Asymmetric synthesis of 1-substituted 1,2,3,4-tetrahydropyrrolo[1,2-a] pyrazines

Article abstract of DOI:10.1055/s-0030-1258436

The reactions of 1-(2-haloethyl)pyrrole-2-carbaldehydes with (1S)-1-phenylglycinol or (1S)-valinol gave the corresponding fused tricyclic oxazolidines as single diastereomers from which 1,2-disubstituted 1,2,3,4-tetrahydropyrrole[1,2-a]pyrazines were obtained by addition of organometallic reagents. The diastereoselectivity was dependent on the nature of both the chiral auxiliary and the organometallic reagent. The best diastereoselectivity (dr ≤ 98:2) was obtained by using Grignard reagents with the oxazolidine derived from (1S)-phenylglycinol. (+)-1-Methyl- and (+)-1-ethyl-1,2,3,4-tetrahydropyrrole[1,2-a]pyrazines were obtained by reductive removal of the N2-substituent. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258436

PAPER
909
Asymmetric Synthesis of 1-Substituted 1,2,3,4-Tetrahydropyrrolo[1,2-a]pyr-
azines
1
, 2,3, 4-Tetrahydro
n
pyrrolo[1,2-
a
]
pyrazines rea Gualandi, Lucia Cerisoli, Magda Monari, Diego Savoia*
Dipartimento di Chimica ‘G. Ciamician’, Università di Bologna, via Selmi 2, 40126 Bologna, Italy
Fax +39(051)2099456; E-mail: diego.savoia@unibo.it
Received 2 December 2010; revised 19 January 2011
Abstract: The reactions of 1-(2-haloethyl)pyrrole-2-carbaldehydes
with (1S)-1-phenylglycinol or (1S)-valinol gave the corresponding
fused tricyclic oxazolidines as single diastereomers from which 1,2-
disubstituted 1,2,3,4-tetrahydropyrrole[1,2-a]pyrazines were ob-
tained by addition of organometallic reagents. The diastereoselec-
tivity was dependent on the nature of both the chiral auxiliary and
the organometallic reagent. The best diastereoselectivity (dr ≤ 98:2)
was obtained by using Grignard reagents with the oxazolidine de-
rived from (1S)-phenylglycinol. (+)-1-Methyl- and (+)-1-ethyl-
1,2,3,4-tetrahydropyrrole[1,2-a]pyrazines were obtained by reduc-
tive removal of the N2-substituent.
R1
R2
R1
N
N
N
N
1
2
R1CHO
NHR2
N
N
NHCOR1
Key words: asymmetric synthesis, diastereoselectivity, Grignard
reagents, heterocycles, oxazolidines, tetrahydropyrrolopyrazines
4
3
Scheme 1 Retrosynthetic pathways for substituted 1,2,3,4-tetrahy-
dropyrrolo[1,2-a]pyrazines 1
Substituted
e.g. 1 (Scheme 1), are extremely useful because of their
antiamnesic, and
antihypoxic,1 psychotropic,2
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines,
have been synthesized by the benzotriazole method using
glutaric dialdehyde.16
antihypersensitive3 activities.4 Moreover, a stereochemi-
cally defined 3,5,5-trisubstituted 2,4-dioxo derivative is a
potent inhibitor of aldose reductase.5 1-Substituted and
1,2-disubstituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyra-
zines 1 have been synthesized by hydrogenation or reduc-
tion of 2-substituted 3,4-dihydropyrrolo[1,2-a]pyrazines
2.1,6–8 The dihydro compounds 2 are, in turn, prepared by
reaction of 2-furylcarbaldehyde or 2-furyl ketones with
ethylenediamine,9–11 or by addition of Grignard reagents
to unsubstituted 2 (R1 = H).12 Furthermore, hydrogenation
of the pyrrole ring under more-forcing conditions has
been used to obtain octahydro derivatives which are use-
ful intermediates for the synthesis of coronary dilators and
neuroleptics.8 Dihydro compounds 2 have also been pro-
duced by phosphorus oxychloride-mediated condensation
of N-[2-(pyrrol-1-yl)ethyl]carboxamides 3, which are ob-
tained, in turn, from 2,5-dimethoxytetrahydrofuran.13,14
The N2-substituted derivatives 1 can be easily prepared
from the N-unsubstituted precursors by routine alkyla-
tion/acylation reactions.2,15 An alternative route to 1 in-
volves the reaction of 1-(2-aminoethyl)pyrroles 4 with two
equivalents of formaldehyde and benzotriazole, followed
by addition of a Grignard reagent that provided the R1 sub-
stituent. Similarly, 5,6,9,10,11,11a-hexahydro-8H-pyrido[1,2-
a]pyrrolo[2,1-c]pyrazines 1 [R1R2 = CH2CH2CH2CH(R)]
The same skeleton is present in compounds 5 and 6
(Figure 1). The former, which is a modulator for human
metabotropic glutamate receptor 5 (mGluR5), is useful in
the control and prevention of chronic neurological
disorders.17 7-(1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazin-
7-yl)quinolones 6 have shown efficacy in vivo in a murine
lethal systemic infection model; this efficacy is dependent
on the position of the methyl group (R2) at C3 of the tet-
rahydropyrazine ring and its S-configuration. In this case,
the 1,2,3,4-tetrahydropyrazine fragment was constructed
stereoselectively starting from (4R)-hydroxy-L-proline,
and the pyrrole ring was obtained by dehydrogenation of
an intermediate pyrroline.18
O
HO2C
F
Cl
N
Cl
N
N
N
MeO
R1
NH
N
N
N
O
R2
5
6
a: R1 = R2 = H
b: R1 = H; R2 = Me
c: R1 = H; R2 = (R)-Me
d: R1 = Me; R2 = H
e: R1 = (S)-Me; R2 = H
f: R1 = R2 = Me
Figure 1 Drugs containing substituted 1,2,3,4-tetrahydropyrro-
lo[1,2-a]pyrazine fragments
SYNTHESIS 2011, No. 6, pp 0909–0918
Advanced online publication: 10.02.2011
x
x
.
x
x
.2
0
1
1
DOI: 10.1055/s-0030-1258436; Art ID: Z50510SS
© Georg Thieme Verlag Stuttgart · New York

910
A. Gualandi et al.
PAPER
Because of the potential value of configurationally pure 1- ring-closure to the iminium ion 9 by subsequent reaction
substituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines, with an optically pure primary amine should occur in a
and taking into account our experience in the stereoselec- single step by consecutive formation of two C–N bonds (b
tive synthesis of 1-(pyrrol-2-yl)alkylamines,19 we decided and c or c and b). The third and final advantage is that the
to develop an efficient asymmetric route to the target enhanced reactivity of the iminium ion in comparison
compound 7 (Scheme 2). Two retrosynthetic pathways with an imine should permit the use of more-convenient
were envisaged, both involving the use of 2-pyrrolecar- Grignard reagents.
baldehyde (10) as a convenient starting material an an op-
tically pure primary amine as a chiral auxiliary. The two
routes differ in the sequence in which the three C–N bonds
(a–c) and one C–C bond (d) are formed, and they there-
We therefore began our investigation by looking for opti-
mal conditions for the conversion of aldehyde 10 into N-
(2-haloethyl) derivatives 11a and 11b (Scheme 3). Treat-
ment with potassium hydroxide in dimethyl sulfoxide at
fore involve 1-(2-pyrrolyl)alkylamines 8 or cyclic imini-
0 °C for one hour followed by slow addition of 1,2-dibro-
um ions 9 as intermediates.20 In both cases, the chiral
moethane (20 equivalents)22 and stirring for twenty-four
auxiliary, i.e. the nitrogen substituent R*, induces asym-
metry during the formation of the new stereocenter. Final-
ly, removal of the chiral auxiliary from 7 should lead to
the desired N-unsubstituted 1-substituted 1,2,3,4-tetrahy-
dropyrrolo[1,2-a]pyrazines in an enantiomerically pure or
enantiomerically enriched form.
