New approach to asymmetrically substituted methoxypyrazines, derivatives of wine flavors

Article abstract of DOI:10.1016/j.tet.2010.01.088

An original synthetic route to asymmetrically substituted methoxypyrazine (MP) derivatives is described. The first step of the synthesis is achieved by condensation of 1,2-aminoalcohols with Boc-protected aliphatic aminoacids followed by cycloimine formation and aromatization via chlorination. Introduction of methoxy group was then achieved by alkoxy-de-halogenation. The use of primary or secondary aminopropanol enabled the direct and selective introduction of methyl group, in 5- or 6-position, which can be easily functionalized. Aromatization of diketopiperazine, prepared from l-valine and l-glutamic acid dimethyl ester, made possible a direct introduction of a functionalized alkyl chain. These reactions are also suitable for the synthesis of naturally-occurring MPs such as wine flavor components and biologically active substances.

Full text of DOI:10.1016/j.tet.2010.01.088

Tetrahedron 66 (2010) 2463–2469
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
New approach to asymmetrically substituted methoxypyrazines,
derivatives of wine flavors
,
,
,
b
,
b,c
Nicolas Candelon a b, Svitlana Shinkaruk b c, Bernard Bennetau a , Catherine Bennetau-Pelissero
,
*
Marie-Laurence Dumartin a b, Marie Degueil a b, Pierre Babin a
,
,
,b
a CNRS, UMR 5255 ISM, F-33405 Talence, France
b Universite´ de Bordeaux, F-33607, France
c ENITA de Bordeaux, UMRS, F-33175, France
a r t i c l e i n f o
a b s t r a c t
Article history:
An original synthetic route to asymmetrically substituted methoxypyrazine (MP) derivatives is described.
Thefirststepof the synthesisis achieved bycondensation of1,2-aminoalcohols withBoc-protectedaliphatic
aminoacids followed by cycloimine formation and aromatization via chlorination. Introduction of methoxy
group was then achieved by alkoxy-de-halogenation. The use of primary or secondary aminopropanol
enabled the direct and selective introduction of methyl group, in 5- or 6-position, which can be easily
Received 1 October 2009
Received in revised form
19 January 2010
Accepted 26 January 2010
Available online 1 February 2010
functionalized. Aromatization of diketopiperazine, prepared from L-valine and L-glutamic acid dimethyl
ester, made possible a direct introduction of a functionalized alkyl chain. These reactions arealso suitable for
the synthesisof naturally-occurring MPs such as wine flavorcomponents and biologicallyactive substances.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
for the control of MP level, we have investigated different synthetic
approaches to a variety of MP analogues in order to synthesize MPs
Methoxypyrazines (MP), namely 2-isobutyl-3-methoxypyrazine
(IBMP), 2-isopropyl-3-methoxy pyrazine (IPMP), and 2-sec-isobutyl-
3-methoxypyrazine (SBMP) (Fig. 1), have been identified in a wide
range ofmaterialsofvegetalorigin1,2 andareparticularlyknowntobe
responsible for the very characteristic green, herbaceous, or vegeta-
tive aromas of Sauvignon blanc and Cabernet Sauvignon wines.3–5
The presence of these compounds may be very pleasing in some
dry white wines, favorably contributing to their herbal/grassy char-
acter, but is often undesirable in red wines. MP levels can have a sig-
nificant impact on wine quality and, as a result, on its market value.
MPs are extremely potent flavor compounds, with particularly
low detection threshold values (1–2 ng/L in water and 5–15 ng/L in
wine and model solution) and the rejection threshold seems to be
around 30 ng/L in water.3,6,7 The final MP level in wine depends on
grape variety and ripening, climate parameters and wine making
practices.5,8,9 During the development of new analytical methods
functionalized with a carboxylic function at 5- or 6-position for
coupling to proteins, and for developing specific antibodies.
In the literature, several alternative syntheses of MP derivatives
have been proposed (Scheme 1). In most of the approaches, an
a-aminoacid amide is condensed with 1,2-dicarbonyl compounds
and good yields were reported when a symmetrical bicarbonyl re-
agent was used.6,10–15 This pathway is not very appropriate for the
preparation of mono-substituted MP derivatives at positions 5- or 6-
because of the formation of different isomers, which are difficult to
separate.14,15 Another approach including the aromatization of
a cyclic dipeptide by chlorination and the subsequent introduction
of methoxy group by alkoxy-de-halogenation, gave a low overall
yield because of the non-selectivity of chlorination.16,17 Different MP
analogues for flavor use were also synthesized by the condensation
of methyl pyruvate and ethylenediamine.18 MPs can be also obtained
by the direct- or side chain alkylation and subsequent nuclear
chlorination of methylpyrazine.19,20 Finally, several novel naturally-
occurring MPs were synthesized by subsequent methoxylation and
Grignard reagent alkylation of 2,6-dichloropyrazines obtained from
pyrazine-N,N0-dioxide.21 In the same work, symmetrically
substituted 2,5-dialkyl MPs were prepared by dimerisation of
O
N
N
O
N
N
O
N
N
IBMP
IPMP
SBMP
a
-azido ketones. This method cannot be applied to the preparation
Figure 1. 2-Alkyl-3-methoxypyrazines present in wine.
of asymmetrically substituted MPs because the dimerisation pro-
cedure yielded a mixture of regio-isomers inseparable by column
chromatography.21 Recently, alternative one-pot pyrazine prepara-
tion involving manganese dioxide-based tandem oxidation of
* Corresponding author. Tel.: þ33 054 000 6275; fax: þ33 054 000 6646.
E-mail address: b.bennetau@ism.u-bordeaux1.fr (B. Bennetau).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.088

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N. Candelon et al. / Tetrahedron 66 (2010) 2463–2469
activation. The oxidation of secondary alcohols 3 and 4 afforded the
corresponding ketones 5 and 6 in 75–80% yields. For this step
TEMPO (tetramethylpiperidinyloxyl radical) mediated oxidation
with household bleach was chosen on green and low cost crite-
ria.23,24 The reaction was generally complete within 45 min and the
crude product was obtained with a sufficient purity to be used
directly for Boc-deprotection, which was achieved by HCl treat-
ment. The quantitative cycloimine formation occurred in anhy-
drous conditions to afford 7 and 8 in 88–90% overall yield from the
corresponding ketones. The aromatization of dihydropyrazinones 7
and 8 via chlorination was achieved by heating with phosphorus
oxychloride and phosphorus pentachloride. Nevertheless, even if in
our case the chlorination was regioselective, this reaction remains
the limiting step because of the need for purification (by vacuum
distillation or by flash chromatography) leading to moderate yields
(40–45%). All attempts to improve the yield were unsuccessful.
Finally, the monochloro-derivatives 9 and 10 were treated with
methanolic sodium methoxide to afford the target 6-methyl
substituted MP derivatives 11 and 12 in 87–90% yield.
It was observed that the intermediate 7 was dehydrogenated to
the corresponding pyrazinone 13 during storage over several days
in the presence of atmospheric oxygen (Scheme 3). As 13 enables
the formation of an ambident anion 14, the methylation reaction
can give both O- and N-alkylation.25 Only N-methylation was ob-
served when potassium salts and dimethyl sulfate were used. The
O-methylation was favored when anion 14 was generated by
treatment with silver carbonate. The site of methylation was
assigned on the basis of 1H and 13C NMR spectra and HMBC cor-
relations (Fig. 2). The signals at 3.47 and at 3.90 ppm were attrib-
uted to N-methyl and O-methyl groups, respectively. IR spectrum of
15 showed strong C]O absorption at 1644 cmꢀ1, which is not
present in the IR spectrum of 11. It seemed to be important for us to
clarify this point because of already-described wrong structure
assignment.12 In our hands, the O-methylation was never selective
and the mixture of 11 and 15 was difficult to separate; only
enriched fractions were obtained either by chromatography or
vacuum distillation.
