One-pot preparation of 1,2-aminoalcohols or pyrroles by CeCl3·7 H2O-mediated Barbier reactions of N,N'-bis[(S)-1-phenylethyl]ethanediimine

Article abstract of DOI:10.1055/s-2002-19343

1,2-Aminoalcohols or pyrroles were obtained from N,N′-bis[(S)-1-phenylethyl]ethanediimine by a one-pot procedure involving two Barbier additions of allylic and/or propargyl zinc reagents alternated with the hydrolysis of the unreacted imine function, followed by a cyclisation/dehydration sequence when a 1-amino-5-pentyne moiety was involved, all these steps being promoted by CeCl₃·7 H₂O.

Full text of DOI:10.1055/s-2002-19343

158
LETTER
One-pot Preparation of 1,2-Aminoalcohols or Pyrroles by CeCl3 7 H2O-
mediated Barbier Reactions of N,N’-Bis[(S)-1-phenylethyl]ethanediimine
One-pot
P
reparatio
i
n
of 1,
a
2-Aminoalc
n
ohols or Pyr
l
roles uca Martelli, Stefano Morri, Diego Savoia*
Dipartimento di Chimica “G. Ciamician”, via Selmi 2, 40126 Bologna, Italy
Fax +39(051)2099456; E-mail: savoia@ciam.unibo.it
Received 31 October 2001
R1
R1
2 R1M
Abstract: 1,2-Aminoalcohols or pyrroles were obtained from
N,N’-bis[(S)-1-phenylethyl]ethanediimine by a one-pot procedure
N
N
NH HN
involving two Barbier additions of allylic and/or propargyl zinc re-
agents alternated with the hydrolysis of the unreacted imine func-
tion, followed by a cyclisation/dehydration sequence when a 1-
amino-5-pentyne moiety was involved, all these steps being pro-
moted by CeCl3 7 H2O.
Ph
Ph
Ph
Ph
1
2
R1M
R1
R2
R1
Key words: 1,2-aminoalcohols, cerium trichloride, 1,2-diamines,
pyrroles, stereoselective synthesis
R2M
NH HN
NH
N
Ph
Ph
Ph
Ph
4
3
The one-pot syntheses of C2-symmetric 1,2-diamines 21
and some unsymmetrically disubstituted 1,2-diamines 42
by organometallic additions to the glyoxal diimine 1 have
been reported. The corresponding preparation of 1,2-ami-
noalcohols 6 would be possible in principle by a three step
sequence involving the hydrolysis of the intermediate imi-
ne 3 to give the -aminoaldehyde 5, but has not been yet
described (Scheme 1). The successful synthesis of 4 and 6
requires the control of the organometallic addition to the
diimine 1, as the second addition of the same reagent R1M
to the second imine function must be avoided. This has
been achieved using of a poorly reactive organometallic
reagent and exploiting the different reactivity of the 1,2-
diimine and -amidoimine moieties. In fact, we have re-
ported that the addition of an excess of prenylzinc bro-
mide to the diimine 1 at low temperature gave almost
exclusively the branched mono-adduct 3 (R = 1,1-dimeth-
yl-2-propenyl, 90% yield, dr 90:10), then the correspond-
ing aldehyde was obtained by hydrolysis (50% yield).1e
We have successively observed that almost the same re-
sult can be obtained by applying a previously described3
Barbier procedure in which the zinc reagent was formed
in situ from prenyl bromide and zinc powder in the pres-
ence of a catalytic amount of CeCl3 7 H2O in THF at
25 °C. In the attempt to prepare the corresponding C2-
symmetric 1,2-diamine 2 using more drastic conditions,
we added an excess of reagents (prenyl bromide, Zn and
salt) to the intermediate mono-adduct 3 avoiding quench-
ing, so triggering an exothermic reaction. Unexpectedly,
the isolated product was the 1,2-disubstituted 1,2-ami-
noalcohol 7 rather than the expected 1,2-diamine 2
(Scheme 2).
