Blue Amino Acids Derived from Azulen-1-ylboronic Acid Pinacol Ester via the Petasis Reaction

Article abstract of DOI:10.1055/s-0036-1588907

Azulen-1-ylboronic acid pinacol ester undergoes a three-component Petasis reaction with amines and glyoxylic acid hydrate to give azulenylglycine derivatives in good yields. The progress of the reaction is indicated by a characteristic color change from violet to blue due to the altered π-conjugation of the azulene chromophore. The azulenylboronic ester is more reactive than its phenyl counterpart and even 2-styryl- and 2-thienylboronic pinacol esters, which have a strong electron-donating organyl group on boron. These results reflect the unique π-electron system of non-alternant azulene.

Full text of DOI:10.1055/s-0036-1588907

SYNTHESIS
0
0
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7
8
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1
1
4
3
7
-
2
1
0
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©
Georg Thieme Verlag Stuttgart · New York
2016, 48, A–F
A
paper
Synthesis
T. Murafuji et al.
Paper
Blue Amino Acids Derived from Azulen-1-ylboronic Acid Pinacol
Ester via the Petasis Reaction
Toshihiro Murafuji*a,b
Yusuke Tasakib
HO C
2
NR2
Bpin
Masayuki Fujinagab
Keisuke Taoc
Shin Kamijoa,c
R NH
2
+
2 2
HO CCH(OH)
MeOH, r.t.
Katsuya Ishiguroa,c
10 examples
up to 92% yield
a
Graduate School of Sciences and Technology for Innovation,
R2N = PhCH2NH, 4-MeOC6H4CH2NH, H2C=CHCH2NH,
Me(CH2)5NH, HOCH2CH2NH, Ph2CHNH,
Yamaguchi University, Yamaguchi 753-8512, Japan
murafuji@yamaguchi-u.ac.jp
Graduate School of Medicine, Yamaguchi University, Yamaguchi
b
Et2N, [Me(CH2)5]2N, piperidinyl, morpholinyl
753-8512, Japan
c
Graduate School of Science and Engineering, Yamaguchi University,
Yamaguchi 753-8512, Japan
Received: 06.09.2016
Accepted after revision: 04.10.2016
Published online: 22.11.2016
Bpin
Ir cat.
pin2B2
DOI: 10.1055/s-0036-1588907; Art ID: ss-2016-f0609-op
Bpin +
Abstract Azulen-1-ylboronic acid pinacol ester undergoes a three-
component Petasis reaction with amines and glyoxylic acid hydrate to
give azulenylglycine derivatives in good yields. The progress of the reac-
tion is indicated by a characteristic color change from violet to blue due
to the altered π-conjugation of the azulene chromophore. The azulenyl-
boronic ester is more reactive than its phenyl counterpart and even 2-
styryl- and 2-thienylboronic pinacol esters, which have a strong elec-
tron-donating organyl group on boron. These results reflect the unique
π-electron system of non-alternant azulene.
1
70%
2 10%
O
O
Bpin =
B
CO2H
6-formylazulene
PhCH2NH2
t-BuNC
Key words amino acids, azulene, boron, multicomponent reactions,
Petasis reaction
O
Ph
NHt-Bu
Much attention has been focused on the design and de-
N
O
velopment of new amino acids and peptidomimetics owing
to the pharmacological limitations of bioactive peptides.1
For constructing a compound library of amino acids and
peptides, multicomponent reactions that incorporate por-
tions of three or more reactants into new products in one-
Scheme 1 Four-component Ugi condensation using azulene deriva-
2
pot procedures are powerful transformations. In connec-
tives
tion with this, we reported the convenient synthesis of azu-
lene-2-carboxylic acid from azulen-2-ylboronic acid pina-
col ester (Bpin; 1) and its preliminary use in the four-com-
ponent Ugi condensation to form a dipeptide-type product
been reported.6 Racemic N-acetyl-β-(azulen-1-yl)alanine
was first synthesized by Anderson in 1964 from (azulen-1-
ylmethyl)trimethylammonium iodide and the sodium salt
of ethyl acetamidocyanoacetate.6a The racemic compound
was successfully resolved by Loidl in 2000 by enzymatic en-
3
containing an azulene skeleton (Scheme 1). Azulene has a
dipole moment whose negative end is directed toward the
five-membered ring. The effect of this polarized π-electron
system on the structure and properties of azulenyl peptides
is interesting, because aromatic noncovalent interactions
are known to play important roles in stabilizing the struc-
6c
antioselective deacetylation, and one of the enantiomers
has been used as a probe in peptide chemistry.6 The pau-
city of this class of compounds is attributed to the limited
synthetic methods for introducing an azulenyl group onto
an amino acid side chain. The three-component Petasis re-
d,e
4
ture of peptides.
