Ring expansion-annulation strategy for the synthesis of substituted azulenes and oligoazulenes. 2. Synthesis of azulenyl halides, sulfonates, and azulenylmetal compounds and their application in transition-metal-mediated coupling reactions

Ring Expansion-Annulation Strategy for the Synthesis of

Substituted Azulenes and Oligoazulenes. 2. Synthesis of Azulenyl

Halides, Sulfonates, and Azulenylmetal Compounds and Their

Application in Transition-Metal-Mediated Coupling Reactions

Aimee L. Crombie, John L. Kane, Jr., Kevin M. Shea, and Rick L. Danheiser*

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139

danheisr@mit.edu

Received July 28, 2004

A “ring expansion-annulation strategy” for the synthesis of substituted azulenes is described based

on the reaction of â′-bromo-R-diazo ketones with rhodium carboxylates. The key transformation

involves an intramolecular Bu¨chner reaction followed by â-elimination of bromide, tautomerization,

and in situ trapping of the resulting 1-hydroxyazulene as a carboxylate or triflate ester. Further

synthetic elaboration of the azulenyl halide and sulfonate annulation products can be achieved by

employing Heck, Negishi, Stille, and Suzuki coupling reactions. Reaction of the azulenyl triflate

84 with pinacolborane provides access to the azulenylboronate 91, which participates in Suzuki

coupling reactions with alkenyl and aryl iodides. The application of these coupling reactions to the

synthesis of biazulenes, terazulene 101, and related oligoazulenes is described, as well as the

preparation of the azulenyl amino acid derivative 110.

Introduction

been focused on their potential utility as components in

“advanced materials” with novel electronic and optical

properties.⁶

This paper describes a general “ring expansion-annu-

lation strategy” for the synthesis of substituted azulenes.

The method is particularly well suited for the preparation

of azulenes bearing halogen and sulfonate substituents,

and the resultant annulation products can be employed

in a variety of transition-metal-catalyzed carbon-carbon

bond-forming reactions. Together, these processes provide

a powerful tandem strategy for the preparation of a wide

range of azulenes substituted on both the five- and seven-

membered rings.¹

The azulenes constitute the best known class of poly-

cyclic nonbenzenoid aromatic compounds and have long

fascinated chemists with their beautiful colors and

unusual electronic properties.²Guaiazulene, a naturally

occurring azulene, has a long history as an additive in

cosmetics and lotions, and more recently, azulenes have

attracted interest in medicine as antiulcer drugs,³anti-

cancer agents,⁴and as antioxidant therapeutics for

neurodegenerative conditions.⁵Other important applica-

tions of azulene derivatives exploit their unique electronic

characteristics, and considerable attention has recently

Few general methods for the synthesis of substituted

azulenes have been reported to date, and consequently

nearly all commercial applications of azulenes have relied

on the availability of the naturally occurring sesquiter-

pene guaiazulene. Early approaches to the synthesis of

azulenes required low-yield dehydrogenation steps and

were limited to the preparation of relatively simple

derivatives. More recently, however, powerful annulation

strategies have been developed that provide access to

azulenes of more complex structure. Particularly useful

annulation methods include the Ziegler-Hafner synthe-

sis,⁷annulation methods based on 2H-cyclohepta[b]furan-

2-ones,⁸[6+4] cycloadditions,⁹and [3+2] annulations

involving the reaction of tropylium cation with allenyl-

silanes.¹⁰Unfortunately, while these methods provide

(4) (a) Asato, A. E.; Peng, A.; Hossain, M. Z.; Mirzadegan, T.;

Bertram, J. S. J. Med. Chem. 1993, 36, 3137. (b) Hong, B.-C.; Jiang,

Y.-F.; Kumar, E. S. Bioorg. Med. Chem. Lett. 2001, 11, 1981. (c)

Hidetsugu, W.; Kana, H.; Keiko, Y.; Ken, H.; Hirotaka, K.; Hirofumi,

N.; Teruo, K.; Kazue, S.; Seiji, S.; Susumu, S.; Shuichi, K.; Hidecki,

N.; Noboru, M.; Hiroshi, S. Anticancer Res. 2003, 23, 4747.

(5) Becker, D. A.; Ley, J. J.; Echegoyen, L.; Alvarado, R. J. Am.

Chem. Soc. 2002, 124, 4678.

(6) For recent representative examples, see: (a) Ito, S.; Inabe, H.;

Okujima, T.; Morita, N.; Watanbe, M.; Imafuku, K. Tetrahedron Lett.

2000, 41, 8343. (b) Ohta, A.; Yamaguchi, K.; Fujisawa, N.; Yamashita,

Y.; Fujimori, K. Heterocycles 2001, 54, 377. (c) Wang, F.; Lai, Y.-H.

Macromolecules 2003, 36, 536. (d) Wang, F.; Lai, Y.-H.; Han, M.-Y.

Org. Lett. 2003, 5, 4791. (e) Ito, S.; Inabe, H.; Morita, N.; Ohta, K.;

Kitamura, T.; Imafuku, K. J. Am. Chem. Soc. 2003, 125, 1669 and

references therein.

(1) For a preliminary account of part of this work, see: Kane, J. L.,

Jr.; Shea, K. M.; Crombie, A. L.; Danheiser, R. L. Org. Lett. 2001, 3,

1081.

(2) For reviews, see: (a) Zeller, K.-P. In Methoden der Organischen

Chemie (Houben-Weyl); Kropf, H., Ed.; Georg Thieme Verlag: Stut-

tgart, Germany, 1985; Vol. V/2c, p 127. (b) Lloyd, D. Nonbenzenoid

Conjugated Carbocyclic Compounds; Elsevier: Amsterdam, The Neth-

erlands, 1984; pp 352-377. (c) Lloyd, D. The Chemistry of Conjugated

Cyclic Compounds; John Wiley and Sons: Chichester, UK, 1989;

Chapter 13. (d) Mochalin, V. B.; Porshnev, Yu. N. Russ. Chem. Rev.

1977, 46, 530.

(7) (a) Hafner, K.; Meinhardt, K.-P. Organic Syntheses; Wiley: New

York, 1990; Collect. Vol. VII, p 15. (b) Reviewed in: Jutz, J. C. Top.

Curr. Chem. 1978, 73, 125.

(3) Yanagisawa, T.; Wakabayashi, S.; Tomiyama, T.; Yasunami, M.;

Takase, K. Chem. Pharm. Bull. 1988, 36, 641.

Published on Web 11/06/2004

8652

J. Org. Chem. 2004, 69, 8652-8667

Synthesis of Substituted Azulenes and Oligoazulenes

SCHEME 1

efficient access to azulenes substituted on the five-

membered ring and to azulene itself, they have limited

utility for the synthesis of derivatives bearing substitu-

ents on the seven-membered ring.

The goal of our research has been the design of a

general strategy for the synthesis of azulenes substituted

on both the five- and seven-membered rings. Since a wide

variety of substituted benzene derivatives are easily

prepared or are commercially available, we have focused

our attention on approaches that might employ these

readily obtained compounds as starting materials. Most

attractive to us in this regard have been "ring-expansion-

annulation strategies": cascade (“tandem”) processes¹¹in

which a benzene ring is expanded to seven carbon atoms

concomitant with the creation of a five-membered ring.

Specifically, our investigations have focused on intramo-

lecular variants of the Bu¨chner cycloheptatriene synthe-

sis, which has previously been applied to the synthesis

of hydroazulenes by Julia, Scott, and McKervey,¹²among

others. Pioneering work in this area was carried out in

the laboratories of Scott, who in 1973 reported the copper-

catalyzed cyclization of diazo ketone 1 to afford the

bicyclic trienone 2 in moderate yield.^13,14Although expo-

sure of 2 to alumina and then P₂O₅in methanesulfonic

acid at 60 °C effects its transformation to azulene,

unfortunately this process proceeds in only 30-50% yield,

and attempts to apply a similar strategy to the synthesis

of substituted azulenes gave the desired compounds in

very low yield.^13b

SCHEME 2

Bu¨chner reaction of substrates of this type could afford

enones of type 5, which we expected would tautomerize

to furnish 1-hydroxyazulenes (6, R ) H). 1-Hydroxyazu-

lenes are known to be quite unstable, readily undergoing

polymerization,¹⁵and we therefore planned to trap this

intermediate in situ as a carboxylate or sulfonate ester.

Thus, as an added bonus, this strategy would provide

azulenes functionalized with hydroxy derivatives at the

C-1 position that potentially could be elaborated via

transition-metal-catalyzed coupling reactions to a wide

variety of functionalized and substituted azulenes.

Unfortunately, all attempts to achieve the desired

transformation produced the desired azulenes accompa-

nied by isomeric naphthalene byproducts. For example,

treatment of diazo enone 7¹⁶with a catalytic amount of

rhodium acetate followed by acetic anhydride led in near-

quantitative yield to a mixture of azulene 8 and the

naphthol derivatives 9 and 10 (Scheme 2). The 2-naph-

thol derivative 9 may arise via an acid-promoted rear-

rangement of the norcaradiene intermediate of type 4,^17,18

while the 1-naphthol 10 most likely is formed via Wolff

Results and Discussion

The aim of our studies in this area has been the design

of a variant of the intramolecular Bu¨chner strategy that

would deliver azulene derivatives directly and without

the need for elevated temperatures or harsh reagents to

effect elimination and/or dehydrogenation steps.

Diazo Enone Strategy. Our first attempt to circum-

vent the need for a dehydrogenation step involved the

cyclization of R′-diazo derivatives of R,â-unsaturated

ketones of general type 3 (Scheme 1). Intramolecular

(8) (a) Yang, P.-W.; Yasunami, M.; Takase, K. Tetrahedron Lett.

1971, 4275. (b) Wakabayashi, H.; Yang, P.-W.; Wu, C.-P.; Shindo, K.;

Ishikawa, S.; Nozoe, T. Heterocycles 1992, 34, 429 and references

therein.

(9) Mukherjee, D.; Dunn, L. C.; Houk, K. N. J. Am. Chem. Soc. 1979,

101, 251 and references therein.

(10) Becker, D. A.; Danheiser, R. L. J. Am. Chem. Soc. 1989, 111,

389.

(11) Reviews: (a) Ho, T.-L. Tandem Organic Reactions; Wiley: New

York, 1992. (b) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed. Engl.

1993, 32, 131. (c) Bunce, R. A. Tetrahedron 1995, 51, 13103.

(12) For a review, see: Doyle, M. P.; McKervey, M. A.; Ye, T. Modern

Catalytic Methods for Organic Synthesis with Diazo Compounds; John

Wiley & Sons: New York, 1998; pp 289-324.

(13) (a) Scott, L. T. J. Chem. Soc., Chem. Commun. 1973, 882. (b)

Scott, L. T.; Minton, M. A.; Kirms, M. A. J. Am. Chem. Soc. 1980, 110,

6311. (c) Scott, L. T.; Sumpter, C. A. Organic Syntheses; Wiley: New

York, 1993, Collect. Vol. VIII, p 196.

(14) In subsequent studies, McKervey found that this process

proceeds more efficiently when catalyzed by rhodium(II) acetate dimer.

See ref 13c and: McKervey, M. A.; Tuladhar, S. M.; Twohig, M. F. J.

Chem. Soc., Chem. Commun. 1984, 129.

(15) (a) Asao, T.; Ito, S.; Morita, N. Tetrahedron Lett. 1989, 30, 6693.

(b) Asao, T. Pure Appl. Chem. 1990, 62, 507.

(16) Prepared from 4,4-diphenylbut-3-en-2-one in 85% yield via

detrifluoroacetylative diazo transfer according to the method of Dan-

heiser et al.: Danheiser, R. L.; Miller, R. F.; Brisbos, R. G.; Park, S. Z.

J. Org. Chem. 1990, 55, 1959.

(17) See: McKervey, M. A.; Tuladhar, S. M.; Twohig, M. F. J. Chem.

Soc., Chem. Commun. 1984, 129.

(18) For the formation of 2-naphthols in the cyclization of related

diazo derivatives of â-keto esters, see: Taylor, E. C.; Davies, H. M. L.

Tetrahedron Lett. 1983, 24, 5453.

J. Org. Chem, Vol. 69, No. 25, 2004 8653

Crombie et al.

SCHEME 3

SCHEME 4

rearrangement of 7 to generate a vinylketene which then

undergoes 6π electrocylic closure.¹⁹

trapped as a sulfonate derivative, which could then be

elaborated via transition-metal-catalyzed coupling reac-

tions to furnish a variety of 1-substituted azulenes. At

the outset we recognized, however, that for this approach

to be successful it would be necessary to identify a leaving

group that would be stable to the conditions of the

carbenoid addition step, that would not undergo prema-

ture elimination at the stage of 15 or intermediate 16,

and whose elimination from 17 would take place more

rapidly than isomerization of the â,γ-double bond to form

a trienone analogous to 2 (eq 1).

Our initial studies focused on â-hydroxy ketone deriva-

tives (e.g., 15, X ) OAc), and in these cases isomerization

indeed proved competitive with the desired elimination.

Ultimately we found that halogens, particularly bromine,

function as the best leaving groups for the desired

transformation. The feasibility of the ring expansion-

annulation strategy was initially demonstrated by using

the known diazo ketone 19.²⁵Optimal conditions involve

dropwise addition of the diazo ketone over 45 min to 0.5

mol % of rhodium(II) pivalate^26,27in dichloromethane at

room temperature. Elimination of bromide and trapping

of the resulting unstable hydroxyazulene is then ac-

complished by addition of excess 4-(dimethylamino)-

pyridine and acetic anhydride. As outlined in eq 2,

1-acetoxyazulene²⁸is obtained as blue needles in up to

72% overall yield with use of this convenient “one-flask”

procedure.

Alkylidenecarbene Strategy. We next turned our

attention to a variant of the Bu¨chner cyclization based

on alkylidenecarbenes of type 12 (Scheme 3). Many

methods are available for the generation of alkylidene-

carbenes from carbonyl compounds,²⁰and Brown has

previously reported the formation of benzazulene in a

reaction in which a related alkylidenecarbene is gener-

ated by vapor phase pyrolysis.²¹We focused our attention

on the convenient generation of alkylidenecarbenes by

reaction of carbonyl compounds with diazomethylphos-

phonate (DAMP).²²Unfortunately, reactions of ketones

of type 11 (e.g., 11, Z ) CH₃) with DAMP failed to take

place under a variety of conditions, and not unexpectedly,

aldehydes (11, Z ) H) reacted with DAMP to form

conjugated enynes via the very facile 1,2 C-H shift that

is well documented for alkylidenecarbenes derived from

aldehydes.^20a-b,23,24

â-Halo Diazo Ketone Strategy. With the failure of

the exploratory studies summarized above, we turned our

attention to the strategy outlined in Scheme 4 in which

the intramolecular Bu¨chner reaction is carried out with

use of a substrate bearing a suitable leaving group “X”.

We anticipated that this process would deliver a bicyclic

ketone of type 17 that would undergo â-elimination and

subsequent tautomerization to afford a 1-hydroxyazulene

derivative. As mentioned earlier, it was hoped that this

type of ring expansion-annulation product could be

(19) Marvell, E. N. Thermal Electrocyclic Reactions; Academic

Press: New York, 1980.

(20) For examples, see: (a) Colvin, E. W.; Hamill, B. J. J. Chem.

Soc., Chem. Commun. 1973, 151. (b) Colvin, E. W.; Hamill, B. J. J.

Chem. Soc., Perkin Trans. 1 1977, 869. (c) Trahanovsky, W. S.; Emeis,

S. L.; Lee, A. S. J. Org. Chem. 1976, 41, 4044. (d) Brown, R. F. C.;

Eastwood, F. W. J. Org. Chem. 1981, 46, 4588.

