Access to optically pure nitrogen heterocycles based on hydrozirconation of unsaturated secondary amines

Article abstract of DOI:10.1055/s-2007-990898

Optically active N-heterocycles with four-, five-, or six-membered rings can be prepared from unsaturated secondary amines, by using a one-pot hydrozirconation/iodination sequence as the key step. The presented method allows the preparation of 2-substituted pyrrolidines enantiomeric to those previously obtained from N-allyloxazolidines. The two approaches use the same reagents (allyl bromide and aldehydes) and the same (R)-2-phenyl-glycinol as the chiral inductor. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990898

PAPER
61
Access to Optically Pure Nitrogen Heterocycles Based on Hydrozirconation of
Unsaturated Secondary Amines
Hydrozirconation of
U
’
nsaturate
h
d
S
econdary
a
Amines med Ahari, Antoine Joosten, Jean-Luc Vasse, Jan Szymoniak*
Réactions Sélectives et Applications, CNRS (UMR 6519) and , Université de Reims, 51687 Reims Cedex 2, France
Fax +33(3)26913166; E-mail: jan.szymoniak@univ-reims.fr
Received 14 September 2007
of the Schwartz reagent, which do not significantly im-
Abstract: Optically active N-heterocycles with four-, five-, or six-
membered rings can be prepared from unsaturated secondary
amines, by using a one-pot hydrozirconation/iodination sequence as
the key step. The presented method allows the preparation of 2-sub-
pede the further hydrozirconation. In contrast, to our
knowledge tolerance to secondary (primary) amino group
has not been reported. In preliminary experiments, we
stituted pyrrolidines enantiomeric to those previously obtained have noticed that simple w-unsaturated amines can be hy-
from N-allyloxazolidines. The two approaches use the same re-
agents (allyl bromide and aldehydes) and the same (R)-2-phenyl-
glycinol as the chiral inductor.
drozirconated by using one equivalent of Schwartz
reagent. The possibility of carrying out alkene hydro-
zirconation in the presence of an amino group opens a ver-
satile new entry to nitrogen heterocycles.
Key words: hydrozirconation, nitrogen heterocycles, pyrrolidines,
enantiomers
In pursuit of our work on the zirconium-mediated deoxy-
genative ring-closing reactions,6 we have recently report-
ed a new diastereoselective synthesis of 2-substituted and
One of the simplest method of creating sp2C–Zr or sp3C–
2,5-disubstituted pyrrolidines starting from N-allyloxazo-
Zr bonds involves hydrozirconation of alkynes and alk-
lidines via a tandem hydrozirconation/TiCl4-catalyzed
enes.1 The organozircononocenes, usually formed in situ
ring-closure sequence (Scheme 1).7
by using readily available Schwartz reagent, Cp2Zr(H)Cl,2
In this paper, we describe an alternative reaction pathway
(carbon–nitrogen bond-forming reaction) which involves
haloamine A, in situ generated by applying hydrozircona-
tion/halogenation sequence to the homoallylic amine B
(Scheme 2). Accordingly, the stereochemistry at the a-
carbon position is controlled through diastereoselective
allylation of the corresponding phenylglycinol derived
imine.
are valuable synthetic intermediates. They give insertion
reactions, can be oxidized and also react, alone or in the
presence of additives, with several carbon- or heteroatom-
based electrophiles.1,3 Particularly, when treated with io-
dine, bromine or N-halosuccinimide, organozirconocenes
are readily converted into the corresponding halides. Hy-
drozirconation/halogenation sequence has recently been
applied in natural product synthesis.4 Furthermore, versa-
tile hydrozirconation-transmetalation sequences could af-
ford a number of transition metal derivatives, thus
opening a wide access to cross-coupling chemistry.3,5 The
functional group compatibility of hydrozirconation is re-
lated to Lewis acidity of zirconium and the hydridic char-
acter of the Schwartz reagent. In general, aldehydes,
ketones, amides, and nitriles are not compatible with hy-
drozirconation conditions, whereas ethers, acetals, some
esters, carbamates, sulfides, and halides are tolerated, es-
pecially when reactive carbon–carbon triple and double
bonds are present. Alcohols react with the first equivalent
Allylation of (R)-phenylglycinol-derived imines by using
allyl bromide in the presence of zinc or indium has proven
to occur with a high level of facial selectivity to afford N-
homoallylamino alcohols 3.8 Therefore, the strategy pre-
sented in Scheme 2 appears complementary from a stere-
ochemical point of view to the hydrozirconation/TiCl4-
mediated cyclization strategy,7 since diastereomers with
the opposite configuration on the newly formed stereo-
genic C2 center would selectively be formed, starting
from the same reagents (allyl bromide and aldehydes) and
the chiral inductor [(R)-2-phenylglycinol] (Scheme 3).