O
R
NH2
NH2
O
O
R'
R'
O
R
N
N
R'
R'
ref 6,10-15
+
R=Alk
R'=H or Alk
H
O
O
O
H2N
H2N
O
R
N
R'
ref 16,17
O
N
R'
ref 18
+
N
H
O
R
N
R=Alk
R'=H or Alk
O
N
N
N
O
R
N
N
R'
ref19, 20
ref 21
N
O
R
R"
this work
O
R
OH
H2N R'
HO R''
+
NHBoc
commercially available
R'=Me; R"=H
R'=H; R"=Me
R'=R"=H
R=Alk
Scheme 1. Synthetic approaches to MP derivatives.
a
-hydroxyketones, in situ trapping with 1,2-diamines, and basic
aromatization gave relatively good yields22 and could be applied to
MP synthesis. In most cases, the multi-step preparation of starting
materials is needed, leading to considerably decreased overall
yields. Moreover, these methods are not very useful for the synthesis
of asymmetrically substituted functional MP derivatives.
In this study, we describe a new synthetic pathway to asymmet-
rical MP derivatives based on the condensation of 1,2-aminoalcohols
with Boc-protected aliphatic aminoacids allowing the direct in-
troduction of alkyl (i-Bu, i-Pr, s-Bu) groups as well as the unique site
for the subsequent introduction of methoxy group via a chlorination
step (Scheme 1). The direct and selective introduction of a methyl
group in 5- or 6-position enables an easyaccess to an IBMP hapten for
furtherdevelopmentofnew immunologicalmethodsforMPanalysis.
To obtain 5-methyl MP derivatives, reactions of Boc-protected
aliphatic aminoacids with 2-aminopropan-1-ol were also carried
out (Scheme 4). In this case primary alcohols 17–19 obtained in
high yield were oxidized to the corresponding aldehydes 20–22.
These aldehydes turned out to be very unstable and were easily
cyclised in dichloromethane over 24 h to give the corresponding
Boc-protected 3-oxo-3,4-dihydropyrazines 23–25.
For further functionalisation, compound 23 was converted
(Scheme 5) to the corresponding asymmetrically substituted
methoxy-derivative 27 (see below Scheme 7). In the first step, Boc-
2. Results and discussion
2.1. Synthesis of asymmetrically substituted MP derivatives
The synthesis began with the amide bond formation between 1-
aminopropan-2-ol and Boc-protected leucine 1 or valine 2 for the
preparation of IBMP and IPMP parent compounds, respectively
(Scheme 2). The best yields were obtained with N-hydrox-
ysuccinimide compared to HOBt (1-hydroxybenzotriazole)
O
O
O
H
Cl
N
N
MeO
R
N
N
R
R
R
a
c
e
b
O
R
N
N
d
OH
N
H
N
H
NH
Boc
NH
OH
NH
O
R
Boc
Boc
1
3 (90%)
4 (75%)
5 (90%)
6 (80%)
7 (88%)
8 (77%)
9 (44%)
11 (87%)
12 (78%)
R = i-Bu
R = i-Pr 2
10 (20%)
Scheme 2. Reagents and conditions: (a) 1-aminopropan-2-ol, DCC, NHS (or HOBt), CH2Cl2; (b) household bleach, TEMPO, NaHCO3, CH2Cl2; (c) i. HCl, CH2Cl2, ii. Et3N, Et2O, 4 Å
molecular sieves; (d) POCl3, PCl5; (e) NaOMe, MeOH.
M+
N
Me
H
N
H
N
O
N
N
MeO
N
N
O
O
O
storage
O -methylation
N
14
N
7
N
13
15
11
Conversion
Reagents and conditions:
K2CO3, Me2SO4, acetone, RT
tBuOK, Me2SO4, THF, RT
Ag2CO3, MeI, toluene, 50°C
97%
100%
23%
3%
-
77%
Scheme 3. Methylation of pyrazinone.

N. Candelon et al. / Tetrahedron 66 (2010) 2463–2469
2465
2.2. Introduction of a spacer bearing a carboxylic function
3.90 ppm
H
3.47 ppm
H
H
H
H
H
For development of immunological assays of MPs in wine and
grape, the synthesis of functionalized derivatives bearing a car-
boxylic function is required for covalent coupling to carrier pro-
teins. The 5-position was first considered as the best choice for
anchorage because it is the most remote site from the discrimi-
nating 2-alkyl substituents. The synthesis of IBMP hapten 32 is
described in Scheme 7.
O
N
N
O
N
N
7.75 ppm
6.93 ppm
15
11
Figure 2. 1H NMR and HMBC correlations for N- and O-methylated pyrazine
derivatives.
Alkylation of the methyl group of 27 at the benzylic position was
already studied by Otah;17 the benzylic carbanion was generated
using potassium diisopropylamide (KDA) and then quenched with
2-bromoethyl tetrahydropyranyl ether. However, in our hands,
using KDA with bromoacetaldehyde diethylacetal was unsuccess-
ful. Therefore, we next examined the benzylic alkylation with
superbases. Heavy alkali metal alkoxides have been described as
dramatically increasing the reactivity of organolithium compounds
(more than 106).26,27 The alkylation of 27 was achieved in the
presence of i-Pr2NH/n-BuLi/t-BuOK and the expected alkylated
pyrazine 30 was obtained in 70% yield. The terminal carboxylic acid
function was generated by the hydrolysis of acetal 30, under acidic
conditions (trifluoroacetic acid/chloroform/water),28 followed by
an oxidation with potassium permanganate, under basic conditions
to provide the target hapten 32 in 42% yield from 27.
H
N
O
O
O
O
R
R
R
R
a
b
c
OH
N
H
N
H
NH
Boc
NH
OH
NH
O
N
Boc
Boc
Boc
17
20
23
(82%)
(77%)
(99%)
R = i-Bu
R = s-Bu
R = i-Pr
1
16
2
18 (76%)
19 (86%)
21 not isolated
22 not isolated
24 (49%)
25 (43%)
Scheme 4. Reagents and conditions: (a) 2-aminopropan-1-ol, DCC, NHS, CH2Cl2; (b)
household bleach, TEMPO, NaHCO3, CH2Cl2; (c) spontaneous cyclisation, 24–36 h.
H
O
R
N
Cl
N
N
MeO
R
N
N
a
b
Given that the synthesis of i-Pr chloro-derivative required for
IPMP hapten preparation gave a modest yield, we attempted a di-
rect introduction of a linker functionalized with a carboxylic group
via the aromatization of a cyclic dipeptide cyclo(Val-Glu) 34
(Scheme 8).
N
R
Boc
23
26 (23%)
27 (80%)
Scheme 5. Reagents and conditions: (a) POCl3, PCl5; (b) NaOMe, MeOH.
The diketopiperazine 34 was prepared from L-valine and L-glu-
tamic acid dimethyl ester hydrochloride29 using a reported pro-
cedure.30 The chlorination of 34 could not be achieved
regioselectively and resulted in a mixture of a dichloropyrazine 36
and both monochloropyrazines 36 and 37. The isolation of
3-chloroderivative 37 was performed by preparative HPLC and gave
a yield of 7%. Finally the methoxylation and deprotection of ter-
minal carboxylic function were achieved by treatment with sodium
methoxide and afforded the IPMP hapten 38 in 81% yield.