H2O
R1
R1
R1(R2)
OH
R1M
NH
NH
O
or R2M
Ph
Ph
5
6
Scheme 1
We reasoned that the product 7 was formed through the
reaction sequence depicted in Scheme 1 (1, 3, 5, 6) and the
hydrolysis of the intermediate imine 3 was due to the wa-
ter released by the hydrated cerium salt.4 By performing
the reaction by stepwise addition of controlled amounts of
reagents and monitoring its course by GC-MS analysis of
quenched samples, we identified the intermediates, partic-
ularly the aldehyde, and optimised the protocol. The first
organometallic addition is preferably performed using
prenyl bromide, Zn and CeCl3 7 H2O (1.5, 4 and 1 molar
equivalents, respectively, with respect to the diimine 1),
so obtaining the mono-adduct 3 with satisfactory selectiv-
ity. Then the hydrolysis of the preserved imine function
was carried out by adding 2 equivalents of the hydrated
salt and heating at reflux temperature for 1 hour (in the
original experiment heat was provided by the exothermic
reaction that was established after the addition of neat pre-
nyl bromide to the reaction mixture containing Zn). The
addition of further prenyl bromide (1.5 equiv) to the so
formed aldehyde 5 at room temperature gave the 1,2-ami-
noalcohol 7 with high yield and stereocontrol. The pure
main diastereomer was obtained after chromatography
and crystallisation with 54% yield. The configuration of 7,
presumably controlled by chelation in the second organo-
metallic step, was determined after routine conversion to
the 1,3-oxazolidin-2-one 8, involving hydrogenolysis of
the N-substituents and concomitant hydrogenation of the
double bonds, followed by reaction with 1,1’-carbonyldi-
Synlett 2002, No. 1, 28 12 2001. Article Identifier:
1437-2096,E;2002,0,01,0158,0160,ftx,en;G32001ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

LETTER
One-pot Preparation of 1,2-Aminoalcohols or Pyrroles
159
give prevalently homopropargylic derivatives have been
reported. Moreover, cyclisations of 1-amino-5-alkynes
catalysed by organolanthanide complexes, apart cerium,
have been reported.7,8 By using propargyl bromide in both
Barbier steps the pyrrole 14 was similarly obtained with
moderate yield. Instead, the reaction performed by using
propargyl bromide and allyl bromide, in the order, gave
the corresponding 1,2-aminoalcohol with 33% yield, but
impure owing to its difficult separation from byproducts.
1
iv-v
i-iii
HN
O
NH
OH
Ph
O
7: 54%, d.r. > 99:1
8: 75%
i, ii, vii
i, ii, vi
In summary, we have described two convenient protocols
for the one-pot conversion of a glyoxal diimine to 1,2-
aminoalcohols and 1,2,5-trisubstituted pyrroles, both
transformations being promoted by CeCl3 7 H2O. The
noteworthy feature of the first reaction is that an imine
group can be hydrolysed to the aldehyde in an anhydrous
solvent and in neutral conditions, which allow to succes-
sively perform Barbier-type organometallic reactions9 of
the intermediate aldehyde in the same flask. As concerns
the synthesis of pyrroles, it is clear that our protocol
should be applied to achiral 1,2-diimines, since the chiral-
ity of the N-substituent has no role in this process. Espe-
cially, the ability of the hydrated or anhydrous cerium salt
to promote or catalyse the cyclisation of homopropargylic
or homoallenylic amines is worth of investigation. The
expeditious synthesis of the 1,2-aminoalcohols and their
derivatives, particularly 710 and 8,11 makes these com-
pounds attractive for their use as ligands and auxiliaries in
a variety of asymmetric transformations.12
1
NH
Ph
OH
NH
OH
Ph
9: 41%, d.r. 90:10
10: 58%, d.r. 90:10
HO
i, ii, ix
1
N
NH
11
OH
Ph
Ph
12
-H2O
viii, ii, vii
N
N
Ph
Ph
13: 41%
14: 40%
Scheme 2 Reagents and conditions: (i) Zn (4 equiv), prenyl bromi-
de (1.5 equiv), CeCl3 7 H2O (1 equiv), THF, 25 °C, 0.5 h; (ii) CeCl3 7
H2O (2 equiv), 65 °C, 1 h; (iii) prenyl bromide (1.5 equiv), 25 °C, 1
h; (iv) H2/Pd/C, MeOH, 6 h; (v) 1,1’-carbonyldiimidazole, CH2Cl2, 2
h; (vi) allyl bromide (1.5 equiv), 25 °C, 1 h; (vii) pentadienyl bromide
(1.5 equiv), 25 °C, 1 h (viii) Zn (4 equiv), propargyl bromide (1.5
equiv), CeCl3 7 H2O (1 equiv), THF, 25 °C, 1 h; (ix) propargyl brom-
ide (1.5 equiv), THF, 25 °C, 1h.