(21) Brown, R. F. C.; Eastwood, F. W.; Harrington, K. J.; McMullen,

G. L. Aust. J. Chem. 1974, 27, 2393.

(22) (a) Seyferth, D.; Marmor, R. S. J. Org. Chem. 1971, 36, 128.

(b) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36,

1379. (c) Regitz, M. Liebigs Ann. Chem. 1971, 748, 207.

(23) After our study, Aoyama and co-workers reported the synthesis

of 2,3-dihydroazulenes via a related strategy involving intramolecular

reactions of alkylidenecarbenes. In their approach, a 4-aryl-2-oxobu-

tanoic ester (ArCH₂CH₂COCO₂R) is reacted with Me₃SiCH(Li)N₂to

generate a carbene that furnishes a 1-carboalkoxy-2,3-dihydroazulene

in moderate yield. See: Hari, Y.; Tanaka, S.; Takuma, Y.; Aoyama, T.

Synlett 2003, 2151.

(24) For earlier, related intramolecular Bu¨chner reactions for the

synthesis of cycloheptapyrrolones, see: (a) Gilbert, J. C.; Blackburn,

B. K. J. Org. Chem. 1986, 51, 4087. (b) Ogawa, H.; Aoyama, T.; Shioiri,

T. Synlett 1994, 757.

Preparation of â′-Bromo-r-Diazo Ketones. Several

synthetic approaches to the requisite diazo ketone ring

expansion-annulation substrates were examined. For

most substrates, the most efficient route begins with

readily available cinnamic acids and employs hydrobro-

(25) Rosenquist, N. R.; Chapman, O. L. J. Org. Chem. 1976, 41,

3326.

(26) Legzdins, P.; Mitchell, R. W.; Rempel, G. L.; Ruddick, J. D.;

Wilkinson, G. J. Chem. Soc. 1970, 3322.

8654 J. Org. Chem., Vol. 69, No. 25, 2004

Synthesis of Substituted Azulenes and Oligoazulenes

TABLE 1. Preparation of â-Bromo Diazo Ketones from

mination to install the â-bromine atom followed by

elaboration of the carboxylic acids to diazo ketones with

use of standard Arndt-Eistert conditions. An attractive

feature of this approach is that many cinnamic acids are

commercially available, and others are easily prepared

in one step from benzaldehydes by using the Knoevenagel

reaction.²⁹

Cinnamic Acids

Initial attempts to add either HCl or HBr to cinnamic

acids were not fruitful, and led to mixtures of the desired

product and recovered starting material. After consider-

able experimentation, a successful protocol was finally

developed based on the general method of Kropp.³⁰

Optimal conditions involve treatment of the cinnamic

acid with a solution of anhydrous HBr in dichloro-

methane in the presence of silica gel³¹(10 g per 0.6-2 g

of alkene) at room temperature. Purification of the

resulting â-bromo carboxylic acids is not necessary, and

reaction with oxalyl chloride and then diazomethane

furnishes the expected â-bromo diazo ketones in good

overall yield (Table 1).

Addition of HBr to cinnamic acids with alkyl-substi-

tuted and electron-rich aryl groups proceeded smoothly

to completion in 22-48 h;³²however, electron-deficient

substrates (Table 1, entries 2-6, 9) were found to require

extended reaction times (90-192 h). For the synthesis

of even more highly electron-deficient systems, an alter-

native synthetic route was developed based on the

benzylic bromination of 3-phenylpropionic acids³³(Table

2). This alternative protocol also proved useful for the

preparation of diazo ketone 67 (entry 3), as 2-methyl-

cinnamic acid was recovered unchanged from attempted

hydrobromination with HBr-SiO₂.

diazo ketone

cinnamic â-bromo

â-bromo

(overall

entry

R

acid

acid chloride

yield^d)

1

2

3

4

5

6

7

8

9

H

21

22

23^e

24^f

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

19 (60%)

48 (51%)

49 (53%)

50 (51-60%)

51 (55%)

52 (30%)

53 (47%)

54 (61%)

55 (45%)

2-Cl

2-I

3-i-Pr

3-Br

3-CF₃

4-CH₃

4-Cl

3,4-di-Cl

^aHBr-SiO₂, CH₂Cl₂, rt, 22-192 h. ^b1.2 equiv of (COCl)₂, PhH,

65 °C, 15-18 h. ^c4.0 equiv of CH₂N₂, Et₂O, 0 °C to rt, 1-3 h.

^dOverall isolated yield (from corresponding cinnamic acids) of

products purified by chromatography on silica gel. ^ePrepared in

88% yield by Knoevenagel reaction of malonic acid with 2-iodo-

benzaldehyde (piperidine, pyridine, reflux, 16 h) as previously

described by Larock and Doty (Larock, R. C.; Doty, M. J. J. Org.

Chem. 1993, 58, 4579). ^fSee Supporting Information and ref 1.

Scope of the Ring Expansion-Annulation Strat-

egy. Table 3 delineates the scope of the ring expansion-

annulation strategy. In a typical reaction, a solution of

the diazo ketone is added dropwise over 45-90 min to a

solution of 0.005 to 0.01 equiv of rhodium(II) pivalate at

room temperature. Base (e.g., 4-DMAP) and a trapping

agent are then added, and after 5 min the reaction is

quenched by addition of methanol. Workup and purifica-

tion by column chromatography then furnishes the

desired azulenes. The overall yields for this multistep

cascade process are generally good, except in the case of

some of the more electron-deficient substrates (e.g.,

entries 9 and 10) where the desired azulenes are pro-

duced in ca. 20% overall yield accompanied by several

uncharacterizable byproducts. Noteworthy is the success

TABLE 2. Preparation of â-Bromo Diazo Ketones from

3-Arylpropionic Acids

â-bromo diazo ketone

(27) Other rhodium(II) catalysts proved to be inferior to the pivalate

for this transformation. Reactions with rhodium(II) acetate, perfluo-

robutyrate, triphenylacetate, and octanoate provided 20 in 19-46%

yield. For a review of the effect of ligands on Rh(II)-catalyzed reactions,

see: Doyle, M. P.; Ren, T. In Progress in Inorganic Chemistry; Karlin,

K. D., Ed.; John Wiley & Sons: New York, 2001; Vol. 49, pp 113-168

and references therein.

propionic â-bromo

acid

(overall

entry

R¹

R²

acid

chloride

yield^d)

1

2

3

4-NO₂

4-CN

H

CH₃

56^e

57^f

58^g

59

60

61

62

63

64

65 (28%)

66 (41%)

67 (60%)

^a1.2 equiv of NBS, cat. AIBN, CCl₄, hυ, 80 °C, 2-4 h. ^b1.2 equiv

of (COCl)₂, PhH, 65 °C, 15-18 h. ^c4.0 equiv of CH₂N₂, Et₂O, 0 °C

to rt, 1-4 h. ^dOverall isolated yield (from corresponding arylpro-

pionic acids) of products purified by chromatography on silica gel.

^eWalter, M.; Besendorf, H.; Schnider, O. Helv. Chim. Acta 1963,

46, 1127. ^fWagner, G.; Garbe, C.; Richter, P. Pharmazie 1973, 28,

724. Also available in 77% yield by alkylation of tert-butyl acetate

(LDA, THF, R-iodo-p-tolunitrile) followed by cleavage of the tert-

butyl ester (TMSCl, NaI, CH₃CN). ^gBrunner, H.; Leitner, W. J.

Organomet. Chem. 1990, 387, 209. Also available in 52% yield by

alkylation of ethyl propionate (LDA, THF, benzyl bromide) fol-

lowed by hydrolysis of the ester (KOH, H₂O).

(28) Asao, T.; Ito, S.; Morita, N. Tetrahedron Lett. 1989, 30, 6693.

(29) For a review, see: Jones, G. Org. React. 1967, 15, 204.

(30) Kropp, P. J.; Daus, K. A.; Tubergen, M. W.; Kepler, K. D.;

Wilson, V. P.; Craig, S. L.; Baillargeon, M. M.; Breton, G. W. J. Am.

Chem. Soc. 1993, 115, 3071.

(31) Merck, Baker, and Silicycle silica gel 60 (230-400 mesh), and

ICN silica gel (32-60 µm) were dried at 200 °C for 48 h at 0.1 mmHg

prior to use.

(32) Although benzylic bromides derived from cinnamic acids with

highly electron-rich aryl groups (e.g., 2-OMe-C₆H₄) can be prepared

by this method, these compounds proved to be highly unstable toward

elimination and polymerization.

(33) For benzylic bromination of 3-phenylpropionic acid itself, see:

McGarvey, J. E. B.; Knipe, A. C. J. Chem. Educ. 1980, 57, 155.

J. Org. Chem, Vol. 69, No. 25, 2004 8655

Crombie et al.

TABLE 3. Synthesis of Substituted Azulenes

^a0.005-0.01 equiv of Rh₂(OCOt-Bu)₄, CH₂Cl₂, rt, 45-90 min; then add 3 equiv of DMAP, 5 equiv of Ac₂O, rt, 5 min. ^bR²) H unless

otherwise indicated. ^cIsolated yields of products purified by chromatography on silica gel. ^dAsao, T.; Ito, S.; Morita, N. Tetrahedron Lett.

1989, 30, 6693. ^eEstimated yield; 22% overall yield from 4-methylcinnamic acid (27). ^fEt₂O used as solvent.

of the ring expansion-annulation in the case of haloge-

nated substrates, which stands in contrast with earlier

reports that halobenzenes do not participate in related

Bu¨chner reactions in good yield.^13cThese haloazulene

annulation products hold particular interest due to their

potential utility as substrates for transition-metal-

catalyzed coupling reactions (vide infra). In the case of

ortho- and meta-substituted substrates (entries 2-6), the

ring expansion-annulation was found to proceed with

carbenoid addition occurring away from the substituent

to afford predominantly a single azulene regioisomer.³⁴

Only trace amounts (<1%) of byproducts tentatively

identified as regioisomeric azulenes were detected in

these reactions.³⁵Interestingly, attempted ring expan-

sion-annulation with the m-isopropyl substrate 50 (entry

4) under the standard conditions produced only traces

of the desired azulene, but this reaction proceeded in good

yield when diethyl ether was employed in place of

dichloromethane as the solvent.

As mentioned earlier, critical to the success of the ring

expansion-annulation reaction is the trapping of the

initially generated unstable 1-hydroxyazulenes as stable

(35) For a review of earlier studies on the regiochemical course of

related intramolecular Bu¨chner reactions, see: Doyle, M. P.; McKervey,

M. A.; Ye, T. Modern Catalytic Methods for Organic Synthesis with

Diazo Compounds; John Wiley & Sons: New York, 1998; pp 298-319.

(34) The regiochemistry of these azulenes was assigned on the basis

of ¹H NMR NOE experiments.

8656 J. Org. Chem., Vol. 69, No. 25, 2004

Synthesis of Substituted Azulenes and Oligoazulenes

SCHEME 5

ester derivatives. In most cases, acetic anhydride was

found to be a convenient esterification agent, reacting in

less than 5 min in the presence of 4-DMAP to afford the

expected azulenyl acetates. As illustrated in eq 3, in situ

esterification can also be accomplished with acyl chlo-

rides, and as discussed later, the application of Tf₂O and

Tf₂NPh provides access to 1-azulenyl sulfonates that

participate in useful palladium-catalyzed coupling reac-

tions.

Interestingly, in most ring expansion-annulation reac-

tions styrene derivatives were isolated as minor byprod-

ucts in 10-15% yield. One possible mechanism to account

for the formation of these side products is outlined in eq

4. The inter- and intramolecular trapping of rhodium

carbenoids derived from diazo ketones by heteroatoms

is well-documented,³⁶and the proposed fragmentation is

related to the â-eliminations that have been observed in

reactions of sulfonium and oxonium ylides generated in

analogous reactions.³⁷This mechanism must be regarded

as speculative, however, in view of our failure to detect

or trap bromoketene in any of these reactions.

1986 Dehmlow reported that certain 6-bromoazulenes

participate in Sonogashira reactions and Negishi cou-

plings with arylzinc compounds,³⁸and in 1991 Horino

described the Heck vinylation of several haloazulenes.^39,40

Concurrent with our studies, further reports of coupling

reactions involving haloazulenes have appeared, includ-

ing additional examples of Sonogashira reactions,⁴¹two

examples of a Stille coupling reaction,^5,42and several

Suzuki reactions.⁴³

As described earlier, application of the ring expansion-

annulation strategy to o-halobenzene substrates provides

convenient access to 4-haloazulenes such as 69. We have

found that 69 participates smoothly in Heck⁴⁴and

Negishi⁴⁵reactions to afford 4-vinyl- and 4-aryl-substi-

tuted azulenes in excellent yield (Scheme 5). In the case

of the Heck reaction, best results are obtained by

employing the indicated modified version of the Jeffery

phase transfer protocol.⁴⁶

(38) Balschukat, D.; Dehmlow, E. V. Chem. Ber. 1986, 119, 2272.

(39) Horino, H.; Asao, T.; Inoue, N. Bull. Chem. Soc. Jpn. 1991, 64,

183.

(40) See also: (a) Homocoupling of 1- and 2-haloazulenes with copper

metal: Morita, T.; Takase, K. Bull. Chem. Soc. Jpn. 1982, 55, 1144.

(b) Formation of oligo- and polyazulenes by Ni-catalyzed coupling of

1-bromo- and 1,3-dibromoazulene: Iyoda, M.; Sato, K.; Oda, M.

Tetrahedron Lett. 1985, 26, 3829.

(41) See ref 6e and: (a) Fabian, K. H. H.; Elwahy, A. H. M.; Hafner,

K. Tetrahedron Lett. 2000, 41, 2855. (b) Elwahy, A. H. M.; Hafner, K.

Tetrahedron Lett. 2000, 41, 4079. (c) Ito, S.; Inabe, H.; Okujima, T.;

Morita, N.; Watanbe, M.; Imafuku, K. Tetrahedron Lett. 2000, 41, 8343.

(d) Ito, S.; Inabe, H.; Okujima, T.; Morita, N.; Watanabe, M.; Harada,

N.; Imafuku, K. J. Org. Chem. 2001, 66, 7090. (e) Elwahy, A. H. M.

Tetrahedron Lett. 2002, 43, 711.

Synthetic Elaboration of Ring Expansion-Annu-

lation Products. An important consideration in the

design of the ring expansion-annulation strategy was the

expectation that it would deliver azulenes with hydroxyl

derivatives (including sulfonates) at C-1 of the five-

membered ring and could also provide products with

multiple substituents, including halogen atoms, on the

seven-membered ring. The next goal in our investigation

was to explore the feasibility of employing these substit-

uents as handles for the further synthetic elaboration of

the azulene annulation products.

Of particular interest to us was the possibility of

employing azulenyl halides and sulfonates in transition-

metal-catalyzed carbon-carbon bond-forming reactions.

At the outset of our investigation, the feasibility of

achieving such transformations was far from clear. It is

well documented that the chemistry of azulenes often

differs significantly from that of more familiar benzenoid

aromatic systems such as naphthalene, and at the time

we began our studies, only four prior reports had ap-

peared describing such reactions. Most significantly, in

(42) Ito, S.; Okujima, T.; Morita, N. J. Chem. Soc., Perkin Trans. 1

2002, 1896.