hours resulted in a good conversion to 11a; this was ac-
companied by small amounts of the corresponding N-vi-
nyl derivative. After purification by column
chromatography, the desired 11a was isolated in 69%
yield, but this compound decomposed slowly when stored
at room temperature. To suppress this decomposition, the
product was stored at 4 °C. On the other hand, when alde-
hyde 10 and 1,2-dichloroethane were stirred overnight in
d
R1
R1
R2
a,b
a two-phase system of 50% aqueous sodium hydroxide
and dichloromethane in the presence of the tetrabutylam-
monium iodide as a phase-transfer catalyst, the air-stable
N-(2-chloroethyl) derivative 11b was obtained cleanly in
92% yield.23
N
N
H
c
a
N
b
HN
R2
7
8
d
c,d
Br
a–c
Br
N
CHO
N
H
KOH, DMSO
N
R2
9
10
CHO
X
N
CHO
N
H
Cl
Scheme 2 Retrosynthetic pathways for chiral 1-substituted 1,2,3,4-
tetrahydropyrrolo[1,2-a]pyrazines 7
Cl
11
10
50% NaOH
TBAI, CH2Cl2
a: X = Br, 69%
b: X = Cl, 92%
We have previously reported a highly diastereoselective
synthesis of N-substituted 1-(2-pyrrolyl)alkylamines 8
from aldehyde 10 through formation of an imine with
(1S)-phenylglycinol, followed by the addition of an orga-
nolithium reagent (paths c and d).19a The products were
converted into the corresponding primary amines by re-
moval of the chiral auxiliary. To obtain the desired com-
pounds 7 from 8, the formation of two C–N bonds would
be required (paths a and b). However, in a preliminary at-
tempt to perform this transformation, the insertion of the
two-carbon tether between the two nitrogen atoms of 1-
(pyrrole-2-yl)-3-butenamine 8 (R = allyl; R* = H) by re-
action with 1,2-dibromoethane by heating with sodium
hydride in tetrahydrofuran failed. It is possible that this
goal could be reached by an appropriate choice of the two-
carbon 1,2-dielectrophilic reactant, e.g. chloroacetyl chlo-
ride, in a three-step sequence.21 However, we reasoned
that the alternative route described in Scheme 2 (se-
quence: a, b, c, d) offers several advantages, The first is
that the electron-withdrawing effect of the formyl func-
tion results in an increased acidity of the pyrrole N–H
bond in aldehyde 10, facilitating metalation of the pyrrole
and the formation of the first C–N bond by reaction with
a 1,2-dihaloethane (step a). The second advantage is that
NH2
CH2Cl2
MgSO4
OH
Y
O
N
NaHCO3
N
OH
–
N
N
+
Y
X
Y
14, Y = Ph, 87% (X = Br)
85% (X = Cl)
15: Y = i-Pr, 90% (X = Br)
12: Y = Ph
13: Y = i-Pr
92% (X = Cl)
Scheme 3 Diastereoselective synthesis of tricyclic oxazolidines 14
and 15 from 1H-pyrrole-2-carbaldehyde
Both halo aldehydes were treated with a slight excess of
(1S)-phenylglycinol or (S)-valinol in anhydrous dichlo-
romethane in the presence of anhydrous magnesium sul-
fate as a dehydrating agent for two days. In all cases, the
corresponding bicyclic iminium ions 12 (Scheme 3) were
observed in the crude products isolated by filtration of the
solid and evaporation of the solvent. The 1H NMR spectra
of 12 in CDCl3 showed an adsorption for the H–C=N+
Synthesis 2011, No. 6, 909–918 © Thieme Stuttgart · New York

PAPER
1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines
911
proton at d = 9.33 ppm that was distinctly higher than that
of the proton of the formyl group in 11a (d = 9.49 ppm).
Minor amounts of starting material and another aldehyde,
possibly 1-vinyl-2-pyrrolecarbaldehyde, were also detect-
ed. Moreover, an equilibrium was slowly established be-
tween the iminium 12 and the corresponding oxazolidine,
and the chemical shift of the O–CH–N proton was ob-
served at d = 5.24 ppm. In practice, the crude iminium
bromide 12 precipitated from its dichloromethane solu-
tion upon addition of diethyl ether and was obtained in
70% yield. However, this result could not be always re-
produced when the same procedure was repeated. On the
other hand, treatment of the dichloromethane solution
with saturated aqueous sodium bicarbonate and extraction
of the organic phase gave the pure tricyclic oxazolidine 14
in 87% yield. This last procedure was therefore used to
prepare the tricyclic compound 15a and 15b from the cor-
responding halides 11a and 11b via the intermediate imi-
nium ion 13.24
The 1H NMR spectra of the tricyclic structures 14 and 15
showed absorptions for the O–CH–N protons of the ox-
azolidine groups as singlets at d = 5.58 and 5.24, respec-
tively. At room temperature, minor amounts (about 5%)
of another diastereoisomer could be observed, with some
difficulty, in the spectrum, but the relevant signals became
narrower and more evident at lower temperatures. The
structure of 14 in the solid state (Figure 2) was confirmed
by means of single-crystal X-ray diffraction studies on
crystals grown by slow evaporation of a tetrahydrofuran
solution of 14.25 This structure was found to corresponds
to that of the most stable of the possible diastereomers (in
which the N atom is also a stereocenter), as calculated at
the MM2 level.
Figure 2 ORTEP drawing of compound 14; thermal ellipsoids are
at 30% probability
The tricyclic oxazolidines 14 and 15 were used as
substrates for reactions with organometallic reagents.26
Reactions of phenylglycinol-derived N-substituted ox-
azolidines with organometallic reagents have been previ-
ously used in the diastereoselective syntheses of
secondary amines.27,28 In our hands, Grignard reagents
proved to be the reagents of choice for the reactions of 14,
giving, in many cases, high yields and high diastereose-
lectivities of 1,2-disubstituted 1,2,3,4-tetrahydropyrrolo-
[1,2-a]pyrazines 16 (Scheme 4 and Table 1).
The addition of methylmagnesium bromide in tetrahydro-
furan at –78 °C was particularly effective in terms of both
the yield and diastereoselectivity; the major diastereomer
16a (dr 98:2) was obtained in a pure form and 95% yield
after column chromatography (entry 1). The stereocontrol
progressively decreased on increasing the length of the
Table 1 Addition of Organometallic Reagents to the Tricyclic Oxazolidine 14
Entrya
RM
Temp (°C)
–78
Time (h)
drb
98:2
Product(s) [Yield (%)]c
16a (95)
1
2
MeMgBr
2
1
1
1
2d
4
1
1
1
1
EtMgBr
–78
92:8
93:7
16b (78) + epi-16b (3)
16d (77) + epi-16d (6)
16e (41) + epi-16e (35)
–
3
Me(CH2)5MgBr
CH2=CHCH2MgCl
CH2=CHMgCl/TiCl4
CH2=CHZnBr
CH2=CHZn(Et2)MgCle
BnMgCl
–78
4
–78
50:50
–
5
–78
6
–78 to 20
–781
62:38
76:24
65:35
>98:2
78:22
16e (47) + epi-16e (24)
16e (38) + epi-16e (14)
16f (53) + epi-16f (29)
[16g + epi-16g] (72)f
[16g + epi-16g] (45)f
7
8
–78
9
PhMgBr
–78
10
PhLi
–78 to 20
a The reactions were performed by adding the organometallic reagents (4 equiv) to a soln of the imine in anhyd THF under N2.
b The diastereomeric ratios (dr) were determined by 1H NMR analyses of the crude reaction product.
c Yields refer to pure diastereoisomers isolated by column chromatography (SiO2).
d No reaction occurred.
e The zincate was prepared by adding allylmagnesium chloride to Et2Zn in THF and stirring for 1 h at 0 °C.
f Pure diastereoisomers could not be obtained because epimerization occurred during chromatography on the SiO2 column.
Synthesis 2011, No. 6, 909–918 © Thieme Stuttgart · New York

912
A. Gualandi et al.
PAPER
Next, we examined the effectiveness of (S)-valinol as a
chiral auxiliary by performing the same organometallic
reactions on the oxazolidine 15 (Scheme 4 and Table 2).
In all cases, we obtained unsatisfactory stereochemical
outcomes, and the diastereomeric ratios ranged from
70:30 to 50:50 when Grignard reagents or butyllithium
were used. Allyl(tributyl)stannane/tin tetrachloride and
–boron trifluoride systems were totally unreactive, where-
as the allyltitanium reagent formed in situ from the Grig-
nard reagent and titanium tetraethoxide afforded 15e with
a lower yield than that obtained with the Grignard reagent
alone, and the dr remained unsatisfactory. Moreover, col-
umn chromatography did not provide adequate separation
of the diastereoisomers of the products 17b,e–g. In partic-
ular, the phenyl-substituted product 17g, initially obtained
with a dr of 65:35, was eluted with an inverted dr of 40:60.
