Syntheses of donor-acceptor-functionalized dihydroazulenes

Article

pubs.acs.org/joc

Syntheses of Donor−Acceptor-Functionalized Dihydroazulenes

Søren Lindbæk Broman,^†Martyn Jevric,^†Andrew D. Bond,^‡,§and Mogens Brøndsted Nielsen*^,†

^†Department of Chemistry, University of Copenhagen, Universitetsparken 5, DK-2100 Copenhagen Ø, Denmark

^‡Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark

S

* Supporting Information

ABSTRACT: The dihydroazulene (DHA)/vinylheptafulvene (VHF)

photo/thermoswitch has been of interest for use in molecular

electronics and advanced materials. The switching between the two

isomers has previously been found to depend strongly on the presence

of donor and acceptor groups. The ﬁne-tuning of optical and switching

properties relies on ready access to new derivatives via eﬃcient synthetic

protocols. The central DHA core is conveniently prepared in a four-step

synthesis starting from acetophenone and tropylium substrates. Here,

the outcome of this reaction as a function of the nature of the

substituent group on the phenyl unit of acetophenone is investigated in

detail. A wide variety of functional groups (nitro, cyano, halo, alkyl,

amido, and thioether) was tolerated, and the route provided access to a

large selection of substituted DHA derivatives (position 2 of DHA).

These compounds were investigated for their ability to undergo subsequent functionalization in the seven-membered ring by a

regioselective bromination−elimination protocol, introducing a bromo substituent at position 7. Halo-substituted DHAs were

subjected to palladium-catalyzed cyanation, Sonogashira, Cadiot−Chodkiewicz, and Suzuki couplings and for the latter reaction;

optimized conditions were developed by varying the palladium catalyst. In general, our focus was on reducing the formation of

fully unsaturated azulene byproducts.

UV−vis absorption,²and single-molecule resistivity⁴). The

INTRODUCTION

■

VHF → DHA back reaction is relatively slow, but it is very

1,8a-Dihydroazulene-1,1-dicarbonitrile (DHA) is a photochro-

solvent-dependent^2,5and can easily be monitored either by

mic molecule that, upon irradiation, undergoes a ring-opening

UV−vis or NMR spectroscopies. We have recently shown that

reaction to form the corresponding vinylheptafulvene (VHF)

(Scheme 1).¹Over time, metastable isomer VHF converts via a

the rate constant, k, for the back reaction obeys linear free-energy

relationships (Hammett correlations) for derivatives with

substituent groups at positions 2 and 7. Thus, more than

70 derivatives with diﬀerent electron-donating and electron-

Scheme 1. Dihydroazulene (DHA)/Vinylheptafulvene (VHF)

Photo/Thermoswitch

a

withdrawing groups were recently subjected to detailed kinetics

studies.⁶

Here, we describe the synthetic protocols for achieving this

large selection of donor−acceptor-substituted DHAs. Through-

out the years, the need for functional-group tolerant and eﬀective

synthetic protocols to synthesize the DHA moiety has expanded,

and the original procedure, starting from benzaldehydes and

cyclooctatetraene,⁷has been supplemented with a more diverse

route starting from acetophenones and tropylium.^5,8To date,

this route has allowed the synthesis of DHAs with a PhX

substituent at position 2 of DHA, where X = H,⁵I,^8fCO₂Me,^8g

CCSiMe₃,^8gand St-Bu.^8h,iAn expansion of this four-step

synthesis to tolerate X = NO₂, CN, NHAc, OMe, Me, Br, and F is

here presented. For X = NH₂, the method was not optimal, and

a

other routes were devised.

The inset shows the structure and numbering of azulene.

In 2009,⁹we reported a regioselective bromination−

elimination procedure for incorporation of a bromine substituent

thermally induced ring-closure reaction back to the more stable

DHA isomer. The ring-opening reaction occurs with a high

quantum yield²and is accompanied by signiﬁcant changes in

the physical properties of the molecule (e.g., dipole moment,³

Received: September 12, 2013

Published: December 6, 2013

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Article

at position 7. This method was recently expanded to

DHAs containing either an iodo- or thioether functionality at

position 2.^4b,8hWe became interested in investigating the

functional-group tolerance and hence the further scope of this

protocol. DHAs with a halo substituent at position 7 or a

halophenyl at position 2 are particularly interesting for further

functionalization by palladium-catalyzed cross-coupling reactions

such as Sonogashira,¹⁰Glaser−Hay,¹¹Cadiot−Chodkiewicz,¹²

and Suzuki¹³reactions. Here, we present optimized conditions for

Suzuki coupling with a wide variety of substrates and diﬀerent

palladium catalysts. One particular challenge in the trans-

formations of DHA compounds is ﬁnding conditions that prevent

azulene formation, that is, generation of the fully unsaturated cores

by elimination of HCN. All of the synthetic endeavors presented in

this article are important for advancing the successful exploitation

of suitably functionalized DHAs in photochromic advanced

materials. In total, we have been able to prepare and study more

than 70 photochromic DHAs as we developed these optimized

conditions.

described in the literature,¹⁶was isolated, and the structure was

conﬁrmed by X-ray crystallography (Figure 2).

Electrophilic addition of (ﬁnely divided or mortared)

tropylium tetraﬂuoroborate⁵to compounds 5.1−5.8 using

Et₃N in CH₂Cl₂at −78 °C gave the VHF precursors in almost

quantitative yields (7.1−7.8). These were then treated with

tritylium tetraﬂouroborate⁵in 1,2-dicloroethane (DCE) fol-

lowed by Et₃N in toluene to yield the VHFs that were then,

without isolation, directly converted into corresponding DHAs

1.1−1.8 by heating (Scheme 3 and Table 1). The DHAs were all

isolated on a large scale and puriﬁed by means of dry column

vacuum chromatography followed by a recrystallization as yellow

crystals stable to light irradiation.

Interestingly, during the preparation of several of the VHF

precursors by electrophilic addition of tropylium to 5.1−5.8

(Scheme 3), we found that if the reaction is not quenched at −78 °C,

then overalkylation occurred in some cases; in one example, the

corresponding product (8.1) was isolated, and the structure was

conﬁrmed by X-ray crystallographic analysis (Figure 3d).

Additionally, in this reaction step, only ﬁnely powdered tropylium

salt reacts smoothly. Thus, even small lumps of the starting

material cause longer reaction times and sluggish reactions with

poorer yields and side reactions such as overalkylation.

The compounds prepared were categorized into four overall

structures, 1−4, as shown in Figure 1.

The hydride abstraction can be conveniently performed by

either heating at reﬂux for 1 h in DCE or simply by stirring

overnight in CH₂Cl₂at rt; no signiﬁcant diﬀerence in isolated

yields was observed, although one or the other procedure may be

more desirable when planning the synthesis.

In Table 1, the yields for the four-step synthesis are shown.

Many of the compounds prepared using this strategy are known

but were prepared by another, less eﬃcient, procedure. The

present methodology demonstrates a highly eﬀective procedure

to prepare DHAs with both electron-withdrawing and -donating

groups in the phenyl ring placed at position 2 on DHA.

Figure 1. Structures of model compounds 1−4.

We note that using the four-step procedure for synthesis of the

DHA 1.2 gave a lower yield than simply reducing nitro derivative

1.1 (Scheme 4).⁷Unfortunately, this procedure was not possible

to perform on a gram scale. Even after some optimization,

reduction of more than 2.5 mmol of 1.1 was not successful.

Reduction using Zn(s) in AcOH also gave a low isolated yield of

1.2 (20%). For this reason, an eﬃcient protocol for the

preparation of 1.2 from either a protected aniline or from a

halogenated DHA became desirable. Amination of iodo-DHA

1.4 using Fe₂O₃/CuI as catalyst¹⁷failed and aﬀorded only

azulenes by elimination of HCN because of basic conditions

(NaOH/NH₃). This elimination is known to occur readily under

basic conditions, in the presence of ﬂuoride, or at high temperatures.¹⁸

A better result was observed using slightly milder basic conditions;

treatment with CuI, ^L-proline, K₂CO₃, and NH₄Cl in dimethyl

sulfoxide (DMSO)¹⁹aﬀorded desired amino-DHA 1.2; unfortu-

nately, it also resulted in azulene formation. Instead, a good result was

RESULTS AND DISCUSSION

■

DHAs were prepared in four steps, expanding, with slight

modiﬁcation, the procedure of Diederich and co-workers.^8fFirst,

a Knoevenagel condensation between substituted acetophenones

and malononitrile either by reﬂux in toluene using AcOH and

NH₄OAc (5.1,¹⁴5.2,¹⁵5.3,¹⁴5.4,^8f5.5, and 5.6¹⁴) or in a hot

mixture of AcOH and hexamethyldisilazane (HMDS) (5.7¹⁶and

5.8¹⁶) gave a series of malononitrile derivatives, as shown in

Scheme 2 and Table 1.

Although both procedures are eﬀective, acetophenones with

electron-withdrawing groups are in danger of a subsequent

condensation between two product molecules if the reaction is

not carefully monitored by TLC and stopped as the desired

Knoevenagel condensation has ﬁnished.¹⁶In one example

(X = NO₂), a signiﬁcant amount of byproduct 6, previously

a

Scheme 2. Knoevenagel Condensations under Two Diﬀerent General Sets of Conditions

a

For yields, see Table 1.

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Table 1. Yields for the Four-Step (or Five-Step) Synthesis of DHAs 1

a

b

c

d

X

compound

yield (%)

71

compound

yield (%)

compound

yield (%)

51

total yield (%)

e

p-NO₂

p-NH₂

p-Me

p-I

5.1

5.2

5.3

5.4

5.5

5.6

5.7

5.8

5.9

7.1

7.2

7.3

7.4

7.5

7.6

7.7

7.8

7.9

99

44

99

94

99

1.1

1.2

1.3

1.4

1.5

1.6

1.7

1.8

1.9

36

e

f

59 (36 )

e

71

56

70

50

34

66

70

39

67

49

31

45

43

40

f

96 (81 )

m-I

99

96

69

p-F

e

p-OMe

p-Br

e

67

g

h

p-NHAc

a

b

Isolated yield of the pure product. Isolated yield of the crude product, with only minor impurities (traces of Et₃N and/or cycloheptatriene).

c

d

e

Isolated yield of the pure crystalline product. Total yield from the commercially available acetophenone derivative. Previously published

f

g

compound but prepared by another procedure. Isolated yield of recrystallized compound for long-term storage. Prepared by acetylation of 5.2.

h

Yield after ﬁve steps.

conjugation with the rest of the double bonds and makes it

susceptible to electrophilic attack.

The para- and meta-functionalized iodo-DHAs, 1.4 and 1.5,

acted as very useful precursors to other functionalized DHAs.

Thus, a palladium-catalyzed cyanation of the iodo-DHAs was

achieved when treated with Zn(CN)₂in dimethylformamide

(DMF) in the presence of catalytic amounts of Pd(PPh₃)₄under

microwave (MW) heating, which gave 1.10 and 1.11 in excellent

yields of 96 and 84%, respectively (Scheme 6). A signiﬁcantly

lower yield was observed using p-bromo-DHA 1.8 because the

reaction did not go to completion and because small amounts of

the corresponding azulenes of starting material and product, 9.8

and 9.10, were isolated.

By the means of Suzuki cross-couplings, functionalization with

heteroaromatics, like thiophene and furan, was achieved. Starting

from either the para- or meta-substituted iodo-DHAs, 1.4 and

Figure 2. (a) Structure of observed byproduct of self-condensation

between two 5.1 molecules. (b) Molecular structure of 6 (CCDC

953909; crystals grown from ethanol), with displacement ellipsoids at

50% probability for non-H atoms.

1.5, and the 2- and 3-furan or thiophene boronic acids allowed

for a large host of functionalized DHAs to be prepared. Using

Pd(OAc)₂/RuPhos (2-dicyclohexylphosphino-2′,6′-diisopro-

poxybiphenyl) as a catalytic system, these reactions had a

tendency to not go to completion in many examples. By using

Pd₂(dba)₃or Pd(OAc)₂with Xantphos (4,5-bis(diphenylphosphino)-

9,9-dimethylxanthene) as the catalytic system instead, better

results were obtained, and eight DHAs were prepared (Scheme 7).

In Table 2, the reaction conditions and yields are shown.

Unfortunately, no systematic behavior with respect to thechoice of

ligand was recognized.

Note that an unreactive ligand system for the Suzuki coupling

often, eventually, resulted in azulene formation. The HCN,

released during the azulene formation then participated in

replacement of the halogen for a nitrile and thus the cyano-DHAs

1.10 and 1.11 were isolated. In the case of the cyanation of the

bromo-DHA 1.8 shown in Scheme 6, azulenes 9.8 and 9.10 were

then obtained as a result of this two-step elimination−cyanation

because both DHA 1.8 and 1.10 can potentially eliminate HCN

and the formed 9.8 can, in principle, also participate in the

observed by simply protecting the aniline earlier in the sequence by

acetylation of malononitrile 5.2. The alkylation, oxidation, and ring

closure now proceeded smoothly in high yield (Table 1), and the

subsequent deprotection of the DHA 1.9 to give 1.2 could be

performed using aqueous HCl (Scheme 4).

The protection was performed by treatment of 5.2 with Ac₂O

in dioxane/water at 70 °C for 30 min, which gave protected

compound 5.9 in quantitative yield (Scheme 5).

Three DHA-derivatives, namely, the methyl-, nitro-, and

methoxy-derivatives 1.3, 1.1, and 1.7, were characterized by

X-ray crystallography, as shown in Figure 3a−c, whereas structures of

the bromo-,^7aiodo-,^8fcyano-,²⁰and hydrogen-derivatives⁵were

previously reported. They all show the characteristic boat-shaped

conformation of the seven-membered ring with the

C7−C8 double bond out of plane, which eliminates eﬀective

Scheme 3. Synthesis of a Series of DHAs by Nucleophilic Addition by Tropylium Tetraﬂuoroborate Followed by a Two-Step

a

Oxidation and Thermally Induced Ring Closure

a

For yields, see Table 1. The yield of X = NH₂is not included.

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Scheme 5. Acetylation of Aniline Derivative 1.2

para- and meta-substituted iodo-DHAs 1.4 and 1.5, which gave

alkyne-functionalized DHAs 1.20,^8g1.21,^8gand 1.22 in good to

excellent yields. Desilylation of the TMS-protected alkyne can be

eﬀected as previously described by using either TBAF/AcOH^6ain

THF/MeOH (53% yield) or, in two steps, with AgNO₃followed

by KI (86%).^8gWith an optimized procedure using 2 mol equiv of

TBAF and 10 mol equiv of AcOH in THF, deprotection was

eﬀected in 58% yield at rt. For the TIPS-protected alkynes, 2 mol equiv

TBAF in reﬂuxing THF/AcOH allowed for the formation of the

terminal acetylenes in excellent yields (Scheme 9). No desilylation of

TIPS-protected DHA 1.22 was observed using KF in THF/MeOH at

reﬂux, and azulene formation and decomposition was achieved only

using TBAF without the presence of AcOH. Both terminal alkynes

are unstable and each one of them converts to an unidentiﬁed product

over a few days under ambient conditions. The present preparations

are improved conditions of those previously reported.^8g

Terminal acetylene DHAs 1.23 and 1.24 act as precursors for a

number of other functional groups. DHA 1.23 was reacted in a

Glaser−Hay coupling with TMS-acetylene, using CuCl/

TMEDA in CH₂Cl₂to give butadiyne 1.25 in 73% yield together

with its homocoupled product (Scheme 10). The TMS-

protection group was removed by TBAF in THF/AcOH,

which gave 1.26 in 92% yield (total yield, 67%). Alternatively,

1.25 can be prepared in two steps from 1.23 by treatment with

NBS and AgNO₃in acetone to give bromoalkyne 1.27²¹in 92%

yield. A subsequent modiﬁed Cadiot−Chodkiewicz¹²coupling

with TMS-acetylene using Pd(PPh₃)₄, CuI, and NEt₃in THF

gave 1.25 in 44% yield. Preparation of the chloroalkyne was

attempted by an in situ deprotection of TMS-ethynyl DHA 1.20

followed by chlorination using trichlorocyanuric acid and AgNO₃

in acetone.²²Although the desired compound was presumably

observed by thin-layer chromatography (TLC) analysis, isolation

failed during the aqueous workup, presumably because of a lack

of stability. However, the bromoalkyne showed stability in

solution and as a solid that was suﬃcient enough for isolation and

characterization.

Figure 3. Molecular structures of (a) 1.1 (CCDC 912892; crystals

grown from MeOH), (b) 1.7 (CCDC 912893; crystals grown from

EtOH), (c) 1.3 (CCDC 912894; crystals grown from CHCl₃/

heptanes), and (d) 8.1 (CCDC 912896; crystals grown from heptanes),

with displacement ellipsoids at 50% probability for non-H atoms.

The thioethers^8h1.28−1.29 were oxidized by treatment with

either 1.0 or 2.2 equiv of meta-chloroperoxybenzoic acid (m-CPBA)

in CH₂Cl₂to give sulfoxides 1.30−1.31 (as a mixture of

diastereoisomers) and sulfones 1.32−1.33, respectively (Scheme 11).

The compounds were generally quite stable solids, although

the VHF precursors, 7.1−7.9, were low-melting solids or oils,

generally diﬃcult to purify, and only stable as solids. All DHAs

are stable for storage under ambient conditions as solids. The

reactions were done on a preparative scale, up to 10−15 g, and

for proof-of-concept, two compounds, 1.3 and 1.7, were

prepared without the use of chromatography.

replacement reaction. The two-step elimination−cyanation

reaction is shown in Scheme 8.

By using a Sonogashira cross-coupling protocol, functionaliza-

tion of the phenyl ring with alkynes was achieved. In THF at

room temperature, both trimethylsilylacetylene (TMS-acetylene)

and triisopropylacetylene (TIPS-acetylene) were treated with the

Scheme 4. Preparation of 1.2 by Either Reduction of Nitro-DHA 1.1 by Means of FeSO₄and NH₃or by Deprotection of

Amide-DHA 1.9 Using Aqueous HCl

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Scheme 6. Palladium-Catalyzed Cyanation of 1.4, 1.5, and 1.8 and Structures of Isolated Azulenes 9.8 and 9.10

Scheme 7. Synthesis of Heteroaromatic-Functionalized DHAs by Suzuki Coupling and Structures of Isolated

Cyano-DHAs 1.10 and 1.11

a

Table 2. Reaction Conditions and Isolated Yields of Heteroaromatic-Substituted DHAs

b

unreacted SM

substituent

catalyst

temp (°C)

time (h)

product

yield (%)

1.4

1.5

c

p-(3-furyl)

p-(2-furyl)

Pd(OAc)₂/RuPhos

Pd₂(dba)₃/Xantphos

Pd(OAc)₂/ Xantphos

Pd(OAc)₂/RuPhos

Pd(OAc)₂/ Xantphos

Pd(OAc)₂/RuPhos

Pd(OAc)₂/ Xantphos

Pd₂(dba)₃/Xantphos

Pd(OAc)₂/RuPhos

Pd₂(dba)₃/Xantphos

Pd(OAc)₂/RuPhos

Pd(OAc)₂/ Xantphos

Pd₂(dba)₃/Xantphos

25

72

48

72

16

4

1.12

1.13

70

none

>20%

none

>20%

<10%

none

d

25

32

50

91

d

p-(2-thienyl)

p-(3-thienyl)

25

1.14

1.15

<30

cd

e

,

50

61

25

<50

c

e

50

77

none

c

m-(2-thienyl)

m-(3-thienyl)

50

2

1.16

1.17

78

none

14%

<5%

d

50

48

16

8

19

c

50

60

cd

,

f

m-(3-furyl)

50

1.18

30

55%

f

reﬂux

50

48

10

6

<20

none

c

reﬂux

25

70

m-(2-furyl)

72

1.19

74

a

General conditions: 5−10 mol % palladium catalyst, 2 equiv K₃PO₄as activator of the boronic acid in toluene/H₂O (9:1) at 25 or 50 °C. RuPhos:

b

c

2-dicyclohexylphosphino-2′,6′-diisopropoxybiphenyl. Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene. SM, starting material. Higher

catalyst loading. Reaction did not go to completion. A small amount of 1.4 or 1.10 and the corresponding azulenes were observed. A small

amount of 1.5 or 1.11 and the corresponding azulenes were observed.

d

e

f

Scheme 8. Base-Facilitated Elimination of HCN and Its Participation in a Palladium-Catalyzed Cyanation

Scheme 9. Functionalization with Alkynes by Sonogashira Cross-Couplings and Subsequent Desilylation

Gratifyingly, our previously reported bromination−elimination

procedure^6a,b,8h,9proved to be possible, with a series of DHAs

demonstrating the tolerance of the procedure toward a variety of

functional groups. In addition to the three recently published

DHAs (X = H, I, and St-Bu),^4b,6a,b,8h,9the two-step incorporation

of a bromo substituent at position 7 of the DHA tolerated a bromo,

nitro, cyano, and methyl functionality. Under the same reaction

conditions, Br₂in CH₂Cl₂at −78 °C, four derivatives of the DHA

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Scheme 10. Preparation of Butadiyne Derivative by Glaser−Hay Coupling and by Bromination Followed by Cadiot−Chodkiewicz

Coupling

Scheme 11. Oxidation of Thioether Using m-CPBA

a

Scheme 12. Bromination−Elimination Procedure

a

LiHMDS, lithium hexamethyldisilazane. For yields, see Table 3.

were selectively brominated at the C7−C8 double bond, and HBr

was selectively eliminated by treatment with lithium hexamethyl-

disilazane (LiHMDS) in THF at 0 °C (Scheme 12). The structure

of 11.1 was determined by X-ray crystallography, conﬁrming the

position of the bromo substituent (Figure 4). No sign of

electrophilic aromatic substitution or bromination directly on

nitrogen was detected.

All dibromides 10.1−10.4, 10.7−10.10, and 10.34 were

isolated as foams or powders and were very unstable. Thus, they

could, in many instances, only be isolated long enough for

characterization by NMR spectroscopy if the spectrum was

acquired directly after evaporation of the solvent. Puriﬁcation of

Figure 4. Molecular structure of 11.1 (CCDC 912891; crystals grown

from CH₂Cl₂/heptanes), with displacement ellipsoids at 50%

7-bromides 11 using column chromatography was not possible

without signiﬁcant loss of compound; thus, the compounds were

used for subsequent reactions in crude form. A sample of each

7-bromide was, however, puriﬁed for characterization by tedious

dry column vacuum chromatography followed by recrystallization.

The crude and isolated yields for the two-step bromination−

elimination reactions are given in Table 3. For comparison, some

previously published data are also shown.

In the case of the methoxy-DHA 1.7, the procedure did not

yield desired dibromide 10.7 as the major product. When

treating 1.7 with bromine in CH₂Cl₂, the reaction mixture

became dark green with a reddish glow. ¹H NMR spectroscopy

did show about 10% conversion to the desired dibromide as well

as signals attributed to the starting material and an unidentiﬁed

compound (presumably an azulene). This mixture was treated

with LiHMDS in THF. Despite a very low yield, a small amount

of 7-bromide 11.7 was isolated relatively pure, for character-

ization by UV−vis spectroscopy, by repeated dry column vacuum

chromatography followed by recrystallization. Alternatively,

probability for non-H atoms.

bromination in AcOH at 0 °C also led to an undesired reaction

product. Upon addition of bromine, the solution took a dark but

bright red color (not from bromine), which eventually became

purple−green. A green precipitate was collected and identiﬁed as

3-bromoazulene 12 in 53% yield (Scheme 13). Simply treating

methoxy-DHA 1.7 with Br₂at −78 °C and then stirring the

reaction mixture for 2 days at rt also gave azulene 12 in about

50% yield, but the compound was not easily isolated by

chromatography via this procedure.

The four 7-bromides 11.1−11.3, 11.8, and 11.10 together

with three of the previously reported compounds 11.34

(X = H),^6a,b,911.4 (X = I),^4band 11.28 (X = St-Bu)^8hnow

acted as the starting point for introduction of para-substituted

benzene rings onto the 7-position. This series of 7-bromides was

subjected to palladium-catalyzed Suzuki cross-coupling reactions

to aﬀord a number of derivatives bearing either one or two

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Table 3. Crude and Isolated Yields for the Bromination−

Table 4. Reaction Conditions and Isolated Yields for Suzuki-

Couplings between 7-Bromides and Para-Substituted Phenyl

Boronic Acids

Elimination Reactions

a

crude isolated

yield

(%)

yield

(%)

yield

(%)

product

X

Y

reactant temp (°C) time (h) yield (%)

X

compound

ref

4.1

4.2

4.3

4.4

4.5

4.6

NO₂

Me

NO₂

OMe

CN

11.1

11.3

11.10

70−75

90

16

24

48

16

24

48

28

NO₂

NH₂

Me

10.1

10.2

10.3

99

11.1

11.2

11.3

>90

24

37

70−75

90

<10

22

99

>90

74

Me

OMe

CN

a

I

10.4

11.4

4b

8h

CN

90

<15

<10

b

OMe

Br

10.7

10.8

10.9

10.10

<10

11.7

11.8

11.9

11.10

b

90

99

>90

72

a

General conditions: Pd(PPh₃)₄, KF·2H₂O in toluene/water.

Reaction did not go to completion.

NHAc

CN

St-Bu

H

b

99

>90

64

20

a

10.28

11.28

a

10.34

11.34

6a, 6b, 9

a

b

Known compound. Only traces (<10%) of the dibromide 10.7 and

7-bromide were reproducibly prepared; however, from both bromination

in CH₂Cl₂(−78 °C) and in AcOH (0 °C), 3-bromoazulene derivative 12

was instead isolated.

Scheme 13. Synthesis of 12 by Bromination of 1.7 in AcOH

Figure 5. Molecular structure of 4.1 (CCDC 912895; crystals grown

from CH₂Cl₂/heptanes), with displacement ellipsoids at 50%

probability for non-H atoms.

During the screening, it was found that using amine bases

(Et₃N or i-Pr₂NH) in THF at up to 100 °C (MW) with 10 mol %

Pd(PPh₃)₄as the catalyst gave no reaction, and if the reaction was

heated at 140 °C, then azulene formation was observed.

Decomposition of the starting material readily occurred in

DMF at 70 °C (60 min), but in toluene, about 5−10% of the

product could be obtained when the mixture was stirred at 120 °C

(MW) for 40 min. Using KF·2H₂O in THF gave decomposition

within hours, but in toluene, 15−20% of the product could be

obtained, whereas a slightly better result was observed using

K₃PO₄in toluene/water. Although most of the attempted

conditions gave poorer results than the initial conditions, K₃PO₄

in toluene/water proved to be better than the initial conditions.

Good yields were ﬁnally obtained by simply changing the ligand

system and employing K₃PO₄as the activator of the boronic acid.

Of the three attempted commercially available electron-donating

phosphine ligands, P(t-Bu)₃and RuPhos, shown in Figure 6, both

gave approximately 50% yield in the ﬁrst attempt (calculated for

three steps), whereas Xantphos gave no reaction. The best sets of

reaction conditions were then repeated for the Suzuki coupling

between 11.3 and 4-methoxyphenylboronic acid, and the isolated

yields of 4.4 are shown in Table 5.

functional groups. Using this methodology, donor−acceptor,

donor−donor, and acceptor−acceptor compounds were pre-

pared to study systematically the inﬂuence of mesomeric and

inductive eﬀects (either electron withdrawing or donating).^6c

Using the previously reported conditions (10−20 mol %

Pd(PPh₃)₄and KF·2H₂O in toluene/H₂O),^6bthree of the six

7-bromo DHAs, 11.1, 11.3, 11.10, were treated with p-methoxy,

p-nitrophenyl, and p-cyanophenyl boronic acid. and the six donor

and acceptor DHAs were isolated in 10−37% yield (Scheme 14

and Table 4).

The structure of compound 4.1 was solved by X-ray

crystallography, as shown in Figure 5, conﬁrming the position

of the nitrophenyl. The functionalization maintains the boat-like

conformation of the DHA moiety, which was also in accordance

with the UV−vis absorption spectroscopy.^6c

Although all of the tested 7-bromides were reactive in the

Suzuki coupling under the same general conditions, the isolated

yields were relatively low. For this reason, other conditions,

solvents, and reagents were tested to improve the procedure.

Strong bases, like NaOH or NaOt-Bu, and the ﬂuoride source

tetrabutylammonium ﬂuoride (TBAF) were deliberately avoided

because of the unwanted elimination of HCN, which is known to

occur readily. Simple 7-bromide 11.34 and p-cyanophenyl

boronic acid were chosen as the main model compounds,

although other substrates were also investigated.

With these very encouraging results, we chose to go with the

Pd(OAc)₂/RuPhos catalyst using K₃PO₄as the activator. The

reactions were performed in toluene/water (9:1) because from

time to time they did not proceed without water (probably

a

Scheme 14. Synthesis of Donor−Acceptor-Functionalized DHAs 4.1−4.6 under Known Conditions

a

b

For yields, see Table 4. Yields calculated over three steps from pure DHA 1.

