (s, 3 H, OMe), 3.19 (s, 3 H, OMe), 2.45–2.41 13.9 ppm. IR (KBr): ν = 3300 (OH), 2900, 1700 (C=O), 1560, 1440,

˜

(m, 1 H, 3-H_exo), 1.79–1.71 (m, 1 H), 1.44–1.17 (m, 9 H), 0.86 (t, 1400, 1260, 1200, 1060, 1000, 940, 840 cm^–1. HRMS (EI): m/z:

J = 6.5 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

calcd. for C₁₂H₁₅BrO₃[M]⁺286.0204; found 286.0207.

206.9, 134.2, 122.4, 116.5, 65.6, 54.8, 52.1, 50.0, 46.2, 31.5, 28.9,

Methyl 5-Bromo-2-butyl-3-methoxybenzoate (11b): R_f= 0.8

28.6, 28.1, 22.5, 14.0 ppm. IR (neat): ν = 2900, 1740 (C=O), 1600,

˜

[EtOAc/hexane 5% (over 7% AgNO₃-impregnated silica gel)]; yield

1440, 1260, 1160, 1120, 1040 cm^–1.

1

42 mg, 36% from ketone 7b; viscous liquid. H NMR (400 MHz,

5,6-Dichloro-7,7-dimethoxy-3-phenylbicyclo[2.2.1]hept-5-en-2-one CDCl₃): δ = 7.48 (d, J = 2.0 Hz, 1 H, Ar-H), 7.05 (d, J = 2.0 Hz,

(7k): R_f= 0.80 [EtOAc/hexane 10% (over 7% AgNO₃-impregnated

silica gel)]; yield 90 mg, 91% from alcohol 9k; solid, m.p. 96–98 °C.

1 H, Ar-H), 3.86 (s, 3 H, OMe), 3.81 (s, 3 H, OMe), 2.82 (t, J =

7.8 Hz, 2 H, ArCH₂), 1.48–1.30 (m, 4 H), 0.89 (t, J = 7.2 Hz, 3 H,

¹H NMR (400 MHz, CDCl₃): δ = 7.28–7.21 (m, 3 H), 6.99–6.98 CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 167.2, 158.6, 132.6,

(m, 2 H), 3.89 (d, J = 3.4 Hz, 1 H, 3-H_exo), 3.48 (d, J = 2.7 Hz, 1

132.5, 124.6, 119.1, 116.6, 55.9, 52.2, 32.2, 26.2, 22.9, 13.9 ppm. IR

H, 1-H), 3.39 (dd, J = 2.7, 3.7 Hz, 1 H, 4-H), 3.30 (s, 3 H, OMe), (neat): ν = 2900, 1700 (C=O), 1560, 1440, 1400, 1240, 1040, 820,

˜

3.29 (s, 3 H, OMe) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 203.6, 720 cm^–1. HRMS (EI): m/z: calcd. for C₁₃H₁₇BrO₃[M]⁺300.0361;

135.3, 134.9, 128.6 (4 C), 127.5, 121.9, 115.8, 66.4, 58.4, 52.2, 51.1, found 300.0364.

50.3 ppm. IR (KBr): ν = 2900, 1740 (C=O), 1600, 1500, 1440, 1260,

˜

Methyl 5-Bromo-3-hydroxy-2-pentylbenzoate (10c): R_f= 0.5

1220, 1160, 1100, 1060, 980, 960, 900 cm^–1.

[EtOAc/hexane 5% (over 7% AgNO₃-impregnated silica gel)]; yield

1

Procedure for Fragmentation of Ketones 7 to Afford the Substituted

68 mg, 53% from ketone 7c; white solid, m.p. 72–74 °C. H NMR

meta-Halophenols 10 and Their Methyl Ether Derivatives 11

(400 MHz, CDCl₃): δ = 7.43 (d, J = 2.0 Hz, 1 H, Ar-H), 7.01 (d,

J = 2.2 Hz, 1 H, Ar-H), 3.82 (s, 3 H, OMe), 2.77 (t, J = 8.1 Hz, 2

H, ArCH₂), 1.49–1.43 (m, 2 H), 1.30–1.23 (m, 4 H), 0.82 (t, J =

7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 167.3,

154.9, 132.7, 129.9, 125.4, 121.5, 118.8, 52.3, 32.0, 29.5, 26.4, 22.5,

Methyl 5-Bromo-3-hydroxy-2-propylbenzoate (10a) and Methyl 5-

Bromo-3-methoxy-2-propylbenzoate (11a): para-Toluenesulfonic

acid monohydrate (84 mg, 0.44 mmol) was added to a solution of

the ketone 7a (162 mg, 0.44 mmol) in toluene (6 mL) and the reac-

tion mixture was heated to reflux at 110–120 °C for 10 h. The end

of the reaction was monitored by TLC with the disappearance of

the ketone 7a. The reaction mixture was diluted with water (5 mL)