Various efficient synthetic methods have been devel-
5
7
oped for azulene derivatives. To the best of our knowledge,
action of arylboronic acid derivatives with glyoxylic acid
however, only a few examples of azulenyl amino acids have
and amines provides a powerful and convenient method for
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

B
Synthesis
T. Murafuji et al.
Paper
I
Li
NIS
PhLi
THF, –78 °C
O
i-PrO
–
B
Bpin
O
pinB(Oi-Pr)
2
H O
+
Li+
2
51%
10%
Scheme 2 Alternative synthesis of 2
8
the one-pot formation of unnatural amino acids. We envis-
aged that the use of azulenylboronic derivatives in the
Petasis reaction could be very useful for constructing azule-
nyl amino acids. We report here the Petasis reaction of azu-
len-2-yl- and azulen-1-ylboronic acid pinacol esters (1 and
ther 3 nor any other aromatic or vinylic protons. In contrast,
when 2 was used instead of 1 in the Petasis reaction, the re-
action was very fast. Thus, the violet reaction mixture,
whose color was due to 2, turned blue over 3 hours with
precipitation of a blue solid, which was identified as the de-
sired 4a (Scheme 3). Such a characteristic color change in
the reaction of 2 is due to the altered π-conjugation of the
azulene chromophore by the loss of the π-electron delocal-
ization to the boron.
2
, respectively), as the boronic components.
Boronic esters 1 and 2 were prepared by direct boryla-
tion of azulene by using our reported method (Scheme
9,10
1).
We found that the borylation proceeds preferentially
at the 2-position to give 1 along with 2 as a minor product.
For convenience, we developed an alternative synthetic ap-
proach to 2 via the halogen–metal exchange of 1-iodoazu-
lene with phenyllithium (Scheme 2).11 The trapping of the
resulting azulen-1-yllithium with isopropoxyboronic acid
pinacol ester gave 2 in 51% yield together with azulene.
The Petasis reaction strongly depends on the solvent.
Jourdan reported that the use of methanol or hexafluo-
roisopropanol is the best of choice to obtain the desired
It should be emphasized that the Petasis reaction of 2
using benzylamine in methanol afforded 4a in good yield
(83%), because even 2-styryl- and 2-thienylboronic pinacol
esters, which have a strong electron-donating organyl
group on boron, react sluggishly at room temperature to
give the corresponding amino acids in only 67% and 40%
yields, respectively.8a For comparison, our attempted Petasis
reaction using phenylboronic acid pinacol ester instead of 2
in methanol resulted in the complete recovery of the start-
ing boronic ester. Hence, these indicate the higher reactivi-
ty of 2. The reason is attributed to the inherent π-polariza-
tion of the azulene core.12 This makes the 1-position of 2
electron-rich and reactive toward electrophilic substitu-
tion.
To understand the scope and limitations of 2, the Petasis
reaction with various amines was examined (Table 1). As in
the case of benzylamine (entry 1), the use of primary
amines gave the corresponding amino acids 4b–d in good
yield (entries 2–4). In toluene and dichloromethane, the re-
actions of 2 with n-hexylamine proceeded slowly (entries 5
and 6), which is consistent with the previously reported
finding that methanol accelerates the reaction.8a Further-
more, in dichloromethane the Petasis reaction of 2 with n-
hexylamine gave 4d in good yield (entry 6) whereas aryl-,
8a
amino acids in good yields. Our first attempt involved
adding benzylamine (0.55 mmol) to a solution of 1 (0.50
mmol) and glyoxylic acid hydrate (0.55 mmol) in methanol
(3 mL), and the resulting blue solution, whose color was
due to 1, was stirred at room temperature (Scheme 3). A
brown solid was gradually deposited and 1 was consumed
after 24 hours. The solid was collected by filtration and the
1
filtrate was evaporated to give a residue. The H NMR spec-
tra of both the solid and residue showed the signals of nei-
HO2CCH(OH)2
CO2H
Bpin
PhCH2NH2
MeOH, r.t., 24 h
2
NHCH Ph
1
3 (not obtained)
2
-styryl-, and 3-thienylboronic acid pinacol esters do not
HO2C
undergo the Petasis reaction with primary amines in the
same solvent. This reflects the higher reactivity of 2. The
presence of a hydroxyl group did not affect the reaction
(entry 7). The use of bulky diphenylmethylamine resulted
in a low yield of 4f (entry 8). The use of secondary amines
gave the desired products 4g–j in moderate to good yields
NHCH2Ph
+
Bpin
HO2CCH(OH)2
8h
PhCH2NH2
MeOH, r.t., 3 h
2
4a 83%
5%
Scheme 3 Petasis reactions applied to 1 and 2
(entries 9–12).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

C
Synthesis
T. Murafuji et al.
Paper
Table 1 Petasis Reaction of 2 Using Various Amines
HO2C
Bpin
NR2
+
HO2CCH(OH)2
R2NH
solvent, r.t.
2
4
Entry
R
2
N
Time (h)
Solvent
Yield of 4 (%)
Yield of azulene (%) Recovery of 2 (%)
1
2
3
4
5
6
7
8
9
PhCH
4-MeOC
C=CHCH
2
NH
3
2
MeOH
MeOH
MeOH
MeOH
toluene
4a (83)
4b (87)
4c (85)
4d (82)
4d (62)
4d (76)
4e (92)
4f (59)
4g (73)
4h (62)
4i (91)
4j (77)
5
2
2
6
0
0
0
1
5
5
0
2
0
0
6
H
4
CH
2
NH
H
2
2
NH
3
0
Me(CH
Me(CH
Me(CH
2
2
2
)
)
)
5
5
5
NH
NH
NH
3
0
24
24
3
25
12
0
2 2
CH Cl
HOCH
Ph CHNH
Et
[Me(CH
2
CH
2
NH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
2
6
0
2
N
6
0
10
11
12
2
)
5
]
2
N
6
0
piperidinyl
morpholinyl
4
0
3
0
In the generally accepted mechanism of the Petasis re-
that (19.3 ppm) observed in the complexation of phenylbo-
8
action (Scheme 4), the amine first condenses with glyoxyl-
ic acid to give the corresponding imine or iminium, whose
carboxyl substituent coordinates with an organoboronic
acid derivative to form a tetracoordinate boronate interme-
diate. Subsequent intramolecular transfer of the organyl
group from the boronate to the iminium carbon gives the
product.