47

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gave 4.10, which indicates the higher reactivity of the

vinylbromide. Reaction for 30 min at 90 °C (MW) gave 2-fold-

coupled DHA 4.11 in 42% yield, but when repeated at room

temperature overnight, DHA 4.10 was almost exclusively

obtained and isolated in 82% yield. In addition, phenyl boronic

acid, bromophenyl boronic acid, and cyanophenyl boronic acid

reacted selectively on the vinylbromide, although the amount of

boronic acid added is crucial for the outcome; thus, the

arylbromide reacts with any excess of boronic acid or if the

temperature is elevated to 50 °C. In the case of bromophenyl

boronic acid, an excess of the reagent was needed because it

Figure 6. Structures of Ruphos (left) and Xantphos (right).

because of the lack of solubility of K₃PO₄in toluene). The eight

7-bromides, 11.1−11.4, 11.8, 11.10, 11.28, and 11.34, were

reacted with a selection of functionalized phenylboronic acids

(Y = OMe, Me, St-Bu, SMe, Br, H, CN, and NO₂) to yield a

selection of donor−acceptor and acceptor−acceptor substituted

DHAs, 2.1−2.4, 3.1−3.5, 4.3−4.6, 4.8−4.14, and 4.16. All

substrates were reactive under the same general conditions, and

the reactions were cleaner with higher isolated yields, lower

catalyst loading, and shorter reaction times compared to the

previously reported conditions.^6bIn the case of 4.7, 4-(N,N-

dimethylamino)phenylboronic pinacol ester was employed, as

4-(N,N-dimethylamino)phenyl boronic acid is very unstable and

only commercially available as the hydrochloride salt. In this case,

the activator was changed to a mixture of K₃PO₄and KF·2H₂O

(1.2 equiv). The products were generally extremely diﬃcult to

purify owing to poor separation by column chromatography in

addition to their light sensitivity. Multiple column chromatog-

raphy puriﬁcations were avoided, if possible, because of the

danger of the loss of compound because of some unavoidable

light exposure, resulting in a mixture of the 7- and 6-isomer as a

result of isomerization.^6,9The general reaction is shown in

Scheme 15. These conditions were also employed in two recently

published papers.^8h,18

1

eventually polymerized. By H and ¹³C HMBC NMR, the

positions of the phenyl substituents were determined.

As a proof of concept, nitro-DHA 3.6 was reduced using Zn(s)

in AcOH to yield corresponding amino-DHA 3.7, which was

isolated crude in 74% yield, as shown in Scheme 17. This gives a

useful alternative to using simply the amino phenyl boronic acid

or ester, as this seemed to complicate the Suzuki coupling,

although the compound, in this speciﬁc example, could not be

puriﬁed.

Finally, the tert-butylthioether^8hwas oxidized using either 1.0

or 2.2 molar equiv of m-CPBA to yield the sulfoxide and the

sulfone, respectively (Scheme 18).

CONCLUSIONS

■

We have expanded the operationally simple large-scale synthesis

of DHAs to tolerate a variety of functional groups: both electron

withdrawing and donating (NO₂, CN, halo, alkyl, amido, and

thioether). Several transition-metal-catalyzed functional-group

transformations and cross couplings have been explored,

demonstrating the usefulness of both para- and meta-substituted

iodo-DHAs as synthetic precursors for larger functionalized

systems. Here, the aim has been to ﬁnd reaction conditions that

reduce the formation of the fully unsaturated azulene, especially

because these conditions usually require base, which can readily

form azulene from DHA. Via a regioselective bromination−

elimination cross-coupling protocol, we have prepared a large

selection of donor−acceptor-functionalized DHAs. Optimum

conditions for performing Suzuki couplings on dihydroazulenes

incorporating halogen substituents were developed that tolerated

both electron-withdrawing and electron-donating groups. These

In Table 6, the recorded yields for the Suzuki couplings using

Pd(OAc)₂/RuPhos together with some functional group trans-

formations are listed.

We have recently reported that the aryliodide unit of DHA

11.4 is more reactive than the vinylbromide in the Suzuki cross-

coupling (Scheme 16) using KF·2H₂O and Pd(PPh₃)₄.^4b,23In

the case of DHA 11.8, the vinylbromide was found to be more

reactive than the arylbromide. Suzuki coupling between 11.8 and

methoxyphenyl boronic acid, using the mentioned conditions,

a

Table 5. Reaction Conditions and Isolated Yields for Suzuki Couplings

product

X

Y

solvent

PhMe

catalyst

ligand

temp (°C)

time (min)

yield (%)

4.4

Me

OMe

PdCl₂(PhCN)₂

Pd(OAc)₂

P(t-Bu)₃

RuPhos

80 (MW)

100 (MW)

80 (MW)

30

nr

51

52

nr

PhMe/H₂O

Pd₂dba₃

Xantphos

a

General conditions: 0.30 mmol 7-bromide and 2 mol equiv K₃PO₄as activator and 5 mol % [Pd] and 10 mol % ligand for RuPhos and P(t-Bu)₃and

5 mol % for Xantphos. nr, no reaction; MW, microwave.

a

Scheme 15. Synthesis of Donor−Acceptor-Functionalized DHAs under Improved Conditions

a

b

For yields, see Table 6. Yields calculated over three steps from pure DHA 1.

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The Journal of Organic Chemistry

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a

Table 6. Reaction Conditions and Isolated Yields for Suzuki Couplings, Reduction, Cyanation, and Oxidations

b

product

X

Y

reactant

temp (°C)

80

time

yield (%)

2.1

4.3

4.4

4.5

Me

CN

H

11.3

1 h

34

46

70

52

41

29

9

CN

11.3

25

72 h

16 h

OMe

CN

11.3

25

11.10

11.1

80 (MW)

30 min

16 h

c

25

4.6

50

8 h

d

4.7

e

NMe₂

H

(1) 110, (2) 50

(1) 1 h, (2) 16 h

20 h

2.2

70

20

55

59

60

59

64

67

74

75

92

65

72

41

82

42

12

2.3

3.1

3.2

3.3

3.4

3.5

NO₂

H

80

1 h

H

SMe

CN

11.34

90 (MW)

15 min

72 h

H

25

H

Me

25

24 h

H

Br

25

48 h

H

St-Bu

NH₂

SOt-Bu

SO₂t-Bu

H

25

16 h

f

g

3.7

H

3.6

25

6 h

h

3.8

h

H

3.5

25

30 min

20 min

60 h

3.9

H

3.5

25

2.4

Br

11.8

11.28

4.14

11.4

25

4.8

Br

25

60 h

4.9

Br

CN

25

16 h

4.10

4.11

4.12

4.13

4.14

Br

OMe

H

25

16 h

C₆H₄OMe

C₆H₅

C₆H₄CN

St-Bu

SO₂t-Bu

C₆H₄SMe

90 (MW)

25

30 min

60 h

i

CN

25

16 h

<5

53

82

46

St-Bu

SO₂t-Bu

SMe

25

16 h

h

4.15

25

20 min

7 h

4.16

50

a

All Suzuki couplings were done using 2 mol equiv K₃PO₄as activator, PhMe/H₂O (9:1) as solvent, 5 mol % Pd(OAc)₂, and 10 mol % RuPhos.

b

c

MW, microwave. The compound was isolated in 41% yield. The rest of an estimated 60% yield was lost because of the lack of separation by

d

e

column chromatography. The boronic ester was used. As activator, a mixture of K₃PO₄and KF·3H₂O was used (1.2 equiv). Prepared by

palladium-catalyzed cyanation using Zn(CN)₂and 5−10 mol % Pd(PPh₃)₄in DMF. Prepared by reduction of 3.7^6b(7-(4-nitrophenyl)-2-phenyl-

f

g

h

1,8a-dihydroazulene-1,1-dicarbonitrile) using Zn(s) in neat AcOH and isolated crude. Prepared according to ref 6b. Prepared by oxidation using

i

m-CPBA in CH₂Cl₂. Isolated as byproducts.

Scheme 16. Observed Selectivity between Aryliodide and Vinylbromide and between Arylbromide and Vinylbromide in the Suzuki

Coupling on Halogen-Substituted DHAs

a

functionalizations are important for tuning the switching

properties. Indeed, recent kinetics studies on the ring-closure

Scheme 17. Reduction of Nitro-DHA 3.6

reaction of the corresponding vinylheptafulvenes showed that

the rate of this reaction was ﬁnely tuned by the electronic

character of the substituent group and its position on the system,

and the kinetics data followed Hammett correlations.

EXPERIMENTAL SECTION

General Methods. All reactions except for the Knoevenagel

condensations were done under an argon atmosphere. All reactions

■

a

Crude yield.

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Scheme 18. Oxidation of Thioether Using m-CPBA

using palladium catalyst were performed in a solvent ﬂushed with argon

by letting argon ﬂow through the solvent for at least 20 min as it was

exposed to ultrasound. All handling of photochromic compounds was

done in the dark. All operations involving DHAs (evaporation of

solvents, column chromatography, and reactions) were done in

glassware wrapped in tinfoil. Large amounts (>200 mg) of DHA

compounds in solution turn red within minutes, whereas small amounts

turn red within seconds in daylight, and traces of the VHF and/or

isomerized DHA can be observed by NMR spectroscopy. Brominations

were done in CH₂Cl₂(stabilized with amylene) using a stock solution of

bromine in CH₂Cl₂(1.00 mL Br₂in 25 mL CH₂Cl₂, 0.78 M).

Elimination reactions were performed in THF (distilled over Na/

benzophenone). THF for column chromatography were used as

purchased. Thin-layer chromatography (TLC) was carried out on

commercially available precoated plates (silica 60) with ﬂuorescence

indicator; color change from yellow to red or violet upon irradiation with

UV light (366 nm, not 254 nm) indicated the presence of a DHA. All

melting points are uncorrected, and if the compounds were not strongly

colored (like the azulenes), then they were measured on an automatic

melting-point apparatus. All spectroscopic measurements (including

photolysis) were performed in a 1 cm path length cuvette. UV−vis

absorption spectra were obtained by scanning the wavelengths from

800 to 200 nm. Absorption data for VHFs were obtained after light-

induced ring opening of the corresponding DHAs using a 150 W Xenon

arc lamp equipped with a monochromator; the DHA absorption

maximum (lowest-energy absorption) for each individual species was

chosen as the wavelength of irradiation (line width 2.5 nm). The

thermal back reaction was performed by heating the sample (cuvette)

using a Peltier unit in the UV−vis spectrophotometer. All NMR spectra

were acquired on a 500 MHz instrument equipped with a (noninverse)

cryoprobe or, in a few examples, with a broadband probe. All chemical

shift values in ¹H and ¹³C NMR spectra are referenced to the residual

solvent peak (CDCl₃δ_H= 7.26 ppm and δ_C= 77.16 ppm; CD₃CN δ_H=

7.90 (d, J = 9.0 Hz, 2H), 7.06 (s, 1H), 6.64 (dd, J = 11.1, 6.1 Hz, 1H), 6.56

(dd, J = 11.1, 6.0 Hz, 1H), 6.47 (d, J = 6.1 Hz, 1H), 6.35 (ddd, J = 10.2, 6.0,

2.1 Hz, 1H), 5.83 (dd, J = 10.2, 3.9 Hz, 1H), 3.84 (dt, J = 3.9, 2.1 Hz, 1H)

ppm. ¹³C NMR (125 MHz, CDCl₃) δ 148.2, 137.9, 137.6, 136.6, 136.3,

132.4, 130.9, 128.1, 127.1, 124.7, 123.6, 119.7, 114.7, 112.4, 51.1, 45.2 ppm.

UV−vis (MeCN) λ_max(ε) = 386 nm (17.8 × 10³M⁻¹cm⁻¹).

2-(4′-Aminophenyl)-1,8a-dihydroazulene-1,1-dicarbonitrile (1.2).

Method 1: A solution of FeSO₄(3.33 g, 124 mmol) in water (60 mL)

was added to a solution of DHA 1.1 (748 mg, 2.48 mmol) in 96% EtOH

(60 mL), and the reaction mixture was heated to reﬂux for 30 min.

Diluted aqueous ammonia (74 mL, 12%, 471 mmol) was added, and the

reaction mixture was reﬂuxed for a further 15 min. The reaction mixture

was diluted with Et₂O (150 mL), and saturated aqueous NH₄Cl

(150 mL) was added. The mixture was ﬁltered, and the organic layer was

separated. The aqueous phase was extracted with Et₂O (2 × 50 mL), the

combined organic phases were dried with MgSO₄and ﬁltered, and the

solvents were removed under vacuum. Puriﬁcation by dry column

vacuum chromatography (SiO₂, 12.6 cm², 0−100% CHCl₃/heptanes,

12.5% steps, 40 mL fractions) gave 1.2 (235 mg, 0.865 mmol, 35%) as a

yellow solid. Method 2: To a stirred suspension of DHA 1.1 (1.01 g,

3.35 mmol) in AcOH (50 mL) under an atmosphere of argon was added

zinc dust (1.01 g, 15.4 mmol), and the reaction mixture was stirred at rt

for 4 h. The resulting dark yellow suspension was diluted with Et₂O

(100 mL), and, while stirring, saturated aqueous NaHCO₃(765 mL)

was carefully added over 4−6 h, until the yellow to red color was

completely transferred into the organic phase. Caution: gas evolution.

The phases were separated, and the organic phase was washed with brine

(50 mL), dried with Na₂SO₄, ﬁltered, and concentrated in vacuo.

Puriﬁcation by dry column vacuum chromatography (SiO₂, 12.6 cm²,

0−100% CHCl₃/heptanes, 12.5% steps, 40 mL fractions) gave 1.2

(183 mg, 0.67 mmol, 20%) as a yellow solid. Method 3: A suspension of

DHA 1.9 (1.57 g, 5.00 mmol) in a mixture of 6 M aqueous HCl

(100 mL) and EtOH (100 mL) was reﬂuxed for 20 min. (The compound

should dissolve. The reaction was monitored by TLC by taking a sample

and neutralizing it with saturated aqueous NaHCO₃and extracting with

Et₂O.) The reaction mixture was allowed to cool, after which it was

carefully transferred (over the course of several hours) into a vigorously

stirring mixture of saturated aqueous NaHCO₃(525 mL) and Et₂O

(100 mL). (The yellow to red color should be in the organic layer. The pH

of the mixture should be checked.) The phases were separated, and the

aqueous layer was extracted with Et₂O (3 × 100 mL). The combined

organic phases was washed with brine (100 mL), dried with Na₂SO₄,

ﬁltered, and concentrated in vacuo. Puriﬁcation by dry column vacuum

chromatography (SiO₂, 12.6 cm², 0−100% CHCl₃/heptanes, 12.5% steps,

40 mL fractions) gave 1.2 (1.01 g, 3.72 mmol, 74%) as a yellow solid. TLC

(CHCl₃): R_f= 0.30. TLC (50% THF/heptanes): R_f= 0.50. mp 184.5−

1.96 ppm and δ_C= 1.94 ppm; DMSO-d₆δ_H= 2.50 ppm and δ_C

=

39.52 ppm), and ¹³C NMR values are given with one decimal except

for the cases with very close signals. All processing of the NMR

spectra, calculating of the coupling constants, peak-picking, and so forth

were done without exponential apodization (line broadening), but

NMR spectra presented in ESI are shown with exponential apodization

equal to 0.3−0.5 Hz.

Synthesis. 2-(4′-Nitrophenyl)-1,8a-dihydroazulene-1,1-dicarbo-

nitrile (1.1). To a stirred solution of VHF precursor 7a (prepared

from 73.24 mmol of 5.1) in 1,2-dichloroethane (250 mL) was added

tritylium tetraﬂuoroborate (25.39 g, 76.90 mmol) (the solution

immediately turned dark red), and the reaction mixture was reﬂuxed

for 1 h. The resulting dark solution was cooled to 0 °C, and Et₃N (10.21 mL,

73.24 mmol) was slowly added over 1 h, after which the temperature was

allowed to rise to rt. The now strongly red reaction mixture was reﬂuxed for

1 h (monitored by TLC) excluded from light. After the reaction mixture

cooled to rt, saturated aqueous NH₄Cl (100 mL) was added, and the

organic layer was separated. This was washed with water (100 mL) and

brine (100 mL), dried with MgSO₄, ﬁltered, and concentrated in vacuo onto

Celite. Puriﬁcation by dry column vacuum chromatography (SiO₂, 113cm²,

0−100% toluene/heptanes, 10% steps, 150 mL fractions) gave 1.1 as

a yellow oil (compounds removed should be triphenylmethane and

triphenylmethanol). Recrystallization from boiling 96% ethanol (600 mL)

gave 1.1 (11.19 g, 37.15 mmol, 51%) as yellow crystals. Crystals suitable

for X-ray crystallography were grown from methanol. TLC (toluene):

R_f= 0.37. mp 139.2−140.1 °C (methanol) (lit.^7amp 145−146 °C

185.5 °C dec (lit.^7amp 188 °C). H NMR (500 MHz, CDCl₃) δ 7.56

1

(d, J = 8.7 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 6.68 (s, 1H), 6.54 (dd, J =

11.2, 6.4 Hz, 1H), 6.41 (dd, J = 11.2, 6.1 Hz, 1H), 6.28 (ddd, J = 10.2, 6.1,

1.9 Hz, 1H), 6.24 (d, J = 6.4 Hz, 1H), 5.80 (dd, J = 10.2, 3.8 Hz, 1H), 3.99

(br s, 2H), 3.76 (dt, J = 3.8, 1.9 Hz, 1H) ppm. ¹³C NMR (125 MHz,

CDCl₃) δ 148.3, 140.6, 139.5, 131.1, 129.8, 128.4, 127.8, 127.6, 120.5,

119.2, 119.1, 115.5, 115.1, 113.0, 51.2, 45.1 ppm. UV−vis (MeCN)

λ_{max DHA}(ε) = 389 nm (37.0 × 10³M⁻¹cm⁻¹). λ_{max VHF}(ε) = 455 nm

(40.2 × 10³M⁻¹cm⁻¹).

2-(4′-Tolyl)-1,8a-dihydroazulene-1,1-dicarbonitrile (1.3). To a stirred

solution of VHF precursor 7.3 (from 73.24 mmol 5.3) in 1,2-dichloro-

ethane (250 mL) was added tritylium tetraﬂuoroborate (25.39 g,

76.90 mmol) (the solution immediately turned dark red), and the

reaction mixture was reﬂuxed for 1 h (TLC (toluene): R_f= 0.51 (7.3),

1

(methanol)). H NMR (500 MHz, CDCl₃) δ 8.34 (d, J = 9.0 Hz, 2H),

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R_f= 0.23 (VHF)). The resulting dark solution was diluted with toluene

(250 mL) and cooled to 0 °C, after which Et₃N (10.21 mL, 73.24 mmol)

was slowly added over 1 h and the temperature was then allowed to rise

to rt. The now strongly red reaction mixture was reﬂuxed for 1 h (TLC

(toluene): R_f= 0.71 (DHA)) excluded from light. The reaction mixture

was then concentrated in vacuo. Puriﬁcation by dry column vacuum

chromatography (SiO₂, 113 cm², 0−40% CH₂Cl₂/heptanes, 5% steps,

150 mL fractions) gave 1.3 (11.11 g, 41.09 mmol, 56%) as yellow

crystals with minor impurities. Recrystallization from boiling heptanes

or EtOH gave 1.3 (9.507 g, 35.17 mmol, 48%) as yellow crystals.

Crystals suitable for X-ray crystallography was grown from CHCl₃/

heptanes. Alternatively, puriﬁcation can also be accomplished by

extraction with boiling heptanes (5 × 250 mL) followed by cooling to rt.

The resulting dark yellow or even black crystals were then recrystallized

from boiling heptanes while treating with activated carbon to give 1.3

(7.097 g, 26.26 mmol to 14.16 g, 51.20 mmol, 36−71%) as yellow

crystals. TLC (50% CH₂Cl₂/heptanes): R_f= 0.48. mp 150.8−152.0 °C

(ethanol) (lit.^7amp 151 °C). ¹H NMR (500 MHz, CDCl₃) δ 7.66−7.62

(m, 2H), 7.30−7.26 (m, 2H), 6.84 (s, 1H), 6.56 (dd,

J = 11.2, 6.4 Hz, 1H), 6.46 (dd, J = 11.2, 6.1 Hz, 1H), 6.31 (dd, J =

10.0, 6.4 Hz), 6.30−6.24 (m, 1H), 5.82 (dd, J = 10.0, 3.6 Hz, 1H), 3.78

(dd, J = 3.6, 1.8 Hz, 1H), 2.41 (s, 3H) ppm. ¹³C NMR

(125 MHz, CDCl₃) δ 140.6, 140.5, 139.1, 131.5, 131.4, 130.8, 130.1,

127.8, 127.7, 126.3, 120.6, 119.6, 115.4, 113.0, 51.3, 45.3, 21.6 ppm. UV−vis

(MeCN) λ_DHA(ε): 358 nm (20.0 ×10³M⁻¹cm⁻¹). λ_VHF(ε): 470 nm (31.4 ×

10³M⁻¹cm⁻¹).

115.2, 112.8, 51.3, 45.5 ppm. Anal. Calcd for C₁₈H₁₁N₂F (274.29): C, 78.81;

H, 4.04; N, 10.22. Found: C, 78.64; H, 3.83; N, 10.22. MS (ESP+): m/z

297 [MNa⁺]. UV−vis (MeCN) λ_DHA(ε): 354 nm (17.8 × 10³M⁻¹cm⁻¹).

λ_VHF(ε): 474 nm (29.0 × 10³M⁻¹cm⁻¹).

2-(4′-Methoxyphenyl)-1,8a-dihydroazulene-1,1-dicarbonitrile

(1.7). Prepared according to the general procedure for 1.1: 7.7

(prepared from 73.24 mmol of 5.7) and tritylium tetraﬂuoroborate

(25.39 g, 76.90 mmol) in 1,2-dichloroethane (250 mL), were reﬂuxed

for 1 h and then diluted with toluene (250 mL). The reaction mixture

was cooled to 0 °C, and Et₃N (10.21 mL, 73.24 mmol) was added over

the course of 1 h. The reaction mixture was allowed to reach rt, after

which it was reﬂuxed for 1 h. The resulting black reaction mixture was

then concentrated on Celite, and puriﬁcation by dry column vacuum

chromatography (SiO₂, 113 cm², 0−75% toluene/heptanes, 6.25%

steps, 80 mL fractions) followed by recrystallization from boiling

heptanes (600 mL) gave 1.7 (13.77 g, 48.09 mmol, 66%) as yellow

crystals. Alternatively, the crude reaction mixture can be puriﬁed without

the use of column chromatography by the following procedure. The

reaction mixture was concentrated in vacuo, and the residue was

extracted with boiling heptanes (6 × 250 mL). The extracts were not

combined but were allowed to cool to rt separately. The resulting yellow

precipitates were then subjected to TLC analysis, and the samples of

similar purity (the two ﬁrst extracts) were combined and recrystallized

separately from boiling heptanes (250−350 mL) using activated carbon,

which gave 1.7 (10.76 g, 37.61 mmol, 51%) as yellow crystals. Crystals

suitable for X-ray crystallography were grown from ethanol. TLC

(toluene): R_f= 0.45. mp 125.8−126.8 °C (heptanes)(lit.^7amp 125−126 °C

(MeOH)). ¹H NMR (500 MHz, CDCl₃) δ 7.69 (d, J = 9.0 Hz, 2H), 6.99

(d, J = 9.0 Hz, 2H), 6.75 (s, 1H), 6.55 (dd, J = 11.2, 6.3 Hz, 1H), 6.44

(dd, J = 11.2, 6.3 Hz, 1H), 6.31−6.28 (m, 2H), 5.82 (dd, J = 10.3, 3.8 Hz,

1H), 3.86 (s, 3H), 3.78 (dt, J = 3.8, 1.9 Hz, 1H) ppm. ¹³C NMR (125 MHz,

CDCl₃) δ 161.2, 140.2, 139.2, 131.1, 130.5, 130.3, 128.0, 127.8, 123.2,

120.1, 119.5, 115.4, 114.9, 113.0, 55.6, 51.3, 45.4 ppm. UV−vis (MeCN)

λ_{max DHA}(ε) = 365 nm (20.0 × 10³M⁻¹cm⁻¹). λ_{max VHF}(ε) = 471 nm

(25.3 × 10³M⁻¹cm⁻¹).

2-(4′-Iodophenyl)-1,8a-dihydroazulene-1,1-dicarbonitrile (1.4).^8f

TLC (toluene): R_f= 0.73. UV−vis (MeCN) λ_DHA(ε): 358 nm

(26.2 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 476 nm (33.8 × 10³M⁻¹cm⁻¹).

2-(3′-Iodophenyl)-1,8a-dihydroazulene-1,1-dicarbonitrile (1.5).

Prepared according to the general procedure for 1.1: 7.5 (prepared

from 22.2 mmol of 5.5) and tritylium tetraﬂuoroborate (7.792 g, 23.31 mmol,

1.05 equiv) in 1,2-dichloroethane (100 mL) were reﬂuxed for 1 h.

Afterward, it was diluted with toluene (100 mL), the reaction mixture

was cooled to 0 °C, and Et₃N (3.09 mL, 22.2 mmol) was added over the

course of 1 h. The reaction mixture was allowed to reach rt, after which it

was reﬂuxed for 1 h. The resulting black reaction mixture was then

concentrated on Celite. Puriﬁcation by dry column vacuum chromatog-

raphy (SiO₂, 28.3 cm², 0−87.5% chloroform/heptanes, 6.25% steps,

80 mL fractions) followed by recrystallization from heptanes (300 mL)

gave 1.5 (4.25 g, 11.11 mmol, 50%) as yellow crystals. TLC (toluene):

R_f= 0.72. mp 101.9−105.4 °C (heptanes). ¹H NMR (500 MHz, CDCl₃) δ

8.02 (t, J = 1.7 Hz, 1H), 7.82−7.68 (m, 2H), 7.22 (t, J = 7.9 Hz, 1H), 6.89

(s, 1H), 6.58 (dd, J = 11.3, 6.3 Hz, 1H), 6.50 (dd, J = 11.3, 6.1 Hz, 1H),

6.37 (d, J = 6.3 Hz, 1H), 6.31 (ddd, J = 10.2, 6.1, 2.1 Hz, 1H), 5.81 (dd,

J = 10.2, 3.8 Hz, 1H), 3.78 (dt, J = 3.9, 2.1 Hz, 1H) ppm. ¹³C NMR

(125 MHz, CDCl₃) δ 139.0, 138.4, 138.3, 135.3, 133.7, 132.8, 131.5, 1310,

130.9, 127.9, 125.3, 121.9, 119.6, 115.0, 112.6, 95.1, 51.2, 45.2 ppm. Anal.

Calcd for C₁₈H₁₁N₂I (382.20): C, 56.57; H, 2.90; N, 7.33. Found: C,

56.58; H, 2.54; N, 7.25. HRMS (ESI+): m/z 383.0025 [MH⁺] calcd for

(C₁₈H₁₂N₂I ⁺): m/z 383.0040. UV−vis (MeCN) λ_DHA(ε): 358 nm

(16.0 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 478 nm (28.3 × 10³M⁻¹cm⁻¹).

2-(4′-Fluorophenyl)-1,8a-dihydroazulene-1,1-dicarbonitrile (1.6).

To a stirring solution 7.6 (8.30 g, 30.0 mmol) in CH₂Cl₂(300 mL) was

added tritylium tetraﬂuoroborate (11.30 g, 34.2 mmol) and the resulting

mixture was stirred 16 h at rt, covered from light. The vessel was placed

in an ice bath and NEt₃(4.5 mL, 31.2 mmol) was added carefully over

10 min and the mixture was allowed to stir for 1 h. The solvent was

removed in vacuum and the crude residue was dissolved in acetonitrile

(50 mL) and the vessel subjected to heating at 50 °C for 20 min. The

solvent was again removed and the crude materialpuriﬁed by ﬂash column

chromatography (SiO₂, eluent: 50% CH₂Cl₂/heptane) to obtain pure

DHA 1.6 as a yellow crystalline solid (2.82 g, 10.3 mmol, 34%). TLC

2-(4′-Bromophenyl)-1,8a-dihydroazulene-1,1-dicarbonitrile (1.8).

Prepared according to the general procedure for 1.1: 7.8 (prepared from

73.24 mmol of 5.8) and tritylium tetraﬂuoroborate (25.39 g, 76.90 mmol)

in 1,2-dichloroethane (250 mL) were reﬂuxed for 1 h and then diluted

with toluene (250 mL). The reaction mixture was cooled to 0 °C, and

Et₃N (10.21 mL, 73.24 mmol) was added over the course of 1 h. The

reaction mixture was allowed to reach rt, after which it was reﬂuxed for 1 h.

Puriﬁcation by dry column vacuum chromatography (SiO₂, 113 cm²,

0−75% CHCl₃/heptanes, 6.25% steps, 160 mL fractions) followed by

recrystallization from boiling heptanes (1150 mL) gave 1.8 (16.32 g,

48.69 mmol, 66%) as yellow crystals. TLC (toluene): R_f= 0.80. mp

157.2−157.8 °C (heptanes) (lit.^7amp 151 °C). H NMR (500 MHz,

1

CDCl₃) δ 7.60 (br s, 4H), 6.88 (s, 1H), 6.57 (dd, J = 11.3, 6.3 Hz, 1H),

6.49 (dd, J = 11.3, 6.1 Hz, 1H), 6.36 (d, J = 6.3 Hz, 1H), 6.31 (ddd, J =

10.2, 6.1, 2.1 Hz, 1H), 5.81 (dd, J = 10.2, 3.8 Hz, 1H), 3.79 (dt, J = 3.8, 2.1

Hz, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 139.1, 138.5, 133.1, 132.7,

131.4, 131.0, 129.5, 127.9, 127.8, 124.6, 121.6, 119.6, 115.1, 112.7, 51.2,

45.3 ppm. UV−vis (MeCN): λ_DHA(ε): 360 nm (19.4 × 10³M⁻¹cm⁻¹).