14.0 ppm. IR (KBr): ν = 3300 (OH), 2900, 1680 (C=O), 1560, 1420,

˜

1400, 1340, 1280, 1220, 1080, 1000, 920, 860 cm^–1. C₁₃H₁₇BrO₃

(301.18): calcd. C 51.84, H 5.69; found C 52.05, H 5.57.

and the aqueous layer was extracted three times with EtOAc Methyl 5-Bromo-3-methoxy-2-pentylbenzoate (11c): R_f= 0.8

(3ϫ15 mL). The combined organic layers were washed with brine

and dried with anhydrous Na₂SO₄. Solvent was removed in vacuo

to furnish a residue, which was purified by silica gel column

[EtOAc/hexane 5% (over 7% AgNO₃-impregnated silica gel)]; yield

50 mg, 37% from ketone 7c; white solid, m.p. 92–94 °C. H NMR

(400 MHz, CDCl₃): δ = 7.48 (d, J = 1.9 Hz, 1 H, Ar-H), 7.05 (d,

1

chromatography to afford methyl 5-bromo-3-hydroxy-2-propylben- J = 2.0 Hz, 1 H, Ar-H), 3.85 (s, 3 H, OMe), 3.81 (s, 3 H, OMe),

zoate (10a) and methyl 5-bromo-3-methoxy-2-propylbenzoate

(11a).

2.81 (t, J = 7.8 Hz, 2 H, ArCH₂), 1.50–1.43 (m, 2 H), 1.35–1.29

(m, 4 H), 0.87 (t, J = 6.9 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 167.2, 158.5, 132.5, 132.4, 124.5, 119.1, 116.6, 55.9,

Compound 10a: R_f= 0.5 [EtOAc/hexane 5% (over 7% AgNO₃-

impregnated silica gel)]; yield 72 mg, 60% from ketone 7a; solid,

m.p. 62–64 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.48 (d, J =

2.0 Hz, 1 H, Ar-H), 7.07 (d, J = 1.9 Hz, 1 H, Ar-H), 3.82 (s, 3 H,

OMe), 2.81 (t, J = 7.8 Hz, 2 H, ArCH₂), 1.58–1.50 (m, 2 H), 0.95

52.2, 32.1, 29.6, 26.4, 22.4, 14.0 ppm. IR (KBr): ν = 2900, 1700

˜

(C=O), 1560, 1440, 1400, 1240, 1040, 820, 720 cm^–1.

Methyl 5-Bromo-2-hexyl-3-hydroxybenzoate (10d): R_f= 0.5 [EtOAc/

hexane 5% (over 7% AgNO₃-impregnated silica gel)]; yield 92 mg,

(t, J = 7.5 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ 56% from ketone 7d; viscous liquid. ¹H NMR (400 MHz, CDCl₃):

2966

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Eur. J. Org. Chem. 2010, 2954–2970

Efficient Synthesis of Substituted meta-Halophenols and Their Methyl Ethers

δ = 7.43 (d, J = 2.0 Hz, 1 H, Ar-H), 7.01 (d, J = 2.0 Hz, 1 H, Ar- 58 mg, 48 % from ketone 7g; solid, m.p. 78–80 °C. ¹H NMR

H), 3.82 (s, 3 H, OMe), 2.76 (t, J = 7.9 Hz, 2 H, ArCH₂), 1.49–

(400 MHz, CDCl₃): δ = 7.35 (d, J = 2.2 Hz, 1 H, Ar-H), 6.92 (d,

1.41 (m, 2 H), 1.33–1.19 (m, 6 H), 0.79 (t, J = 6.7 Hz, 3 H, J = 2.2 Hz, 1 H), 5.42 (br. s, 1 H, D₂O exchangeable, OH), 3.87 (s,

CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 167.6, 155.1, 132.6,

129.9, 125.2, 121.5, 118.8, 52.4, 31.6, 29.8, 29.6, 26.5, 22.6,

3 H, OMe), 2.82 (t, J = 7.8 Hz, 2 H, ArCH₂), 1.58–1.52 (m, 2 H),

0.96 (t, J = 7.3 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃):

δ = 167.6, 154.9, 132.4, 131.4, 129.1, 122.4, 118.6, 52.4, 28.3, 23.2,

14.1 ppm. IR (neat): ν = 3300 (OH), 2900, 1700 (C=O), 1560, 1420,

˜

1400, 1260, 1080, 1000, 900, 840, 720 cm^–1. C₁₄H₁₉BrO₃(315.21):

calcd. C 53.35, H 6.08; found C 53.71, H 5.98.

