Straightforward access to enantioenriched pyrazyl alcohols using chiral organomagnesiates

Article abstract of DOI:10.1016/j.tetasy.2012.11.003

The clean iodine-metal exchange of iodopyrazine and subsequent enantioselective addition of the intermediate pyrazyl magnesiate to aldehydes using ((R,R)-TADDOLate)Bu₂MgLi₂ is reported. New chiral pyrazylalcohols were obtained in ena

Full text of DOI:10.1016/j.tetasy.2012.11.003

Tetrahedron: Asymmetry 23 (2012) 1678–1682
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Tetrahedron: Asymmetry
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Straightforward access to enantioenriched pyrazyl alcohols using chiral
organomagnesiates
Olivier Payen a, Floris Chevallier b, Florence Mongin b, Philippe C. Gros a,
⇑
a Groupe SOR, UMR SRSMC, Université de Lorraine, CNRS, Bât Victor Grignard, Boulevard des Aiguillettes, 54506 Vandoeuvre-Lès-Nancy, France
b Équipe Chimie et Photonique Moléculaires, Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS–Université de Rennes 1, Bât. 10A, Case 1003, Campus de Beaulieu, Avenue du
Général Leclerc, 35042 Rennes Cédex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 October 2012
Accepted 8 November 2012
The clean iodine-metal exchange of iodopyrazine and subsequent enantioselective addition of the inter-
mediate pyrazyl magnesiate to aldehydes using ((R,R)-TADDOLate)Bu2MgLi2 is reported. New chiral pyr-
azylalcohols were obtained in enantiomeric excesses of up to 90%.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Heteroaryl carbinols and related compounds are valuable
precursors of biologically relevant molecules1 and chiral ligands
for asymmetric catalysis and kinetic resolution.2 Their preparation
generally involves enantioselective reduction either by hydride
transfer3 or by catalytic hydrogenation4 of the corresponding
heteroarylketones. Diastereoselective syntheses by trapping
2-pyridyllithium intermediates with naturally occurring optically
active ketones have also been reported.5 In contrast, direct access
to chiral heteroaryl alcohols via reaction between a heteroaromatic
metallic derivative and a prochiral carbonyl electrophile is still an
underdeveloped topic.6
We first investigated the reactivity of iodopyrazine10 towards a
range of butylmagnesiate containing chiral ligands (Fig. 1).
The chiral alcohol or diol was first deprotonated using n-BuLi
(1 and 2 equiv for the alcohol and diol, respectively) in THF and
the resulting alkoxide was reacted successively with n-BuMgCl
(1 equiv) and n-BuLi (1 equiv). The magnesiates were then reacted
with iodopyrazine under various conditions to perform the I–Mg
exchange, followed by a trapping step using p-anisaldehyde as
the electrophile to obtain the enantioenriched pyrazylcarbinols
(Scheme 1, Table 1).
In preliminary experiments, we first checked the reactivity of
Bu3MgLi towards iodopyrazine. While 0.33 equiv of this reagent
was reported to promote complete I–Mg exchange,11 in our hands
all butyl chains could not be transferred and 0.5 equiv was neces-
sary to complete the reaction. The same behaviour was observed
with ((R,R)-TADDOLate)Bu2MgLi2. In fact, no exchange occurred
using 0.5 equiv of the reagent (run 1); 1 equiv was needed for
the exchange to occur cleanly after 1 h (run 2). This suggested that
one butyl chain was non-transferable using both Bu3MgLi and
((R,R)-TADDOLate)Bu2MgLi2.
In this context, the use of chiral organomagnesiates7 is a prom-
ising route that allows us to build a stabilized bimetallic reagent
with saturated metal coordination sites thus avoiding side aggrega-
tion and the subsequent loss of chirality.8 Pyrazine derivatives are
heterocyclic compounds of great interest but the number of deriv-
atives synthesized via metallation processes is much lower than for
pyridines due to their higher electrophilicity.9 Furthermore, the
presence of two nitrogen atoms at the 1,4-positions can perturb
the coordination in the chiral intermediates and thus the enantiose-
lective process. To the best of our knowledge, no chiral pyrazyl alco-
hol has been synthesized yet from a pyrazyl halide and an aldehyde.
In addition, only pyrazyl o-tolyl methanol has been reported using a
ruthenium-catalysed asymmetric hydrogenation of pyrazyl o-tolyl
ketone.4c Herein we report our investigations on the first reaction
of iodopyrazine with chiral organomagnesiates and the synthesis
of new enantioenriched pyrazyl alcohols.