λ_VHF(ε): 474 nm (30.8 × 10³M⁻¹cm⁻¹).

2-(4′-Acetaminophenyl)-1,8a-dihydroazulene-1,1-dicarbonitrile

(1.9). To a stirred solution of VHF precursor 7.9 (6.30 g, 20.0 mmol) in

1,2-dichloroethane (200 mL) was added tritylium tetraﬂuoroborate

(7.26 g, 22.0 mmol). The reaction mixture was heated to reﬂux for 1 h,

after which it was cooled to 0 °C, and NEt₃(3.00 mL, 22.0 mmol) was

added dropwise. The now strongly red reaction mixture was allowed to

reach rt over 1 h and was then stirred for 3 h. The now red reaction

mixture was then concentrated on Celite, and puriﬁcation by dry column

vacuum chromatography (SiO₂, 28.3 cm², 0−100% EtOAc/heptanes,

6.25% steps, then 6× fractions of neat EtOAc to collect product, 80 mL

fractions; the compound moved very diﬀerently on the column

compared to the movement on TLC) gave 1.9 (4.40 g, 14.1 mmol,

70%) as a yellow solid (crude fractions can be recrystallized from boiling

EtOAc/heptanes). TLC (60% EtOAc/heptanes) R_f= 0.23−0.33. mp

207−209 °C dec. ¹H NMR (500 MHz, DMSO-d₆) δ 10.23 (s, 1H), 7.74

(s, 4H), 7.34 (s, 1H), 6.58 (dd, J = 11.3, 6.5 Hz, 1H), 6.45 (d, J = 11.3,

1

(50% CH₂Cl₂/heptane): R_f= 0.38. mp 119.5−121.0 °C. H NMR

(500 MHz, CDCl₃) δ 7.73 (dd, J = 8.7, 5.1 Hz, 2H), 7.17 (dd, J = 8.7, 8.7

Hz, 2H), 6.82 (s, 1H), 6.57 (dd, J = 11.3, 6.3 Hz, 1H), 6.48 (dd, J = 11.3,

6.1 Hz, 1H), 6.35−6.30 (m, 2H), 5.81 (dd, J = 10.2, 3.8 Hz, 1H), 3.79 (dt,

J = 3.8, 1.9 Hz, 1H)ppm. ¹³C NMR (125 MHz, CDCl₃) δ 163.7 (d, J = 252

Hz), 139.2, 138.6, 132.4 (d, J = 2.0 Hz), 131.1 (d, J = 9.5 Hz), 128.4

(d, J = 8.4 Hz), 127.8, 127.0 (d, J = 3.6 Hz), 121.2, 119.5, 116.7, 116.6,

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The Journal of Organic Chemistry

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6.5, 1H), 6.43 (d, J = 6.2, 1H), 6.35 (ddd, J = 10.2, 6.2, 2.1 Hz, 1H), 5.71

(dd, J = 10.2, 3.7 Hz, 1H), 3.92 (dt, J = 3.7, 2.1 Hz, 1H), 2.08

(s, 3H) ppm. ¹³C NMR (125 MHz, DMSO-d₆) δ 168.7, 140.7, 138.7,

138.5, 132.1, 130.9, 130.3, 127.7, 126.8, 124.7, 120.9, 119.5, 119.2, 115.1,

113.1, 50.6, 44.9, 24.1 ppm. Anal. Calcd for C₂₀H₁₅N₃O (313.35): C,

76.66; H, 4.82; N, 13.41. Found: C, 76.56; H, 4.82; N, 13.47. MS

(MALDI−): m/z 313 [M⁻]. UV−vis (MeCN): λ_DHA(ε): 369 nm

(27.5 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 472 nm (24.8 × 10³M⁻¹cm⁻¹).

2-(4′-Cyanophenyl)-1,8a-dihydroazulene-1,1-dicarbonitrile

(1.10). Method 1: To a solution of iodo-DHA 1.4 (1.77 g, 4.63 mmol) in

dry argon-ﬂushed DMF (10 mL) in a glass container suitable for

microwave irradiation were added tetrakis(triphenylphosphine)-

palladium(0) (107 mg, 92.6 μmol, 2 mol %) and Zn(CN)₂(326 mg,

2.78 mmol), and the reaction mixture was heated by microwave

irradiation at 70 °C for 2 h. The reaction mixture was allowed to cool to

rt, and it was then poured into EtOAc (100 mL) and washed with brine

(3 × 50 mL). The water phases were kept and extracted with EtOAc

(3 × 50 mL). The combined organic phases were washed with water

(3 × 50 mL), dried with MgSO₄, ﬁltered, and concentrated in vacuo.

Puriﬁcation by dry column vacuum chromatography (SiO₂, 12.6 cm²,

0−100% toluene/heptanes, 10% steps, then 10 × 40 mL neat toluene,

40 mL fractions) gave 1.10 (1.25 g, 4.44 mmol, 96%) as a yellow solid.

Recrystallization from EtOH (150 mL) gave 1.10 (950 mg, 3.38 mmol,

73%) as yellow crystals. TLC (toluene): R_f= 0.23. mp 214 °C dec. ¹H

NMR (500 MHz, CDCl₃) δ 7.83 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8 Hz,

2H), 7.01 (s, 1H), 6.60 (dd, J = 11.2, 6.1 Hz, 1H), 6.55 (dd, J = 11.2,

6.0 Hz, 1H), 6.45 (d, J = 6.1 Hz, 1H), 6.34 (ddd, J = 10.2, 6.0, 2.1 Hz,

1H), 5.82 (dd, J = 10.2, 3.8 Hz, 1H), 3.82 (dt, J = 3.8, 2.1 Hz, 1H) ppm.

¹³C NMR (125 MHz, CDCl₃) δ 138.0, 137.9, 135.6, 134.8, 133.1, 132.3,

(d, J =9.8Hz, 1H), 8.49 (d, J = 9.8 Hz, 1H), 8.14 (d, J = 8.6 Hz, 2H), 7.88

(t, J = 9.8 Hz, 1H), 7.81 (d, J = 8.6 Hz, 2H), 7.61 (t, J = 9.8 Hz, 1H), 7.57

(s, 1H), 7.56 (t, J = 9.8 Hz, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ

149.3, 145.7, 142.6, 140.4, 139.4, 138.9, 137.2, 133.0, 129.2, 128.7, 128.4,

118.7, 117.6, 117.0, 112.8, 94.6 ppm. Anal. Calcd for C₁₈H₁₀N₂

(256.30): C, 84.35; H, 4.72; N, 10.93. Found: C, 83.91; H, 4.94; N,

10.82. MS (MALDI−): m/z 256 [M⁻].

2-(3′-Cyanophenyl)-1,8a-dihydroazulene-1,1-dicarbonitrile

(1.11). To a stirred solution of 1.5 (526 mg, 1.38 mmol) in argon-

ﬂushed DMF (8 mL) in a glass container suitable for microwave

irradiation were added Pd(PPh₃)₄(31.8 mg, 27.5 μmol, 2 mol %) and

Zn(CN)₂(96.9 mg, 0.826 mmol), and the reaction mixture was heated

by microwave irradiation at 70 °C for 3 h. The reaction mixture was

allowed to cool to rt and was then poured into EtOAc (100 mL) and

washed with brine (3 × 50 mL). The water phases were kept and

extracted with EtOAc (3 × 50 mL). The combined organic phases were

then washed with water (3 × 50 mL), dried with MgSO₄, ﬁltered, and

concentrated in vacuo. Puriﬁcation by dry column vacuum chromatog-

raphy (SiO₂, 12.6 cm², 0−100% toluene/heptanes, 10% steps, then 10 ×

40 mL neat toluene, 40 mL fractions) gave 1.11 (325 mg, 1.16 mmol,

84%) as a yellow solid. Recrystallization from heptanes (75 mL) gave

1.11 (268 mg, 0.953 mmol, 69%) as a yellow powder. TLC (toluene):

1

R_f= 0.27. mp 146.0−147.3 °C. H NMR (500 MHz, CDCl₃) δ 7.99

(ddd, J = 7.9, 2.0, 1.1 Hz, 1H), 7.99−7.96 (m, 1H), 7.71 (dt, J = 7.9, 1.3,

1H), 7.63 (dt, J = 7.9, 0.7 Hz, 1H), 6.96 (s, 1H), 6.60 (ddt, J = 11.3, 6.3,

0.7 Hz, 1H), 6.54 (dd, J = 11.3, 6.1 Hz, 1H), 6.43 (d, J = 6.3 Hz, 1H),

6.34 (dddt, J = 10.2, 6.1, 2.1, 0.7 Hz, 1H), 5.81 (dd, J = 10.2, 3.8 Hz, 1H),

3.81 (dt, J = 3.9, 2.1 Hz, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ

137.9, 137.6, 134.9, 133.0, 132.04, 132.02, 130.9, 130.4, 130.04, 129.95,

128.0, 122.8, 119.6, 118.0, 114.7, 114.1, 112.4, 51.1, 45.3 ppm. Anal.

Calcd for C₁₉H₁₁N₃(281.31): C, 81.12; H, 3.94; N, 14.94. Found: C,

81.23; H, 3.71; N, 15.06. HRMS (ESP+): m/z 304.0846 [MNa⁺],

130.9, 128.1, 126.8, 123.2, 119.7, 118.2, 114.8, 113.4, 112.4, 51.1, 45.1

ppm. Anal. Calcd for (C₁₉H₁₁N₃): C, 81.12; H, 3.94; N, 14.94. Found: C,

1

81.22; H, 4.02; N, 14.83. Corresponding VHF: H NMR (500 MHz,

calcd for (C₁₉H₁₁N₃Na⁺): m/z 304.0845. UV−vis (MeCN) λ_DHA

351 nm. λ_VHF: 479 nm.

:

CDCl₃) δ 7.79 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 6.80−6.73

(m, 1H), 6.52−6.46 (m, 2H), 6.41−6.35 (m, 1H), 6.35 (d, J = 4.2 Hz,

1H), 6.00 (dd, J = 12.0, 8.0 Hz, 1H), 5.79 (dd, J = 12.0, 2.9 Hz, 1H) ppm.

¹³C NMR (125 MHz, CDCl₃) δ 166.3, 154.4, 142.6, 139.8, 136.6, 135.7,

135.4, 135.0, 134.9, 133.6, 129.3, 118.3, 117.9, 114.9, 114.6, 114.1 ppm

2-[4′-(3″-Furyl)phenyl]-1,8a-dihydroazulene-1,1-dicarbonitrile

(1.12). To a stirred solution of iodo-DHA 1.4 (143.0 mg, 0.3741 mmol)

in a mixture of argon-ﬂushed toluene (4.5 mL) and water (0.5 mL) were

added 3-furyl boronic acid (69.3 mg, 0.619 mmol), K₃PO₄(319 mg,

1.50 mmol), RuPhos (48.4 mg, 0.10 mmol, 27 mol %), and Pd(OAc)₂

(11.6 mg, 0.05 mmol, 13 mol %), and the reaction mixture was stirred for

72 h at rt. The reaction mixture was diluted with Et₂O (50 mL), washed

with saturated aqueous NH₄Cl (2 × 50 mL), dried with MgSO₄, ﬁltered,

and concentrated in vacuo. The residue was redissolved in CH₂Cl₂and

concentrated on Celite. Puriﬁcation by dry column vacuum chromatog-

raphy (SiO₂, 12.6 cm², 0−40% toluene/heptanes, 5% steps, then 40−65%

toluene/heptanes, 2.5% fractions, 40 mL fractions) gave 1.12 (84.4 mg,

0.262 mmol, 70%) as a yellow to red solid. TLC (toluene): R_f= 0.62

(orange to red). mp 161.7−162.7 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.81

(dd, J = 1.4, 0.9 Hz, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.59 (d, J = 8.7 Hz, 2H),

7.51 (dd, J = 1.9, 1.4 Hz, 1 H), 6.89 (s, 1H), 6.74 (dd, J = 1.9, 0.9 Hz, 1H),

6.58 (dd, J = 11.3, 6.4 Hz, 1H), 6.48 (dd, J = 11.3, 6.1 Hz, 1H), 6.35 (d, J =

6t.4 Hz, 1H), 6.31 (ddd, J = 10.2, 6.1, 2.1 Hz, 1H), 5.83 (dd, J = 10.2, 3.8

Hz, 1H), 3.80(dt, J = 3.8, 2.1 Hz, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃)

δ 144.2, 140.0, 139.4, 138.9, 134.3, 131.9, 131.1, 131.0, 129.1, 127.8, 126.9,

126.6, 125.8, 121.0, 119.6, 115.3, 112.9, 108.7, 51.3, 45.3 ppm. Anal. Calcd

for C₂₂H₁₄N₂O (322.36): C, 81.97; H, 4.38; N, 8.69. Found: C, 81.37; H,

4.01; N, 8.64. HRMS (ESP+): m/z 345.1001 [MNa⁺], calcd for

(C₂₂H₁₄N₂ONa⁺): m/z 345.0998. UV−vis (MeCN) λ_DHA(ε): 370 nm

(18.5 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 475 nm (20.7 × 10³M⁻¹cm⁻¹).

2-[4′-(2″-Furyl)phenyl]-1,8a-dihydroazulene-1,1-dicarbonitrile

(1.13). To a stirred solution of iodo-DHA 1.4 (104.9 mg, 0.274 mmol)

in a mixture of argon-ﬂushed toluene (9 mL) and water (1 mL) were

added 2-furyl boronic acid (122.6 mg, 1.100 mmol), K₃PO₄(122 mg,

0.574 mmol), Xantphos (11.2 mg, 0.019 mmol, 7.1 mol %), and

Pd₂(dba)₃(8.9 mg, 0.0097 mmol, 3.5 mol %) (the reaction mixture took

a red color, which slowly faded to yellow). The reaction mixture was

stirred for 48 h at 50 °C. The reaction mixture was diluted with Et₂O

(50 mL),washed with saturated aqueous NH₄Cl (2 × 50 mL), dried with

MgSO₄, ﬁltered, and concentrated in vacuo. The residue was redissolved

in CH₂Cl₂and concentrated on Celite. Puriﬁcation by dry column

(1 signal is missing because of overlap). UV−vis (MeCN) λ_DHA

:

368 nm. λ_VHF: 482 nm. Method 2: To a solution of bromo-DHA 1.8

(3.84 g, 11.4 mmol) in argon-ﬂushed DMF (15 mL) in a glass container

suitable for microwave irridiation were added Pd(OAc)₂(64.3 mg,

286 μmol), RuPhos (267 mg, 573 umol), and Zn(CN)₂(803 mg, 6.84 mmol),

and the reaction mixture was heated by means of microwave irradiation at 70 °C

for 30 min followed by 90 °C for 30 min. No reaction was observed. To the

resulting black reaction mixture was added tetrakis(triphenylphosphine)-

palladium(0) (662 mg, 573 μmol, 5 mol %), and the reaction mixture was

heated by microwave irridiation at 90 °C for 60 min. The reaction mixture

was allowed to cool to rt and was then poured into Et₂O (200 mL), washed

with brine (100 mL), water (2 × 100 mL), and then with brine (100 mL)

again (to prevent emulsions). The combined organic phases were dried

with MgSO₄, ﬁltered, and concentrated in vacuo. Puriﬁcation by dry

column vacuum chromatography (SiO₂, 12.6 cm², 0−100% toluene/

heptanes, 10% steps, 40 mL fractions) gave 1.8 (1.54 g, 4.56 mmol, 40%) as

a yellow solid, 2-(4-bromophenyl)azulene-1-carbonitrile 9.8 as a purple

solid with minor impurities, 1.10 (1.13g, 3.99 mmol, 35%) as a yellow solid,

and 2-(4-cyanophenyl)azulene-1-carbonitrile 9.10 (312 mg, 1.25 mmol,

11%) as a purple solid. For 1.10: spectroscopic data are identical to those of

1.10 described above. For 9.8: recrystallization from EtOH (50 mL) gave

2-(4-bromophenyl)azulene-1-carbonitrile 9.8 (316 mg, 1.03 mmol, 9%) as

a purple solid. mp 162.5−163.0 °C (ethanol). ¹H NMR (500 MHz, CDCl₃)

δ 8.65 (d, J = 9.8 Hz, 1H), 8.42 (d, J = 9.7 Hz, 1H), 7.93 (d, J = 8.5 Hz, 2H),

7.81 (t, J = 9.8 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.56 (t, J = 9.8 Hz, 1H),

7.52 (s, 1H), 7.50 (t, J = 9.8 Hz, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ

150.8, 145.8, 142.7, 139.4, 138.4, 136.2, 133.4, 132.5, 130.2, 128.4, 128.1,

124.1, 118.0, 116.4, 94.2 ppm. Anal. Calcd for C₁₇H₁₀BrN (308.17): C,

66.26; H, 3.27; N, 4.55. Found: C, 66.18; H, 3.06; N, 4.45. MS (MALDI+):

m/z 307, 309 [MH⁺Br^79/81]. For 9.10: recrystallization from EtOH

(80 mL) gave 2-(4-cyanophenyl)azulene-1-carbonitrile 9.10 (145 mg,

0.572 mmol, 5.0%) as dark-purple needles. For 9.10: TLC (toluene): R_f=

1

0.10. mp 220−222 °C (ethanol). H NMR (500 MHz, CDCl₃) δ 8.71

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vacuum chromatography (SiO₂, 12.6 cm², 0−70% toluene/heptanes,

10% steps, then 70−90% toluene/heptanes, 5% steps, 40 mL fractions)

gave 1.13 (79.7 mg, 0.247 mmol, 91%) as a yellow solid. TLC (75%

toluene/heptanes): R_f= 0.38 (yellow → red). mp 158.4−160.8 °C. ¹H

NMR (500 MHz, CDCl₃) δ 7.76 (s, 1H), 7.52 (dd, J = 1.8, 0.7 Hz, 1H),

6.90(s, 1H), 6.76 (dd, J = 3.4, 0.7 Hz, 1H), 6.57 (dd, J = 11.2, 6.4 Hz,

1H), 6.51 (dd, J = 3.4, 1.8 Hz, 1H), 6.47 (dd, J = 11.2, 6.1 Hz, 1H), 6.35

(d, J = 6.4 Hz, 1H), 6.31 (ddd, J = 10.2, 6.1, 2.1 Hz, 1H), 5.83 (dd, J =

10.2, 3.9 Hz, 1H), 3.80 (dt, J = 3.9, 2.1 Hz, 1H) ppm. ¹³C NMR (125

MHz, CDCl₃) δ 153.1, 143.1, 139.9, 138.9, 132.3, 132.0, 131.1, 131.0,

129.2, 127.8, 126.8, 124.5, 121.0, 119.6, 115.3, 112.9, 112.2, 106.9, 51.3,

45.2 ppm. Anal. Calcd for C₂₂H₁₄N₂O (322.36): C, 81.97; H, 4.38; N,

8.69. Found: C, 81.92; H, 4.25; N, 8.77. HRMS (ESP+): m/z 345.0997

[MNa⁺], calcd for (C₂₂H₁₄N₂ONa⁺): m/z 345.0998. UV−vis

(MeCN) λ_DHA(ε): 382 nm (25.2 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 476 nm

(21.3 × 10³M⁻¹cm⁻¹).

2-[3′-(2″-Thienyl)phenyl]-1,8a-dihydroazulene-1,1-dicarbonitrile

(1.16). To a stirred solution of 1.5 (164 mg, 0.429 mmol) in a mixture of

argon-ﬂushed toluene (18 mL) and water (2 mL), were added 2-thienyl

boronic acid (110 mg, 0.857 mmol), K₃PO₄(182 mg, 0.857 mmol),

Pd₂(dba)₃(19.6 mg, 0.0214 mmol), and Xantphos (12.4 mg, 0.0215 mmol),

and the reaction mixture was stirred at 50 °C for 2 h. The resulting dark

yellow reaction mixture was diluted with Et₂O (100 mL), washed with

saturated aqueous NH₄Cl (3 × 50 mL), dried with MgSO₄, ﬁltered, and

concentrated in vacuo. The residue was redissolved in CH₂Cl₂and

concentrated on Celite. Puriﬁcation by dry column vacuum chromato-

graphy (SiO₂, 12.6 cm², 0−50% toluene/heptanes, 10% steps, then 50−

75%, 5% steps, 40 mL fractions) gave 1.16 (133 mg, 0.335 μmol, 78%)

as a bright yellow solid. TLC (75% toluene/heptanes): R_f= 0.41

(yellow → red). mp 135.1−136.2 °C. ¹H NMR (500 MHz, CDCl₃) δ

7.96 (dt, J = 1.9, 0.5 Hz, 1H), 7.68−7.65 (m, 2H), 7.52 (t, J = 7.8 Hz,

1H), 7.41 (dd, J = 3.6, 1.0 Hz, 1H), 7.37 (dd, J = 5.1, 1.0 Hz, 1H), 7.15

(dd, J = 5.1, 3.6 Hz, 1H), 6.97 (s, 1H), 6.61 (dd, J = 11.3, 6.3 Hz, 1H),

6.52 (dd, J = 11.3, 6.1 Hz, 1H), 6.41 (d, J = 6.3 Hz, 1H), 6.32 (ddd, J =

10.2, 6.1, 2.1 Hz, 1H), 5.83 (dd, J = 10.2, 3.8 Hz, 1H), 3.84 (dt, J = 3.8,

2.1 Hz, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 143.3, 139.9, 138.7,

135.7, 133.1, 131.3, 131.2, 131.0, 130.0, 128.4, 127.8, 127.7, 125.8, 125.2,

124.1, 123.9, 121.4, 119.7, 115.3, 112.8, 51.3, 45.5 ppm. Anal. Calcd for

C₂₂H ₁₄N₂S (338.43): C, 78.08; H, 4.17; N, 8.28. Found: C, 77.98; H,

4.21; N, 8.20. HRMS (ESP+): m/z 361.0761 [MNa⁺], calcd for

(C₂₂H ₁₄N₂S): m/z 361.0770. UV−vis (MeCN) λ_DHA(ε): 358 nm

(22.8 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 475 nm (23.1 × 10³M⁻¹cm⁻¹).

2-[3′-(3″-Thienyl)phenyl]-1,8a-dihydroazulene-1,1-dicarbonitrile

(1.17). Method 1: To a stirred solution of iodo-DHA 1.5 (152.2 mg,

0.3532 mmol) in a mixture of argon-ﬂushed toluene (4.5 mL) and water

(0.5 mL) were added 3-thienyl boronic acid (108.4 mg, 0.847 mmol),

K₃PO₄(113 mg, 0.532 mmol), RuPhos (16.6 mg, 0.035 mmol, 10 mol %),

and Pd(OAc)₂(4.0 mg, 0.018 mmol, 5 mol %), and the reaction mixture

was stirred for 16 h at 50 °C. To the dark yellow reaction mixture, RuPhos

(16.6 mg, 0.035 mmol, 10 mol %) and Pd(OAc)₂(4.0 mg, 0.018 mmol,

5 mol %) were added again, and it was then stirred for another 16 h at

50 °C. The reaction mixture was diluted with ether (50 mL), washed with

saturated aqueous NH₄Cl (2 × 50 mL), dried with MgSO₄, ﬁltered, and

concentrated in vacuo. The residue was redissolved in CH₂Cl₂and

concentrated on Celite. Puriﬁcation by dry column vacuum chromatog-

raphy (SiO₂, 12.6 cm², 0−50% toluene/heptanes, 5% steps, then

50−62.5% toluene/heptanes, 2.5% steps, 40 mL fractions) gave 1.17

(24.9 mg, 0.0736 mmol, 19%) as a yellow to red solid and 1.5 (21.2 mg,

0.0555 mmol, 14%) as a yellow solid. Method 2: To the stirred solution of

iodo-DHA 1.5 (106.8 mg, 0.279 mmol) in a mixture of argon-ﬂushed

toluene (9 mL) and water (1 mL) were added 3-thienyl boronic acid

(60.2 mg, 0.470 mmol), K₃PO₄(122 mg, 0.574 mmol), Xantphos (12.6 mg,

0.0218 mmol, 7.8 mol %), and Pd₂(dba)₃(10.3 mg, 0.0112 mmol, 3.9 mol %),

and the reaction mixture was stirred for 16 h at 50 °C. The reaction

mixture was diluted with ether (50 mL), washed with saturated aqueous

NH₄Cl (2 × 50 mL), dried with MgSO₄, ﬁltered, and concentrated in

vacuo. The residue was redissolved in CH₂Cl₂and concentrated on Celite.

Puriﬁcation by dry column vacuum chromatography (SiO₂, 12.6 cm²,

0−50% toluene/heptanes, 5% steps, then 50−62.5% toluene/heptanes,

2.5% steps, 40 mL fractions) gave 1.17 (57.2 mg, 0.169 mmol, 60%)

as a yellow solid. For 1.17: TLC (75% toluene/heptanes): R_f= 0.41

2-[4′-(2″-Thienyl)phenyl]-1,8a-dihydroazulene-1,1-dicarbonitrile

(1.14). To a stirred solution of iodo-DHA 1.4 (148.6 mg, 0.3888 mmol)

in a mixture of argon-ﬂushed toluene (9 mL) and water (1 mL) were

added 2-thienyl boronic acid (128.0 mg, 1.000 mmol), K₃PO₄(212 mg,

1.000 mmol), Xantphos (39 mg, 0.068 mmol, 18 mol %), and Pd(OAc)₂

(7.6 mg, 0.034 mmol, 9 mol %), and the reaction mixture was stirred for

16 h at 50 °C. The resulting dark yellow reaction mixture was diluted

with Et₂O (50 mL), washed with saturated aqueous NH₄Cl (2 × 50 mL),

dried with MgSO₄, ﬁltered, and concentrated in vacuo. The residue was

redissolved in CH₂Cl₂and concentrated on Celite. Puriﬁcation by dry

column vacuum chromatography (SiO₂, 12.6 cm², 0−60% toluene/

heptanes, 5% steps, then 60−75% toluene/heptanes, 2.5% steps, 40 mL

fractions) gave 1.14 (80.7 mg, 238 μmol, 61%) as a dark yellow solid. A

stable crystalline solid can be obtained by recrystallization from CHCl₃/

1

heptanes. TLC (toluene): R_f= 0.69. mp 159.0−159.6 °C. H NMR

(500 MHz, CDCl₃) δ 7.75 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H),

7.40 (dd, J = 3.6, 1.1 Hz, 1H), 7.35 (dd, J = 5.1, 1.1 Hz, 1H), 7.12 (dd, J =

5.1, 3.6 Hz, 1H), 6.90 (s, 1H), 6.58 (dd, J = 11.2, 6.3 Hz, 1H), 6.48

(dd, J = 11.2, 6.1 Hz, 1H), 6.36 (d, J = 6.3 Hz, 1H), 6.32 (ddd, J = 10.2,

6.1, 2.1 Hz, 1H), 5.83 (dd, J = 10.2, 3.8 Hz, 1H), 3.80 (dt, J = 3.8, 2.1 Hz,

1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 143.2, 139.8, 138.9, 136.1,

132.1, 131.1, 131.1, 129.4, 128.5, 127.8, 126.9, 126.6, 126.1, 124.2, 121.1,

119.6, 115.3, 112.9, 51.3, 45.2 ppm. Anal. Calcd for C₂₂H₁₄N₂S

(338.43): C, 78.08; H, 4.17; N, 8.28. Found: C, 77.90; H, 3.76; N, 8.26.

HRMS (ESP+): m/z 361.0793 [MNa⁺] calcd for (C₂₂H₁₄N₂SNa⁺): m/z

361.0770. UV−vis (MeCN) λ_DHA(ε): 380 nm (23.3 × 10³M⁻¹cm⁻¹).

λ_VHF(ε): 476 nm (20.5 × 10³M⁻¹cm⁻¹).

2-[4′-(3″-Thienyl)phenyl]-1,8a-dihydroazulene-1,1-dicarbonitrile

(1.15). To a stirred solution of iodo-DHA 1.4 (146.2 mg, 0.3825 mmol)

in a mixture of argon-ﬂushed toluene (9 mL) and water (1 mL) were

added 3-thienyl boronic acid (108.2 mg, 0.847 mmol), K₃PO₄(201 mg,

0.948 mmol), Xantphos (39.3 mg, 0.068 mmol, 18 mol %), and

Pd(OAc)₂(7.6 mg, 0.034 mmol, 9 mol %), and the reaction mixture was

stirred for 4 h at 50 °C. The resulting dark yellow reaction mixture was

diluted with Et₂O (50 mL), washed with saturated aqueous NH₄Cl

(2 × 50 mL), dried with MgSO₄, ﬁltered, and concentrated in vacuo.

The residue was redissolved in CH₂Cl₂and concentrated on Celite.