(43) Kurotobi, K.; Tabata, H.; Miyauchi, M.; Murafuji, T.; Sugihara,

Y. Synthesis 2002, 1013.

(44) For reviews, see: (a) Jeffery, T. In Advances in Metal-Organic

Chemistry; Liebeskind, L. S., Ed.; JAI: London, UK, 1996; Vol. 5, pp

153-260. (b) Brase, S.; de Meijere, A. In Metal-catalyzed Cross-coupling

Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York,

1998; pp 99-166. (c) Crisp, G. T. Chem. Soc. Rev. 1998, 27, 427. (d)

Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. (e)

Beller, M.; Riermeier, T. H.; Stark, G. In Transition Metals for Organic

Synthesis: Building Blocks and Fine Chemicals; Beller, M., Bolm, C.,

Eds.; Wiley-VCH: Weinheim, Germany, 1998; Vol. 1, pp 208-240. (f)

Handbook of Organopalladium Chemistry for Organic Synthesis;

Negishi, E.-i., de Meijere, A., Eds.; Wiley-Interscience: New York, 2002;

Vol 1, pp 1133-1367.

(36) For a review, see: Padwa, A.; Hornbuckle, S. F. Chem. Rev.

1991, 91, 263.

(37) For examples, see: (a) Moody, C. J.; Taylor, R. J. Tetrahedron

Lett. 1988, 29, 6005. (b) Roskamp, E. J.; Johnson, C. R. J. Am. Chem.

Soc. 1986, 108, 6062.

(45) For a review of coupling reactions with organozinc reagents,

see: Negishi, E.-i.; Liu, F. In Metal-catalyzed Cross-coupling Reactions;

Diederich, F., Stang, P. J., Eds.; Wiley-VCH: New York, 1998; pp 1-48.

(46) Gu¨rtler, C.; Buchwald, S. L. Chem. Eur. J. 1999, 3107.

J. Org. Chem, Vol. 69, No. 25, 2004 8657

Crombie et al.

TABLE 4. Suzuki Coupling Reactions of Azulenyl

Triflates

We next turned our attention to the key issue of

effecting transition-metal-catalyzed coupling reactions at

the C-1 position of the ring expansion-annulation prod-

ucts. In situ trapping of the annulation products with

N-phenyltriflimide⁴⁷provided the expected triflates (e.g.,

84-86), but initial attempts to utilize these azulenes in

efficient coupling reactions with various organotin, boron,

zinc, aluminum, copper, silicon, and magnesium reagents

met with dismal failure. The azulenyl triflate 84 is

formed in 91% yield (as estimated by ¹H NMR analysis)

and is stable to storage at 0 °C in dichloromethane or

diethyl ether. However, this triflate was found to rapidly

decompose upon concentration and also upon exposure

to dipolar aprotic solvents such as NMP, DMF, and DMA,

which are often preferred solvents for Pd-catalyzed

coupling reactions.⁴⁸To our dismay, conditions that led

to efficient coupling reactions in control experiments with

the triflate derivative of 1-naphthol resulted only in the

formation of uncharacterizable polymeric products in the

case of azulenyl triflate 84.

Successful coupling was ultimately realized by exploit-

ing recent advances in the development of highly active

catalysts for palladium-mediated cross-coupling and ami-

nation reactions. In particular, we have found that

Suzuki coupling reactions⁴⁹of azulenyl triflates to afford

1-alkyl- and 1-arylazulenes can be achieved in high yield

by using Buchwald’s o-(dicyclohexylphosphino)biphenyl

ligand.^50,51Our preliminary report¹of this process dis-

closed the first successful examples of Suzuki coupling

reactions involving azulenyl halides or sulfonates. Table

4 summarizes the results of our studies to date. Best

overall yields are obtained by employing azulenyl triflates

in the Suzuki coupling reaction without prior purification.

Alkylboranes are superior to boronic acid and ester

derivatives for this coupling, and complete reaction takes

place in THF under the indicated conditions either at

room temperature for several hours or alternatively at

reflux for several minutes. Cesium carbonate proved to

be the optimal base for the reaction, although KF and

CsF are equally effective in some cases. Interestingly,

coupling was found to take place at similar rates at C-1

and C-6 of the 6-chloroazulenyl triflate 86; reaction with

excess triethylborane provided the diethylazulene 90 in

good overall yield (entry 4). The Suzuki reaction leading

to 89 (entry 3) comprises the key step in our synthesis of

the antiulcer drug egualen sodium (“KT1-32”, 92).⁵²

^a1 mol % of Rh₂(OCOt-Bu)₄, CH₂Cl₂, rt, 45 min; then add 3

equiv of DMAP, 1 equiv of Tf₂NPh, rt, 10 min. ^bBorane, 5 mol %

of Pd(OAc)₂, 7.5-10 mol % of (o-biphenyl)PCy₂(20 mol % in entry

5), 3 equiv of Cs₂CO₃, (4.0 equiv of Et₃N in entry 5), THF. ^cOverall

isolated yield (from diazo ketone) of products purified by column

chromatography on silica gel.

Overall, our approach delivers 92 in eight steps beginning

with commercially available m-isopropylphenol, a con-

siderable improvement over the previously published

route.⁵²

(47) Hendrickson, J. B.; Bergeron, R. Tetrahedron Lett. 1973, 4607.

(48) The decomposition of aryl triflates in dipolar aprotic solvents

has been observed previously. See: Eschavarren, A. M.; Stille, J. K.

J. Am. Chem. Soc. 1987, 109, 5478 and references therein.

(49) For reviews, see: (a) Suzuki, A. J. Organomet. Chem. 1999,

576, 147. (b) Miyaura, N. In Advances in Metal-Organic Chemistry;

Liebeskind, L. S., Ed.; JAI: London, UK, 1998; Vol. 6, pp 187-243. (c)

Suzuki, A. In Metal-catalyzed Cross-coupling Reactions; Diederich, F.,

Stang, P. J., Eds.; Wiley-VCH: New York, 1998; pp 49-97. (d)

Stanforth, S. P. Tetrahedron 1998, 54, 263. (e) Miyaura, N.; Suzuki,

A. Chem. Rev. 1995, 95, 2457.

(50) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am.

Chem. Soc. 1999, 121, 9550.

(51) Exploratory studies on Heck and Stille couplings of 84 were

not fruitful and were not pursued further once successful Suzuki

reactions had been achieved.

(52) (a) Yanagisawa, T.; Wakabayashi, S.; Tomiyama, T.; Yasunami,

M.; Takase, K. Chem. Pharm. Bull. 1988, 36, 641. See also: (b)

Yanagisawa, T.; Kosakai, K.; Tomiyama, T.; Yasunami, M.; Takase,

K. Chem. Pharm. Bull. 1990, 38, 3355. (c) Yanagisawa, T.; Kosakai,

K.; Izawa, C.; Tomiyama, T.; Yasunami, M. Chem. Pharm. Bull. 1991,

39, 2429. (d) Mochizuki, S.; Matsumoto, M.; Wakabayashi, S.; Kosakai,

K.; Tomiyama, A.; Kishimoto, S. J. Gastroenterol. 1996, 31, 785.

Particularly noteworthy in Table 4 is the palladium-

catalyzed borylation of 84 to afford the 1-azulenyl-

boronate 91. Because of the instability of C-1 azulenyl

triflates to long-term storage, we sought a more robust

azulene derivative that could serve as an intermediate

for the synthesis of a variety of 1-substituted derivatives.

8658 J. Org. Chem., Vol. 69, No. 25, 2004

Synthesis of Substituted Azulenes and Oligoazulenes

SCHEME 6^a

SCHEME 7^a

^aReagents and conditions: 1.0 equiv of 79, 5 mol % of Pd(OAc)₂,

20 mol % of (o-biphenyl)PCy₂, 3.0 equiv of Ba(OH)₂, dioxane-H₂O,

45-65 °C, 30 min. ^b2.0 equiv of 91 relative to 1,3-diiodoazulene

was employed for this reaction.

^aReagents and conditions: 1.5 equiv of 91, 5 mol % of Pd(OAc)₂,

20 mol % of (o-biphenyl)PCy₂, 3.0 equiv of Ba(OH)₂, dioxane-H₂O,

65 °C, 15 min.

Synthesis of Oligoazulenes. π-Conjugated organic

oligomers and polymers have attracted enormous atten-

tion in recent years due to their utility as advanced

materials for the construction of molecular devices.⁶⁰The

unusual electronic and optical properties of azulenes has

led to significant interest in the design and synthesis of

oligomers and polymers incorporating these novel aro-

matic systems.⁶For the most part, research in this area

to date has relied on the availability of the natural

product guaiazulene and a very limited suite of substi-

tuted azulenes available by de novo synthetic routes. In

our view, the ability of our ring expansion-annulation

strategy to provide efficient access to a variety of azulenes

substituted on both the five- and seven-membered ring

makes it an especially powerful method for the prepara-

tion of azulene building blocks for the construction of

advanced materials. To demonstrate the potential utility

of the ring expansion-annulation strategy in this con-

nection, we undertook the synthesis of several represen-

tative bi-, tri-, and related oligoazulenes.

The importance of biaryls as components in liquid

crystals and other novel materials is well established.

The Suzuki coupling of the azulenylboronate 91 with

iodoazulene 79 (Scheme 7) illustrates one approach to

the preparation of biazulenes based on our ring expan-

sion-annulation products. To our knowledge, 99 repre-

sents the first example of a biazulene with a C-1 to C-4

linkage. In a similar fashion, reaction of boronate 91 with

1,3-diiodoazulene^41aprovides the terazulene 101 as me-

tallic green crystals in good yield. This route to 101 is

markedly superior to the prior synthesis of this compound

that generated the terazulene in only 13% yield as one

component of a mixture of oligoazulenes.^40b

Initially, we attempted to effect borylation of 84 using

bis(pinacolato)diboron according to the general method

of Miyuara.⁵³Unfortunately, only decomposition of 84

was observed upon attempted reaction with the diboron

reagent under a variety of conditions and with a wide

range of phosphine ligands.^54,55Successful borylation of

84 was finally achieved by employing the much less

expensive borylation agent pinacolborane.⁵⁶Best results

were obtained by using Buchwald’s ligand (o-biphenyl)-

PCy₂as recommended by Baudoin,⁵⁷and in this fashion

the azulenylboronate 91 could be isolated in 45-51%

overall yield from the diazo ketone 19 (Table 4, entry 5).

The azulenylboronate is a dark purple solid, stable to

purification by column chromatography and to storage

at 0 °C in CH₂Cl₂or benzene.

As illustrated in Scheme 6, the azulenyl boronate 91

reacts smoothly in Suzuki coupling reactions with 4-iodo-

acetophenone and alkenyl iodides 95⁵⁸and 97⁵⁹to afford

the expected 1-substituted azulenes. These coupling

reactions were generally carried out employing the iodide

as the limiting reagent; alternatively, reaction of 1.0

equiv of 91 with 1.1-1.5 equiv of the organoiodine

compound provided the desired azulenes in 73%, 44%,

and 37% yield, respectively.

(53) (a) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995,

60, 7508. (b) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron

Lett. 1997, 38, 3447. (c) Reviewed in: Ishiyama, T.; Miyaura, N. J.

Organomet. Chem. 2000, 611, 392.

(54) In contrast, borylation of the triflate derivative of 1-naphthol

was achieved in high yield under similar conditions.

(55) During the course of our work, Sugihara reported the borylation

of 2- and 6-haloazulenes using this reagent. See ref 43 and: Kurotobi,

K.; Miyauchi, M.; Takakura, K.; Murafuji, T.; Sugihara, Y. Eur. J. Org.

Chem. 2003, 3663.

We next turned our attention to the application of the

ring expansion-annulation products in the synthesis of

azulenyl thiophene oligomers. The goal of this model

(56) Murata, M.; Oyama, T.; Watanabe, S.; Masuda, Y. J. Org. Chem.

2000, 65, 164.

(57) Baudoin, O.; Gue´nard, D.; Gue´ritte, F. J. Org. Chem. 2000, 65,

9268.

(58) Irifune, S.; Kibayashi, T.; Ishii, Y.; Ogawa, M. Synthesis 1988,

366.

(60) (a) Handbook of Conducting Polymers; Skotheim, T. A., Elsen-

baumer, P. L., Reynolds, J. R., Eds.; Marcel Decker: New York, 1998.

(b) Electronic Materials: The Oligomer Approach; Mu¨llen, K., Wegner,

G., Eds.; Wiley-VCH: Weinheim, Germany, 1997.

(59) Piers, E.; Grierson, J. R.; Lau, C. K.; Nagakura, I. Can. J. Chem.

1982, 60, 210.

J. Org. Chem, Vol. 69, No. 25, 2004 8659

Crombie et al.

SCHEME 8^a

lene moieties is an interesting problem that has received

surprisingly little attention to date.⁶⁷Azulenyl amino

acids have potential utility as fluorescent probes, and

azulenyl analogues of tryptophan and phenylalanine are

expected to exhibit unusual behavior due to the unique

electronic characteristics of the azulenyl system. Loidl’s

six-step synthesis of â-(1-azulenyl)-^L-alanine 106^67c(from

expensive azulene itself) represents the most significant

work in this area to date. It occurred to us that the

azulenyl halides, sulfonates, boronates, and stannane

derivatives available via our ring expansion-annulation

methodology might serve as valuable building blocks for

the synthesis of azulenyl amino acids. Particularly at-

tractive to us was the prospect of employing our azulenes

in Negishi couplings with Jackson’s iodoalanine deriva-

tives⁶⁸and in Heck reactions with amidoacrylates.⁶⁹

^aReagents and conditions: 10 mol % of Pd(Ph₃P)₄, toluene,

reflux, 24 h. ^b2.0 equiv of 79 relative to 102 was employed for this

c

To explore the feasibility of the latter approach, we

examined the reaction of iodoazulene annulation product

79 with the readily available amidoacrylate 107.⁷⁰As

outlined in eq 6, the desired Heck reaction can be

reaction. 1.6 equiv.

study was to develop synthetic chemistry with potential

utility for the preparation of conducting polymers and

other electroactive materials. Our initial efforts focused

on coupling reactions involving haloazulenes and thiophen-

ylboron derivatives, but when these approaches proved

inefficient, we turned our attention to the application of

Stille couplings with thiophenylstannanes.⁶¹In the event,

we were pleased to find that iodoazulene 79 undergoes

efficient Stille coupling with the bis-stannane 102⁶²to

furnish 103 as a dark green solid in 73% yield (Scheme

8). Also noteworthy is the successful reaction of 79 with

hexamethylditin^63,64to afford the azulenylstannane 104.

Our interest in 104 derived from the expectation that it

might serve as a useful precursor to the 4,4′-biazulene

system. Only one inefficient previous synthesis of this

biazulene has been reported previously.⁶⁵In fact, treat-

ment of 104 with CuCl in DMF according to the general

method of Piers⁶⁶furnished the desired biazulene 105

as turquoise crystals in excellent yield (eq 5). Interest-

ingly, to date our attempts to effect Stille coupling of 104

with iodoazulene 79 have not been successful, and these

experiments have led to recovery of the unreacted azu-

lenes accompanied by 1-trimethylacetoxy-4-methylazu-

lene.

achieved in good yield, but surprisingly affords a mixture

of Z and E dehydroamino acids in a ratio of 83:17.⁷¹The

stereochemistry of the isomeric esters was assigned based

(62) Prepared from 2,2′-dithiophene by metalation with n-BuLi

followed by reaction with trimethylstannyl chloride. We thank Phoebe

Kwan and Professor Timothy Swager for providing us with a sample

of this compound.