14.2 ppm. IR (KBr): ν = 3300 (OH), 2900, 1680 (C=O), 1560, 1440,

˜

1400, 1340, 1280, 1200, 1080, 1000, 920, 860 cm^–1. C₁₁H₁₃ClO₃

(228.67): calcd. C 57.78, H 5.73; found C 57.60, H 5.65.

Methyl 5-Bromo-2-hexyl-3-methoxybenzoate (11d): R_f= 0.8

[EtOAc/hexane 5% (over 7% AgNO₃-impregnated silica gel)]; yield

54 mg, 32% from ketone 7d; viscous liquid. H NMR (400 MHz,

Methyl 5-Chloro-3-methoxy-2-propylbenzoate (11g): R_f= 0.9

1

[EtOAc/hexane 5% (over 7% AgNO₃-impregnated silica gel)]; yield

1

CDCl₃): δ = 7.43 (d, J = 1.7 Hz, 1 H, Ar-H), 7.00 (d, J = 1.7 Hz,

1 H, Ar-H), 3.80 (s, 3 H, OMe), 3.76 (s, 3 H, OMe), 2.75 (t, J =

7.8 Hz, 2 H, ArCH₂), 1.44–1.37 (m, 2 H), 1.31–1.22 (m, 6 H), 0.81

(t, J = 6.8 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

167.2, 158.5, 132.6, 132.5, 124.5, 119.1, 116.6, 55.9, 52.2, 31.6, 29.9,

44 mg, 35% from ketone 7g; viscous liquid. H NMR (400 MHz,

CDCl₃): δ = 7.33 (d, J = 2.0 Hz, 1 H, Ar-H), 6.92 (d, J = 1.7 Hz,

1 H, Ar-H), 3.86 (s, 3 H, OMe), 3.80 (s, 3 H, OMe), 2.81 (t, J =

7.8 Hz, 2 H, ArCH₂), 1.54–1.47 (m, 2 H), 0.93 (t, J = 7.3 Hz, 3 H,

CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 167.4, 158.6, 132.3,

131.7, 131.6, 121.6, 113.8, 55.9, 52.2, 28.3, 23.3, 14.3 ppm. IR

29.6, 26.5, 22.6, 14.1 ppm. IR (neat): ν = 2900, 1700 (C=O), 1560,

˜

1440, 1400, 1240, 1040, 820, 720 cm^–1. C₁₅H₂₁BrO₃(329.23): calcd.

C 54.72, H 6.43; found C 55.07, H 6.30.

(neat): ν = 2900, 1720 (C=O), 1580, 1440, 1400, 1220, 1180, 1040,

˜

880, 840 cm^–1.

Methyl 5-Bromo-3-hydroxy-2-phenylbenzoate (10e): R_f= 0.5

[EtOAc/hexane 12% (over 7 % AgNO₃-impregnated silica gel)];

yield 86 mg, 51 % from ketone 7e; viscous liquid. ¹H NMR

(400 MHz, CDCl₃): δ = 7.56 (d, J = 1.9 Hz, 1 H, Ar-H), 7.45–7.37

(m, 3 H), 7.24 (d, J = 2.0 Hz, 1 H, Ar-H), 7.20–7.18 (m, 2 H), 3.53

(s, 3 H, OMe) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 166.5, 154.1,

133.7, 132.5, 129.3 (2 C), 129.2 (2 C), 128.6, 127.5, 124.9, 121.9,

Methyl 2-Butyl-5-chloro-3-hydroxybenzoate (10h): R_f= 0.6 [EtOAc/

hexane 5% (over 7% AgNO₃-impregnated silica gel)]; yield 52 mg,

44% from ketone 7h; solid, m.p. 86–88 °C. ¹H NMR (400 MHz,

CDCl₃): δ = 7.35 (d, J = 2.2 Hz, 1 H, Ar-H), 6.92 (d, J = 2.0 Hz,

1 H, Ar-H), 3.87 (s, 3 H, OMe), 2.84 (t, J = 7.9 Hz, 2 H, ArCH₂),

1.54–1.46 (m, 2 H), 1.42–1.33 (m, 2 H), 0.91 (t, J = 7.2 Hz, 3 H,

CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 167.6, 154.9, 132.4,

131.4, 129.3, 122.5, 118.6, 52.3, 32.1, 26.2, 22.9, 13.9 ppm. IR

121.8, 52.2 ppm. IR (neat): ν = 3300 (OH), 2900, 1700 (C=O),

˜

1400, 1280, 1140, 1000, 920, 900, 840 cm^–1. C₁₄H₁₁BrO₃(307.14):

calcd. C 54.75, H 3.61; found C 54.69, H 3.57.