Puriﬁcation by dry column vacuum chromatography (SiO₂, 12.6 cm²,

0−60% toluene/heptanes, 5% steps, then 60−75% toluene/heptanes,

2.5% steps, 40 mL fractions) gave 1.15 (99.6 mg, 294 μmol, 77%) as a

dark yellow solid. A stable crystalline solid can be obtained by

recrystallization from CHCl₃/heptanes. TLC (toluene): R_f= 0.67. mp

1

(yellow → orange-red). mp 128.3−129.2 °C (CHCl₃/heptanes). H

NMR (500 MHz, CDCl₃) δ 7.94 (dt, J = 1.9, 0.4 Hz, 1H), 7.67 (ddd, J =

7.8, 1.9, 1.0 Hz, 1H), 7.65 (ddd, J = 7.8, 1.7, 1.0 Hz, 1H), 7.52(dd, J = 2.8,

1.5 Hz, 1H), 7.51 (td, J = 7.5, 0.4 Hz, 1H), 7.43 (m, 2 H), 6.94 (s, 1H),

6.58 (dd, J = 11.3, 6.4 Hz, 1H), 6.49 (dd, J = 11.3, 6.1 Hz, 1H), 6.37 (d, J =

6.4 Hz, 1H), 6.32 (ddd, J = 10.2, 6.1, 2.1 Hz, 1H), 5.84 (dd, J = 10.2, 3.8

Hz, 1H), 3.81(dt, J = 3.8, 2.1 Hz, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃)

δ 141.5, 140.2, 138.8, 137.1, 132.8, 131.18, 131.14, 131.05, 129.9, 128.3,

127.8, 126.9, 126.4, 125.0, 124.5, 121.4, 121.3, 119.7, 115.3, 112.9, 51.3,

45.5 ppm. Anal. Calcd for C₂₂H₁₄N₂S (338.43): C, 78.08; H, 4.17; N, 8.28.

Found: C, 77.81; H, 3.90; N, 8.28. HRMS (ESP+): m/z 699.1638

[2MNa⁺], calcd for (C₄₄H₂₈N₄S₂Na⁺): m/z 699.1648. UV−vis

(MeCN) λ_DHA(ε): 359 nm (14.7 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 474 nm

(29.0 × 10³M⁻¹cm⁻¹).

1

151.1−152.1 °C (CHCl₃/heptanes). H NMR (500 MHz, CDCl₃) δ

7.78 (d, J = 8.7 Hz, 2H), 7.70 (d, J = 8.7 Hz, 2H), 7.56−7.54 (m, 1H),

7.43 (s, 1H), 7.43−7.42 (m, 1H), 6.90 (s, 1H), 6.58 (dd, J = 11.2, 6.4 Hz,

1H), 6.48 (dd, J = 11.2, 6.1 Hz, 1H), 6.35 (d, J = 6.4 Hz, 1H), 6.32 (ddd,

J = 10.2, 6.1, 2.2 Hz, 1H), 5.84 (dd, J = 10.2, 3.8 Hz, 1H), 3.81 (dt, J = 3.8,

2.0 Hz, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 141.2, 139.9, 138.9,

137.4, 132.0, 131.1, 131.0, 129.2, 127.8, 127.2, 126.9, 126.9, 126.2, 121.6,

121.0, 119.6, 115.3, 112.9, 51.3, 45.3 ppm. Anal. Calcd for C₂₂H₁₄N₂S

(338.43): C, 78.08; H, 4.17; N, 8.28. Found: C, 78.25; H, 3.85; N, 8.18.

MS (MALDI TOF+): m/z 339 [MH⁺]. UV−vis (MeCN) λ_DHA(ε):

373 nm (22.8 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 475 nm (23.1 × 10³M⁻¹cm⁻¹).

53

dx.doi.org/10.1021/jo4020326 | J. Org. Chem. 2014, 79, 41−64

The Journal of Organic Chemistry

Article

2-[3′-(3″-Furyl)phenyl]-1,8a-dihydroazulene-1,1-dicarbonitrile

(1.18). To a stirred solution of 1.5 (257 mg, 0.672 mmol) in a mixture of

argon-ﬂushed toluene (18 mL) and water (2 mL) were added 3-furyl

boronic acid (150 mg, 1.34 mmol), K₃PO₄(301 mg, 1.34 mmol),

Pd(OAc)₂(13.2 mg, 0.0588 mmol, 9 mol %), and RuPhos (56.1 mg,

0.1176 mmol), and the reaction mixture was stirred at 50 °C for 16 h.

The resulting black reaction mixture was diluted with Et₂O (80 mL),

washed with saturated aqueous NH₄Cl (3 × 50 mL), dried with MgSO₄,

ﬁltered, and concentrated in vacuo. The residue was redissolved in

CH₂Cl₂and concentrated on Celite. Puriﬁcation by dry column vacuum

chromatography (SiO₂, 12.6 cm², 0−75% toluene/heptanes, 7.5% steps,

40 mL fractions) gave 1.18 (153 mg, 0.474 mmol, 70%) as a yellow oil or

solid. (In case the compound comes out as an oil, a stable solid was

obtained by simply passing the compound through a plug of silica using

CH₂Cl₂/heptanes 2:1.) TLC (toluene): R_f= 0.64. mp 99.9−101.4 °C

(CHCl₃/heptanes). ¹H NMR (500 MHz, CDCl₃) δ 7.82 (app t, J = 1.9

Hz, 1H), 7.79 (app dd, J = 1.5, 0.9 Hz, 1H), 7.65 (ddd, J = 7.7, 2.0,

1.1 Hz, 1H), 7.54 (dt, J = 7.7, 1.4 Hz, 1 H), 7.51 (app dd, J = 2.0, 1.6 Hz,

1 H), 7.48 (dt, J = 7.7, 0.5 Hz, 1H), 6.93 (s, 1H), 6.74 (app dd, J = 1.9, 0.9

Hz, 1H), 6.58 (ddt, J = 11.2, 6.2, 0.5 Hz, 1H), 6.49 (dd, J = 11.2, 6.1 Hz,

1H), 6.37 (d, J = 6.2 Hz, 1H), 6.32 (dddt, J = 10.2, 6.1, 2.1, 0.5 Hz, 1H),

5.83 (dd, J = 10.2, 3.8 Hz, 1H), 3.81 (dt, J = 3.8, 2.1 Hz, 1H) ppm. Anal.

Calcd for C₂₂H₁₄N₂O (322.36): C, 81.97; H, 4.38; N, 8.69. Found: C,

81.89; H, 4.46; N, 7.52. HRMS (ESP+): m/z 345.0991 [MNa⁺], calcd

for (C₂₂H₁₄N₂ONa⁺): m/z 345.0998. UV−vis (MeCN) λ_DHA(ε): 357 nm

(14.7 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 474 nm (26.7 × 10³M⁻¹cm⁻¹).

2-(3′-(2″-Furyl)phenyl)-1,8a-dihydroazulene-1,1-dicarbonitrile

(1.19). To a stirred solution of iodo-DHA 1.5 (101.2 mg, 0.265 mmol)

in a mixture of argon-ﬂushed toluene (9 mL) and water (1 mL) were

added 2-furyl boronic acid (122.6 mg, 1.100 mmol), K₃PO₄(122 mg,

0.574 mmol), Xantphos (12.4 mg, 0.0214 mmol, 8.1 mol %), Pd₂(dba)₃

(8.9 mg, 0.0097 mmol, 3.6 mol %) (the reaction mixture took a red

color, which slowly faded to yellow), and the reaction mixture was

stirred for 72 h at 25 °C. The reaction mixture was diluted with ether

(50 mL), washed with saturated aqueous NH₄Cl (2 × 50 mL), dried

with MgSO₄, ﬁltered, and concentrated in vacuo. The residue was

redissolved in CH₂Cl₂and concentrated on Celite. Puriﬁcation by dry

column vacuum chromatography (SiO₂, 12.6 cm², 0−75% toluene/

heptanes, 7.5% steps, 40 mL fractions) gave 1.19 (65.4 mg, 0.203 mmol,

74%) as a yellow solid. TLC (toluene): R_f= 0.67. mp 126.2−127.7 °C

(CHCl₃/heptanes), dec > 150 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.02

(app t, J = 1.8 Hz, 1H), 7.71 (app ddd, J = 7.8, 1.6, 1.0 Hz, 1H), 7.64 (app

ddd, J = 7.8, 2.0, 1.0 Hz, 1H), 7.51 (app dd, J = 1.8, 0.8 Hz, 1H), 7.49

(app dt, J = 7.8, 0.5 Hz, 2H), 6.96 (s, 1H), 6.75 (app dd, J = 3.4, 0.7 Hz,

1H), 6.58 (dd, J = 11.3, 6.3 Hz, 1H), 6.51 (dd, J = 3.4, 1.8 Hz, 1H), 6.49

(dd, J = 11.3, 6.2, 1H), 6.37 (d, J = 6.3 Hz, 1H), 6.32 (ddd, J = 10.2, 6.2,

2.1 Hz, 1H), 5.84 (dd, J = 10.2, 3.8 Hz, 1H), 3.81 (dt, J = 3.8, 2.1 Hz, 1H)

ppm. ¹³C NMR (125 MHz, CDCl₃) δ 153.0, 142.8, 140.1, 138.7, 133.0,

132.0, 131.2, 131.1, 131.0, 129.8, 127.8, 125.4, 125.0, 121.6, 121.3, 119.7,

115.3, 112.8, 112.0, 106.3, 51.3, 45.4 ppm. HRMS (ESP+): m/z

345.0995 [MNa⁺], calcd for (C₂₂H₁₄N₂ONa⁺): m/z 345.0998. UV−vis

(MeCN) λ_DHA(ε): 358 nm (14 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 475 nm

(27 × 10³M⁻¹cm⁻¹).

16 h at rt, after which saturated aqueous NH₄Cl (50 mL) was added, and

the mixture was extracted with Et₂O (3 × 100 mL). The combined

organic phases were washed with saturated aqueous NH₄Cl (3 × 75 mL),

dried with MgSO₄, ﬁltered, and concentrated in vacuo. Puriﬁcation by dry

column vacuum chromatography (SiO₂, 12.6 cm², 0−45% toluene/

heptanes, 7.5% steps, then 45−75% toluene/heptanes, 5% steps, 40 mL

fractions) gave 1.21 (1.00 g, 2.29 mmol, 87%) as a dark yellow solid

(a purple band at slightly lower R_fwas observed). TLC (50% toluene/

heptanes): R_f= 0.42 and (75% toluene/heptanes): R_f= 0.71. UV−vis

(MeCN) λ_DHA(ε): 371 nm (28.3 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 479 nm

(29.7 × 10³M⁻¹cm⁻¹). Other spectroscopic analyses are in accordance

with the literature.^8g

2-[3′-(Triisopropylsilylethynyl)phenyl]-1,8a-dihydroazulene-1,1-

dicarbonitrile (1.22). To a stirred mixture of 1.5 (469 mg, 1.22 mmol),

Pd(PPh₃)₄(30 mg, 0.026 mmol, 2 mol %), and CuI (10 mg, 0.053

mmol) in argon-ﬂushed THF (10 mL) were added TIPS-acetylene

(1.0 mL, 0.81 g, 4.5 mmol) and argon-ﬂushed (i-Pr)₂NH (1.0 mL, 0.72 g,

7.1 mmol). The reaction mixture was stirred for 4 h at rt, after which

saturated aqueous NH₄Cl (20 mL) was added, and the mixture was

extracted with Et₂O (2 × 50 mL). The combined organic phases were

washed with water (3 × 50 mL), dried with MgSO₄, ﬁltered, and

concentrated in vacuo. Puriﬁcation by dry column vacuum chromatog-

raphy (SiO₂, 12.6 cm², 0−70% toluene/heptanes, 5% steps, 40 mL

fractions) gave 1.22 (499 mg, 1.11 mmol, 94%) as a dark yellow solid.

TLC (75% toluene/heptanes): R_f= 0.61 (yellow → red). mp 128.9−

129.8 °C (CHCl₃/heptanes). ¹H NMR (500 MHz, CDCl₃) δ 7.76 (app.

td, J = 1.7, 0.5 Hz, 1H), 7.72 (app. ddd, J = 7.9, 2.0, 1.0 Hz, 1H), 7.52 (app.

dt, J = 7.9, 1.3 Hz, 1H), 7.43 (app. td, J = 7.9, 0.5 Hz, 1H), 6.91 (s, 1H),

6.58 (dd, J = 11.3, 6.2 Hz, 1H), 6.49 (dd, J = 11.3, 6.1 Hz, 1H), 6.36 (d, J =

6.2 Hz, 1H), 6.31 (ddd, J = 10.2, 6.1, 2.1 Hz, 1H), 5.81 (dd, J = 10.2, 3.8

Hz, 1H), 3.79 (dt, J = 3.8, 2.1 Hz, 1H), 1.14 (s, 21H) ppm. ¹³C NMR (125

MHz, CDCl₃) δ 139.4, 138.6, 133.6, 133.3, 131.3, 131.0, 130.9, 130.0,

129.3, 127.8, 125.8, 124.9, 121.5, 119.7, 115.1, 112.7, 106.0, 92.5, 51.3,

45.4, 18.8, 11.4 ppm. Anal. Calcd for C₂₉H₃₂N₂Si (436.66): C, 79.77;

H, 7.39; N, 6.42. Found: C, 79.35; H, 7.42; N, 6.41. MS (ESP+): m/z

437.2 [MH⁺], 459.2 [MNa⁺]. UV−vis (MeCN) λ_DHA(ε): 358 nm

(15.7 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 476 nm (27.3 × 10³M⁻¹cm⁻¹).

2-(4′-Ethynylphenyl)-1,8a-dihydroazulene-1,1-dicarbonitrile

(1.23). To a stirred solution of DHA 1.20 (252 mg, 0.714 mmol) in

THF (5 mL) were added AcOH (0.08 mL, 1.4 mmol) and a solution of

tetrabutylammonium ﬂuoride (1.43 mL, 1.43 mmol, 1 M) in THF, and

the reaction mixture was stirred at rt for 2 h. The resulting dark yellow

solution was diluted with Et₂O (50 mL), washed with water (3 × 50 mL)

and brine (25 mL), dried with Na₂SO₄, ﬁltered, and concentrated

in vacuo. Puriﬁcation by dry column vacuum chromatography (SiO₂,

12.6 cm², 0−50% toluene/heptanes, 12.5% steps, then 50−100%

toluene/heptanes, 6.25% steps, 40 mL fractions) gave 1.23 (117 mg,

0.417 mmol, 58%) as a yellow foam or solid. TLC (50% toluene/

heptanes): R_f= 0.24 (yellow → red). UV−vis (MeCN) λ_DHA(ε): 366 nm

(22.1 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 478 nm (29.5 × 10³M⁻¹cm⁻¹). Other

spectroscopic analyses are in accordance with the literature.^8g

2-(3′-Ethynylphenyl)-1,8a-dihydroazulene-1,1-dicarbonitrile

(1.24). To a stirred solution of 1.22 (230.3 mg, 0.527 mmol) in THF

(40 mL) were added dropwise AcOH (0.30 mL, 0.32 g, 5.3 mmol) and a

solution of tetrabutyl ammonium ﬂuoride (1.05 mL, 1.05 mmol, 1 M,

2 equiv) in THF. The reaction mixture was reﬂuxed for 4 h (the yellow

solution took a light yellow-brown color), after which it was diluted with

Et₂O (50 mL), washed with water (3 × 50 mL), dried with Na₂SO₄,

ﬁltered, and concentrated in vacuo. Puriﬁcation by dry column vacuum

chromatography (SiO₂, 12.6 cm², 0−50% toluene/heptanes, 5 steps,

then 50−65% toluene/heptanes, 2.5% steps, 40 mL fractions) gave 1.24

(134.3 mg, 0.479 mmol, 91%) as a yellow solid. TLC (75% toluene/

2-[4′-(Trimethylsilylethynyl)phenyl]-1,8a-dihydroazulene-1,1-di-

carbonitrile (1.20). To a stirred solution of DHA 1.4 (390 mg, 1.02 mmol),

(PPh₃)₄Pd (56 mg, 49 μmol, 5 mol %), and CuI (4.1 mg, 22 μmol) in

argon-ﬂushed THF (10 mL) were added (i-Pr₂)NH (0.57 mL, 4.1 mmol)

and trimethylsilylacetylene (0.58 mL, 4.1 mmol), and the reaction mixture

was stirred at rt for 16 h. The dark yellow reaction mixture was

concentrated in vacuo. Puriﬁcation by dry column vacuum chromatog-

raphy (SiO₂, 12.6 cm², 0−30% THF/heptanes, 5% steps, 40 mL fractions)

gave 1.20 (252 mg, 0.714 mmol, 70%) as a yellow oil that solidiﬁes. TLC

(30% THF/heptanes): R_f= 0.54. Other spectroscopic analyses are in

accordance with the literature.^8g

2-[4′-(Triisopropylsilylethynyl)phenyl]-1,8a-dihydroazulene-1,1-

dicarbonitrile (1.21). To a stirred mixture of DHA 1.4 (1.02 g,

2.62 mmol), (PPh₃)₄Pd (60 mg, 0.052 mmol, 2 mol %), and CuI (5 mg,

0.026 mmol, 1 mol %) in argon-ﬂushed THF (40 mL) were added

triisopropylacetylene (1.18 mL, 0.956 g, 5.24 mmol) and Et₃N

(1.46 mL, 1.06 g, 10.5 mmol). The reaction mixture was stirred for

1

heptanes): R_f= 0.41 (yellow → red). mp 108.0−108.8 °C. H NMR

(500 MHz, CDCl₃) δ 7.82 (t, J = 1.6 Hz, 1H), 7.74 (ddd, J = 7.8, 2.0, 1.1

Hz, 1H), 7.54 (dt, J = 7.8, 1.2 Hz, 1H), 7.45 (td, J = 7.8, 0.4 Hz, 1H), 6.91

(s, 1H), 6.58 (dd, J = 11.2, 6.3 Hz, 1H), 6.50 (dd, J = 11.2, 6.1 Hz, 1H),

6.36 (d, J = 6.3 Hz, 1H), 6.32 (ddd, J = 10.2, 6.1, 2.1 Hz, 1H), 5.82 (dd,

J = 10.2, 3.9 Hz, 1H), 3.79 (dt, J = 3.9, 2.1 Hz, 1H), 3.15 (s, 1H) ppm.

¹³C NMR (125 MHz, CDCl₃) δ 139.2, 138.5, 133.5, 133.5, 131.4,

130.99, 130.95, 130.0, 129.5, 127.9, 126.4, 123.6, 121.7, 119.6, 115.1,

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112.7, 82.7, 78.7, 51.3, 45.3 ppm. Anal. Calcd for C₂₀H ₁₂N₂(280.32): C,

85.69; H, 4.31; N, 9.99. Found: C, 85.38; H, 4.05; N, 9.93. HRMS

(ESP+): m/z 303.0940 [MNa⁺], calcd for (C₂₀H₁₂N₂Na⁺): m/z 303.0898.

UV−vis (MeCN) λ_DHA(ε): 357 nm (24.6 × 10³M⁻¹cm⁻¹). λ_VHF(ε):

477 nm (46.2 × 10³M⁻¹cm⁻¹).

separated, and the organic phase was dried over sodium sulfate.

Filtration and removal of the solvent under reduced pressure gave an

orange residue, which was subjected to ﬂash column chromatography

(gradient elution 0−10% EtOAc/CH₂Cl₂) to furnish 1.30 (66 mg, 69%)

as a gummy orange oil. In addition, unreacted starting material 1.28

(20 mg, 22%) and sulfone 1.32 (11 mg, 8%) were isolated. TLC

(10% EtOAc/CH₂Cl₂): R_f= 0.44. ¹H NMR (500 MHz,CDCl₃) δ 7.84

(d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.6 Hz, 1H), 6.99 (s, 1H), 6.58−6.51 (m,

1H), 6.50 (dd, J = 11.2, 6.1 Hz, 1H), 6.40 (br d, J = 6.2 Hz, 1H), 6.32

(ddd, J = 10.1, 6.1, 2.0 Hz, 1H), 5.83−5.80 (m, 1H), 3.81−3.79 (m, 1H),

1.20 (s, 9H) ppm.¹³¹³C NMR (125 MHz, CDCl₃) δ 142.2, 138.7, 138.2,

138.2, 134.3, 134.3, 131.6, 131.0, 127.9, 127.9, 127.3, 126.1, 122.2, 119.6,

119.5, 115.0, 115.0, 112.6, 112.6, 56.7, 51.2, 51.2, 45.2, 45.2, 22.9 ppm

(mixture of two diastereoisomers). HRMS (ESP+): m/z 383.1205

[MNa⁺], 743.2494 [2MNa⁺], calcd for (C₂₂H₂₀N₂OSNa⁺): 383.1189,

calcd for (C₄₄H₄₀N₄O₂S₂Na⁺): 743.2485. UV−vis (MeCN) λ_DHA(ε):

365 nm (17.8 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 477 nm (24.3 × 10³M⁻¹cm⁻¹).

2-[3′-(tert-Butylsulﬁnyl)phenyl]-1,8a-dihydroazulene-1,1-dicar-

bonitrile (1.31). To a solution of DHA 1.29 (82 mg, 0.238 mmol) in

CH₂Cl₂(5 mL) was added m-CPBA (60 mg, 0.27 mmol, 70% w/w), and

the resulting solution was stirred for 20 min at rt. The solution was

treated simultaneously with saturated aqueous sodium thiosulfate

(1 mL) and saturated aqueous sodium bicarbonate (1 mL) and was then

diluted with both water (10 mL) and CH₂Cl₂(10 mL). The phases were

separated, and the organic phase was dried over sodium sulfate.

Filtration and removal of the solvent under reduced pressure gave an

orange residue, which was subjected to ﬂash column chromatography

(gradient elution 0−10% EtOAc/CH₂Cl₂) to furnish pure sulfoxide

1.31 (73 mg, 85%) as a viscous orange oil. In addition, unreacted

starting material 1.29 (5 mg 6%) and sulfone 1.33 (4 mg, 4%) were

obtained. TLC (10% EtOAc/CH₂Cl₂): R_f= 0.42. ¹H NMR (500 MHz,

CDCl₃) δ 7.91 (br m, 1H), 7.88−7.86 (m, 1H), 7.61−7.60 (m, 1H), 7.00

and 7.01 (s, 1H), 6.60−6.56 (m, 1H), 6.50 (dd, J = 11.2, 6.0 Hz, 1H),

6.38 (br d, J = 6.2 Hz, 1H), 6.31 (dd, J = 10.0, 6.0 Hz, 1H), 5.81 (dd, J =

10.0, 3.6 Hz, 1H), 3.81−3.79 (m, 1H), 1.21 (s, 9H) ppm. ¹³C NMR

(125 MHz, CDCl₃) δ 141.9, 138.7, 138.3, 138.2, 134.2, 134.2, 129.4, 128.5,

127.9, 127.6, 123.9, 122.1, 122.1, 119.6, 119.5, 115.0, 114.9, 112.6, 112.6,

56.5, 51.2, 51.1, 45.3, 45.3, 22.9 ppm (mixture of two diastereoisomers).

HRMS (ESP+): m/z 383.1186 [MNa⁺], 743.2474 [2MNa⁺], calcd for

C₂₂H₂₀N₂OSNa⁺: 383.1189, calcd for C₄₄H₄₀N₄O₂S₂Na⁺: 743.2485.

UV−vis (MeCN) λ_DHA(ε): 355 nm (11.9 × 10³M⁻¹cm⁻¹). λ_VHF(ε):

475 nm (19.2 × 10³M⁻¹cm⁻¹).

2-[4′-(tert-Butylsulfonyl)phenyl]-1,8a-dihydroazulene-1,1-dicar-

bonitrile (1.32). To a solution of DHA 1.28 (71 mg, 0.206 mmol) in

CH₂Cl₂(5 mL) was added m-CPBA (116 mg, 70% w/w, 0.52 mmol),

and the resulting solution was stirred for 20 min at rt. The solution was

treated simultaneously with saturated aqueous sodium thiosulfate

(1 mL) and saturated aqueous sodium bicarbonate (1 mL) and was then

diluted with both water (10 mL) and CH₂Cl₂(10 mL). The phases were

separated, and the organic phase was dried over sodium sulfate.

Filtration and removal of the solvent under reduced pressure gave an

orange residue, which was subjected to ﬂash column chromatography

(gradient elution 0−2% EtOAc/CH₂Cl₂) to furnish pure 1.32 (74 mg,

95%) as a crystalline yellow solid. This compound could be crystallized

from CH₂Cl₂/methanol. TLC (2% EtOAc/CH₂Cl₂): R_f= 0.63. mp

210−223 °C (decomposes). ¹H NMR (500 MHz,CDCl₃) δ 7.98 (d, J =

8.7 Hz, 2H), 7.89 (d, J = 8.7 Hz, 2H), 7.05 (s, 1H), 6.60 (dd, J = 11.2, 6.2

Hz, 1H), 6.54 (dd, J = 11.2, 6.0 Hz, 1H), 6.45 (broad d, J = 6.2 Hz, 1H),

6.34 (ddd, J = 10.2, 6.0, 2.0 1H), 5.83 (dd, J = 10.2, 3.8 Hz, 1H), 3.83

(dt, J = 3.8, 2.0 Hz, 1H), 1.37 (s, 9H) ppm. ¹³C NMR (125 MHz,

CDCl₃) δ 138.0, 137.9, 136.5, 135.7, 135.5, 132.2, 131.48, 130.9, 128.0,

126.4, 123.1, 119.7, 114.8, 112.4, 60.4, 51.2, 45.2, 23.8 ppm. Anal.

Calcd for C₂₂H₂₀N₂O₂S (376.47): C, 70.19; H, 5.35; N, 7.44. Found: C,

69.95; H, 5.13; N, 7.46. MS (ESP+): m/z 399 [MNa⁺]. UV−vis

(MeCN) λ_DHA(ε): 367 nm (17.9 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 481 nm

(24.6 × 10³M⁻¹cm⁻¹).

2-[4′-(Trimethylsilyl-1,3-butadiynyl)phenyl]-1,8a-dihydroazu-

lene-1,1-dicarbonitrile (1.25). Method 1: To a stirred solution of 1.23

(218 mg 0.779 mmol) in CH₂Cl₂(20 mL) were added CuCl (16 mg,

0.163 mmol), TMS-acetylene (1.11 mL, 7.80 mmol), and TMEDA

(0.12 mL, 0.77 mmol), and the mixture was stirred for 1 h while passing

through oxygen and then overnight under an oxygen atmosphere. The

reaction mixture was washed with brine (3 × 50 mL), dried with MgSO₄,

ﬁltered, and concentrated in vacuo. Puriﬁcation by dry column vacuum

chromatography (SiO₂, 12.6 cm², 0−50% toluene/heptanes, 6.25%

steps, then 50−85% toluene/heptanes, 5% steps, then neat toluene, then

0−15% EtOAc/toluene, 5% steps (to collect homocoupled byproduct of

1.23 by chromatography, TLC (75% toluene/heptanes): R_f= 0.26

(yellow → orange)), 40 mL fractions) gave 1.25 (214 mg, 0.568 mmol,

73%) as a yellow oil. Method 2: To a stirred solution of 1.27 (72 mg,

0.20 mmol) in argon-ﬂushed THF (20 mL) were added argon-ﬂushed

Et₃N (0.28 mL, 2.0 mmol), TMS-acetylene (0.29 mL, 2.0 mmol),

Pd(PPh₃)₄(12 mg, 0.010 mmol, 5 mol %), and CuI (0.4 mg, 2 μmol,

1 mol %), and the reaction mixture was stirred at rt overnight. The

reaction mixture was diluted with Et₂O (100 mL), washed with saturated

aqueous NH₄Cl (2 × 50 mL), dried with MgSO₄, ﬁltered, and

concentrated in vacuo. Puriﬁcation by dry column vacuum chromatog-

raphy (SiO₂, 12.6 cm², 0−60% toluene/heptanes, 6.25% steps, then neat

toluene, then 0−15% EtOAc/toluene, 5% steps (to collect homo-

coupled byproduct of 1.23 by chromatography, TLC (75% toluene/

heptanes): R_f= 0.26 (yellow → orange)), 40 mL fractions) gave 1.25

(33 mg, 87 μmol, 44%) as a yellow oil that solidiﬁes. A stable compound

was obtained by recrystallization from CHCl₃/heptanes. For 1.25: TLC

(75% toluene/heptanes): R_f= 0.52 (yellow → red). mp 107.3−109.0 °C

(CHCl₃/heptanes). ¹H NMR (500 MHz, CDCl₃) δ 7.68 (d, J = 8.7 Hz,

2H), 7.57 (d, J = 8.7 Hz, 2H), 6.91 (s, 1H), 6.57 (dd, J = 11.3, 6.3 Hz,

1H), 6.50 (dd, J = 11.3, 6.1 Hz, 1H), 6.37 (d, J = 6.3 Hz, 1H), 6.31 (ddd,

J = 10.2, 6.1, 2.1 Hz, 1H), 5.81 (dd, J = 10.2, 3.8 Hz, 1H), 3.79 (dt, J = 3.8,

2.1 Hz, 1H), 0.25 (s, 9H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 139.2,

138.5, 133.6, 133.5, 131.5, 131.1, 131.0, 127.9, 126.2, 123.2, 122.0, 119.6,

115.0, 112.6, 92.6, 87.7, 76.8, 75.9, 51.2, 45.1, −0.3 ppm. Anal. Calcd for

C₂₅H₂₀N₂Si (376.53): C, 79.75; H, 5.35; N, 7.44. Found: C, 79.89; H,

5.45; N, 7.52. HRMS (ESP+): m/z 399.1281 [MNa⁺], calcd for

(C₂₅H₂₀N₂SiNa⁺): m/z 399.1288. UV−vis (MeCN) λ_DHA(ε): 376 nm

(33.8 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 480 nm (27.8 × 10³M⁻¹cm⁻¹).