R2
R1
R2M
THF
O
N
N
OH
N
N
R1
14: R1 = Ph
15: R1 = i-Pr
16: R1 = Ph
17: R1 = i-Pr
a: R2 = Me
e: R2 = allyl
b: R2 = Et
f: R2 = Bn
g: R2 = Ph
c: R2 = n-Bu
d: R2 = n-Hex
Scheme 4 Addition of organometallic reagents to the tricyclic oxa-
zolidines 14 and 15
alkyl group in the Grignard reagents (entries 2 and 3). Al-
lylmagnesium chloride showed no stereoselectivity (entry
4) and gave no reaction in the presence of titanium tetra-
chloride (entry 5). We therefore examined the reaction of
allylzinc bromide; however, the diastereoselectivity in-
creased only slightly (entry 6). Better stereocontrol (dr
76:24) was achieved by using a preformed mixed zincate
(entry 7). Benzylmagnesium chloride gave only a moder-
ate diastereoselectivity (dr 65:35; entry 8). Finally, phe-
nylmagnesium bromide reacted with almost complete
stereocontrol to give a high yield of the crude secondary
amine with a better than 99:1 dr (entry 9), whereas phe-
nyllithium reacted sluggishly even when the temperature
was increased to 20 °C (entry 10). Unfortunately, at-
tempts to purify the crude phenyl-substituted product 16g
(entry 9) by chromatography on a silica-gel column result-
ed in epimerized product in all the eluted fractions. This
can be explained by the acidity present in the silica induc-
ing heterolytic cleavage of the benzydrylic C–N bond to
form a carbenium ion that is stabilized by both adjacent
aromatic rings.
The absolute stereochemistry of the main diastereoiso-
mers could not be unambiguously demonstrated; howev-
er, an R-configuration can reasonably be postulated by
analogy with all the previously reported outcomes of
Grignard reactions performed on various N-substituted
oxazolidines derived from (S)-phenylglycinol.25 We as-
sume that the same mechanism considered for those reac-
tions also operates with our substrate 14, as shown in
Scheme 5. The Lewis acidity of the Grignard reagent is a
determinant for a successful reaction, which therefore
proceeds by preliminary O–Mg coordination. This leads
to the formation of the incipient carbenium ion 18 that un-
dergoes attack of the R nucleophile from the side of the C–
O bond being broken. In this way, adduct 20 is formed
with an R-configuration at the newly formed stereocenter.
The formation of a true carbenium ion 19 cannot be ex-
cluded and, in this case, a reduced diastereoselectivity
might be expected owing to the possible rotation of the ni-
trogen substituent around the C*–N bond. Moreover, the
Table 2 Addition of Organometallic Reagents to the Tricyclic Oxazolidine 15
Entrya
RM
Temp (°C)
–78
Time (h)
drb
Product(s) [Yields (%)]c
17a (49) + epi-17a (17)
[17b + epi-17b] (68)d
17cf
1
2
3
4
5
6
7
8
9
MeMgBr
2
1
1
1
1
4
4
1
1
70:30
65:35
70:30e
50:50
54:46
EtMgBr
–78
BuLi
–78
CH2=CHCH2MgCl
CH2=CHCH2MgCl/Ti(OEt)4
CH2=CHCH2SnBu3/SnCl4
CH2=CHCH2SnBu3/BF3
BnMgCl
–78
[17e + epi-17e] (64)d
[17e + epi-17e] (50)d
–
–78
f
–78 to 20
–78 to 20
–78
–
f
–
–
50:50
65:35
[17f + epi-17f] (76)d
[17g + epi-17g] (78)d
PhMgBr
–78
a The reactions were performed by adding the organometallic reagents (4 equiv) to a soln of the imine in anhyd THF under argon.
b The diastereomeric ratios (dr) were determined by 1H NMR analysis of the crude reaction product.
c Yields refer to pure diastereoisomers isolated by column chromatography (SiO2).
d The diastereomers could not be separated by column chromatography.
e No reaction occurred.
f The reaction mixture contained mainly unreacted 15 and minor amount of the addition product 17c (~10%).
g The product was not isolated.
Synthesis 2011, No. 6, 909–918 © Thieme Stuttgart · New York

PAPER
1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines
913
lower diastereoselectivity of allylic reagents can be ex- cause considerable epimerization occurred. The chiral
plained in terms of an unfavorable transition state for the auxiliary was removed from 1-methyl- and 1-ethyl-substi-
g-attack.
tuted products by hydrogenolysis to give the correspond-
ing unsubstituted cyclic amines with a presumed R-
configuration at the C1 stereocenter.
X
δ-
Mg
R
RMgX
O
N
O
N
Melting points are uncorrected. Optical rotations were measured on
Nδ+
N
20
a digital polarimeter in a 1-dm cell, and [a]D values are given in
10–1 deg cm3 g–1. 1H NMR spectra were recorded on Varian MR400
and Gemini 200 instruments for samples in CDCl3 which was stored
over Mg. The H chemical shifts are reported in ppm relative to
Ph
14
18
Ph
1
X
CHCl3 (dH = 7.27) and the J-values are given in Hz. IR spectra were
recorded on a Nicolet FT-380 spectrometer, and IR assignments are
reported in wave numbers (cm–1). MS spectra were recorded at an
ionizing voltage of 70 eV on a Hewlett-Packard 5975 spectrometer
with GC injection from a HP-5 column (30 m; ID 0.25 mm). Molec-
ular weights were determined on an Agilent Technologies MS 1100
instrument. Chromatographic separations were performed on col-
umns of SiO2 (Merck; 230–400 mesh) at medium pressure. All the
organic, inorganic, and organometallic reagents and anhydrous sol-
vents were purchased from Aldrich.
–
R
Mg
R
N
O
N
OMgX
N
+
N
Ph
Ph
20
19
Scheme 5 Mechanism and stereochemical model for the organo-
metallic addition to oxazolidine 14
Finally, we directed our efforts to the removal of the chiral
auxiliary. Unfortunately, all efforts to achieve this goal by
oxidative reactions of the amine 16 or amine 17, including
the use of periodic acid/methylamine and lead tetraace-
1-(2-Bromoethyl)-1H-pyrrole-2-carbaldehyde (11a)
KOH (5.88 g, 100 mmol) was added in one portion to a stirred soln
of 1H-pyrrole-2-carbaldehyde (10; 1.00 g, 10 mmol) in anhyd
DMSO (6 mL) at r.t. After 1 h, Br(CH2)2Br (18.1 mL, 0.2 mol) was
tate, were unsuccessful. Furthermore, hydrogenolysis of slowly added at 0 °C and the resulting soln was stirred overnight at
r.t. The reaction was quenched by addition of H2O (10 mL), and the
organic layer was extracted with EtOAc (3 × 20 mL). The collected
16b with ammonium formate and palladium/carbon gave
a complex mixture of products. Finally, when 16a or 16b
organic layers were washed with brine (20 mL), dried (Na2SO4),
was subjected to 7 bar of hydrogen pressure in the pres-
and concentrated to give a crude product that was purified by flash
ence of 10% palladium/carbon in methanol for two days,
column chromatography [SiO2, cyclohexane–EtOAc (9:1)] to give
a yellow oil; yield: 1.59 g (75%).
the desired secondary amines 21a and 21b, respectively,
were obtained in about 80% yield together with 2-phe-
nylethanol and trace amounts of the corresponding fully
hydrogenated compounds 22 (Scheme 6).
IR (neat): 3111, 2947, 2807, 2722, 1660, 1530, 1479, 1321, 1208,
1075, 822, 623, 607 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.49 (s, 1 H), 7.04–6.99 (m, 2 H),
6.29–6.25 (m, 1 H), 4.80 (t, J = 5.8 Hz, J = 6.2 Hz, 2 H), 3.70 (t,
J = 5.8 Hz, J = 6.2 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 179.4, 150.9, 132.5, 125.6, 109.6,
50.6, 31.7.
H
R
R
H
2 (7 atm)
R
N
OH
N
+
N
10% Pd/C
MeOH
N
NH
NH
MS (EI): m/z = 122 (100), 94 (36), 201 (14), 203 (12), 202 (3).
Ph
22, trace
21a: 81%
b: 79%
Anal. Calcd for C7H8BrNO (202.05): C, 41.61; H, 3.99; N, 6.93.
Found: C, 41.50; H, 4.01; N, 6.91.