These stoichiometries contrast with those used with
2-bromopyridine which underwent the exchange quantitatively
using 0.33 equiv of Bu3MgLi7a or 0.5 equiv of ((R,R)-
TADDOLate)Bu2MgLi2.7 Such
a
difference could result from
stereoelectronic features exhibited by the pyrazine nucleus. Due
to its -deficient character, pyrazyl was expected to be less coordi-
p
nated to the central magnesium metal than pyridyl, thus making
the transfer of the remaining magnesiate butyl chain more
difficult. The quantitative exchange obtained using 1 equiv of
((R,R)-TADDOLate)Bu2MgLi2 followed by trapping with p-anisalde-
hyde gave the expected alcohol 2a with enantiocontrol in most
cases. The enantiomeric excesses were found to be highly
⇑
Corresponding author. Tel.: +33 383684979; fax: +33 383684785.
E-mail address: philippe.gros@univ-lorraine.fr (P.C. Gros).
0957-4166/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2012.11.003

O. Payen et al. / Tetrahedron: Asymmetry 23 (2012) 1678–1682
1679
LH* =
OH
OH
OH
OH
OH
HO
OH
(-)-menthol
(R)-BINOL
(R)-BIPHEN H2
(S,S)-hydrobenzoin
Ar
Ar
Me
Me
(R,R)-TADDOL, Ar= Ph
T1, Ar=
O
OH
T2, Ar=
OH
Ar
O
Ar
Figure 1. Chiral ligands used herein.
Li
Bu
Bu
OH
OH
O
1) n-BuLi (2 equiv)
solvent 1, -5°C, 20 min
Mg
Li
*
*
2) n-BuMgCl (1 equiv)
O
-5°C, 20 min
3) n-BuLi (1 equiv)
LH*
-5°C, 20 min
L*Bu2MgLi2
N
1)
N
I
N
OMe
L*Bu2MgLi2
(n equiv,
solvent 2, -10 °C, 1 h
prepared in
solvent 1)
N
2) p-anisaldehyde (n' equiv)
-100°C, 1 h
OH
2a
3) Hydrolysis
Scheme 1. Preparation of chiral organomagnesiates and reaction with iodopyrazine.
H
N
O
Ar
attack of Re face
(S)
Ar
O
N
O
O
O
OH
Mg
N
Li
major
N
Scheme 2. Proposed intermediate for enantioselective addition of pyrazylmagnesiate.
dependent on the aldehyde stoichiometry and solvent employed.
Increasing of the organometallic/aldehyde ratio improved the
enantioselectivity. Indeed, ee’s ranging from 40% to 80% (runs
2–4) (however with a yield decrease from 51% to 8%) were ob-
tained by decreasing the amount of aldehyde from 1.5 to 1 equiv.
An increase in the aldehyde amount (2.5 equiv) was found to be
detrimental for both the ee and the yield (run 5). Good ee (76%)
was obtained in a THF-toluene mixture (magnesiate prepared in
THF and iodopyrazine added in toluene) but a poor yield was
obtained (run 6). Performing the whole reaction in toluene and
keeping 1.5 equiv of aldehyde gave 2a in 60% ee with an acceptable
33% yield. Other chiral ligands were screened in this solvent.
Substitution of the (R,R)-TADDOL phenyl groups by a para-tert-
butyl or two (3,5-) methyls (runs 9 and 10) ensured a less efficient

1680
O. Payen et al. / Tetrahedron: Asymmetry 23 (2012) 1678–1682
Table 1
Run
LH⁄ (n equiv)
Solvent 1
Solvent 2
n0 equiv
2aa,b (%)
eec (%)
e
1
2
3
4
5
6
7
8
(R,R)-TADDOL (0.5)
(R,R)-TADDOL (1)
(R,R)-TADDOL (1)
(R,R)-TADDOL (1)
(R,R)-TADDOL (1)
(R,R)-TADDOL (1)
(R,R)-TADDOL (1)
(R,R)-TADDOL (1)
T1 (1)
T2 (1)
(R)-BINOL (1)
(R)-BIPHEN H2 (1)
(S,S)-Hydrobenzoin (1)
(ꢀ)-Menthol (1)
(R,R)-TADDOL (1)
THF
THF
THF
THF
THF
THF
THF
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
THF
THF
THF
1.5
1.5
1.2
1.0
2.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.5
—
—
51
11
8
7
8
26
33
35
27
26
23
27
7
40
74
80
66
76
32
60
48
40
4
THF
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
9
10
11
12
13
14
15
32d
rac
8
22
72
a
I–Mg exchange complete unless stated otherwise.