2-[4′-(1,3-Butadiynyl)phenyl]-1,8a-dihydroazulene-1,1-dicarbo-

nitrile (1.26). To a stirred solution of 1.25 (11.3 mg, 30.0 μmol) in THF

(20 mL) were added acetic acid (17 μL, 0.30 mmol) and a solution of

TBAF (60 μL, 60 μmol, 1 M) in THF. The reaction mixture was stirred

for 20 min at rt, after which it was diluted with Et₂O (40 mL), washed

with aqueous NH₄Cl (2 × 25 mL), dried with MgSO₄, ﬁltered, and

concentrated in vacuo. Puriﬁcation by dry column vacuum chromatog-

raphy (SiO₂, 12.6 cm², 0−60% toluene/heptanes, 6.25% steps, 40 mL

fractions) gave 1.26 (8.4 mg, 28 μmol, 92%) as a yellow to red oil (that

solidiﬁes). mp < 80 °C dec. ¹H NMR (500 MHz, CDCl₃) δ 7.70 (d, J =

8.3 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 6.92 (s, 1H), 6.58 (dd, J = 11.3,

6.3 Hz, 1H), 6.50 (dd, J = 11.3, 6.1 Hz, 1H), 6.38 (d, J = 6.3 Hz, 1H),

6.34−6.30 (m, 1H), 5.82 (dd, J = 10.2, 3.8 Hz, 1H), 3.79 (br s, 1H), 2.57

(s, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 139.0, 138.3, 133.6, 133.5,

131.4, 131.3, 130.9, 127.8, 126.1, 122.6, 122.0, 119.5, 114.9, 112.5,

76.0, 74.5, 72.7, 67.9, 51.1, 45.0 ppm. HRMS (ESP+): m/z 327.0890

[MNa⁺], calcd for (C₂₂H₁₂N₂Na⁺): m/z 327.0893. UV−vis

(MeCN) λ_DHA(ε): 375 nm (24.0 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 480 nm

(23.3 × 10³M⁻¹cm⁻¹).

2-[4′-(tert-Butylsulﬁnyl)phenyl]-1,8a-dihydroazulene-1,1-dicar-

bonitrile (1.30). To a solution of DHA 1.28 (92 mg, 0.267 mmol) in

CH₂Cl₂(5 mL) was added m-CPBA (72 mg, 0.32 mmol, 70% w/w), and

the resulting solution was stirred for 20 min at rt. The solution was

treated simultaneously with saturated aqueous sodium thiosulfate

(1 mL) and saturated sodium bicarbonate (1 mL) and was then diluted

with both water (10 mL) and CH₂Cl₂(10 mL). The phases were

2-[3′-(tert-Butylsulfonyl)phenyl]-1,8a-dihydroazulene-1,1-dicar-

bonitrile (1.33). To a solution of DHA 1.29 (89 mg, 0.258 mmol) in

CH₂Cl₂(5 mL) was added m-CPBA (146 mg, 0.65 mmol, 70% w/w),

and the resulting solution was stirred for 20 min at rt. The solution was

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treated simultaneously with saturated aqueous sodium thiosulfate (1 mL)

and saturated aqueous sodium bicarbonate (1 mL) and was then diluted

with both water (10 mL) and CH₂Cl₂(10 mL). The phases were

separated, and the organic phase was dried over sodium sulfate.

Filtration and removal of the solvent under reduced pressure gave an

orange residue, which was subjected to ﬂash column chromatography

(gradient elution 0−2% EtOAc/CH₂Cl₂) to give sulfone 1.33 (87 mg,

90%) as a pale yellow solid. TLC (2% EtOAc/CH₂Cl₂): R_f= 0.66. mp

(dt, J = 4.0, 1.8 Hz, 1H), 5.99 (d, J = 4.6 Hz, 1H), 3.87 (dd, J = 4.6,

1.8 Hz, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 140.3, 139.9, 139.7,

138.9, 134.8, 134.7, 133.4, 133.1, 132.3, 128.8, 128.4, 127.8, 126.8,

122.5, 118.2, 116.2, 114.8, 113.5, 112.6, 50.9, 45.0 ppm. Anal. Calcd

for C₂₅H₁₅N₃(357.41): C, 84.00; H, 4.23; N, 11.76. Found: C, 84.01;

H, 4.04; N, 11.72. MS (ESP+): m/z 380 [MNa⁺]. UV−vis (MeCN)

λ_DHA(ε): 364 nm (17.3 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 502 nm

(35.2 × 10³M⁻¹cm⁻¹).

1

144−164 °C dec. H NMR (500 MHz, CDCl₃) δ 8.18 (t, J = 1.7 Hz,

7-Phenyl-2-(4′-nitrophenyl)-1,8a-dihydroazulene-1,1-dicarboni-

trile (2.3). Prepared according to the general procedure for 2.1: 7-

bromide 11.1 (crude, prepared in two steps from 1.1 (1.00 mmol) with a

purity of >90%), phenyl boronic acid (244 mg, 2.00 mmol), K₃PO₄

(425 mg, 2.00 mmol), RuPhos (47 mg, 0.10 mmol), and palladium-

(II)acetate (11 mg, 0.050 mmol) in toluene (9 mL) and water (1 mL).

Heating for 1 h at 80 °C. (TLC (60% toluene/heptanes: R_f= 0.20

(starting material, orange) and R_f= 0.26 (products, purple). TLC (60%

CH₂Cl₂/heptanes: R_f= 0.42 (starting material, orange-red) and R_f=

0.58 (products, orange-purple.) Worked up according to the general

procedure for 2.1. Puriﬁcation by dry column vacuum chromatography

(SiO₂, 12.6 cm², 0−100% toluene/heptanes, 6.25% steps, 40 mL

fractions) gave 2.3 (208 mg, 550 mmol, 55%) as a yellow crystalline

solid. (A stable solid can be obtained by recrystallization from ethanol.)

1H), 8.03 (ddd, J = 7.9, 1.7, 1.0 Hz, 1H), 7.93 (ddd, J = 7.9, 1.7, 1.0 Hz,

1H). 7.70 (t, J = 7.9 Hz, 1H), 7.02 (s, 1H), 6.60 (dd, J = 11.3, 6.3 Hz,

1H), 6.53 (dd, J = 11.3, 6.1 Hz, 1H), 6.42 (br d, J = 6.3 Hz, 1H), 6.33

(ddd, J = 10.2, 6.1, 2.1 Hz, 1H), 5.82 (dd, J = 10.2, 3.8 Hz, 1H), 3.82 (dt,

J = 3.8, 2.1 Hz, 1H), 1.39 (s, 9H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ

138.0, 137.0, 134.8, 131.9, 131.6, 131.3, 131.0, 130.6, 130.0, 128.4, 128.0,

122.7, 119.6, 114.8, 112.5, 60.4, 51.1, 45.4, 23.8 ppm (one signal is

missing due to overlap). Anal. Calcd for C₂₂H₂₀N₂O₂S (376.47): C,

70.19; H, 5.35; N, 7.44. Found: C, 69.93; H, 5.35; N, 7.28. MS (ESP+):

m/z 399.1133 [MNa⁺], calcd for (C₂₂H₂₀N₂SO₂Na⁺): m/z 399.1138.

UV−vis (MeCN) λ_DHA: 359 nm. λ_VHF: 478 nm.

7-Phenyl-2-(4′-tolyl)-1,8a-dihydroazulene-1,1-dicarbonitrile (2.1).

General Procedure. To a stirred solution of 7-bromide 11.3 (crude,

prepared in two steps from 1e (1.00 mmol) with a purity of >90%) in a

mixture of thoroughly argon-ﬂushed toluene (9 mL) and water (1 mL)

were added phenyl boronic acid (244 mg, 2.00 mmol), K₃PO₄(425 mg,

2.00 mmol), RuPhos (47 mg, 0.10 mmol), and Pd(OAc)₂(11 mg, 0.050

mmol). (Pellets of K₃PO₄can be added before degassing of the solvent.)

The reaction mixture was heated at 80 °C for 1 h (Progress of reaction

was monitored by TLC. A dark red or purple spot is sign of formation of

product, whereas starting material is orange or red), after which it was

diluted with Et₂O (100 mL), washed with brine (3 × 50 mL), dried with

MgSO₄, and ﬁltered, and the solvents were removed in vacuo. The

residue was redissolved in CH₂Cl₂and concentrated on Celite.

Puriﬁcation by dry column vacuum chromatography (SiO₂, 12.6 cm²,

(1) 0−75% toluene/heptanes, 5% steps, (2) 0−20% EtOAc/heptanes,

1% steps (the product is isolated as the ﬁrst of two yellow bands), 40 mL

fractions) gave 2.1 (118 mg, 340 μmol, 34%) as a yellow solid. (The

product is only stable as a crystalline solid. If not already crystalline after

chromatographic puriﬁcation, then this can be obtained by a careful

recrystallization from CHCl₃/heptanes. The compound is dissolved in

CHCl₃(3 mL), after which heptanes (3 mL) is carefully put on top of

the CHCl₃. The mixture is left in the dark in a container that allows for a

slow evaporation of the more volatile CHCl₃. After evaporation to

approximately half of the volume, a bright yellow crystalline solid can be

collected.) TLC (75% toluene/heptanes): R_f= 0.50 (yellow → purple).

mp 123.3−124.6 °C (CHCl₃/heptanes). ¹H NMR (500 MHz, CDCl₃)

δ 7.78−7.73 (m, 2H), 7.50−7.42 (m, 3H), 7.30 (d, J = 8.0 Hz, 2H), 7.17

(d, J = 8.0 Hz, 2H), 6.90 (s, 1H), 6.80−6.75 (m, 2H), 6.36 (d, J = 5.5 Hz,

1H), 5.97 (d, J = 4.6 Hz, 1H), 3.83 (dd, J = 4.6, 1.7 Hz, 1H), 2.36 (s, 3H)

ppm. ¹³C NMR (125 MHz, CDCl₃) δ 141.2, 140.7, 139.8, 138.1, 137.3,

132.42, 132.38, 131.8, 130.6, 130.3, 129.4, 129.4, 127.7, 126.5, 120.4,

115.6, 115.4, 113.1, 51.1, 45.2, 21.3 ppm. Anal. Calcd for C₂₅H₁₈N₂

(346.42): C, 86.68; H, 5.24; N, 8.09. Found: C, 86.56; H, 4.79; N, 8.05.

HRMS (ESP+): m/z 369.1362 [MNa⁺], calcd for (C₂₅H₁₈N₂Na⁺): m/z

369.1362. UV−vis (MeCN) λ_DHA(ε): 358 nm (18.0 × 10³M⁻¹cm⁻¹).

λ_VHF(ε): 488 nm (34.8 × 10³M⁻¹cm⁻¹).

1

TLC (toluene): R_f= 0.50. mp 174.8−175.6 °C (ethanol). H NMR

(500 MHz, CDCl₃) δ 8.35 (d, J = 9.0 Hz, 2H), 7.91 (d, J = 9.0 Hz, 2H),

7.45−7.33 (m, 5H), 7.07 (s, 1H), 6.91−6.80 (m, 2H), 6.50 (dd, J = 4.8,

1.6 Hz, 1H), 6.00 (d, J = 4.6 Hz, 1H), 3.89 (dd, J = 4.6, 1.6 Hz, 1H) ppm.

¹³C NMR (125 MHz, CDCl₃) δ 140.4, 139.9, 139.7, 138.6, 136.6, 135.5,

133.6, 132.3, 128.8, 128.4, 128.1, 127.8, 127.2, 124.7, 122.8, 116.3, 114.8,

112.6, 51.0, 45.1 ppm. Anal. Calcd for C₂₄H₁₅N₃O₂(377.39): C, 76.38;

H, 4.01; N, 11.13. Found: C, 76.58; H, 3.70; N, 11.07. HRMS (ESP+):

m/z 400.1087 [MNa⁺], calcd for (C₂₄H₁₅N₃O₂Na⁺): m/z 400.1056.

UV−vis (MeCN) λ_DHA(ε): 383 nm (15.3 × 10³M⁻¹cm⁻¹). λ_VHF(ε):

506 nm (24.0 × 10³M⁻¹cm⁻¹).

7-Phenyl-2-(4′-bromophenyl)-1,8a-dihydroazulene-1,1-dicarbo-

nitrile (2.4). Prepared according to the general procedure for 2.1:

7-bromide 11.8 (crude, prepared in two steps from 1.8 (1.07 mmol with

a purity of >90%), phenyl boronic acid (126 mg, 1.07 mmol), K₃PO₄

(254 mg, 2.14 mmol), RuPhos (49.9 mg, 107 μmol), and palladium-

(II)acetate (12.0 mg, 53.5 μmol) in toluene (18 mL) and water (2 mL).

Stirred for 60 h at rt (TLC (30% EtOAc/heptanes: R_f= 0.36 (starting

material, yellow → orange) and R_f= 0.43 (products, yellow → purple)).

Worked up according to the procedure of 2.1. Puriﬁcation by dry

column vacuum chromatography (SiO₂, 12.6 cm², 0−50% toluene/

heptanes, 5% steps, then 50−65% toluene/heptanes, 2.5% steps, 40 mL

fractions) gave 2.4 (286 mg, 0.696 mmol, 65%) and 4.12 (52.5 mg,

0.128 mmol, 12%) as yellow to red solids. For 2.4: TLC (60% toluene/

heptanes): R_f= 0.38. mp 122.4−124.6 °C. ¹H NMR (500 MHz, CDCl₃)

δ 7.62 (s, 4H), 7.40−7.36 (m, 5H), 6.90 (s, 1H), 6.82−6.79 (m, 2H),

6.42−6.36 (m, 1H), 5.98 (d, J = 4.6 Hz, 1H), 3.84 (dd, J = 4.6, 1.7 Hz,

1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 140.3, 140.07, 140.06,

140.03, 132.7, 132.52, 132.48, 132.3, 129.5, 128.7, 128.3, 127.8, 124.7,

120.9, 116.2, 115.1, 112.9, 51.0, 45.1 ppm (one signal missing due to

overlap). HRMS (ESP+): m/z 433.0303, 435.0279 [MNa^{+ 79/81}Br],

calcd for (C₂₄H₁₅N₂BrNa⁺): m/z 433.0311, 435.0291. UV−vis (MeCN)

λ_DHA(ε): 357 nm (17.5 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 494 nm (33.2 × 10³

M⁻¹cm⁻¹). For 4.12: TLC (60% toluene/heptanes): R_f= 0.32. mp

1

209−211 °C dec. H NMR (500 MHz, CDCl₃) δ7.84 (d, J = 8.6 Hz,

7-Phenyl-2-(4′-cyanophenyl)-1,8a-dihydroazulene-1,1-dicarboni-

trile (2.2). Prepared according to the general procedure for 2.1:

7-bromide 11.10 (crude, prepared in two steps from 1.1 (1.00 mmol)

with a purity of >90%), phenyl boronic acid (240 mg, 2.04 mmol),

K₃PO₄(855 mg, 4.03 mmol), RuPhos (95 mg, 0.204 mmol), and

palladium(II)acetate (22 mg, 0.098 mmol) in toluene (50 mL) and

water (10 mL). Heating for 20 h at 70 °C. Worked up according to the

general procedure for 2.1. The residue was subsequently puriﬁed by

ﬂash column chromatography (SiO₂, 0.5% ethyl acetate/toluene) to

aﬀord the title compound, which was crystallized from concentrated

ethanol to give 2.2 as a ﬂuﬀy yellow solid (72 mg, 20% over the three

steps). R_f= 0.38 (0.5% ethyl acetate/toluene). mp 155−158 °C.

¹H NMR (500 MHz, CDCl₃) δ 7.85 (d, J = 8.8 Hz, 2H), 7.77 (dd, J = 8.8

Hz, 2H), 7.41−7.35 (m, 5H), 7.03 (s, 1H), 6.86−6.81 (m, 2H), 6.47

2H), 7.72 (d, J = 8.6 Hz, 2H), 7.63 (d, J = 7.6 Hz, 2H), 7.48 (t, J = 7.6 Hz,

2H), 7.44−7.32 (m, 6H), 6.95 (s, 1H), 6.84−6.77 (m, 2H), 6.39 (d, J =

5.7 Hz, 1H), 6.02 (d, J = 4.6 Hz, 1H), 3.87 (dd, J = 4.6, 1.6 Hz, 1H) ppm.

¹³C NMR (125 MHz, CDCl₃) δ 143.0, 140.9, 140.8, 140.2, 140.0, 139.9,

132.6, 132.2, 131.5, 129.4, 129.1, 128.7, 128.21, 128.18, 128.0, 127.8,

127.2, 126.9, 120.4, 116.3, 115.4, 113.2, 51.1, 45.1 ppm. HRMS (ESP+):

m/z 431.1526 [MNa⁺], calcd for (C₃₀H₂₀N₂Na⁺): m/z 431.1519.

7-(4-Thiomethoxyphenyl)-2-phenyl-1,8a-dihydroazulene-1,1-di-

carbonitrile (3.1). Prepared according to the general procedure for 2.1:

7-bromide 10.34 (85.9 mg, 256 μmol), 4-thiomethoxyphenyl boronic

acid (64.6 mg, 384 μmol), K₃PO₄(109 mg, 513 mg), RuPhos (12.0 mg,

25.6 μmol), and palladium(II)acetate (2.9 mg, 13 μmol) in toluene

(5 mL) and water (0.5 mL). Heated by microwave irradiation at 90 °C

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The Journal of Organic Chemistry

Article

for 15 min. Worked up according to the general procedure for 2.1.

Puriﬁcation by dry column vacuum chromatography (SiO₂, 12.6 cm²,

(1) 0−100% CHCl₃/heptanes, 10% steps, 40 mL fractions. (2) 0−30%

toluene/CS₂, 3% steps, 40 mL fractions) gave 3.1 (56.8 mg, 150 μmol,

59%) as a dark yellow to red solid. TLC (CH₂Cl₂): R_f= 0.90. mp 145−

155 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.76 (d, J = 7.5 Hz, 2H), 7.49−

7.44 (m, 3H), 7.33 (d, J = 8.5 Hz, 2H), 7.24 (d, J = 8.6 Hz, 2H), 6.90 (s,

1H), 6.81 (dd, J = 11.5, 6.0 Hz, 1H), 6.74 (d, J = 11.5 Hz, 1H), 6.36 (d,

J = 6.0 Hz, 1H), 5.97 (d, J = 4.6 Hz, 1H), 3.82 (dd, J = 4.6, 1.6 Hz, 1H),

2.50 (s, 3H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 141.3, 140.8, 139.3,

138.9, 136.9, 132.7, 132.0, 131.7, 130.6, 130.3, 129.4, 128.2, 126.6, 126.5,

120.3, 115.8, 115.3, 113.1, 51.1, 45.2, 15.9 ppm. Anal. Calcd for

C₂₅H₁₈N₂S (378.49): C, 79.33; H, 4.79; N, 7.40. Found: C, 79.03; H,

4.63; N, 7.45. HRMS (ESP+): m/z 401.1080 [MNa⁺], calcd for

(C₂₅H₁₈N₂SNa⁺): m/z 401.1083. UV−vis (MeCN) λ_DHA(ε): 348 nm

(15 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 500 nm (33 × 10³M⁻¹cm⁻¹).

7-(4-Cyanophenyl)-2-phenyl-1,8a-dihydroazulene-1,1-dicarboni-

trile (3.2). Prepared according to the general procedure for 2.1:

7-bromide 10.34 (312 mg, 931 μmol), 4-cyanophenyl boronic acid

(150 mg, 1.02 mmol), K₃PO₄(395 mg, 1.86 mg), RuPhos (21.7 mg,

46.5 μmol), and palladium(II)acetate (5.22 mg, 23.3 μmol) were stirred

for 72 h at 25 °C. Worked up according to the procedure of 2.1.

Puriﬁcation by dry column vacuum chromatography (SiO₂, 12.6 cm²,

(1) 0−50% THF/heptanes, 5% steps, 40 mL fractions, (2) 0−30%

EtOAc/heptanes, 3.75% steps, 40 mL fractions, (3) 0−100% CHCl₃/

heptanes, 20% steps, 40 mL fractions, 400 mL neat CHCl₃was passed

through) gave 3.2 (200 mg, 0.559 mmol, 60%) as a dark yellow solid.

TLC (CH₂Cl₂): R_f= 0.86. mp 181.2−181.8 °C. ¹H NMR (500 MHz,

CDCl₃) δ 7.78−7.74 (m, 2H), 7.67 (d, J = 8.5 Hz, 2H), 7.52−7.48 (m,

5H), 6.92 (s, 1H), 6.87 (dd, J = 11.5, 6.2 Hz, 1H), 6.71 (d, J = 11.5 Hz,

1H), 6.40 (d, J = 6.2 Hz, 1H), 6.04 (d, J = 4.7 Hz, 1H), 3.86 (dd, J = 4.7,

1.6 Hz, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 144.5, 141.8, 140.9,

138.5, 133.6, 132.6, 131.5, 130.7, 130.6, 130.3, 129.5, 128.4, 126.5,

120.4, 118.8, 118.4, 115.1, 113.00, 111.9, 51.0, 45.1 ppm. Anal. Calcd

for C₂₅H₁₅N₃(357.41): C, 84.01; H, 4.23; N, 11.76. Found: C, 83.96;

H, 3.78; N, 11.75. MS (MALDI−): m/z 357 [M⁻]. UV−vis (MeCN)

λ_DHA(ε) = 357 nm (18.4 × 10³M⁻¹cm⁻¹), λ_VHF(ε) = 479 nm

(41.7 × 10³M⁻¹cm⁻¹).

7-(4-Tolyl)-2-phenyl-1,8a-dihydroazulene-1,1-dicarbonitrile (3.3).

Prepared according to the general procedure for 2.1: 7-Bromide 11.34

(crude, prepared in two steps from 1.00 mmol with a purity of >90%),

4-tolyl boronic acid (272 mg, 2.00 mmol), K₃PO₄(225 mg, 2.00 mmol),

RuPhos (46.7 mg, 100 μmol), and palladium(II)acetate (11.2 mg,

50.0 μmol) in toluene (9 mL) and water (1 mL) were stirred for 24 h at

rt. Worked up according to the general procedure for 2.1. Puriﬁcation by

dry column vacuum chromatography (SiO₂, 12.6 cm², 0−60% toluene/

heptanes, 7.5% steps, then 60−85% toluene/heptanes, 5% steps, 40 mL

fractions) gave 3.3 (204 mg, 0.589 mmol, 59%) as a yellow solid. TLC

(toluene): R_f= 0.73. mp 120.9−122.2 °C. ¹H NMR (500 MHz, CDCl₃)

δ 7.78−7.74 (m, 2H), 7.51−7.41 (m, 3H), 7.30 (d, J = 8.1 Hz, 2H), 7.17

(d, J = 8.1 Hz, 2H), 6.90 (s, 1H), 6.82−6.74 (m, 2H), 6.36 (dd, J = 4.7,

0.8 Hz, 1H), 5.97 (d, J = 4.6 Hz, 1H), 3.83 (dd, J = 4.6, 1.7 Hz, 1H), 2.36

(s, 3H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 141.2, 140.7, 139.8, 138.1,

137.3, 132.42, 132.39, 131.8, 130.6, 130.3, 129.42, 129.39, 127.7, 126.5,

120.4, 115.7, 115.4, 113.1, 51.1, 45.2, 21.3 ppm. HRMS (ESP+): m/z

369.1361 [MNa⁺], calcd for (C₂₅H₁₈N₂Na⁺): m/z 369.1362. UV−vis

(MeCN) λ_DHA(ε): 352 nm (13.2 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 494 nm

(32.1 × 10³M⁻¹cm⁻¹).

7.30 (d, J = 8.1 Hz, 2H), 7.18−7.17 (m, 2H), 6.90 (s, 1H), 6.84−6.71

(m, 2H), 6.36 (d, J = 5.5 Hz, 1H), 5.97 (d, J = 4.6 Hz, 1H), 3.83 (dd, J =

4.6, 1.7 Hz, 1H), 2.36 (s, 3H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ

141.5, 140.8, 139.1, 138.9, 133.0, 131.8, 131.6, 131.5, 130.5, 130.4,

129.46, 129.45, 126.5, 122.5, 120.3, 116.6, 115.2, 113.1, 51.0, 45.1 ppm.

Anal. Calcd for C₂₄H₁₅N₂Br (410.29): C, 70.09; H, 3.68; N, 6.81.

Found: C, 70.01; H, 3.72; N, 6.89. HRMS (ESP+): m/z 433.0295,

435.0290 [MNa⁺], calcd for (C₂₄H₁₅N₂BrNa⁺): m/z 433.0311,

435.0291. UV−vis (MeCN) λ_DHA(ε): 355 nm (14.9 × 10³M⁻¹cm⁻¹).

λ_VHF(ε): 486 nm (32.1 × 10³M⁻¹cm⁻¹).

7-(4-Aminophenyl)-2-phenyl-1,8a-dihydroazulene-1,1-dicarboni-

trile (3.7). To a stirred solution of 3.6 (50.1 mg, 133 μmol) in AcOH

(5 mL) was added zinc powder (17.4 mg, 266 μmol), and the reaction

mixture was stirred overnight. The reaction mixture was diluted with

Et₂O (50 mL), and saturated aqueous NaHCO₃(2 mL) was added

followed by saturated aqueous NH₄Cl (50 mL). The organic phase was

separated, dried with Na₂SO₄, ﬁltered, and concentrated in vacuo.

Puriﬁcation by dry column vacuum chromatography (SiO₂, 12.6 cm²,

0−50% EtOAc/heptanes, 5% steps, 40 mL fractions) gave 3.7 (34 mg,

98 μmol, 74%) as a crude yellow oil. Attempted puriﬁcation by

recrystallization failed. ¹H NMR (300 MHz, CDCl₃) δ 7.80−7.71 (m,

2H), 7.55−7.38 (m, 4H), 7.21 (dd, J = 5.5, 5.1 Hz, 2H), 6.89 (s, 1H),

6.82−6.72 (m, 2H), 6.72−6.63 (m, 2H), 6.37−6.30 (m, 1H), 5.90

(dd, J = 4.7, 0.8 Hz, 1H), 3.86−3.64 (m, 3H) ppm.

7-[4-(tert-Butylsulﬁnyl)phenyl]-2-phenyl-1,8a-dihydroazulene-

1,1-dicarbonitrile (3.8). To a solution of DHA 3.5 (77 mg, 0.183 mmol)

in CH₂Cl₂(5 mL) was added m-CPBA (45 mg, 0.20 mmol, 70% w/w),

and the resulting solution was stirred for 30 min at rt. The solution was

treated simultaneously with saturated aqueous sodium thiosulfate

(1 mL) and saturated aqueous sodium bicarbonate (1 mL) and was then

diluted with both water (10 mL) and CH₂Cl₂(10 mL). The phases were

separated, and the organic phase was dried over sodium sulfate.

Filtration and removal of the solvent under reduced pressure gave an

orange residue, which was subjected to ﬂash column chromatography

(SiO₂, gradient elution: 0−10% EtOAc/CH₂Cl₂) to furnish pure 3.8

(60 mg, 75%) as a viscous orange oil. In addition, unreacted starting

material (5 mg, 6%) and corresponding sulfone 3.9 (5 mg, 6%) were also

obtained. TLC (5% EtOAc/CH₂Cl₂): R_f= 0.42. ¹H NMR (500 MHz,

CDCl₃) δ 7.77−7.75 (m, 2H), 7.60−7.58 (d, 2H), 7.53−7.43 (m, 5H),

6.91 (s, 1H), 6.87−6.83 (m, 1H), 6.75 (d, J = 11.4 Hz, 1H), 6.39−6.38

(m, 1H), 6.05−6.04 (m, 1H), 3.86 (dd, J = 4.7, 1.6 Hz, 1H), 1.18 and

1.17 (s, 9H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 143.0, 142.9, 141.5,

140.8, 140.8, 139.0, 133.1, 131.6, 131.4, 130.4, 129.5, 127.7, 126.7,

126.7, 126.5, 120.4, 117.5, 117.5, 115.2, 113.1, 56.2, 51.0, 45.1, 22.9 ppm.

Anal. Calcd for C₂₈H₂₄N₂OS (436.57): C, 77.04; H, 5.55; N, 6.42.

Found: C, 76.95; H, 5.64; N, 6.42. MS (ESP+) = 459 [MNa⁺]. UV−vis

(MeCN) λ_DHA(ε): 355 nm (14.6 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 485 nm

(33.8 × 10³M⁻¹cm⁻¹).

7-[4-(tert-Butylsulfonyl)phenyl]-2-phenyl-1,8a-dihydroazulene-

1,1-dicarbonitrile (3.9). To a solution of DHA 3.5 (95 mg, 0.226 mmol)

in CH₂Cl₂(5 mL) was added m-CPBA (161 mg, 0.72 mmol, 70% w/w),

and the resulting solution was stirred for 20 min at rt. The solution was

treated simultaneously with saturated aqueous sodium thiosulfate

(1 mL) and saturated aqueous sodium bicarbonate (1 mL) and was then

diluted with both water (10 mL) and CH₂Cl₂(10 mL). The phases were

separated, and the organic phase was dried over sodium sulfate.

