A colourful azulene-based protecting group for carboxylic acids

Accepted Manuscript

A Colourful azulene-based protecting group for carboxylic acids

Thomas W. Bevan, James Francis-Taylor, Helena Wong, Peter T. Northcote, Joanne

E. Harvey

PII:

S0040-4020(18)30470-8

10.1016/j.tet.2018.04.066

TET 29481

DOI:

Reference:

To appear in: Tetrahedron

Received Date: 23 January 2018

Revised Date: 19 April 2018

Accepted Date: 20 April 2018

Please cite this article as: Bevan TW, Francis-Taylor J, Wong H, Northcote PT, Harvey JE, A Colourful

azulene-based protecting group for carboxylic acids, Tetrahedron (2018), doi: 10.1016/j.tet.2018.04.066.

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ACCEPTED MANUSCRIPT

Graphical abstract:

ACCEPTED MANUSCRIPT

A Colourful Azulene-Based Protecting Group for Carboxylic Acids

Thomas W. Bevan, James Francis-Taylor, Helena Wong, Peter T. Northcote, Joanne E.

Harvey*

School of Chemical and Physical Sciences, Centre for Biodiscovery, Victoria University of

Wellington, PO Box 600, Wellington 6140, NEW ZEALAND.

Email address: joanne.harvey@vuw.ac.nz

Abstract

An intensely blue-coloured protecting group for carboxylic acids has been developed. The

protecting group is introduced through a Steglich esterification that couples 6-(2-

hydroxyethyl)azulene (AzulE) and the carboxylic acid substrate. Deprotection is effected

under basic conditions by the addition of the amidine base DBU, whereupon cleavage occurs,

accompanied by a colour change. A two-step deprotection methodology comprising

activation with oxalyl chloride and deprotection with a very mild base was developed for use

with base-sensitive substrates. The AzulE esters were found to be compatible with other

commonly employed protecting groups – silyl ethers, MOM acetals – by studying their

orthogonal and concomitant deprotections. The stability of the new protecting group towards

various synthetic processes – oxidation, reduction, cross-coupling, olefination and treatment

with base – provided the basis of a versatility profile. This indicated that AzulE esters are

sensitive to strongly oxidising and basic agents while being compatible with reducing

conditions and selected other reactions. The convenience of a highly coloured protecting

group for tracking material (and avoiding loss of compound) through laboratory processes

warrants further investigation of this and/or related species.

Keywords

Azulene derivative; 6-(2-hydroxyethyl)azulene; protecting group; carboxylic acid; basic

deprotection.

Introduction

Target-oriented synthetic chemistry still relies overwhelmingly on the use of protecting

groups to temporarily disable unwanted reactivity of functional groups in complex organic

molecules, despite the ideals of protecting group-free synthesis.^1,2Protecting groups may also

improve handling properties compared to the unprotected substrate, such as decreased

polarity and increased solubility in organic solvents.³Much attention is paid to the

orthogonality of different protecting groups to each other and compatibility with key

synthetic transformations in order to avoid undesired reactivity.^4,5

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The protecting groups typically used for carboxylic acids are ester-based (Scheme 1),³with

the methyl ester being most common (Scheme 1a). Regeneration of the carboxylic acid is

usually achieved by saponification or other hydrolytic methods, although non-basic reagents,

such as lithium halides, are employed if the need arises.³Alternatively, more specialist esters

may be used in cases where the methyl ester or its deprotection protocol is unsuitable.³These

include, but are certainly not limited to, tert-butyl esters, deprotected by acid/heat (Scheme

1b), trimethylsilylethyl esters, deprotected with tetra-n-butylammonium fluoride (TBAF)

(Scheme 1c), or 3-propionitrile (2-cyanoethyl) esters, deprotected by mild base (Scheme 1d).³

The last type presents a useful orthogonality profile, in that mild base leads to few other

reactions, including deprotective events. Deprotection of the propionitrile ester is achieved by

elimination through an E1_cBmechanism beginning with deprotonation of the acidic centre

adjacent to the nitrile.

Scheme 1. Ester-based protecting groups for carboxylic acids and their typical deprotection

methods

Coloured protecting groups increase reaction efficiency by allowing the user to more

effectively track the protected compound through all processes, including chromatography

and workup.⁶Further advantage could be achieved by developing a protecting group that is

colour-indicating for deprotection, orthogonal to other protecting groups, yet easy to

deprotect.

With these principles in mind, we sought to develop a coloured ester protecting group for

carboxylic acids. The bicyclic aromatic species azulene⁷is a non-alternant hydrocarbon,

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whose deep-blue colour arises from a visible-wavelength electronic transition; this is caused

primarily by the geometric dissimilarity between the HOMO and LUMO of azulene, which

decreases electronic repulsion in the singlet excited state.⁸Further beneficial features are the

small molecular weight and low polarity of azulene relative to other dye molecules. Despite

these virtues, azulene-based protecting groups have only been sparingly employed

previously: azulen-1-yl-oxoacetates for carbohydrate-based alcohols⁹and guaiazulene-based

esters and carbamates for carbohydrate alcohols and glycoconjugate amines, respectively.^10,11

Design of the new protecting group revolved around the stabilisation of anionic charges on

centres adjacent to the seven-membered ring of azulene, due to the cyclopentadienyl anion

resonance structure (Figure 1). The consequent acidity of these positions^12,13should enable

deprotection under basic conditions by an E1_cBmechanism, analogous to the propionitrile

esters described above. This, coupled with the obvious symmetry and consequent ease of

spectroscopic analysis in the case of the 6-substituted azulene species, led to identification of

6-(2-hydroxyethyl)azulene as an ideal candidate to generate the so-named AzulE esters

(Schemes 1e and 2).

Figure 1. Resonance stabilisation of anionic charge at the 6-methyl(ene) position of 6-

substituted azulenes

Scheme 2. Generation of AzulE esters (1) from carboxylic acids and 6-(2-

hydroxyethyl)azulene (2)

Results and Discussion

6-(2-Hydroxyethyl)azulene (2)¹⁴was prepared from 6-methylazulene (3), itself readily

available through a recent advance involving microwave heating,¹⁵by deprotonation with

lithium diisopropylamide (LDA) followed by addition of paraformaldehyde (Scheme 3). It

was found that cannulation of formaldehyde vapour, generated by cracking of

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paraformaldehyde, into a solution of the 6-methylazulene anion provided the best yields of 6-

(2-hydroxyethyl)azulene.

Scheme 3. Preparation of 6-(2-hydroxyethyl)azulene (2)

Protection of carboxylic acids as the corresponding 6-(2-hydroxyethyl)azulene (AzulE) esters

was undertaken through Steglich-type esterification, which has benefits of providing reliably

high yields and being relatively insensitive to air and moisture. A range of carboxylic acids

was thus protected to form the corresponding AzulE esters (Table 1). High yields were

typically obtained from reaction of aromatic (entries 1,2 and 12), heteroaromatic (entry 3),

conjugated olefinic (entries 4–5) and aliphatic (entries 6–10) acids with 6-(2-

hydroxyethyl)azulene in the presence of either N,N′-dicyclohexylcarbodiimide (DCC) or N-

ethyl-N′-3-(dimethylamino)propylcarbodiimide (EDCI) and 4-(dimethylamino)pyridine

(DMAP) catalyst at ambient temperature. The trichloroacetate (entry 11) was instead

prepared by reaction of 6-(2-hydroxyethyl)azulene with the acid chloride.

Table 1. Protection of carboxylic acids as their AzulE esters^a

Entry Carboxylic acid,

RCO₂H

Product Yield

1^b

2^c

3^c

4

Benzoic acid

1-Naphthoic acid

2-Furoic acid

84%

1a

83%

1b

83%

1c

Cinnamic acid

Sorbic acid

93%

72%

59%

80%

73%

93%

77%

1d

1e

1f

1g

1h

1i

5

6

Acetic acid

7

8

5-Bromovaleric acid

(Benzyloxy)acetic acid

Fmoc-Gly-OH

Cyclohexanecarboxylic

acid

Trichloroacetic acid

Azulene-1-carboxylic

acid

9

10^b

1j

11^d

12^e

53%

77%

1k

1l

4

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^aUnless stated otherwise, protections of carboxylic acids were performed with 6-(2-

hydroxyethyl)azulene (1.0-1.25 equiv.), DCC (1.1–1.5 equiv.), DMAP (0.16–0.39 equiv.) in

CH₂Cl₂at r.t. for 3–5 hours.

^bThe reaction took 16 hours to reach completion.

^cEDCI (1.6–2.2 equiv.) was used in place of DCC.

^dProtection was achieved by reaction of trichloroacetyl chloride (5 equiv.) with 6-(2-

hydroxyethyl)azulene and pyridine in CH₂Cl₂at r.t. for 3 hours.

^eMore forcing conditions were required in this case: DMAP (1 equiv.) and heating at reflux

overnight in CH₂Cl₂.

The deprotection of AzulE cinnamate (1d) with base was studied under a range of conditions

(Table 2). Efficient deprotection was achieved through the use of either TBAF (entry 1) or

the amidine bases 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (entries 2–4) and 1,5-

diazabicyclo[4.3.0]non-5-ene (DBN) (entry 5) at ambient temperature. The amine base

piperidine did not fully deprotect the AzulE ester under the conditions usually employed for

9-fluorenylmethyloxycarbonyl (Fmoc)¹⁶deprotection (piperidine in DMF at ambient

temperature, entry 8) but, with heating at reflux in acetonitrile, the deprotection proceeded

with high conversion (entry 14). These results indicate a potential for orthogonality between

Fmoc-protected amines and AzulE-protected carboxylic acids (see also Table 5 results).

Weaker bases did not deprotect the AzulE ester efficiently (entries 15–23) and a control

experiment in the absence of base (entry 24) led solely to recovery of the starting material 1d,

indicating that no thermally induced background reaction occurs. 6-Vinylazulene (4)¹⁴was

the main by-product of most of these deprotection reaction, except with the nucleophilic base

piperidine (entries 8–14) from which the base adduct 5 was obtained. This demonstrates that

the 6-vinylazulene by-product may be intercepted with sufficiently nucleophilic bases,¹⁷

which fits with the expected electron demand pattern of the azulene system.

Table 2. Deprotection studies on AzulE cinnamate

base

solvent

O

time, temperature

then HCl aq. (10%)

4

or

RCOOH

+

1d

N

5

Entry

Base^a

Solvent

Reaction

time

Temperature Conversion^b

1

2

3

TBAF

DBU

THF

MeCN

EtOH

20 min

3 hours

r.t.

100%

Partial^c

5

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4

5

6

7

8

9

10

11

12

13

14

15

DBU

DBN

THF

MeCN

3 hours

r.t.

Reflux

r.t.

100%

2%

(-)-Sparteine DMF

(-)-Sparteine MeCN

Overnight

0%

Piperidine

NaOH

DMF

70%^d

0%

MeCN

EtOH

THF

EtOH

THF

0%

23%^d

18%^d

100%^d

37%

MeCN

1:1

H₂O/THF

MeCN

DMF

MeCN

16

17

18

19

20

21

22

23

24

DIPEA

NEt₃

Overnight

r.t.

Reflux

r.t.

Reflux

r.t.