Yield after column chromatography.
Determined by chiral GC.
The opposite enantiomer was obtained.
No exchange, starting material recovered.
b
c
d
e
and (ꢀ)-menthol (run 14). Interestingly, BIPHEN H2 gave the other
enantiomer in 32% ee (run 12). Finally, 72% ee could be obtained by
using ((R,R)-TADDOLate)Bu2MgLi2 and 2.5 equiv of aldehyde (run
15). A larger excess (5 equiv) did not improve the results.
Table 2
Synthesis of chiral pyrazyl alcohols
1) ((R,R)-TADDOLate)Bu2MgLi2
N
N
In order to investigate the scope of the new enantioselective
process, the conditions determined in Table 1, run 15 were applied
to the preparation of various chiral pyrazyl alcohols (Table 2). The
effect of the stereoelectronic features of the aldehydes was found
to be critical. The substitution of the ring with electron-donating
groups markedly improved the ee’s which increased as a function
of the donating ability. Indeed, ee’s increased from 72% to 86%
when p-dimethylamino was used instead of the p-methoxy group
(runs 1 and 2). In contrast, the electron withdrawing p-CF3 group
led to much lower enantiocontrol (12% ee, run 3). The introduction
of a substituent at the ortho position gave even better results with
methoxy and dimethylamino groups. o-Anisaldehyde and
o-dimethylaminobenzaldehyde led to alcohols 2d and 2e in very
good ee’s of 80% and 90% (runs 4 and 5). It is worthy of note that
the enantioselectivity of the magnesiate procedure is comparable
to that of hydrogenation since 2d was obtained in 84% ee via asym-
metric hydrogenation of the corresponding ketone.4c Non-coordi-
nating and less electron-donating methyl and chloro substituents
gave lower ee’s (64% and 46%, respectively, runs 6 and 7). The
enantiocontrol was also efficient in the naphthalene series since
2-methoxy-1-naphthaldehyde gave alcohol 2h in 78% ee (run 8).
Finally, pivalaldehyde led to a racemic alcohol, which indicated
that the aromatic part of the aldehyde was essential to ensure
enantiodiscrimination (run 9).
N
N
(1 equiv), toluene
-30 to -10°C, 1 h
R
2) RCHO (2.5 equiv)
-100°C, 1 h
I
OH
3) Hydrolysis
2a-i
Run
1
R
Product, yielda (%)
eeb (%)
72
2a, 22
2b, 17
2c, 14
OMe
NMe2
CF3
2
3
86
12
MeO
Me2N
Me
4
5
6
7
2d, 25
2e, 10
2f, 40
2g, 13
80
90
64
46
A
coordination intermediate explaining the enantiocontrol
upon the addition of pyrazylmagnesiates to aldehydes is depicted
in Scheme 2. After the reaction of iodopyrazine with ((R,R)-
TADDOLate)Bu2MgLi2, a butyl group is transferred and replaced
by a pyrazyl ligand on magnesium. In agreement with the model
proposed by Seebach and co-workers,12 the pseudo axially ori-
ented phenyl group of (R,R)-TADDOL sterically forces the aldehyde
to preferentially display its Re-face for attack of the carbonyl by the
pyrazyl ligand.13 A major enantiomer with the the S configuration
is then expected. This was verified by 1H NMR of the corresponding
Mosher esters.14 The increase in enantiomeric excess when coordi-
nating substituents are present ortho to the carbonyl of the
aldehyde could be explained by an additional chelation of the
lithium cation. The consequence is a decrease of rotational freedom
and a better enantiocontrol. This interaction is expected to be
highly favoured in a non-coordinating solvent like toluene used
Cl
8
9
2h, 11
2i, 15
78
MeO
t-Bu
rac
a
Yield after column chromatography.
Determined by chiral GC.
b
enantiocontrol (48 and 40% ee, respectively). (R)-BINOL gave 2a in
almost racemic form (run 11) as did (S,S)-hydrobenzoin (run 13)

O. Payen et al. / Tetrahedron: Asymmetry 23 (2012) 1678–1682
1681
here. It can be also be seen that the stability of the chiral interme-
diate should be dependent on the electronic character of the
aldehyde. The reaction of the chiral pyrazyl intermediate is ex-
pected to be slower with an electron rich aldehyde (e.g. bearing
a methoxy group) thus allowing the depicted coordination to occur
and formation of the adequate complex.
acetate. The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The crude product was then
purified by column chromatography over silica gel and analysed by
chiral GC to determine enantiomeric ratios.