Ph
Ph
N
R
Cp2Zr(H)Cl
N
TiCl4
N
O
Ti
OH
O
[Zr]
R
Ph
R
1
2
R = alkyl, aryl
31–62%, dr up to 15:1
[Zr] = Cp2ZrCl
Scheme 1 Diastereoselective synthesis of 2-substituted pyrrolidines from N-allyloxazolidines
SYNTHESIS 2008, No. 1, pp 0061–0068
x
x
.
x
x
.2
0
0
7
Advanced online publication: 15.11.2007
DOI: 10.1055/s-2007-990898; Art ID: Z21807SS
© Georg Thieme Verlag Stuttgart · New York

62
M. Ahari et al.
PAPER
halogenation
[Zr]
X
R
N
R
NH
R
NH
A
hydrozirconation
RCHO
NH2
M
OH
R
NH
Ph
Aux
B
Scheme 2 Alternative C–N bond-forming strategy
Ph
R
Ph
N
OH
Ph
HN
OH
H2N
O
R
1
3
1) H[Zr]
2) I2
1) H[Zr]
C–N bond
formation
C–C bond
formation
ref. 7
2) TiCl4
Ph
Ph
OH
OH
N
R
N
R
Scheme 3 Stereochemically complementary approaches
In a model experiment, N-homoallylamino alcohol 3a
(Table 1) was prepared from N-phenylglycinol-derived
benzaldimine in good yield and with almost total diaste-
reoselectivity (dr up to 95:5). At this stage, and since the
OH group is known to react with the Schwartz reagent, it
was first protected as a silyloxy group before the hydrozir-
conation reaction was carried out. As expected, also in
this case, the hydrozirconation was proven to occur
smoothly in the presence of a secondary amine, by using
one equivalent of Cp2Zr(H)Cl. Subsequent treatment with
iodine, and in situ internal displacement in the presence of
an acid scavenger (Et3N) afforded the desired pyrrolidine.
Additional alcohol deprotection led to 4a in 61% yield
starting from 3a. We noticed that the reaction can also be
carried out with the unprotected amino alcohol. In this
case, two equivalents of the Schwartz reagent are re-
quired, but the reaction sequence is significantly short-
ened.
Table 1 Diastereoselective Synthesis of Pyrrolidines 4
R
Br
1) Cp2Zr(H)Cl
2) I2, Et3N
R
N
N
HN
R
Zn or In
OH
OH
OH
Ph
Ph
Ph
4a–h
3a–h
Entry
R
Compound
Yield (%)a
1
2
Ph
4a
4b
4c
4d
4e
4f
68
60
60
62
45
67
57
66
64
40
2-BrC6H4
3-MeOC6H4
4-FC6H4
3-furyl
3
4
5
6
2-thienyl
cinnamyl
C5H11
7
4g
4h
4i
A wide range of amino alcohols were prepared by allyla-
tion of the corresponding amines in good yields and ste-
reoselectivities (de up to 95%). Diastereomerically pure
amino alcohols 3a–h, isolated after purification by col-
umn chromatography on silica gel, were next engaged
into the hydrozirconation/iodination sequence to afford
the expected pyrrolidines. The results are shown in
Table 1.
8
9b
10
Pr
2-N-Boc-indolyl
4j
a Isolated yields.
b Product isolated in its TBS-protected form.
