Synthesis of 4-aminoguaiazulene and its δ-lactam derivatives

Article abstract of DOI:10.1016/j.tetlet.2011.01.016

A method for nitrogen insertion into guaiazulene hydrocarbons is developed. A one-pot reaction of 7-isopropyl-1-methylazulene-4-carboxylic acid, diphenylphosphoryl azide, and an alcohol (MeOH, ^tBuOH or BnOH) affords the corresponding carbamates. Deprotection of benzyl (7-isopropyl-1-methylazulen-4-yl)carbamate under basic conditions gave 4-aminoguaiazulene, which undergoes ring annulation reactions with 1,2-dicarbonyl reagents to yield tricyclic δ-lactams.

Full text of DOI:10.1016/j.tetlet.2011.01.016

Tetrahedron Letters 52 (2011) 1151–1153
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Tetrahedron Letters
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Synthesis of 4-aminoguaiazulene and its d-lactam derivatives
⇑
Alexandros Kiriazis, Ingo B. Aumüller, Jari Yli-Kauhaluoma
Division of Pharmaceutical Chemistry, Faculty of Pharmacy, PO Box 56 (Viikinkaari 5 E), FI-00014 University of Helsinki, Finland
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for nitrogen insertion into guaiazulene hydrocarbons is developed. A one-pot reaction of 7-iso-
propyl-1-methylazulene-4-carboxylic acid, diphenylphosphoryl azide, and an alcohol (MeOH, BuOH or
BnOH) affords the corresponding carbamates. Deprotection of benzyl (7-isopropyl-1-methylazulen-4-
yl)carbamate under basic conditions gave 4-aminoguaiazulene, which undergoes ring annulation reac-
tions with 1,2-dicarbonyl reagents to yield tricyclic d-lactams.
t
Received 19 November 2010
Revised 16 December 2010
Accepted 4 January 2011
Available online 13 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Azulene
Conjugation
Amine
Heterocycle
Lactam
The present synthetic study details the chemical modification of
azulene1 based hydrocarbons belonging to the sesquiterpene class
of natural products. Guaiazulene (1), an azulene derivative, is
found in Nature as a constituent of pigments in mushrooms, guaiac
wood oil, and some marine invertebrates, and currently, these nat-
ural resources also serve as its commercial sources. Guaiazulene is
an FDA-approved cosmetic color additive and has potential appli-
cations as an anti-ulcer drug.
In our previous studies, we developed a one-pot transformation
of azulene derivatives into complex tricyclic heptafulvenes and,
subsequently, into tropones under mild reaction conditions.2 Guai-
azulene (1) was found to undergo electrophilic substitution reac-
tions (SE) with doubly activated 1,2-dicarbonyl compounds to
yield 10-hydroxyalkyl azulenes. After isolation, these azulenes were
treated with the base to furnish new tricyclic azulene derivatives
that possessed a fused six-membered ring containing various
substituents.
As part of our ongoing studies to modify the guaiazulene struc-
ture, we became interested in introducing a heteroatom into this
structure. This modification would be especially interesting as
nitrogen-substituted azulene derivatives are scarcely documented
in the literature. Herein, we focus on the insertion of nitrogen into
the 4-position of the guaiazulene seven-membered ring. This
approach offered the possibility of synthesizing a number of new
heterocyclic azulene derivatives. Previously, Hamajima et al.
reported the synthesis of 3-aminoguaiazulene, where the amino
group is attached to the five-membered ring.3 Modification of the
4-position of guaiazulene is feasible due to the enhanced acidity
of the C–H bond in its methyl group, a procedure that reflects a
common strategy in the field of azulene chemistry.4
We have previously utilized this strategy for the three-step syn-
thesis of 7-isopropyl-1-methylazulene-4-carboxylic acid (2)5 start-
ing from 1. This crystalline and stable aryl carboxylic acid 2 was
prepared and used as a starting material for our syntheses.
The key reaction in the preparation of amine 3 was the use of
the modified Curtius–Schmidt rearrangement.6 Carboxylic acid 2
was first converted into the corresponding isocyanate via an acyl
azide intermediate using diphenylphosphoryl azide (DPPA).7
A
one-pot reaction in the presence of triethylamine and an alcohol
(methanol, tert-butanol or benzyl alcohol) gave carbamates 4a–c
in variable yields (Scheme 1). For example, when methanol and
tert-butanol were used, the yields were only moderate (12–33%).
However, in the case of benzyl alcohol the reaction proceeded well,
and benzyl (7-isopropyl-1-methylazulen-4-yl)carbamate (4c) was
isolated in 82% yield after silica gel column chromatography.
Subsequent deprotection of Cbz-protected amine 4c turned out
to be challenging, as standard methods, such as catalytic hydroge-
nation or acid hydrolysis with HBr, suffered from the participation
of the azulene moiety in numerous side reactions. Removal of ben-
zyl carbamate was achieved in the presence of potassium hydrox-
ide in an aqueous solution of THF and MeOH. When compound 4c
was heated with KOH in THF–MeOH–H2O, the color of the reaction
mixture changed quickly from blue to deep purple. The hydrolysis
was complete in 1–1.5 h (TLC monitoring) and 7-isopropyl-1-
methylazulen-4-amine (3) was isolated in good yield (76%) after
column chromatography on silica gel. Amine 3 was found to be rel-
atively stable when stored under an inert atmosphere in a refriger-
ated toluene solution (concentration approx. 0.10 mM).
⇑
Corresponding author. Tel.: +358 9 191 59170; fax: +358 9 191 59556.
E-mail address: Jari.yli-kauhaluoma@helsinki.fi (J. Yli-Kauhaluoma).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.016