4.2.1. (S)-(4-Methoxyphenyl)(pyrazin-2-yl)methanol 2a11
2-Iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv), p-anisalde-
hyde (0.221 mL, 1.82 mmol, 2.5 equiv). Yield: 25% (40 mg). Pale
yellow oil. Rf = 0.38 (ethyl acetate/cyclohexane: 8/2). ee = 72%.
3. Conclusion
½
a 2D7:5
ꢂ
¼ þ43:9 (c 1.0, CHCl3). Chiral GC conditions: (135 °C, pres-
We have achieved the first synthesis of enantioenriched
pyrazyl alcohols using
TADDOLate)Bu2MgLi2 performed
a
chiral organomagnesiate. ((R,R)-
clean iodine–magnesium
sure = 60 kPa, flow rate: 120 mL/min), tR1 = 20.22 min (major enan-
tiomer), tR2 = 22.92 min. 1H NMR (200 MHz, CDCl3) d 3.81 (s, 3H),
4.49 (s, 1H), 5.84 (s, 1H), 6.90 (d, J = 8.5 Hz, 2H), 7.31 (d,
J = 8.5 Hz, 2H), 8.48 (s, 1H), 8.52 (s, 1H), 8.60 (s, 1H) ppm. 13C
NMR (62.5 MHz, CDCl3) d 55.2, 73.7, 114.2 (2C), 128.2 (2C),
134.0, 142.8, 143.2, 143.4, 157.2, 159.5 ppm. HRMS calcd for
a
exchange while transferring its chiral ligand to pyrazine organo-
metallics, then inducing enantioselective addition. Despite moder-
ate yields, due to the low temperature of the aldehyde trapping
step, a range of new chiral pyrazyl alcohols have been prepared
with up to 90% enantiomeric excess. The best results were ob-
tained with electron rich aromatic aldehydes. This concomitant
generation of a sensitive pyrazyl organometallic under non-cryo-
genic conditions and the enantioselective addition to carbonyl
derivatives using an all-in-one reagent is a promising concept for
the synthesis of chiral heterocyclic compounds.
C12H12N2NaO2 [M+Na]: 239.0791. Found: 239.0790.
4.2.2. (S)-(4-Dimethylaminophenyl)(pyrazin-2-yl)methanol 2b
2-Iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv),
4-(dimethylamino)benzaldehyde (0.272 g, 1.82 mmol, 2.5 equiv)
as a toluene solution (2 mL). Yield: 17% (0.028 g). Yellow oil.
Rf = 0.34 (ethyl acetate/cyclohexane: 8/2). ee: 86%. ½a D29
¼ þ72:9
ꢂ
4. Experimental section
4.1. General
(c 1.0, CHCl3). Chiral GC conditions: (140 °C, pressure = 60 kPa, flow
rate:
120 mL/min),
tR1 = 40.02 min
(major
enantiomer),
tR2 = 43.27 min. 1H NMR (200 MHz, CDCl3) d 2.93 (s, 6H), 4.25 (s,
1H), 5.78 (s, 1H), 6.69 (d, J = 8.6 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H),
8.44 (s, 1H), 8.49 (s, 1H), 8.59 (s, 1H) ppm. 13C NMR (62.5 MHz,
CDCl3) d 40.5 (2C), 74.0, 112.5 (2C), 127.9 (2C), 129.6, 142.7,
142.9, 143.4, 150.4, 157.6 ppm. HRMS calcd for C13H15N3NaO
[M+Na]: 252.1107. Found: 252.1106.
All reactions were carried out under an argon atmosphere. All
glassware were flame-dried before use. All reagents, ligands and
aldehydes were commercially available and used as received, ex-
cept for 2-iodopyrazine15 and 2-dimethylamino-benzaldehyde.16
THF and toluene were purified by a solvent purification device.
Column chromatography was performed on silica gel Si 60
4.2.3. (Pyrazin-2-yl)(4-(trifluoromethyl)phenyl)methanol 2c
(63–200 lm). Solvents were used as purchased. Thin-layer chro-
2-Iodopyrazine
(0.150 g,
0.728 mmol,
1.0 equiv),
p-
matography (TLC) was performed on silica gel 60 with fluorescent
indicator UV254 (0.2 mm) with UV detection. 1H and 13C NMR spec-
tra were obtained on a 200 MHz spectrometer. Coupling constants
are reported in Hertz (Hz). For reactions performed in the asym-
metric version, enantiomeric ratios were measured with a gas
(trifluoromethyl)benzaldehyde (0.249 mL, 1.82 mmol, 2.5 equiv).