(63) For reviews of the Stille coupling reaction, see: (a) Farina, V.;

Krishnamurthy, V.; Scott, W. J. Org. React. 1997, 50, 1. (b) Mitchell,

T. N. In Metal-catalyzed Cross-coupling Reactions; Diederich, F., Stang,

P. J., Eds.; Wiley-VCH: New York, 1998; pp 167-202.

(64) Concurrent with our studies, Ito reported the preparation of

6-(tributylstannyl)azulene and its reaction with aryl halides. See:

Okujima, T.; Ito, S.; Morita, N. Tetrahedron Lett. 2002, 43, 1261 and

ref 42.

(65) Huenig, S.; Ort, B. Liebigs Ann. 1984, 12, 1905.

(66) Piers, E.; Yee, J. G. K.; Gladstone, P. L. Org. Lett. 2000, 2, 481.

(67) (a) Anderson, A. G., Jr.; Gale, D. J.; McDonald, R. N.; Anderson,

R. G.; Rhodes, R. C. J. Org. Chem. 1964, 29, 1373. (b) Klemm, L. H.;

Hudson, B. S.; Lu, J. Org. Prep. Proced. Int. 1989, 21, 633. (c) Loidl,

G.; Musiol, H.-J.; Budisa, N.; Huber, R.; Poirot, S.; Fourmy, D.;

Moroder, L. J. Peptide Sci. 2000, 6, 139.

Synthesis of Azulenyl Amino Acids. The design and

synthesis of “unnatural” amino acids incorporating azu-

(68) Review: Gair, S.; Jackson, R. F. W. Curr. Org. Chem. 1998, 2,

527.

(61) For a review of Pd-catalyzed coupling reactions of thiophene

derivatives, see: Li, J. J.; Gribble, G. W. Palladium in Heterocyclic

Chemistry; Pergamon: Oxford, UK, 2000; Chapter 5.

(69) (a) Carlstro¨m, A.-S.; Frejd, T. Synthesis 1989, 414. (b) Carl-

stro¨m, A.-S.; Frejd, T. Acta Chem. Scand. 1992, 46, 163.

8660 J. Org. Chem., Vol. 69, No. 25, 2004

Synthesis of Substituted Azulenes and Oligoazulenes

1

glass stoppers were replaced with the gas inlet and outlet used

previously, and HBr was again bubbled through the reaction

mixture for 40 min. The flask was stoppered and stirred for 4

h and then the orange suspension was filtered with the aid of

400 mL of diethyl ether. The filtrate was washed with two 300-

mL portions of water and 300 mL of brine, dried over MgSO₄,

filtered, and concentrated to provide 9.36 g of 3-bromo-3-

phenylpropionic acid (30) as a white solid used in the next step

without purification.

on H NMR chemical shifts and was confirmed by NOE

experiments. Initially, the formation of isomeric dehy-

droamino acids was not a concern, since Burk has

reported conditions for the asymmetric hydrogenation of

related isomeric mixtures to afford a single amino acid

enantiomer.⁷²Unfortunately, to date we have not identi-

fied conditions under which hydrogenation of 108 and

109 with Burk’s DuPhos catalyst system proceeds at a

reasonable rate. On the other hand, hydrogenation of the

mixture of dehydroamino acids in the presence of Wilkin-

son’s catalyst proceeds as expected to afford the desired

azulenyl amino acid deriviative 110 in good yield (eq 7).

Separation of enantiomers can be effected by HPLC with

use of a Daicel Chiracel OD column, thus providing access

to both the ^D- and L-azulenyl amino acids in pure form.

A 250-mL, one-necked, flask equipped with a reflux con-

denser fitted with an argon inlet adapter was charged with

the bromo acid 30 prepared as described above (4.50 g, ca. 19.6

mmol), oxalyl chloride (3.59 g, 2.40 mL, 28.3 mmol, ca. 1.40

equiv), and 60 mL of benzene. As the suspension was heated

to 65 °C, the solid acid dissolved and vigorous gas evolution

began. After 30 min, gas evolution had ceased, and the reaction

mixture was stirred for an additional 16 h at 65 °C. After this

time, the reaction mixture was allowed to cool to room

temperature and then concentrated to a volume of ca. 10 mL.

A 500-mL, one-necked, round-bottomed flask (note: clearseal

73

joint) was charged with a solution of CH₂N₂(ca. 67 mmol,

3.4 equiv, generated from Diazald (21.5 g, 100.5 mmol) in 300

mL of diethyl ether). The yellow solution was cooled to 0 °C

and rapidly stirred while the benzene solution of the acid

chloride prepared above was added via pipet over 1 min (the

flask containing the acid chloride was rinsed with two 5-mL

portions of diethyl ether). The ice bath was removed after 10

min, stirring was stopped, and the reaction mixture was

allowed to warm to room temperature. After 1 h, excess

diazomethane was distilled off under reduced pressure (ca. 20

mmHg) into an Erlenmeyer flask cooled at -78 °C and

quenched by addition of acetic acid. The bright yellow reaction

mixture was concentrated to provide 5.24 g of a yellow oil,

which was dissolved in 15 mL of CH₂Cl₂, concentrated onto

10.4 g of silica gel, and transferred to the top of a column of

100 g of silica gel. Elution with 20% ethyl acetate-hexanes

afforded 4.09 g (71% overall from cinnamic acid 21) of 4-bromo-

1-diazo-4-phenyl-2-butanone (19) as a yellow solid with spec-

tral data consistent with that previously reported for this

compound:²⁵mp 65-66 °C; IR (CHCl₃) 3087, 2110, and 1627

cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 7.42-7.44 (m, 2 H), 7.34-

7.38 (m, 2 H), 7.29-7.33 (m, 1 H), 5.48 (dd, J ) 5.8, 9.15 Hz,

1 H), 5.31 (br s, 1 H), and 3.23 (ABX, J_ax) 9.3, J_bx) 5.5, J_ab

) 15.4 Hz, δ_a) 3.31, δ_b) 3.15, 2 H); ¹³C NMR (125 MHz,

CDCl₃) δ 190.3, 141.1, 129.1, 128.9, 127.4, 56.1, 50.2, and 48.3.

General Procedure for the Synthesis of â′-Bromo-r-

diazo Ketones via Benzylic Bromination with NBS:

4-Bromo-1-diazo-3-methyl-4-phenyl-2-butanone (67). A

250-mL, three-necked, round-bottomed flask equipped with an

argon inlet adapter, reflux condenser, and glass stopper was

charged with 2-methyl-3-phenylpropionic acid⁷⁴(58) (2.00 g,

12.2 mmol), N-bromosuccinimide (2.60 g, 14.6 mmol), and 60

mL of carbon tetrachloride. The resulting suspension was

heated at 80 °C while being irradiated with a sunlamp. After

2 h, the yellow reaction mixture was filtered (while hot),

allowed to cool to room temperature, filtered again, and then

concentrated to provide 3.21 g of 3-bromo-2-methyl-3-phenyl-

propionic acid as a light brown solid.

Conclusions

The ring expansion-annulation strategy described herein

provides efficient access to a variety of azulenes substi-

tuted on both the five and seven-membered rings. This

method is particularly well suited for the preparation of

azulenyl halides, sulfonates, and boronates, and these

annulation products function as valuable and versatile

building blocks for the construction of highly substituted

azulenes and oligoazulenes.

Experimental Section

Materials. Commercial grade reagents and solvents were

used without further purification except as indicated below.

Acetonitrile, benzene, N,N-dicyclohexylmethylamine, and tri-

ethylamine were distilled under argon from calcium hydride.

Diethyl ether and tetrahydrofuran were distilled under argon

from sodium benzophenone ketyl or dianion or purified by

pressure filtration through activated alumnia. Dichloromethane

and toluene were purified by pressure filtration through

activated alumina and Cu(II) oxide. Oxalyl chloride was

distilled under argon. Acetic anhydride was distilled from

quinoline. Activated silica gel was prepared by heating at 200

°C for 48 h at 0.1 mmHg prior to use.

General Procedure for the Synthesis of â-Bromo

Diazo Ketones via Hydrobromination with HBr: 4-Bro-

mo-1-diazo-4-phenyl-2-butanone (19). A 500-mL, three-

necked, round-bottomed flask was equipped with a glass

stopper, gas dispersion tube attached to a cylinder of HBr, and

a gas outlet adapter attached via Tygon tubing to an Erlen-

meyer flask filled with water. The reaction flask was charged

with cinnamic acid 21 (7.04 g, 47.2 mmol), 70 g of activated

silica gel, and 240 mL of dichloromethane. HBr was bubbled

through the reaction mixture for 40 min, and then the gas inlet

and outlet were replaced by glass stoppers. The orange

suspension was stirred at room temperature for 20 h. The two

Conversion of this material to the desired diazo ketone was

accomplished according to the general procedure described

above by reaction with oxalyl chloride (1.86 g, 1.30 mL, 14.6

mmol) in 60 mL of benzene, followed by treatment with CH₂N₂

(ca. 35 mmol, generated from Diazald (10.4 g, 48.8 mmol)) in

150 mL of diethyl ether. The crude diazo ketone (3.57 g of

yellow oil) was purified by column chromatography on 60 g of

(70) Yokoyama, Y.; Takahashi, M.; Takashima, M.; Mitsuru, K.;

Kohno, Y.; Kobayashi, H. Chem. Pharm. Bull. 1994, 42, 832.

(71) Heck reactions of aryl halides with 107 normally produce

exclusively Z dehydroamino acid derivatives. For an exception, see ref

69a.

(73) Diazomethane was generated from Diazald by using a mini-

diazomethane apparatus as described in: Black, T. H. Aldrichim. Acta

1983, 16, 3.

(72) (a) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J.

Am. Chem. Soc. 1993, 115, 10125. See also: (b) Burk, M. J.; Gross, M.

F.; Martinez, J. P. J. Am. Chem. Soc. 1995, 117, 9375. (c) Burk, M. J.;

Wang, Y. M.; Lee, J. R. J. Am. Chem. Soc. 1996, 118, 5142.

(74) Prepared in 52% yield by alkylation of ethyl propionate (LDA,

THF, benzyl bromide) followed by ester hydrolysis (KOH, H₂O). For a

previous synthesis of this compound, see: Brunner, H.; Leitner, W. J.

Organomet. Chem. 1990, 387, 209.

J. Org. Chem, Vol. 69, No. 25, 2004 8661

Crombie et al.

silica gel (compound adsorbed on 8 g of silica gel, elution with

20% ethyl acetate-hexanes) to afford 1.96 g (60% overall yield

from 2-methyl-3-phenylpropionic acid) of 4-bromo-1-diazo-3-

methyl-4-phenyl-2-butanone (67) (mixture of diastereomers)

as a yellow solid: mp 51.0-61.0 °C; IR (CCl₄) 2890, 2080, 1635,

and 1535 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 7.22-7.39 (m, 5

H), 5.42 (br s, 1 H, minor isomer), 5.14 (app t, J ) 8.8, 10.3

Hz, 1 H), 5.06 (br s, 1 H, major isomer), 3.03-3.11 (m, 1 H),

1.47 (d, J ) 7.1 Hz, 3 H, major isomer), 0.92 (d, J ) 7.0 Hz, 3

H, minor isomer); ¹³C NMR (75 MHz, CDCl₃) δ 195.4, 194.3,

140.5, 139.4, 128.8, 128.4, 127.8, 127.6, 57.5, 55.1, 55.0, 54.1,

52.8, 17.7, 17.0; UV (CH₃CN) λ_max(ꢀ) 247 (20 145), 192 (35 500)

nm; HRMS (EI) m/z calcd for C₁₁H₁₁BrN₂O 266.0055, found

266.0048.

(22 260) nm. Anal. Calcd for C₁₂H₉IO₂: C, 46.18; H, 2.91.

Found: C, 46.08; H, 2.83.

1-Acetoxy-5-isopropylazulene (70). Application of the

general procedure (except that Et₂O was employed as solvent

in place of dichloromethane) gave 0.151 g (54%) of 70 as a blue

1

oil. IR (thin film) 2960, 2920, 2860, 1755, and 1580 cm^-1; H

NMR (300 MHz, CDCl₃) δ 8.20 (d, J ) 1.8 Hz, 1H), 8.08 (d, J

) 10.0 Hz, 1H), 7.75 (d, J ) 4.3 Hz, 1H), 7.49 (d, J ) 9.5 Hz,

1H), 7.17 (d, J ) 4.3 Hz, 1H), 7.01 (app t, J ) 9.5, 10.0 Hz,

1H), 3.03 (sept, J ) 6.9 Hz, 1H), 2.40 (s, 3H), and 1.33 (d, J )

6.9 Hz, 6H); ¹³C NMR (75 MHz, CDCl₃) δ 169.4, 142.7, 138.1,

137.0, 135.7, 130.6, 127.9, 125.6, 121.6, 121.5, 112.9, 38.4, 24.4,

and 21.0; UV-vis max (hexane) λ_max(ꢀ) 614 (119), 352 (2170),

279 (21 570), and 225 (67 000) nm. Anal. Calcd for C₁₅H₁₆O₂:

C, 78.92; H, 7.06. Found: C, 79.14; H, 6.87.

General Procedure for the Synthesis of Acetoxyazu-

lenes: 1-Acetoxyazulene (20). A 500-mL, three-necked,

round-bottomed flask equipped with a rubber septum, 125-

mL pressure-equalizing addition funnel, and an argon inlet

adapter was charged with rhodium pivalate⁷⁵(0.022 g, 0.040

mmol) and 120 mL of dichloromethane. The addition funnel

was charged with 4-bromo-1-diazo-4-phenyl-2-butanone (19)

(2.00 g, 7.89 mmol) and 75 mL of dichloromethane. The

solution of the diazo ketone was added dropwise over 1.5 h to

the rapidly stirred solution of the catalyst. After 5 min, acetic

anhydride (4.02 g, 3.70 mL, 39.5 mmol) was added in one

portion via syringe, and then 4-DMAP (2.89 g, 23.7 mmol) was

immediately added in one portion. The resulting deep blue

solution was stirred for 5 min and then treated with 10 mL of

methanol. After stirring an additional 10 min, the reaction

mixture was poured into 100 mL of dichloromethane and 200

mL of 3% HCl solution. The organic phase was separated,

washed with 150 mL of 3% HCl solution and 200 mL of brine,

dried over MgSO₄, filtered, and concentrated to provide 1.40

g of a blue oil. Column chromatography on 50 g of silica gel

(elution with 5% ethyl acetate-hexanes) afforded 0.948 g (64%)

of 1-acetoxyazulene as blue needles: mp 53.5-54.5 °C (lit.²⁸

mp 47.5-50.2 °C); IR (CCl₄) 3030, 2810, 1765, 1580, 1545, and

1-Acetoxy-5-bromoazulene (71). Application of the gen-

eral procedure gave 0.109 g (39%) of 71 as an olive green solid,

mp 60.5-61.5 °C. IR (CCl₄) 2900, 1765, 1580, and 1545 cm^-1

;

¹H NMR (300 MHz, CDCl₃) δ 8.49 (d, J ) 2.1 Hz, 1 H), 8.13

(d, J ) 9.8 Hz, 1 H), 7.90-7.84 (m, 2 H), 7.24 (d, J ) 4.3 Hz,

1 H), 6.83 (app t, J ) 9.9 Hz, 1 H), 2.42 (s, 3 H); ¹³C NMR (75

MHz, CDCl₃) δ 168.9, 141.0, 140.9, 138.6, 133.6, 131.3, 129.9,

126.2, 120.7, 117.4, 114.7, 21.0; UV-vis (hexane) λ_max(ꢀ) 690

(273), 632 (302), 601 (250), 371 (3230), 362 (2440), 351 (3980),

347 (2860), 337 (2070), 278 (28 900) nm. Anal. Calcd for C₁₂H₉-

BrO₂: C, 54.37; H, 3.42. Found: C, 54.59; H, 3.29.