Both haptens 32 and 38 were coupled to bovine serum protein
(BSA) to afford the corresponding immunogenic hapten–protein
conjugates for antibody production.
deprotection, chlorination and aromatization reactions were ach-
ieved simultaneously with classical chlorinating agents POCl3–PCl5
and the chloro-derivatives 26 was obtained in 23% yield after
purification.
In both synthetic pathways (Schemes 2 and 4) the yields and
purities of the intermediates were generally better for i-Bu and s-Bu
series compared to the i-Pr derivatives.
In a similar manner, our new synthetic approach was applied to
the synthesis of naturally-occurring IBMP. The coupling Boc–leu-
cine with aminoethanol gave the alcohol 28, which was trans-
formed to 29 without any isolation of intermediates. In the same
manner as above, 29 was chlorinated and methoxylated. After only
one purification procedure by distillation, IBMP was obtained in
10% overall yield (Scheme 6), that is, comparable to previously
described IBMP preparation.11
3. Conclusion
In this study, we have described an original synthetic route to
asymmetrically substituted MP derivatives based on the conden-
sation of 1,2-aminoalcohols with Boc-protected aliphatic amino-
acids. The pathway utilized commercially available inexpensive
starting materials and involved three to five steps with a few pu-
rifications. The direct and selective introduction of methyl group in
5 or 6 position on the pyrazine ring was performed using primary
or secondary aminopropanols, respectively. The methyl group was
then easily functionalized to afford an IBMP hapten for further use
in the development of immunological methods for MP quantifica-
tion in agricultural commodities. Our synthetic pathway was also
validated by the preparation of naturally-occurring IBMP and
proved to be competitive compared to previously published
syntheses.11
H
O
O
R
N
R
a
b
c
N
H
1
IBMP
NH
OH
N
Boc
Boc
28
29
R = i-Bu
(81%)
(54%)
(24%)
Scheme 6. Reagents and conditions: (a) 2-aminoethanol, DCC, NHS, CH2Cl2;
(b) i. household bleach, TEMPO, NaHCO3, then spontaneous cyclisation during the
storage in CH2Cl2 for 24 h; (c) i. POCl3, PCl5; ii. NaOMe, MeOH.
OEt
OEt
O
O
a
c
b
MeO
R
N
MeO
R
N
N
MeO
R
N
N
27
OH
N
30 (70%)
31 (90%)
32 (66%)
R = i-Bu
Scheme 7. Reagents and conditions: (a) KDA, BuLi, THF, BrCH2CH(OEt)2; (b) CF3COOH, CHCl3, H2O; (c) KMnO4, Na2CO3, H2O.

2466
N. Candelon et al. / Tetrahedron 66 (2010) 2463–2469
O
H
N
O
O
O
a
b
O
O
OH
NH2
HN
N
H
O
NH2
L-Val
O
O
O
33
34 (36%)
O
O
c
O
O
O
O
Cl
N
N
N
Cl
N
MeO
N
N
d
O
O
O
OH
+
+
N
Cl
Cl
N
35 (25%)
36 (10%)
37 (7%)
38 (81%)
Scheme 8. Reagents and conditions: (a) ClCOOCCl3, THF; (b) Et3N, THF, CH2Cl2; (c) i. POCl3, PCl5, ii. HPLC separation; (d) NaOMe in MeOH, then H2O.
Furthermore, our approach presents a special interest for the
(CDCl3,
d
(ppm)): 0.90 (d, 3J¼7 Hz, 3H, CH(CH3)2), 0.92 (d, 3J¼7 Hz,
synthesis of other MP derivatives like recently identified novel MP
metabolites,31 as well as for the synthesis of known biologically
active compounds like Arglecin17 or Argvalin.16 It could be useful
for the preparation of deuterated standards12,32 and for the syn-
thesis of pyrazine-like flavoring agents.
3H, CH(CH3)2), 1.15 (d, 3J¼7 Hz, 3H, CHOHCH3), 1.40 (s, 9H, C(CH3)3),
1.60 (m, 1H, CH(CH3)2), 1.64 (m, 2H, CH2CH(CH3)2), 3.15 (m, 1H,
NHCH2),3.41 (m, 1H, NHCH2), 3.90, (1H, CHOH), 4.10 (m, 1H,
NCHCO), 4.99 (s, 1H, OH), 5.25 (s, 1H, NH), 7.05 (s, 1H, NH). 13C NMR
(CDCl3,
d (ppm)): 20.8 (CH3), 21.1 (CH3), 22.2 (CH3), 25.2 (CH), 28.6
(CH3), 41.6 (CH2), 47.3 (CH2), 52.6 (CH), 64.5 (CH), 79.9 (C), 156.3 (C),
4. Experimental
4.1. General
174.4 (C). IR (n
(cmꢀ1)): 3437, 1539. HRMS (ESIþ) m/z calcd for
C14H28N2O4, 311.1942 [MþNa]þ; found, 311.1948.
The procedure described above for 3 was employed for the
synthesis of isopropyl analogue 4 using Boc-valine and 1-amino-
propan-2-ol; compounds 17–19 and 29 were synthesized likewise
using corresponding Boc-protected aminoacid and 2-amino-
propan-1-ol or 2-aminoethanol, respectively.
Chemical reagents and solvents were purchased from Sigma
Aldrich Chemical Co. (Saint Quentin Fallavier, France), Alfa Aesar.
(Bisheim, France), or Acros Organics France (Noisy, France). All
moisture sensitive reactions were performed under an argon at-
mosphere in ovendried or flame-dried glassware.
Instruments. Melting points were determined with a Stuart Sci-
entific melting point apparatus SMP3 and are uncorrected. 1H and
13C NMR spectra were recorded with a Bruker AC-300 FT (1H,
300 MHz; 13C, 75 MHz) or with a Bruker AC-250 (1H, 250 MHz; 13C,
4.2.2. N2-(tert-Butoxycarbonyl)-N-(2-hydroxypropyl)valinamide
(4). Brown oil, yield 75%. 1H NMR (CDCl3,
d (ppm)): 0.90 (d,
3J¼7 Hz, 3H, CH(CH3)2), 0.93 (d, 3J¼7 Hz, 3H, CH(CH3)2), 1.18 (d,
3J¼7 Hz, 3H, CHOHCH3), 1.43 (s, 9H, C(CH3)3), 2.10 (m, 1H,
CH(CH3)2), 3.11 (m, 1H, CH2), 3.37 (m, 1H, CH2), 3.93–3.88 (m, 2H,
NHCHCO, CHOH), 5.16 (s, 1H, NH), 6.66 (m, 2H, NH, OH). 13C NMR
63 MHz) using TMS as an internal standard. The chemical shifts (d)
and coupling constants (J) are respectively expressed in parts per
million and hertz. IR spectra were recorded with a Perkin–Elmer
Paragon 1000 FTIR spectrophotometer. Merck silica gel 60 (70–
230 mesh, 0.063–0.200 mm) was used for flash chromatography.
Thin-layer chromatography (TLC) was performed using TLC plates
(CDCl3,
d (ppm)): 18.3 (CH3), 19.7 (CH3), 21.0 (CH3), 28.7 (CH3), 31.1
(CH), 47.4 (CH2), 60.8 (CH), 67.3 (CH), 80.6 (C), 156.6 (C), 173.2 (C). IR
(n
(cmꢀ1)): 3430, 1539. HRMS (ESIþ) m/z calcd for C13H26N2O4,
297.1784 [MþNa]þ; found, 297.1791.
(0.25 mm, particle size 15
m
m, pore size 60 Å) purchased from SDS
4.2.3. N2-(tert-Butoxycarbonyl)-N-(2-hydroxy-1-methyl-
(Peypin, France). TLC plates were run in the same solvent system as
flash chromatography. The spots were visualized with a UV lamp.