A number of 2-substituted pyrrolidines, many of them
new, were obtained. The reaction was found to be compat-
Synthesis 2008, No. 1, 61–68 © Thieme Stuttgart · New York

PAPER
Hydrozirconation of Unsaturated Secondary Amines
63
ible in the presence of various aryl, heteroaryl, and alkyl residue can be kept in its original state (X = H) (in this
fragments. Remarkably, furyl, thienyl, indolyl (entries 5, case, two equivalents of the Schwartz reagent are re-
6 and 10), and also an a,b-unsaturated group (entry 7) can quired) or converted into its O-protected analogue
efficiently be introduced into the 2-position of the pyrro- (X = TBS), prior to cyclization. Subsequent hydrozircon-
lidine. In all cases, a unique stereoisomer, having the op- ation-iodination sequence led to the expected 2,3-disub-
posite configuration with respect to that formed from the stituted pyrrolidine
6
in good yield. The cis-
corresponding N-allyloxazolidine, was isolated. An easy stereochemistry in 6 originated from the syn-stereoselec-
removal of the phenylglycinol residue in 4h by tive crotylzincation reaction.15 Furthermore, the accesses
hydrogenolysis9 produced (S)-2-pentylpyrrolidine (98% to 2-substituted azetidines and piperidines have been ini-
yield), that is, enantiomeric to that obtained previously by tiated, by using phenylglycinol benzaldimine. These com-
applying the oxazolidine-based method. The pyrrolidine pounds can be prepared by shortening (– 1 C) or
ring is common to numerous natural products and medic- lengthening (+ 1 C) of the organometallic carbon chain.
inal drugs.10 Additionally, pyrrolidines have been used as Thus, the azetidine 8 and the piperidine 10 were obtained
catalysts,11 chiral auxiliairies,12 and also as scaffolds in in good yields, by using, respectively, vinyl- or homoallyl
ligand design for asymmetric synthesis.13 Despite the re- Grignard reagents.
ports on several syntheses of optically active pyrro-
In conclusion, the synthetic method described in this pa-
lidines,14 methodologies which allow a controlled and
per allows the preparation of a wide range of optically
selective access to each stereoisomer are rare. They are of
particular interest since in many cases chiral auxiliaries
are readily available in only one enantiomeric form.
pure 2-substituted pyrrolidines through a hydrozircona-
tion–iodination sequence applied to N-homoallylamino
alcohols. This was made possible by the discovery that
Additionally, the examples given below show that the hy- performing alkene hydrozirconation in the presence of a
drozirconation-iodination sequence can be applied, both secondary amine can be achieved. This straightforward
to the asymmetric synthesis of disubstituted pyrrolidines, approach leads to the opposite configuration at the 2-posi-
and to the synthesis of four- and six-membered heterocy- tion in comparison to that obtained by the previously re-
cles (Scheme 4).
ported tandem hydrozirconation/TiCl4-mediated cycliza-
tion method.7 The two methods thus appear complemen-
tary from a stereochemical point of view, making it possi-
ble to selectively prepare both 2R- or 2S-configured
pyrrolidines by using the same initial reagents (allyl bro-
mide and aldehydes) and (R)-2-phenylglycinol as the
chiral inductor. In addition, the stereoselective access to
cis-2,3-disubstituted pyrrolidines as well as optically ac-
tive azetidines and piperidines has been exemplified.
To prepare the 2,3-disubstituted pyrrolidine 6, Barbier-
type crotylation of the phenylglycinol-derived imine was
first performed by using 3-bromo-1-phenylpropene, Zn,
and a catalytic amount of CeCl3·H2O. The resulting amino
alcohol 5 was obtained in good yield and stereoselectivity,
and isolated as a single stereoisomer after purification by
column chromatography. At this stage, the phenylglycinol
Ph
Ph
Ph
Br
, Zn
S
H
S
1) Cp2Zr(H)Cl
N
N
cat. CeCl3·7H2O
43%
2) Et3N, I2
OX
OTBS
Ph
60%
Ph
5
6
5: X = H
5': X = TBS
TBSCl, Et3N,
cat. DMAP
R
Ph
1) Cp2Zr(H)Cl
H
MgBr
78%
N
Ph
N
N
2) Et3N, I2
53%
OTBS
OX
OH
Ph
Ph
dr = 12:1
Ph
8
7: X = H
TBSCl, Et3N,
cat. DMAP
7': X = TBS
H
MgBr
Ph
N
1) Cp2Zr(H)Cl
Ph
N
OH
OH
39%
2) Et3N, I2
62%
Ph
Ph
9
10
dr = 8:1
dr = 8:1
Scheme 4 Diastereoselective approach to 2,3-disubstituted pyrrolidines, 2-substituted azetidines, and 2-substituted piperidines
Synthesis 2008, No. 1, 61–68 © Thieme Stuttgart · New York

64
M. Ahari et al.
PAPER
All reactions were conducted under argon using standard Schlenk
techniques. Prior to use, THF and Et2O were distilled under argon
from sodium benzophenone ketyl; Et3N and CH2Cl2 were distilled
under argon from CaH2; and Cp2Zr(H)Cl was prepared according to
known procedure.16 Other reagents (Aldrich) were used as received.