1-Acetoxy-5-(trifluoromethyl)azulene (72). Application

of the general procedure gave 0.109 g (40%) of 72 as a blue

solid, mp 43.5-44.5 °C. IR (CCl₄) 2920, 2840, 1770, 1580, and

1

1500 cm^-1; H NMR (300 MHz, CDCl₃) δ 8.45 (d, J ) 1.4 Hz,

1 H), 8.29 (d, J ) 9.5 Hz, 1 H), 7.92 (d, J ) 4.3 Hz, 1 H), 7.83

(d, J ) 4.3 Hz, 1 H), 7.47 (d, J ) 4.3 Hz, 1 H), 7.09 (app t, J

) 9.8 Hz, 1 H), 2.43 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃) δ

168.8, 140.5, 134.8, 134.7, 134.4, 134.1, 134.0, 133.3, 129.4,

126.2, 120.5, 118.6, 21.0; UV-vis (hexane) λ_max(ꢀ) 608 (255),

583 (221), 352 (8474), 278 (61 858), 215 (11 863) nm. Anal.

Calcd for C₁₃H₉F₃O₂: C, 61.42; H, 3.56. Found: C, 61.43; H,

3.63.

1

1500 cm^-1; H NMR (300 MHz, CDCl₃) δ 8.25 (d, J ) 9.3 Hz,

1 H), 8.21 (d, J ) 10.0 Hz, 1 H), 7.80 (d, J ) 4.2 Hz, 1 H), 7.58

(app t, J ) 9.8 Hz, 1 H), 7.27 (d, J ) 4.2 Hz, 1 H), 7.09 (dt, J

) 4.2, 10.0 Hz, 2 H), 2.43 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃)

δ 169.2, 138.5, 138.1, 137.8, 135.5, 132.1, 127.8, 126.1, 122.6,

121.7, 113.8, 20.9; UV-vis (hexane) λ_max(ꢀ) 732 (101), 663

(258), 608 (292), 586 (252), 347 (2933), 277 (30 166), 238 (8845),

213 (3352) nm.

1-Acetoxy-6-methylazulene (73). Application of the gen-

eral procedure gave 0.076 g (22% overall from 4-methyl-

cinnamic acid 27, estimated 47% yield for ring expansion-

annulation step) of 73 as a blue solid, mp 67.0-67.5 °C. IR

1

(CCl₄) 3030, 2920, 2880, 1765, and 1580 cm^-1; H NMR (300

MHz, CDCl₃) δ 8.08 (d, J ) 9.4 Hz, 1 H), 8.04 (d, J ) 10.2 Hz,

1 H), 7.67 (d, J ) 4.3 Hz, 1 H), 7.21 (d, J ) 4.3 Hz, 1 H), 6.99

(d, J ) 9.4 Hz, 1 H), 6.98 (d, J ) 10.2 Hz, 1 H), 2.60 (s, 3 H),

2.41 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃) δ 169.4, 150.5, 138.1,

137.3, 134.1, 131.1, 126.4, 125.0, 123.9, 123.6, 114.0, 28.3, 21.1;

UV-vis (CH₃CN) λ_max(ꢀ) 714 (105), 645 (270), 596 (300), 368

(3000), 352 (5700), 349 (5890), 335 (4390), 281 (72 290), 234

(18 120) nm. Anal. Calcd for C₁₃H₁₂O₂: C, 77.98; H, 6.04.

Found: C, 77.84; H, 6.04.

1-Acetoxy-4-chloroazulene (68). Application of the gen-

eral procedure gave 0.157 g (58%) of 68 as a blue-gray solid,

mp 55.5-56.5 °C. IR (CCl₄) 3020, 1760, 1585, and 1550 cm^-1

;

¹H NMR (300 MHz, CDCl₃) δ 8.22 (d, J ) 9.7 Hz, 1 H), 7.80

(d, J ) 4.2 Hz, 1 H), 7.52 (d, J ) 4.2 Hz, 1 H), 7.44 (app t, J

) 10.2 Hz, 1 H), 7.29 (d, J ) 10.8 Hz, 1 H), 7.06 (app t, J )

9.6 Hz, 1 H), 2.41 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃) δ 169.1,

144.0, 139.4, 136.0, 132.4, 130.1, 128.0, 126.3, 124.5, 121.1,

114.3, 21.0; UV-vis (hexane) λ_max(ꢀ) 657 (267), 605 (311), 520

(114), 351 (4130), 337 (2970), 284 (35 440), 245 (23 670), 219

(8960) nm. Anal. Calcd for C₁₂H₉ClO₂: C, 65.32; H, 4.11.

Found: C, 65.31; H, 3.99.

1-Acetoxy-6-chloroazulene (74). Application of the gen-

eral procedure gave 0.569 g (61%) of 74 as metallic blue flakes,

mp 66.5-67.0 °C. IR (CCl₄) 2880, 1750, 1565, and 1510 cm^-1

;

¹H NMR (300 MHz, CDCl₃) δ 8.01 (d, J ) 10.2 Hz, 1 H), 8.00

(d, J ) 10.6 Hz, 1 H), 7.77 (d, J ) 4.3 Hz, 1 H), 7.27 (d, J )

4.3 Hz, 1 H), 7.23-7.16 (m, 2 H), 2.42 (s, 3 H); ¹³C NMR (75

MHz, CDCl₃) δ 169.0, 145.6, 139.6, 135.8, 133.9, 130.3, 128.0,

124.7, 122.8, 122.3, 116.1, 21.0; UV-vis (hexane) λ_max(ꢀ) 777

(100), 664 (252), 606 (290), 582 (250), 561 (212), 304 (6730),

283 (61 500), 237 (9270), 217 (10 205) nm. Anal. Calcd for

C₁₂H₉ClO₂: C, 65.32; H, 4.11; Cl, 16.07. Found: C, 65.16; H,

4.17; Cl, 15.88.

1-Acetoxy-4-iodoazulene (69). Application of the general

procedure gave 0.792 g (73%) of 69 as a metallic blue solid,

mp 76.0-77.0 °C. IR (CCl₄) 2950, 2920, 1754, and 1550 cm^-1

;

¹H NMR (500 MHz, CDCl₃) δ 8.18 (d, J ) 9.5 Hz, 1 H), 7.87-

7.89 (m, 2 H), 7.39 (d, J ) 4.3 Hz, 1 H), 7.20 (app t, J ) 10.1

Hz, 1 H), 7.13 (app t, J ) 9.6 Hz, 1 H), and 2.45 (s, 3 H); ¹³C

NMR (125 MHz, CDCl₃) δ 169.3, 140.4, 136.6 (2 C), 135.0,

132.2, 129.2, 125.7, 123.0, 121.9, 117.2, and 21.3; UV-vis

(hexane) λ_max(ꢀ) 611 (380), 352 (7075), 316 (15 710), 296

(53 475), 279 (47 230), 261 (61 175), 231 (15 810), and 192

1-Acetoxy-5,6-dichloroazulene (75). Application of the

general procedure gave 0.054 g (19%) of 75 as a green solid,

mp 73.0-76.0 °C. IR (CCl₄) 3020, 2920, 1770, 1570, and 1505

1

cm^-1; H NMR (300 MHz, CDCl₃) δ 8.37 (s, 1H), 7.89 (d, J )

(75) Rhodium(II) pivalate was prepared by reaction of rhodium(III)

chloride with 5.0 equiv of trimethylacetic acid and 2.0 equiv of

trimethylacetic acid sodium salt in EtOH (reflux, 3 h) according to the

procedure of: Legzdins, P.; Mitchell, R. W.; Rempel, G. L.; Ruddick,

J. D.; Wilkinson, G. J. Chem. Soc. 1970, 3322.

11.0 Hz, 1H), 7.82 (d, J ) 4.4 Hz, 1H), 7.27 (d, J ) 11.0 Hz,

1H), 7.22 (d, J ) 4.4 Hz, 1H), and 2.41 (s, 3H); ¹³C NMR (75

MHz, CDCl₃) δ 168.6, 142.7, 140.0, 137.3, 132.5, 130.3, 128.1,

126.6, 125.5, 121.8, 116.4, and 21.1; UV-vis max (hexane) λ_max

8662 J. Org. Chem., Vol. 69, No. 25, 2004

Synthesis of Substituted Azulenes and Oligoazulenes

(ꢀ) 797 (110), 626 (320), 352 (7780), and 287 (81 050) nm. Anal.

Calcd for C₁₂H₈Cl₂O₂: C, 56.50; H, 3.16. Found: C, 56.24; H,

2.98.

reflux condenser fitted with an argon inlet adapter, and the

suspension was stirred at 65 °C for 16 h. The resulting dark

green suspension was allowed to cool to room temperature,

diluted with 10 mL of diethyl ether, and washed with 20 mL

of H₂O. The aqueous layer was back-extracted with two 10-

mL portions of ether, and the combined organic layers were

washed with 10 mL of H₂O and 10 mL of brine, dried over

MgSO₄, filtered, and concentrated to yield 0.221 g of a dark

green oil. Column chromatography on 22 g of silica gel (elution

with 15% EtOAc-hexane) afforded 0.129 g (96%) of 82 as a

green solid: mp: 56-57 °C; IR (CCl₄) 2940, 1760, 1720, and

1540 cm^-1; ¹H NMR (500 MHz, CDCl₃) δ 8.57 (d, J ) 15.9 Hz,

1 H), 8.26 (d, J ) 9.8 Hz, 1 H), 7.86 (d, J ) 4.6 Hz, 1 H), 7.57

(app t, J ) 10.1 Hz, 1 H), 7.53 (d, J ) 4.6 Hz, 1 H), 7.35 (t, J

) 10.7 Hz, 1 H), 7.12 (t, J ) 9.6 Hz, 1 H), 6.69 (d, J ) 15.9 Hz,

1 H), 3.89 (s, 3 H), and 2.45 (s, 3 H); ¹³C NMR (125 MHz,

CDCl₃) δ 169.5, 167.1, 144.6, 142.0, 139.5, 137.8, 133.2, 132.8,

128.2, 127.6, 124.3, 122.4, 121.6, 111.6, 52.4, and 21.4; UV-

vis (hexane) λ_max(ꢀ) 649 (378), 352 (4080), 292 (63 520), 257

(58 035), and 192 (6505) nm. Anal. Calcd for C₁₆H₁₄O₄: C,

71.10; H, 5.22. Found: C, 70.97; H, 5.05.

1-Acetoxy-6-nitroazulene (76). Application of the general

procedure gave 0.065 g (21%) of 76 as a brown solid, mp 97.0-

1

97.5 °C. IR (CCl₄) 2920, 1770, and 1535 cm^-1; H NMR (300

MHz, CDCl₃) δ 8.29-8.33 (m, 2 H), 8.00-8.14 (m, 3 H), 7.44

(d, J ) 4.3 Hz, 1 H), 2.46 (s, 3 H); ¹³C NMR (75 MHz, CDCl₃)

δ 168.5, 154.0, 140.2, 136.8, 134.7, 132.8, 129.8, 126.2, 117.1,

116.3, 114.6, 21.0; UV-vis (CH₃CN) λ_max(ꢀ) 686 (310), 352

(565), 291 (51 500), 246 (19 850), 221 (16 700), 205 (16 300),

198 (26 900), 193 (29 300) nm. Anal. Calcd for C₁₂H₉NO₄: C,

62.34; H, 3.92; N, 6.06. Found: C, 62.39; H, 3.83; N, 5.74.

1-Acetoxy-6-cyanoazulene (77). Application of the general

procedure gave 0.111 g (39%) of 77 as a green solid, mp 112.0-

113.0 °C. IR (CCl₄) 3010, 2930, 2190, 1765, and 1575 cm^-1; ¹H

NMR (300 MHz, CDCl₃) δ 8.16 (d, J ) 10.0 Hz, 1 H), 8.14 (d,

J ) 9.5 Hz, 1 H), 8.01 (d, J ) 4.3 Hz, 1 H), 7.38 (d, J ) 4.3 Hz,

1 H), 7.26 (d, J ) 9.5 Hz, 1 H), 7.18 (d, J ) 10.0 Hz, 1 H), 2.44

(s, 3 H); ¹³C NMR (75 MHz, CDCl₃) δ 168.6, 140.0, 136.7, 136.1,

132.2, 130.9, 126.4, 125.4, 123.3, 120.8, 120.6, 116.9, 20.9; UV-

vis (methanol) λ_max(ꢀ) 662 (342), 283 (86 600) nm. Anal. Calcd

for C₁₃H₉NO₂: C, 73.92; H, 4.29; N, 6.63. Found: C, 73.65; H,

4.04; N, 6.45.

1-Acetoxy-2-methylazulene (78). Application of the gen-

eral procedure gave 0.149 g (58%) of 78 as blue needles, mp

58.5-59.5 °C. IR (CCl₄) 3020, 2970, 2870, 1765, 1580, 1540,

and 1500 cm^-1; ¹H NMR (300 MHz, CDCl₃) δ 8.10 (d, J ) 9.4

Hz, 1 H), 7.97 (d, J ) 9.7 Hz, 1 H), 7.48 (app t, J ) 9.9 Hz, 1

H), 7.03-7.10 (m, 3 H), 2.46 (s, 3 H), 2.43 (s, 3 H); ¹³C NMR

(75 MHz, CDCl₃) δ 169.9, 140.2, 136.7, 136.5, 135.9, 135.6,

130.1, 127.3, 123.0, 122.2, 114.5, 20.6, 13.4; UV-vis (CH₃CN)

λ_max(ꢀ) 684 (120), 641 (270), 621 (270), 585 (310), 573 (280),

550 (250), 346 (4270), 283 (49 840), 279 (47 465), 274 (45 570)

nm. Anal. Calcd for C₁₃H₁₂O₂: C, 77.98; H, 6.04. Found: C,

77.73; H, 5.66.

1-Trimethylacetoxy-4-iodoazulene (79). A 250-mL, three-

necked, round-bottomed flask equipped with a rubber septum,

60-mL pressure-equalizing addition funnel, and an argon inlet

adapter was charged with rhodium pivalate⁷⁵(0.017 g, 0.030

mmol, 0.01 equiv) and 45 mL of dichloromethane. A solution

of diazo ketone 49 (1.08 g, 2.80 mmol) in 30 mL of dichlo-

romethane was added dropwise via the addition funnel over 1

h to the rapidly stirred green solution of rhodium catalyst, and

the resulting dark green mixture was stirred for 5 min.

Trimethylacetyl chloride (0.37 g, 0.38 mL, 3.08 mmol) was then

rapidly added via syringe, and then 4-DMAP (1.03 g, 8.40

mmol) was added in one portion. The resulting deep green

solution was stirred at room temperature for 5 min and then

poured into 60 mL of diethyl ether and 30 mL of 1 M aq HCl

solution. The organic phase was separated and washed with

two 30-mL portions of 1 M aq HCl solution and 30 mL of brine,

dried over MgSO₄, filtered, and concentrated to yield 1.06 g of

a green oil. Column chromatography on 30 g and then 10 g of

silica gel (gradient elution with 0-2% EtOAc-hexane) afforded

0.756 g (76%) of 79 as a green solid: mp 39-40 °C; IR (CH₂-

Cl₂) 2973, 1751, and 1552 cm^-1; UV (CH₂Cl₂) λ_max353 nm; ¹H

NMR (500 MHz, CDCl₃) δ 8.14 (d, J ) 9.5 Hz, 1 H), 7.85-7.88

(m, 2 H), 7.39 (d, J ) 4.3 Hz, 1 H), 7.19 (app t, J ) 9.8 Hz, 1

H), 7.11 (app t, J ) 9.5 Hz, 1 H), and 1.48 (s, 9 H); ¹³C NMR

(125 MHz, CDCl₃) δ 176.7, 140.7, 136.6, 136.5, 134.8, 132.0,

129.2, 125.8, 123.0, 121.8, 117.1, 39.7, and 27.6; HRMS-ESI

(m/z) [M + H] calcd for C₁₅H₁₅IO₂355.0189, found 355.0179.