Yield: 14% (0.026 g). Orange oil. Rf = 0.43 (ethyl acetate/cyclohex-
ane: 8/2). ee: 12%. ½a D27
¼ þ2:0 (c 1.0, CHCl3). Chiral GC conditions:
ꢂ
(135 °C, pressure = 60 kPa, flow rate: 120 mL/min), tR1 = 8.06 min
(major enantiomer), tR2 = 9.73 min. 1H NMR (200 MHz, CDCl3) d
4.53 (s, 1H), 5.93 (s, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.62 (d,
J = 8.0 Hz, 2H), 8.52 (s, 2H), 8.59 (s, 1H) ppm. 13C NMR
(62.5 MHz, CDCl3) d 73.5, 125.8 (q, JCF = 4.4 Hz), 127.1 (4C), 130.5
(d, JCF = 40 Hz), 143.0, 143.3, 143.8, 145.6, 155.9 ppm.19F NMR
(235 MHz, CDCl3) d ꢀ62.6 (s) ppm. HRMS calcd for C12H10F3N2O
[M+H]+: 255.0740. Found: 255.0748.
chromatograph equipped with
a CP-Chirasil-DexCB column
(5 m ꢁ 0.25 mm) using nitrogen as the carrier gas (Injection port
temperature: 250°C, detector temperature: 275°C). Optical rota-
tions of the enantiomers (k = 589 nm, c 1.0 g/100 mL, CHCl3) were
measured by a MCP 300 Anton Paar Polarimeter.
4.2. Procedure for the I–Mg exchange reaction using
((R,R)-TADDOLate)Bu2MgLi2 and the synthesis of
enantioenriched pyrazylcarbinols
4.2.4. (S)-(2-Methoxyphenyl)(pyrazin-2-yl)methanol 2d
2-Iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv), o-anisaldehyde
(0.248 g, 1.82 mmol, 2.5 equiv) as a toluene solution (2 mL). Yield:
25% (0.039 g). Orange paste. Rf = 0.38 (ethyl acetate/cyclohexane:
In a Schlenk tube, flushed under argon, (R,R)-TADDOL (0.340 g,
0.728 mmol, 1.0 equiv) was dissolved in anhydrous toluene
(C = 0.08 M). Next, n-BuLi (1.4 M in hexanes, 2.0 equiv) was slowly
added at ꢀ10°C. After stirring at this temperature for 20 min,
n-BuMgCl (2.0 M in THF, 1.0 equiv) was added at ꢀ10°C and the
resulting solution was stirred for additional 20 min at the same
temperature. n-BuLi (1.4 M in hexanes, 1.0 equiv) was added at
ꢀ10°C and the mixture was stirred for 20 min at ꢀ10°C.
2-Iodopyrazine (0.150 g, 1.0 equiv) was then added at ꢀ30°C. The
mixture was stirred for 1 h between ꢀ30 and ꢀ10°C. The reaction
was monitored by TLC (eluent: ethyl acetate/cyclohexane 8/2). The
medium was then cooled to ꢀ100°C and the aldehyde (1.82 mmol,
2.5 equiv) was added. The mixture was left at ꢀ100°C and stirred
for 2 h. The reaction was quenched with a saturated aqueous
solution of NH4Cl. The aqueous layer was extracted with ethyl
acetate and acidified (pH = 3–4) using a sulphuric acid aqueous
solution. The aqueous solution was then extracted with ethyl
8/2). ee: 80%. ½a D29
¼ þ98:4 (c 1.0, CHCl3). Chiral GC conditions:
ꢂ
(130 °C, pressure = 60 kPa, flow rate: 120 mL/min), tR1 = 13.32 min,
tR2 = 15.01 min (major enantiomer). 1H NMR (200 MHz, CDCl3) d
3.85 (s, 3H), 4.60 (s, 1H), 6.23 (s, 1H), 6.89–7.03 (m, 2H), 7.27–7.41
(m, 2H), 8.46 (s, 1H), 8.50 (s, 1H), 8.70 (s, 1H) ppm. 13C NMR
(62.5 MHz, CDCl3) d 55.3, 69.2, 110.7, 120.9, 127.6, 129.2, 130.0,
142.8, 143.0, 143.6, 156.3, 157.1 ppm. HRMS calcd for
C12H12N2NaO2 [M+Na]: 239.0791. Found: 239.0794.