Mass spectra were acquired by the CESAMO (Bordeaux, France) on
a QStar Elite mass spectrometer (Applied Biosystems). The in-
strument was equipped with an electrospray ionization (ESI) source
and spectra were recorded in the positive mode. The electrospray
needle was maintained at 4500 V and operated at room tempera-
ethyl)leucinamide (17). Brown oil, yield 82%. 1H NMR (CDCl3,
d
(ppm)): 0.87 (d, 3J¼7 Hz, 3H, CH(CH3)2), 0.89 (d, 3J¼7 Hz, 3H,
CH(CH3)2),1.18 (d, 3J¼7 Hz, 3H, CHCH3),1.40 (s, 9H, C(CH3)3),1.65 (m,
3H, CH2CH, CH2CH), 3.40 (m, 1H, CH2OH), 3.58 (m, 2H, CH2OHCH,
CH2OH), 4.00 (m, 2H, OH, COCHNH), 5.35 (m, 1H, NH), 6.80 (m, 1H,
NH). 13C NMR (CDCl3,
d
(ppm)): 16.8 (CH3), 22.2 (CH3), 23.5 (CH3),
25.0 (C), 28.8 (CH3), 41.5 (CH2), 47.5 (CH), 53.6 (CH), 66.9 (CH2), 80
ture. Samples were introduced by injection through a 10
mL sample
(C), 156.2 (C), 173.0 (C). IR (n
(cmꢀ1)): 3435, 1648. HRMS (ESIþ) m/z
loop into a 200
m
L minꢀ1 flow of methanol from the LC pump.
calcd for C14H28N2O4Na, 311.1941 [MþNa]þ; found, 311.1947.
4.2. Chemical synthesis
4.2.4. N2-(tert-Butoxycarbonyl)-N-(2-hydroxy-1-methyl-
ethyl)isoleucinamide (18). Brown oil, yield 76%. 1H NMR (CDCl3,
4.2.1. N2-(tert-Butoxycarbonyl)-N-(2-hydroxypropyl)leucinamide
(3). A solution of DCC (2.88 g, 14 mmol) in dichloromethane
(50 mL) was added dropwise to an ice-cooled solution of N-(tert-
butoxycarbonyl)leucine (3 g, 13 mmol) and N-hydroxysuccinimide
(1.61 g, 14 mmol) in dichloromethane (50 mL). The reaction mix-
ture was allowed to warm at room temperature, stirred for 4 h and
filtered. A solution of 1-aminopropan-2-ol (2.9 g, 39 mmol) in
dichloromethane (10 mL) was added to the filtrate. The mixture
was stirred overnight and washed with water (100 mL). The
aqueous layer was extracted with dichloromethane (2ꢁ50 mL).
Combined organic layers were washed with water (50 mL) and
brine (50 mL), dried over magnesium sulfate, filtered, and con-
centrated under reduced pressure to give 3 as a brown oil (3.37 g;
90%). It was used for the next step without any purification. 1H NMR
d
(ppm)): 0.85 (t, 3J¼7 Hz, 3H, CH2CH3), 0.89 (d, 3J¼7 Hz, 3H,
CHCH3), 1.11 (d, 3J¼7 Hz, 3H, NHCHCH3), 1.37 (s, 9H, C(CH3)3), 1.65
(m, 3H, CH2CH, CH2CH), 3.50 (m, 2H, CH2OH), 3.86 (m, 2H,
CH2OHCH, NHCHCO), 5.47 (m, 1H, NH), 5.50 (m, 1H, NH), 7.01 (m,
1H, OH). 13C NMR (CDCl3,
d
(ppm)): 11.1 (CH3),15.3 (CH3),16.8 (CH3),
24.7 (CH2), 28.2 (CH3), 37.0 (CH), 47.6 (CH), 60.0 (CH), 66.2 (CH2),
79.7 (C), 155.9 (C), 172.2 (C). IR (n
(cmꢀ1)): 3450, 1539. HRMS (ESIþ)
m/z calcd for C14H28N2O4Na, 311.1941 [MþNa]þ; found, 311.1949.
4.2.5. N2-(tert-Butoxycarbonyl)-N-(2-hydroxy-1-methyl-
ethyl)valinamide (19). Brown oil, yield 86%. 1H NMR (CDCl3,
d
(ppm)): 0.90 (d, 3J¼7 Hz, 3H, CHCH3), 0.94 (d, 3J¼7 Hz, 3H,
CHCH3), 1.16 (d, 3J¼7 Hz, 3H, CH3), 1.43 (s, 9H, C(CH3)3), 2.10 (m, 1H,
CH), 3.50 (m, 2H, CH2OH), 3.85 (m, 1H, CH), 4.10 (m, 1H, CH), 5.30

N. Candelon et al. / Tetrahedron 66 (2010) 2463–2469
2467
(m, 2H, NH), 6.50 (m, 1H, OH). 13C NMR (CDCl3,
16.8 (CH3), 17.4 (CH3), 28.3 (CH3), 33.7 (CH), 47.8 (CH), 66.3 (CH),
d
(ppm)): 14.2 (CH3),
4.2.10. tert-Butyl 2-isobutyl-5-methyl-3-oxo-3,4-dihydropyrazine-
1(2H)-carboxylate (23). Brown oil, yield 99%. 1H NMR (CDCl3,
66.7 (CH), 80.1 (C), 156.1 (C), 172.1 (C). IR (
n
(cmꢀ1)): 3436, 1647.
d
(ppm)): 0.95 (t, 3J¼7 Hz, 6H, CH(CH3)2), 1.35 (m, 3H, CH(CH3)2,
HRMS (ESIþ) m/z calcd for C13H27N2O4, 275.1965 [MþH]þ; found,
CH2), 1.48 (s, 9H, C(CH3)3), 1.85 (s, 3H, CH3), 4.80–4.58 (m, 1H, CHN),
275.1978.
6.00 (s, 1H, C]CH), 8.10 (s, 1H, NH). 13C NMR (CDCl3,
d (ppm)): 17.0
(CH3), 21.0 (CH3), 22.0 (CH), 28.1 (CH3), 41.1 (CH2), 54.9 (CH), 80.9
(C), 103.7 (C), 118.5 (CH), 152.3 (C), 168.8 (C).
4.2.6. N2-(tert-Butoxycarbonyl)-N-(2-hydroxyethyl)leucinamide
(28). 2-Aminoethan-1-ol was used. Brown oil, yield 81%. 1H NMR
(CDCl3,
d
(ppm)): 0.86 (d, 3J¼7 Hz, 3H, CHCH3), 0.89 (d, 3J¼7 Hz, 3H,
4.2.11. tert-Butyl 2-sec-butyl-5-methyl-3-oxo-3,4-dihydropyrazine-
CHCH3), 1.37 (s, 9H, CH3), 1.50 (m, 3H, CH2CH), 3.40 (m, 2H, CH2),
3.64 (m, 2H, CH2), 4.10 (m, 1H, CH), 4.73 (s, 1H, OH), 5.45 (m, 1H,
1(2H)-carboxylate (24). Brown oil, yield 49% from 18. 1H NMR
(CDCl3,
d
(ppm)): 0.84 (t, 3J¼7 Hz, 3H, CH2CH3), 0.91 (d, 3J¼7 Hz, 3H,
NH), 7.26 (m, 1H, NH). 13C NMR (CDCl3,
d
(ppm)): 22.3 (CH3), 23.3
(CH3), 25.1 (CH), 28.7 (CH3), 41.9 (CH2), 42.7 (CH2), 53.7 (CH), 61.9
(CH2), 80.4 (C), 156.4 (C), 174.4 (C). IR (
(cmꢀ1)): 3530, 1738.