ronic acid with glyoxylic acid (δ = 33.5 for phenylboronic
8b
acid vs. δ = 14.2 for the complex). After one day, the boron
signal at δ = 19.0 remained unchanged, but the 1H NMR
spectrum revealed the complete conversion of 2 into 1,3-di-
deuterioazulene. Therefore, the remaining signal at δ = 19.0
was assigned to the boronic ester derived from pinacol
and/or glyoxylic acid hydrate and not to the expected
tetracoordinate boronate complex. This is in good agree-
+
11
ment with the B NMR spectrum of a boronic ester, iso-
R2N
R2NH
+
2
OHCCO H
–
CO2
propoxyboronic acid pinacol ester (δ = 23.0) in the same
solvent. The formation of 1,3-dideuterioazulene from 2 is
explained by the deuteriodeboronation at the 1-position
through the coordination of the carboxylate anion with the
boron atom.14 In the Petasis reaction of 2, the formation of
azulene as a byproduct is similarly understood by its pro-
todeboronation with glyoxylic acid hydrate, and this unde-
sired side reaction is suppressed in the presence of amines.
The attempted Petasis reaction of 1 did not give the cor-
responding product. To get more information about this, we
compared the reactivity of 2 with that of 1 toward glyoxylic
acid hydrate in methanol. The reaction of 2 with an equi-
molar amount of glyoxylic acid hydrate was complete with-
in one hour at room temperature. The formation of azulene
–
H2O
ArB(OR')2
OR'
–
R2N
Ar
H2O
Ar
+
B
OR'
CO2H
R2N
O
O
Scheme 4 General mechanism of the Petasis reaction
The tetracoordinate boronate intermediate produced
from the boronic acid derivative and glyoxylic acid has been
1
1
8b,13
1
detected by B NMR spectroscopy.
Hence, we followed
was confirmed by TLC, as shown in the above H NMR
11
the reaction of 2 with glyoxylic acid hydrate by B NMR in
study. Concentration of the resulting solution, however,
gave azulene only in 20% yield along with insoluble blue
gummy substances. When the reaction was quenched with
10% aqueous potassium carbonate or an equimolar amount
of benzylamine, azulene was obtained in 94% and 99%
CD OD at room temperature (see Supporting Information).
3
The signal due to 2 (δ = 30.5) gradually decreased as a new
signal at δ = 19.0 increased. The difference in chemical shift
between these signals (11.5 ppm) was much smaller than
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

D
Synthesis
T. Murafuji et al.
Paper
yields, respectively. These suggest that azulene underwent
polymerization under the acidic conditions. In fact, azulene
reacted with an equimolar amount of glyoxylic acid hydrate
in methanol to give insoluble blue polymeric substances
and the polymerization was accelerated under concentrat-
ed conditions. For comparison, an attempted reaction of
azulene with acetic acid in methanol resulted in the com-
plete recovery of azulene and no polymerization was ob-
served. Hence, we propose that the polymerization is initi-
ated by the nucleophilic attack of the negatively polarized
1-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)azulene (2)
A round-bottomed flask (100 mL) equipped with a magnetic stirring
bar was charged with CH Cl (60 mL) and azulene (256 mg, 2 mmol).
NIS (450 mg, 2 mmol) was added to this solution and the mixture was
stirred for 30 min at r.t. The reaction was quenched with sat. aq NaHCO3
2
2
(10 mL). The organic layer was separated off and the aqueous layer
was extracted with CH Cl (2 × 20 mL). The organic layer was com-
2
2
bined with the extracts and the resulting solution was dried (Na SO )
2
4
and concentrated to leave the crude 1-iodoazulene quantitatively,
which was used in the next step without further purification owing
to its low stability.
1
- or 3-position of azulene toward the formyl carbon of gly-
A round-bottomed flask (50 mL) equipped with a magnetic stirring
bar was charged with THF (6 mL) and 1-iodoazulene (508 mg, 2
oxylic acid. It is known that azulene reacts with aldehydes
under acidic conditions to give calix[4]azulene, in which
four azulene units are linked by single carbon bridges at the
mmol). A 1.06 M solution of PhLi (2.4 mmol) in cyclohexane–Et O
2
was added to this solution at –78 °C, and the mixture was stirred for
30 min at this temperature. Then isopropoxyboronic acid pinacol es-
- and 3-positions.1
5
1
ter (558 mg, 3 mmol) was added to the solution containing azulen-1-
yllithium and the resulting solution was stirred for 3 h, during which
time the temperature was raised to r.t. The reaction was quenched
Next, 1 was allowed to react with glyoxylic acid hydrate
in methanol. Unlike in the case of 2, azulene did not form
and the reaction was slow. Thus, most of 1 remained un-
changed after one hour and concentration of the reaction
mixture accelerated the polymerization to give only green
gummy polymeric substances. When the reaction was sub-
jected to the same aqueous workup as above for 2, azulen-
with H
mL). The combined extracts were dried (Na SO ) and concentrated to
O (20 mL) and the mixture was extracted with hexane (2 × 10
2
2
4
leave an oily residue, which was purified by chromatography (silica
gel, hexane–EtOAc, 20:1) to give 2.