0%

11%

3%

94%

0%

NEt₃

DABCO

DMAP

Morpholine

–

Reflux

^aBase loading was 3% v/v. Bases are listed in (approximately) decreasing order of base

strength.

^bConversion was determined by integration of relevant signals in the ¹H NMR spectrum of

the reaction mixture. The azulene species produced in the deprotection was 6-vinylazulene

(4), unless otherwise noted.

^cRelevant ¹H NMR peaks partially obscured. Conversion estimated at 90% deprotection

according to baseline subtraction of the overlapping peaks.

^dThe azulene species formed in the deprotection was the corresponding base adduct 5.

Using the effective deprotection conditions of DBU in acetonitrile, a selection of AzulE

esters were converted to the corresponding carboxylic acids in excellent isolated yields

(Table 3). Thus, aromatic (entries 1 and 2), heteroaromatic (entry 3), conjugated unsaturated

(entries 4 and 5) and aliphatic carboxylic acids (entries 7–8) were liberated from their AzulE

esters. The product obtained by deprotection of AzulE 5-bromovalerate (1g) was δ-

valerolactone (entry 6), which presumably arises by substitutive lactonisation of the ω-

bromocarboxylate that forms upon elimination.

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Table 3. Deprotection of AzulE esters

DBU

MeCN, r.t.

O

+

R

4

RCOOH

then

HCl aq.

1

Entry AzulE

ester

Deprotected acid

Reaction

time

Yield^a

1

2

3

4

5

6

7

8

Benzoic acid

1-Naphthoic acid

2-Furoic acid

Cinnamic acid

Sorbic acid

5-Bromovaleric acid

(Benzyloxy)acetic acid

Cyclohexanecarboxylic

acid

3 hours

4 hours

8 hours

overnight

99%

97%

94%

77%

0%^b

85%

65%

1a

1b

1c

1d

1e

1g

1h

1j

^aIsolated yield.

^bThe isolated product was δ-valerolactone, presumably formed by intramolecular

nucleophilic attack on the bromoalkane by the carboxylate revealed in the deprotection.

With careful observation, the colour change that occurs during the deprotection can be used

as a visual indicator of reaction progress. During cleavage of the protecting group, a subtle

but nonetheless noticeable colour change from indigo/purple to blue can be observed. Visible

light spectroscopy reveals a shift from λ_max= 571 nm for AzulE cyclohexanecarboxylate (1j)

to λ_max= 608 nm for 6-vinylazulene (4) (Figure 2a). Visually, the change is distinct, with the

starting esters appearing purple while the vinylazulene product is blue (Figure 2b and c).

This enables facile TLC analysis of the reaction progress with no need for UV light or a stain

to visualise the components (Figure 2d). It is also possible to tell from the colour of a

reaction mixture whether the eliminative deprotection is complete or on-going (Figure 2e).

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a)

0.4

0.35

0.3

t=0

t=3 hours

0.25

0.2

0.15

0.1

0.05

0

400

450

500

550

600

650

700

750

800

Wavelength

b)

c)

d)

e)

Figure 2. Colour change on deprotection. a) Visible light absorption spectrum of a

deprotection reaction: AzulE cyclohexanecarboxylate (1j) in acetonitrile (solid line) and after

3 hours of reaction with DBU (dashed line); b) 6-(2-hydroxyethyl)azulene cinnamate (1d) in

acetonitrile before addition of DBU; c) reaction of 6-(2-hydroxyethyl)azulene cinnamate (1d)

in acetonitrile with DBU after 3 hours; d) TLC plate (silica gel, no stain required) showing

AzulE cinnamate (left band), reaction with DBU in acetonitrile after 30 minutes showing

starting material remaining and some 6-vinylazulene developing (middle band) and after 4

hours showing nearly full conversion (right band); e) AzulE cinnamate in 1:1

acetonitrile:dichloromethane (left, purple), during reaction with DBU: after 40 minutes

(middle, purple-blue) and after 8 hours resulting in full conversion to 6-vinylazulene (right,

blue).

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Based on the similarity of AzulE esters to 3-propionitrile and related esters,³an E1_cB

mechanism was initially proposed for these eliminative deprotections. This is questionable

given the relative acidities of 6-methylazulene (pKa ~ 25.4 in organic solvent,^12,13assumed to

be somewhat higher for 6-(2-hydroxyethyl)azulene) and the conjugate acid of DBU (pKa =

24.3).¹⁸Kinetic experiments measuring the rate of deprotection of various AzulE esters were

then conducted (Table 4, see Supporting Information for details of the experiments). There

was a distinct correlation between pKa of the liberated carboxylic acid, as a surrogate for

leaving group ability, and the rate of deprotection. This indicates that loss of the carboxylate

is the rate-determining step, which is consistent with either an E1_cBor an E2 mechanism.

Further deconvolution of the mechanisms has not been accomplished to date.

Table 4. Rates of deprotection of AzulE esters and pKa of the corresponding carboxylic

acids^a

AzulE Deprotection rate

Ester

pKa of

carboxylic acid

*1000/L·mol^-1s^-1

2.20 ± 0.64

3.12

1c

1.48 ± 0.34

1.12 ± 0.43

1.15 ± 0.26

0.54 ± 0.15

3.69

4.44

4.9

1b

1d

1j

6.99

1l

^aReactions were conducted with DBU (230 equiv.) in acetonitrile and monitored by visible

spectroscopy.

Following these favourable results, a two-step, or “two-stage”, deprotection strategy⁴was

investigated for cases where the substrate would be sensitive to the standard basic conditions.

Substitution of the azulene ring with an electron-withdrawing group would activate the

protecting group towards deprotection, which could therefore be conducted with milder

conditions. Treatment of AzulE cinnamate (1d) with oxalyl chloride, followed sequentially

by methanol and pyridine gave the orange-red ketoester 6 in a near-quantitative yield

(Scheme 4). Subjecting this activated AzulE ester to base treatment led to deprotection and

isolation of the carboxylic acid (Table 5, entries 1–5). It is noteworthy that efficient

deprotection of the activated AzulE ester occurred even with the weak bases trimethylamine

and morpholine, which did not deprotect unactivated AzulE esters (viz. Table 2).

Comparison of the results for the unactivated and activated AzulE esters indicate a rate

acceleration between seven and eight orders of magnitude (see Supporting Information for

details). It was possible to perform the activation and deprotection in a single pot, without

isolation of the intermediate 6.

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Scheme 4. Two-step activation-deprotection sequence

Table 5. Deprotection of activated AzulE ester 6^a

Base^b

Conversion^c

Entry

Time

1

2

3

4

5

6

DBU

Piperidine

NEt₃

DABCO

Morpholine Overnight

<10 seconds 100%

<25 minutes 100%

5 hours

100%

97%

0%

<1 minute

2,4,6-

Overnight

Collidine

Pyridine

7

Overnight

0%

^aReactions were conducted in acetonitrile at room temperature.

^bBases are listed in decreasing strength (i.e. decreasing pKa of the conjugate acid).

^cConversion was determined by integration of the relevant signals in the ¹H NMR spectrum

of the crude reaction mixture.

Preliminary assessment of the compatibility of the AzulE esters with other protecting groups

and various reactions was then undertaken. Firstly, the orthogonality of AzulE esters with

common alcohol and amine protecting groups was evaluated. Selective removal of the AzulE

ester in the presence of the other protecting group, and vice versa, was sought. Conditions for

global deprotection were not considered a requirement for orthogonality, but nevertheless

would provide versatility benefits. In this study, the AzulE ester and other protecting group

were usually contained within separate molecular entities for simplicity of analysis. The

extent of deprotection of both species was assessed through integration of the relevant peaks

in the ¹H NMR spectrum of the crude reaction mixture. For TBS ether 7,¹⁹mildly acidic

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conditions (pyridinium para-toluenesulfonate) removed the silyl group only (Table 6, entry

1), while mildly basic conditions (DBU) caused cleavage of only the AzulE ester 1d (entry

2). In contrast, the basic fluoride reagent TBAF caused global deprotection of both the silyl

ether and AzulE ester (entry 3). Similarly, methoxymethyl ether 8²⁰was selectively

deprotected under acidic conditions in the presence of AzulE cinnamate (1d) (entry 4), while

the reverse was achieved with DBU, as expected (entry 5). The AzulE ester of Fmoc-

protected glycine (1i) provided a more challenging scenario, wherein both protecting groups

are typically cleaved by base.¹⁶When treating with DBU, global deprotection was achieved

(entry 6). In contrast, use of the milder base piperidine allowed selective Fmoc deprotection

(entry 7). In order to selectively cleave the AzulE group, the two-step activation-deprotection

methodology was invoked. To this end, protected glycine 1i was treated with oxalyl chloride,

followed by methanol and pyridine to afford the ketoester 9. This activated the azulene ring

sufficiently for deprotection with morpholine. In this way, the AzulE group was removed

although the Fmoc group was also partially cleaved (entry 8). Further study with this latter

case might allow determination of more orthogonal conditions for the selective deprotection

of AzulE in the presence of Fmoc.

Table 6. Orthogonality of AzulE esters with other protecting groups

Entry Other

PG

Mixture Reaction conditions

Effect on

AzulE^a

Effect on other

PG^a

1

TBS

1d + 7

PPTS, MeCN, reflux, None

Deprotection

overnight

2

3

4

TBS

MOM

1d + 7

1d + 8

DBU, THF, r.t., 7 hs

TBAF, THF, r.t., 3.5 h Deprotection

PPTS, 3:1

Deprotection

None

Deprotection

None

EtOH/MeCN, reflux,

overnight

5

6

MOM

Fmoc

1d + 8

DBU, MeCN, r.t.,

overnight

DBU, MeCN, r.t., 8 h Deprotection

Deprotection

None

Deprotection

1i

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7

8

Fmoc

Piperidine, MeCN,

r.t., 30 min

(COCl)₂, CH₂Cl₂,

MeOH, pyridine, 0⁰C,

50 s; then 9, NEt₃,

MeCN, 0⁰C, 3 h

None

Deprotection

1i

Deprotection

Partial^b

deprotection

^aDetermined by integration of the relevant peaks in the ¹H NMR spectrum of the crude

reaction mixture.

^b25% deprotection of Fmoc group.

Assessment of the compatibility of a protecting group with a selection of salient and

representative reactions allows its utility in the wider context of synthetic chemistry to be

determined. The reactivity of the azulene ring presents risks for the AzulE esters that should

be evaluated. For instance, the 1-position of azulene is unusually nucleophilic for an aromatic

hydrocarbon and may react with strong electrophiles. The base sensitivity of the protecting

group may also need to be factored into synthetic planning.

The susceptibility of the AzulE ester to basic conditions was explored first. Given the basic

deprotection conditions, it was a concern that the general application of AzulE esters in

synthesis might be limited by their lability. This might be particularly pronounced with the

strong bases used for reactions such as alkylations, olefinations, alkynylations, aldol reactions

and ether formation (such as for base-promoted hydroxyl group protection with MOM, PMB,

benzyl ethers, etc). A compatibility study to determine whether an AzulE-protected ester is

susceptible to cleavage by the moderately strong organic base potassium

bis(trimethylsilyl)amide (KHMDS) was therefore undertaken. This was performed by adding

an excess of KHMDS to AzulE cinnamate (1d) in dry THF at -78 °C and monitoring the

reaction by NMR analysis of aliquots over 90 minutes (see Supporting Information). It was

found that, within 6 minutes, Azule cinnamate was fully converted to cinnamic acid and 6-

vinylazulene (Scheme 5). This experiment confirms the incompatibility of this protecting

group with strong base and hence the need to appropriately adapt synthetic sequences to

avoid reaction of AzulE esters with strong bases.