16a,b
Scheme 6 Removal of the chiral auxiliary from 1,2-disubstituted
1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines 16a,b
1-(2-Chloroethyl)-1H-pyrrole-2-carbaldehyde (11b)23
1,2-Dichloroethane (9.7 mL, 0.12 mol), Bu4NI (1.94 g, 5.3 mmol),
and 50% aq NaOH (5 mL) were added to a soln of 1H-pyrrole-2-
carbaldehyde (10; 0.500 g, 5.3 mmol) in CH2Cl2 (2 mL), and the
mixture was vigorously stirred overnight. H2O (2 mL) was added
and the organic layers were extracted with CH2Cl2 (2 × 30 mL) and
washed with 1 M HCl (2 × 20 mL), sat. aq NaHCO3 (2 × 20 mL),
and brine (2 × 20 mL). After drying (Na2SO4), the organic layers
were concentrated in vacuo to give an orange slurry that was puri-
fied by column chromatography [SiO2, cyclohexane–EtOAc (9:1)]
to give a yellow oil; yield: 0.76 g (92%).
In conclusion, we have developed the first asymmetric
synthesis of 1-substituted 1,2,3,4-tetrahydropyrrolo[1,2-
a]pyrazines by a four-step route starting from 1H-pyrrole-
2-carbaldehyde. The key intermediate, a tricyclic oxazo-
lopyrrolopyrazine, was formed efficiently and diastereo-
selectively by condensation of a 1-(2-haloethyl)-2-
pyrrolecarbaldehyde with (1S)-phenylglycinol. This inter-
mediate reacted with Grignard reagents to give 1,2-disub-
stituted 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazines with
variable levels of diastereoselectivity that decreased with
increasing the length of the alkyl group in the Grignard re-
agent. The highest diastereomeric ratios were obtained
with methylmagnesium bromide (98:2) and phenylmag-
nesium bromide (>98:2). In the latter case, the product
could not be purified by chromatography on silica gel be-
IR (neat) 3111, 2959, 2809, 1663, 1655, 1479, 882, 766, 705, 678,
656, 608 cm–1.
1H NMR (200 MHz, CDCl3): d = 9.51 (s, 1 H), 7.03–6.97 (m, 2 H),
6.23 (t, J = 2.6 Hz, 1 H), 4.57 (t, J = 5.8 Hz, J = 5.4 Hz, 2 H), 3.79
(t, J = 5.8 Hz, J = 5.4 Hz, 2 H).
13C NMR (50 MHz, CDCl3): d = 179.2, 132.7, 130.7, 125.4, 109.5,
50.5, 43.7.
Synthesis 2011, No. 6, 909–918 © Thieme Stuttgart · New York

914
A. Gualandi et al.
PAPER
MS (EI): m/z = 122 (100), 94 (50), 157 (34), 53 (19), 108 (18), 80
(14).
13C NMR (50 MHz, CDCl3): d = 124.7, 119.2, 108.6, 107.5, 85.7,
72.7, 67.6, 48.7, 44.9, 31.9, 20.3, 18.9.
Anal. Calcd for C7H8ClNO (157.6): C, 53.35; H, 5.12; N, 8.89.
Found: C, 53.19; H, 5.14; N, 8.86.
MS (EI): m/z = 205 (100), 161 (90), 176 (13).
Anal. Calcd for C12H18N2O (206.28): C, 69.87; H, 8.80; N, 13.58.
Found: C, 69.60; H, 8. 83; N, 13.54.
2-[(1S)-2-Hydroxy-1-phenylethyl]-3,4-dihydropyrrolo[1,2-
a]pyrazin-2-ium bromide (12)
(2S)-2-[(1R)-1-Methyl-3,4-dihydropyrrolo[1,2-a]pyrazin-
2(1H)-yl]-2-phenylethanol (16a); Typical Procedure
A mixture of carbaldehyde 11a (0.203 g, 1.0 mmol), (1S)-phenyl-
glycinol (0.138 g, 1.2 mmol), and MgSO4 (0.5 g) in anhyd CH2Cl2
(4 mL) was protected from light and magnetically stirred for 2 d un-
der an inert atmosphere. The mixture was then filtered through a
small pad of Celite that was washed with CH2Cl2. The filtered soln
was concentrated under reduced pressure to a final volume of 1 mL,
and Et2O (3 mL) was slowly added to give a brown precipitate;
yield: 0.228 g (71%).
A 3.0 M soln of MeMgCl in Et2O (1.3 mL, 4.0 mmol) was added to
a magnetically stirred soln of tricycle 14 (0.240 g, 1.0 mmol) in an-
hyd THF (15 mL) at –78 °C, and the mixture was stirred until no
starting material remained (TLC). The reaction then was quenched
by adding sat. aq NaHCO3 (10 mL), and the organic material was
extracted with Et2O (3 × 10 mL). The collected ethereal layers were
dried (Na2SO4) and concentrated to give an oil. The diastereomeric
1
IR (neat): 3381, 2962, 2924, 2848, 1646, 1629, 1491, 1377, 1103,
1067 cm–1.
1H NMR (400 MHz, CDCl3): d = 9.33 (s, 1 H), 7.39–7.26 (m, 7 H),
6.44–6.36 (m, 1 H), 5.56–5.49 (m, 1 H), 5.39 (br s, 1 H), 4.60–4.20
(m, 3 H), 4.10–3.93 (m, 2 H), 3.80–3.60 (m, 1 H).
13C NMR (100 MHz, CDCl3): d = 151.8, 134.5, 132.7, 129.5, 127.9,
127.3, 122.6, 115.4, 72.5, 60.1, 45.9, 43.4.
ratio was determined by H NMR analysis of a sample soln in
CDCl3. Flash column chromatography [SiO2, cyclohexane–EtOAc
(9:1]) gave a yellow oil; yield: 0.253 g (99%): [a]D –21.4 (c 1.3,
CHCl3).
20
IR (neat): 3415, 3101, 3050, 2970, 2928, 1601, 1492, 1453, 1266,
1186, 1056, 735, 609 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.45–7.29 (m, 5 H), 6.50 (t,
J = 1.7 Hz, 1 H), 6.15 (t, J = 3.0 Hz, 1 H), 5.85–5.80 (m, 1 H), 4.30
(q, J = 6.8 Hz, J = 13.0 Hz, 1 H), 4.02–3.90 (m, 3 H), 3.82–3.75 (m,
1 H), 3.43 (t, J = 6.7 Hz, 1 H), 3.38–3.21 (m, 1 H), 3.10–3.02 (m, 1
H), 1.39 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 140.4, 132.1, 128.6, 128.4, 128,
3, 117.9, 107.8, 102.9, 65.4, 63.2, 50.8, 43.38, 41.3, 19.2.
MS (ES): m/z = 241.1 [M – HBr + H]+ (100).
(3S,10bR)-3-Phenyl-2,3,5,6-tetrahydro-10bH-[1,3]oxazolo[3,2-
a]pyrrolo[2,1-c]pyrazine (14); Typical Procedure
A mixture of carbaldehyde 11a (1.515 g, 7.5 mmol), (1S)-phenylg-
lycinol (1.233 g, 9.0 mmol), and MgSO4 (5 g) in anhyd CH2Cl2 (15
mL) was protected from light and stirred for 2 d under an inert at-
mosphere. The mixture was then filtered through a small pad of
Celite that was washed with CH2Cl2. The collected organic layers
were washed with sat. aq NaHCO3 (20 mL) and brine (20 mL), and
the organic phase was concentrated under reduced pressure to give
MS (ES): m/z = 257.2 [M + H]+ (100).
Anal. Calcd for C16H20N2O (256.34): C, 74.97; H, 7.86; N, 10.93.
Found: C, 74.75; H, 7.88; N, 10.90.
20
(2S)-2-[(1R)-1-Ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-
yl]-2-phenylethanol (16b)
a white solid; yield: 1.531 g (85%); mp 85.1–85.5 °C; [a]D +8.5
(c 1.0, CHCl3).
Yellowish oil; yield: 0.210 g (78%); [a]D20 –10.5 (c 0.5, CHCl3).
IR (KBr): 3101, 3027, 2847, 1600, 1449, 1212, 1190, 873, 798, 757,
698 cm–1.
IR (neat): 3411, 3109, 3046, 2974, 2921, 1605, 1457, 1174, 1050,
736 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.49–7.34 (m, 5 H), 6.63 (dd,
J = 1.6 Hz, J = 2.8 Hz, 1 H), 6.28 (d, J = 2.2 Hz, 1 H), 6.20 (t,
J = 3.0 Hz, 1 H), 5.53 (s, 1 H), 4.50 (t, J = 7.9 Hz, 1 H), 4.30 (t,
J = 6.8 Hz, 1 H), 4.14–4.03 (m, 2 H), 3.76 (dd, J = 6.6 Hz, J = 8.5
Hz, 1 H), 3.37–3.27 (m, 1 H), 3.16–3.07 (m, 1 H).