Petroleum ether (PE) used refers to the fraction boiling in the range
40–65 °C. 1H and 13C NMR spectra were recorded in CDCl3 using
TMS as an internal standard on a Bruker AC-250 spectrometer.
Mass spectra were recorded on a Micromass Q-TOF micro MS
spectrometer.
13C NMR (62.5 MHz, CDCl3): d = 41.4, 59.3, 61.6, 65.8, 115.1 (d,
J = 16.7 Hz), 117.6, 127.1, 127.3, 128.5, 128.6, 128.7, 134.6, 135.3
(d, J = 3.0 Hz), 140.9, 161.8 (d, J = 243 Hz).
19F NMR (235 MHz, CDCl3): d = –116.7.
HRMS-ESI: m/z [M + H]+ calcd for C18H21FNO: 286.1607; found:
286.1609.
2-[(R)-1-(3-Furyl)but-3-enylamino]-(R)-2-phenylethanol (3e)
Orange oil; yield: 71%; [a]D23 –34.6 (c 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 2.22 (br s, 2 H), 2.28–2.49 (m, 2
H), 3.47 (dd, J = 10.7, 7.6 Hz, 1 H), 3.61–3.69 (m, 2 H), 3.84 (dd,
J = 7.5, 4.7 Hz, 1 H), 5.00 (dm, J = 9.0 Hz, 1 H), 5.02 (dm, J = 18.9
Hz, 1 H), 5.66 (m, 1 H), 6.22 (s, 1 H), 7.20–7.28 (m, 6 H).
13C NMR (62.5 MHz, CDCl3): d = 39.6, 51.05, 61.4, 65.9, 108.9,
117.6, 127.2, 127.6, 128.6, 134.5, 139.4, 143.1.
HRMS-ESI: m/z [M + H]+ calcd for C16H20NO2: 258.1494; found:
258.1507.
Amino Alcohols 3a–f; General Procedure A
To a mixture of phenylglycinol-derived imine (3 mmol), Zn dust
(0.82 g, 7.5 mmol), and CeCl3·7H2O (0.11 g, 0.5 mmol) in THF (12
mL) was added dropwise allyl bromide (0.78 mL, 7.5 mmol) at
0 °C. The resulting mixture was stirred for 2 h and quenched with
H2O (10 mL). The layers were separated and the aqueous layer was
extracted with Et2O (3 × 10 mL). The organic layers were com-
bined, dried (Na2SO4), filtered, and concentrated. The residue was
purified by column chromatography on silica gel using a mixture of
PE–EtOAc as solvent to give the amino alcohol (Table 1).
(R)-2-Phenyl-2-[(R)-1-(2-thienyl)but-3-enylamino]ethanol (3f)
Yellow oil; yield: 69%; [a]D23 –35.8 (c 1, CH2Cl2).
(R)-2-Phenyl-2-[(R)-1-phenylbut-3-enylamino]ethanol (3a)17
Pale yellow oil; yield: 79%; [a]D23 –41.8 (c 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 1.98 (br s, 2 H), 2.50 (m, 2 H),
3.52 (dd, J = 10.7, 7.0 Hz, 1 H), 3.71 (m, 2 H), 3.83 (dd, J = 9.0, 4.6
Hz, 1 H), 4.98–5.06 (m, 2 H), 5.66 (m, 1 H), 7.18–7.32 (m, 10 H).
1H NMR (250 MHz, CDCl3): d = 2.29 (br s, 2 H), 2.57 (m, 2 H),
3.55 (dd, J = 10.8, 7.2 Hz, 1 H), 3.74 (dd, J = 10.8, 4.5 Hz, 1 H),
3.93 (dd, J = 7.2, 4.5 Hz, 1 H), 4.01 (dd, J = 6.5, 6.0 Hz, 1 H), 5.03–
5.14 (m, 2 H), 5.72 (m, 1 H), 6.83 (m, 1 H), 6.90 (m, 1 H), 7.17 (d,
J = 5.0 Hz, 1 H), 7.24–7.34 (m, 5 H).