Scheme 5. Reaction of AzulE cinnamate with KHMDS

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Several representative reactions were selected for explorations with the AzulE protecting

group, including metal-catalysed cross coupling, aldehyde olefination, carbonyl reduction and

alcohol oxidation. For each reaction, two experiments were performed in tandem on a model

substrate: one control reaction and one reaction spiked with AzulE benzoate (1a). The

relative abundance of each species was assessed through ¹H NMR integration, and the effect

on the AzulE protecting group (as well as any impact of the protecting group on the reaction)

was determined (Table 7). The Suzuki reaction was selected as a non-toxic and relatively

benign cross coupling.²¹Investigation of Suzuki cross-coupling reactions demonstrated that,

while the use of elevated temperatures caused significant amounts of deprotection (entry 1),

the reaction at room temperature with a mild base was sufficiently compatible with the AzulE

protecting group (entry 2). Wittig-type olefinations are very broadly employed for

homologation of carbon chains;²²the Horner-Wadsworth-Emmons variant²³introduces two-

carbon units in a manner that evokes polyketide synthesis, and is widely used in target

synthesis. The basic conditions of the standard Horner-Wadsworth-Emmons reaction were

expected to cause deprotection of the AzulE ester (vide supra), so Masamune-Roush

conditions²⁴were employed and found to be compatible (entry 3). Oxidation and reduction

processes are widely used synthetic operations and so a knowledge of the compatibility of the

new AzulE ester protecting group under typical reaction conditions is paramount. Sodium

borohydride reduction of benzophenone in the presence of AzulE-benzoate (1a) led to no loss

of AzulE ester (entry 4) and hence ketone/aldehyde reduction represents a compatible

reaction. As anticipated, Swern oxidation²⁵conditions elicited reaction at the azulene ring of

the AzulE ester as well as performing the desired alcohol oxidation (entry 5). Similarly,

Dess-Martin,²⁶pyridinium chlorochromate (PCC)²⁷and TEMPO-BAIB²⁸oxidation

conditions caused degradation of the azulene moiety and low yields of the oxidised product

(entries 5–8). Thus, oxidations with strongly electrophilic reagents or catalysts represent a

limitation of this protecting group. Encouragingly, manganese dioxide²⁹was compatible with

the AzulE esters and therefore oxidation of allylic (and, presumably, propargylic) alcohols to

the corresponding aldehydes is possible in the presence of an AzulE protecting group.

Further investigations into the scope of the manganese dioxide oxidations will be conducted.

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Table 7. Compatibility of AzulE esters with Suzuki, Masamune-Roush, oxidation and

reduction reactions.

Entry

Reaction

Conversion of

control rxn^a

Conversion of 1a-

Effect on AzulE

benzoate (1a)^a

17% deprotection

8% hydrolysis

none

spiked reaction^a

45%

1

2

3

4

5

6

7

8

9

Suzuki @ 111°C 70%

Suzuki @ r.t.

Masamune-Roush Quant.

NaBH₄reduction Quant.

Swern oxidation

Dess-Martin

PCC oxidation

TEMPO-BAIB

MnO₂oxidation

Quant.

75%

72%

31%

none

87%

93%

100%

90%

98%

degradation

none

68%

98%

^aDetermined through integration of the relevant peaks in the ¹H NMR spectrum of the crude

reaction mixture.

Conclusion

A new carboxylic acid protecting group, the AzulE ester, has been developed that is

deprotected under basic conditions accompanied by a visible colour change. The AzulE

esters display orthogonality with commonly used alcohol protecting groups (TBS ether,

14

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MOM ether) and partial orthogonality with the amine protecting group Fmoc. They are

stable under reduction, olefination and mild cross-coupling reaction conditions and in

oxidations with manganese dioxide. However, the electron-rich azulene is susceptible to

strongly electrophilic oxidation reagents. The reactivity of this protecting group with base

also means it should be considered only for syntheses without such oxidation or strong bases.

Nonetheless, the convenience of the colour in tracking protected material through various

laboratory manipulations should encourage consideration of its use for target-based syntheses

requiring protection of carboxylic acids. Further studies into the scope of this protecting

group through its inclusion in synthetic endeavours are on-going in our laboratory.

Experimental Section

6-(2-Hydroxyethyl)azulene, 2.¹⁴An LDA solution was prepared by mixing THF (6 mL) and

diisopropylamine (0.18 mL, 1.27 mmol, 1.15 eq.) at -30 ⁰C (dry ice/ethylene glycol bath),

followed by addition of n-BuLi (0.71 mL of a 1.77 M in cyclohexane solution, 1.25 mmol,

1.13 eq.). To this reaction mixture, a chilled (-30 ⁰C) solution of 6-methylazulene¹³(157 mg,

1.10 mmol, 1 eq.) in THF (3 mL) was added via cannula. The reaction mixture rapidly

changed colour from indigo to golden brown. A vial containing paraformaldehyde (129.5 mg,

4.3 mmol, 3.9 eq.) was heated to the point of sublimation and formaldehyde gas was

transferred from this vessel into the reaction mixture via cannula, upon which the reaction

mixture returned to a blue colour. Water (3 mL) was added and the reaction was stirred for

one minute before workup. A separation was performed using CH₂Cl₂/H₂O and the organic

layer was washed with saturated aqueous brine and concentrated by rotary evaporation.

Column chromatography was performed on the residue using silica gel prepared with 2%

NEt₃in pet. ether, delivering recovered starting material (22.2 mg, 14%) by elution in 1:1 pet.

ether/CH₂Cl₂, and the title compound 2 (138.6 mg, 73% yield) as an indigo solid eluting in

1:2 pet. ether/EtOAc. mp 82.3-83.8 ⁰C [lit.¹⁴mp 78-80 ⁰C]. IR (ATR): ν_max3218, 2944, 2895,

1

1577, 1392, 1039, 822, 751, 744 cm^-1. H NMR (500 MHz, CDCl₃) δ 8.29 (d, J=9.5 Hz, 2H,

H-4,8), 7.87 (t, J=3.5 Hz, 1H, H-2), 7.39 (d, J=3.5 Hz, 2H, H-1,3), 7.11 (d, J=9.5 Hz, 2H, H-

5,7), 3.96 (t, J=7.0 Hz, 2H, H-10), 3.05 (t, J=6.5 Hz, 2H, H-9). ¹³C NMR (125 MHz, CDCl₃)

δ 148.9 (C, C-6), 139.0 (C, C-3a,8a), 136.3 (CH, C-2), 135.9 (CH, C-4,8), 124.2 (CH, C-5,7),

118.3 (CH, C-1,3), 64.3 (CH₂, C-10), 45.3 (CH₂, C-9). HRMS: m/z C₁₂H₁₃O⁺[M+H]⁺

Calculated 173.0961, found 173.0964. The ¹H NMR data correspond with those reported

previously.¹⁴

2-(Azulen-6-yl)ethyl benzoate (AzulE benzoate), 1a. Benzoic acid (40 mg, 0.32 mmol, 1.01

eq.), 2 (55 mg, 0.32 mmol, 1 eq.), DCC (77 mg, 0.37 mmol, 1.16 eq.) and DMAP (10 mg,

0.082 mmol, 0.26 eq.) were added together and dissolved in CH₂Cl₂(6 mL). After 16 hours, a

separation was performed with CH₂Cl₂/H₂O and the organic fraction was concentrated by

rotary evaporation. Column chromatography was performed on the crude material using

CH₂Cl₂to obtain 1a (67 mg, 75% yield) as an indigo semi-crystalline solid. mp 119.6-120.0

⁰C. λ_max: 566 nm. IR (ATR): ν_max3067, 2952, 1711, 1580, 1261, 1105, 835, 743, 701 cm^-1.

¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J=10.0 Hz, 2H, H-4,8), 8.01 (d, J=7.0 Hz, 2H, H-13),

15

ACCEPTED MANUSCRIPT

7.87 (t, J=3.5 Hz, 1H, H-2), 7.56 (t, J=7.0 Hz, 1H, H-15), 7.43 (t, J=7.5 Hz, 2H, H-14), 7.38

(d, J=4.0 Hz, 2H, H-1,3), 7.18 (d, J=10.0 Hz, 2H, H-5,7), 4.65 (t, J=7.0 Hz, 2H, H-10), 3.27

(t, J=7.0 Hz, 2H, H-9). ¹³C NMR (125 MHz, CDCl₃) δ 166.4 (C, C-11), 148.0 (C, C-6), 139.1

(C, C-3a,8a), 136.5 (CH, C-2), 135.9 (CH, C-4,8), 133.0 (CH, C-15), 130.1 (C, C-12), 129.6

(CH, C-13), 128.4 (CH, C-14), 124.2 (CH, C-5,7), 118.3 (CH, C-1,3), 65.7 (CH₂, C-10), 41.3

+

(CH₂, C-9). HRMS: m/z C₁₉H₁₇O₂[M+H]⁺Calculated 277.1223, found 277.1224.

2-(Azulen-6-yl)ethyl 1-naphthoate (AzulE 1-naphthoate), 1b. 1-Naphthoic acid (96 mg,

0.55 mmol, 1 eq.), 2 (120 mg, 0.70 mmol, 1.25 eq.), EDCI (188 mg, 1.2 mmol, 2.2 eq.) and

DMAP (12 mg, 0.094 mmol, 0.17 eq.) were added together in a RBF and dissolved in CH₂Cl₂

(4 mL). After 4 hours, a separation was performed using CH₂Cl₂/H₂O and the organic

fraction was concentrated by rotary evaporation and purified by column chromatography in

CH₂Cl₂to afford AzulE naphthoate 1b (167 mg, 82% yield) as an indigo solid. mp 87.4-88.3

⁰C. λ_max: 568 nm. IR (ATR): ν_max3052, 2949, 2890, 1701, 1575, 1393, 1234, 1194, 1130,

1013, 778, 760 cm^-1. ¹H NMR (500 MHz, CDCl₃) δ 8.78 (d, J=8.5 Hz, 1H, H-19), 8.31 (d,

J=10.5 Hz, 2H, H-4,8), 8.12 (dd, J=7.5, 1.5 Hz, 1H, H-13), 8.01 (d, J=8.0 Hz, 1H, H-15),

7.88 (t, J=3.5 Hz, 1H, H-2), 7.87 (d, J=6.5 Hz, 1H, H-16), 7.51 (m, 2H, H-17, H-18), 7.47

(m, 1H, H-14), 7.40 (d, J=3.5 Hz, 2H, H-1,3), 7.22 (d, J=10.5 Hz, 2H, H-5,7). 4.75 (t, J=7.0

Hz, 2H, H-10), 3.33 (t, J=7.0 Hz, 2H, H-9). ¹³C NMR (125 MHz, CDCl₃) δ 167.4 (C, C-11),

148.0 (C, C-6), 139.1 (C, C-3a,8a), 136.4 (CH, C-2), 135.9 (CH, C-4,8), 133.7 (C, C-15a),

133.4 (CH, C-15), 131.2 (C, C-19a), 130.2 (CH, C-13), 128.5 (CH, C-16), 127.7 (CH, C-18),

127.0 (C, C-12), 126.2 (CH, C-17), 125.7 (CH, C-19), 124.4 (CH, C-14), 124.2 (CH, C-5,7),

118.3 (CH, C-1,3), 65.9 (CH₂, C-10), 41.2 (CH₂, C-9). HRMS: m/z C₂₃H₁₉O₂[M+H]⁺

+

Calculated 327.1380, found 327.1388.