1-Acetoxy-4-(2-thienyl)azulene (83). A 50-mL, three-

necked, round-bottomed flask equipped with a rubber septum,

glass stopper, and an argon inlet adapter was charged with

2-thienyllithium (1.0 M in THF, 0.96 mL, 0.960 mmol) and 5

mL of THF. ZnCl₂(0.131 g, 0.961 mmol) was then added, and

the resulting mixture was stirred for 30 min. To the greenish-

gray mixture was then added tris(dibenzylideneacetone)-

dipalladium (0.023 g, 0.026 mmol) and triphenylarsine (0.031

g, 0.103 mmol). A 10-mL, one-necked, pear-shaped flask was

charged with 1-acetoxy-4-iodoazulene (69) (0.200 g, 0.641

mmol) and 4 mL of THF. The azulene solution was transferred

dropwise via cannula into the reaction mixture over 1 min and

the flask was rinsed with two 1.5-mL portions of THF. After

30 min, the reaction mixture was poured into 30 mL of

saturated ammonium chloride solution and 50 mL of diethyl

ether. The organic phase was separated and washed with 30

mL of saturated ammonium chloride solution and 30 mL of

brine, dried over MgSO₄, filtered, and concentrated to provide

0.223 g of a greenish brown oil. Column chromatography on

20 g of silica gel (elution with 5% ethyl acetate-hexanes,

compound applied adsorbed onto 0.500 g silica gel) afforded

0.140 g (81%) of 1-acetoxy-4-(2-thienyl)azulene (83) as an olive

green solid. An analytical sample was prepared by recrystal-

lization from hexanes at -20 °C: mp 98.0-99.0 °C; IR (CCl₄)

1

3020, 2910, 1760, 1585, and 1535 cm^-1; H NMR (300 MHz,

CDCl₃) δ 8.25 (d, J ) 9.4 Hz, 1H), 7.76 (d, J ) 4.6 Hz, 1H),

7.48-7.53 (m, 4 H), 7.28 (d, J ) 10.6 Hz, 1H), 7.18 (dd, J )

3.8, 4.2 Hz, 1H), 7.04 (app t, J ) 9.4, 9.8 Hz, 1H), and 2.44 (s,

3H); ¹³C NMR (75 MHz, CDCl₃) δ 169.3, 160.5, 144.0, 143.8,

138.9, 137.1, 132.6, 132.2, 128.4, 127.3, 127.1, 126.8, 126.2,

120.9, 114.4, and 21.1; UV-vis (hexane) λ_max(ꢀ) 625 (438), 599

(377), 352 (4725), 280 (28 350), and 239 (3,30) nm. Anal. Calcd

for C₁₆H₁₂O₂S: C, 71.62; H, 4.51. Found: C, 71.45; H, 4.59.

General Procedure for the Preparation of 1-(Trifluo-

romethanesulfonyloxy)azulene (84). A 100-mL, three-

necked, round-bottomed flask equipped with a rubber septum,

60-mL pressure-equalizing addition funnel, and an argon inlet

adapter was charged with rhodium pivalate⁷⁵(0.006 g, 0.010

mmol) and 18 mL of dichloromethane. The addition funnel was

charged with diazo ketone 19 (0.253 g, 1.00 mmol) and 16 mL

of dichloromethane, and the bright yellow solution of the diazo

ketone was added dropwise over 45 min to the rapidly stirred

green solution of catalyst. After 5 min, Tf₂NPh (0.357 g, 1.00

mmol) was added in one portion, and then a solution of

4-DMAP (0.367 g, 3.00 mmol) in 2 mL of dichloromethane was

immediately added via cannula. The resulting deep blue

solution was stirred for 10 min and then treated with 1 mL of

piperidine. After being stirred for an additional 15 min, the

reaction mixture was poured into a separatory funnel contain-

ing 30 mL of diethyl ether and 30 mL of 1 M HCl solution.

The organic phase was separated and washed with two 30-

Methyl 3-[4-(1-Acetoxyazulenyl)]acrylate (82). A 10-mL,

two-necked, round-bottomed flask equipped with two rubber

septa and an argon inlet needle was charged with azulenyl

iodide 69 (0.172 g, 0.55 mmol), Pd(OAc)₂(0.003 g, 0.015 mmol,

0.03 equiv), Et₄NCl (0.083 g, 0.50 mmol), 2.0 mL of dimethyl-

acetamide, N,N-dicyclohexylmethylamine (0.147 g, 0.160 mL,

0.75 mmol), and methyl acrylate (0.043 g, 0.045 mL, 0.50

mmol) in that order. One of the rubber septa was replaced with

a glass stopper and the other septum was replaced with a

J. Org. Chem, Vol. 69, No. 25, 2004 8663

Crombie et al.

mL portions of 1 M HCl and 30 mL of brine, dried over MgSO₄,

and filtered to afford a blue solution of the triflate that was

used immediately in the next reaction without further puri-

fication. A sample of the product of another reaction was

purified by column chromatography on silica gel (elution with

5% ethyl acetate-hexanes) to afford the azulenyl triflate 84

as an unstable purple-blue oil: IR (CCl₄) 3000, 1580, and 1550

NaOH solution and 30 mL of brine, dried over MgSO₄, filtered,

and concentrated to yield 0.345 g of a turquoise oil. Purification

by column chromatography on silica gel (elution with pentane)

afforded 0.124 g (60% overall from diazo ketone 19) of

1-phenylazulene as a dark blue solid: mp 51-53 °C (lit.⁸⁰mp

58 °C); IR (thin film) 3050, 3000, 2960, 1600, and 1570 cm^-1

;

¹H NMR (500 MHz, CDCl₃) δ 8.62 (d, J ) 9.8 Hz, 1 H), 8.40

(dd, J ) 9.8, 0.6 Hz, 1 H), 8.09 (d, J ) 4.0 Hz, 1 H), 7.70-7.67

(m, 2 H), 7.63 (t, J ) 9.8 Hz, 2 H), 7.55 (appar t, J ) 7.8 Hz,

1 H), 7.50 (d, J ) 3.7 Hz, 1 H), 7.41 (m, 1 H), 7.19 (t, J ) 9.9

Hz, 2 H); ¹³C NMR (125 MHz, CDCl₃) δ 141.6, 138.2, 137.5,

137.2, 137.1, 135.6, 135.2, 131.3, 129.7, 128.6, 126.2, 123.3,

123.0, 117.4. Anal. Calcd for C₁₆H₁₂: C, 94.08; H, 5.92.

Found: C, 94.05; H, 6.28.

1

cm^-1; H NMR (300 MHz, CDCl₃) δ 8.35 (d, J ) 9.7 Hz, 1 H),

8.34 (d, J ) 9.4 Hz, 1 H), 7.68-7.74 (m, 2 H), 7.22-7.31 (m, 3

H); ¹³C NMR (75 MHz, CDCl₃) δ 139.7, 139.6, 136.1, 134.5,

132.5, 127.2, 126.7, 124.4, 124.1, 116.8, 113.7.

1-Ethylazulene (87). A solution of azulenyl triflate 84 (ca.

1.00 mmol) in diethyl ether-dichloromethane prepared ac-

cording to the general procedure was concentrated with use

of a rotary evaporator to a volume of ca. 5 mL. The flask was

then equipped with a stirbar and argon inlet adapter and the

solution was concentrated further at 0.1 mmHg with vigorous

stirring to a volume of 0.2-0.5 mL.⁷⁶The argon inlet adapter

was immediately removed and replaced with a rubber septum

and argon inlet needle, and 1.0 mL of THF was added to

produce a dark purple solution. Palladium acetate (0.011 g,

0.05 mmol), o-(dicyclohexylphosphino)biphenyl (0.026 g, 0.075

mmol), and Cs₂CO₃(0.977 g, 3.0 mmol) were then added,

followed by a solution of B-ethyl-9-BBN⁷⁷(prepared by stirring

10 mL of a 0.5 M solution of 9-BBN in THF under a positive

pressure of ethylene for 2 h). The resulting mixture was stirred

at room temperature for 2 h and the resulting black suspension

was then diluted with 30 mL of diethyl ether and washed with

30 mL of 2 M NaOH solution and 30 mL of brine, dried over

MgSO₄, filtered, and concentrated to yield 1.17 g of a turquoise

oil. Purification by column chromatography on silica gel

(elution with pentane) afforded 0.088 g (56% overall from diazo

ketone 19) of 1-ethylazulene⁷⁸as a dark blue oil: IR (thin film)

1-Ethyl-5-isopropylazulene (89). A solution of azulenyl

triflate 85 (ca. 1.05 mmol) in diethyl ether prepared according

to the general procedure (except that Et₂O was employed as

solvent in place of dichloromethane) was concentrated with

use of a rotary evaporator to a volume of ca. 5 mL. The flask

was then equipped with a stir bar and argon inlet adapter and

the remaining solvent was removed at 0.1 mmHg with vigor-

ous stirring.⁷⁶The argon inlet adapter was immediately

removed and replaced with a rubber septum and argon inlet

needle, and 1.0 mL of THF was added to produce a dark blue

solution. Pd(OAc)₂(0.012 g, 0.053 mmol), o-(dicyclohexylphos-

phino)biphenyl (0.028 g, 0.079 mmol), and Cs₂CO₃(1.03 g, 3.15

mmol) were then added, followed by a solution of B-ethyl-9-

BBN⁷⁷(prepared by stirring 10 mL of a 0.5 M solution of

9-BBN in THF under a positive pressure of ethylene for 2 h).

The resulting mixture was stirred at room temperature for 5

h. The black suspension was diluted with 15 mL of diethyl

ether and washed with 15 mL of 2 M NaOH solution and 15

mL of brine, dried over MgSO₄, filtered, and concentrated to

yield 1.18 g of a green oil. Purification by column chromatog-

raphy on 36 g and then on 20 g of silica gel (elution each time

with pentane) afforded 0.075 g (36% overall from diazo ketone

50) of 1-ethyl-5-isopropylazulene as a dark blue oil: IR (thin

1

3010, 2960, 2920, 2860, 1570, 1530, and 1500 cm^-1; H NMR

(500 MHz, CDCl₃) δ 8.28 (d, J ) 9.2 Hz, 1 H), 8.25 (d, J ) 9.5

Hz, 1 H), 7.82 (d, J ) 3.7 Hz, 1 H), 7.53 (t, J ) 9.8 Hz, 1 H),

7.35 (d, J ) 3.7 Hz, 1 H), 7.08 (t, J ) 9.8 Hz, 1 H), 7.06 (t, J

) 9.6 Hz, 1 H), 3.12 (q, J ) 7.6 Hz, 2 H), 1.40 (t, J ) 7.6 Hz,

3 H); ¹³C NMR (125 MHz, CDCl₃) δ 140.4, 137.3, 136.3, 136.2,

135.3, 133.2, 133.0, 121.9, 121.2, 116.6, 20.4, 15.7. Anal. Calcd

for C₁₂H₁₂: C, 92.24; H, 7.76. Found: C, 91.96; H, 8.06.

1

film): 2950, 2920, 2860, 1570, and 1505 cm^-1; H NMR (500

MHz, CDCl₃) δ 8.21 (d, J ) 1.9 Hz, 1 H), 8.17 (d, J ) 9.6 Hz,

1 H), 7.77 (d, J ) 3.8 Hz, 1 H), 7.43-7.48 (m, 1 H), 7.24 (d, J

) 3.8 Hz, 1 H), 7.02 (t, J ) 10.0 Hz, 1 H), 3.02-3.10 (m, 3 H),

1.33-1.39 (m, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 141.8, 140.5,

136.2, 136.1, 136.0, 134.7, 131.9, 131.8, 120.8, 115.7, 38.3, 24.5,

20.4, 15.8. Anal. Calcd for C₁₅H₁₈: C, 90.83; H, 9.17. Found:

C, 90.80; H, 9.19.

1-Phenylazulene (88). A solution of azulenyl triflate 84

(ca. 1.00 mmol) in diethyl ether-dichloromethane prepared

according to the general procedure was concentrated with use

of a rotary evaporator to a volume of ca. 5 mL. The flask was

then equipped with a stirbar and argon inlet adapter and the

solution was concentrated further at 0.1 mmHg with vigorous

stirring to a volume of 0.2-0.5 mL.⁷⁶The argon inlet adapter

was immediately removed and replaced with a rubber septum

and argon inlet needle, and 1.0 mL of THF was added to

produce a dark purple solution. Palladium acetate (0.011 g,

0.050 mmol), o-(dicyclohexylphosphino)biphenyl (0.035 g, 0.100

mmol), Cs₂CO₃(0.977 g, 3.0 mmol), and B-phenyl-9-BBN⁷⁹

(0.277 g, 1.4 mmol) were then added, and the septum was

replaced with a reflux condenser fitted with an argon inlet

adapter. The dark purple suspension was heated at reflux

(preheated oil bath) for 15 min and then allowed to cool to

room temperature. The resulting black suspension was diluted

with 30 mL of diethyl ether and washed with 30 mL of 2 M

1,6-Diethylazulene (90). A solution of azulenyl triflate 86

(ca. 1.00 mmol) in diethyl ether-dichloromethane prepared

according to the general procedure was concentrated to a

volume of ca. 5 mL in a 25-mL, one-necked, round-bottomed

flask. The flask was then equipped with a rubber septum and

argon inlet needle and the remaining solvent was removed

with vigorous stirring at 0.02 mmHg.⁷⁶THF (1.0 mL) was

immediately added to produce a dark purple solution. Pd(OAc)₂

(0.011 g, 0.05 mmol, 0.05 equiv), o-(dicyclohexylphosphino)-

biphenyl (0.026 g, 0.075 mmol, 0.075 equiv), Cs₂CO₃(0.977 g,

3.0 mmol), and 2.4 mL of Et₃B solution (1.0 M in THF, 2.4

mmol) were added, and the dark purple suspension was stirred

at room temperature for 2 h. The resulting dark green

suspension was diluted with 20 mL of diethyl ether and

extracted with two 10-mL portions of aq 2 M NaOH solution

and 10 mL of brine, dried over MgSO₄, filtered, and concen-

trated to yield 0.265 g of a dark green oil. Column chroma-

tography on 26 g of silica gel (elution with pentane) afforded

0.091 g (49% overall from diazo ketone 54) of 90 as a dark

blue oil: IR (CH₂Cl₂) 2964, 2930, 2869, 1579, 1401, and 832

cm^-1; UV (CH₂Cl₂) λ_max351 nm; ¹H NMR (500 MHz, CDCl₃) δ

8.20 (d, J ) 10.1 Hz, 1 H), 8.17 (d, J ) 10.1 Hz, 1 H), 7.71 (d,

J ) 3.7 Hz, 1 H), 7.27 (d, J ) 2.8 Hz, 1 H), 7.01 (d, J ) 9.8 Hz,

1 H), 6.98 (d, J ) 9.5 Hz, 1 H), 3.09 (q, J ) 7.5 Hz, 2 H), 2.81

(76) Though stable in solution, the azulenyl triflate is unstable in

concentrated form where it has a tendency to decompose to form an

intractable black solid. Concentration to dryness on the rotary

evaporator usually led to decomposition; this could be avoided by

removing the last several milliliters of solvent under high vacuum and

then venting the flask to argon.