CHCH3), 1.42 (s, 9H, C(CH3)3), 1.79 (m, 2H, CH2), 1.77 (s, 3H, CH3),
4.29–4.46 (d, 1H, CHN), 6.00 (s, 1H, C]CH), 8.78 (s, 1H, NH). 13C
n
NMR (CDCl3,
d (ppm)): 12.3 (CH3), 16.0 (CH3), 21.5 (CH3), 25.2 (CH2),
26.1 (CH3), 37.6 (CH), 55.9 (CH), 81.8 (C), 104.6 (C), 119.2 (CH), 151.5
4.2.7. N2-(tert-Butoxycarbonyl)-N-(2-oxopropyl)leucinamide
(5). NaHCO3 (6 g, 71 mmol) and TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy, free radical, 0.2 g, 1.3 mmol) were added to an ice-
(C), 169.9 (C). IR (n
(cmꢀ1)): 3430, 1676. HRMS (ESIþ) m/z calcd for
C14H24N2O3Na, 291.1679 [MþNa]þ; found, 291.1676.
cooled solution of
3
(7.6 g, 26 mmol) in dichloromethane
4.2.12. tert-Butyl 2-isopropyl-5-methyl-3-oxo-3,4-dihydropyrazine-
(100 mL). Household bleach (4.8% NaOCl, 100 mL) was then added
dropwise and the resulting mixture was stirred at room tempera-
ture overnight. The product was extracted with dichloromethane
(3ꢁ100 mL). Combined organic layers were washed with water
(3ꢁ50 mL) and brine (50 mL), dried over magnesium sulfate, fil-
tered, and concentrated under reduced pressure to give 5 as an oil
(7 g, 90%). It was used for the next step without any purification. 1H
1(2H)-carboxylate (25). Brown oil, yield 43%. 1H NMR (CDCl3,
d
(ppm)): 0.85 (d, 3J¼7 Hz, 3H, CH(CH3)2), 0.92 (d, 3J¼7 Hz, 3H,
CH(CH3)2), 1.42 (s, 9H, C(CH3)3), 1.47 (m, 1H, CH), 1.76 (s, 3H, CH3),
4.20–4.36 (d,1H, CHN), 6.00 (s,1H,C]CH), 8.55 (s, 1H, NH). 13C NMR
(CDCl3,
d (ppm)): 19.3 (CH3), 21.7 (CH3), 28.3 (CH3), 32.6 (CH), 55.6
(CH), 79.9 (C), 102.7 (C), 118.6 (CH), 153.3 (C), 168.9 (C).
NMR (CDCl3,
d
(ppm)): 0.93 (2d, 3J¼7 Hz, 6H, CH(CH3)2), 1.38 (s, 9H,
4.2.13. tert-Butyl 2-isobutyl-3-oxo-3,4-dihydropyrazine-1(2H)-car-
C(CH3)3), 1.58–1.40 (m, 3H, CH2CH(CH3)2), 2.14 (s, 3H, COCH3), 4.08
(d, 3J¼5 Hz, 2H, COCH2), 4.18 (m, 1H, NHCHCO), 5.27 (s, 1H, NH), 7.18
boxylate (29). Brown oil, yield 54%. 1H NMR (CDCl3,
d (ppm)): 0.98
(d, 3J¼7 Hz, 3H, CH(CH3)2), 1.01 (d, 3J¼7 Hz, 3H, CH(CH3)2), 1.50 (s,
(s, 1H, NH). 13C NMR (CDCl3,
d (ppm)): 21.8 (CH3), 22.9 (CH3), 24.6
9H, C(CH3)3), 1.66 (m, 3H, CH2CH), 4.66 (t, 3J¼7 Hz, 1H, CH), 5.70
(CH), 27.1 (CH3), 28.2 (CH3), 41.4 (CH2), 49.7 (CH2), 52.9 (CH), 79.8
(t, 3J¼5 Hz, 1H, CH), 6.14 (d, 3J¼5 Hz, 1H, CH), 8.03 (s, 1H, NH). 13
C
(C), 155.7 (C), 173.2 (C), 203.2 (C). IR (
n
(cmꢀ1)): 1539. HRMS (ESIþ)
NMR (CDCl3, d (ppm)): 22.5 (CH3), 22.6 (CH3), 24.4 (CH), 28.2 (CH3),
m/z calcd for C14H26N2O4Na, 309.1790 [MþNa]þ; found, 309.1783.
The NaOCl/TEMPO system was used for the oxidation of primary
and secondary alcohols 4, 17–19, and 28 into corresponding alde-
hydes and ketones 6, 20–22, and 29.
38.7 (CH2), 55.7 (CH), 82.0 (C), 108.2 (CH), 108.6 (CH), 152.3 (C),
168.2 (C).
4.2.14. 3-Isobutyl-5-methyl-3,6-dihydropyrazin-2(1H)-one (7). A
solution of 5 (2 g, 6.9 mmol) in dichloromethane (20 mL) was
bubbled with HCl gas at room temperature over 4 h. The solvent
was removed under reduced pressure to afford a white residue,
which was immediately placed under inert atmosphere. Anhydrous
diethylether (30 mL), freshly distilled Et3N (1.4 g, 14 mmol), and
activated 4 Å molecular sieves (1 g) were added and the mixture
was stirred at room temperature overnight. After filtration, the
diethylether was evaporated under reduced pressure to give the
target compound as a brown oil (1.15 g, 88%), of sufficient purity for
4.2.8. N2-(tert-Butoxycarbonyl)-N-(2-oxopropyl)valinamide
(6). Colorless oil, yield 80%. 1H NMR (CDCl3,
d (ppm)): 0.87 (d,
3J¼7 Hz, 3H, CH(CH3)2), 0.93 (d, 3J¼7 Hz, 3H, CH(CH3)2), 1.41 (s, 9H,
C(CH3)3), 2.11 (m, 1H, CH(CH3)2), 2.17 (s, 3H, CH3CO), 4.01 (m, 1H,
COCHNH), 4.13 (d, 3J¼5 Hz, 2H, COCH2), 5.19 (s, 1H, NH), 6.87 (s, 1H,
NH). 13C NMR (CDCl3,
d (ppm)): 17.6 (CH3), 19.2 (CH3), 27.3 (CH3),
28.3 (CH3), 30.9 (CH2), 49.6 (CH2), 59.7 (CH), 79.9 (C), 155.8 (C),
171.9 (C), 202.8 (C). IR (n
(cmꢀ1)): 2929,1539. HRMS (ESIþ) m/z calcd
for C13H24N2O4Na, 295.1628 [MþNa]þ; found, 295.1637.
use in the following reaction. 1H NMR (CDCl3,
d (ppm)): 0.91 (2d,
3J¼7 Hz, 6H, CH(CH3)2), 1.45 (m, 1H, CHCH2CH), 1.68 (m, 1H,
CHCH2CH), 1.91 (m, 1H, CH(CH3)2), 2.08 (s, 3H, CH3), 3.95 (s, 2H,
4.2.9. N2-(tert-Butoxycarbonyl)-N-(1-methyl-2-oxoethyl)-
leucinamide (20). TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy,
free radical, 0.02 g, 0,135 mmol) and saturated NaHCO3 solution
(27,5 mL) were added to an ice-cooled solution of 17 (3.88 g,
13.45 mmol) in dichloromethane (50 mL). Household bleach (4.8%
NaOCl, 35 mL) was then added dropwise and the resulting mixture
was stirred at room temperature during 4 h. Organic layer was
washed with saturated NH4Cl solution (3ꢁ50 mL), dried over
magnesium sulfate, and filtered. Organic layer was concentrated
under reduced pressure to give 20 as an oil (2.77 g, 77%). 1H NMR
NHCH2), 4.06 (m, 1H, CHCO), 8.11 (br s, 1H, NH). 13C NMR (CDCl3,
d
(ppm)): 22.0 (CH3), 23.1 (CH3), 23.9 (CH), 24.6 (CH3), 42.7
(CH2), 45.6 (CH2), 59.1 (CH), 161.4 (C), 171.6 (C). IR (
1710.