Yield: 259 mg, 1.05 mmol (51%); purple solid; mp 56–57 °C (Lit.10 56–
57 °C).
2-ylboronic acid (5) was obtained in 54% yield along with
1
H NMR (400 MHz, CDCl ): δ = 1.43 (s, 12 H, CH ), 7.30 (t, J = 9.7 Hz, 1
3
3
the recovery of 1 (33%). This indicates that 1 does not act as
a donor for the azulen-2-yl group in the Petasis reaction.
Furthermore, 1 did not react with acetic acid at all, even un-
der concentrated conditions. Taking into account the reac-
tivity of azulene toward glyoxylic acid hydrate, 1 may also
react with glyoxylic acid at the reactive 1-position to give
the polymeric substances along with concomitant hydroly-
sis of the boronic acid pinacol ester.
H), 7.40 (t, J = 9.9 Hz, 1 H), 7.43 (d, J = 3.7 Hz, 1 H, H-3), 7.68 (t, J = 9.9
Hz, 1 H, H-6), 8.36 (d, J = 3.7 Hz, 1 H, H-2), 8.42 (d, J = 9.5 Hz, 1 H, H-4),
9.20 (d, J = 9.7 Hz, 1 H, H-8).
13
C NMR (100 MHz, CDCl ): δ = 25.0, 82.9, 119.0, 124.6, 125.1, 136.4,
3
1
37.4, 138.2, 144.6, 145.6, 147.1; one azulene skeleton carbon signal
was not observed.
11
B NMR (128 MHz, CD OD): δ = 30.5.
3
In summary, we have revealed that the Petasis reaction
of 2 with glyoxylic acid hydrate and amines gives azulenyl-
glycine derivatives 4 in good yields. The progress of the re-
action was easily indicated by the characteristic color
change. The reactivity of 2 was quite different from that of
2
-(Azulen-1-yl)glycines 4; General Procedure
A round-bottomed flask (10 mL) equipped with a magnetic stirring
bar was charged with MeOH (3 mL), glyoxylic acid hydrate (51 mg,
0.55 mmol), and 2 (127 mg, 0.50 mmol). The resulting solution was
stirred for 1 min and then the appropriate amine (0.55 mmol) was
added. The mixture was stirred for 2–6 h, during which time 4 was
precipitated. Concentration of the resulting suspension gave a solid
residue, which was dissolved in CHCl3 and purified by chromatogra-
1
, and higher than the reactivities of previously reported
boronic esters with strong electron-donating organyl
groups on boron. The present reaction tolerates the intro-
duction of the azulen-1-yl group onto the α-carbon of N-al-
kylglycines under mild conditions.
phy (silica gel, CHCl –MeOH, 6:1) to give 4.
3
2
-(Azulen-1-yl)-N-benzylglycine (4a)
Yield: 121 mg, 0.42 mmol (83%); blue solid; mp 164 °C (dec.).
IR (ATR): 3030, 2850, 1615, 1580, 1455, 1400, 1365 cm–1
1H NMR (400 MHz, CD
OD): δ = 4.11 (d, J = 13.2 Hz, 1 H, PhCH
d, J = 13.2 Hz, 1 H, PhCH ), 5.24 (s, 1 H, CHCO), 7.31 (t, J = 10.0 Hz, 1 H,
.
All reactions were carried out under argon, unless otherwise noted.
1
13
3
), 4.19
2
H and C NMR spectra were recorded of samples prepared in CD OD
3
(
2
or DMSO-d on a Bruker Avance III-400 (400 MHz) or Bruker DRX500
6
11
H-7), 7.32 (t, J = 9.6 Hz, 1 H, H-5), 7.40–7.44 (m, 6 H, Ph and H-3), 7.74
t, J = 10.0 Hz, 1 H, H-6), 8.04 (d, J = 4.0 Hz, 1 H, H-2), 8.37 (d, J = 10.0
Hz, 1 H, H-8), 8.44 (d, J = 9.6 Hz, 1 H, H-4).
13C NMR (125 MHz, CD
OD): δ = 51.4, 60.1, 119.1, 121.7, 125.4, 125.8,
(
500 MHz) spectrometer with TMS as an internal standard. B NMR
(
spectra of samples prepared in CD OD were recorded on a Bruker
3
Avance III-400 spectrometer at 128 MHz with proton decoupling rela-
tive to BF ·OEt as the external reference. IR spectra were recorded on
3
2
3
a JASCO FT/IR-4100 (ATR) spectrophotometer. HRMS was carried out
on a Bruker Daltonics micrOTOF II (APCI) instrument. Analytical TLC
was carried out by using aluminum-backed plates pre-coated (0.25
mm) with Merck Silica Gel 60 F254. Boronic esters 1 and 2 were pre-
pared by direct borylation of azulene by using our reported method.
130.5, 130.8, 131.5, 133.2, 135.2, 137.8, 139.0, 139.1, 140.0, 143.7,
173.2.