Filtration and removal of the solvent under reduced pressure gave an

orange residue, which was subjected to ﬂash column chromatography

(SiO₂, gradient elution: 0−2% EtOAc/CH₂Cl₂) to furnish pure the 3.9

(94 mg, 92%) as a yellow powder. TLC (2% EtOAc/CH₂Cl₂): R_f= 0.69.

mp 176.5−179.0 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.88 (d, J = 8.6 Hz,

2H), 7.76 (d, J = 7.6 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.53−7.43 (m,

3H), 6.93 (s, 1H), 6.87 (dd, J = 11.5, 6.1 Hz, 1H), 6.73 (d, J = 11.5 Hz,

1H), 6.40 (dd, J = 6.1, 1.7 Hz, 1H), 6.07 (d, J = 4.7 Hz, 1H), 3.88 (dd, J =

4.7, 1.7 Hz, 1H), 1.35 (s, 9H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ

145.3, 141.7, 140.9, 138.5, 134.9, 133.4, 131.6, 130.9, 130.9, 130.5, 129.5,

128.0, 126.5, 120.4, 118.5, 115.1, 113.0, 60.1, 51.0, 45.1, 23.8 ppm, 1 C

masked. Anal. Calcd for C₂₈H₂₄N₂O₂S (452.57): C, 74.31; H, 5.35; N,

6.19. Found: C, 74.70; H, 5.21; N, 6.18. MS (ESP+) = 475 [MNa⁺].

7-(4-Bromophenyl)-2-phenyl-1,8a-dihydroazulene-1,1-dicarboni-

trile (3.4). Prepared according to the general procedure for 2.1:

7-Bromide 11.34 (crude, prepared in two steps from 1.00 mmol with a

purity of >90%), 4-bromophenyl boronic acid (402 mg, 2.00 mmol),

K₃PO₄(225 mg, 2.00 mmol), RuPhos (46.7 mg, 100 μmol) and

palladium(II)acetate (11.2 mg, 50.0 μmol) in toluene (9 mL) and water

(1 mL) were stirred for 48 h at rt. Worked up according to the general

procedure for 2.1. Puriﬁcation by dry column vacuum chromatography

(SiO₂, 12.6 cm², 0−75% toluene/heptanes, 7.5% steps, 40 mL fractions)

gave 3.4 (264 mg, 0.641 mmol, 64%) as a yellow solid. TLC (75%

toluene/heptanes): R_f= 0.55 (yellow → purple). mp 157.2−157.8 °C.

¹H NMR (500 MHz, CDCl₃) δ 7.77−7.74 (m, 2H), 7.50−7.42 (m, 3H),

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UV−vis (MeCN) λ_DHA(ε): 355 nm (24.5 × 10³M⁻¹cm⁻¹). λ_VHF(ε):

(1 mL) were stirred for 72 h at rt. Worked up according to the general

procedure for 2.1. Puriﬁcation by dry column vacuum chromatography

(SiO₂, 12.6 cm², 0−100% toluene/heptanes, 10% steps, 40 mL fractions)

gave followed by a careful recrystallization from CHCl₃/heptanes gave 4.3

(172 mg, 0.462 mmol, 46%) as a yellow solid. TLC (toluene): R_f= 0.36. mp

177.8−178.3 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.66 (d, J = 8.6 Hz, 2H),

7.66 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 8.4 Hz, 2H),

6.89 (s, 1H), 6.86 (dd, J = 11.8, 6.1 Hz, 1H), 6.68 (d, J = 11.8 Hz, 1H), 6.36

(dd, J = 6.1, 1.7 Hz, 1H), 6.03 (d, J = 4.7 Hz, 1H), 3.84 (dd, J = 4.7, 1.7 Hz,

1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 144.6, 141.9, 141.2, 141.1, 138.4,

133.6, 132.5, 130.5, 130.4, 130.2, 128.4, 127.6, 126.4, 119.9, 118.8, 118.4,

115.1, 113.1, 111.9, 51.0, 45.1, 21.6 ppm. Anal. Calcd for C₂₆H₁₉N₃

(371.43): C, 84.07; H, 4.61; N, 11.31. Found: C, 84.19; H, 4.46; N,

11.40. HRMS (ESP+): m/z 765.2738 [2MNa⁺], calcd for (C₅₂H₃₄N₆Na⁺):

m/z 765.2738. UV−vis (MeCN) λ_DHA(ε) = 361 nm (23.7 × 10³

M⁻¹cm⁻¹). λ_VHF(ε) = 478 nm (46.2 × 10³M⁻¹cm⁻¹).

7-(4-Methoxyphenyl)-2-(4′-Tolyl)-1,8a-dihydroazulene-1,1-dicar-

bonitrile (4.4). Method 1: To a solution of 7-bromide 11.8 (50 mg,

0.14 mmol) in a mixture of argon-ﬂushed toluene (25 mL) and water

(25 mL) were added methoxyphenyl boronic acid (22 mg, 0.14 mmol),

KF·2H₂O (14 mg, 0.14 mmol), and tetrakis(triphenylphosphine)-

palladium(0) (16 mg, 14 μmol, 10 mol %), and the reaction mixture was

stirred at 90 °C for 16 h. The reaction mixture was diluted with toluene

(100 mL), washed with brine (50 mL), dried with MgSO₄, and ﬁltered,

and the mixture was concentrated in vacuo. Puriﬁcation by dry column

vacuum chromatography (SiO₂, 12.6 cm², (1) 0−100% toluene/

heptanes, 20% steps, 40 mL fractions, (2) 0−40% THF/heptanes, 5%

steps, 40 mL fractions) gave 4.4 (11.8 mg, 31 μmol, 22%) as a dark

yellow solid. Method 2: Prepared according to the general procedure for

2.1: 7-bromide 11.3 (crude, prepared in two steps from 1.00 mmol with

a purity of >90%), 4-methoxyphenyl boronic acid (304 mg, 2.00 mmol),

K₃PO₄(425 mg, 2.00 mmol), RuPhos (47 mg, 0.10 mmol), and

palladium(II)acetate (11 mg, 0.050 mmol) in toluene (9 mL) and water

(1 mL) were stirred for 16 h at rt. Puriﬁcation by dry column vacuum

chromatography (SiO₂, 12.6 cm², 0−100% toluene/heptanes, 10%

steps, 40 mL fractions) gave 4.4 (263 mg, 0.701 mmol, 70%, >95%

purity) as a dark yellow solid. An analytically pure sample was prepared

by recrystallization from EtOH, yielding 4.4 (83 mg, 0.22 mmol, 22%) as

thin yellow needles. TLC (toluene): R_f= 0.40. mp 137.4−139.5 °C. ¹H

NMR (500 MHz, CDCl₃) δ 7.65 (d, J = 8.0 Hz, 2H), 7.34 (d, J = 8.7 Hz,

2H), 7.28 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 6.84 (s, 1H), 6.79

(dd, J = 11.3, 5.8 Hz, 1H), 6.73 (d, J = 11.3 Hz, 1H), 6.32 (d, J = 5.8 Hz,

1H), 5.92 (d, J = 4.6 Hz, 1H), 3.82 (s, 3H), 3.80 (d, J = 4.6 Hz, 1H),

2.41 (s, 3H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 159.8, 141.4, 141.0,

140.7, 139.3, 132.9, 132.5, 132.1, 130.7, 130.1, 129.1, 127.8, 126.4, 119.8,

115.5, 114.9, 114.0, 113.2, 55.5, 51.1, 45.2, 21.6 ppm. Anal. Calcd for

C₂₆H₂₀N₂O (376.45): C, 82.95; H, 5.35; N, 7.44. Found: C, 82.83;

H, 5.24; N, 7.42. MS (MALDI TOF+): m/z 377 [MH⁺]. UV−vis

(MeCN): λ_DHA(ε) = 353 nm (15.8 × 10³M⁻¹cm⁻¹), λ_VHF(ε) = 503 nm

(30.8 × 10³M⁻¹cm⁻¹).

7-(4-Methoxyphenyl)-2-(4′-cyanophenyl)-1,8a-dihydroazulene-

1,1-dicarbonitrile (4.5). Prepared according to the general procedure

for 2.1: 7-bromide 11.10 (crude, prepared in two steps from 1.00 mmol

with a purity of >90%), methoxyphenyl boronic acid (304 mg, 2.00 mmol),

K₃PO₄(425 mg, 2.00 mmol), RuPhos (46.7 mg, 0.10 mmol), and

palladium(II)acetate (11.2 mg, 0.050 mmol) in toluene (9 mL) and water

(1 mL) were stirred for 16 h at rt. Worked up according to the general

procedure for 2.1. Puriﬁcation by dry column vacuum chromatography

(SiO₂, 12.6 cm², 0−100% toluene/heptanes, 12.5% steps, 40 mL fractions,

toluene was passed through to collect the product) gave 4.5 (320 mg,

0.826 mmol, 41%) as a dark yellow solid. (This is an extremely diﬃcult

puriﬁcation because of the lack of separation. A very short column was

chosen (3−4 cm) to prevent band broadening; thus, an eluent with low

R_fwas chosen. The column was repeated ﬁve times to get an overall

acceptable yield of reasonably pure compound, but much material was

discarded.) Analytically pure samples were prepared by recrystallization

from CHCl₃/heptanes or EtOH. TLC (toluene): R_f= 0.23. mp 177.9−

178.3 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.84 (dd, J = 8.8 Hz, 2H), 7.77

(dd, J = 8.8 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.02 (s, 1H), 6.90 (d, J = 8.8

Hz, 2H), 6.84−6.81 (m, 2H), 6.47−6.45 (m, 1H), 5.91 (d, J = 4.6 Hz, 1H),

479 nm (53.5 × 10³M⁻¹cm⁻¹).

7-(4-Nitrophenyl)-2-(4′-nitrophenyl)-1,8a-dihydroazulene-1,1-di-

carbonitrile (4.1). To a stirred solution of 7-bromide 11.1 (¹/₉of a batch

made in two steps from 2.25 mmol 1.1) in a mixture of argon-ﬂushed

toluene (15 mL) and water (10 mL) were added nitrophenyl boronic

acid (46 mg, 0.25 mmol), KF·2H₂O (26 mg, 0.25 mmol), and

tetrakis(triphenylphosphine)palladium(0) (29 mg, 25 μmol, 10 mol %),

and the reaction mixture was stirred at 70−75 °C overnight. The

reaction mixture was diluted with Et₂O (200 mL), washed with saturated

aqueous NH₄Cl (50 mL) and brine (50 mL), dried with MgSO₄, and

ﬁltered, and the solvents were evaporated in vacuo. Puriﬁcation by dry

column vacuum chromatography (SiO₂, 12.6 cm², 0−100% toluene/

heptanes, 20% steps, then neat toluene, 40 mL fractions) gave 4.1

(29.6 mg, 70.1 μmol, 28%) as a dark yellow solid. TLC (toluene): R_f=

0.25. mp > 210 °C dec. ¹H NMR (500 MHz, CDCl₃) δ 8.35 (d, J = 9.0

Hz, 1H), 8.24 (d, J = 8.9 Hz, 1H), 7.92 (d, J = 9.0 Hz, 2H), 7.56 (d, J =

8.9 Hz, 1H), 7.11 (s, 1H), 6.93 (dd, J = 11.5, 6.1 Hz, 1H), 6.81 (d, J =

11.5 Hz, 1H), 6.55 (dd, J = 6.1, 1.6 Hz, 1H), 6.08 (d, J = 4.7 Hz, 1H),

3.92 (dd, J = 4.7, 1.6 Hz, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ

148.4, 147.8, 146.0, 139.9, 139.1, 138.5, 136.2, 135.3, 133.4, 131.9, 128.6,

127.2, 124.7, 124.1, 122.8, 118.8, 114.5, 112.4, 50.8, 45.0 ppm. Anal.

Calcd for C₂₄H₁₄N₄O₄(422.39): C, 68.24; H, 3.34; N, 13.26. Found: C,

68.06; H, 3.02; N, 13.19. MS (MALDI TOF+): m/z 423 [MH⁺].

UV−vis (MeCN) λ_DHA(ε) = 382 nm (25.8 × 10³M⁻¹cm⁻¹). λ_VHF(ε) =

493 nm (39.2 × 10³M⁻¹cm⁻¹).

7-(4-Methoxyphenyl)-2-(4′-nitrophenyl)-1,8a-dihydroazulene-

1,1-dicarbonitrile (4.2). To a solution of 7-bromide 11.1 (¹/₉of a batch

made in two steps from 2.25 mmol 1.1) in a mixture of argon-degassed

toluene (15 mL) and water (10 mL) were added methoxyphenyl

boronic acid (0.25 mmol), KF·2H₂O (26 mg, 0.25 mmol), and

tetrakis(triphenylphosphine)palladium(0) (29 mg, 25 μmol, 10 mol %),

and the reaction mixture was stirred at 90 °C for 24 h (reaction progress

1

cannot be monitored by TLC (no suitable eluent was found), but H

NMR was used (decay of signal at δ = 6.13 ppm)). The reaction mixture

was diluted with Et₂O (200 mL), washed with saturated aqueous NH₄Cl

(50 mL) and brine (50 mL), dried with MgSO₄, and ﬁltered, and the

solvents were removed in vacuo. Puriﬁcation by dry column vacuum

chromatography (SiO₂, 12.6 cm², (1) 0−65% THF/heptanes, 5% steps,

40 mL fractions, (2) 0−100% toluene/heptanes, 12.5% steps, 40 mL

fractions) followed by recrystallization from CH₂Cl₂/heptanes gave 4.2

(37.7 mg, 92.5 μmol, 37%) as yellow crystals. TLC (toluene): R_f= 0.37.

mp 190−200 °C dec. ¹H NMR (500 MHz, CDCl₃) δ 8.34 (d, J = 9.0 Hz,

2H), 7.91 (d, J = 9.0 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.07 (s, 1H), 6.90

(d, J = 8.8 Hz, 2H), 6.86−6.77 (m, 2H), 6.51−6.45 (m, 1H), 5.92 (d, J =

4.6 Hz, 1H), 3.85 (dd, J = 4.6, 1.6 Hz, 1H), 3.83 (s, 3H) ppm. ¹³C NMR

(125 MHz, CDCl₃) δ 159.9, 148.2, 139.8, 139.7, 138.5, 136.6, 135.5,

133.8, 132.5, 132.3, 129.1, 127.1, 124.7, 122.8, 114.8, 114.1, 112.6, 55.5,

50.9, 45.1 ppm (one signal is missing because of overlap). Anal.

Calcd for C₂₅H₁₇N₃O₃(407.42): C, 73.70; H, 4.21; N, 10.31. Found: C,

73.62; H, 4.05; N, 10.27. UV−vis (MeCN) λ_DHA= 373 nm.

λ_VHF= 519 nm.

7-(4-Cyanophenyl)-2-(4′-Tolyl)-1,8a-dihydroazulene-1,1-dicarbo-

nitrile (4.3). Method 1: To a stirred solution of 7-bromoide 11.3 (crude,

prepared in two steps from 0.25 mmol with a purity of >90%) in a

mixture of argon-ﬂushed toluene (20 mL) and water (20 mL) were

added cyanophenyl boronic acid (37 mg, 0.25 mmol), KF·2H₂O (26 mg,

0.25 mmol), and tetrakis(triphenylphosphine)palladium(0) (29 mg,

25 μmol, 10 mol %), and the reaction mixture was stirred at 70−75 °C

for 48 days. The reaction mixture was diluted with Et₂O (200 mL),

washed with saturated aqueous NH₄Cl (50 mL) and brine (50 mL),

dried with MgSO₄, and ﬁltered, and the solvent was concentrated in

vacuo. Puriﬁcation by dry column vacuum chromatography (SiO₂, 12.6 cm²,

0−100% toluene/heptanes, 20% steps, followed by 0−100% CHCl₃/

heptanes, 20% steps, 40 mL fractions) gave 4.3 (9.3 mg, 0.025 mmol,

10%) as a dark yellow solid. Method 2: Prepared according to the

general procedure for 2.1: 7-bromide 11.3 (crude, prepared in two steps

from 1.00 mmol with a purity of >90%), tolyl boronic acid (272 mg, 2.00 mmol),

K₃PO₄(425 mg, 2.00 mmol), RuPhos (46.7 mg, 0.10 mmol), and

palladium(II)acetate (11.2 mg, 0.050 mmol) in toluene (9 mL) and water

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3.84 (dd,J = 4.6, 2.0 Hz,1H), 3.83 (s, 3H) ppm. ¹³C NMR (125 MHz,

CDCl₃) δ 159.9, 139.8, 139.6, 138.9, 134.8, 134.8, 133.6, 133.1, 132.5, 132.3,

129.1, 126.8, 122.4, 118.2, 114.8, 114.8, 114.1, 113.4, 112.7, 55.5, 50.9,

45.0 ppm. ¹H NMR (500 MHz, CD₃CN) δ 7.96 (d, J = 8.8 Hz, 2H), 7.88

(d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.9 Hz, 2H), 7.32 (s, 1H), 6.97 (d, J = 8.9Hz,

2H), 6.90−6.81 (m, 2H), 6.57 (d, J = 5.7 Hz, 1H), 5.91 (d, J = 4.5 Hz, 1H),

3.90 (dd, J = 4.5, 1.7 Hz, 1H), 3.82 (s, 3H) ppm. ¹³C NMR (125 MHz,

CD₃CN) δ 161.4, 141.8, 140.3, 140.0, 137.6, 136.5, 134.7, 134.4, 134.2,

133.9, 130.3, 128.4, 124.1, 119.8, 117.0, 116.6, 115.6, 114.6, 114.3, 56.6,

52.1, 46.6 ppm. Anal. Calcd for C₂₆H ₁₇N₃O (387.43): C, 80.60; H, 4.42; N,

10.85. Found: C, 80.37; H, 4.21; N, 10.92. MS (MALDI−): m/ z 387 [M⁻].

UV−vis (MeCN) λ_DHA(ε): 354 nm (32.6 × 10³M⁻¹cm⁻¹). λ_VHF(ε):

518 nm (60.6 × 10³M⁻¹cm⁻¹).

HRMS (ESP+): m/z 401.1760 [MH⁺], calcd for (C₂₇H₂₁N₄⁺): m/z

401.1761. UV−vis (MeCN) λ_DHA(ε): 362 nm (18.5 × 10³M⁻¹cm⁻¹).

λ_VHF(ε): 563 nm (24.0 × 10³M⁻¹cm⁻¹).

7-(4-Bromophenyl)-2-(4′-bromophenyl)-1,8a-dihydroazulene-

1,1-dicarbonitrile (4.8). Prepared according to the general procedure

for 2.1: 7-bromide 11.8 (crude, prepared in two steps from 1.07 mmol

with a purity of >90%), 4-bromophenyl boronic acid (215 mg, 1.07 mmol),

K₃PO₄(254 mg, 2.14 mmol), RuPhos (49.9 mg, 107 μmol), and

palladium(II)acetate (12.0 mg, 53.5 μmol) in toluene (18 mL) and water

(2 mL) were stirred for 60 h at rt. (TLC (35% toluene/CS₂): R_f= 0.50

(4.8), R_f= 0.40 (photochromic byproduct) and R_f= 0.30 (photochromic

byproduct). By TLC analysis and NMR spectroscopy two byproducts

arising from a second and third coupling can be recognized, although these

were never obtained analytically pure.) Worked up according to the general

procedure for 2.1. Puriﬁcation by dry column vacuum chromatography

(SiO₂, 12.6 cm², 0−100% CS₂/heptanes, 20% steps, then 0−50% toluene/

CS₂, 2.5% steps, 40 mL fractions, multiple columns were necessary to obtain

a pure sample) gave 4.8 (378 mg, 0.770 mmol, 72%) as a yellow to red solid.

7-(4-Cyanophenyl)-2-(4′-cyanophenyl)-1,8a-dihydroazulene-1,1-

dicarbonitrile (4.6). Prepared according to the general procedure for

2.1: 7-bromide 11.10 (crude, prepared in two steps from 0.5 mmol with

a purity of >90%), cyanophenyl boronic acid (146 mg, 1.00 mmol),

K₃PO₄(119 mg, 1.00 mmol), RuPhos (23 mg, 50 μmol), and

palladium(II)acetate (5.6 mg, 25 μmol) in toluene (18 mL) and water

(2 mL) were stirred for 8 h at 50 °C. Worked up according to the general

procedure for 2.1. Puriﬁcation by dry column vacuum chromatography

(SiO₂, 12.6 cm², (1) 0−100% toluene/heptanes, 20% steps, 40 mL

fractions, then neat toluene 200 mL (A purple band was separated. The

elution of toluene was not stopped before the purple band was well

ahead of the following yellow band), then: 0−6% EtOAc/toluene, 1%

steps, (2) 0−100% toluene/heptanes, 20% steps, then: neat toluene

200 mL, 0−100% CHCl₃/toluene, 20% steps, 0−5% EtOAc/heptanes,

1% steps, (3) 0−100% toluene/heptanes, 20% steps, 0−13% MeNO₂/

toluene, 1% steps, 40 mL fractions) gave (56 mg, 14.6 μmol, 29%) as a

yellow solid. (Multiple columns were nessesary to get a complete

separation from a UV-active spot with a slightly lower R_fthan the desired

product. An analytically pure sample can also be obtained by careful

recrystallization from CHCl₃/heptanes.) TLC (75% toluene/

1

TLC (35% toluene/CS₂): R_f= 0.50. mp 169.7−170.6 °C. H NMR

(300 MHz, CDCl₃) δ 7.62 (br s, 4H), 7.50 (d, J = 8.4 Hz, 2H), 7.27 (d, J =

8.4 Hz, 2H), 6.90 (s, 1H), 6.82 (dd, J = 11.5, 6.0 Hz, 1H), 6.72 (d, J = 11.5

Hz, 1H), 6.39 (dd, J = 6.0, 1.6 Hz, 1H), 5.96 (d, J = 4.6 Hz, 1H), 3.82

(dd, J = 4.6, 1.6 Hz, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 140.5, 140.3,

139.0, 139.0, 132.9, 132.7, 132.2, 131.9, 131.8, 129.4, 127.8, 124.8, 122.6,

120.9, 116.5, 115.0, 112.9, 51.0, 45.1 ppm (one signal missing because of

overlap). Anal. Calcd for C₂₄H₁₄Br₂N₂(490.19): C, 58.81; H, 2.88; N, 5.71.

Found: C, 58.72; H, 2.55; N, 5.64. HRMS (ESP+): m/z 488.9598

[MH⁺], calcd for (C₂₄H₁₅Br₂N₂⁺): m/z 488.9597. UV−vis (MeCN):

λ_DHA(ε) = 359 nm (16.3 × 10³M⁻¹cm⁻¹), λ_VHF(ε) = 492 nm

(30.1 × 10³M⁻¹cm⁻¹).

7-(4-Cyanophenyl)-2-(4′-bromophenyl)-1,8a-dihydroazulene-

1,1-dicarbonitrile (4.9). Prepared according to the general procedure

for 2.1: 7-bromide 11.8 (crude, prepared in two steps from 0.50 mmol

with a purity of >90%), cyanophenyl boronic acid (75.9 mg,

0.500 mmol), K₃PO₄(212 mg, 0.999 mmol), RuPhos (23.3 mg,

49.9 μmol), and palladium(II)acetate (5.6 mg, 25 μmol) in toluene

(9 mL) and water (1 mL) were stirred for 16 h at rt. Worked up

according to the general procedure for 2.1. Puriﬁcation by dry column

vacuum chromatography (SiO₂, 12.6 cm², 0−100% toluene/heptanes,

10% steps, 40 mL) gave 4.9 (89 mg, 0.21 μmol, 41%) as a yellow solid.

TLC (toluene): R_f= 0.29 (yellow → purple). mp 185.2−186.2 °C. ¹H

NMR (500 MHz, CDCl₃) δ 7.68 (d, J = 8.6 Hz, 2H), 7.64−7.62 (s, 4H),

7.51 (d, J = 8.6 Hz, 2H), 6.92 (s, 1H), 6.88 (dd, J = 11.6, 6.2 Hz, 1H),

6.73 (d, J = 11.6 Hz, 1H), 6.42 (dd, J = 6.2, 1.7 Hz, 1H), 6.03 (d, J = 4.7

Hz, 1H), 3.86 (dd, J = 4.7, 1.7 Hz, 1H) ppm. ¹³C NMR (125 MHz,

CDCl₃) δ 144.4, 140.6, 140.6, 138.6, 133.5, 132.8, 132.6, 132.1, 131.0,

129.3, 128.4, 127.9, 125.0, 120.9, 118.7, 118.3, 114.8, 112.8, 112.0, 50.9,

45.0 ppm. Anal. Calcd for C₂₅H₁₄BrN₃(436.04): C, 68.82; H, 3.23; N,

9.63. Found: C, 68.69; H, 3.15; N, 9.58. HRMS (ESP+): m/ z 893.0627,

895.0618 [2MNa⁺, ^79/81Br], calcd for (C₅₀H₂₈Br₂N₆Na⁺): m/z

893.0635, 895.0614. UV−vis (MeCN) λ_DHA(ε): 361 nm (17.6 ×

10³M⁻¹cm⁻¹). λ_VHF(ε): 484 nm (33.1 × 10³M⁻¹cm⁻¹).

7-(4-Methoxyphenyl)-2-(4′-bromophenyl)-1,8a-dihydroazulene-

1,1-dicarbonitrile (4.10). Prepared according to the general procedure

for 2.1: 7-bromide 11.8 (crude, prepared in two steps from 1.07 mmol

with a purity of >90%), 4-methoxyphenyl boronic acid (146 mg,

1.07 mmol), K₃PO₄(254 mg, 2.14 mmol), RuPhos (49.9 mg, 107 μmol),

and palladium(II)acetate (12.0 mg, 53.5 μmol) in toluene (18 mL) and

water (2 mL) were stirred for 16 h at rt. Worked up according to the

general procedure for 2.1. Puriﬁcation by dry column vacuum

chromatography (SiO₂, 12.6 cm², 0−75% toluene/heptanes, 7.5% steps,

40 mL, 75−87.5% toluene/heptanes, 2.5% steps, 40 mL fractions) gave

4.10 (385 mg, 872 μmol, 82%) as a yellow solid. Recrystallization from

CHCl₃/heptanes gave 4.10 (135.9 mg, 0.308 mmol, 29%) as yellow

needles. TLC (80% toluene/heptanes): R_f= 0.33. TLC (toluene): R_f=

0.56. mp 148−151 °C dec. ¹H NMR (500 MHz, CDCl₃) δ 7.61 (br s,

4H), 7.33 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz,2H), 6.89 (s, 1H), 6.81−

6.76 (m, 2H), 6.37 (t, J = 8.4 Hz, 1H), 5.91 (d, J = 4.6 Hz, 1H), 3.83 (s,

3H), 3.81 (dd, J = 4.6, 1.6 Hz, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ

159.8, 140.5, 140.0, 139.4, 132.7, 132.7, 132.7, 132.4, 132.3, 129.6, 129.1,

1

heptanes): R_f= 0.09 (yellow → light purple). mp > 215 °C dec. H

NMR (500 MHz, CDCl₃) δ 7.85 (d, J = 10.5 Hz, 2H), 7.78 (d, J = 10.5

Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 7.04 (s, 1H),

6.90 (dd, J = 11.5, 6.1 Hz, 1H), 6.77 (d, J = 11.5 Hz, 1H), 6.50 (d, J = 6.1

Hz, 1H), 6.03 (d, J = 4.7 Hz, 1H), 3.88 (dd, J = 4.7, 1.5 Hz, 1H) ppm. ¹³C

NMR (125 MHz, CDCl₃) δ 144.2, 140.0, 139.4, 138.8, 134.6, 134.5,

133.4, 133.2, 132.6, 131.9, 128.4, 126.9, 122.4, 118.7, 118.3, 118.1, 114.5,

113.8, 112.5, 112.2, 50.8, 44.9 ppm. Anal. Calcd for C₂₆H₁₄N₄(382.42):

C, 81.66; H, 3.69; N, 14.65. Found: C, 81.79; H, 3.71; N, 14.53. HRMS

(ESP+): m/z 405.1100 [MNa⁺], calcd for (C₂₆H₁₄N₄Na⁺): m/z

405.1111. UV−vis (MeCN) λ_DHA(ε): 366 nm (10.7 × 10³M⁻¹cm⁻¹).

λ_VHF(ε): 490 nm (19.4 × 10³M⁻¹cm⁻¹).

7-(4-N,N-Dimethylaminophenyl)-2-(4′-cyanophenyl)-1,8a-dihy-

droazulene-1,1-dicarbonitrile (4.7). To a stirred solution of 11.10

(crude, prepared in two steps from 0.5 mmol with a purity of >90%)

were added 4-N,N-dimethylaminophenyl boronic pinacol ester

(289 mg, 1.19 mmol), K₃PO₄(252 mg, 1.19 mmol), KF·2H₂O

(67 mg, 0.71 mmol), Pd(OAc)₂(12.6 mg, 0.0564 mmol), and RuPhos

(52.7 mg, 0.113 mmol). The reaction mixture was reﬂuxed for 1 h and

then stirred at 50 °C overnight. (TLC (toluene): R_f= 0.10 (product,

yellow → purple, low photoactivity), R_f= 0.30 (starting material,

yellow →red).) The reaction mixture was diluted with Et₂O (100 mL), washed

with brine (100 mL), dried with Na₂SO₄, and ﬁltered, and the solvents

were removed. Puriﬁcation by dry column vacuum chromatography

(SiO₂, 12.6 cm², 0−100% toluene/heptanes, 20% steps, 40 mL fractions,

then neat toluene (10 × 100 mL) to collect product (unreacted starting

material elutes, then a purple band which is followed by the desired

product), very short column) followed by recrystallization from CHCl₃/

heptanes gave 4.7 (20 mg, 0.050 mmol, 9%) as a dark yellow or slightly

brown solid. TLC (toluene): R_f= 0.10 (yellow → purple). mp 190−220 °C

dec, darkens at ca. 140 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.84 (d, J = 8.8

Hz, 2H), 7.76 (d, J = 8.8 Hz, 2H), 7.29 (d, J = 8.5 Hz, 2H), 7.01 (s, 1H),

6.87−6.78 (m, 2H), 6.71 (br d, J = 8.5 Hz, 2H), 6.44 (d, J = 5.7 Hz, 1H),

5.89 (d, J = 4.6 Hz, 1H), 3.82 (dd, J = 4.6, 1.6 Hz, 1H), 2.98 (s, 6H) ppm.