n
(cmꢀ1)): 3308,
4.2.15. 3-Isopropyl-5-methyl-3,6-dihydropyrazin-2(1H)-one
(8). The same procedure as described for 7 was used for cyclisation
of 6 and gave 8 as a brown oil in 77% yield. 1H NMR (CDCl3,
d
(ppm)): 0.81 (d, 3J¼7 Hz, 6H, CH(CH3)2), 2.05 (s, 3H, CH3), 2.40 (m,
(CDCl3,
d
(ppm)): 0.89 (d, 3J¼7 Hz, 3H, CH(CH3)2), 0.90 (d, 3J¼7 Hz,
1H, CH(CH3)2), 3.95 (s, 2H, CH2), 4.02 (s, 1H, COCHNH), 7.53 (s, 1H,
3H, CH(CH3)2), 1.35 (d, 3J¼7 Hz, 3H, CHCH3), 1.45 (s, 9H, C(CH3)3),
1.60 (m, 3H, CH2, CH2CH), 4.17 (m, 1H, NHCHCO), 4.42 (m, 1H,
NHCHCHO), 5.11 (m, 1H, NH), 7.00 (m, 1H, NH), 9.50 (s, 1H, CHO).
HRMS (ESIþ) m/z calcd for C14H26N2O4Na, 309.1784 [MþNa]þ;
found, 309.1796.
NH). 13C NMR (CDCl3,
d (ppm)): 19.3 (CH3), 23.8 (CH3), 32.6 (CH),
46.9 (CH2), 65.5 (CH), 161.8 (C), 170.5 (C).
4.2.16. 2-Chloro-3-isobutyl-5-methyl-pyrazine (9). A mixture of 7
(3.78 g, 22.5 mmol), POCl3 (6.7 g, 43.7 mmol), and PCl5 (5 g,
24 mmol) was stirred at 100 ꢂC for 4 h. Excess POCl3 was removed
by distillation under reduced pressure. A saturated aqueous K2CO3
solution was added to the residue until pH 8–9. The aqueous layer
The aldehydes 20–22 cyclised spontaneously during storage in
dichloromethane over 24 h to give the corresponding Boc-
protected 3,4-dihydropyrazines 23–25 in quantitative yield.

2468
N. Candelon et al. / Tetrahedron 66 (2010) 2463–2469
was extracted with dichloromethane (3ꢁ30 mL). Combined organic
layers were washed with brine (50 mL), dried over magnesium
sulfate, filtered, and concentrated under reduced pressure to give 9
as a brown oil (1.82 g; 44%), of sufficient purity for use in the fol-
(CDCl3, d (ppm)): 21.6 (CH3), 22.4 (CH3), 25.6 (CH), 43.4 (CH2), 120.6
(CH), 132.6 (C), 156.9 (C), 159.2 (C).
4.2.24. 5-(3,3-Diethoxy-propyl)-2-isobutyl-3-methoxy-pyrazine
(30). Toasolution of t-BuOK (1.12 g,10 mmol)in 40 mLofanhydrous
THF, i-Pr2NH (1.01 g, 10 mmol) was added with a syringe for 15 min,
at room temperature. n-Butyllithium (2 M/Hexane, 10 mmol, 5 mL)
was added at ꢀ50 ꢂC then stirred at ꢀ30 ꢂC for 30 min. A solution of
2-isobutyl-3-methoxy-5-methylpyrazine27 (1,6 g, 8.9 mmol)inTHF
(13 mL) was added at ꢀ50 ꢂC. The mixture was stirred at ꢀ30 ꢂC for
2 h, and bromoacetaldehyde diethylacetal (2 g,10 mmol) was added.
This solution was stirred for 3 h at ꢀ30 ꢂC, left overnight at room
temperature then concentrated underreduced pressure. The residue
was hydrolyzed with 30 mL of NH4Cl and extracted with dieth-
ylether (3ꢁ20 mL). The combined organic extracts were with
washed distilled water (2ꢁ0 mL) and dried over MgSO4 and con-
centrated in vacuo to yield 30 as a viscous oil (1.7 g, 70%). This
product was used without further purification. 1H NMR (CDCl3,
lowing reaction. 1H NMR (CDCl3,
d
(ppm)): 0.92 (d, 3J¼6 Hz, 6H,
CH(CH3)2), 2.26 (m, 1H, CH(CH3)2), 2.47 (s, 3H, CCH3), 2.74 (d,
3J¼7 Hz, 2H, CCH2), 8.00 (s, 1H, CH). 13C NMR(CDCl3,
d (ppm)): 19.9
(CH3), 22.2 (CH3), 28.2 (CH), 43.3 (CH2), 140.9 (CH), 146.3 (C), 151.2
(C), 154.4 (C). IR (n
(cmꢀ1)): 2925, 732.
The same procedure was used for chlorination of 8 and 23, 24 to
give corresponding products 10, 26.
4.2.17. 2-Chloro-3-isopropyl-5-methyl-pyrazine (10). Brown oil,
yield 20%. 1H NMR (CDCl3,
d
(ppm)): 1.27 (d, 3J¼6 Hz, 6H, CH(CH3)2),
2.51 (s, 3H, CCH3), 3.55–3.40 (m, 1H, CH(CH3)2), 8.02 (s, 1H, CH). 13
C
NMR (CDCl3,
d (ppm)): 20.7 (CH3), 20.8 (CH3), 31.6 (CH), 140.4 (CH),
145.0 (C), 151.5 (C), 158.8 (C).
4.2.18. 3-Chloro-2-isobutyl-5-methylpyrazine (26). Brown oil, yield
d
(ppm)): 0.89 (d, 6H, CH(CH3)2),1.18 (t, 3J¼6 Hz, 6H, OCH2CH3),1.98–
23%. 1H NMR (CDCl3,
d
(ppm)): 0.95 (d, 3J¼6 Hz, 6H, CH(CH3)2), 2.18
2.18 (m 3H, CH(CH3)2, CH2CH(OCH2CH3)2), 2.62 (s, 2H, NCCH2), 2.72
(t, 3J¼6 Hz, 2H, NCCH2), 3.64–3.67and 3.51–3.48(2q, 3J¼6 Hz, 4H,
OCH2CH3), 3.91 (s, 3H, OCH3), 4.54 (t, 3J¼6 Hz, 1H, CH(OCH2CH3)2),
(m,1H, CH(CH3)2), 2.51 (s, 3H, CCH3), 2.80 (d, 3J¼6 Hz, 2H, CH2), 8.29
(s, 1H, CH). 13C NMR (CDCl3,
d (ppm)): 20.6 (CH3), 22.4 (CH3), 28.0
(CH), 43.1 (CH2), 141.6 (CH), 147.0 (C), 151.0 (C), 152.3 (C).