HRMS (APCI): m/z [M – H]– calcd for C19H16NO : 290.1187; found:
2
290.1186.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

E
Synthesis
T. Murafuji et al.
Paper
13
2-(Azulen-1-yl)-N-(4-methoxybenzyl)glycine (4b)
C NMR (100 MHz, CD OD): δ = 58.2, 60.5, 118.8, 121.5, 125.3, 125.6,
3
1
35.1, 137.6, 138.9, 139.1, 139.7, 143.5, 172.9; one carbon signal was
Yield: 140 mg, 0.44 mmol (87%); blue solid; mp 141 °C (dec.).
IR (ATR): 3030, 2840, 1630, 1580, 1520, 1460, 1400, 1370, 1250 cm–1
not detected due to overlapping with solvent peak.
HRMS (APCI): m/z [M – H]– calcd for C14H14NO : 244.0979; found:
.
1
3
H NMR (400 MHz, CD OD): δ = 3.81 (s, 3 H, CH ), 4.04 (d, J = 12.8 Hz,
3
3
244.0989.
1
H, MeOC H CH ), 4.12 (d, J = 12.8 Hz, 1 H, MeOC H CH ), 5.20 (s, 1 H,
6
4
2
6
4
2
CHCO), 6.95 (d, J = 8.8 Hz, 2 H, MeOC H ), 7.28–7.34 (m, 4 H, H-5, H-7
6
4
2-(Azulen-1-yl)-N-(diphenylmethyl)glycine (4f)
and MeOC H ), 7.41 (d, J = 4.0 Hz, 1 H, H-3), 7.74 (t, J = 9.7 Hz, 1 H, H-
6
4
6), 8.03 (d, J = 4.0 Hz, 1 H, H-2), 8.36 (d, J = 9.6 Hz, 1 H, H-8), 8.43 (d, J =
Yield: 108 mg, 0.30 mmol (59%); blue solid; mp 111 °C (dec.).
9
.6 Hz, 1 H, H-4).
IR (ATR): 3130, 3060, 3030, 1610, 1580, 1540, 1500, 1460, 1440, 1400,
13
–1
C NMR (100 MHz, CD OD): δ = 50.8, 55.9, 59.6, 115.5, 118.8, 121.9,
1370, 1340 cm
.
3
1
1
24.8, 125.1, 125.5, 132.7, 135.0, 137.5, 138.8 (2 C), 139.7, 143.4,
62.1, 173.0.
1
H NMR (400 MHz, DMSO-d ): δ = 4.73 (s, 1 H, NCH), 4.75 (s, 1 H,
6
NCH), 7.14 (t, J = 9.7 Hz, 1 H, H-7), 7.20–7.40 (m, 12 H, Ph, H-3 and H-
5), 7.68 (t, J = 9.7 Hz, 1 H, H-6), 7.92 (d, J = 4.0 Hz, 1 H, H-2), 8.08 (d, J =
10.0 Hz, 1 H, H-8), 8.41 (d, J = 9.6 Hz, 1 H, H-4).
HRMS (APCI): m/z [M – H]– calcd for C20H18NO : 320.1292; found:
3
320.1282.
13
C NMR (100 MHz, DMSO-d ): δ = 56.5, 64.3, 117.2, 122.8, 123.5,
6
N-Allyl-2-(azulen-1-yl)glycine (4c)
127.0, 127.2 (2 C), 127.3, 127.4, 128.6 (2 C), 133.7, 135.7, 135.9, 137.3,
38.3, 141.1, 143.7, 143.8, 174.1.
HRMS (APCI): m/z [M – H]– calcd for C25H20NO : 366.1500; found:
1
Yield: 102 mg, 0.43 mmol (85%); blue solid; mp 148 °C (dec.).
IR (ATR): 2980, 2820, 1620, 1580, 1480, 1400, 1360 cm–1
.
2
366.1517.
1
H NMR (400 MHz, CD OD): δ = 3.48 (dd, J = 13.4, 6.8 Hz, 1 H,
3
CH =CHCH ), 3.58 (dd, J = 13.4, 6.8 Hz, 1 H, CH =CHCH ), 5.25 (s, 1 H,
2
2
2
2
2-(Azulen-1-yl)-N,N-diethylglycine (4g)
CHCO), 5.40 (dd, J = 13.2, 1.2 Hz, 1 H, CH =CHCH), 5.44 (dd, J = 5.2, 1.2
2
Hz, 1 H, CH =CHCH), 5.88–5.98 (m, 1 H, CH =CHCH), 7.33 (t, J = 10.0
Yield: 94 mg, 0.37 mmol (73%); blue solid; mp 126 °C (dec.).
2
2
Hz, 1 H, H-5), 7.39 (t, J = 10.0 Hz, 1 H, H-7), 7.43 (d, J = 4.0 Hz, 1 H, H-
), 7.77 (t, J = 10.0 Hz, 1 H, H-6), 8.03 (d, J = 4.0 Hz, 1 H, H-2), 8.45 (d,
J = 9.6 Hz, 1 H, H-4), 8.62 (d, J = 10.0 Hz, 1 H, H-8).
IR (ATR): 2980, 2940, 2530, 1630, 1570, 1400, 1340, 1320, 1300 cm–1
.