13C NMR(100 MHz, CDCl3): d = 141.4, 134.9, 128.7, 127.3, 126.5,
119.5, 108.7, 107.6, 86.6, 71.2, 67.8, 47.4, 44.1.
1H NMR (400 MHz, CDCl3): d = 7.40–7.29 (m, 5 H), 6.52 (t,
J = 1.8 Hz, 1 H), 6.12 (t, J = 3.2 Hz, 1 H), 5.79–6.75 (m, 1 H), 4.04
(dt, J = 4.6 Hz, J = 11.8 Hz, 1 H), 3.96–3.88 (m, 3 H), 3.82–3.73 (m,
2 H), 3.46–3.36 (m, 1 H), 3.22–3.14 (m, 1 H), 1.86–1.74 (m, 1 H),
1.71–1.58 (m, 1 H), 0.92 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 140.5, 130.0, 128.5, 127.7, 118.3,
107.4, 104.0, 65.2, 63.6, 56.4, 41.6, 40.9, 26.8, 11.0.
MS (EI): m/z = 239 (100), 210 (20), 106 (15).
MS (ES): m/z = 271.2 [M + H]+ (100).
Anal. Calcd for C15H16N2O (240.30): C, 74.97; H, 6.71; N, 11.66.
Found: C, 74.78; H, 6.74; N, 11.62.
Anal. Calcd for C17H22N2O (270.37): C, 75.52; H, 8.20; N, 10.36.
Found: C, 75.68; H, 8.21; N, 10.32.
(3S,10bR)-3-Isopropyl-2,3,5,6-tetrahydro-10bH-[1,3]oxazo-
lo[3,2-a]pyrrolo[2,1-c]pyrazine (15)
This was prepared by the same procedure as 14, starting from 11a
epi-16b
Yellowish oil; yield: 0.008 g (3%); [a]D20 +6.8 (c 1.2, CHCl3).
(1.515 g, 7.5 mmol).
Yellow oil; yield: 1.443 g (92%). [a]D20 –13.0 (c 1.2, CHCl3).
IR (neat): 3414, 3107, 3054, 2978, 2923, 1611, 1497, 1451, 1263,
1051, 736 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.38–7.24 (m, 5 H), 6.47 (t,
J = 1.8 Hz, 1 H), 6.12 (t, J = 2.9 Hz, 1 H), 5.85–5.81 (m, 1 H), 4.20
(dd, J = 5.2 Hz, J = 9.6 Hz, 1 H), 4.07 (dd, J = 10.4 Hz, 1 H), 3.98
(t, J = 4.2 Hz, 1 H), 3.96–3.84 (m, 2 H), 3.76 (dd, J = 4.9 Hz,
J = 10.8 Hz, 1 H), 3.28–3.20(m, 1 H), 3.02 (br s, 1 H), 2.54–2.45 (m,
1 H), 2.21–2.14 (m, 1 H), 1.98–1.88 (m, 1 H), 0.92 (t, J = 7.3 Hz, 3
H).
IR (neat): 3101, 2957, 2868, 1663, 1494, 1469, 1299, 1195, 1037,
861, 769, 609 cm–1.
1H NMR (400 MHz, CDCl3): d = 6.59 (s, 1 H), 6.28–6.24 (m, 1 H),
6.19 (t, J = 2.9 Hz, 1 H), 5.24 (s, 1 H), 4.14 (t, J = 8.0 Hz, 1 H), 4.06
(ddd, J = 3.5 Hz, J = 12.0 Hz, 1 H), 3.98–3.88 (m, 1 H), 3.50 (dd,
J = 6.0 Hz, J = 8.1 Hz, 1 H), 3.21 (dt, J = 3.4 Hz, J = 11.5 Hz, 1 H),
2.86–2.78 (m, 1 H), 2.74–2.64 (m, 1 H), 1.74–1.64 (m, 1 H) 1.07 (d,
J = 6.4 Hz, 3 H), 0.88 (d, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 135.3, 129.9, 129.0, 128.4, 118.1,
107.9, 103.5, 62.4, 60.7, 55.9, 44.3, 41.7, 25.6, 8.3.
Synthesis 2011, No. 6, 909–918 © Thieme Stuttgart · New York

PAPER
1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines
915
MS (ES): m/z = 271.2 [M + H]+ (100).
(2S)-2-[(1R)-1-Benzyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-
yl]-2-phenylethanol (16f)
(2S)-2-[(1R)-1-Hexyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-
yl]-2-phenylethanol (16d)
Yellowish oil; yield: 0.176 g (53%); [a]D20 –86.2 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.34–7.03 (m, 10 H), 6.48 (dd,
J = 1.7 Hz, J = 2.6 Hz, 1 H), 6.06 (t, J = 3.1 Hz, 1 H), 5.48 (dd,
J = 1.4 Hz, J = 3.4 Hz, 1 H), 4.14 (t, J = 7.4 Hz, 1 H), 4.10–3.98 (m,
1 H), 3.90 (t, J = 5.1 Hz, 1 H), 3.79–3.70 (m, 2 H), 3.67–3.58 (m, 1
H), 3.36–3.24 (m, 2 H), 3.13 (dd, J = 7.9 Hz, J = 13.2 Hz, 1 H), 2.83
(dd, J = 6.3 Hz, J = 13.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 140.0, 139.2, 131.2, 129.6, 129.1,
128.5, 128.4, 128.2, 128.1, 127.7, 127.6, 127.5, 126.2, 118.3, 107.4,
104.2, 66.1, 63.8, 56.3, 41.5, 41.3, 40.9.
Light-brown oil; yield: 0.251 g (77%); [a]D20 –5.9 (c 0.6, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.39–7.28 (m, 5 H), 6.52 (t,
J = 2.2 Hz, 1 H), 6.11 (t, J = 3.2 Hz, 1 H), 5.78–5.76 (m, 1 H), 4.05
(dt, J = 4.7 Hz, J = 11.7 Hz, 1 H), 3.97–3.91 (m, 3 H), 3.80–3.74 (m,
1 H), 3.50–3.38 (m, 1 H), 3.21–3.16 (m, 1 H), 1.85–1.71 (m, 1 H),
1.70–1.55 (m, 1 H), 1.41–1.18 (m, 10 H), 0.90 (t, J = 6.7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 140.5, 128.6, 128.4, 127.8, 118.3,
107.5, 104.0, 65.3, 63.8, 54.9, 41.4, 40.9, 34.1, 31.8, 29.2, 26.4,
22.6, 14.0.
MS (ES): m/z = 333.2 [M + H]+ (100).
MS (ES): m/z = 327.1 [M + H]+ (100).
Anal. Calcd for C22H24N2O (332.44): C, 79.48; H, 7.28; N, 8.43.
Found: C, 79.28; H, 7.31; N, 8.41.
Anal. Calcd for C21H30N2O (326.48): C, 77.26; H, 9.26; N, 8.58.
Found: C, 77.56; H, 9.29; N, 8.55.
epi-16f
epi-16d
Yellowish oil; yield: 0.096 g (29%); [a]D20 +14.3 (c 1.6, CHCl3).
Yellow oil; yield: 0.020 g (6%); [a]D20 +5.4 (c 0.9, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.32–7.12 (m, 10 H), 6.46 (m, 1
H), 6.12 (t, J = 3.1 Hz, 1 H), 5.77 (m, 1 H), 4.38 (t, J = 6.4 Hz, 1 H),
4.04 (dd, J = 4.9 Hz, J = 7.1 Hz, 1 H), 3.75 (dd, J = 7.7 Hz, J = 11.0
Hz, 1 H), 3.71–3.54 (m, 3 H), 3.30–3.21 (m, 2 H), 3.10 (dd, J = 5.8
Hz, J = 13.2 Hz, 1 H), 2.75 (ddd, J = 4.2 Hz, J = 5.8 Hz, J = 13.2
Hz, 1 H).
1H NMR (400 MHz, CDCl3): d = 7.41–7.28 (m, 5 H), 6.60 (t,
J = 2.2 Hz, 1 H), 6.20 (t, J = 2.5 Hz, 1 H), 5.80–5.75 (m, 1 H), 4.36–
4.26 (m, 1 H), 4.25–4.16 (m, 2 H), 3.72–3.66 (m, 1 H), 3.37–3.27
(m, 1 H), 3.15–3.08 (m, 1 H), 2.04–1.98 (m, 2 H), 1.40–1.18 (m, 10
H), 0.90 (t, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 139.4, 131.3, 128.6, 127.8, 127.5,
118.6, 107.9, 104.9, 72.7 63.0, 42.2, 31.8, 30.1, 29.6, 29.4, 26.8,
23.6, 22.6, 14.1.