4.2.5. (S)-(2-Dimethylaminophenyl)(pyrazin-2-yl)methanol 2e
2-Iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv), 2-(dimethyl-
amino)benzaldehyde (0.272 g, 1.82 mmol, 2.5 equiv) as a toluene
solution (4 mL). Yield: 10% (0.017 g). Orange oil. Rf = 0.46 (ethyl
acetate/cyclohexane: 8/2). ee: 90%. ½a D23
¼ þ5:3 (c 1.0, CHCl3).
ꢂ
Chiral GC conditions: (125 °C, pressure = 60 kPa, flow rate:
120 mL/min), tR1 = 16.66 min (major enantiomer), tR2 = 18.81 min.

1682
O. Payen et al. / Tetrahedron: Asymmetry 23 (2012) 1678–1682
1H NMR (200 MHz, CDCl3) d 2.65 (s, 6H), 3.65 (s, 1H), 6.17 (s, 1H),
7.15 (m, 2H), 7.29 (m, 2H), 8.45 (s, 1H), 8.49 (s, 1H), 8.83 (s, 1H)
ppm. 13C NMR (62.5 MHz, CDCl3) d 45.9 (2C), 74.4, 121.9, 125.5,
128.8, 129.1, 136.4, 142.9, 143.1, 143.4, 151.9, 158.6 ppm. HRMS
calcd for C13H15N3NaO [M+Na]: 252.1107. Found: 252.1111.
(major enantiomer). HRMS calcd for
239.0791. Found: 239.0793.
C12H12N2NaO2 [M+Na]:
4.4. General procedure for esterification of chiral
pyrazylcarbinols with (R)-MPA4b,7b
4.2.6. (S)-(Pyrazin-2-yl)(o-tolyl)methanol 2f4c
2-Iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv), o-tolualdehyde
(0.210 mL, 1.82 mmol, 2.5 equiv). Yield: 40% (0.059 g). Pale yellow
oil. Rf = 0.47 (ethyl acetate/cyclohexane: 8/2). ee: 64%.
The alcohol was dissolved in dry CH2Cl2 (Concentration equal to
0.033 M). (R)-Methoxyphenylacetic acid [(R)-MPA] (3.0 equiv),
DMAP (0.2 equiv) and dicyclohexylcarbodiimide (2.0 equiv) were
then added to the solution in a Schlenk tube under argon. The
resulting mixture was stirred for 15 h at room temperature. After
the solvent was removed, the crude residue was directly analysed
by NMR. It consisted of a mixture of (R,S)- and (R,R)-diastereoiso-
mers. The 1H NMR in CDCl3 showed a specific chemical shift for
the H3 proton of pyrazine in each diasteroisomer, the most
shielded corresponding to the (R,R) form.4b For each ester, the
absolute configuration of the major diastereoisomer was (R,S). It
is deduced for each alcohol that the configuration of the major
enantiomer was (S). The chemical shifts of the H-3 protons in the
diastereoisomers are given in chiral product characterization. Data
for the (R)-MPA ester of (S)-(4-methoxyphenyl)(pyrazin-2-yl)
methanol 2a. 1H NMR (200 MHz, CDCl3) d H3 8.06 (R,R), 8.53 (R,S)
ppm.
½
a 3D0
ꢂ
¼ þ41:7 (c 1.0, CHCl3). Chiral GC conditions: (120 °C, pressur-
e = 60 kPa, flow rate: 120 mL/min), tR1 = 18.15 min (major enantio-
mer), tR2 = 20.93 min. 1H NMR (200 MHz, CDCl3) d 2.35 (s, 3H),
4.71 (s, 1H), 6.08 (s, 1H), 7.20–7.22 (m, 3H), 7.29–7.33 (m, 1H),
8.44 (s, 1H), 8.50 (s, 2H) ppm. 13C NMR (62.5 MHz, CDCl3) d 19.4,
71.7, 126.3, 127.3, 128.1, 130.9, 135.9, 139.5, 142.9, 143.0, 143.3,
157.1 ppm. HRMS calcd for C12H13N2O [M+H]+: 201.1022. Found:
201.1020.