3
1
H NMR (400 MHz, DMSO-d ): δ = 1.07 (t, J = 7.2 Hz, 6 H, CH ), 2.81–
6
3
2
.89 (m, 2 H, CH ), 2.94–3.03 (m, 2 H, CH ), 5.08 (s, 1 H, CHCO), 7.29 (t,
2
2
13
C NMR (100 MHz, CD OD): δ = 59.9, 118.8, 121.4, 123.9, 125.2,
3
J = 9.6 Hz, 1 H, H-5), 7.31 (t, J = 9.6 Hz, 1 H, H-7), 7.40 (d, J = 4.0 Hz, 1
H, H-3), 7.74 (t, J = 9.6 Hz, 1 H, H-6), 8.02 (d, J = 4.0 Hz, 1 H, H-2), 8.43
125.6, 129.7, 135.1, 137.5, 138.9 (2 C), 139.8, 143.5, 172.8; one carbon
signal was not detected due to overlapping with solvent peak.
(d, J = 9.6 Hz, 1 H, H-4), 8.72 (d, J = 9.6 Hz, 1 H, H-8).
HRMS (APCI): m/z [M – H]– calcd for C15H14NO : 240.1027; found:
13
2
C NMR (100 MHz, DMSO-d ): δ = 9.5, 44.2, 65.2, 117.4, 122.4, 123.5,
6
240.1030.
124.0, 134.7, 137.0, 137.3, 137.5, 138.7, 141.2, 168.3.
HRMS (APCI): m/z [M – H]– calcd for C16H18NO : 256.1343; found:
2
2-(Azulen-1-yl)-N-hexylglycine (4d)
256.1353.
Yield: 117 mg, 0.41 mmol (82%); blue solid; mp 176 °C (dec.).
IR (ATR): 2960, 2860, 1580, 1480, 1460, 1400, 1370 cm–1
.
2-(Azulen-1-yl)-N,N-dihexylglycine (4h)
1
H NMR (400 MHz, CD OD): δ = 0.87 (t, J = 6.8 Hz, 3 H, hexyl), 1.25–
Yield: 114 mg, 0.31 mmol (62%); blue solid; mp 112 °C (dec.).
3
1
.34 (m, 6 H, hexyl), 1.60–1.76 (br m, 2 H, hexyl), 2.77–2.84 (m, 1 H,
hexyl), 2.93–3.01 (m, 1 H, hexyl), 5.23 (s, 1 H, CHCO), 7.32 (t, J = 9.6
Hz, 1 H, H-5), 7.39 (t, J = 9.6 Hz, 1 H, H-7), 7.43 (d, J = 4.0 Hz, 1 H, H-3),
IR (ATR): 2960, 2930, 2860, 1630, 1580, 1470, 1400, 1350 cm–1
.
1
H NMR (400 MHz, DMSO-d ): δ = 0.72 (t, J = 7.2 Hz, 6 H, hexyl), 0.99–
6
1
.08 (m, 12 H, hexyl), 1.45 (br m, 4 H, hexyl), 2.61–2.68 (m, 2 H, hex-
yl), 2.79–2.87 (m, 2 H, hexyl), 5.12 (s, 1H, CHCO), 7.28 (t, J = 9.6 Hz, 1
H, H-5), 7.29 (t, J = 9.6 Hz, H-7), 7.39 (d, J = 4.0 Hz, 1 H, H-3), 7.74 (t, J =
10.0 Hz, 1 H, H-6), 7.93 (d, J = 4.0 Hz, 1 H, H-2), 8.42 (d, J = 9.6 Hz, 1 H,
H-4), 8.67 (d, J = 10.0 Hz, 1 H, H-8).
7.76 (t, J = 9.6 Hz, 1 H, H-6), 8.04 (d, J = 4.0 Hz, 1 H, H-2), 8.45 (d, J = 9.2
Hz, 1 H, H-4), 8.65 (d, J = 9.6 Hz, 1 H, H-8).
13
C NMR (125 MHz, CD OD): δ = 14.5, 23.7, 27.5, 27.7, 32.6, 48.0, 60.9,
3
1
1
19.0, 121.9, 125.4, 125.8, 135.3, 137.7, 139.1, 139.2, 140.0, 143.7,
73.3.
13
C NMR (100 MHz, DMSO-d ): δ = 13.7, 21.8, 24.6, 25.8, 30.6, 50.2,
6
HRMS (APCI): m/z [M – H]– calcd for C18H22NO : 284.1656; found:
2
64.7, 116.9, 122.7, 123.1, 123.7, 134.4, 136.9, 137.1, 137.2, 138.4,
41.0 169.7.
HRMS (APCI): m/z [M – H]– calcd for C24H34NO : 368.2595; found:
284.1653.
1
2
2
-(Azulen-1-yl)-N-(2-hydroxyethyl)glycine (4e)
368.2578.
Yield: 113 mg, 0.46 mmol (92%); blue solid; mp 128 °C (dec.).
IR (ATR): 3180, 3020, 2840, 1610, 1580, 1460, 1450, 1390, 1370, 1340,
2-(Azulen-1-yl)-2-(piperidin-1-yl)acetic Acid (4i)
–1
1080, 1030 cm .
Yield: 122 mg, 0.46 mmol (91%); blue solid; mp 156 °C (dec.).