2-(Azulen-6-yl)ethyl 2-furoate (AzulE 2-furoate), 1c. 2-Furoic acid (67 mg, 0.59 mmol, 1

eq.), 2 (106 mg, 0.61 mmol, 1.03 eq.), EDCI (148 mg, 0.95 mmol, 1.6 eq.) and DMAP (25

mg, 0.2 mmol, 0.35 eq.) were added to a RBF and dissolved in CH₂Cl₂(4 mL). After 4

hours, a separation was performed in CH₂Cl₂/H₂O and the organic fraction was concentrated

by rotary evaporation. The crude mixture was subjected to column chromatography using

CH₂Cl₂to obtain AzulE furoate 1c (133 mg, 83% yield) as an indigo solid. mp 92.8-93.7 ⁰C.

λ_max: 569 nm. IR (ATR): ν_max3131, 3117, 2984, 2946, 1703, 1571, 1472, 1398, 1302, 1279,

1111, 792, 750 cm^-1. ¹H NMR (500 MHz, CDCl₃) δ 8.29 (d, J=10.0 Hz, 2H, H-4,8), 7.87 (t,

J=4.5 Hz, 1H, H-2), 7.58 (app. s, 1H, H-15), 7.38 (d, J=4.0 Hz, 2H, H-1,3), 7.15 (m, 3H, H-

5,7, H-13), 6.50 (dd, J=1.5, 0.5 Hz, 1H, H-14), 4.62 (t, J=7.0 Hz, 2H, H-10), 3.24 (t, J=7.0

Hz, 2H, H-9). ¹³C NMR (125 MHz, CDCl₃) δ 158.5 (C, C-11), 147.6 (C, C-6), 146.4 (CH, C-

15), 144.5 (C, C-12), 139.1 (C, C-3a,8a), 136.5 (CH, C-2), 135.9 (CH, C-4,8), 124.2 (CH, C-

5,7), 118.3 (CH, C-1,3), 118.1 (CH, C-13), 111.9 (CH, C-14), 65.6 (CH₂, C-10), 41.2 (CH₂,

+

C-9). HRMS: m/z C₁₇H₁₅O₃[M+H]⁺Calculated 267.1016, found 267.1016.

2-(Azulen-6-yl)ethyl (E)-cinnamate (AzulE cinnamate), 1d. Cinnamic acid (161 mg, 1.08

mmol, 1 eq.), DMAP (23 mg, 0.18 mmol, 0.16 eq.), DCC (255 mg, 1.23 mmol, 1.14 eq.) and

6-(2-hydroxyethyl)azulene (2) (207 mg, 1.20 mmol, 1.1 eq.) were added to a RBF and

dissolved in CH₂Cl₂(10 mL). After 3 hours, a phase separation was performed with

H₂O/CH₂Cl₂and the organic fraction was concentrated by rotary evaporation. Column

16

ACCEPTED MANUSCRIPT

chromatography using CH₂Cl₂was performed on the resulting product, eluting AzulE

cinnamate 1d (305 mg, 93% yield) as an indigo powder. mp 144.6-146.0 ⁰C. λ_max: 567 nm.

IR (ATR): ν_max3079, 2944, 1710, 1633, 1562, 1307, 1168, 979, 837, 761, 740 cm^-1. ¹H NMR

(500 MHz, CDCl₃) δ 8.30 (d, J=10.5 Hz, 2H, H-4,8), 7.87 (t, J=4.0 Hz, 1H, H-2), 7.68 (d,

J=16.0 Hz, 1H, H-13), 7.52 (m, 2H, H-15), 7.40-7.38 (complex m, 5H, H-1, H-3, H-16, H-

17), 7.15 (d, J=10.5 Hz, 2H, H-5,7), 6.42 (d, J=16.0 Hz, 1H, H-12), 4.54 (t, J=7.0 Hz, 2H, H-

10), 3.21 (t, J=7.0 Hz, 2H, H-9). ¹³C NMR (125 MHz, CDCl₃) δ 166.8 (C, C-11), 148.0 (C,

C-6), 145.1 (CH, C-13), 139.1 (C, C-3a,8a), 136.4 (CH, C-2), 135.9 (CH, C-4,8), 134.3 (C,

C-14), 130.4 (CH, C-17), 128.9 (CH, C-16), 128.1 (CH, C-15), 124.2 (CH, C-5,7), 118.3

+

(CH, C-1,3), 117.8 (CH, C-12), 65.3 (CH₂, C-10), 41.3 (CH₂, C-9). HRMS: m/z C₂₁H₁₉O₂

[M+H]⁺Calculated 303.1380, found 303.1388.

2-(Azulen-6-yl)ethyl (2E, 4E)-hexa-2,4-dienoate (AzulE sorbate), 1e. Sorbic acid (44 mg,

0.39 mmol, 1.0 eq.), 6-(2-hydroxyethyl)azulene (70 mg, 0.41 mmol, 1.1 eq.), DCC (134 mg,

0.65 mmol, 1.7 eq.) and DMAP (13 mg, 0.11 mmol, 0.27 eq.) were added to dry DCM (5

mL) under nitrogen and stirred overnight under an atmosphere of nitrogen. An indigo

solution was obtained which was washed with distilled water. The aqueous layer extracted

with DCM (three times) and concentrated to dryness under reduced pressure to yield an

indigo solid. Column chromatographic purification, using silica as the solid phase and DCM

as the mobile phase afforded AzulE sorbate 1e as an indigo oil (69 mg, 0.26 mmol, 66%).

λ_max: 568 nm. IR (ATR): ν_max1706, 1644, 1324, 1241, 1185, 1134, 1088, 993, 841, 746 cm^-1.

¹H NMR (500 MHz, CDCl₃) δ 8.27 (d, J = 10.5 Hz, 2H, H-4,8), 7.85 (t, J = 3.5 Hz, 1H, H-2),

7.36 (d, J = 3.5 Hz, 2H, H-1,3), 7.23 (dd, J = 15.5, 10.0 Hz, 1H, H-13), 7.12 (d, J = 10.5 Hz,

2H, H-5,7), 6.23 – 6.07 (complex m, 2H, H-14,15), 5.75 (d, J = 15.0 Hz, 1H, H-12), 4.45 (t, J

= 7.0 Hz, 2H, H-10), 3.15 (t, J = 7.0 Hz, 2H, H-9), 1.85 (d, J = 5.5 Hz, 3H, H-16). ¹³C NMR

(126 MHz, Chloroform-d) δ 167.1, 148.1, 145.4, 139.7, 139.1, 136.4, 135.9, 129.7, 124.2,

+

118.6, 118.2, 65.0, 41.3, 18.7. HRMS: m/z C₁₈H₁₉O₂[M+H]⁺Calculated 267.1380, found

267.1377.

2-(Azulen-6-yl)ethyl acetate (AzulE acetate), 1f.¹⁴Acetic acid (0.034 mL, 0.60 mmol, 1.0

eq.), 6-(2-hydroxyethyl)azulene (114 mg, 0.66 mmol, 1.1 eq.), DCC (148 mg, 0.72 mmol, 1.2

eq.) and DMAP (15 mg, 0.12 mmol, 0.2 eq.) were dissolved in dry DCM under N₂. The

reaction mixture was allowed to stir at room temperature for 3 hours until complete according

to thin layer chromatographic analysis. The reaction mixture was diluted with DCM and

washed with brine followed by water. The solvent was removed under reduced pressure.

Chromatographic purification (petroleum ether/ethyl acetate, 1:1) yielded the protected

carboxylic acid, AzulE acetate 1f as an indigo oil (76 mg, 0.35 mmol, 59%). ¹H NMR (500

MHz, CDCl₃): 8.31 (d, J = 10.5 Hz, 2 H), 7.94 (t, J = 4.0 Hz, 1 H), 7.44 (d, J = 4.0 Hz, 2 H),

7.12 (d, J = 10.5 Hz, 2 H), 4.43 (t, J = 7.0 Hz, 2 H), 3.14 (t, J = 7.0 Hz, 2 H), 2.08 (s, 3 H).

¹³C NMR (500 MHz): 170.7, 147.7, 138.9, 136.3, 135.7, 123.9, 118.1, 65.0, 40.8, 20.7. The

¹H NMR data were consistent with those reported previously.¹⁴

2-(Azulen-6-yl)ethyl 5-bromopentanoate (AzulE 5-bromovalerate), 1g. 5-Bromovaleric

acid (70 mg, 0.39 mmol, 1.0 eq.), 6-(2-hydroxyethyl)azulene (74 mg, 0.43 mmol, 1.1 eq.),

DCC (100 mg, 0.48 mmol, 1.3 eq.) and DMAP (9 mg, 0.07 mmol, 0.2 eq.) were dissolved in

17

ACCEPTED MANUSCRIPT

dry DCM (10 mL) and stirred overnight at room temperature under an atmosphere of N₂. The

reaction mixture was then diluted with DCM and washed with brine followed by water. The

solvent was removed under reduced pressure. Chromatographic purification

(dichloromethane) yielded the protected carboxylic acid 1g as an indigo oil (104 mg, 0.31

mmol, 80%). λ_max: 570 nm. IR (ATR): ν_max3080, 2955, 1729, 1579, 1395, 1168, 836, 751

cm^-1. ¹H NMR (500 MHz, CDCl₃) δ 8.28 (d, J=10.0 Hz, 2H, H-4,8), 7.86 (t, J=3.5 Hz, 1H,

H-2), 7.37 (d, J=3.5 Hz, 2H, H-1,3), 7.10 (d, J=10.0 Hz, 2H, H-5,7), 4.40 (t, J=7.0 Hz, 2H,

H-10), 3.33 (t, J=6.5 Hz, 2H, H-15), 3.13 (d, J=7.0 Hz, 2H, H-9), 2.32 (t, J=7.0 Hz, 2H, H-

12), 1.85-1.78 (m, 2H, H-14), 1.77-1.69 (m, 2H, H-13). ¹³C NMR (126 MHz, CDCl₃) δ 173.0

(C, C-11), 147.9 (C, C-6), 139.1 (C, C-3a,8a), 136.5 (CH, C-2), 135.8 (CH, C-4,8), 124.1

(CH, C-5,7), 118.3 (CH, C-1,3), 65.2 (CH₂, C-10), 41.1 (CH₂, C-9), 33.2 (CH₂, C-12), 33.0

(CH₂, C-15), 31.9 (CH₂, C-14), 23.4 (CH₂, C-13). HRMS: m/z C₁₇H₂₀O₂Br⁺[M+H]⁺

Calculated 335.0641, found 335.06501.