Acknowledgement
We are grateful to the Ministero dell’Università e della Ricerca Sci-
entifica e Tecnologica, Roma, (National Project: “Stereoselezione
in Sintesi Organica. Metodologie ed Applicazioni”) and The Uni-
versity of Bologna for financial support.
imidazole. While the configuration of the stereocentre
created in the first addition step was known from previous
studies,1 the relative trans-configuration of the ring sub-
stituents at C4 and C5 was indicated by the coupling con-
stant of the corresponding protons (J = 2.1 Hz) and NOE
studies, as no response at H4 was observed by irradiating
H5, and vice versa. The optimised protocol was then ex-
ploited to prepare two new aminoalcohols by varying the
allylic bromide used in the second Barbier step: by using
allyl bromide and pentadienyl bromide the corresponding
products 9 and 10 were isolated as oils with moderate
yields after chromatography, but the diastereomers (dr
90:10) were not separated.
References
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In a further experiment we used first prenyl bromide, then
propargyl bromide after the hydrolysis step and were sur-
prised to find that the final product was the 1,2,5-trisubsti-
tuted pyrrole 13, which was isolated with 41% yield by
column chromatography and identified by GC-MS, IR
and 1H NMR analysis. The pyrrole 13 can be formed from
the intermediate bis-adduct 11 through CeCl3-promoted
5-exo-cyclisation of the 1-amino-5-pentyne moiety and
dehydration steps. As a fact, the additions of propargylic/
allenic zinc bromides to both imines5 and aldehydes6 to
(4) The deprotection of O-MEM ethers by CeCl3 7 H2O in
refluxing acetonitrile was reported when we had already
obtained this results: (a) Sabitha, G.; Babu, R. S.; Rajkumar,
M.; Srividya, R.; Yadav, J. S. Org. Lett. 2001, 3, 1149.
Similarly, FeCl3 6 H2O has been used to deprotect acetals
and thioacetals in CH2Cl2: (b) Sen, S. E.; Roach, S. L.;
Boggs, J. K.; Ewing, G. J.; Magrath, J. J. Org. Chem. 1997,
62, 6684. See also: (c) Khamal, A.; Laxman, E.; Reddy, P. S.
M. Synlett 2000, 1476. Carbonyl compounds have been
obtained from N,N-dimethylhydrazones by employing Ni,
Hg and Mn complexes and 1 drop of water in CHCl3: (d)
Khamal, A.; Arifuddin, M.; Rao, M. V. Synlett 2000, 1482.
Synlett 2002, No. 1, 158–160 ISSN 0936-5214 © Thieme Stuttgart · New York

160
G. Martelli et al.
LETTER
(5) (a) Poisson, J.-F.; Normant, J. F. J. Org. Chem. 2000, 65,
6553. (b) Poisson, J.-F.; Chemla, F.; Normant, J. F. Synlett
2001, 305. (c) Poisson, J.-F.; Normant, J. F. Org. Lett. 2001,
3, 1889.
(6) (a) Gaudemar, M. Bull. Soc. Chim. Fr. 1962, 974.
(b) Yanagisawa, A.; Habaue, S.; Yamamoto, H. J. Org.
Chem. 1989, 54, 5198. (c) Marshall, J. A.; Adams, N. D. J.
Org. Chem. 1998, 63, 3812. (d) Marshall, J. A.; Johns, B. A.
J. Org. Chem. 1998, 63, 7885. (e) Marshall, J. A.; Adams,
N. D. J. Org. Chem. 1999, 64, 5201. (f) Aurrecoechea, J.
M.; Arrate, M.; López, B. Synlett 2001, 872.