IR (ATR): 3360, 2940, 2860, 2710, 1620, 1440, 1400, 1350 cm–1
1
H NMR (400 MHz, CD OD): δ = 2.93–2.99 (m, 1 H, HOCH CH N),
3
2
2
.
3
.07–3.13 (m, 1 H, HOCH CH N), 3.76 (t, J = 5.6 Hz, 2 H, HOCH CH N),
2
2
2
2
1
H NMR (400 MHz, CD OD): δ = 1.46–1.95 (br m, 6 H, piperidinyl),
3
7.33 (t, J = 9.8 Hz, 1 H, H-5), 7.39 (t, J = 9.8 Hz, 1 H, H-7), 7.43 (d, J = 4.0
2
.66–2.75 (br s, 2 H, piperidinyl), 3.13 (br s, 1 H, piperidinyl), 3.92 (br
Hz, 1 H, H-3), 7.76 (t, J = 9.8 Hz, 1 H, H-6), 8.04 (d, J = 4.0 Hz, 1 H, H-2),
.45 (d, J = 9.6 Hz, 1 H, H-4), 8.66 (d, J = 9.8 Hz, 1 H, H-8).
s, 1 H, piperidinyl), 5.21 (s, 1 H, CHCO), 7.36 (t, J = 9.6 Hz, 1 H, H-5),
8
7
1
.42 (t, J = 9.6 Hz, 1 H, H-7), 7.45 (d, J = 4.0 Hz, 1 H, H-3), 7.78 (t, J =
0.0 Hz, 1 H, H-6), 8.11 (d, J = 4.0 Hz, 1 H, H-2), 8.47 (d, J = 9.6 Hz, 1 H,
H-4), 8.68 (d, J = 10.0 Hz, 1 H, H-8).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F

F
Synthesis
T. Murafuji et al.
Paper
1
3
C NMR (100 MHz, CD OD): δ = 23.1, 24.2 (br s), 49.9, 69.4, 119.1,
(6) (a) Anderson, A. G. Jr.; Gale, D. J.; McDonald, R. N.; Anderson, R.
G.; Rhodes, R. C. J. Org. Chem. 1964, 29, 1373. (b) Klemm, L. H.;
Hudson, B. S.; Lu, J. J. Org. Prep. Proced. Int. 1989, 21, 633.
3
1
19.5, 125.6, 125.9, 135.2, 138.3, 139.0, 139.9, 140.1, 143.8, 172.3.
HRMS (APCI): m/z [M – H]– calcd for C17H18NO : 268.1332; found:
2
2
(c) Loidl, G.; Musiol, H.-J.; Budisa, N.; Huber, R.; Poirot, S.;
68.1334.
Fourmy, D.; Moroder, L. J. Pept. Sci. 2000, 6, 139. (d) Venanzi, M.;
Valeri, A.; Palleschi, A.; Stella, L.; Moroder, L.; Formaggio, F.;
Toniolo, C.; Pispisa, B. Biopolymers 2004, 75, 128. (e) Moroz, Y.
S.; Binder, W.; Nygren, P.; Caputo, G. A.; Korendovych, I. V.
Chem. Commun. 2013, 49, 490. (f) Shao, J.; Korendovych, I. V.;
Broos, J. Amino Acids 2015, 47, 213.
2
-(Azulen-1-yl)-2-(morpholin-4-yl)acetic Acid (4j)
Yield: 104 mg, 0.39 mmol (77%); blue solid; mp 142 °C (dec.).
IR (ATR): 2960, 1620, 1580, 1400, 1360, 1130, 1080 cm–1
.
1
H NMR (400 MHz, CD OD): δ = 2.91 (br s, 2 H, NCHCH ), 3.32 (s, 2 H,
3
2
(
7) (a) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997, 119, 445.
NCHCH ), 3.79–3.84 (m, 4 H, OCH ), 5.21 (s, 1 H, CHCO), 7.35 (t, J = 9.6
2
2
(b) Petasis, N. A.; Akrftopoulou, I. Tetrahedron Lett. 1993, 34,
Hz, 1 H, H-5), 7.42 (t, J = 9.6, Hz, 1 H, H-7), 7.45 (d, J = 3.8 Hz, 1 H, H-3),
.78 (t, J = 9.6 Hz, 1 H, H-6), 8.11 (d, J = 3.8 Hz, 1 H, H-2), 8.47 (d, J = 9.6
Hz, 1 H, H-4), 8.71 (d, J = 9.6 Hz, 1 H, H-8).
583.
7
(
8) (a) Jourdan, H.; Gouhier, G.; Van Hijfte, L.; Angibaud, P.; Piettre,
S. R. Tetrahedron Lett. 2005, 46, 8027. (b) Schlienger, N.; Bryce,
M. R.; Hansen, T. K. Tetrahedron 2000, 56, 10023. (c) Voisin, A.
S.; Bouillon, A.; Lancelot, J.-C.; Lesnard, A.; Oulyadi, H.; Rault, S.
Tetrahedron Lett. 2006, 47, 2165. (d) Candeias, N. R.; Cal, P. M. S.