(KBr): ν = 3300 (OH), 2900, 1680 (C=O), 1560, 1420, 1400, 1320,

˜

1220, 1180, 1080, 1000, 920, 900, 840 cm^–1. C₁₂H₁₅ClO₃(242.70):

calcd. C 59.39, H 6.23; found C 59.33, H 6.10.

Methyl 4-Bromo-6-methoxybiphenyl-2-carboxylate (11e): R_f= 0.8

[EtOAc/hexane 12% (over 7 % AgNO₃-impregnated silica gel)];

yield 56 mg, 32% from ketone 7e; solid, m.p. 106–108 °C. ¹H NMR

(400 MHz, CDCl₃): δ = 7.58 (d, J = 2.0 Hz, 1 H, Ar-H), 7.44–7.38

(m, 3 H), 7.26 (d, J = 1.7 Hz, 1 H, Ar-H), 7.25–7.24 (m, 2 H),

3.78 (s, 3 H, OMe), 3.58 (s, 3 H, OMe) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 167.4, 157.6, 135.6, 134.3, 130.1, 129.3 (2 C), 127.7 (2

Methyl 2-Butyl-5-chloro-3-methoxybenzoate (11h): R_f= 0.9 [EtOAc/

hexane 5% (over 7% AgNO₃-impregnated silica gel)]; yield 47 mg,

37% from ketone 7h; viscous liquid. ¹H NMR (400 MHz, CDCl₃):

δ = 7.28 (d, J = 2.2 Hz, 1 H, Ar-H), 6.86 (d, J = 2.0 Hz, 1 H, Ar-

H), 3.82 (s, 3 H, OMe), 3.76 (s, 3 H, OMe), 2.77 (t, J = 7.7 Hz, 2

H, ArCH₂), 1.43–1.27 (m, 4 H), 0.85 (t, J = 7.2 Hz, 3 H, CH₃) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 167.4, 158.5, 132.2, 131.9, 131.5,

C), 127.4, 124.1, 121.5, 116.9, 56.2, 52.1 ppm. IR (KBr): ν = 1700

˜

(C=O), 1560, 1440, 1400, 1300, 1260, 1180, 1040, 880, 840 cm^–1.

HRMS (EI): m/z: calcd. for C₁₅H₁₃BrO₃[M]⁺320.0048; found

320.0048.

121.6, 113.8, 55.9, 52.2, 32.2, 26.1, 22.9, 13.9 ppm. IR (neat): ν =

˜

2900, 1720 (C=O), 1560, 1440, 1400, 1260, 1240, 1040, 880,

840 cm^–1. C₁₃H₁₇ClO₃(256.73): calcd. C 60.82, H 6.67; found C

60.36, H 6.51.

Methyl 3-Bromo-5-hydroxybenzoate (10f): R_f= 0.4 [EtOAc/hexane

15% (over 7% AgNO₃-impregnated silica gel)]; yield 60 mg, 42%

from ketone 7f; solid, m.p. 124–126 °C. ¹H NMR (400 MHz,

CDCl₃): δ = 7.67 (br. d, J = 1.4 Hz, 1 H, Ar-H), 7.42 (br. d, J =

1.0 Hz, 1 H, Ar-H), 7.16 (br. d, J = 2.4 Hz, 1 H, Ar-H), 5.85 (br.

s, 1 H, D₂O exchangeable, OH), 3.85 (s, 3 H, OMe) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 166.3, 156.7, 132.4, 124.8, 123.5, 122.9,

Methyl 5-Chloro-3-hydroxy-2-pentylbenzoate (10i): R_f= 0.6

[EtOAc/hexane 5% (over 7% AgNO₃-impregnated silica gel)]; yield

50 mg, 41 % from ketone 7i; solid, m.p. 54–56 °C. ¹H NMR

(400 MHz, CDCl₃): δ = 7.31 (d, J = 2.2 Hz, 1 H, Ar-H), 6.87 (d,

J = 2.2 Hz, 1 H, Ar-H), 5.14 (br. s, 1 H, D₂O exchangeable, OH),

3.82 (s, 3 H, OMe), 2.78 (t, J = 7.9 Hz, 2 H, ArCH₂), 1.49–1.43

(m, 2 H), 1.31–1.24 (m, 4 H), 0.82 (t, J = 7.0 Hz, 3 H, CH₃) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 167.4, 154.8, 132.5, 131.4, 129.3,

115.4, 52.8 ppm. IR (KBr): ν = 3300 (OH), 2900, 1700 (C=O),

˜

1580, 1420, 1300, 1260, 1220, 1180, 1100, 980, 900, 860, 820 cm^–1.