7.88 (s,1H, C]CH). 13C NMR (CDCl3,
d (ppm)): 15.3 (CH3), 22.5 (CH3),
27.5 (CH), 29.6 (CH2), 32.6 (CH2), 40.9 (CH2), 53.1 (CH3), 61.1 (CH2),
102.3 (CH), 134.1 (CH), 144.2 (C), 150.4 (C), 158.1 (C). Anal. Calcd for
C16H28N2O3: C, 64.83; H, 9.52; N, 9.45; O, 16.19. Found: C, 65.08; H,
4.2.19. 3-Isobutyl-2-methoxy-5-methyl-pyrazine (11). A solution of
9 (1.35 g, 7.3 mmol) in anhydrous methanol (5 mL) was added to
a solution of sodium methoxide (freshly prepared by addition of
sodium (0.84 g, 36.5 mmol) to 10 mL of anhydrous methanol). The
mixture was refluxed for 5 h. The residue obtained after elimina-
tion of the methanol by distillation was triturated with diethylether
and filtered. The filtrate was evaporated to afford the target com-
pound as a light brown oil (1.13 g, 87%), of 95% purity by NMR. 1H
9.37; N, 9.48; O, 16.07. IR (n
(cmꢀ1)): 2956, 1171.
4.2.25. 3-(5-Isobutyl-6-methoxy-pyrazin-2-yl)-propionaldehyde
(31). To a stirred solution of trifluoroacetic acid (0.8 mL) in distilled
water (0.8 mL), a solution of 5-(3,3-diethoxy-propyl)-2-isobutyl-3-
methoxy-pyrazine (1.04 g, 3.5 mmol) in chloroform (3.2 mL) was
added at room temperature then warmed to 50 ꢂC for 5 h. Then, the
mixture was quenched by the addition of NaHCO3 (powder, up to
pH¼7.5) and extracted with chloroform (3ꢁ20 mL). The combined
organic layers were washed with brine (2ꢁ10 mL), dried over
MgSO4 and evaporated to dryness to give 31 (0.7 g, 90%) as a col-
orless oil, which was used without further purification. 1H NMR
(CDCl3, d (ppm)): 0.90 (d, 6H, CH(CH3)2), 2.04–2.18 (m, 3J¼6 Hz, 1H,
CH(CH3)2), 2.62 (d, 3J¼6 Hz, 2H, NCCH2), 2.86 (t, 3J¼6 Hz, 2H,
NCCH2), 3.03 (t, 3J¼6 Hz, 2H, OCCH2), 3.88 (s, 3H, OCH3), 7.92 (s, 1H,
NMR (CDCl3,
d
(ppm)): 0.91 (d, 3J¼6 Hz, 6H, CH(CH3)2), 2.24 (m, 1H,
CH(CH3)2), 2.41 (s, 3H, CH3), 2.63 (d, 3J¼7 Hz, 2H, CH2), 3.90 (s, 3H,
OCH3), 7.74 (s, 1H, CH). 13C NMR (CDCl3,
d (ppm)): 20.1 (CH3), 22.2
(CH3), 27.6 (CH), 41.1 (CH2), 53.1 (CH3), 136.4 (CH), 143.6 (C), 146.1
(C), 157.0 (C). IR (n
(cmꢀ1)): 2956, 1172. HRMS (ESIþ) m/z calcd for
C10H17N2O, 181.1335 [MþH]þ; found, 181.1337.
The same procedure was employed for the methoxylation of
10 and 26 into corresponding alkylated methoxypyrazines 12 and
27.
C]CH), 9.90 (s, 1H, HCO). 13C NMR (CDCl3,
d (ppm)): 22.5 (CH3),
4.2.20. 3-Isopropyl-2-methoxy-5-methyl-pyrazine (12). Brown oil,
26.7.(CH), 27.5(CH2), 40.9 (CH2), 42 (CH2), 53.3 (CH3), 134.0 (CH),
144.8 (C), 148.6 (C), 158.1 (C), 201.4 (C). Anal. Calcd for C12H18N2O2:
C, 64.84, H, 8.16, N, 12.60, O, 14.40. Found: C, 65.12, H, 8.21, N, 12.52,
O, 14.15. HRMS (ESIþ) m/z calcd for C12H19N2O2, 223.1441 [MþH]þ;
found, 223.1440.
yield 78%. 1H NMR (CDCl3,
d
(ppm)): 1.20 (d, 3J¼6 Hz, 6H, CH(CH3)2),
2.30 (s, 3H, CH3), 3.47 (m, 1H, CH(CH3)2), 3.90 (s, 3H, OCH3), 7.70 (s,
1H, CH). 13C NMR (CDCl3,
d (ppm)): 20.7 (CH3), 20.8 (CH3), 32.0 (CH),
53.7 (CH3), 136.6 (CH), 144.1 (C), 151.9 (C), 159.2 (C).
4.2.21. 2-Isobutyl-3-methoxy-5-methylpyrazine (27). Brown oil,
4.2.26. 3-(5-Isobutyl-6-methoxy-pyrazin-2-yl)-propanoic
(32). A solution of Na2CO3 (0.17 g) in water (1.7 mL) was added to
3-(5-isobutyl-6-methoxy-pyrazin-2yl)-propionaldehyde (1.7 g,
acid
yield 80%. 1H NMR (CDCl3,
d
(ppm)): 0.95 (d, 3J¼6 Hz, 6H, CH(CH3)2),
2.18 (m, 1H, CH(CH3)2), 2.39 (s, 3H, CH3), 2.65 (d, 3J¼6 Hz, 2H, CH2),
3.90 (s, 3H, OCH3), 7.90 (s, 1H, CH). 13C NMR (CDCl3,
d
(ppm)): 20.6
7.6 mmol) under stirring at room temperature. The mixture was
cooled down to 4 ꢂC and a solution of KMnO4 (1.52 g, 0.96 mmol) in
water (30 mL) was added. After stirring for 4 h at 4 ꢂC and 24 h at
room temperature, the mixture was filtered off and the aqueous
phase was concentrated in vacuo. The solid residue was dissolved in
a few drops of water and acidified (pH¼5) with citric acid. The
resulting solution was extracted with chloroform (3ꢁ5 mL), dried
over with MgSO4, and concentrated to dryness yielding compound
32 (1.2 g, 66%). 1H NMR (CDCl3, d (ppm)): 0.89 (br s, 6H, CH(CH3)2),
1.98–2.18 (m, 1H, CH(CH3)2), 2.62 (br s, 2H, NCCH2), 2.78 (br s, 2H,
NCCH2), 3.01 (br s, 2H, OCCH2), 3.87 (s, 3H, OCH3), 7.91(s, 1H,
C]CH). 13C NMR (CDCl3, d (ppm)): 22.4 (CH3), 27.5 (CH), 29.3 (CH2),
29.6 (CH2), 40.5 (CH2), 53.2 (CH3), 133.4 (CH), 144.2 (C), 149.6 (C),
158.1 (C), 178.2 (C). Anal. Calcd for C12H18N2O3: C, 60.48, H, 7.61, N,
(CH3), 22.4 (CH3), 27.5 (CH), 40.8 (CH2), 53.2 (CH3), 134.3 (CH), 143.8
(C), 147.4 (C), 157.9 (C). HRMS (ESIþ) m/z calcd for C10H17N2O,
181.1335 [MþH]þ; found, 181.1337.
4.2.22. 2-Isobutyl-3-methoxypyrazine (IBMP). Brown oil, yield 24%.
1H NMR (CDCl3,
d
(ppm)): 0.88 (d, 3J¼6 Hz, 3H, CH(CH3)2), 0.90 (d,
3J¼6 Hz, 3H, CH(CH3)2), 1.95 (m, 1H, CH), 2.64 (d, 3J¼6 Hz, 2H, CH2),
3.89 (s, 3H, OCH3), 7.87 (d, 3J¼2.5 Hz, 1H, CH), 7.98 (d, 3J¼2.5 Hz, 1H,
CH). IR (n
(cmꢀ1)): 2956,1172. HRMS (ESIþ) m/z calcd for C10H17N2O,
181.1335 [MþH]þ; found, 181.1332.