(77) (a) Knights, E. F.; Brown, H. C. J. Am. Chem. Soc. 1968, 90,

5283. For alternative methods for the preparation of this reagent,

see: (b) Kramer, G. W.; Brown, H. C. J. Organomet. Chem. 1974, 73,

1. (c) Brown, C. A. J. Org. Chem. 1975, 40, 3154.

(78) Anderson, A. G.; Breazeale, R. D. J. Org. Chem. 1969, 34, 2375.

(79) Prepared by reaction of 9-BBN with 1 equiv of phenyllithium

and 1 equiv of methyl iodide according to the procedure of Brown (ref

77b).

(80) Plattner, P. A.; Furst, A.; Gordon, M.; Zimmermann, K. Helv.

Chim. Acta 1950, 33, 1910. See also: Oda, M.; Kajioka, T.; Haramoto,

K.; Miyatake, R.; Kuroda, S. Synthesis 1999, 8, 1349.

8664 J. Org. Chem., Vol. 69, No. 25, 2004

Synthesis of Substituted Azulenes and Oligoazulenes

(q, J ) 7.5 Hz, 2 H), 1.39 (t, J ) 7.5 Hz, 3 H), and 1.34 (t, J )

7.6 Hz, 3 H); ¹³C NMR (125 MHz, CDCl₃) δ 155.3, 139.3, 136.1,

135.0, 134.2, 133.2, 133.1, 122.7, 122.1, 116.7, 35.6, 20.6, 17.1,

and 16.0; HRMS-ESI (m/z) [M⁺] calcd for C₁₄H₁₆184.1247,

found 184.1244.

the suspension was stirred at 65 °C for 15 min. The resulting

dark blue-green suspension was cooled to room temperature,

filtered through 1 g of silica gel in a glass pipet with the aid

of diethyl ether, and concentrated to yield 0.163 g of a dark

blue-green oil. Column chromatography on 16 g of silica gel

(gradient elution with 0-10% EtOAc-hexane) afforded 0.054

g (73%) of 94 as a dark blue-green semisolid.

2-(1-Azulenyl)prop-2-en-1-ol (96). Reaction of azulenyl

boronate 91 (0.110 g, 0.29 mmol) with vinyl iodide 95⁵⁸(0.053

g, 0.29 mmol) in the presence of Pd(OAc)₂(0.003 g, 0.01 mmol,

0.050 equiv), o-(dicyclohexylphosphino)biphenyl (0.020 g, 0.058

mmol, 0.20 equiv), and barium hydroxide (0.149 g, 0.870 mmol)

in 1.8 mL of 1,4-dioxane and 1.0 mL of H₂O according to

general procedure A provided 1.67 g of a blue green oil. Column

chromatography on 15 g of silica gel (gradient elution with

10-20% EtOAc-hexane) afforded 0.035 g (66%) of 96 as a

green oil.

2-(1-Azulenyl)-4,4,5,5-tetramethyl-[1,3,2]-dioxaboro-

lane (91). A solution of azulenyl triflate 84 (ca. 3.00 mmol) in

diethyl ether-dichloromethane prepared according to the

general procedure was concentrated to a volume of ca. 5 mL

in a 50-mL, one-necked, round-bottomed flask. The flask was

then equipped with a rubber septum and argon inlet needle

and the remaining solvent was removed with vigorous stirring

at 0.02 mmHg.⁷⁶THF (8.4 mL) was immediately added to

produce a dark purple solution. Pd(OAc)₂(0.034 g, 0.15 mmol,

0.05 equiv), o-(dicyclohexylphosphino)biphenyl (0.21 g, 0.60

mmol, 0.20 equiv), triethylamine (1.69 mL, 1.22 g, 12.0 mmol),

and 6.0 mL of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane solution

(1.0 M in THF, 6.0 mmol) were added, and the dark purple

suspension was stirred at room temperature for 16 h. The

resulting deep purple suspension was diluted with 15 mL of

diethyl ether and extracted with 10 mL of H₂O and 10 mL of

brine, dried over MgSO₄, filtered, and concentrated to yield

1.93 g of a deep purple oil. Column chromatography on 50 g

of silica gel (gradient elution 0-5% EtOAc-hexane) afforded

0.477 g of a purple oil that was repurified on 15 g of silica gel

(gradient elution with 0-3% EtOAc-hexane) to afford 0.368

g (48% overall from diazo ketone 19) of 91 as a dark purple

solid: mp 56-58 °C; IR (CH₂Cl₂) 2977, 2930, 1579, and 1500

Alternatively, reaction of azulenyl boronate 91 (0.277 g, 1.09

mmol) with vinyl iodide 95 (0.302 g, 1.64 mmol) in the presence

of Pd(OAc)₂(0.012 g, 0.055 mmol, 0.050 equiv), o-(dicyclohexyl-

phosphino)biphenyl (0.076 g, 0.22 mmol, 0.20 equiv), and

barium hydroxide (0.560 g, 3.27 mmol) in 6.0 mL of 1,4-dioxane

and 3.6 mL of H₂O according to general procedure B provided

2.09 g of a dark green oil. Column chromatography on 30 g of

silica gel (gradient elution with 10-20% EtOAc-hexane)

afforded 0.089 g (44%) of 96 as a green oil: IR (CH₂Cl₂) 3356,

2920, 1570, and 1559 cm^-1; UV (CH₂Cl₂) λ_max280, 238, and

1

345 nm; H NMR (500 MHz, CDCl₃) δ 8.64 (d, J ) 9.8 Hz, 1

1

cm^-1; UV (CH₂Cl₂) λ_max345 and 362 nm; H NMR (500 MHz,

H), 8.33 (d, J ) 9.5 Hz, 1 H), 7.91 (d, J ) 4.0, 1 H), 7.61 (app

t, J ) 9.8 Hz, 1 H), 7.38 (d, J ) 4.0, 1 H), 7.18 (app q, J ) 10.0

Hz, 2 H), 5.64 (app q, J ) 1.6 Hz, 1 H), 5.37 (td, J ) 0.9 and

1.8 Hz, 1 H), 4.61 (s, 2 H), and 1.72 (s, 1 H); ¹³C NMR (125

MHz, CDCl₃) δ 143.8, 141.7, 138.5, 137.3, 136.9, 135.8, 135.3,

128.4, 123.6, 123.4, 117.4, 113.6, and 67.0; HRMS-ESI (m/z)

[M + H] calcd for C₁₃H₁₂O 185.0961, found 185.0965.

CDCl₃) δ 9.18 (d, J ) 9.5 Hz, 1 H), 8.43 (d, J ) 9.5 Hz, 1 H),

8.35 (d, J ) 3.7 Hz, 1 H), 7.68 (app t, J ) 9.8 Hz, 1 H), 7.38-

7.42 (m, 2 H), 7.31 (app t, J ) 9.8 Hz, 1 H), and 1.42 (s, 12 H);

¹³C NMR (125 MHz, CDCl₃) δ 147.3, 145.8, 144.8, 138.5, 137.6,

136.9, 136.7, 125.4, 124.9, 119.3, 83.1, and 25.2; HRMS-ESI

(m/z) [M + H] calcd for C₁₆H₁₉BO₂255.1551, found 255.1555.

3-(1-Azulenyl)cyclohex-2-enone (98). Reaction of azu-

lenyl boronate 91 (0.057 g, 0.22 mmol) with vinyl iodide 97⁵⁹

(0.33 g, 0.15 mmol) in the presence of Pd(OAc)₂(0.002 g, 0.008

mmol, 0.050 equiv), o-(dicyclohexylphosphino)biphenyl (0.011

g, 0.030 mmol, 0.20 equiv), and barium hydroxide (0.077 g,

0.45 mmol) in 1.0 mL of 1,4-dioxane and 0.5 mL of H₂O

according to general procedure A provided 0.093 g of a dark

green oil. Column chromatography on 10 g of silica gel

(gradient elution with 20-25% EtOAc-hexane) afforded 0.027

g (82%) of 98 as a dark green solid.

General Procedure A for Suzuki Coupling Reactions

of Azulenyl Boronate 91: 4-(1-Azulenyl)acetophenone

(94). A 25-mL, one-necked, pear-shaped flask equipped with

a rubber septum and argon inlet needle was charged with

azulenyl boronate 91 (0.168 g, 0.66 mmol), p-iodoacetophenone

(0.108 g, 0.44 mmol), Pd(OAc)₂(0.005 g, 0.02 mmol, 0.05 equiv),

o-(dicyclohexylphosphino)biphenyl (0.031 g, 0.088 mmol, 0.20

equiv), barium hydroxide (0.226 g, 1.32 mmol), 2.75 mL of 1,4-

dioxane, and 1.65 mL of H₂O. The rubber septum was replaced

with a reflux condenser fitted with an argon inlet adapter and

the suspension was stirred at 65 °C for 15 min. The resulting

dark blue-green suspension was allowed to cool to room

temperature, filtered through 1 g of silica gel in a glass pipet

with the aid of diethyl ether, and concentrated to yield 0.357

g of a dark blue-green oil. Column chromatography on 36 g

and then 11 g of silica gel (gradient elution with 5-10%

MTBE-pentane) afforded 0.106 g (98%) of 94 as a dark blue-

Alternatively, reaction of azulenyl boronate 91 (0.229 g,

0.900 mmol) with vinyl iodide 97 (0.306 g, 1.35 mmol) in the

presence of Pd(OAc)₂(0.010 g, 0.045 mmol, 0.050 equiv),

o-(dicyclohexylphosphino)biphenyl (0.063 g, 0.18 mmol, 0.20

equiv), and barium hydroxide (0.463 g, 2.70 mmol) in 5.0 mL

of 1,4-dioxane and 3.0 mL of H₂O according to general

procedure B provided 0.578 g of a dark green oil. Column

chromatography on 30 g of silica gel (elution with 20% EtOAc-

hexane) afforded 0.073 g (37%) of 98 as a dark green solid:

mp 62-63 °C; IR (CH₂Cl₂) 2943, 1646, and 1575 cm^-1; UV

(CH₂Cl₂) λ_max(ꢀ) 249 (33 933), 280 (20 898), 316 (22 795), 328

green semisolid: IR (CH₂Cl₂) 3028, 1675, 1600, and 1573 cm^-1

;

1

UV (CH₂Cl₂) λ_max306, 328, and 383 nm; H NMR (500 MHz,

CDCl₃) δ 8.60 (d, J ) 10.1 Hz, 1 H), 8.40 (d, J ) 9.2 Hz, 1 H),

8.10-8.11 (m, 2 H), 8.07 (d, J ) 4.0 Hz, 1 H), 7.73-7.75 (m, 2

H), 7.66 (app t, J ) 9.8 Hz, 1 H), 7.48 (d, J ) 4.0 Hz, 1 H),

7.24 (app t, J ) 9.8 Hz, 2 H), and 2.68 (s, 3 H); ¹³C NMR (125

MHz, CDCl₃) δ 198.1, 142.7, 142.6, 138.8, 137.9, 137.4, 135.8,

135.7, 134.9, 130.0, 129.7, 129.0, 124.3, 124.1, 118.2, and 26.9;

HRMS-ESI (m/z) [M + H] calcd for C₁₈H₁₄O 247.1117, found

247.1111.

1

(21 890), and 392 (19 824) nm; H NMR (500 MHz, CDCl₃) δ

8.73 (d, J ) 9.9 Hz, 1 H), 8.38 (d, J ) 9.6 Hz, 1 H), 8.03 (d, J

) 4.1 Hz, 1 H), 7.70 (t, J ) 9.8 Hz, 1 H), 7.41 (d, J ) 4.1 Hz,

1 H), 7.27-7.33 (m, 2 H), 6.47 (s, 1 H), 2.97 (t, J ) 5.8 Hz, 2

H), 2.58 (t, J ) 6.71 Hz, 2 H), and 2.22-2.27 (m, 2 H); ¹³C

NMR (125 MHz, CDCl₃) δ 199.9, 157.2, 143.9, 139.3, 138.1,

136.7, 136.45, 136.48, 128.6, 126.0, 125.6, 125.3, 118.6, 37.7,

31.2, and 23.3; HRMS-ESI (m/z) [M + H] calcd for C₁₆H₁₄O

223.1117, found 223.1116.

General Procedure B for Suzuki Coupling Reactions

of Azulenyl Boronate 91: 4-(1-Azulenyl)acetophenone

(94). A 10-mL, one-necked, pear-shaped flask equipped with

a rubber septum and argon inlet needle was charged with

azulenyl boronate 91 (0.076 g, 0.30 mmol), p-iodoacetophenone

(0.081 g, 0.33 mmol), Pd(OAc)₂(0.003 g, 0.02 mmol, 0.05 equiv),

o-(dicyclohexylphosphino)biphenyl (0.021 g, 0.060 mmol, 0.20

equiv), barium hydroxide (0.154 g, 0.900 mmol), 1.9 mL of 1,4-

dioxane, and 1.1 mL of H₂O. The rubber septum was replaced

with a reflux condenser fitted with an argon inlet adapter and

1′-Trimethylacetoxy-1,4′-biazulene (99). Reaction of azu-

lenyl boronate 91 (0.197 g, 0.775 mmol) with azulenyl iodide

79 (0.274 g, 0.775 mmol) in the presence of Pd(OAc)₂(0.009 g,

0.04 mmol, 0.05 equiv), o-(dicyclohexylphosphino)biphenyl

(0.054 g, 0.16 mmol, 0.20 equiv), and barium hydroxide (0.398

g, 2.33 mmol) in 4.3 mL of 1,4-dioxane and 2.6 mL of H₂O at

45 °C for 30 min according to the general procedure B provided

J. Org. Chem, Vol. 69, No. 25, 2004 8665

Crombie et al.

0.616 g of a dark green oil. Purification by preparative HPLC

on a Waters Prep Nova Pak HR column (6 µ silica, 19 mm ×

30 cm; gradient elution with 5-10% EtOAc-hexane) afforded

0.073 g (27%) of 99 as a green oil: IR (CH₂Cl₂) 2973, 1749,

and 1546 cm^-1; UV (CH₂Cl₂) λ_max(ꢀ) 240 (27 893), 278 (45 314),

and 424 (5768) nm; ¹H NMR (500 MHz, CDCl₃) δ 8.46 (d, J )

9.5 Hz, 1 H), 8.36 (d, J ) 9.8 Hz, 1 H), 8.30 (d, J ) 9.5 Hz, 1

H), 8.22 (d, J ) 4.0 Hz, 1 H), 7.72 (d, J ) 4.3 Hz, 1 H), 7.66

(app t, J ) 9.6 Hz, 1 H), 7.59 (app t, J ) 9.8 Hz, 1 H), 7.54 (d,

J ) 3.7 Hz, 1 H), 7.35 (d, J ) 10.4 Hz, 1 H), 7.27 (t, J ) 9.8

Hz, 1 H), 7.08-7.15 (m, 2 H), 7.00 (d, J ) 4.6 Hz, 1 H), and

1.52 (s, 9 H); ¹³C NMR (125 MHz, CDCl₃) δ 177.1, 147.6, 142.1,

138.93, 138.85, 138.6, 137.7, 136.90, 136.85, 136.0, 134.0,

132.5, 131.9, 127.8, 126.93, 126.86, 124.1, 123.9, 120.6, 117.6,

115.1, 39.6, and 27.7; HRMS-ESI (m/z) [M + H] calcd for

C₁₅H₂₂O₂355.1693, found 355.1685.

equiv), and 9 mL of toluene. The solution was degassed by 4

freeze-pump-thaw cycles (-196 °C, 0.02 mmHg), and the

tube was then sealed under argon with a threaded Teflon cap.