C₈H₇BrO₃(231.05): calcd. C 41.59, H 3.05; found C 41.67, H 2.98.

122.6, 118.6, 52.3, 32.0, 29.6, 26.4, 22.5, 14.0 ppm. IR (KBr): ν =

˜

3300 (OH), 2900, 1680 (C=O), 1560, 1440, 1400, 1280, 1220, 1180,

1080, 1000, 920, 840 cm^–1. C₁₃H₁₇ClO₃(256.73): calcd. C 60.82, H

6.67; found C 60.71, H 6.56.

Methyl 3-Bromo-5-methoxybenzoate (11f): R_f= 0.7 [EtOAc/hexane

15% (over 7% AgNO₃-impregnated silica gel)]; yield 24 mg, 16%

from ketone 7f; viscous liquid. ¹H NMR (400 MHz, CDCl₃): δ =

7.69 (t, J = 1.5 Hz, 1 H, Ar-H), 7.42 (dd, J = 1.3, 2.3 Hz, 1 H, Ar-

H), 7.17 (t, J = 2.1 Hz, 1 H, Ar-H), 3.85 (s, 3 H, OMe), 3.77 (s, 3

H, OMe) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 165.7, 160.2,

Methyl 5-Chloro-3-methoxy-2-pentylbenzoate (11i): R_f= 0.9

[EtOAc/hexane 5% (over 7% AgNO₃-impregnated silica gel)]; yield

50 mg, 39% from ketone 7i; viscous liquid. ¹H NMR (400 MHz,

CDCl₃): δ = 7.28 (d, J = 2.0 Hz, 1 H, Ar-H), 6.86 (d, J = 2.0 Hz,

1 H, Ar-H), 3.80 (s, 3 H, OMe), 3.75 (s, 3 H, OMe), 2.76 (t, J =

7.9 Hz, 2 H, ArCH₂), 1.43–1.39 (m, 2 H), 1.28–1.24 (m, 4 H), 0.82

(t, J = 7.1 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

132.7, 124.9, 122.7, 122.2, 113.5, 55.8, 52.5 ppm. IR (neat): ν =

˜

2900, 1700 (C=O), 1560, 1440, 1380, 1240, 1220, 1180, 1060 cm^–1.

HRMS (EI): m/z: calcd. for C₉H₉BrO₃[M]⁺243.9735; found

243.9736.

Methyl 5-Chloro-3-hydroxy-2-propylbenzoate (10g): R_f= 0.6 167.4, 158.5, 132.2, 131.9, 131.5, 121.6, 113.8, 55.9, 52.2, 32.1, 29.7,

[EtOAc/hexane 5% (over 7% AgNO₃-impregnated silica gel)]; yield 26.3, 22.4, 14.0 ppm. IR (neat): ν = 2900, 1700 (C=O), 1560, 1440,

˜

Eur. J. Org. Chem. 2010, 2954–2970

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2967

F. A. Khan, S. Choudhury

FULL PAPER

1400, 1260, 1040, 880, 840 cm^–1. HRMS (EI): m/z: calcd. for

1 H, 3-H_exo), 1.96 (s, 3 H, OCOCH₃), 1.34–1.13 (m, 6 H), 0.83 (t,

J = 7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

171.0, 121.7, 118.6, 114.9, 73.4, 57.8–57.1 (m, 2 C attached to D),

C₁₄H₁₉ClO₃[M]⁺270.1023; found 270.1020.

Methyl 5-Chloro-2-hexyl-3-hydroxybenzoate (10j): R_f= 0.6 [EtOAc/

51.9, 49.7, 41.9, 30.7, 25.8, 22.7, 20.7, 14.0 ppm. IR (neat): ν =

˜

hexane 5% (over 7% AgNO₃-impregnated silica gel)]; yield 45 mg,

2950, 1740 (C=O), 1580, 1460, 1370, 1210, 1040 cm^–1.

1

45% from ketone 7j; viscous liquid. H NMR (400 MHz, CDCl₃):

5,6-Dibromo-3-butyl-1,4-dideuterio-7,7-dimethoxybicyclo[2.2.1]hept-

5-en-2-ol (14): R_f= 0.4 [EtOAc/hexane 5% (over 7% AgNO₃-im-

pregnated silica gel)]; yield 168 mg, 90% from 13, solid; m.p. 74–

δ = 7.30 (d, J = 2.0 Hz, 1 H, Ar-H), 6.87 (d, J = 2.2 Hz, 1 H, Ar-

H), 5.21 (br. s, 1 H, D₂O exchangeable, OH), 3.82 (s, 3 H, OMe),

2.78 (t, J = 7.9 Hz, 2 H, ArCH₂), 1.48–1.42 (m, 2 H), 1.33–1.21

(m, 6 H), 0.81 (t, J = 7.0 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 167.4, 154.8, 132.4, 131.4, 129.3, 122.5, 118.6, 52.3,