D.; André, V.; Duarte, M. T.; Veiros, L. F.; Gois, P. M. P. Tetrahe-
dron 2010, 66, 2736. (e) Southwood, T. J.; Curry, M. C.; Hutton,
C. A. Tetrahedron 2006, 62, 236. (f) Cornier, P. G.; Delpiccolo, C.
M. L.; Boggián, D. B.; Mata, E. G. Tetrahedron Lett. 2013, 54,
13
C NMR (100 MHz, CD OD): δ = 44.9, 65.2, 69.9, 119.1, 119.4, 125.6,
3
125.9, 135.4, 138.2, 139.0, 139.9, 140.2, 143.8, 172.3.
HRMS (APCI): m/z [M – H]– calcd for C16H16NO : 270.1136; found:
3
270.1122.
Acknowledgment
4742. (g) Selander, N.; Kipke, A.; Sebelius, S.; Szabó, K. J. J. Am.
This work was supported by JSPS KAKENHI Grant Number 16K05697
to T.M. We are grateful to the Center of Instrumental Analysis,
Yamaguchi University.
Chem. Soc. 2007, 129, 13723. (h) Koolmeister, T.; Södergren, M.;
Scobie, M. Tetrahedron Lett. 2002, 43, 5965. (i) Tao, J.; Li, S. Chin.
J. Chem. 2010, 28, 41. (j) Sridhar, T.; Berrée, F.; Sharma, G. V. M.;
Carboni, B. J. Org. Chem. 2014, 79, 783.
(
9) Fujinaga, M.; Murafuji, T.; Kurotobi, K.; Sugihara, Y. Tetrahedron
Supporting Information
2009, 65, 7115.
(
10) Kurotobi, K.; Miyauchi, M.; Takakura, K.; Murafuji, T.; Sugihara,
Y. Eur. J. Org. Chem. 2003, 3663.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588907.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
(
11) (a) Ito, S.; Kubo, T.; Morita, N.; Matsui, Y.; Watanabe, T.; Ohta,
A.; Fujimori, K.; Murafuji, T.; Sugihara, Y.; Tajiri, A. Tetrahedron
Lett. 2004, 45, 2891. (b) Recently, 2 was synthesized by the
amine-mediated electrophilic borylation of azulene; see:
Bagutski, V.; Del Grosso, A.; Ayuso Carrillo, J.; Cade, I. A.; Helm,
M. D.; Lawson, J. R.; Singleton, P. J.; Solomon, S. A.; Marcelli, T.;
Ingleson, M. J. J. Am. Chem. Soc. 2013, 135, 474.
References
(
(
1) Mann, E.; Kessler, H. Org. Lett. 2003, 5, 4567.
2) (a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
b) Petasis, N. A. Multicomponent Reactions with Organoboron
(
(
12) Mustafizur Rahman, A. F. M.; Murafuji, T.; Shibasaki, T.; Suetake,
K.; Kurotobi, K.; Sugihara, Y. Organometallics 2007, 26, 2971.
13) For the boronate complex obtained from phenylboronic acid
and copper salt in the copper-catalyzed Petasis reaction, see:
Frauenlob, R.; García, C.; Bradshaw, G. A.; Burke, H. M.; Bergin,
E. J. Org. Chem. 2012, 77, 4445.
Compounds, In Multicomponent Reactions; Zhu, J.; Bienaymé, H.,
Eds.; Wiley-VCH: Weinheim, 2005, 199. (c) Candeias, N. R.;
Montalbano, F.; Cal, P. M. S. D.; Gois, P. M. P. Chem. Rev. 2010,
(
110, 6169. (d) Carboni, B.; Berree, F. In Science of Synthesis; Vol.
1; Müller, T. J. J., Ed.; Thieme: Stuttgart, 2014, 219.
(3) Fujinaga, M.; Suetake, K.; Gyoji, K.; Murafuji, T.; Kurotobi, K.;
Sugihara, Y. Synthesis 2008, 3745.
(
14) It has been reported that an intermediate tetracoordinate boro-
nate complex is detected in the protodeboronation of an alkyl
boronate complex, see: Nave, S.; Sonawane, R. P.; Elford, T. G.;
Aggarwal, V. K. J. Am. Chem. Soc. 2010, 132, 17096.
(
4) (a) Meyer, E. A.; Castellano, R. K.; Diederich, F. Angew. Chem. Int.
Ed. 2003, 42, 1210. (b) Aravinda, S.; Shamala, N.; Das, C.;
Sriranjini, A.; Karle, I. L.; Balaram, P. J. Am. Chem. Soc. 2003, 125,
(
15) (a) Shoji, T.; Higashi, J.; Ito, S.; Toyota, K.; Iwamoto, T.; Morita, N.
Eur. J. Org. Chem. 2009, 5948. (b) Sprutta, N.; Maćkowiak, S.;
Kocik, M.; Szterenberg, L.; Lis, T.; Latos-Grażyński, L. Angew.
Chem. Int. Ed. 2009, 48, 3337. (c) Colby, D. A.; Lash, T. D. J. Org.
Chem. 2002, 67, 1031. (d) Asao, T.; Ito, S.; Morita, N. Tetrahedron
Lett. 1988, 29, 2839.
5308.
(5) For recent work, see: (a) Cowper, P.; Jin, Y.; Turton, M. D.;
Kociok-Köhn, G.; Lewis, S. E. Angew. Chem. Int. Ed. 2016, 55,
2564. (b) Shoji, T.; Maruyama, A.; Araki, T.; Ito, S.; Okujima, T.
Org. Biomol. Chem. 2015, 13, 10191.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–F