4.2.23. 3-Isobutyl-5-methylpyrazin-2(1H)-one (13). 1H NMR (CDCl3,
d
(ppm)): 0.94 (d, 3J¼6 Hz, 6H, CH(CH3)2), 2.10 (m, 1H, CH), 2.27 (s,
3H, CH3), 2.66 (d, 3J¼7 Hz, 2H, CH2), 6.95 (s, 1H, CH). 13C NMR
11.75, O, 20.14. Found: C, 60.73, H, 7.58, N, 11.69, O, 19.98. IR (n

N. Candelon et al. / Tetrahedron 66 (2010) 2463–2469
2469
(cmꢀ1)): 3510, 1711, 1177. HRMS (ESIþ) m/z calcd for C12H19N2O3,
239.1390 [MþH]þ; found, 239.1398.
after elimination of the methanol by distillation was triturated with
diethylether and filtered. The filtrate was evaporated to afford
crude methyl 3-(5-isopropyl-6-methoxypyrazin-2-yl)propanoate
in 90% yield, which was characterized by NMR. 1H NMR (CDCl3,
4.2.27. Methyl 3-(5-isopropyl-3,6-dioxopiperazin-2-yl)propanoate
(34). A solution of 33 (15.8 g, 110 mmol), prepared as previously
described30 in dry THF (130 mL), was added dropwise to a stirred
d
(ppm)): 1.23 (d, 3J¼7 Hz, 6H, 2CH3), 2.77 (t, 3J¼6 Hz, 2H, CH2), 3.01
(t, 3J¼6 Hz, 2H, CH2), 3.30 (m,1H, CH), 3.69 (s, 3H, OCH3), 3.92 (s, 3H,
solution of
L
-glutamic acid dimethyl ester hydrochloride29 (23.2 g,
OCH3), 7.92 (s, 1H, Har). 13C NMR (CDCl3,
d (ppm)): 20.8 (CH3), 29.3
110 mmol) and triethylamine (24 g, 240 mmol) in dry dichloro-
methane (120 mL) at ꢀ80 ꢂC. The resulting suspension was stirred
for 3 h at ꢀ70 ꢂC and then allowed to warm to room temperature.
The precipitated triethylamine hydrochloride was removed by fil-
tration, and the filtrate was concentrated in vacuo. The crude res-
idue was heated to reflux in toluene (300 mL) for 12 h. Upon
cooling, the precipitate was filtered off and dehydrated in vacuo to
give a white power (10 g, 36%, mp 175 ꢂC). 1H NMR (DMSO-d6,
(CH2), 29.5 (CH), 32.8 (CH2), 51.9 (CH3), 53.4 (CH3), 134.1 (CH), 148.8
(C), 149.7 (C), 157.3 (C), 173.6 (C).
The crude obtained after elimination of the methanol was dis-
solved in water (5 mL), stirred for 15 min at room temperature,
then acidified with citric acid up to pH 3. Extraction with dieth-
ylether gave 38 as a colorless oil (1.2 g, 81% from 37). 1H NMR
(CDCl3,
d
(ppm)): 1.21 (d, 3J¼7,5 Hz, 6H, 2CH3), 2.27 (t, 3J¼6 Hz, 2H,
CH2), 3.01 (t, 3J¼7.1 Hz, 2H, CH2), 3.29 (m, 1H, CH), 3.90 (s, 3H,
d
(ppm)): 1.22 (d, 3J¼7 Hz, 3H, CH3), 1.33 (d, 3J¼7 Hz, 3H, CH3), 2.35
OCH3), 7.95 (s, 1H, Har). 13C NMR (CDCl3,
d(ppm)): 20.8 (CH3), 29.1
(m, 2H, CH2), 2.53 (m, 1H, CH), 2.80 (m, 2H, CH2), 3.97 (s, 3H, OCH3),
4.05 (m, 1H, CH), 4.26 (m, 1H, CH), 8.48 (s, 1H, NH), 8.57 (s, 1H, NH).
(CH2), 29.6 (CH), 32.8 (CH2), 53.7 (CH3), 133.9 (CH), 149.1 (C), 149.8
(C), 157.6 (C), 178.6 (C). IR (n
(cmꢀ1)): 3408, 1713. HRMS (ESIþ) m/z
13C NMR (DMSO-d6,
d
(ppm)): 18,3 (CH3), 19.8 (CH3), 30.1 (CH2),
calcd for C11H17N2O3, 225.1233 [MþH]þ; found, 225.1236.
30.5 (CH2), 32.3 (CH), 52.6 (OCH3), 54.3 (CH), 60.6 (CH), 168.4 (C),
168.9 (C), 174.1 (C).
Acknowledgements
4.2.28. Methyl
3-(6-chloro-5-isopropylpyrazin-2-yl)propanoate
This work was funded by Conseil Interprofessionnel des Vins de
Bordeaux (CIVB). We gratefully thank Russell Wallace for careful
reading of the manuscript.
(37). Compound 34 (2 g, 8.2 mmol) was slowly added to the mix-
ture of POCl3 (5 mL, 54 mmol), and PCl5 (1 g, 4.8 mmol). The mix-
ture was stirred at 110 ꢂC for an hour. Excess of POCl3 was removed
by distillation under reduced pressure. A saturated aqueous K2CO3
solution was added to the residue until pH 8–9. The aqueous layer
was extracted with diethylether (3ꢁ30 mL). Combined organic
layers were washed with brine (50 mL), dried over magnesium
sulfate, filtered, and concentrated to dryness yielding a mixture of
35, 36, and 37. Compound 35 was separated by flash chromatog-
raphy (pentane/diethylether 6:4, Rf¼0.9).
References and notes
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d
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The mixture of 36 and 37 (Rf¼0.55) recovered was then separated
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4.2.30. Methyl
3-(3-chloro-5-isopropylpyrazin-2-yl)propanoate
(36). Brown oil, yield 10%. 1H NMR (CDCl3,
d (ppm)): 1.26 (d,
3J¼6.8 Hz, 6H, CH(CH3)2), 2.79 (t, 3J¼6.8 Hz, 2H, CH2), 3.01 (m, 1H,
CH), 3.18 (t, 3J¼6.8 Hz, 2H, CH2), 3.66 (s, OCH3), 8.24 (s, 1H, Har). 13
C
NMR (CDCl3, d (ppm)): 20.6 (CH3), 28.5 (CH2), 29.9 (CH2), 30.6 (CH),
51.7 (CH3), 144.6 (CH), 144.6 (C), 150.4 (C), 157.6 (C), 172.8 (C).
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4.2.31. Methyl 3-(6-chloro-5-isopropylpyrazin-2-yl)propanoate
(37). After elimination of solvents, the target compound 37 was
obtained as a light brown oil (0,14 g, 7%). 1H NMR (CDCl3,
d (ppm)):
1.26 (d, 3J¼5.7 Hz, 6H, CH(CH3)2), 2.79 (t, 3J¼6.8 Hz, 2H, CH2), 3.06
(t, 3J¼6.8 Hz, 2H, CH2), 3.47 (m,1H, CH), 3.66 (s, 3H, OCH3), 8.34 (s,1H,
Har).13CNMR(CDCl3,
d(ppm)):20.9(CH3), 28.9(CH2), 29.9(CH2), 32.4
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(CH), 52.8 (CH3), 141.6 (CH), 1456.8 (C), 150.5 (C), 159.9 (C),173.1 (C).
4.2.32. 3-(5-Isopropyl-6-methoxy-pyrazin-2-yl)-propanoic acid (38). A
solution of 37 (1.6 g, 6.6 mmol) in anhydrous methanol (5 mL) was
added to a solution of sodium methoxide (freshly prepared by
careful addition of sodium (0.76 g, 33 mmol) to 10 mL of anhydrous
methanol). The mixture was refluxed for 5 h. The crude obtained