1

76 °C. H NMR (400 MHz, CDCl₃): δ = 4.59 (d, J = 7.8 Hz, 1 H,

2-H_exo), 3.17 (s, 3 H, OMe), 3.13 (s, 3 H, OMe), 2.44–2.38 (m, 1

H, 3-H_exo), 1.45–1.13 (m, 7 H, OH peak buried under the peaks of

6 H of alkyl chain), 0.89 (t, J = 6.6 Hz, 3 H, CH₃) ppm. ¹³C NMR:

δ = 122.6, 118.0, 114.9, 72.1, 60.5–59.9 (m, C attached to D), 58.1–

57.3 (m, C attached to D), 51.9, 49.6, 42.3, 30.9, 25.5, 22.8,

31.6, 29.9, 29.6, 26.4, 22.6, 14.1 ppm. IR (neat): ν = 3300 (OH),

˜

2900, 1700 (C=O), 1560, 1420, 1400, 1280, 1220, 1080, 1000, 920,

840 cm^–1. C₁₄H₁₉ClO₃(270.76): calcd. C 62.10, H 7.07; found C

61.82, H 6.91.

14.0 ppm. IR (KBr): ν = 3450 (OH), 2950, 1580, 1460, 1260,

˜

Methyl 5-Chloro-2-hexyl-3-methoxybenzoate (11j): R_f= 0.9 [EtOAc/

1040 cm^–1. HRMS (ESI): m/z: calcd. for C₁₃H₁₈Br₂D₂NaO₃[M +

hexane 5% (over 7% AgNO₃-impregnated silica gel)]; yield 41 mg,

Na]⁺406.9802; found 406.9745.

1

38% from ketone 7j; viscous liquid. H NMR (400 MHz, CDCl₃):

5,6-Dibromo-3-butyl-1,4-dideuterio-7,7-dimethoxybicyclo[2.2.1]hept-

5-en-2-one (15): R_f= 0.7 [EtOAc/hexane 5% (over 7% AgNO₃-

impregnated silica gel)]; yield 124 mg, 92% from alcohol 14; vis-

δ = 7.28 (d, J = 2.2 Hz, 1 H, Ar-H), 6.87 (d, J = 2.0 Hz, 1 H, Ar-

H), 3.81 (s, 3 H, OMe), 3.76 (s, 3 H, OMe), 2.76 (t, J = 7.8 Hz, 2

H, ArCH₂), 1.43–1.37 (m, 2 H), 1.29–1.18 (m, 6 H), 0.81 (t, J =

6.8 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 167.4,

158.5, 132.2, 131.9, 131.5, 121.6, 113.8, 55.9, 52.2, 31.6, 30.0, 29.6,

1

cous liquid. H NMR (400 MHz, CDCl₃): δ = 3.26 (s, 3 H, OMe),

3.19 (s, 3 H, OMe), 2.43 (dd, J = 4.6, 10.5 Hz, 1 H, 3-H_exo), 1.80–

1.72 (m, 1 H), 1.45–1.18 (m, 5 H), 0.88 (t, J = 7.1 Hz, 3 H,

CH₃) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 206.8, 127.5, 117.2,

114.4, 67.6–67.3 (m, C attached to D), 56.6–56.1 (m, C attached to

26.4, 22.6, 14.1 ppm. IR (neat): ν = 2900, 1700 (C=O), 1560, 1440,

˜

1400, 1040, 880, 840, 720 cm^–1. HRMS (EI): m/z: calcd. for

C₁₅H₂₁ClO₃[M]⁺284.1179; found 284.1173.

D), 52.2, 50.1, 46.2, 30.5, 28.2, 22.3, 13.9 ppm. IR (neat): ν = 2950,

˜

Methyl 4-Chloro-6-hydroxybiphenyl-2-carboxylate (10k): R_f= 0.6

[EtOAc/hexane 12% (over 7 % AgNO₃-impregnated silica gel)];

yield 46 mg, 44 % from ketone 7k; viscous liquid. ¹H NMR

(400 MHz, CDCl₃): δ = 7.50–7.41 (m, 5 H), 7.25–7.23 (m, 1 H),

7.14 (d, J = 2.0 Hz, 1 H, Ar-H), 5.23 (br. s, 1 H, OH), 3.58 (s, 3

H, OMe) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 166.6, 154.0,

134.3, 133.7, 132.3, 129.3 (4 C), 128.7, 127.0, 122.1, 119.1,

1750 (C=O), 1580, 1460, 1260, 1100 cm^–1.