4.2.7. (S)-(2-Chlorophenyl)(pyrazin-2-yl)methanol 2g
2-Iodopyrazine
(0.150 g,
0.728 mmol,
1.0 equiv),
2-chlorobenzaldehyde (0.205 mL, 1.82 mmol, 2.5 equiv). Yield:
13% (0.021 g). Yellow oil. Rf = 0.56 (ethyl acetate/cyclohexane: 8/
2). ee: 46%. ½a 2D9
ꢂ
¼ þ61:6 (c 1.0, CHCl3). 1H NMR (200 MHz, CDCl3)
Data for the (R)-MPA ester of (S)-(2-chlorophenyl)(pyrazin-2-yl)
methanol 2g. 1H NMR (200 MHz, CDCl3) d H3 8.22 (R,R), 8.55 (R,S)
ppm.
d 4.69 (s, 1H), 6.37 (s, 1H), 7.29 (t, J = 3.5 Hz, 2H), 7.40–7.51 (m,
2H), 8.53 (s, 1H), 8.56 (s, 1H), 8.64 (s, 1H) ppm. 13C NMR
(62.5 MHz, CDCl3) d 70.2, 127.4, 128.6, 129.4, 129.7, 132.6, 139.1,
143.0, 143.6 (2C), 155.7 ppm. HRMS calcd for C11H9ClN2NaO
[M+Na]: 243.0296. Found: 243.0307.
Acknowledgment
The authors gratefully acknowledge the financial support of
Agence Nationale de la Recherche (ACTIVATE program) to O.P.
4.2.8. (S)-(2-Methoxy-1-naphthyl)(pyrazin-2-yl)methanol (2h)
2-Iodopyrazine
(0.150 g,
0.728 mmol,
1.0 equiv),
References
2-methoxy-1-naphthaldehyde (mL, 1.82 mmol, 2.5 equiv). Yield:
11% (0.021 g). Yellow oil. Rf = 0.37 (ethyl acetate/cyclohexane: 8/
1. (a) Barouh, V.; Dall, H.; Patel, D.; Hite, G. J. Med. Chem. 1971, 14, 834–838; (b)
Rennison, D.; Bova, S.; Cavalli, M. Bioorg. Med. Chem. 2007, 15, 2963–2974.
2. (a) Drury, W. J.; Zimmerman, N.; Keenan, M.; Hayashi, M.; Kaiser, S.; Goddard,
R.; Pfaltz, A. Angew. Chem., Int. Ed. 2004, 43, 70–74; (b) Kang, J.; Kim, H. Y.; Kim,
J. P. Tetrahedron: Asymmetry 1999, 10, 2523–2533; (c) Vedejs, E.; Chen, X. J. Am.
Chem. Soc. 1996, 118, 1809–1810.
3. (a) Bolm, C.; Zehnder, M.; Bur, D. Angew. Chem., Int. Ed. Engl. 1990, 29, 205–207;
(b) Okano, K.; Murata, K.; Ikariya, T. Tetrahedron Lett. 2000, 41, 9277–9280.
4. (a) Ohkuma, T.; Koizumi, M.; Makato, Y.; Noyori, R. Org. Lett. 2000, 2, 1749–
1751; (b) Maerten, E.; Agbossou-Nidercorn, F.; Castanet, Y.; Mortreux, A.
Tetrahedron 2008, 64, 8700–8708; (c) Tao, X.; Li, W.; Ma, X.; Li, X.; Fan, W.; Xie,
X.; Ayad, T.; Ratovelomanana-Vidal, V.; Zhang, Z. J. Org. Chem. 2012, 77, 612–
616.
2). ee: 78%. ½a 2D1
¼ þ61:0 (c 1.0, CHCl3). Chiral GC conditions:
ꢂ
(145 °C, pressure = 60 kPa, flow rate: 120 mL/min), tR1 = 65.41 min
(major enantiomer), tR2 = 73.54 min. 1H NMR (200 MHz, CDCl3) d
3.93 (s, 3H), 6.93 (s, 1H), 7.29–7.45 (m, 3H), 7.82 (d, J = 8.4 Hz,
1H), 7.90 (d, J = 9.2 Hz, 1H), 8.04 (d, J = 8.2 Hz, 1H), 8.45 (s, 1H),
8.56 (s, 2H) ppm. 13C NMR (62.5 MHz, CDCl3) d 56.6, 67.7, 113.2,
121.5, 123.7 (2C), 126.9, 128.7, 129.7, 130.9, 132.2, 142.5, 142.6,
143.1, 155.2, 158.1 ppm. HRMS calcd for C16H14N2NaO2 [M+Na]:
289.0947. Found: 289.0937.
5. (a) Chelucci, G.; Soccolini, F. Tetrahedron: Asymmetry 1992, 3, 1235–1238; (b)
Genov, M.; Kostova, K.; Dimitrov, V. Tetrahedron: Asymmetry 1997, 8, 1869–
1876; (c) Kwong, H.-L.; Lee, W.-S. Tetrahedron: Asymmetry 1999, 10, 3791–
3801.