¹³C NMR (125 MHz, CDCl₃) δ 150.6, 139.9, 139.8, 138.7, 134.9, 134.1,

133.1, 132.1, 128.7, 126.8, 122.4, 118.3, 115.0, 113.3, 113.3, 112.7, 112.3,

50.9, 45.0, 40.6 ppm (2 signals missing because of overlapping signals).

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127.8, 124.6, 120.8, 115.2, 114.8, 114.1, 113.0, 55.5, 51.0, 45.1 ppm. Anal.

Calcd for C₂₅H₁₇BrN₂O (441.32): C, 68.04; H, 3.88; N, 6.35. Found: C,

67.62; H, 3.61; N, 6.33. MS (MALDI TOF−): m/z 440, 442 [M^−79/81Br].

UV−vis (MeCN) λ_DHA(ε): 352 nm (16.8 × 10³M⁻¹cm⁻¹). λ_VHF(ε):

509 nm (32.5 × 10³M⁻¹cm⁻¹).

(d, J = 4.2 Hz, 1H), 1.38 (s, 9H), 1.35 (s, 9H) ppm.¹³¹³C NMR

(125 MHz, CDCl₃) δ 145.0, 140.0, 138.8, 1369, 135.2, 135.1, 134.8,

133.2, 132.0, 131.6, 131.0, 128.0, 126.5, 122.4, 118.5, 114.6, 112.6, 60.4,

60.1, 50.9, 45.0, 23.8 ppm (two signals are missing because of overlap).

Anal. Calcd for C₃₂H₃₂N₂O₄S₂(572.74): C, 67.11; H, 5.63; N, 4.89.

Found: C, 67.31; H, 5.61; N, 4.89. MS (ESP+): m/z 595 [MNa⁺].

2-(4′-(Methylthio)-[1,1′-biphenyl]-4-yl)-7-(4-(methylthio)phenyl)-

1,8a-dihydroazulene-1,1-dicarbonitrile (4.16). To a stirred solution of

11.4 (prepared from 216.9 mg, 0.5675 mmol of DHA 1.4) in toluene

(18 mL) and water (2 mL) were added Pd(OAc)₂(6.3 mg, 28 μmol, 5

mol %), RuPhos (26.5 mg, 56.8 μmol, 10 mol %), 4-thiomethoxy phenyl

boronic acid (95.4 mg, 0.568 mmol, 1 equiv), and K₃PO₄(240.6 mg,

1.135 mmol), and the reaction mixture was stirred for 24 h at rt.

TLC analysis showed formation of DHA 11.35 (TLC(toluene):

R_f= 0.53 (11.35, light yellow → orange)). Additional catalyst, Pd(OAc)₂

(6.3 mg, 28 μmol), and RuPhos (26.5 mg, 56.8 μmol) were added, and the

temperature was elevated to 50 °C. After 1 h, TLC analysis showed

signiﬁcant formation of DHA 4.16 (TLC(toluene): R_f= 0.44 (4.16, dark

yellow → purple). Spectroscopic analysis in accordance with literature^4b).

Additional 4-thiomethoxyphenyl boronic acid (143.0 mg, 0.8513 mmol, 1.5

equiv) was added, and the reaction mixture was stirred for an additional 6 h

at 50 °C. The resulting black reaction mixture was quenched and worked up

according to the procedure of 2.1. Puriﬁcation by dry column vacuum

chromatography (SiO₂, 12.6 cm², 0−75% toluene/heptanes, 7.5% steps,

75−90% toluene/heptanes, 2.5% steps, 40 mL fractions) gave 4.16

(130 mg, 0.259 mmol, 46%) as a yellow to red solid.

2-[1-(4-Nitrophenyl)ethylidene]malononitrile (5.1). To a stirring

solution of 4-nitroacetophenone (28.1 g, 170 mmol) and malononitrile

(12.4 g, 187 mmol) in toluene (500 mL), were added NH₄OAc (10.0 g,

187.1 mmol) and glacial acetic acid (31.5 g, 30 mL, 524 mmol), and the

ﬂask was equipped with a Dean−Stark trap. The reaction mixture was

reﬂuxed and stirred overnight. The reaction mixture was washed with

water (2 × 150 mL) and brine (2 × 150 mL). The organic phase was

concentrated in vacuo, which gave a light brown oil, with minor

impurities, that solidiﬁed upon standing (under vacuum). Recrystalliza-

tion from boiling 96% EtOH (ca. 300 mL) gave 5.1 (25.75 g, 121 mmol,

71%) as light or dark yellow crystals. TLC (30% EtOAc/heptanes): R_f=

0.33. mp 120.5−122.0 °C (lit.¹⁴mp 154 °C (EtOH)). ¹H NMR (500 MHz,

DMSO-d₆) δ 8.39 (d, J = 8.7 Hz, 2H), 7.93 (d, J = 8.7 Hz, 2H), 2.65 (s, 3H)

ppm. ¹³C NMR (125 MHz, DMSO-d₆) δ 175.3, 149.0, 142.2, 129.2, 123.9,

112.6, 112.6, 86.0, 24.6 ppm.

2-(1-(4-Aminophenyl)ethylidene)malononitrile (5.2). To a mixture

of 4-aminoacetophenone (13.53 g, 100 mmol) and malononitrile

(6.99 g, 106 mmol) in toluene (500 mL) were added NH₄OAc (2.90 g,

0.035 mmol) and glacial acetic acid (2.90 g, 2.76 mL, 0.046 mmol), and

the round-bottomed ﬂask was equipped with a Dean−Stark trap. The

reaction mixture was reﬂuxed and stirred for 3 h. The reaction mixture

was ﬁltered and allowed to cool to rt, which gave 5.2 (10.75 g, 58.7

mmol, 59%) as a yellow powder, with minor impurities (a one time

evaporation of the solvent to half of the volume was necessary to

accomplish the crystallization). Recrystallization from boiling 96%

EtOH (250 mL) gave 5.2 (6.68 g, 36.4 mmol, 36%) as yellow needles.

TLC (CH₂Cl₂): R_f= 0.36. mp 197.6−198.4 °C (96% EtOH) (lit.¹⁵mp

205−206 °C (benzene)). ¹H NMR (500 MHz, DMSO-d₆) δ 7.60 (d, J =

8.9 Hz, 2H), 6.63 (d, J = 8.9 Hz, 2H), 6.44 (s, 2H), 2.52 (s, 3H) ppm. ¹³C

NMR (125 MHz, DMSO-d₆) δ 173.6, 154.3, 131.0, 121.4, 115.7, 115.3,

112.9, 73.7, 22.8 ppm.

2-[1-(4-Methylphenyl)ethylidene]malononitrile (5.3). To a mixture

of 4-methylacetophenone (22.81 g, 22.70 mL, 170.0 mmol) and

malononitrile (12.35 g, 187.0 mmol) in toluene (500 mL) were added

NH₄OAc (10.0 g, 187.1 mmol) and glacial acetic acid (31.5 g, 30 mL,

524 mmol), and the round-bottomed ﬂask was equipped with a Dean−

Stark trap. The reaction mixture was reﬂuxed and stirred for 16 h. The

reaction mixture was allowed to cool to rt, after which it was washed with

saturated aqueous NH₄Cl (100 mL), water (3 × 100 mL), and brine

(100 mL), dried with MgSO₄, ﬁltered, and concentrated in vacuo. The

resulting yellow solid was recrystallized from boiling 96% EtOH, which

gave 5.3 (21.98 g, 120.6 mmol, 71%) as pale needles. ¹H NMR (CDCl₃,

500 MHz) δ 7.48 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 2.62 (s,

3H), 2.42 (s, 3H) ppm. ¹³C NMR (CDCl₃, 125 MHz) δ 175.4, 143.5,

7-(4-Methoxyphenyl)-2-(4′-methoxybiphenyl)-1,8a-dihydroazu-

lene-1,1-dicarbonitrile (4.11). Prepared according to the general

procedure for 2.1: 7-bromide 11.8 (crude, prepared in two steps from

0.460 mmol with a purity of >90%), 4-methoxyphenyl boronic acid

(280 mg, 1.84 mmol), K₃PO₄(195 mg, 0.920 mmol), RuPhos (21 mg,

46 μmol), and palladium(II)acetate (5.1 mg, 23 μmol) in toluene

(9 mL) and water (1 mL) were heated by microwave irradiation for

30 min at 90 °C. Worked up according to the general procedure for 2.1.

Puriﬁcation by dry column vacuum chromatography (SiO₂, 12.6 cm²,

0−90% toluene/heptanes, 10% steps, 40 mL fractions, then 90−100%

toluene/heptanes, 2.5% steps, 40 mL fractions, 120 mL neat toluene was

passed through to collect the product) gave 4.11 (98.4 mg, 0.212 μmol,

42%) as a yellow solid. TLC (toluene): R_f= 0.33. mp 221−223 °C dec.

¹H NMR (500 MHz, CDCl₃) δ 7.81 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 8.7

Hz, 2H), 7.58 (d, J = 8.9 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.01 (d, J =

8.9 Hz, 2H), 6.91 (s, 1H), 6.90 (d, J = 8.8 Hz, 2H), 6.83−6.72 (m, 2H),

6.36 (d, J = 5.8 Hz, 1H), 5.95 (d, J = 4.6 Hz, 1H), 3.87 (s, 1H), 3.84

(d, J = 4.6, 1.7 Hz, 1H), 3.83 (s, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃)

δ 159.9, 159.8, 142.6, 141.0, 141.0, 139.3, 132.9, 132.5, 132.4, 132.3,

131.1, 129.1, 128.8, 128.3, 127.4, 126.9, 120.1, 115.5, 114.9, 114.6, 114.0,

113.2, 55.5, 55.5, 51.0, 45.1 ppm. Anal. Calcd for C₃₂H₂₄N₂O ₂(468.55):

C, 82.03; H, 5.16; N, 5.98. Found: C, 81.95; H, 4.90; N, 6.01. MS

(MALDI−): m/z 468 [M⁻]. UV−vis (MeCN) λ_DHA(ε): 373 nm

(32.6 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 506 nm (38.4 × 10³M⁻¹cm⁻¹).

2-([1,1′-Biphenyl]-4-yl)-7-phenyl-1,8a-dihydroazulene-1,1-dicar-

bonitrile (4.12). For preparation, see the synthesis of compound 2.4.

7-[4-(tert-Butylthio)phenyl]-2-(4′-(tert-butylthio)phenyl)-1,8a-di-

hydroazulene-1,1-dicarbonitrile (4.14). Prepared according to the

general procedure for 2.1: 7-bromide 11.28 (crude, prepared in two

steps from 1.00 mmol with a purity of >90%), 4-(tert-butylthio)phenyl

boronic acid (235 mg, 1.12 mmol), K₃PO₄(440 mg, 2.07 mmol),

Pd(OAc)₂(17 mg, 0.0757 mmol), and RuPhos (74 mg, 0.159 mmol) in

toluene (50 mL) and water (5.0 mL) were stirred for 16 h at rt. The

contents of the vessel were diluted with toluene (100 mL) and water

(100 mL), and the phases were separated. The organic phase was dried

over Na₂SO₄and ﬁltered, and the solvent was removed by rotary

evaporation. The residue was subsequently puriﬁed by ﬂash column

chromatography (SiO₂, gradient elution: 50−100% toluene/heptane)

to give 4.14 (215 mg, 42%) as a yellow powder. TLC (60% toluene/

heptane): R_f= 0.43. mp 140−142 °C.¹¹H NMR (500 MHz, CDCl₃) δ

7.71 (d, J = 8.6, 2H), 7.63 (d, J = 8.6, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.36

(d, J = 8.4 Hz, 2H), 6.93 (s, 1H), 6.83 (dd, J = 11.4, 5.8 Hz, 1H), 6.78

(d, J = 11.4 Hz, 1H), 6.39 (d, 5.8 Hz, 1H), 6.02 (d, J = 4.7 Hz, 1H), 3.85

(dd, J = 4.7, 1.7 Hz, 1H), 1.34 (s, 9H), 1.29 (s, 9H) ppm. ¹³C NMR (125

MHz, CDCl₃) δ 140.6, 140.4, 139.3, 137.9, 137.7, 136.0, 133.0, 132.7,

132.2, 132.1, 130.5, 127.8, 126.2, 120.8, 116.8, 115.1, 113.0, 51.1, 47.1,

46.4, 45.0, 31.2, 31.1 ppm (one signal missing because of overlap). Anal.

Calcd for C₃₂H₃₂N₂S₂(508.74): C, 75.55; H, 6.34; N, 5.51. Found: C,

75.68; H, 6.01; N, 5.40.

7-[4-(tert-Butylsulfonyl)phenyl]-2-(4′-[tert-butylsulfonyl)phenyl]-

1,8a-dihydroazulene-1,1-dicarbonitrile (4.15). To a solution of 4.14

(65 mg, 0.128 mmol) in CH₂Cl₂(5 mL) was added m-CPBA (170 mg,

0.76 mmol, 70% w/w), and the resulting solution was stirred for 20 min

at rt. The solution was treated simultaneously with saturated aqueous

sodium thiosulfate (1 mL) and saturated aqueous sodium bicarbonate

(1 mL) and was then diluted with both water (10 mL) and CH₂Cl₂

(10 mL). The phases were separated, and the organic phase was dried

over sodium sulfate. Filtration and removal of the solvent under reduced

pressure gave an orange residue, which was subjected to ﬂash column

chromatography (SiO₂, 15% EtOAc/CH₂Cl₂) to furnish DHA 4.15

(60 mg, 82%) as an oﬀ yellow solid. TLC (5% EtOAc/CH₂Cl₂): R_f=

0.39. mp 197−199 °C. ¹H NMR (500 MHz, CDCl₃) δ 8.00 (d, J = 8.4

Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H), 7.57 (d, J =

8.2 Hz, 2H), 7.08 (s, 1H), 6.90 (dd, J = 11.5, 6.0 Hz, 1H), 6.80 (d, J =

11.5 Hz, 1H), 6.51 (d, J = 6.0 Hz, 1H), 6.07 (d, J = 4.2 Hz, 1H), 3.91

60

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133.1, 129.9, 127.6, 113.3, 113.1, 83.7, 24.2, 21.7 ppm. GC-MS (EI⁺):

m/z 182.1 [M⁺].

2-[1-(4-Bromophenyl)ethylidene]malononitrile (5.8). Slowly,

1,1,1,3,3,3-hexamethyl-disilazane (48.7 g, 63.2 mL, 301 mmol) was

added to acetic acid (177 g, 168 mL, 2.94 mol) while keeping the

temperature below 75 °C. The mixture was added to a solution of 4-

bromoacetophenone (50.00 g, 251.2 mmol) and malononitrile (33.19 g,

502.4 mmol) in acetic acid (87 g, 83 mL, 1.5 mol). The reaction mixture

was heated at 75 °C for 72 h, after which it was allowed to cool to rt. The

reaction mixture was diluted with toluene (250 mL), water was added

(100 mL), and the acetic acid layer was separated and extracted with

toluene (2 × 150 mL). The combined toluene phases were washed with

water (4 × 100 mL), dried with MgSO₄, and ﬁltered, and the solvent was

evaporated in vacuo. Recrystallization by dissolving the residue in

chloroform (50 mL) and adding boiling heptanes (400 mL) gave 5.8

(41.7 g, 169 mmol, 67%) as slightly yellow needles. mp 94.5−95.6 °C.

(lit.^16bmp 93.5−94.5 °C (heptanes)). ¹H NMR (500 MHz, CDCl₃) δ

7.65 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 2.62 (s, 3H) ppm. ¹³C

NMR (125 MHz, CDCl₃) δ 174.0, 134.6, 132.5, 128.9, 127.2, 112.6,

112.5, 85.2, 24.2 ppm.

2-[1-(4-Iodophenyl)ethylidene]malononitrile (5.4). To a stirring

solution of 4-iodoacetophenone (26.3 g, 103 mmol) and malononitrile

(18.9 g, 287 mmol) in toluene (500 mL) was added NH₄OAc (26 g,

337 mmol) dissolved in AcOH (40 mL, 667 mmol), and the ﬂask was

equipped with a Dean−Stark trap. The reaction mixture was heated to

reﬂux and stirred for 2 h (oil temperature, 180 °C). After cooling the

reaction mixture, it was diluted with diethylether (300 mL), washed with

water (2 × 300 mL) and brine (300 mL), and dried with MgSO₄.

Evaporation of the solvents gave 5.4 (29.6 g, 98.9 mmol, 96%) as pale

yellow crystals. Recrystallization from boiling 96% ethanol (650 mL)

gave 5.4 (23.6 g, 82.3 mmol, 81%) as slightly yellow crystals. mp 122.5−

123.5 °C (ethanol) (lit.^8fmp 117 °C). ¹H NMR (500 MHz, CDCl₃) δ

7.85 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 8.7 Hz, 2H), 2.60 (s, 3H) ppm. ¹³C

NMR (125 MHz, CDCl₃) δ 174.2, 138.5, 135.2, 128.8, 112.6, 112.5,

99.4, 85.2, 24.1 ppm. MS (ESP+): m/z 295 [MH⁺].

2-[1-(3-Iodophenyl)ethylidene]malononitrile (5.5). To a stirred

solution of m-iodoacetophenone (5.00 g, 20.3 mmol) and malononitrile

(3.60 g, 54.5 mmol) in toluene (250 mL) was added NH₄OAc (5.2 g,

67.5 mmol) dissolved in AcOH (8.05 mL, 8.44 g, 141 mmol), the ﬂask

was equipped with a Dean−Stark trap, and the reaction mixture was

heated to reﬂux and stirred for 2 h (oil temperature, 180 °C). After

cooling the reaction mixture, it was diluted with diethylether (150 mL),

washed with water (2 × 200 mL) and brine (100 mL), and dried with

MgSO₄. Evaporation of the solvents gave 5.5 (5.92 g, 20.1 mmol, 99%)

as a pale yellow solid. Recrystallization from CHCl₃/heptanes gave 5.5

(4.22 g, 14.4 mmol, 71%) as oﬀ-white ﬂake-like crystals. (An insoluble

black oil was discarded by decanting. Boiling CHCl₃(40−50 mL) was

added to a slurry of 5.5 in hot heptanes (100 mL) to dissolve the

compound. The solution was allowed to stand overnight and slowly cool

to rt while CHCl₃evaporated.) TLC (CH₂Cl₂): R_f= 0.79. mp 117.2−

119.5 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.88 (ddd, J = 7.9, 1.7, 1.0 Hz,

1H), 7.82 (t, J = 1.7 Hz, 1H), 7.52 (ddd, J = 7.9, 1.7, 1.0 Hz, 1H), 7.24 (t,

J = 7.9 Hz, 1H), 2.61 (s, 3H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ

173.7, 141.1, 137.9, 135.9, 130.8, 126.6, 112.4, 94.7, 86.1, 24.4 ppm (one

signal missing because of overlap). Anal. Calcd for C₁₁H₇N₂I (294.09):

C, 44.92; H, 2.40; N, 9.53. Found: C, 44.97; H, 2.00; N, 9.58. GC-MS

(EI⁺): m/z 294.0 [M⁺].

2-[1-(4-Acetaminophenyl)ethylidene]malononitrile (5.9). Method

1: To a stirred suspension of 5.2 (519 mg, 2.83 mmol) in freshly

destilled dioxane (10 mL) and water (10 mL) at −5 °C was added Ac₂O

(0.40 mL, 4.25 mmol) dropwise over 30 min. The temperature was

allowed to reach rt, and the reaction mixture was stirred overnight. Ac₂O

(0.40 mL, 4.25 mmol) was added, and the reaction mixture was heated

until a clear solution was achieved. The reaction mixture was stirred for

1 h. Evaporation of the solvent gave 5.9 (636 mg, 2.83 mmol, >99%) as a

slightly yellow powder. Recrystallization from 96% EtOH gave 5.9

(435 mg, 1.93 mmol, 68%) as slightly yellow needles. Method 2: To a

stirred suspension of 5.2 (8.45 g, 46.1 mmol) in dioxane (80 mL) and

water (80 mL) was added Ac₂O (12.8 mL, 68 mmol), and the reaction

mixture was heated at 70 °C for 30 min. Evaporation of the solvent

gave 5.9 (10.3 g, 46.1 mmol, >99%) as a slightly yellow powder.

Recrystallization from 96% EtOH gave 5.9 (6.57 g, 29.2 mmol, 63%) as

slightly yellow needles. TLC (CH₂Cl₂): R_f= 0.05. mp 176.6−177.5 °C.¹

¹H NMR (500 MHz, DMSO-d₆) δ 10.33 (s, 1H), 7.74 (d, J = 9.0 Hz,

2H), 7.70 (d, J = 9.0 Hz, 2H), 2.60 (s, 3H), 2.09 (s, 3H) ppm. ¹³C NMR

(125 MHz, DMSO-d₆) δ 175.8, 169.0, 143.1, 129.9, 129.2, 118.4, 113.9,

113.7, 81.1, 24.2, 23.8 ppm. Anal. Calcd for C₁₃H₁₁N₃O (225.25): C,

69.32; H, 4.92; N, 18.66. Found: C, 69.37; H, 4.69; N, 18.75. MS

(MALDI−): m/z 225 [M⁻].

2-[1-(4-Fluorophenyl)ethylidene]malonitrile (5.6). To a stirring

solution of 4-ﬂuoroacetophenone (6.22 g, 45.0 mmol) and malononi-

trile (9.64 g, 146 mmol) in toluene (200 mL) was added NH₄OAc

(13.50 g, 175 mmol) dissolved in AcOH (20 mL), and the ﬂask was

equipped with a Dean-Stark trap. The reaction mixture was heated to

reﬂux point and stirred for 2 h (oil temperature 180 °C). After cooling

the reaction mixture, it was diluted with diethyl ether (100 mL), washed

with water (3 × 200 mL) and brine (200 mL) and the organic phase

dried over MgSO₄. Filtration and evaporation of the solvents gave 5.6

(8.02 g, 43.1 mmol, 96%) as a pale yellow solid. mp 120.2−122.1 °C

(lit.¹⁴mp 122 °C (ethanol)). ¹H NMR (500 MHz, CDCl₃) δ 7.59 (dd,

J = 8.9, 5.0 Hz, 2H), 7.20 (dd, J = 8.9, 8.2 Hz, 2H), 2.63 (s, 3H). ¹³C NMR

(125 MHz, CDCl₃) δ 174.0, 165.0 (d, J = 255 Hz), 132.0 (d, J = 3.6 Hz),

130.1 (d, J = 9.0 Hz), 116.7 (d, J = 22.2 Hz), 112.9, 112.7, 84.9, 24.4.

2-[1-(4-Methoxyphenyl)ethylidene]malononitrile (5.7). Slowly,

1,1,1,3,3,3-hexamethyl-disilazane (19.37 g, 25.02 mL, 120.0 mmol)

was added to acetic acid (67 mL) while keeping the temperature below

75 °C. The mixture was added to a solution of 4-methoxyacetophenone

(15.02 g, 100.0 mmol) and malononitrile (13.21 g, 200.0 mmol) in

acetic acid (33 mL). The reaction mixture was heated at 65 °C for 48 h,

after which it was allowed to cool to rt. The reaction mixture was diluted

with toluene (100 mL), and the acetic acid layer was separated and

extracted with toluene (100 mL). The combined toluene phases were

washed with water (4 × 100 mL), dried with MgSO₄, and ﬁltered, and

the solvent was concentrated in vacuo. Recrystallization (a yellow

insoluble oil was discarded) from boiling heptanes (700 mL) gave 5.7

(13.66 g, 68.91 mmol, 69%) as colorless needles. mp 87.2−90.1 °C

(lit.^16bmp 79.5−80.5 °C (heptanes)). ¹H NMR (500 MHz, CDCl₃) δ

7.62 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 3.88 (s, 3H), 2.62 (s,

3H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 174.1, 163.2, 123.0, 128.1,

114.6, 113.8, 113.5, 82.1, 55.7, 24.0 ppm.

5′-Amino-3′-methyl-4,4″-dinitro-[1,1′:3′,1′-terphenyl]-

4′,4′,6′(3′H)-tricarbonitrile (6). The preparation of this compound has

been thoroughly discussed in the literature.¹⁶Crystals suitable for X-ray

crystallography were grown from EtOH. TLC (CH₂Cl₂): R_f= 0.20. mp

1

145−150 °C (evolution of gas while melting). H NMR (500 MHz,

DMSO-d₆) δ 8.32 (d, J = 9.0 Hz, 4H), 8.27 (s, 2H), 7.94 (d, J = 9.0 Hz,

2H), 7.73 (d, J = 9.0 Hz, 2H), 6.05 (s, 1H), 1.91 (s, 3H) ppm. ¹³C NMR

(125 MHz, DMSO-d₆) δ 148.4, 147.9, 147.5, 144.2, 143.5, 134.8, 130.1,

129.0, 123.8, 123.6, 122.0, 116.3, 111.6, 111.5, 74.9, 48.3, 20.9 ppm (one signal

missing) (both NMR spectra appear with a molar equivalent of EtOH).

2-[2-Cyclohepta-2,4,6-trienyl-1-(4′-nitrophenyl)ethylidene]-

malononitrile (7.1). To a stirred suspension of ﬁnely divided or

mortared tropylium tetraﬂuoroborate (13.03 g, 73.24 mmol) and 5.1

(15.61 g, 73.24 mmol) in CH₂Cl₂kept at −78 °C under an argon

atmosphere was added Et₃N (10.21 mL, 73.24 mmol) slowly over 2 h

(in portions of 0.5 mL per 5 min to avoid a build-up of a strongly colored

red anion). The reaction mixture was stirred at −78 °C for 4 h, after

which the reaction was quenched, while cold, by addition of saturated

aqueous NH₄Cl (100 mL). (The reaction was completed when all

tropylium tetraﬂuoroborate had come into solution; thus, there were no

ﬂowing bits and pieces. In one instance, the reaction was not complete

because of lower purity of tropylium tetraﬂuoroborate or perhaps high

water content of the solvent. An additional 0.1 equiv of tropylium

tetraﬂuoroborate was added, and the reaction was completed when the

reaction mixture changed color from red to yellow.) The organic layer

was separated and washed with water (100 mL) and brine (100 mL),

dried with MgSO₄, ﬁltered, and concentrated in vacuo, which gave 7.1

(21.92 g, 72.29 mmol, 99%) as a slightly yellow oil. TLC (CH₂Cl₂): R_f=

1

0.77, TLC (toluene): R_f= 0.31. H NMR (500 MHz, CDCl₃) δ 8.34

(d, J = 8.9 Hz, 2H), 7.59 (d, J = 8.9 Hz, 2H), 6.66−6.60 (m, 2H),

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6.27−6.21 (m, 2H), 5.17 (dd, J = 9.1, 6.4 Hz, 2H), 3.24 (d, J = 8.0 Hz,

2H), 1.98 (p, J = 7.7 Hz, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ

175.8, 149.3, 140.6, 131.2, 128.5, 126.7, 124.4, 122.3, 111.6, 111.6, 88.9,

38.9, 37.3 ppm. GC-MS (EI⁺): m/z 301.1 [M⁺− 2H].

C₁₈H₁₃N₂F (276.31): C, 78.24; H, 4.74; N, 10.14. Found: C, 78.19; H, 4.59;

N, 9.98.

2-[2-Cyclohepta-2,4,6-trienyl-1-(4′-methoxyphenyl)ethylidene]-

malononitrile (7.7). Prepared according to the general procedure for

7.1: to 5.7 (14.52 g, 73.24 mmol) and tropylium tetraﬂuoroborate

(13.68 g, 76.90 mmol, 1.05 equiv) in CH₂Cl₂(500 mL) was added Et₃N

(10.21 mL, 73.24 mmol) at −78 °C over the course of 1 h, and the

mixture was stirred for an additional 3 h. The reaction was worked up

according to the general procedure for 7.1 and yielded 7.7 (22.30 g) as a

bright cloudy yellow viscous oil. TLC (toluene): R_f= 0.31. mp 78.4−

81.2 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.45 (d, J = 9.0 Hz, 2H), 6.96

(d, J = 9.0 Hz, 2H), 6.61−6.57 (m, 2H), 6.21−6.16 (m, 2H), 5.15 (dd,

J = 9.0, 6.3 Hz, 2H), 3.86 (s, 3H), 3.19 (d, J = 7.9 Hz, 2H), 2.01−1.94 (m,

1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 177.2, 162.9, 131.2, 129.8,

126.6, 126.4, 123.2, 114.8, 113.5, 113.2, 84.2, 55.7, 38.7, 38.3 ppm. Anal.

Calcd for C₁₉H₁₆N₂O (288.34): C, 79.14; H, 5.59; N, 9.72. Found: C,

78.76; H, 5.41; N, 9.66. HRMS (ESP+): m/z 311.1142 [MNa⁺], calcd

for (C₁₉H₁₆N₂ONa⁺): m/z 311.1155.