2-(Azulen-6-yl)ethyl (benzyloxy)acetate (AzulE benzyloxyacetate), 1h. 2-Benzyloxyacetic

acid (0.060 mL, 0.42 mmol, 1.0 eq.), 6-(2-hydroxyethyl)azulene (79 mg, 0.46 mmol, 1.1 eq.),

DCC (103 mg, 0.50 mmol, 1.2 eq.) and DMAP (15 mg, 0.12 mmol, 0.3 eq.) were dissolved in

dry DCM (10 mL) and stirred overnight at room temperature under an atmosphere of N₂. The

reaction mixture was then diluted with DCM and washed with brine followed by water. The

solvent was removed under reduced pressure. Chromatographic purification (petroleum

ether/ethyl acetate, 5:1) yielded the protected carboxylic acid 1h as an indigo oil (98 mg, 0.31

mmol, 73%). λ_max: 569 nm. IR (ATR): ν_max3065, 3029, 2954, 2892, 1750, 1579, 1452, 1395,

1

1190, 1118, 836, 746, 697 cm^-1. H NMR (500 MHz, CDCl₃) δ 8.25 (d, J=10.0 Hz 2H, H-

4,8), 7.87 (t, J = 4.0 Hz, 1H, H-2), 7.37 (d, J = 4.0 Hz, 2H, H-1,3), 7.36-7.28 (complex m,

5H, H-15,16,17,18,19), 7.08 (d, J = 10.0 Hz, 2H, H-5,7), 4.58 (s, 2H), 4.49 (t, J = 7.0 Hz, 2H,

H-10), 4.08 (s, 2H, H-12), 3.15 (t, J = 7.0 Hz, 2H, H-9). ¹³C NMR (126 MHz, Chloroform-d)

δ 170.3 (C, C-11), 147.5 (C, C-6), 139.1 (C, C-3a,8a), 137.0 (C, C-14), 136.5 (CH, C-2),

135.8 (CH, C-4,8), 128.5 (CH, C-15,19 or C-16,18 or C-17), 127.99 (CH, C-15,19 or C-16,18

or C-17), 127.96 (CH, C-15,19 or C-16,18 or C-17), 124.1 (CH, C-5,7), 118.3 (CH, C-1,3),

73.3 (CH₂, C-13), 67.1 (CH₂, C-12), 65.5 (CH₂, C-10), 41.0 (CH₂, C-9). HRMS: m/z

C₂₁H₂₁O₃[M+H]⁺Calculated 321.1485, found 321.1491.

+

N-Fluorenylmethyloxycarbonyl glycine 2-(azulen-6-yl)ethyl ester (Fmoc-Gly-OazulE),

1i. Fmoc-Gly-OH (159 mg, 0.5 mmol, 1 eq.), 2 (99 mg, 0.57 mmol, 1.07 eq.), DCC (149 mg,

0.72 mmol, 1.35 eq.) and DMAP (26 mg, 0.21 mmol, 0.39 eq.) were added to a RBF and

dissolved in CH₂Cl₂(10 mL). After 3 hours, a separation was performed with CH₂Cl₂/H₂O,

and the organic fraction was purified by column chromatography using 9:1 CH₂Cl₂/Et₂O to

obtain AzulE-protected glycine 1i (225 mg, 93% yield) as an indigo-coloured gummy oil.

λ_max: 568 nm. IR (ATR): ν_max3336, 3065, 3013, 2950, 1703, 1578, 1515, 1447, 1395, 1181,

1

1048, 1001, 737 cm^-1. H NMR (500 MHz, CDCl₃) δ 8.29 (d, J=10.0 Hz, 2H, H-4,8), 7.89 (t,

J=3.5 Hz, 1H, H-2), 7.79 (d, J=7.5 Hz, 2H, H-20), 7.62 (d, J=8.0 Hz, 2H, H-17), 7.47 (t,

J=8.0 Hz, 2H, H-19), 7.39 (d, J=4.0 Hz, 2H, H-1,3), 7.34 (t, J=7.0 Hz, 2H, H-18), 7.07 (d,

J=10.0 Hz, 2H, H-5,7), 5.30 (br. s, 1H, N-H), 4.48 (t, J=7.0 Hz, 2H, H-10), 4.43 (d, J=7.0 Hz,

2H, H-14), 4.25 (t, J=7.0 Hz, 1H, H-15), 3.98 (d, J=5.5 Hz, 2H, H-12), 3.14 (t, J=7.0 Hz, 2H,

18

ACCEPTED MANUSCRIPT

H-9). ¹³C NMR (125 MHz, CDCl₃) δ 169.9 (C, C-11), 156.2 (C, C-13), 147.3 (C, C-6), 143.8

(C, C-16), 141.3 (C, C-21), 139.1 (C, C-3a,8a), 136.6 (CH, C-2), 135.9 (CH, C-4,8), 127.7

(CH, C-19), 127.1 (CH, C-18), 125.0 (CH, C-17), 124.1 (CH, C-5,7), 120.0 (CH, C-20),

118.4 (CH, C-1,3), 67.2 (CH₂, C-14), 66.1 (CH₂, C-10), 47.1 (CH, C-15), 42.7 (CH₂, C-12),

+

41.0 (CH₂, C-9). HRMS: m/z C₂₉H₂₆NO₄[M+H]⁺Calculated 452.1856, found 452.1875.

2-(Azulen-6-yl)ethyl cyclohexanecarboxylate (AzulE cyclohexanecarboxylate), 1j.

Cyclohexanecarboxylic acid (41 mg, 0.32 mmol, 1 eq., heated to 32 ⁰C and added as liquid),

2 (57 mg, 0.33 mmol, 1.02 eq.), DCC (73 mg, 0.35 mmol, 1.1 eq.) and DMAP (12 mg, 0.1

mmol, 0.3 eq.) were added together in a RBF and dissolved in CH₂Cl₂(6 mL). The reaction

was stirred overnight. A separation was performed in CH₂Cl₂/H₂O and the organic fraction

was concentrated by rotary evaporation. The crude mixture was subjected to column

chromatography using CH₂Cl₂to afford 1j (70 mg, 77% yield) as an indigo crystalline solid.

mp 85.4-85.9 ⁰C. λ_max: 571 nm. IR (ATR): ν_max3079, 2930, 2849, 1723, 1578, 1395, 1167,

1

1130, 839, 743 cm^-1. H NMR (500 MHz, CDCl₃) δ 8.28 (d, J=10.5 Hz, 2H, H-4,8), 7.87 (t,

J=3.5 Hz, 1H, H-2), 7.38 (d, J=3.5 Hz, 2H, H-1,3), 7.11 (d, J=10.0 Hz, 2H, H-5,7), 4.39 (t,

J=7.0 Hz, 2H, H-10), 3.12 (t, J=7.0 Hz, 2H, H-9), 2.28 (tt, J=11.5, 3.5 Hz, 1H, H-12), 1.87

(dd, J=13.5, 2.5 Hz, 2H, H-13a), 1.74 (m, 2H, H-14a), 1.63 (m, 1H, H-15a), 1.42 (qd, J=12.0,

3.5 Hz, 2H, H-13b), 1.25 (m, 3H, H-14b, 15b). ¹³C NMR (125 MHz, CDCl₃) δ 176.0 (C, C-

11), 148.2 (C, C-6), 139.1 (C, C-3a,8a), 136.4 (CH, C-2), 135.8 (CH, C-4,8), 124.2 (CH, C-

5,7), 118.2 (CH, C-1,3), 64.9 (CH₂, C-10), 43.2 (CH, C-12), 41.2 (CH₂, C-9), 29.0 (CH₂, C-

13), 25.7 (CH₂, C-15), 25.4 (CH₂, C-14). HRMS: m/z C₁₉H₂₃O₂[M+H]⁺Calculated

+

283.1693, found 283.1700.

2-(Azulen-6-yl)ethyl trichloroacetate (AzulE trichloroacetate), 1k. 6-(2-

Hydroxyethyl)azulene (21.8 mg, 0.12 mmol, 1 eq.) was dissolved in CH₂Cl₂(5 mL) and

trichloroacetyl chloride (0.07 mL, 0.62 mmol, 5 eq.) was added, followed by pyridine (0.2

mL, 2.5 mmol, 20 eq.). After 3 hours a colour change towards maroon was observed. A

separation was performed with CH₂Cl₂/H₂O and the organic fraction was concentrated by

rotary evaporation. The crude mixture was purified by column chromatography with 1:1 pet.

ether/CH₂Cl₂to afford 1k (22 mg, 53% yield) as an indigo oil. λ_max: 568 nm. ¹H NMR (500

MHz, CDCl₃) δ 8.28 (d, J=10.5 Hz, 2H, H-4,8), 7.88 (t, J=3.5 Hz, 1H, H-2), 7.39 (d, J=3.5

Hz, 2H, H-1,3), 7.12 (d, J=10.5 Hz, 2H, H-5,7), 4.66 (t, J=7.0 Hz, 2H, H-10), 3.25 (t, J=7.0

Hz, 2H, H-9). ¹³C NMR (125 MHz, CDCl₃) δ 161.9 (C, C-11), 146.2 (C, C-6), 139.2 (C, C-

3a,8a), 136.8 (CH, C-2), 135.9 (CH, C-4,8), 124.1 (CH, C-5,7), 118.5 (CH, C-1,3), 89.7 (C,

+

CCl3), 69.8 (CH2, C-10), 40.7 (CH2, C-9). HRMS: m/z C₁₄H₁₂Cl₃O₂[M+H]⁺Calculated

316.9897, found 316.9885.

2-(Azulen-6-yl)ethyl azulene-1-carboxylate (AzulE azulenecarboxylate), 1l. Azulene-1-

carboxylic acid (SI2) (43 mg, 0.25 mmol), 2 (43 mg, 0.25 mmol, 1 eq.), DCC (76 mg, 0.37

mmol, 1.5 eq.) and DMAP (9 mg, 0.08 mmol, 0.3 eq.) were added to a RBF and dissolved in

CH₂Cl₂(6 mL). After 3 hours, further DMAP (41 mg, 0.34 mmol, 1.3 eq.) was added and the

reaction was heated at reflux overnight. A separation was performed in CH₂Cl₂/H₂O and the

organic fraction was concentrated by rotary evaporation. The crude mixture was subjected to

column chromatography using CH₂Cl₂to afford 1l (64 mg, 78% yield) as a purple solid. mp

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ACCEPTED MANUSCRIPT

116.5-117.4 ⁰C. λ_max: 514, 530 nm. IR (ATR): ν_max3068, 2956, 2928, 2850, 1660, 1574,

1392, 1224, 1136, 1006, 120, 754 cm^-1. ¹H NMR (500 MHz, CDCl₃) δ 9.56 (d, J=10.0 Hz,

1H, H-19), 8.45 (d, J=10.0 Hz, 1H, H-15), 8.35 (d, J=4.0 Hz, 1H, H-13), 8.32 (d, J=10.0 Hz,

2H, H-4,8), 7.87 (t, J=4.0 Hz, 1H, H-2), 7.70 (t, J=10.0 Hz, 1H, H-17), 7.47 (t, J=10.0 Hz,

1H, H-18), 7.44 (t, J=10.0 Hz, 1H, H-16), 7.39 (d, J=3.5 Hz, 2H, H-1,3), 7.29 (d, J=4.0 Hz,

1H, H-14), 7.24 (d, J=10.0 Hz, 2H, H-5,7), 4.71 (t, J=6.5 Hz, 2H, H-10), 3.32 (t, J=7.0 Hz,

2H, H-9). ¹³C NMR (125 MHz, CDCl₃) δ 165.2 (C, C-11), 148.7 (C, C-6), 144.8 (C, C-14a),

140.8 (C, C-19a), 140.2 (CH, C-13), 139.1 (C, C-3a,8a), 139.0 (CH, C-17), 138.2 (CH, C-

15), 137.8 (CH, C-19), 136.3 (CH, C-2), 135.9 (CH, C-4,8), 127.7 (CH, C-18), 126.8 (CH, C-

16), 124.4 (CH, C-5,7), 118.2 (CH, C-1,3), 117.7 (CH, C-14), 116.6 (C, C-12), 64.7 (CH₂, C-

+

10), 41.6 (CH₂, C-9). HRMS: m/z C₂₃H₁₉O₂[M+H]⁺Calculated 327.1380, found 327.1387.