Phenolic Compound 16: This compound was obtained from 15 by

treatment with PTSA (Scheme 11): R_f= 0.5 [EtOAc/hexane 5%

(over 7% AgNO₃-impregnated silica gel)]; yield 42 mg, 48% from

1

ketone 15; solid, m.p. 96–98 °C. H NMR (400 MHz, CDCl₃): δ =

7.49 (d, J = 1.7 Hz, 1 H, Ar-H), 7.06 (d, J = 2.0 Hz, 1 H, Ar-H),

5.37 (br. s, 1 H, OH), 3.87 (s, 3 H, OMe), 2.83 (t, J = 7.9 Hz, 2 H,

ArCH₂), 1.54–1.46 (m, 2 H), 1.42–1.33 (m, 2 H), 0.91 (t, J = 7.2 Hz,

3 H, CH₃) ppm. ³C NMR (100 MHz, CDCl₃): δ = 167.4, 155.0,

132.7, 129.8, 125.4, 121.5, 118.8, 52.4, 31.9, 26.2, 22.9, 13.9 ppm.

52.1 ppm. IR (neat): ν = 3300 (OH), 2900, 1700 (C=O), 1400, 1280,

˜

1140, 1000, 920, 900, 840 cm^–1. HRMS (EI): m/z: calcd. for

C₁₄H₁₁ClO₃[M]⁺262.0397; found 262.0392.

Methyl 4-Chloro-6-methoxybiphenyl-2-carboxylate (11k): R_f= 0.9

[EtOAc/hexane 12% (over 7 % AgNO₃-impregnated silica gel)];

yield 40 mg, 39% from ketone 7k; solid, m.p. 108–110 °C. ¹H NMR

(400 MHz, CDCl₃): δ = 7.43–7.34 (m, 5 H), 7.24 (d, J = 1.7 Hz, 1

H, Ar-H), 7.08 (d, J = 2.0 Hz, 1 H, Ar-H), 3.77 (s, 3 H, OMe),

3.56 (s, 3 H, OMe) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 167.6,

157.6, 135.7, 134.0, 133.9, 129.7, 129.4 (2 C), 127.8 (2 C), 127.4,

IR (KBr): ν = 3300 (OH), 2900, 1700 (C=O), 1560, 1440, 1400,

˜

1260, 1200, 1060, 1000, 940, 840 cm^–1. HRMS (ESI): m/z: calcd.

for C₁₂H₁₅BrNaO₃[M + Na]⁺309.0102; found 309.0093.

Phenolic Ether 17: This compound was obtained from 15 by treat-

ment with PTSA (Scheme 11): R_f= 0.8 [EtOAc/hexane 5% (over

7% AgNO₃-impregnated silica gel)]; yield 30 mg, 32% from ketone

1

15; viscous liquid. H NMR (400 MHz, CDCl₃): δ = 7.43 (d, J =

121.2, 114.2, 56.2, 52.1 ppm. IR (KBr): ν = 1720 (C=O), 1560,

˜

0.8 Hz, 1 H, Ar-H), 7.00 (d, J = 1.2 Hz, 1 H, Ar-H), 3.81 (s, 3 H,

OMe), 3.76 (s, 3 H, OMe), 2.77 (t, J = 7.8 Hz, 2 H, ArCH₂), 1.43–

1.27 (m, 4 H), 0.85 (t, J = 7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 167.2, 158.6, 132.6, 132.5, 124.6, 119.1,

1440, 1400, 1300, 1260, 1180, 1040, 880, 840 cm^–1. HRMS (EI):

m/z: calcd. for C₁₅H₁₃ClO₃[M]⁺276.0553; found 276.0553.

Methyl 4-Bromo-6-ethoxybiphenyl-2-carboxylate (12): R_f= 0.8

[EtOAc/hexane 12% (over 7 % AgNO₃-impregnated silica gel)];

yield 6 mg, 7% from ketone 7e; solid, m.p. 88–90 °C. ¹H NMR

(400 MHz, CDCl₃): δ = 7.44 (d, J = 1.7 Hz, 1 H, Ar-H), 7.32–7.23

(m, 3 H), 7.15–7.11 (m, 3 H), 3.89 (q, J = 7.0 Hz, 2 H, OCH₂),

3.47 (s, 3 H, OMe), 1.17 (t, J = 6.9 Hz, 3 H, CH₃) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 167.6, 156.9, 135.8, 134.4, 130.5, 129.3 (2

C), 127.6 (2 C), 127.2, 124.1, 121.4, 118.3, 64.8, 52.1, 14.4 ppm. IR

116.6, 55.9, 52.2, 32.2, 26.2, 22.9, 13.9 ppm. IR (neat): ν = 2900,

˜

1700 (C=O), 1560, 1440, 1400, 1240, 1040, 820, 720 cm^–1. HRMS

(ESI): m/z: calcd. for C₁₃H₁₈BrO₃[M + H]⁺301.0439; found 301.