6. For an example using a lithium superbase, see: Fort, Y.; Gros, P. C.; Rodriguez,
A. L. Tetrahedron: Asymmetry 2001, 12, 2631–2635.
7. (a) Catel, D.; Chevallier, F.; Mongin, F.; Gros, P. C. Eur. J. Org. Chem. 2012, 53–57;
(b) Catel, D.; Payen, O.; Chevallier, F.; Mongin, F.; Gros, P. C. Tetrahedron 2012,
68, 4018–4028.
8. Noyori, R.; Suga, S.; Kawai, K.; Okada, S.; Kitamura, M. Pure Appl. Chem. 1988,
60, 1597–1606.
4.2.9. 2,2-Dimethyl-1-(pyrazin-2-yl)-1-propanol 2i17
2-Iodopyrazine (0.150 g, 0.728 mmol, 1.0 equiv), trimethylacet-
aldehyde (0.198 mL, 1.82 mmol, 2.5 equiv). Yield: 8% (0.010 g). Yel-
low oil. Rf = 0.49 (ethyl acetate/cyclohexane: 8/2). Racemic
product. Chiral GC conditions: (80 °C, pressure = 60 kPa, flow rate:
120 mL/min), tR1 = 15.71 min, tR2 = 19.24 min. 1H NMR (200 MHz,
CDCl3) d 0.94 (s, 9H), 3.66 (s, 1H), 4.45 (s, 1H), 8.49 (d, J = 2.2 Hz,
1H), 8.54 (s, 1H), 8.56 (s, 1H) ppm. 13C NMR (62.5 MHz, CDCl3) d
25.7 (3C), 36.5, 78.9, 142.9, 143.4, 144.4, 155.8 ppm. HRMS calcd
for C9H15N2O [M+H]+: 167.1179. Found: 167.1178.
9. The presence of a second nitrogen atom induces an important decrease of their
LUMO level see: Quéguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J. Adv.
Heterocycl. Chem. 1991, 52, 187–304.
10. Attempts to promote Cl–Mg or Br–Mg exchange of 2-chloro- and 2-
bromopyrazines using Bu3MgLi were unsuccessful, see Ref. 11.
11. Buron, F.; Plé, N.; Turck, A.; Marsais, F. Synlett 2006, 1586–1588.
12. Seebach, D.; Plattner, D. A.; Beck, A. K.; Wang, Y. M.; Hunziker, D.; Petter, W.
Helv. Chim. Acta 1992, 75, 2171–2209.
4.3. Preparation of (R)-(4-methoxyphenyl)(pyrazin-2-yl)meth-
anol (R)-2a using (R)-BIPHEN H2
13. Braun, M. Angew. Chem., Int. Ed. 1996, 35, 519–522.
The procedure used with (R,R)-TADDOL was repeated using
(R)-BIPHEN H2 (0.258 g, 0.728 mmol, 1.0 equiv), 2-iodopyrazine
(0.150 g, 0.728 mmol, 1.0 equiv), p-anisaldehyde (0.133 mL,
14. For methodologies using 1H NMR of Mosher esters see the literature4b,7b and
Seco, J. M.; Quinoa, E.; Riguera, R. Chem. Rev. 2004, 104, 17–118. and references
cited therein.
15. Plé, N.; Turck, A.; Heynderickx, A.; Quéguiner, G. Tetrahedron 1998, 54, 9701–
9710.
16. Gao, A.; Mu, Y.; Zhang, J.; Yao, W. Eur. J. Inorg. Chem. 2009, 3613–3621.
17. Gomez, I.; Alonso, E.; Ramon, D. J.; Yus, M. Tetrahedron 2000, 56, 4043–4052.
1.09 mmol,
¼ ꢀ19:35 (c 1.0, CHCl3). Chiral GC conditions: (135 °C, pressur-
e = 60 kPa, flow rate: 120 mL/min), tR1 = 21.32 min, tR2 = 23.90 min
1.5 equiv).
Yield:
32%
(0.051 g).
ee% = 32.
½ ꢂ
a 2D6