Deprotection studies on AzulE cinnamate (general procedure). AzulE (E)-cinnamate (10

mg, 0.03 mmol) was dissolved in solvent (3 mL) under open air, and base (approx. 0.1 mL)

was added. The reaction was performed either at r.t. or reflux. The extent of reaction was

monitored qualitatively through observed colour change and by TLC analysis and the

reaction was stopped once no evidence of SM remained, or otherwise after overnight

reaction. If the solvent and base were low boiling, the reaction mixture was concentrated by

rotary evaporation was employed to give the crude reaction residue. Otherwise, an aqueous

separation was employed using CH₂Cl₂and 10% aqueous HCl, followed by concentration of

the organic fraction by rotary evaporation to give the crude residue. This residue was

subjected to quantitative ¹H NMR analysis and the principal peaks integrated to determine the

extent of reaction (see details in Supporting Information). The results are shown in Table 2.

In most deprotections, 6-vinylazulene (4) was generated as the by-product, but when using

piperidine as the base, piperidine adduct 5 was obtained.

6-Vinylazulene, 4.¹⁴A blue crystalline solid was obtained as a by-product of AzulE ester

deprotection, typically in yields corresponding to the extent of deprotection, and identified as

1

6-vinylazulene. λ_max: 608 nm. H NMR (500 MHz, CDCl₃) δ 8.31 (d, J=10.5 Hz, 2H, H-4,8),

7.85 (t, J=3.5 Hz, 1H, H-2), 7.36 (d, J=3.5 Hz, 2H, H-1,3), 7.31 (d, J=10.0 Hz, 2H, H-5,7),

6.92 (dd, J=17.5, 10.5 Hz, 1H, H-9), 5.97 (d, J=17.5 Hz, 1H, H-10b), 5.47 (d, J=10.5 Hz, 1H,

H-10a). ¹³C NMR (125 MHz, CDCl₃) δ 145.7 (C, C-6), 141.3 (CH, C-9), 139.3 (C, C-3a,8a),

136.8 (CH, C-2), 135.6 (CH, C-4,8), 121.4 (CH, C-5,7), 118.4 (CH, C-1,3), 117.6 (CH₂, C-

10). HRMS: m/z C₁₂H₁₁⁺[M+H]⁺Calculated 155.0855, found 155.0857. ¹H NMR data are

consistent with those reported previously.¹⁴

N-2-(Azulen-6-yl)ethylpiperidine, 5. An indigo oil, formed in Azul deprotections involving

the use of piperidine, was obtained in quantities concordant with the extent of deprotection

and identified as the title compound. This material was contaminated with a small amount of

piperidine that was identifiable in the NMR spectra. λ_max: 562 nm. ¹H NMR (500 MHz,

CDCl₃) δ 8.26 (d, J=10.5 Hz, 2H, H-4,8), 7.83 (t, J=4.0 Hz, 1H, H-2), 7.35 (d, J=4.0 Hz, 2H,

H-1,3), 7.09 (d, J=10.0 Hz, 2H, H-5,7), 3.00 (m, 2H, H-9), 2.67 (m, 2H, H-10), 2.50 (broad s,

4H, H-11), 1.64 (quin, J=6.0 Hz, 4H, H-12), 1.50-1.45 (m, 2H, H-13). ¹³C NMR (125 MHz,

CDCl₃) δ 151.4 (C, C-6), 138.9 (C, C-3a,8a), 135.9 (CH, C-4,8), 135.8 (CH, C-2), 124.2 (CH,

C-5,7), 117.9 (CH, C-1,3), 62.1 (CH₂, C-10), 54.5 (CH₂, C-11), 39.9 (CH₂, C-9), 26.0 (CH₂,

20

ACCEPTED MANUSCRIPT

C-12), 24.3 (CH₂, C-13). HRMS: m/z C₁₇H₂₂N⁺[M+H]⁺Calculated 240.1747, found

240.1751.

Deprotection of AzulE esters (optimised procedure). The AzulE ester (0.5 mmol) was

dissolved in MeCN (3 mL), DBU (0.2 mL) was added and the reaction mixture stirred, open

to the air, for the time shown in Table 3. After this time, a colour change from indigo to blue

was observed. Then HCl (2 mL, 10% in H₂O) was added and a phase separation was

performed using CH₂Cl₂and H₂O. The aqueous layer was washed three times with CH₂Cl₂

then twice with EtOAc. The organic phase was then concentrated by rotary evaporation. The

crude mixture was purified by gradient column chromatography whereby 6-vinylazulene

eluted with pet. ether and the deprotected carboxylic acid was obtained by elution with a

mixture of pet. ether/ethyl acetate (typically 2:1 v/v). Occasionally a green tint remained in

the product from degraded azulene material; this was a very minor impurity and could be

removed by filtering through a silica plug. The yields of the carboxylic acids are shown in

Table 3; all of these (and δ-valerolactone) are commercially available.

2-(1-(2-Methoxy-2-oxoacetyl)azulen-6-yl)ethyl (E)-cinnamate, 6. AzulE cinnamate (1a)

(79 mg, 0.26 mmol, 1 eq.) was dissolved in CH₂Cl₂(3 mL). Oxalyl chloride (0.1 mL, 1.16

mol, 4.5 eq.) was added, followed 20 seconds later by methanol (0.3 mL, 7.4 mmol, 28 eq.)

and after another 40 seconds by pyridine (0.4 mL, 5 mmol, 19 eq.). Immediately, this reaction

mixture was subjected to workup using CH₂Cl₂/H₂O and the organic fraction was

concentrated by rotary evaporation and purified by column chromatography in 2:1 pet.

ether/ethyl acetate to give activated species 6 as an orange-red oil (99 mg, 98% yield). λ_max

:

1

505 nm. IR (ATR): ν_max3002, 2950, 1732, 1710, 1623, 1409, 1305, 1174, 850, 769 cm^-1. H

NMR (500 MHz, CDCl₃) δ 9.79 (d, J=10.5 Hz, 1H, H-8), 8.45 (d, J=10.0 Hz, 1H, H-4), 8.40

(d, J=4.0 Hz, 1H, H-2), 7.70 (d, J=10.0 Hz, 1H, H-7), 7.66 (d, J=16.0 Hz, 1H, H-13), 7.58 (d,

J=10.5 Hz, 1H, H-5), 7.50 (m, 2H, H-15), 7.39-7.37 (m, 3H, H-16, H-17), 7.26 (d, J=4.0 Hz,

1H, H-3), 6.39 (d, J=16.0 Hz, 1H, H-12), 4.56 (t, J=7.0 Hz, 2H, H-10), 3.99 (s, 3H, O-Me),

3.31 (t, J=6.5 Hz, 2H, H-9). ¹³C NMR (125 MHz, CDCl₃) δ 180.6 (C, C-18), 166.7 (C, C-19),

164.8 (C, C-11), 152.1 (C, C-6), 146.1 (C, C-3a), 145.5 (CH, C-13), 142.3 (CH, C-2), 141.8

(C, C-8a), 138.9 (CH, C-8), 138.1 (CH, C-4), 134.1 (C, C-14), 132.4 (CH, C-7), 131.0 (CH,

C-5), 130.5 (CH, C-17), 128.9 (CH, C-16), 128.2 (CH, C-15), 120.9 (C, C-1), 119.4 (CH, C-

3), 117.4 (CH, C-12), 64.7 (CH₂, C-10), 52.6 (CH₃, O-Me), 41.1 (CH₂, C-9). HRMS: m/z

+

C₂₄H₂₁O₅[M+H]⁺Calculated 389.1384, found 389.1386.

Deprotection of activated AzulE cinnamate (general procedure). Deprotection of

activated AzulE cinnamate 6 was conducted in acetonitrile with bases as described in Table

5. Reaction completion was determined by NMR spectroscopic analysis of the crude reaction

mixture (see details in Supporting Information).

Deprotection of activated AzulE cinnamate (optimised procedure). Activated AzulE

cinnamate 6 (16 mg, 0.041 mmol) was dissolved in acetonitrile (3 ml) and treated with

morpholine (0.1 mL, 1.2 mmol). The reaction mixture was stirred for 19 hours before

evaporation under reduced pressure to afford the crude product mixture as an orange oil.

21

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Column chromatography (DCM) provided cinnamic acid as a pale orange oil (6 mg, 0.04

mmol, 99%).

AzulE – O-TBS competitive deprotection studies. Cyclohexanemethyl tert-

butyldimethylsilyl ether (7) and AzulE cinnamate were used in the following experiments.

The extent of reaction was measured through comparison of ¹H NMR integration of the

starting materials and the products (see details in Supporting Information).

Selective O-TBS deprotection in the presence of AzulE ester. 11 mg of a mixture of

AzulE cinnamate (1d) and TBS-protected cyclohexanemethanol¹⁹was added to a flask

[equivalent to AzulE cinnamate (1d) (0.029 mmol, 1.4 eq.) and 7 (0.021 mmol, 1 eq.)], PPTS

(85 mg, 0.33 mmol, 16 eq.) was added and the reaction was dissolved in MeCN (3 mL) and

heated at reflux overnight open to air. A separation was performed with CH₂Cl₂/H₂O and the

organic phase was concentrated by rotary evaporation (taking care not to subject the mixture

to prolonged vacuum to avoid loss of cyclohexanemethanol) and this mixture was subjected

to NMR analysis (see details in Supporting Information). This indicated that the deprotection

of the TBS-ether proceeded to completion without interference of the AzulE ester.

Selective AzulE deprotection in the presence of O-TBS. AzulE cinnamate (1d) (10.1 mg,

0.033 mmol, 1 eq.) and TBS-protected cyclohexanemethanol (7)¹⁹(8.4 mg, 0.037 mmol, 1.07

eq.) were dissolved in THF (3 mL), and DBU (0.1 mL, 0.67 mmol, 18.5 eq.) was added.

After stirring overnight, a phase separation was performed using H₂O/Et₂O and the separated

organic phase was washed four times with H₂O. The organic phase was reduced via rotary

evaporation under low vacuum. The aqueous phase was treated with 3 mL HCl (10% aq.) and

washed twice with CH₂Cl₂. This organic fraction was concentrated by rotary evaporation.