13C NMR (100 MHz, CDCl3): d = 138.8, 137.2, 129.5, 128.7, 128.4,
128.3, 128.2, 128.0, 126.5, 118.2, 104.2, 64.4, 61.7, 56.7, 42.5,
41.9, 40.4.
MS (ES): m/z = 327.1 [M + H]+ (100).
MS (ES): m/z = 333.1 [M + H]+ (100).
(2S)-2-[(1R)-1-Allyl-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-
yl]-2-phenylethanol (16e)
(2S)-2-Phenyl-2-[(1R/1S)-1-phenyl-3,4-dihydropyrrolo[1,2-
a]pyrazin-2(1H)-yl]ethanol (16g + epi-16g)
Oil; yield: 0.141 g (45%); dr 60:40.
Light-brown oil; yield: 0.107 g (38%); [a]D20 +18.3 (c 0.9, CHCl3).
IR (neat): 3416, 3068, 2924, 2852, 1639, 1569, 1492, 1333, 1290,
1069, 1029, 914, 702 cm–1.
Representative signals for 16g in the 1H NMR spectrum (400 MHz,
CDCl3) of the mixture were observed at d = 6.61 (dd, J = 2.0 Hz,
J = 2.8 Hz, 1 H), 6.15 (dd, J = 2.8 Hz, J = 3.6 Hz, 1 H), 5.59 (m, 1
H), 5.06 (s, 1 H), 3.29 (m, 1 H), 3.21 (m, 1 H).
1H NMR (400 MHz, CDCl3): d = 7.39–7.26 (m, 5 H), 6.52 (t,
J = 1.7 Hz, 1 H), 6.11 (t, J = 2.9 Hz, 1 H), 5.88–5.80 (m, 1 H), 5.79–
5.76 (m, 1 H), 5.09–4.99 (m, 2 H), 4.06 (t, J = 6.7 Hz, 1 H), 4.03–
3.93 (m, 2 H), 3.92–3.87 (m, 2 H), 3.79–3.72 (m, 1 H), 3.46–3.38
(m, 1 H), 3.20–3.13 (m, 1 H), 2.63–2.52 (m, 1 H), 2.47–2.38 (m, 1
H).
MS (ES): m/z = 319.1 [M + H]+ (100).
Representative 1H NMR signals for epi-16g: d = 6.51 (t, J = 1.6 Hz,
1 H), 6.03 (t, J = 3.2 Hz, 1 H), 5.27 (m, 1 H), 4.79 (s, 1 H), 4.22 (dd,
J = 4.6 Hz, J = 10.6 Hz, 1 H), 4.22 (ddd, J = 1.9 Hz, J = 3.0 Hz,
J = 12.1 Hz, 1 H), 2.59 (ddd, J = 3.7 Hz, J = 12.1 Hz, J = 12.2 Hz,
1 H).
13C NMR (100 MHz, CDCl3): d = 140.2, 136.1, 129.5, 128.5, 128.4,
127.8, 118.4, 116.8, 107.5, 103.9, 65.7, 63.4, 54.6, 41.7, 41.6, 38.8.
MS (ES): m/z = 283.2 [M + H]+ (100), 305.2 [M + Na]+ (15).
MS (ES): m/z = 319.1 [M + H]+ (100).
Anal. Calcd for C18H22N2O (282.38): C, 76.56; H, 7.85; N, 9.92.
Found: C, 76.58; H, 7.87; N, 9.90.
Anal. Calcd for C21H22N2O (318.41): C, 79.21; H, 6.96; N, 8.80.
Found: C, 79.02; H, 6.97; N, 8.78.
epi-16e
(2S)-3-Methyl-2-[(1R)-1-methyl-3,4-dihydropyrrolo[1,2-
a]pyrazin-2(1H)-yl]butan-1-ol (17a)
Yellowish oil; yield: 0.039 g (14%); [a]D20 –13.4 (c 0.8, CHCl3).
Yellowish oil; yield: 0.033 g (15%); [a]D20 +23.4 (c 1.0, CHCl3).
IR (neat): 3415, 3078, 2975, 2926, 2849, 2793, 1639, 1496, 1485,
1339, 1219, 1119, 1002, 849, 704 cm–1.
IR (neat): 3361, 2968, 2934, 2853, 1466, 1449, 1367, 1315, 1114,
1080, 1069, 1019, 886, 733, 715 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.38–7.23 (m, 5 H), 6.47 (t,
J = 1.6 Hz, 1 H), 6.12 (t, J = 3.3 Hz, 1 H), 5.89–5.86 (m, 1 H), 5.80–
5.67 (m, 1 H), 5.22 (s, 1 H), 5.14 (t, J = 11.6 Hz, 1 H), 4.22 (dd,
J = 4.8 Hz, J = 9.7 Hz, 1 H), 4.13 (t, J = 4.1 Hz, 1 H), 4.05 (t,
J = 10.6 Hz, 1 H), 3.94–3.87 (m, 2 H), 3.73 (dd, J = 4.8 Hz, J = 10.9
Hz, 1 H), 3.26–3.18 (m, 1 H), 2.94–2.85 (m, 1 H), 2.76–2.68 (m, 1
H), 2.55–2.47 (m, 1 H), 1.57 (br s, 1 H).
1H NMR (400 MHz, CDCl3): d = 6.56–6.53 (m, 1 H), 6.18 (t,
J = 3.3 Hz, 1 H), 5.91–5.89 (m, 1 H), 4.34 (q, J = 6.2 Hz, J = 12.2
Hz, 1 H), 4.00–3.92 (m, 2 H), 3.62 (dd, J = 5 Hz, J = 10.2 Hz, 1 H),
3.31 (t, J = 10.6 Hz, 1 H), 3.19–3.12 (m, 1 H), 3.10–3.00 (m, 1 H),
2.99–2.90 (m, 1 H), 2.00–1.90 (m, 1 H), 1.47 (d, J = 6.4 Hz, 3 H),
1.08 (d, J = 6.4 Hz, 3 H), 0.90 (d, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 136.0, 134.6, 128.9, 128.4, 128.2,
118.2, 117.7, 108.0, 103.8, 62.7, 60.6, 54.7, 44.2, 41.5, 38.3.
13C NMR (100 MHz, CDCl3): d = 132.5, 118.4, 108.0, 103.2, 63.1,
58.8, 53.0, 45.7, 41.4, 27.9, 22.6, 20.9, 19.9.
MS (ES): m/z = 283.2 [M + H]+ (100), 305.1 [M + Na]+ (23).
MS (EI): m/z = 207 (100), 121 (53), 191 (35), 222 (1).
MS (ES): m/z = 223.1 [M + H]+ (100).
Synthesis 2011, No. 6, 909–918 © Thieme Stuttgart · New York

916
A. Gualandi et al.
PAPER
Anal. Calcd for C13H22N2O (222.33): C, 70.23; H, 9.97; N, 12.60.
Found: C, 70.19; H, 10.00; N, 12.58.
J = 12.3 Hz, 1 H), 3.78 (ddd, J = 4.3 Hz, J = 5.3 Hz, J = 12.3 Hz, 1
H), 3.44 (dd, J = 4.3 Hz, J = 8.3 Hz, J = 13.1 Hz, 1 H), 2.65 (t,
J = 7.7 Hz, 1 H), 2.58 (ddd, J = 3.8 Hz, J = 6.3 Hz, J = 10.2 Hz, 1
H), 1.80 (m, 1 H), 0.89 (d, J = 6.8 Hz, 3 H), 0.85 (d, J = 6.8 Hz, 3
H).
epi-(17a)
Yellow oil; yield: 0.011 g (5%); [a]D20 –15.2 (c 1.0, CHCl3).
IR (neat) 3407, 2954, 2921, 1581, 1450, 1348, 1066, 1029, 731, 702
cm–1.
MS (ES): m/z = 299.2 [M + H]+ (100).
Anal. Calcd for C19H26N2 (298.42): C, 76.47; H, 8.78; N, 9.39.
Found: C, 76.45; H, 8.78; N, 9.37.