0439.

Phenolic Compound 18: This compound was obtained from 7b by

treatment with [D]TFA (Scheme 12): R_f= 0.5 [EtOAc/hexane 5%

(over 7% AgNO₃-impregnated silica gel)]; yield 48 mg, 80% from

(KBr): ν = 1720 (C=O), 1560, 1440, 1400, 1300, 1260, 1180, 1040,

˜

1

ketone 7b; solid, m.p. 96–98 °C. H NMR (400 MHz, CDCl₃): δ =

880, 840 cm^–1. C₁₆H₁₅BrO₃(335.20): calcd. C 57.33, H 4.51; found

C 57.34, H 4.47.

7.44 (s, 1 H, Ar-H of minor component), 7.01 (s, 1 H, Ar-H of

minor component), 5.49 (br. s, 1 H, OH), 3.82 (s, 3 H, OMe), 2.78

(t, J = 7.8 Hz, 2 H, ArCH₂), 1.49–1.41 (m, 2 H), 1.37–1.28 (m, 2

H), 0.86 (t, J = 7.2 Hz, 3 H, CH₃) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 167.4, 154.9, 132.5, 129.9, 125.4–124.8 (m, Ar-C-6

5,6-Dibromo-3-butyl-1,4-dideuterio-7,7-dimethoxybicyclo[2.2.1]hept-

5-en-2-yl Acetate (13): R_f= 0.6 [EtOAc/hexane 5 % (over 7 %

AgNO₃-impregnated silica gel)]; yield 216 mg, 72% from 4b, vis-

1

cous liquid. H NMR (400 MHz, CDCl₃): δ = 5.35 (d, J = 7.8 Hz, attached to D), 121.5–120.9 (m, Ar-C-4 attached to D), 118.6, 52.4,

1 H, 2-H_exo), 3.12 (s, 3 H, OMe), 3.11 (s, 3 H, OMe), 2.55–2.49 (m,

31.9, 26.2, 22.9, 13.9 ppm. IR (KBr): ν = 3300 (OH), 2900, 1700

˜

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Eur. J. Org. Chem. 2010, 2954–2970

Efficient Synthesis of Substituted meta-Halophenols and Their Methyl Ethers

(C=O), 1560, 1440, 1400, 1260, 1200, 1060, 1000, 940, 840 cm^–1.

HRMS (ESI): m/z: calcd. for C₁₂H₁₃BrD₂NaO₃[M + Na]⁺

311.0228; found 311.0204.

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Supporting Information (see also footnote on the first page of this

article): Five pages with graphics and related discussions; 75 pages

with copies of ¹H and ¹³C NMR spectra of all the compounds and

HRMS spectra of some of the compounds.

Acknowledgments

We thank the Council of Scientific & Industrial Research (CSIR),

New Delhi, for financial assistance. S.C. thanks the CSIR for a

fellowship.

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2969

F. A. Khan, S. Choudhury

FULL PAPER

maining almost the same. These results are clearly indicative of

an intermolecular reaction mechanism.

was utilized in this case to avoid the overlapping of peaks in

the aliphatic region in the H NMR spectrum of the reaction

mixture and in order to facilitate easy detection of the ethyl

ether product.

1

[21] a) Decomposition of 7e or 7f took place in tightly stoppered

RB flasks on prolonged storage at room temperature. Slow de-

composition was observed from the gradual color change from

white to reddish-brown, resulting in the formation of MeBr

together with the usual products (i.e. 10e and 11e, or 10f and

11f). Decomposition took place even in a refrigerator (5–

10 °C), but the time required was much longer; b) MeBr being

a gas with a low boiling point, special precautions were taken

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Med. Chem. 2008, 16, 9948–9956; b) S. Sakami, M. Maeda,

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1

during H NMR sample preparation.

[22] Although compound 7b, bearing an n-butyl substituent (R =

n-C₄H₉), had been used as the model substrate for most of the

experiments, substrate 7e, with a phenyl substituent (R = Ph),

[24] H.-J. Albert, W. P. Neumann, Synthesis 1980, 942–943.

Received: January 20, 2010

Published Online: April 14, 2010

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Article Doi

An efficient synthesis of substituted meta-halophenols and their methyl ethers: insight into the reaction mechanism

DOI: 10.1002/ejoc.201000071

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Article abstract of DOI:10.1002/ejoc.201000071

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