NMR analysis of these fractions indicated the deprotection of AzulE cinnamate proceeded

cleanly to completion without interference from the TBS-ether (see details in Supporting

Information).

Deprotection of TBS ether and AzulE Ester. AzulE cinnamate (1d) (8.3 mg, 0.027 mmol,

1 eq.) and TBS-protected cyclohexanemethanol (7)¹⁹(6.2 mg, 0.027 mmol, 1 eq.) were

dissolved in THF (3 mL), and TBAF (0.4 mL of a 1 M solution in THF, 0.4 mmol, 15 eq.)

was added. A colour change was visible after 10 minutes. After 70 minutes, 1 mL of 10% aq.

HCl was added and a phase separation was performed with CH₂Cl₂/H₂O. The organic fraction

was concentrated by rotary evaporation and the crude mixture submitted for NMR analysis.

This indicated that full deprotection had occurred (see details in Supporting Information).

AzulE – O-MOM competitive deprotection studies. A standardised mixture of AzulE

cinnamate (1d) (69.7 mg, 1 eq.) and MOM-protected cetyl alcohol 8²⁰(71 mg, 1.07 eq.), was

made for use in the following experiments. The extent of reaction was measured through

comparison of ¹H NMR integration of the starting materials [AzulE cinnamate (1d) and cetyl

MOM ether 8] and the products [6-vinylazulene (4), cinnamic acid and cetyl alcohol].

Selective O-MOM deprotection in the presence of AzulE ester. The standardised MOM

deprotection mixture [43 mg, equivalent to 0.070 mmol AzulE cinnamate (1d) and 0.076

mmol MOM-protected cetyl alcohol (8)²⁰] and PPTS (73 mg, 0.29 mmol, 4.1 eq.) were added

22

ACCEPTED MANUSCRIPT

to a RBF fitted with condenser and dissolved in ethanol (3 mL) and MeCN (1 mL). The

reaction was heated at reflux overnight. A separation was performed using CH₂Cl₂/sat. aq.

NaHCO₃and the organic layer was submitted for NMR analysis (see details in Supporting

Information). This indicated that the deprotection of the MOM ether proceeded to

completion without interference from the AzulE ester.

Selective AzulE deprotection in the presence of O-MOM. The standardised MOM

deprotection mixture [16 mg, equivalent to 0.025 mmol AzulE cinnamate (1d) and 0.027

mmol MOM-protected cetyl alcohol (8)²⁰] was dissolved in THF (3 mL), and DBU (0.1 mL,

0.66 mmol) was added under open air. The reaction was stirred for 19 hours. 10 drops of 10%

HCl (aq.) were added to the reaction mixture, and a separation was performed in

CH₂Cl₂/H₂O. The organic layer was concentrated by rotary evaporation and submitted for

NMR analysis. This indicated that the deprotection of AzulE cinnamate proceeded cleanly to

completion without interference from the MOM ether (see details in Supporting Information).

AzulE – Fmoc competitive deprotection studies. Extent of reaction was measured through

comparison of ¹H NMR integration of the starting material, Fmoc-Gly-OAzulE (1i), and the

products, 6-vinylazulene (4), H-Gly-OAzulE, dibenzofulvene, 1-(fluoren-9-

ylmethyl)piperidine.¹⁶

Deprotection of NH-Fmoc and AzulE Ester. Fmoc-Gly-OAzulE (1i) (23 mg, 0.05 mmol, 1

eq.) was dissolved in THF (3 mL) and DBU (0.1 mL, 0.66 mmol, 13 eq.) was added. After 9

hours, the reaction mixture had changed colour from indigo to blue. HCl (1 mL, 10% aqueous

solution) was added and a phase separation was performed with CH₂Cl₂/H₂O, followed by

rotary evaporation of the organic fraction. The crude mixture was submitted for quantitative

NMR analysis (see details in Supporting Information). This indicated that complete

deprotection of both the Fmoc and the AzulE group occurred.

Selective NH-Fmoc deprotection in the presence of AzulE ester. Fmoc-Gly-OAzulE (1i)

(36 mg, 0.079 mmol, 1 eq.) was dissolved in MeCN (3 mL) and piperidine (0.1 mL, 1 mmol,

13 eq.) was added to this mixture. After 30 minutes, the reaction was complete by TLC. The

reaction mixture was concentrated by rotary evaporation and the crude mixture submitted for

quantitative NMR analysis (see details in Supporting Information). This indicated that

complete and selective Fmoc deprotection was achieved.

AzulE deprotection in the presence of NH-Fmoc. AzulE-protected Fmoc glycine 1i (189

mg, 0.42 mmol, 1 eq.) was dissolved in CH₂Cl₂(4 mL) and oxalyl chloride (0.2 mL, 2.3

mmol, 5.5 eq.) was added at 0 ⁰C, followed 20 seconds later by MeOH (0.4 mL, 9.9 mmol,

23 eq.) and another 30 seconds later by pyridine (0.5 mL, 6.2 mmol, 15 eq.). A phase

separation was performed using CH₂Cl₂/H₂O, and the organic fraction was concentrated by

rotary evaporation. The crude material was purified by column chromatography in ethyl

acetate to afford activated species 9 as an orange-red solid (209 mg, 92%). mp 63.6-65.7 ⁰C.

λ_max: 507 nm. IR (ATR): ν_max3355, 3040, 2951, 1720, 1621, 1395, 1255, 1182, 1048, 783 cm^-

1

¹. H NMR (500 MHz, CDCl₃) δ 9.77 (d, J=10.0 Hz, 1H, H-8), 8.42 (d, J=10.5 Hz, 1H, H-4),

8.40 (d, J=4.5 Hz, 1H, H-2), 7.76 (d, J=7.5 Hz, 2H, H-20), 7.63 (d, J=10.0 Hz, 1H, H-7), 7.58

23

ACCEPTED MANUSCRIPT

(d, J=7.5 Hz, 2H, H-17), 7.51 (d, J=10.0 Hz, 1H, H-5), 7.40 (t, J=7.5 Hz, 2H H-19), 7.31 (t,

J=7.5 Hz, 2H, H-18), 7.25 (d, J=4.5 Hz, 1H, H-3), 5.22 (t, J=5.5 Hz, 1H, N-H), 4.51 (d,

J=7.0 Hz, 2H, H-10), 4.40 (d, J=7.0 Hz, 2H, H-14), 4.22 (t, J=7.0 Hz, 1H, H-15), 3.99 (s, 3H,

O-Me), 3.96 (d, J=5.5 Hz, 2H, H-12), 3.26 (t, J=7.0 Hz, H, H-9). ¹³C NMR (125 MHz,

CDCl₃) δ 180.6 (C, C-22), 169.8 (C, C-11), 164.7 (C, C-23), 156.2 (C, C-13), 151.3 (C, C-6),

146.0 (C, C-3a or 8a), 143.7 (C, C-16), 142.4 (CH, C-2), 141.8 (C, C-3a or 8a), 141.3 (C, C-

21), 138.8 (CH, C-8), 138.1 (CH, C-4), 132.2 (CH, C-7), 130.9 (CH, C-5), 127.7 (CH, C-19),

127.1 (CH, C-18), 125.0 (CH, C-17), 120.9 (C, C-1), 120.0 (CH, C-20), 119.6 (CH, C-3),

67.2 (CH₂, C-14), 65.6 (CH₂, C-10), 52.6 (CH₃, O-Me), 47.1 (CH, C-15), 42.7 (CH₂, C-12),

+

40.8 (CH₂, C-9). HRMS: m/z C₃₂H₂₈NO₇[M+H]⁺Calculated 538.1860, found 538.1876.

Activated ketoester compound 9 (38 mg, 0.07 mmol, 1 eq.) was dissolved in MeCN (3 mL) at

0 ⁰C. NEt₃(0.1 mL, 0.7 mmol, 10 eq.) was added and the reaction left to stir for 3 hours at 0

⁰C. The reaction mixture was concentrated by rotary evaporation at r.t. and the crude mixture

was submitted for quantitative NMR analysis (see details in Supporting Information). This

indicated full AzulE deprotection, accompanied by partial (25%) Fmoc deprotection.

Compatibility of AzulE with strong base. KHMDS (0.79 mL of a 0.5 M in toluene

solution, 0.40 mmol, 3 eq.) was added dropwise to a stirred solution of AzulE cinnamate (40

mg, 0.13 mmol, 1.0 eq.) in dry THF (6 mL) at -78 °C under an atmosphere of argon. Aliquots

(0.25 mL) were taken at 0 minutes (before KHMDS addition), and subsequently at 6, 31, 61,

90 and 180 minutes. Each aliquot was treated with 10% aqueous HCl solution and extracted

with ethyl acetate before concentrating to dryness under reduced pressure and analysing by

NMR spectroscopy (see details in Supporting Information). This indicated that the

conversion of AzulE cinnamate into cinnamic acid and 6-vinylazulene was complete within 6

minutes.

Compatibility of AzulE with Suzuki cross-coupling at reflux. Phenylboronic acid (69 mg),

palladium tetrakis[triphenylphosphine] (65 mg), and potassium carbonate (131 mg) were

added together and the powders mixed thoroughly with a spatula. This mixture was

partitioned into two portions – the control (135 mg) and the AzulE benzoate-containing

sample (129 mg). To the control sample (containing a calculated 1.2 eq. phenylboronic acid,

0.11 eq. Pd(PPh₃)₄and 2 eq. K₂CO₃), toluene (3.2 mL) and 2-bromoanisole (0.03 mL, 0.24

mmol, 1 eq.) were added, and the reaction vessel was fitted with a reflux condenser and

heated at reflux for 2 hours, during which time the reaction mixture changed colour from

yellow to red to brown. A phase separation was performed with CH₂Cl₂/H₂O and the organic

fraction was concentrated by rotary evaporation and subjected to NMR analysis (see details

in Supporting Information and results in Table 7). For the spiked reaction, to a flask

containing AzulE benzoate (1a) (71 mg, 0.25 mmol, 1.06 eq.) and the powdered mixture

described above (containing a calculated 1.15 eq. phenylboronic acid, 0.11 eq. Pd(PPh₃)₄, and

1.9 eq. K₂CO₃), toluene (3.2 mL) and 2-bromoanisole (0.03 mL, 1 eq.) were added, and the

reaction vessel was fitted with a reflux condenser and heated at reflux for 2 hours, during

which time a colour change from indigo to purple and back to indigo was observed. A phase

separation was performed with CH₂Cl₂/H₂O, and the organic fraction was concentrated by

rotary evaporation and subjected to NMR analysis (see details in Supporting Information and

24

ACCEPTED MANUSCRIPT

results in Table 7). These indicated that this reaction is not compatible with AzulE

protection.

Compatibility of AzulE with Suzuki cross-coupling at ambient temperature.

Phenylboronic acid (72 mg), palladium acetate (16 mg), p-iodonitrobenzene (108.6 mg) and

potassium carbonate (158 mg) were added together and mixed as powders with a spatula.