(7) (a) Li, Y.; Fu, P.-F.; Marks, T. J. Organometallics 1994, 13,
439. (b) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118,
707. (c) Li, Y.; Marks, T. J. Organometallics 1996, 15,
3770. (d) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1998, 120,
1757. (e) Li, Y.; Marks, T. J. J. Am. Chem. Soc. 1996, 118,
9295. For a review of metal-initiated amination of alkenes
and alkynes: (f)Müller, T. E.; Beller, M. Chem. Rev. 1998,
98, 675.
(8) The pyrrole should be also obtained by the analogous
cyclisation of the partially formed aminoallene: Arredondo,
V. M.; McDonald, F. E.; Marks, T. J. J. Am. Chem. Soc.
1998, 120, 4871.
1.8 Hz, 1 H), 2.51 (d, J = 1.8 Hz,1 H), 1.32 (d, J = 6.6 Hz, 3
H), 1.05 (s, 3 H), 1.0 (s, 3 H), 0.92 (s, 3 H), 0.84 (s, 3 H);
IR(nujol): 3317, 3300(broad), 1639 cm–1; MS: m/z =
105(100), 232(20), 128(16), 69(13), 106(13), 98(12),
60(11), 79(10), 77(6), 202(5). Anal. Calcd for C20H31NO: C,
79.67; H, 10.37; N, 4.65. Found: C, 79.65; H, 10.39; N, 4.63.
Spectroscopic data of selected products are reported in the
following; all products gave satisfactory elemental analyses.
4(R),5(R)-N-[1(S)-Phenylethyl]-5-amino-6,6-dimethyl-3-
vinyl-1,7-octadien-4-ol 10: dr 90:10; [ ]D25 –16.2 (c 1.10,
CHCl3); 1H NMR (200 MHz, CDCl3–D2O): = 5.85 (dd, J
= 10.8 and 17.4 Hz, 1 H), 5.81–5.61 (m, 1 H), 5.50–5.28 (m,
1 H), 5.17–4.80 (m, 4 H), 4.72 (d, J = 17.2 Hz, 1 H), 4.42 (dd,
J = 1.8 and 18.0 Hz, 1 H), 3.81 (q, J = 6.6 Hz, 1 H), 3.24 (dd,
J = 1.4 and 9.2 Hz, 1 H), 2.46 (d, J = 1.4 Hz, 1 H), 1.67 (m,
1 H), 1.37 (d, J = 6.6 Hz, 3 H), 1.04 (s, 3 H), 1.01 (s, 3 H);
IR: 3332, 3320(broad) cm–1; MS: m/z = 105(100), 230(36),
126(15), 79(11), 106(10), 202(7). 5-Methyl-1-[1(S)-
phenylethyl]-2-propynylpyrrole 14: 1H NMR (200 MHz,
CDCl3): = 7.4–7.2 (m, 3 H), 7.03 (m, 2 H), 6.025 (d, J =
3.2 Hz, 1 H), 5.83 (d, J = 3.2 Hz, 1 H), 5.59 (q, J = 6.7 Hz, 1
H), 3.41 (dd, J = 2.6 and 7.0 Hz, 2 H), 2.08 (t, J = 2.6 Hz, 1
H), 2.0 (s, 3 H), 1.89 (d, J = 6.7 Hz, 3 H); IR: 3292, 3069,
3056, 3020, 2140, 1680, 1662, 1592 cm–1; MS: m/z =
105(100), 119(54), 223(49), 118(24), 77(23), 104(23),
79(18), 103(17)
(9) It should be observed that even heating CeCl3 7 H2O at
150 °C and 0.03 Torr for 12 h forms a material containing
approximately 1 equiv of water, which reacts with MeLi to
form methane: Evans, W. J.; Feldman, J. D.; Ziller, J. W. J.
Am. Chem. Soc. 1996, 118, 4581.