1H NMR (400 MHz, CDCl3): d = 6.53–6.50 (m, 1 H), 6.15 (t,
J = 3.0 Hz, 1 H), 5.88–5.84 (m, 1 H), 4.21 (q, J = 6.4 Hz, J = 12.7
Hz, 1 H), 4.00–3.86 (m, 2 H), 3.81 (dd, J = 3.7 Hz, J = 11.2 Hz, 1
H), 3.69 (dd, J = 7.1 Hz, J = 11.1 Hz, 1 H), 3.24–314 (m, 1 H),
2.68–2.60 (m, 1 H), 2.03–190 (m, 1 H), 2.00–1.90 (m, 1 H), 1.41 (d,
J = 6.2 Hz, 3 H), 1.02 (d, J = 6.8 Hz, 3 H), 0.98 (d, J = 6.8 Hz, 3 H).
(2S)-3-Methyl-2-[(1R/1S)-1-phenyl-3,4-dihydropyrrolo[1,2-
a]pyrazin-2(1H)-yl]butan-1-ol (17g + epi-17g)
Light-red oil; yield: 0.221 g (78%); dr 40:60.
1H NMR (400 MHz, CDCl3): d (representative signals for
17g) = 7.36–7.28 (m, 5 H), 6.58 (m, 1 H), 6.08 (dd, J = 2.8 Hz,
J = 3.5 Hz, 1 H), 5.32 (m, 1 H), 5.19 (s, 1 H), 4.15 (ddd, J = 4.0 Hz,
J = 11.3 Hz, J = 11.4 Hz, 1 H), 4.08 (ddd, J = 2.1 Hz, J = 3.9 Hz,
J = 11.4 Hz, 1 H), 3.42 (dd, J = 5.2 Hz, J = 10.7 Hz, 1 H), 3.35 (t,
J = 10.7 Hz, 1 H), 3.29 (ddd, J = 1.9 Hz, J = 4.0 Hz, J = 12.1 Hz, 1
H), 3.16 (m, 1 H), 2.61 (ddd, J = 5.4 Hz, J = 6.4 Hz, J = 11.6 Hz, 1
H), 2.04 (m, 1 H), 1.05 (d, J = 6.4 Hz, 3 H), 0.83 (d, J = 6.4 Hz, 3
H).
13C NMR (100 MHz, CDCl3): d = 141.8, 131.8, 129.4, 128.6, 128.0,
118.2, 108.3, 105.7, 63.7, 62.5, 58.5, 45.7, 42.0, 26.9, 22.9, 19.6.
1H NMR (400 MHz, CDCl3): d (representative signals for epi-
17g) = 6.55 (m, 1 H), 6.05 (dd, J = 2.8 Hz, J = 3.6 Hz, 1 H), 5.30
(m, 1 H), 5.10 (s, 1 H), 3.94 (dd, J = 2.9 Hz, J = 11.7 Hz, 1 H), 3.72
(dd, J = 5.7 Hz, J = 11.7 Hz, 1 H), 2.26 (m, 1 H), 0.93 (d, J = 6.6 Hz,
3 H), 0.80 (d, J = 6.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 133.2 118.0, 107.8, 102.8, 66.2,
60.2, 52.2, 45.7, 44.9, 27.6, 21.7, 20.9, 20.1.
MS (EI): m/z = 207 (100), 121 (51), 191 (19), 222 (1).
MS (ES): m/z = 223.1 [M + H]+ (100).
(2S)-2-[(1R/1S)-1-Ethyl-3,4-dihydropyrrolo[1,2-a]pyrazin-
2(1H)-yl]-3-methylbutan-1-ol (17b + epi-17b)
Yellow oil; yield: 0.160 g (68%); dr 65:35.
1H NMR (400 MHz, CDCl3): d (representative signals for 17b) =
4.23 (t, J = 4.6 Hz, 1 H), 3.64 (dd, J = 5.2 Hz, J = 10.4 Hz, 1 H),
3.35 (t, J = 10.4 Hz, 1 H), 3.04 (dt, J = 3.2 Hz, J = 11.7 Hz, 1 H),
2.77 (m, 1 H); d (representative signals for epi-17b) = 4.08 (t,
J = 4.7 Hz, 1 H), 3.82 (dd, J = 3.5 Hz, J = 11.4 Hz, 1 H), 3.69 (dd,
J = 6.1 Hz, J = 6.8 Hz, 1 H), 3.20 (dt, J = 4.0 Hz, J = 12.3 Hz, 1 H),
2.50 (m, 1 H).
Anal. Calcd for C18H24N2O (284.40): C, 76.02; H, 8.51; N, 9.85.
Found: C, 76.16; H, 8.50; N, 9.83.
Anal. Calcd for C14N24N2 (236.25): C, 71.14; H, 10.23; N, 11.85.
Found: C, 71.11; H, 10.25; N, 11.84.
(1R)-1-Methyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (21a);
Typical Procedure
(2S)-2-[(1R/1S)-1-Allyl-3,4-dihydropyrrolo[1,2-a]pyrazin-
2(1H)-yl]-3-methylbutan-1-ol (17e + epi-17e)
Yellowish oil; yield: 0.158 g (64%); dr 50:50.
1H NMR (400 MHz, CDCl3): d (representative signals for 17e) =
6.57–6.55 (m, 1 H), 5.95–5.88 (m, 1 H), 5.62–5.49 (m, 1 H), 4.39 (t,
J = 4.2 Hz, 1 H), 4.23 (t, J = 5.1 Hz, 1 H), 3.36 (t, J = 10.4 Hz, 1 H),
3.09–2.93 (m, 2 H), 1.05 (d, J = 6.8 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 3
H); d (representative signals for epi-17e) = 6.54–6.50 (m, 1 H),
5.87–5.84 (m, 1 H), 5.83–5.71 (m, 1 H), 3.28 (dt, J = 4.6 Hz,
J = 12.8 Hz, 1 H), 2.85–2.77 (m, 1 H), 0.87 (t, J = 7.2 Hz, 3 H).
10% Pd/C (0.048 g) was added to a soln of 16a (0.476 g, 1.9 mmol)
in MeOH (10 mL) inside an autoclave and the mixture was kept un-
der H2 (7 bar) for 2 d. The catalyst was filtered off on a small pad of
Celite and the organic soln was concentrated under vacuum. The
oily residue was purified by column chromatography [SiO2,
CH2Cl2–MeOH (95:5)] to give an orange oil; yield: 0.205 g (81%);
[a]D20 +8.3 (c 0.7, CHCl3).
1H NMR (400 MHz, CDCl3): d = 6.54 (t, J = 2.4 Hz, 1 H), 6.15 (dd,
J = 2.8 Hz, J = 3.6 Hz, 1 H), 5.90–5.80 (m, 1 H), 4.06 (q, J = 6.8 Hz,
1 H), 3.95–3.90 (m, 2 H), 3.38–3.31 (m, 1 H), 3.24–3.15 (m, 1 H),
1.06 (d, J = 6.8 Hz, 3 H).
Anal. Calcd for C15H24N2 (248.36): C, 72.54; H, 9.74; N, 11.28.
Found: C, 72.28; H, 9.76; N, 11.24.
13C NMR (100 MHz, CDCl3): d = 132.9, 119.0, 107.7, 102.3, 49.5,
(2S)-2-[(1R/1S)-1-Benzyl-3,4-dihydropyrrolo[1,2-a]pyrazin-
2(1H)-yl]-3-methylbutan-1-ol (17f + epi-17f)
Light-red oil; yield: 0.226 g (76%); dr 50:50.
45.4, 43.4, 31.0.
MS (ES): m/z = 136.1 [M + H]+.
1H NMR (400 MHz, CDCl3): d (representative signals for 17f) =
7.33–7.21 (m, 4 H), 6.95 (m, 1 H), 6.54 (m, 1 H), 6.11 (dd, J = 2.8
Hz, J = 3.6 Hz, 1 H), 5.64 (ddd, J = 0.7 Hz, J = 1.6 Hz, J = 3.5 Hz,
1 H), 4.54 (dd, J = 4.8 Hz, J = 6.1 Hz, 1 H), 3.86 (dt, J = 3.9 Hz,
J = 12.1 Hz, 1 H), 3.64 (dd, J = 5.1 Hz, J = 10.7 Hz, 1 H), 3.54 (m,
1 H), 3.33 (t, J = 10.7 Hz, 1 H), 3.17 (dd, J = 4.6 Hz, J = 13.1 Hz, 1
H), 3.00–2.87 (m, 3 H), 2.82 (ddd, J = 5.1 Hz, J = 7.9 Hz, J = 13.1
Hz, 1 H), 1.87 (m, 1 H), 0.97 (d, J = 6.7 Hz, 3 H), 0.87 (d, J = 6.7
Hz, 3 H).