This mixture was partitioned into two portions, the control (185 mg) and the AzulE benzoate-

spiked sample (168 mg). To the control sample (containing a calculated 1.34 eq.

phenylboronic acid, 0.16 eq. palladium acetate, 1 eq. p-iodonitrobenzene, and 2.6 eq.

potassium carbonate), methanol (3 mL) was added and the reaction was left to stir at r.t.

under open air for three days. A separation was performed using CH₂Cl₂/H₂O, and the

organic layer was concentrated by rotary evaporation and submitted for NMR analysis. For

the spiked reaction, to a RBF containing AzulE benzoate (1a) (75 mg, 0.27 mmol, 1.3 eq.)

and the powdered mixture described above (containing a calculated 1.34 eq. phenylboronic

acid, 0.16 eq. palladium acetate, 1 eq. p-iodonitrobenzene and 2.61 eq. potassium carbonate),

methanol (3 mL) was added and the reaction was left to stir at r.t. under open air for three

days. A separation was performed using CH₂Cl₂/H₂O, and the organic layer was submitted

for NMR analysis (see details in Supporting Information and results in Table 7). These

indicated that this reaction is compatible with AzulE protection.

Compatibility of AzulE with Masamune-Roush reaction. A solution of

triethylphosphonoacetate (0.2 mL), triethylamine (0.28 mL) in THF (4 mL) was prepared and

divided into two portions. For the control reaction, 2 mL of the above solution (containing a

calculated 1 eq. triethylphosphonoacetate and 2 eq. NEt₃) was added to a RBF containing

LiBr (108 mg, 1.24 mmol, 2.5 eq) and left to stir for 30 minutes. Anisaldehyde (0.24 mL,

0.98 mmol, 2 eq.) was then added and the reaction was left to proceed overnight. A

separation was performed using CH₂Cl₂/H₂O, and the organic layer was submitted for NMR

analysis. For the AzulE benzoate-spiked reaction, 2 mL of the above solution (containing a

calculated 1 eq. triethylphosphonoacetate and 2 eq. NEt₃) was added to a RBF containing

LiBr (102 mg, 1.18 mmol, 2.4 eq.) and AzulE benzoate (105 mg, 0.38 mmol, 0.32 eq.) and

left to stir for 30 minutes. Anisaldehyde (0.24 mL, 0.98 mmol, 2 eq.) was then added and the

reaction was left to proceed overnight. A separation was performed using CH₂Cl₂/H₂O, and

the organic layer was submitted for NMR analysis (see details in Supporting Information and

results in Table 7). These indicated that this reaction is compatible with AzulE protection.

Compatibility of AzulE with NaBH₄reduction. Benzophenone (146 mg) and NaBH₄(86

mg) were added together and mixed as solids. This mixture was partitioned into two portions,

the control (112 mg) and the AzulE benzoate-spiked sample (120 mg). To the control sample

(containing a calculated 1 eq. benzophenone and 2.8 eq. NaBH₄), methanol (2 mL) was added

and the reaction was allowed to stir for 5 hours. A separation was performed using

CH₂Cl₂/H₂O, and the organic layer was submitted for NMR analysis. For the spiked reaction,

to a sample containing AzulE benzoate (1a) (112 mg, 1.04 eq.) and the mixture described

above (containing a calculated 1 eq. benzophenone and 2.8 eq. NaBH₄), methanol (2 mL) was

added and the reaction was allowed to stir for 5 hours. A separation was performed using

CH₂Cl₂/H₂O, and the organic layer was submitted for NMR analysis (see details in

25

ACCEPTED MANUSCRIPT

Supporting Information and results in Table 7). These indicated that this reaction is

compatible with AzulE protection

Compatibility of AzulE with Swern oxidation. DMSO (0.5 mL), (COCl)₂(0.2 mL) and

CH₂Cl₂(5 mL) were added together at -78 ⁰C and left for 30 minutes. For the control

reaction, cetyl alcohol (54 mg, 0.22 mmol, 1 eq.) was dissolved in THF (4 mL) at -78 ⁰C, and

the above oxidising mixture (2 mL, containing a calculated 4.2 eq. chlorodimethylsulfonium

chloride) was added. The solution became cloudy. After two hours, NEt₃(0.3 mL, 2.15

mmol, 9.7 eq.) was added and the reaction was maintained at -78 ⁰C for a further 30 minutes

before allowing it to warm up to r.t. over an hour. 1 mL 10% HCl (aq.) was added to the

reaction mixture, followed by water and a separation was performed using CH₂Cl₂/H₂O, and

the organic layer was submitted for NMR analysis. For the AzulE benzoate-spiked reaction,

AzulE benzoate (1a) (52 mg, 0.19 mmol, 0.94 eq.) and cetyl alcohol (49 mg, 0.2 mmol, 1 eq.)

were mixed in THF (4 mL) at -78 ⁰C, and the above oxidising mixture (2 mL, containing a

calculated 4.6 eq. chlorodimethylsulfonium chloride) was added. The indigo reaction mixture

rapidly became magenta. Triethylamine (0.3 mL, 2.15 mmol, 10.8 eq.) was added after 130

minutes, and the reaction was kept at -78 ⁰C for a further 30 minutes before being allowed to

warm up to r.t. over an hour. 1 mL 10% HCl (aq.) was added, followed by water and a

separation was performed using CH₂Cl₂/H₂O, and the organic layer was submitted for NMR

analysis (see details in Supporting Information and results in Table 7). These indicated that

this reaction is not compatible with AzulE protection: there was evident degradation of the

AzulE protecting group and most of the colour (azulene material) remained in the aqueous

layer during phase separation.

Compatibility of AzulE with Dess-Martin oxidation. Cetyl alcohol (18 mg, 0.072 mmol,

1.0 eq.) was dissolved in dry DCM (2 mL) and added to a solution of DMP (38 mg, 0.089

mmol, 1.2 eq.) in dry DCM (2 mL) under argon gas and left to stir. After 4 hours the reaction

mixture was diluted with diethyl ether (4 mL) and poured into a solution of saturated aqueous

NaHCO₃(6 mL) containing Na₂S₂O₃.5H₂O (180 mg, 0.72 mmol, 10 eq.). The organic layer

was separated and extracted with saturated aqueous NaHCO₃(6 mL), then distilled water (6

mL), before drying over MgSO₄. The organic layer was concentrated to dryness under

reduced pressure and the white solid reaction product subjected to ¹H NMR analysis (see

details in Supporting Information and results in Table 7). These indicated that this reaction is

not compatible with AzulE protection.

Compatibility of AzulE with pyridinium chlorochromate oxidation. For the control

reaction, cetyl alcohol (18 mg, 0.072 mmol, 1.0 eq.) was dissolved in dry DCM (2.5 mL) and

added quickly to an orange solution of PCC (25 mg, 0.116 mmol, 1.6 eq.) dissolved in dry

DCM (2.5 mL) under argon gas. The reaction was left to stir and the colour changed to brown

over time. At 2 hours, the reaction mixture was diluted with DCM (10 mL) and filtered

through a sintered funnel containing a Celite pad, followed by washing with diethyl ether.

The reaction mixture was concentrated to dryness under reduced pressure to recover a crude

mass of 16.5 mg, as an off-white solid, which was submitted for NMR analysis. For the

spiked reaction, cetyl alcohol (18 mg, 0.074 mmol, 1.0 eq.) and AzulE benzoate (20 mg,

0.073 mmol, 1.0 eq.) were dissolved in dry DCM (2.5 mL) and added quickly to an orange

26

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solution of PCC (25 mg, 0.116 mmol, 1.6 eq.) in dry DCM (2.5 mL) under argon gas. The

reaction turned to a dark murky brown colour and was left to stir for 2 hours, by which time it

had changed to a dark muddy green. The reaction mixture was diluted with DCM (10 mL)

and filtered through a sinter funnel containing a Celite pad, washing with diethyl ether. The

filtrate was concentrated to dryness under reduced pressure to afford a dark green solid. This

was submitted to NMR analysis (see details in Supporting Information and results in Table

7). These indicated that the PCC oxidation is not compatible with the AzulE protecting

group.

Compatibility of AzulE with TEMPO/BAIB oxidation. Cetyl alcohol (18 mg, 0.072 mmol,

1.0 eq.), BAIB (26 mg, 0.080 mmol, 1.1 eq.) and TEMPO (1 mg, 0.0072 mmol, 0.1 eq.) were

dissolved in dry DCM (2 mL) and left to stir open to the atmosphere. After 3.5 hours the

reaction mixture was diluted with DCM (5 mL) and to this a saturated aqueous solution of

Na₂S₂O₃(10 mL) was added. The mixture was stirred for 5 min before extracting with DCM

(4x5 mL). The combined organic extracts were washed with saturated aqueous NaHCO₃(5

mL), then brine (5 mL) before being dried over Na₂SO₄and concentrated to dryness under

reduced pressure to recover a crude mass of 17.9 mg, as a white solid. The same experimental

procedure was followed for the spiked reaction but AzulE benzoate (20 mg, 0.072 mmol, 1

eq.) was additionally dissolved with cetyl alcohol, TEMPO and BAIB in dry DCM (2 mL) to

produce an indigo solution. After dilution, work-up and concentration to dryness under

reduced pressure an indigo solid was obtained. NMR analysis of both reaction mixtures (see

details in Supporting Information and results in Table 7) indicated that the TEMPO-BAIB

oxidation is not compatible with the AzulE protecting group.

Compatibility of AzulE with activated MnO₂. For the control reaction, E-non-2-en-1-ol (21

mg, 0.148 mmol, 1.0 eq.) in dry DCM (2 mL) was added to activated MnO₂(129 mg, 1.484

mmol, 10.0 eq.) in dry DCM under argon gas and left to stir. After 23 hours the reaction

mixture was filtered through a sinter funnel with a Celite pad before being concentrated to

dryness under reduced pressure to recover a crude mass of 21 mg, as a yellow oil. For the

spiked reaction, the same experimental procedure was followed but AzulE benzoate (40 mg,

0.145 mmol, 1 eq.) was additionally dissolved with E-non-2-en-1-ol in dry DCM (2 mL).

After filtration and concentration to dryness under reduced pressure a crude mass of 59 mg,

as an indigo solid, was recovered. NMR analysis of both reaction mixtures (see details in

Supporting Information and results in Table 7) indicated that manganese dioxide oxidations

of allylic alcohols are compatible with the AzulE protecting group.

Acknowledgments

Drs Paul Teesdale-Spittle and Justin Hodgkiss are recognised for helpful discussions during

the course of this research. Ian Vorster and Teresa Gen are gratefully thanked for instrument

support. A referee is acknowledged for suggesting the control deprotection reaction under

thermal-only conditions. We are grateful to Victoria University of Wellington for supporting

this research and to the University of York for providing the MChem Project Abroad scheme

(JFT, HW).

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ACCEPTED MANUSCRIPT

Supporting Information available: General experimental procedures and conditions,

synthetic methods and analytical data for deprotection of AzulE esters, data on colour change

during deprotection, kinetic studies on deprotection, details of protecting group and reaction

compatibility studies, synthesis of azulene-1-carboxylic acid, ¹H and ¹³C NMR spectra for all

new compounds.

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Article Doi

A colourful azulene-based protecting group for carboxylic acids

DOI: 10.1016/j.tet.2018.04.066

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