2-[2-Cyclohepta-2,4,6-trienyl-1-(4′-bromophenyl)ethylidene]-

malononitrile (7.8). Prepared according to the general procedure for

7.1: to 5.8 (18.10 g, 73.24 mmol) and tropylium tetraﬂuoroborate

(13.68 g, 76.90 mmol, 1.05 equiv) in CH₂Cl₂(500 mL) was added Et₃N

(10.21 mL, 73.24 mmol) at −78 °C over the course of 1 h, and the

mixture was stirred for an additional 3 h. The reaction was worked up

according to the general procedure for 7.1 and yielded 7.8 (24.38 g,

72.29 mmol, 99%) as a bright yellow viscous oil. (A sample (1.16 g,

3.43 mmol) was puriﬁed for characterization by dry column vacuum

chromatography (SiO₂, 12.6 cm², 0−83.3% toluene/heptanes, 8.33%

steps, 40 mL fractions), which gave 7.8 (0.742 g, 2.20 mmol, 64%

recovered) as a nearly colorless oil.) TLC (toluene): R_f= 0.54. ¹H NMR

(500 MHz, CDCl₃) δ 7.62 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H),

6.64−6.58 (m, 2H), 6.24−6.16 (m, 2H), 5.14 (dd, J = 9.3, 6.4 Hz, 2H),

3.16 (d, J = 8.0 Hz, 2H), 2.01−1.93 (m, 1H) ppm. ¹³C NMR (125 MHz,

CDCl₃) δ 176.8, 133.4, 132.6, 131.2, 128.8, 126.7, 126.6, 122.6, 112.3,

112.2, 87.0, 38.7, 37.7 ppm. Anal. Calcd for C₁₈H₁₃N₂Br (337.21): C,

64.11; H, 3.89; N, 8.31. Found: C, 64.55; H, 4.02; N, 7.97.

2-[2-Cyclohepta-2,4,6-trienyl-1-(4′-tolyl)ethylidene]malononitrile

(7.3). To a stirred suspension of ﬁnely divided or mortared tropylium

tetraﬂuoroborate (13.68 g, 76.90 mmol, 1.05 equiv.) and 5.3 (13.35 g,

73.24 mmol) in CH₂Cl₂kept at −78 °C under an argon atmosphere was

added Et₃N (10.21 mL, 73.24 mmol) slowly over 2 h (in portions of

0.5 mL per 5 min to avoid a build-up of the anion). The reaction mixture

was stirred at −78 °C for 2 h, after which the reaction was quenched,

while cold, by addition of saturated aqueous NH₄Cl (100 mL). (TLC

(toluene): R_f= 0.42 (starting material).) The organic layer was

separated and washed with water (100 mL) and brine (100 mL), dried

with MgSO₄, ﬁltered, and concentrated in vacuo, which gave 7.3

(19.89 g, 73.03 mmol, >99%) as an almost colorless oil. (In case of

impurities, puriﬁcation by dry column vacuum chromatography (SiO₂,

12.6 cm², 0−100% toluene/heptanes, 6.25% steps, 40 mL fractions)

gave a colorless oil.) TLC (CH₂Cl₂): R_f= 0.83, TLC (toluene): R_f= 0.47

(goes slightly red upon standing). ¹H NMR (300 MHz, CDCl₃) δ 7.34

(d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 6.64−6.61 (m, 2H), 6.24−

6.20 (m, 2H), 5.16 (dd, J = 9.3, 6.4 Hz, 2H), 3.19 (d, J = 7.9 Hz, 2H),

2.41 (s, 3H), 2.00 (dt, J = 7.9, 6.4 Hz, 1H) ppm. ¹³C NMR (125 MHz,

CDCl₃) δ 178.2, 143.0, 131.8, 131.2, 130.0, 127.5, 126.4, 123.1, 113.0,

112.9, 85.6, 38.9, 38.0, 21.7 ppm. HRMS (ESP+): m/z 295.1177

[MNa⁺], calcd for (C₁₉H₁₆N₂Na⁺): m/z 295.1206.

2-(2-Cyclohepta-2,4,6-trienyl)-1-(3′-iodophenyl)ethylidenemalo-

nonitrile (7.5). To a stirred suspension of ﬁnely divided or mortared

tropylium tetraﬂuoroborate (3.76 g, 21.1 mmol) and 5.3 (5.92 g,

20.1 mmol) in CH₂Cl₂kept at −78 °C under an argon atmosphere was

added Et₃N (2.94 mL, 21.1 mmol) slowly over 1 h. The reaction mixture

was stirred at −78 °C for 1 h, after which the reaction was quenched,

while cold, by addition of saturated aqueous NH₄Cl (100 mL). The

organic layer was separated and washed with water (100 mL) and brine

(100 mL), dried with MgSO₄, ﬁltered, and concentrated in vacuo, which

gave 7.3 (7.66 g, 19.94 mmol, >99%) as an almost colorless oil. A sample

of was taken for puriﬁcation by dry column vacuum chromatography

(SiO₂, 12.6 cm², 0−40% EtOAc/heptanes, 10% steps, 40 mL fractions)

followed by recrystallization from CHCl₃/heptanes, giving 7.5 (62% was

recovered) as colorless crystals. TLC (toluene): R_f= 0.52. mp 108.5−

109.7 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.84 (br d, J = 7.8 Hz, 1H),

7.68 (t, J = 1.6 Hz, 1H), 7.36 (br d, J = 7.8 Hz, 1H), 7.21 (t, J = 7.8 Hz,

1H), 6.64−6.61 (m, 2H), 6.25−6.19 (m, 2H), 5.15 (dd, J = 9.4, 6.5 Hz,

2H), 3.11 (d, J = 8.0 Hz, 2H), 2.10−1.98 (m, 1H) ppm. ¹³C NMR (125

MHz, CDCl₃) δ 176.3, 140.7, 136.6, 135.5, 131.2, 130.8, 126.7, 126.6,

122.7, 112.11, 112.08, 94.7, 87.7, 38.7, 37.6 ppm. Anal. Calcd for

C₁₈H₁₃N₂I (384.21): C, 56.27; H, 3.41; N, 7.29. Found: C, 56.51; H,

3.07; N, 7.21. HRMS (ESP+): m/z 407.0009 [MNa⁺], calcd for

(C₁₈H₁₃N₂INa⁺): m/z 407.0016.

2-[2-Cyclohepta-2,4,6-trienyl-1-(4′-ﬂuorophenyl)ethylidene]-

malononitrile (7.6). To a vigorously stirring solution of 5.6 (6.02 g, 32.3

mmol) and freshly pulverized tropylium tetraﬂuoroborate (6.91 g, 38.8

mmol) in dry CH₂Cl₂(200 mL) at −78 °C was added dropwise NEt₃

(5.9 mL, 41 mmol) during the course of 1 h. The contents were stirred

for a further 10 min, and then the contents of the reaction vessel were

allowed to reach rt. The crude reaction mixture was treated with 2 M

aqueous HCl (20 mL), and the contents of the reaction vessel were

diluted with water (100 mL). The phases were separated, and the

organic phase was washed with water (100 mL). The organic phase was

then dried over MgSO₄and ﬁltered, and the solvent was removed in

vacuo to aﬀord 7.6 as a viscous yellow oil (8.42 g, 94%), which was

essentially pure aside from minor impurities. A small amount was

subjected to ﬂash column chromatography (SiO₂, eluent: toluene) for

characterization purposes, which gave 7.6 as a pale yellow oil. TLC

(toluene): R_f= 0.44. ¹H NMR (500 MHz, CDCl₃)δ7.43 (dd, J = 8.7, 5.1 Hz,

2H), 7.17 (dd, J = 8.7, 8.7 Hz, 2H), 6.61−6.60 (m, 2H), 6.22−6.19 (m, 2H),

5.14 (dd, J = 9.1, 6.4 Hz, 2H), 3.18 (d, J = 8.0 Hz, 2H), 1.99−1.93 (m, 1H)

ppm. ¹³C NMR (125 MHz, CDCl₃,) δ 176.9, 164.8 (d, J = 255 Hz),

131.3, 130.6 (d, J = 3.5 Hz), 129.8 (d, J = 8.9 Hz), 126.6, 122.8, 116.7

(d, J = 22.2 Hz), 112.6, 112.4, 86.7, 39.0, 37.9 ppm. Anal. Calcd for

2-[2-Cyclohepta-2,4,6-trienyl-1-(4′-acetaminophenyl)-

ethylidene]malononitrile (7.9). Prepared according to the general

procedure for 7.1: to 5.9 (5.00 g, 22.2 mmol) and tropylium

tetraﬂuoroborate (4.15 g, 23.3 mmol, 1.05 equiv) in CH₂Cl₂(150

mL) was added Et₃N (3.09 mL, 22.2 mmol) at −78 °C over the course

of 1 h, and the mixture was stirred for an additional 4 h. The reaction was

worked up according to the general procedure for 7.1 and yielded 7.9

(6.94 g, 22.0 mmol, 99%) as a yellow viscous oil. A sample was puriﬁed

by dry column vacuum chromatography (SiO₂, 12.6 cm², 0−80%

EtOAc/heptanes, 10% steps, 40 mL fractions) followed by recrystalliza-

tion from CHCl₃/heptanes, giving 7.9 (64% recovered) as colorless

1

needleshaped crystals. mp 167−172 °C dec. H NMR (500 MHz,

CDCl₃) δ 7.63 (d, J = 8.7 Hz, 2H), 7.43 (d, J = 8.7 Hz, 2H), 7.35 (s, 1H),

6.62−6.56 (m, 2H), 6.22−6.15 (m, 2H), 5.14 (dd, J = 9.1, 7.1 Hz, 2H), 3.19

(d, J = 7.1 Hz, 2H), 2.21 (s, 3H), 1.97 (p, 7.1 Hz, 1H) ppm. ¹³C NMR (125

MHz, CDCl₃) δ 177.1, 168.6, 141.6, 131.3, 129.8, 128.9, 126.5, 123.0, 119.7,

113.1, 112.9, 85.4, 38.8, 38.1, 24.9 ppm. HRMS (ESP+): m/z 338.1269

[MNa⁺], calcd for (C₂₀H₁₇N₃ONa⁺): m/z 338.1264.

Bis(cyclohepta-2,4,6-trienyl)-1-(4′-nitrophenyl)ethylidene malo-

nonitrile (8.1). To a stirred suspension of tropylium tetraﬂuoroborate

(5.06 g, 34.0 mmol) in CH₂Cl₂(250 mL) under an argon atmosphere

was added 5.1 (6.06 g, 28.4 mmol). The reaction mixture was cooled to

−78 °C, and Et₃N (3.96 mL, 2.88 g, 28.4 mmol) was added dropwise.

For every drop, the solution took a red color, which faded away. After all

base was added, the reaction mixture was stirred as it was allowed to

reach rt. The solvent was then removed in vacuo. Puriﬁcation by dry

column vacuum chromatography (SiO₂, 113 cm², 0−80% CHCl₃/

heptanes, 15% steps, 40 mL fractions, followed by 80−100%, 8.3% steps,

40 mL fractions) gave 7.1 (7.58 g, 25.0 mmol, 88%) as a slightly yellow

oil and 8.1 (1.12 g, 2.84 mmol, 10%) as a slightly yellow oil that solidiﬁed

upon standing. Crystals of 8.1 suitable for X-ray crystallography were

grown from CDCl₃/ heptanes. For 7.1: see earlier. For 8.1: mp 141.5−

143.0 °C (CHCl₃/heptanes). ¹H NMR (500 MHz, CDCl₃) δ 8.25 (d,

J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 6.79−6.70 (m, 4H), 6.35−6.26

62

dx.doi.org/10.1021/jo4020326 | J. Org. Chem. 2014, 79, 41−64

The Journal of Organic Chemistry

Article

(m, 4H), 5.31 (d, J = 7.0 Hz, 1H), 5.29 (d, J = 6.8 Hz, 1H), 4.93 (d, J =

7.5 Hz, 1H), 4.92 (d, J = 7.4 Hz, 1H), 3.85 (t, J = 9.8 Hz, 1H), 1.96 (t, J =

6.7 Hz, 1H), 1.95 (br s, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃, d1 = 4.0

s) δ 179.3, 149.1, 140.1, 131.8, 130.8, 129.2, 126.4, 125.9, 124.1, 118.9,

117.0, 111.3, 111.2, 92.8, 48.9, 40.6 ppm (one signal missing because of

overlap). Anal. Calcd for C₂₅H₁₉N₃O₂(393.44): C, 76.32; H, 4.87; N,

10.68. Found: C, 76.24; H, 4.59; N, 10.65. HRMS (ESP+): m/z

416.1414 [MNa⁺], calcd for (C₂₅H₁₉N₃O₂Na⁺): m/z 416.1369.

2-(4-Bromophenyl)azulene-1-carbonitrile (9.8). For preparation,

see the synthesis of compound 1.10.

7-Bromo-2-(4′-nitrophenyl)-1,8a-dihydroazulene-1,1-dicarboni-

trile (11.1). To a stirred solution of freshly prepared dibromide 10.1

(218 mg, 0.473 mmol) in dry THF (10 mL, <15 ppm H₂O) under an

argon atmosphere at 0 °C was added a solution of LiHMDS (0.60 mL,

0.47 mmol, 1.0 M) in toluene dropwise. The reaction mixture was stirred

for 1 h as the temperature was allowed to reach rt. The reaction mixture

was diluted with Et₂O (100 mL), washed with saturated aqueous NH₄Cl

(2 × 50 mL), dried with MgSO₄, and ﬁltered. Evaporation of the

solvents gave 11a as a black solid with minor impurities. An analytically

pure sample was obtained by puriﬁcation by dry column vacuum

chromatography (SiO₂, 12.6 cm², 0−40% THF/heptanes, 5% steps,

40 mL fractions) followed by recrystallization from CHCl₃/heptanes

(3:5), which gave 11a (42.9 mg, 0.113 mmol, 24%) as yellow crystals,

with some suitable for X-ray crystallography. mp 172.5−174.5 °C.¹¹H

NMR (500 MHz, CDCl₃) δ 8.34 (d, J = 9.0 Hz, 2H), 7.89 (d, J = 9.0 Hz,

2H), 7.06 (s, 1H), 6.63−6.54 (m, 2H), 6.44 (dd, J = 6.0 Hz, 1.7 Hz, 1H),

6.12 (d, J = 4.4 Hz, 1H), 3.84 (dd, J = 4.4, 1.7 Hz, 1H) ppm. ¹³C NMR

(125 MHz, CDCl₃) δ 148.5, 140.1, 139.0, 136.1, 135.5, 134.3, 131.9,

127.3, 124.7, 122.5, 120.4, 120.1, 114.1, 111.9, 51.1, 44.7 ppm. Anal.

Calcd for C₁₈H₁₃N₃O₂(303.31): C, 56.86; H, 2.65; N, 11.05. Found: C,

56.27; H, 2.31; N, 10.78. MS (MALDI−): m/z 379, 381 [M⁻Br^79/81].

UV−vis (MeCN) λ_DHA: 378 nm. λ_VHF: 476 nm.

7-Bromo-2-(4′-tolyl)-1,8a-dihydroazulene-1,1-dicarbonitrile

(11.3). Prepared according to the general procedure for 11.1: to 10.3

(860 mg, 2.00 mmol) in dry THF (20 mL) was added a solution of

LiHMDS (2.00 mL, 2.00 mL, 1 M) in toluene, which yielded 11.3

(>90% purity) as a black oil. An analytically pure sample was obtained by

puriﬁcation by dry column vacuum chromatography (SiO₂, 12.6 cm², 0−

40% THF/heptanes, 5% steps, 40 mL fractions) to give 11.3 (517 mg,

1.48 mmol, 74%) as a yellow solid. mp 167.7−169.1 °C dec. ¹H NMR

(500 MHz, CDCl₃) δ 7.63 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H),

6.84 (s, 1H), 6.53−6.50 (m, 2H), 6.30−6.27 (m, 1H), 6.12 (d, J = 4.4

Hz, 1H), 3.78 (dd, J = 4.4, 1.8 Hz, 1H), 2.41 (s, 3H) ppm. ¹³C NMR

(125 MHz, CDCl₃) δ 142.0, 141.4, 141.3, 132.7, 132.2, 130.7, 130.2,

127.4, 126.5, 120.3, 120.0, 119.6, 114.8, 112.6, 51.2, 44.8, 21.6 ppm.

Anal. Calcd for C₁₉H₁₃N₂Br (349.22): C, 65.35; H, 3.75; N, 8.02.

Found: C, 65.23; H, 3.50; N, 8.01. MS (MALDI TOF+): m/z 348, 350

[M^{+ 79/81}Br]. UV−vis (MeCN) λ_DHA: 362 nm. λ_VHF: 471 nm.

2-(4′-Bromophenyl)-7-bromo-1,8a-dihydroazulene-1,1-dicarbo-

nitrile (11.8). Prepared according to the general procedure for 11.1: to

10.8 (1.00 g, 2.03 mmol) in dry THF (40 mL) was added a solution of

LiHMDS (2.00 mL, 2.00 mmol, 1 M) in toluene, which yielded 11f

(>90% purity) as a black oil with minor impurities. Puriﬁcation by

dry column vacuum chromatography (SiO₂, 12.6 cm², 0−40% THF/

heptanes, 5% steps, 40 mL fractions) followed by a recrystallization from

CHCl₃and heptanes gave 11f (596 mg, 1.44 mmol, 72%) as a dark

yellow solid. mp 184.5−186.8 °C. ¹H NMR (500 MHz, CDCl₃) δ 7.63−

7.58 (m, 2H), 6.89 (s, 1H), 6.58−6.50 (m, 2H), 6.34 (d, J = 5.8 Hz, 1H),

6.11 (d, J = 4.4 Hz, 1H), 3.80 (dd, J = 4.4, 1.7 Hz, 1H) ppm. ¹³C NMR

(125 MHz, CDCl₃) δ 140.8, 140.6, 133.3, 132.8, 132.3, 132.1, 129.1, 127.9,

125.1, 120.6, 120.3, 120.1, 114.5, 112.3, 51.1, 44.7 ppm. Anal. Calcd for

C₁₈H₁₀Br₂N₂(414.09): C, 52.21; H, 2.43; N, 6.76. Found: C, 52.04; H,

2.22; N, 6.71. UV−vis (MeCN) λ_DHA: 360 nm. λ_VHF: 467 nm.

7-Bromo-2-(4′-cyanophenyl)-1,8a-dihydroazulene-1,1-dicarboni-

trile (11.10). Prepared according to the general procedure for 11.1: to

10.10 (350 mg, 0.80 mmol) in dry THF (20 mL) was added a solution

of LiHMDS (0.80 mL, 0.80 mmol, 1 M) in toluene, which yielded 11.10

as a black solid with minor impurities. Puriﬁcation by dry column

vacuum chromatography (SiO₂, 12.6 cm², 0−40% THF/heptanes, 5%

steps, 40 mL fractions) followed by a recrystallization from CHCl₃and

heptanes gave 11.10 (184 mg, 0.512 mmol, 64%) as a yellow solid. ¹H

NMR (500 MHz, CDCl₃) δ 7.83 (d, J = 8.8 Hz, 2H), 7.78 (d, J = 8.8 Hz,

2H), 7.01 (s, 1H), 6.61 (d, J = 11.6 Hz, 1H), 6.55 (dd, J = 11.6, 6.1 Hz,

1H), 6.42 (dd, J = 6.1, 1.8 Hz, 1H), 6.12 (d, J = 4.4 Hz, 1H), 3.83 (dd, J =

4.4, 1.8 Hz, 1H).¹³C NMR (125 MHz, CDCl₃) δ 140.1, 139.4, 134.8,

134.3, 134.1, 133.2, 131.9, 127.0, 122.2, 120.4, 120.1, 118.1, 114.2, 113.9,

112.00, 51.1, 44.6 ppm. Anal. Calcd for C₁₉H₁₀N₃Br (360.21): C, 63.35;

H, 2.80; N, 11.67. Found: C, 63.45; H, 2.49; N, 11.45. HRMS

(ESP+): m/z 740.9994 (51), 742.0012 (22), 742.9987 (100),

744.0017 (45), 744.9974 (54), 745.9981 (23) [2MNa^{+ 79/81}Br], calcd for

2-(4-Cyanophenyl)azulene-1-carbonitrile (9.10). For preparation,

see the synthesis of compound 1.10.

2-(4′-Nitrophenyl)-7,8-dibromo-7,8,1,8a-tetrahydroazulene-1,1-

dicarbonitrile (10.1). To a stirred solution of DHA 1.1 (143 mg,

0.473 mmol) in CH₂Cl₂(5 mL) under an argon atmosphere at −78 °C

was added a solution of Br₂in CH₂Cl₂(0.61 mL, 0.78 M, 0.47 mmol)

dropwise. The brown mixture was then stirred for 30 min, after which

the solution took a yellow color. Evaporation of the solvents gave

dibromide 10.1 (218 mg, 0.47 mmol, >99%) as a yellow solid. ¹H NMR

(500 MHz, CDCl₃) δ 8.35 (d, J = 9.0 Hz, 2H), 7.91 (d, J = 9.0 Hz, 2H),

7.15 (s, 1H), 6.42 (dd, J = 7.5, 2.3 Hz, 1H), 6.13 (dd, J = 12.2, 7.5 Hz,

1H), 6.00 (dd, J = 12.2, 5.6 Hz, 1H), 5.32−5.30 (m, 1H), 5.05−5.04 (m,

1H), 4.70 (br s, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 148.3, 143.9,

137.9, 137.1, 136.0, 130.2, 127.2, 125.5, 124.8, 123.9, 114.2, 111.3, 53.3,

51.0, 48.9, 44.6 ppm. Anal. Calcd for C₁₈H₁₃N₃O₂(303.31): C, 46.89; H,

2.40; N, 9.11. Found: C, 46.94; H, 2.31; N, 8.82.

2-(4′-Tolyl)-7,8-dibromo-7,8,1,8a-tetrahydroazulene-1,1-dicarbo-

nitrile (10.3). To a stirred solution of DHA 1.3 (560.1 mg, 2.07 mmol)

in CH₂Cl₂(40 mL) under an argon atmosphere at −78 °C was added a

solution of Br₂in CH₂Cl₂(2.65 mL, 2.07 mmol, 0.78 M) dropwise. The

solution was stirred for 30 min, after which the solvent was removed in

vacuo, which gave 10.3 (891 mg, 2.07 mmol, >99%) as a dark yellow

1

solid. H NMR (500 MHz, CDCl₃) δ 7.65 (d, J = 8.2 Hz, 2H), 7.28

(d, J = 8.2 Hz, 2H), 6.92 (s, 1H), 6.23 (dd, J = 7.6, 2.2 Hz, 1H), 6.08 (dd,

J = 12.1, 7.6 Hz, 1H), 5.89 (dd, J = 12.1, 5.6 Hz, 1H), 5.34−5.30 (m,

1H), 5.06−5.03 (m, 1H), 4.64 (br s, 1H), 2.41 (s, 3H) ppm. ¹³C NMR

(125 MHz, CDCl₃) δ 144.8, 141.0, 140.0, 133.1, 130.2, 128.3, 127.4,

126.4, 126.0, 120.6, 114.8, 111.9, 53.3, 51.7, 49.3, 44.7, 21.6 ppm. Anal.

Calcd for C₁₉H₁₄N₂Br₂(430.14): C, 53.05; H, 3.28; N, 6.51. Found: C,

52.73; H, 3.05; N, 6.31.

2-(4′-Bromophenyl)-7,8-dibromo-1,7,8,8a-tetrahydroazulene-

1,1-dicarbonitrile (10.8). To a stirred solution of DHA 1.8 (679.7 mg,

2.028 mmol) in CH₂Cl₂(40 mL) under an argon atmosphere, excluded

from light and cooled to −78 °C, was added a solution of Br₂in CH₂Cl₂

(2.62 mL, 0.78 M, 2.03 mmol) dropwise. The brown mixture was then

stirred for 30 min, after which the solution took a yellow color.

Evaporation of the solvents gave dibromide 10.8 (1.00 g, 2.03 mmol,

1

> 99%) as a yellow solid. mp 130−150 °C dec. H NMR (500 MHz,

CDCl₃) δ 7.61 (br s, 4H), 6.97 (s, 1H), 6.29 (dd, J = 7.5, 2.3 Hz, 1H),

6.09 (dd, J = 12.2, 7.5 Hz, 1H), 5.93 (dd, J = 12.2, 5.7 Hz, 1H), 5.33−

5.28 (m, 1H), 5.06−5.02 (m, 1H), 4.65 (s, 1H) ppm. ¹³C NMR

(125 MHz, CDCl₃) δ 144.4, 138.6, 134.7, 132.8, 129.1, 129.0, 127.9,

125.8, 124.9, 121.8, 114.5, 111.6, 53.3, 51.4, 49.1, 44.6 ppm. Anal. Calcd

for C₁₉H₁₄N₂Br₂· 0.2 CH₂Cl₂(511.99): C, 42.70; H, 2.24; N, 5.47.

Found: C, 43.07; H, 1.87; N, 5.54.

2-(4′-Cyanophenyl)-7,8-dibromo-7,8,1,8a-tetrahydroazulene-

1,1-dicarbonitrile (10.10). To a stirred solution of DHA 10.10 (284.3

mg, 1.011 mmol) in CH₂Cl₂(30 mL) under an argon atmosphere and

cooled to −78 °C was added a solution of Br₂in CH₂Cl₂(1.29 mL,

1.01 mmol, 0.78 M) dropwise. The solution was stirred for 30 min, after

which the solvent was removed in vacuo, which gave 10.10 (445.8 mg,

1

1.011 mmol, >99%) as a yellow solid or foam. H NMR (500 MHz,

CDCl₃) δ 7.85 (d, J = 8.7 Hz, 2H), 7.77 (d, J = 8.7 Hz, 2H), 7.10 (s, 1H),

6.38 (dd, J = 7.5, 2.3 Hz, 1H), 6.12 (dd, J = 12.2, 7.5 Hz, 1H), 5.99 (dd,

J = 12.2, 5.5 Hz, 1H), 5.35−5.27 (m, 1H), 5.08−5.00 (m, 1H), 4.68

(s, 1H) ppm. ¹³C NMR (125 MHz, CDCl₃) δ 143.9, 137.4, 137.2, 134.3,

133.2, 129.9, 126.9, 125.5, 123.5, 118.1, 114.2, 113.6, 111.4, 53.3, 51.1,

48.9, 44.5 ppm. Anal. Calcd for C₁₉H₁₁N₃Br₂(441.12): C, 51.73; H,

2.51; N, 9.53. Found: C, 51.73; H, 2.39; N, 9.54.

63

dx.doi.org/10.1021/jo4020326 | J. Org. Chem. 2014, 79, 41−64

The Journal of Organic Chemistry

Article

(C₃₈H₂₀N₆Br ₂Na⁺): m/z 741.0008 (51), 742.0042 (21), 742.9988 (100),

744.0022 (41), 744.9968 (49), 746.0002. UV−vis (MeCN) λ_DHA(ε):

363 nm (21 × 10³M⁻¹cm⁻¹). λ_VHF(ε): 472 nm (30 × 10³M⁻¹cm⁻¹).

3-Bromo-2-(4-methoxyphenyl)azulene-1-carbonitrile (12). To a

stirred mixture of DHA 1.4 (120.5 mg, 0.421 mmol) in acetic acid

(10 mL) under an argon atmosphere, excluded from light and cooled to

0 °C, was added a solution of Br₂(0.54 mL, 0.78 M, 0.42 mmol) in

CH₂Cl₂dropwise. The red mixture was then stirred for 4 days, after

which the solution took a dark green color and a green precipitate

appeared. Product 12 (75.5 mg, 0.223 mmol, 53%) was collected by

ﬁltration as a green powder. mp 192.4−193.1 °C. ¹H NMR (500 MHz,

CDCl₃) δ 8.61 (d, J = 9.7 Hz, 1H), 8.57 (d, J = 10.0 Hz, 1H), 7.85 (t, J =

10.0 Hz, 1H), 7.84 (d, J = 8.9 Hz, 3H), 7.62 (t, J = 9.7 Hz, 1H), 7.59

(t, J = 10.0 Hz, 1H), 7.10 (d, J = 8.9 Hz, 2H), 3.29 (s, 3H) ppm. ¹³C

NMR (125 MHz, CDCl₃) δ 160.8, 150.7, 143.8, 139.9, 139.5, 137.8,

136.1, 131.9, 128.6, 128.4, 125.5, 117.1, 114.4, 104.3, 96.2, 55.6 ppm.

Anal. Calcd for C₁₈H₁₂BrNO (338.20): C, 63.92; H, 3.58; N,

4.14. Found: C, 63.94; H, 3.38; N, 4.04. MS (MALDI+): m/z

444 [MAg⁺].

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ASSOCIATED CONTENT

* Supporting Information

NMR spectra, X-ray crystal structure details, and guide for dry

column vacuum chromatography. This material is available free

of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: mbn@kiku.dk. Fax: +45 3532 0212.

■

Present Address

^§Department of Pharmacy, University of Copenhagen, Uni-

versitetsparken 2, DK-2100 Copenhagen Ø, Denmark.

Notes

The authors declare no competing ﬁnancial interest.

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ACKNOWLEDGMENTS

■

We gratefully acknowledge The Lundbeck Foundation and The

Danish Council for Independent Research | Natural Sciences

(no. 10-082088) for their ﬁnancial support. Dr. Theis Brock-

Nannestad is acknowledged for recording HRMS spectra.

(21) The bromoalkyne 1.27 was not stable under ambient conditions.

(22) Vilhelmsen, M. H.; Andersson, A. S.; Nielsen, M. B. Synthesis

2009, 1469−1472.

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64

dx.doi.org/10.1021/jo4020326 | J. Org. Chem. 2014, 79, 41−64

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Syntheses of donor-acceptor-functionalized dihydroazulenes

DOI: 10.1021/jo4020326

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