The reaction mixture was heated in an oil bath at 120 °C for

24 h. The resulting blue suspension was allowed to cool to room

temperature, filtered through 5 g of silica gel with the aid of

75 mL of diethyl ether, and concentrated to yield 0.635 g of a

blue oil. Column chromatography on 30 g of silica gel (gradient

elution with 0-5% EtOAc-hexane) afforded 0.339 g (88%) of

104 as a blue solid: mp 51-53 °C; IR (CH₂Cl₂) 2975, 1751,

and 1480 cm^-1; UV (CH₂Cl₂) λ_max(ꢀ) 246 (21 919), 285 (35 105),

and 347 (5057) nm; ¹H NMR (500 MHz, CDCl₃) δ 8.17 (d, J )

9.5 Hz, 1 H), 7.84 (d, J ) 4.3 Hz, 1 H), 7.49 (app t, J ) 9.8 Hz,

1 H), 7.31 (d, J ) 9.8 Hz, 1 H), 7.23 (d, J ) 4.1 Hz, 1 H), 7.05

(app t, J ) 9.5 Hz, 1 H), 1.48 (s, 9 H), and 0.50 (s, 9 H); ¹³C

NMR (125 MHz, CDCl₃) δ 177.0, 161.8, 141.1, 138.1, 136.9,

132.2, 130.0, 127.4, 125.4, 121.8, 116.2, 39.6, 27.7, and -7.2;

HRMS-ESI (m/z) [M + H] calcd for C₁₈H₂₄O₂Sn 393.0871, found

393.0859.

1,1′-Bis(trimethylacetoxy)-4,4′-biazulene (105). A 25-

mL, two-necked, round-bottomed flask equipped with a rubber

septum and an argon inlet adapter was charged with azulenyl

stannane 104 (0.175 g, 0.450 mmol), CuCl (0.111 g, 1.12 mmol),

and 5.0 mL of DMF. The resulting blue suspension was stirred

at room temperature for 3 h. The resulting turquoise suspen-

sion was diluted with 20 mL of diethyl ether and washed with

two 10-mL portions of H₂O and 10 mL of brine. The combined

aqueous layers were back-extracted with two 10-mL portions

of ether, and the combined organic layers were dried over

MgSO₄, filtered, and concentrated to yield 0.230 g of a

turquoise oil. Column chromatography on 12 g of silica gel

(gradient elution with 0-5% EtOAc-hexane) afforded 0.088

g (86%) of 105 as a turquoise solid: mp 200-201 °C; IR (CH₂-

Cl₂) 2974, 1751, and 1555 cm^-1; UV (CH₂Cl₂) λ_max(ꢀ) 247

(62 915), 278 (81 548), 349 (11 119), and 369 (7632) nm; ¹H

NMR (500 MHz, CDCl₃) δ 8.31 (d, J ) 9.6 Hz, 2 H), 7.67 (d, J

) 4.4 Hz, 2 H), 7.61 (app t, J ) 10.0 Hz, 2 H), 7.22 (d, J )

10.4 Hz, 2 H), 7.15 (app t, J ) 9.6 Hz, 2 H), 6.80 (d, J ) 4.3

Hz, 2 H), and 1.49 (s, 18 H); ¹³C NMR (125 MHz, CDCl₃) δ

176.9, 151.0, 139.0, 137.7, 133.0, 132.7, 128.0, 127.8, 125.2,

121.6, 114.5, 39.7, and 27.6; HRMS-ESI (m/z) [M⁺] calcd for

C₃₀H₃₀O₄454.2139, found 454.2157.

(Z)-2-Acetylamino-3-[1-trimethylacetoxyazulen-4-yl]-

acrylic Acid Methyl Ester (108) and (E)-2-Acetylamino-

3-[1-trimethylacetoxyazulen-4-yl]-acrylic Acid Methyl

Ester (109). A 25-mL, one-necked, round-bottomed flask

equipped with a rubber septum and an argon inlet needle was

charged sequentially with azulenyl iodide 79 (0.584 g, 1.65

mmol), Pd(OAc)₂(0.010 g, 0.045 mmol, 0.03 equiv), Et₄NCl

(0.249 g, 1.50 mmol), 6.5 mL of dimethylacetamide, N,N-

dicyclohexylmethylamine (0.440 g, 0.480 mL, 2.25 mmol), and

methyl-2-acetamidoacrylate⁸²(0.215 g, 1.50 mmol). The rubber

septum was replaced with a reflux condenser fitted with an

argon inlet adapter and the suspension was stirred at 65 °C

for 48 h. The resulting blue suspension was allowed to cool to

room temperature, diluted with 20 mL of diethyl ether, washed

with two 15-mL portions of H₂O and 15 mL of brine, dried

over MgSO₄, filtered, and concentrated to yield 0.979 g of a

blue oil. Column chromatography on 90 g of silica gel (elution

with 40-60% EtOAc-hexane) afforded 0.393 g (71%) of a 5:1

mixture of 108 and 109 as a blue solid:⁸³mp 59-61 °C; IR

(CH₂Cl₂) 2975, 1734, 1675, and 1506 cm^-1; UV (CH₂Cl₂) λ_max

244, 285, and 623 nm; ¹H NMR (500 MHz, CDCl₃) δ 8.69 (s, 1

H, minor isomer), 8.21 (d, J ) 9.2, 1 H, major isomer), 8.18 (d,

J ) 9.8 Hz, 1 H, minor isomer), 7.80 (d, J ) 4.3 Hz, 1 H, major

isomer), 7.72-7.77 (m, 3 H, both isomers), 7.55 (app t, J )

[1,1′,3′,1′′]-Terazulene (101). Reaction of azulenyl boronate

91 (0.259 g, 1.02 mmol) with 1,3-diiodoazulene⁸¹(0.194 g, 0.51

mmol) in the presence of Pd(OAc)₂(0.006 g, 0.026 mmol, 0.05

equiv), o-(dicyclohexylphosphino)biphenyl (0.035 g, 0.100 mmol,

0.20 equiv), and barium hydroxide (0.262 g, 1.53 mmol) in 2.8

mL of 1,4-dioxane and 1.7 mL of H₂O according to the general

procedure B provided 0.259 g of a green oil. Column chroma-

tography on 26 g of silica gel (gradient elution with 0-2%

EtOAc-hexane) afforded 0.165 g of a green solid that was

further purified on 8 g of silica gel (gradient elution with 0-5%

EtOAc-hexane) to afford 0.135 g (69%) of 101 as a metallic

green solid with spectral data consistent with that previously

reported for this compound:^40bmp 97-98 °C; IR (CH₂Cl₂) 1569,

1447, and 1393 cm^-1; UV (CH₂Cl₂) λ_max(ꢀ) 242 (186 900), 264

1

(240 372), 312 (190 778), and 400 (93 016) nm; H NMR (500

MHz, CDCl₃) δ 8.50 (d, J ) 9.5 Hz, 2 H), 8.41 (d, J ) 9.5 Hz,

4 H), 8.36 (s, 1 H), 8.22 (d, J ) 3.4 Hz, 2 H), 7.54-7.62 (m, 5

H), 7.18 (d, J ) 9.6 Hz, 2 H), 7.07 (app td, J ) 9.8, 20.8 Hz, 4

H); ¹³C NMR (125 MHz, CDCl₃) δ 141.7, 139.9, 139.2, 138.8,

138.5, 137.9, 137.3, 136.9, 136.8, 136.6, 126.6, 126.3, 123.15,

123.11, 117.9 (one resonance corresponds to two overlapping

carbons); HRMS-ESI (m/z) [M⁺] calcd for C₃₀H₂₀380.1560,

found 380.1558.

5,5′-Bis(1-trimethylacetoxyazulen-4-yl)-2,2′-bithio-

phene (103). A 10-mL, one-necked, round-bottomed flask

equipped with a rubber septum and argon inlet needle was

charged with azulenyl iodide 79 (0.143 g, 0.400 mmol), 5,5′-

bis(trimethylstannyl)-2,2′-bithiophene⁶²(0.099 g, 0.20 mmol),

(Ph₃P)₄Pd (0.023 g, 0.020 mmol, 0.10 equiv), and 3.6 mL of

toluene. The rubber septum was replaced with a reflux

condenser fitted with an argon inlet adapter and the suspen-

sion was heated at reflux for 24 h. The resulting dark green

suspension was allowed to cool to room temperature, filtered

through 5 g of silica gel with the aid of 100 mL of methylene

chloride, and concentrated to yield 0.192 g of a dark green oil.

Column chromatography on 20 g of silica gel (gradient elution

with 0-10% CH₂Cl₂-benzene) afforded 0.091 g (73%) of 103

as a dark green solid: mp 218-219 °C; IR (CH₂Cl₂) 2973, 1750,

and 1506 cm^-1; UV (CH₂Cl₂) λ_max(ꢀ) 244 (85 407), 286

(129 967), and 424 (53 225) nm; ¹H NMR (500 MHz, CDCl₃) δ

8.24 (d, J ) 9.4 Hz, 2 H), 7.82 (d, J ) 4.4 Hz, 2 H), 7.62 (d, J

) 4.4 Hz, 2 H), 7.58 (app t, J ) 10.1 Hz, 2 H), 7.50 (d, J ) 3.7

Hz, 2 H), 7.32-7.36 (m, 4 H), 7.06 (app t, J ) 9.6 Hz, 2 H),

and 1.50 (s, 18 H); ¹³C NMR (125 MHz, CDCl₃) δ 176.9, 143.6,

143.1, 139.6, 138.7, 137.4, 132.8, 132.0, 129.8, 127.7, 127.6,

125.9, 124.4, 121.1, 114.6, 39.7, and 27.7; HRMS-ESI (m/z)

[M⁺] calcd for C₃₈H₃₄O₄S₂618.1893, found 618.1894.

1-Trimethylacetoxy-4-trimethylstannylazulene (104).

A threaded Pyrex tube (ca. 20 mL capacity) equipped with a

rubber septum and argon inlet needle was charged with

azulenyl iodide 79 (0.350 g, 0.990 mmol), hexamethylditin

(0.518 g, 1.58 mmol), (Ph₃P)₄Pd (0.114 g, 0.099 mmol, 0.100

(82) Methyl-2-acetamidoacrylate was prepared by reaction of methyl

pyruvate with 2.0 equiv of acetamide in benzene (reflux, 2.5 h)

according to the procedure of Yokoyama, see ref 70.

(81) 1,3-Diiodoazulene was prepared by the reaction of azulene with

2.1 equiv of NIS in methylene chloride (rt, 12 h) according to the

procedure of Hafner, see ref 41a.

(83) Partial separation of this mixture was accomplished by pre-

parative HPLC (Waters Prep Nova Pak HR column, 6 µm silica, 19

mm × 30 cm; gradient elution with 40-60% EtOAc-hexane).

8666 J. Org. Chem., Vol. 69, No. 25, 2004

Synthesis of Substituted Azulenes and Oligoazulenes

10.1 Hz, 1 H, major isomer), 7.50 (app t, J ) 10.4 Hz, 1 H,

minor isomer), 7.21-7.23 (m, 2 H, both isomers), 7.08-7.13

(m, 2 H, major isomer), 6.97-7.06 (m, 3 H, minor isomer), 3.93

(s, 3 H, major isomer), 3.37 (s, 3 H, minor isomer), 2.21 (s, 3

H, minor isomer), 1.91 (br s, 3 H, major isomer), and 1.48 (s,

18 H, both isomers); ¹³C NMR (125 MHz, CDCl₃) δ 177.0, 176.9,

169.2, 168.7, 165.2, 164.9, 145.8, 142.5, 139.3, 138.8, 137.7,

136.8, 132.5, 132.1, 131.9, 131.7, 129.3, 129.1, 128.1, 127.6,

127.5, 127.1, 125.9, 124.7, 123.2, 122.3, 121.2, 112.5, 112.0,

53.2, 52.7, 39.65, 39.62, 27.62, 27.60, 25.0, and 23.2 (one

resonance corresponds to two overlapping carbons); HRMS-

ESI (m/z) [M + Na] calcd for C₂₁H₂₃NO₅392.1468, found

392.1451.

2-Acetylamino-3-(1-trimethylacetoxyazulen-4-yl)-pro-

pionic Acid Methyl Ester (110). A 500-mL Parr hydrogena-

tion bottle was charged with a 5:1 mixture of azulenyl pivalates

108 and 109 (0.080 g, 0.22 mmol), (PPh₃)₃RhCl (0.030 g, 0.032

mmol, 0.15 equiv), and 20 mL of degassed ethanol. The bottle

was evacuated and filled with hydrogen three times, and then

shaken under 95 psi of hydrogen for 24 h. The reaction mixture

was then concentrated to yield 0.115 g of a blue oil. Column

chromatography on 10 g of silica gel (elution with 5-10% IPA-

hexane) afforded 0.057 g (71%) of 110 as a blue oil:⁸⁴IR (CH₂-

Cl₂) 3282, 2973, 1748, 1658, 1562, and 1504 cm^-1; UV (CH₂Cl₂)

λ_max245, 285, and 348 nm; ¹H NMR (500 MHz, CDCl₃) δ 8.19

(d, J ) 9.5 Hz, 1 H), 7.79 (d, J ) 4.6 Hz, 1 H), 7.51 (app t, J

) 10.1 Hz, 1 H), 7.39 (d, J ) 4.6 Hz, 1 H), 7.05 (app t, J ) 9.6

Hz, 1 H), 6.99 (d, J ) 10.4 Hz, 1 H), 6.01 (d, J ) 7.6 Hz, 1 H),

5.06 (q, J ) 6.9 Hz, 1 H), 3.66 (dd, J ) 1.5, 6.7 Hz, 2 H), 3.59

(s, 3 H), 1.91 (s, 3 H), and 1.48 (s, 9 H); ¹³C NMR (125 MHz,

CDCl₃) δ 176.9, 172.2, 169.9, 145.7, 139.2, 137.7, 133.9, 132.6,

127.2, 127.0, 125.7, 121.5, 111.4, 53.7, 52.6, 39.64, 39.61, 27.6,

and 23.4; HRMS-ESI (m/z) [M + Na] calcd for C₂₁H₂₅NO₅

394.1625, found 394.1607.

Acknowledgment. We thank the National Insti-

tutes of Health (GM 28273), Pharmacia, Kotobuki

Seiyaku Co., Ltd., and Merck Research Laboratories for

generous financial support. We are grateful to Ronald

A. Brisbois and Dr. Hiroo Koyama for exploratory

experiments on the diazo enone route.

Supporting Information Available: Experimental pro-

cedures and characterization data for diazo ketones 48-55,

65, and 66 and ¹H NMR spectra for all azulene and diazo

ketone products. This material is available free of charge via

the Internet at http://pubs.acs.org.

JO048698C

(84) Separation of enantiomers could be effected by HPLC, using a

Daicel Chiracel OD column (elution with 10% IPA-hex); t_R) 14.164

and 17.796 min; [R]_D-24 (c 2.86, CH₂Cl₂); [R]_D+22 (c 2.76, CH₂Cl₂).

J. Org. Chem, Vol. 69, No. 25, 2004 8667

Article Doi

Ring expansion-annulation strategy for the synthesis of substituted azulenes and oligoazulenes. 2. Synthesis of azulenyl halides, sulfonates, and azulenylmetal compounds and their application in transition-metal-mediated coupling reactions

DOI: 10.1021/jo048698c

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