1152
A. Kiriazis et al. / Tetrahedron Letters 52 (2011) 1151–1153
R1OH
DPPA, Et3N
KOH (10equiv)
THF-MeOH-H2O
75 oC, 1.5-2 h
PhMe, 100 o
20-22 h
C
N
O
R1
N
H
OH
, 24%
O
H
H
O
1
2
: R1 = Me, 33%
4a
4b
3
, 76%
(over 3 steps)
: R1 = tBu, 12%
4c: R1 = Bn, 82%
Scheme 1. The synthesis of 4-aminoguaiazulene (3) from guaiazulene (1) via carboxylic acid 2.5
O
O
O
O
5c
5a-b
R3O
Cl
Et3N
Cl
R2
PhMe, -15 oC to rt,
PhMe, -60 oC, 1 h
OH
R2
HN
N
3-21 h, -R3OH
HN
H
H
O
O
O
3
2
6a
6b
: R = CF3, 88%
6c
, 30%
: R2 = CO2Et, 85%
Scheme 2. Cyclization of 4-aminoguaiazulene (3) to give d-lactams 6a–c.
1. -H+
2. +H+
H
H
OH
CF3
F3C
O
O
OH
CF3
O
-MeOH
OH
NH2
N
HN
NH2
CF3
O-
MeO
MeO
MeO
O
3
5a
7
8
6a
Scheme 3. Proposed reaction mechanism for the formation of d-lactam 6a.
In agreement with our previous work,2 7-isopropyl-1-methy-
lazulen-4-amine (3) reacted with various 1,2-dicarbonyl com-
pounds 5a–c (Scheme 2). The cascade reactions between 3 and
5a–c produced d-lactams 6a–c under mild reaction conditions
without the need for a catalyst.
tween amine 3 and oxalyl chloride (5c) (Scheme 2). When the
reaction temperature was as low as ꢀ60 °C and an excess of the
tertiary base (Et3N) was used, d-lactam 6c was obtained in moder-
ate (30%) yield after purification. In contrast to the
tams 6a and 6b, product (6c) contains a different functional group
and is an -ketolactam.
a-hydroxy lac-
The one-pot reaction between azulenyl amine 3 and methyl
3,3,3-trifluoropyruvate (5a) proceeded efficiently and yielded d-
lactam 6a in 88% yield after purification by column chromatogra-
phy. Theoretically, this reaction could have led to two regioisomer-
ic products, but only one product was isolated. The azulenyl amine
reacts in a similar fashion to that reported for the pure hydrocar-
bon guaiazulene,2 as rationalized in Scheme 3. The high nucleophi-
licity of the electron-rich 3-position ensures that electrophilic
substitution of this carbon atom is the predominant reaction be-
tween 3 and 5a to yield 7. This is followed by a ring closure to fur-
nish 8. Finally, the elimination of methanol produces d-lactam 6a.
The regioselectivity is further explained by the high electrophilicity
of the central carbon atom of the doubly activated dicarbonyl
reagent.
a
In summary, we have developed a method for the synthesis of
Cbz-protected aminoazulene 4c via a Curtius–Schmidt rearrange-
ment. Deprotection under basic conditions gave the surprisingly
stable 7-isopropyl-1-methylazulen-4-amine (3), which was found
to undergo a cascade reaction with 1,2-dicarbonyl electrophiles
to produce a new six-membered ring fused to the azulene aromatic
system. These cyclization products were isolated and characterized
as tricyclic d-lactams 6a–c. Further work is being conducted in an
effort to expand the scope of the reaction and to investigate the
biological properties of these compounds as potential inhibitors
of protein kinases.8
Acknowledgments
The reaction with diethyl ketomalonate (5b) is comparable to
that of 5a (Scheme 2). Reaction of amine 3 at room temperature
for 21 h yielded the corresponding lactam 6b in 85% isolated yield
after purification by column chromatography. In contrast, these
types of cyclizations do not run smoothly with carbonyl reagents
that are not additionally activated, such as ethyl pyruvate, 2,3-
butanedione, and ethyl glyoxylate. In these cases, we were unable
to obtain any lactam product. However, other very reactive dicar-
bonyl reagents can be successfully employed, demonstrating that
a broader structure variety is accessible by analogous reaction pro-
cedures. For example, we found that a rapid reaction occurs be-
We thank the Graduate School of Pharmaceutical Research and
the European Commission (Contract No. LSHB-CT-2004-503467)
for financial support.
Supplementary data
Supplementary data (experimental procedures, compound
characterization data, and 1H and 13C NMR spectra) associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.01.016.

A. Kiriazis et al. / Tetrahedron Letters 52 (2011) 1151–1153
1153
5. Aumüller, I. Ph.D. Dissertation, University of Kiel, Germany, 2002.
6. Curtius, T. Chem. Ber. 1890, 23, 3023.
References and notes
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(b) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron 1974, 30, 2151–2157.
8. Some of the azulenes synthesized were preliminarily tested against a panel of
serine/threonine kinases, which belong to the CAMK (calcium/calmodulin-
regulated kinases) family of kinases. Further work to characterize these
bioactivities is now in progress in our collaborators’ laboratory.
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