13C NMR (100 MHz, CDCl3): d (representative signals for 17f)
= 138.3, 129.7, 128.5, 128.1, 126.3, 118.3, 107.4, 104.5, 66.8, 50.1,
44.9, 43.8, 43.0, 40.6, 28.4, 22.0, 19.7.
MS (ES): m/z = 299.2 [M + H]+ (100).
1H NMR (400 MHz, CDCl3): d (representative signals for epi-
17f) = 4.34 (t, J = 6.7 Hz, 1 H), 3.93 (ddd, J = 4.3 Hz, J = 8.3 Hz,
Anal. Calcd for C8H12N2 (136.19): C, 70.55; H, 8.88; N, 20.57.
Found: C, 70.28; H, 8.91; N, 20.50.
(1R)-1-Ethyl-(1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (21b)
This was prepared from 16b (0.156 g, 0.6 mmol) as described
above.
Orange oil; yield: 0.156 g (79%); [a]D20 +11.8 (c 0.7, CHCl3).
1H NMR (400 MHz, CDCl3): d = 6.55 (t, J = 2.1 Hz, 1 H), 6.15 (t,
J = 3.4 Hz, 1 H), 5.90–5.88 (m, 1 H), 3.95–3.87 (m, 3 H), 3.38–3.35
(m, 1 H), 3.20–3.12 (m, 1 H), 2.03–1.94 (m, 1 H), 1.74–1.62 (m, 1
H), 1.06 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 131.5, 118.8, 107.5, 102.3, 55.0,
45.3, 42.9, 28.2, 10.2.
MS (ES): m/z = 151.1 [M + H]+ (100).
Synthesis 2011, No. 6, 909–918 © Thieme Stuttgart · New York

PAPER
1,2,3,4-Tetrahydropyrrolo[1,2-a]pyrazines
917
Anal. Calcd for C9H14N2 (150.22): C, 71.96; H, 9.39; N, 18.65.
Found: C, 71.63; H, 9.43; N, 18.58.
ters to the nonhydrogen atoms. All hydrogen atoms were located in
the Fourier map. The aromatic and methylene hydrogen atoms were
placed in the calculated positions, refined with isotropic thermal pa-
rameters U(H) = 1.2 Ueq(C), and allowed to ride on their carrier
carbons, whereas the methine H atoms were located in the Fourier
map and refined isotropically [U(H) = 1.2 Ueq(C)]. Crystal data and
details of the data collection for 14 are reported in Table 3.
X-ray Crystallographic Study of Oxazolopyrrolopyrazine 14
The X-ray intensity data for 14 were measured on a Bruker SMART
Apex II diffractometer equipped with a CCD area detector and a
graphite monochromated Mo-Ka radiation source (l = 0.71073 Å).
Cell dimensions and the orientation matrix were initially deter-
mined from a least-squares refinement on reflections measured in
three sets of 20 exposures, collected in three different w regions, and
eventually refined against all data. For all crystals, a full sphere of
reciprocal space was scanned by 0.3° w steps. The software
SMART29 was used for collecting frames of data, indexing reflec-
tions, and determining lattice parameters. The collected frames
were then processed for integration by SAINT29 software, and an
empirical absorption correction was applied with SADABS.30 The
structure was solved by direct methods (SIR 97)31 and subsequent
Fourier syntheses, and refined by full-matrix least-squares calcula-
tions on F2 (SHELXTL),32 attributing anisotropic thermal parame-
Acknowledgment
This work was carried out within the Prin Project ‘Sintesi e stereo-
controllo di molecole organiche per lo sviluppo di metodologie in-
novative’. We are grateful to Mr Matteucci Elia and Mrs Moylan
Claire for their help with the experimental work.
References
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Table 3 Crystal Data and Structure Refinement for 14
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Compound
Formula
M
14
C15H16N2 O
240.30
296(2)
T, K
Crystal symmetry
Space group
a (Å)
monoclinic
P21
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8.2411(4)
7.3720(4)
11.1066(6)
90
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b (Å)
c (Å)
a (°)
b (°)
110.220(3)
90
g (°)
V (Å3)
633.18(6)
2
Z
Dc (Mg m–3)
m(Mo-Ka) (mm–1)
F(000)
1.260
0.080
256
Crystal size (mm)
q limits (°)
Reflections collected
0.30 × 0.28 × 0.25
1.95–26.99
9380
Unique obs. reflections [Fo > 4s(Fo)] 2761 [R(int) = 0.0529]
Goodness-of-fit-on F2
1.114
R1 (F)a, wR2 (F2)b
0.0436, 0.1008
0.323 and -0.217
Largest diff. peak and hole, e. (Å–3)
a R1 = S||Fo| – |Fc||/S|Fo|.
(18) Zhu, B.; Marinelli, B. A.; Goldschmidt, R.; Foleno, B. D.;
Hilliard, J. J.; Bush, K.; Macielag, M. Bioorg. Med. Chem.
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b wR2 = [Sw(Fo2 – Fc2)2/Sw(Fo2)2]1/2 where w = 1/[s2(Fo ) + (aP)2 +
2
bP] where P = (Fo2 + Fc )/3.
2
Synthesis 2011, No. 6, 909–918 © Thieme Stuttgart · New York

918
A. Gualandi et al.
PAPER
(19) (a) Alvaro, G.; Di Fabio, R.; Gualandi, A.; Savoia, D. Eur. J.
Org. Chem. 2007, 5573. (b) Albano, G.; Gualandi, A.;
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(20) 3,4-Dihydropyrrolo[1.2-a]pyrazine and achiral iminium
ions analogous to 9 have been prepared from 1-(2-
aminoethyl)pyrrole; see: de Pablo, M. S.; Gandásegui, T.;
Vaquero, J. J.; García Navío, J. L.; Alvarez-Builla, J.
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(22) The following procedure was used to prepare methyl 1-(2-
bromoethyl)-2-pyrrolecarboxylate: Blaszykowski, C.;
Aktoudianakis, E.; Alberico, D.; Bressy, C.; Hulcoop, D. G.;
Jafarpour, F.; Joushaghani, A.; Laleu, B.; Lautens, M.
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chirality of the norephedrine. However, the potential of such
compounds as precursors of chiral iminium ions, which
could serve as suitable substrates for the addition of
Grignard reagents, was not considered during the work
reported here.
(27) (a) Takahashi, H.; Chida, Y.; Higashiyama, K.; Onishi, H.
Chem. Pharm. Bull. 1985, 33, 4662. (b) Yamato, M.;
Hashigaki, K.; Ishikawa, S.; Qais, N. Tetrahedron Lett.
1988, 29, 6949. (c) Takahashi, H.; Hsieh, B. C.;
Higashiyama, K. Chem. Pharm. Bull. 1990, 38, 2429.
(d) Yamato, M.; Hashigaki, K.; Qais, N.; Ishikawa, S.
Tetrahedron 1990, 46, 5909. (e) Hashigaki, K.; Kan, K.;
Qais, N.; Takeuchi, Y.; Yamato, M. Chem. Pharm. Bull.
1991, 39, 1126. (f) Higashiyama, K.; Nakahata, K.;
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(g) Higashiyama, K.; Nakahata, K.; Takahashi, H.
Tetrahedron 1994, 50, 1083. (h) Higashiyama, K.; Inoue,
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(i) Yamauchi, T.; Higashiyama, K.; Kubo, H.; Ohmiya, S.
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(24) Other reaction conditions were also tested by varying the
solvent (DMF), the dehydrating agent (molecular sieves),
and the temperature, but less satisfactory results were
obtained. Moreover, mixtures of products 12a and 13a were
obtained by carrying out the reactions in the presence of a
base (K2CO3 or Et3N).
(25) Crystallographic data for compound 14 have been deposited
with the Cambridge Crystallographic Data Centre as
supplementary publications CCDC 792774; copies can be
obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [fax: +44 (1223)336033 or
email: deposit@ccdc.cam.ac.uk].
(26) It is noteworthy that tricyclic tetrahydrooxazolopyrazolo-
pyridine structures with three carbon stereocenters have
been prepared as single diastereomers from 2-pyrrole-
carboxaldehyde, (S)- or (R)-a-amino acid esters, and (+)- or
(–)-norephedrine. The configuration of the newly formed
stereocenter in the oxazolidine ring depends only on the
(28) Demir, A. S.; Subasi, N. T.; Sahin, E. Tetrahedron:
Asymmetry 2006, 17, 2625.
(29) SMART & SAINT, Software Reference Manuals, Version
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(32) Sheldrick, G. M. SHELXTLplus, Version 5.1 (Windows NT
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Synthesis 2011, No. 6, 909–918 © Thieme Stuttgart · New York