(11) 4(R), 5(R)-Di-(2-methyl-2-butyl)-1,3-oxazolidin-2-one 8:
In a Parr apparatus a mixture of MeOH (50 mL), 7 (0.62 g, 2
mmol), 10% Pd/C (60 mg) was submitted to H2 pressure (45
psi) for 6 h. The mixture was filtered through a Celite pad
and the filtered solution was concentrated to leave 5(R)-
amino-3,3,6,6-tetramethyloctan-4(R)-ol as an oil: 0.35 g
(87%). [ ]D25 +12.6 (c 0.88, CHCl3); 1H NMR (300 MHz,
CDCl3): = 3.26 (s, 1 H), 2.73 (s, 1 H), 1.50–1.10 (m, 4 H),
0.85 (m, 12 H), 0.73 (2 s, 6 H); MS: m/z = 100(100), 130(79),
60(38), 71(22), 55(17), 59(16). A solution of this compound
(0.35 g, 1.7 mmol) and 1,1-carbonyldiimidazole (0.324 g, 2
mmol) in CH2Cl2 (8 mL) was stirred for 2 h, then H2O (5
mL) was added and the mixture was stirred for further 0.5 h.
The organic phase was separated and the aq phase was
extracted with CH2Cl2 (2 5 mL). The combined organic
layers were washed with brine, dried (Na2SO4) and
concentrated to leave 8 as a white solid: 0.33 g (86%); mp
85 °C; crystallisation from Et2O gave an analytical sample:
mp 89 °C; [ ]D25 +71.8 (c 0.5, CHCl3); 1H NMR (300 MHz,
CDCl3): = 6.24 (broad, 1 H), 4.06 (d, J = 2.1 Hz, 1 H), 3.27
(d, J = 2.1 Hz, 1 H), 1.50–1.15 (m, 4 H), 0.92–0.80 (m, 18
H); IR(nujol): 3265, 1751 cm–1; irradiating the absorption at
either = 4.06 (d) or = 3.27 (d) only a response (8%) at
0.81 (m) was observed; MS: m/z = 128(100), 86(58), 71(29),
156(13), 55(12), 129(10), 142(7). Anal. Calcd for
(10) Representative Procedure for the Preparation of 1,2-
Aminoalcohols and Pyrroles: Zn powder (1.40 g, 20 mmol)
was heated at 150 °C for 5 min in a 50 mL two-neck flask
under magnetic stirring in a flow of Ar, then was covered
with anhyd THF (20 mL) at r.t. To the stirred mixture were
added, in the order, the diimine 1 (1.32 g, 5 mmol), CeCl3 7
H2O (1.86 g, 5 mmol) and then, slowly, a solution of prenyl
bromide (1.12 g, 7.5 mmol) in THF (7 mL). After that the
heterogeneous mixture had become greenish (ca 0.5 h),
CeCl3 7 H2O (3.72 g, 10 mmol) was then added and the
mixture was heated at reflux temperature for 1 h, a yellowish
colour being observed after that time. Then neat prenyl
bromide (1.12 g, 7.5 mmol) was added and the mixture was
stirred for 1 h at r.t. The reaction mixture was quenched by
addition of sat. NaHCO3 solution (10 mL) and the organic
materials were extracted with Et2O (3 20 mL). The
collected ethereal layers were dried over Na2SO4 and
concentrated to leave a solid residue, which was
chromatographed through a short column of SiO2 to give
4(R),5(R)-N-[1(S)-phenylethyl]-5-amino-3,3,6,6-
tetramethyl-1,7-octadien-4-ol 7 as a white solid: 1.00 g
(66%). Crystallisation from n-pentane gave pure 7: 0.81 g
(54%); mp 65 °C; [ ]D25 –10.7 (c 0.68, CHCl3); 1H NMR
(300 MHz, CDCl3): = 7.38–7.20 (m, 5 H), 5.84 (dd, J =
10.8 and 17.4 Hz, 1 H), 5.78 (dd, J = 10.8 and 17.4 Hz, 1 H),
5.09 (dd, J = 0.9 and 10.8 Hz, 1 H), 5.03 (dd, J = 0.9 and 17.4
Hz, 1 H), 4.90 (dd, J = 0.9 and 17.4 Hz, 1 H), 4.89 (dd, J =
0.9 and 10.8 Hz, 1 H), 3.88 (q, J = 6.6 Hz, 1 H), 3.24 (d, J =
C13H25NO2: C, 68.68; H, 11.08; N, 6.16. Found C, 68.65; H,
11.10; N, 6.15.
(12) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev. 1996, 96,
835.
Synlett 2002, No. 1, 158–160 ISSN 0936-5214 © Thieme Stuttgart · New York