13C NMR (62.5 MHz, CDCl3): d = 41.3, 55.0, 61.3, 65.9, 117.9,
124.0 (2 C), 126.4, 127.2, 127.5, 128.5, 134.3, 140.7, 148.3.
13C NMR (62.5 MHz, CDCl3): d = 41.1, 59.8, 61.3, 65.6, 117.5,
127.2, 127.4, 127.5, 128.3, 128.6, 135.0, 141.1, 143.5.
Amino Alcohols 3g–j; General Procedure B7
2-[(R)-1-(2-Bromophenyl)but-3-enylamino]-(R)-2-phenyl-
ethanol (3b)
To a mixture of phenylglycinol-derived imine (1 mmol) and In
(0.29 g, 2 mmol) in MeOH (5 mL) was added allyl bromide (0.31
mL, 3 mmol). The resulting mixture was stirred r.t. for 2 h. Aq 10%
NaHCO3 (5 mL) was added and the mixture extracted with EtOAc
(3 × 5 mL). The organic layers were combined, dried (MgSO4), fil-
tered, and concentrated under vacuum. The residue was purified by
column by column chromatography on silica gel using a mixture of
PE–EtOAc as solvent to give the amino alcohol 3g–j (Table 1).
Yellow oil; yield: 72%; [a]D23 –37.2 (c 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 2.14 (br s, 2 H), 2.46 (m, 2 H),
3.58 (dd, J = 10.0, 5.5 Hz, 1 H), 3.70–3.82 (m, 2 H), 4.32 (t, J = 6.4
Hz, 1 H), 5.06 (dm, J = 9.1 Hz, 1 H), 5.08 (dm, J = 19.0 Hz, 1 H),
5.75 (m, 1 H), 7.03 (t, J = 7.8 Hz, 1 H), 7.19–7.35 (m, 7 H), 7.46 (d,
J = 7.9 Hz, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 40.7, 58.4, 61.5, 65.1, 117.8,
123.8, 127.1, 127.3, 128.3, 132.7, 134.5, 141.1, 142.3 (2 C are miss-
ing).
2-[(R)-1-(Cinnamyl)but-3-enylamino-(R)-2-phenylethanol
(3g)17
Yellow oil; yield: 78%; [a]D23 +25.9 (c 1, CH2Cl2).
HRMS-ESI: m/z [M + H]+ calcd for C18H21BrNO: 346.0807; found:
1H NMR (250 MHz, CDCl3): d = 2.03 (br s, 2 H), 2.42 (m, 2 H),
3.41 (dd, J = 13.9, 5.8 Hz, 1 H), 3.60 (dd, J = 10.7, 7.6 Hz, 1 H),
3.79 (dd, J = 10.7, 4.6 Hz, 1 H), 3.96 (dd, J = 7.6, 4.6 Hz, 1 H),
5.13–5.22 (m, 2 H), 5.86 (m, 1 H), 6.03 (dd, J = 16.1, 8.0 Hz, 1 H),
6.46 (d, J = 16.1 Hz, 1 H), 7.24–7.42 (m, 10 H).
346.0805.
2-[(R)-1-(3-Methoxyphenyl)but-3-enylamino]-(R)-2-phenyl-
ethanol (3c)17
Yellow oil; yield: 75%; [a]D23 –39.0 (c 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 2.05 (br s, 2 H), 2.50 (m, 2 H),
3.53 (dd, J = 10.6, 6.9 Hz, 1 H), 3.71 (dd, J = 10.6, 4.6 Hz, 1 H),
3.74 (s, 3 H), 3.82 (m, 2 H), 4.32 (t, J = 6.4 Hz, 1 H), 5.07 (m, 2 H),
5.69 (m, 1 H), 6.74 (m, 3 H), 7.19–7.35 (m, 6 H).
13C NMR (62.5 MHz, CDCl3): d = 39.8, 58.1, 61.6, 66.1, 117.7,
126.2, 127.4, 127.5, 127.6, 128.5, 128.7, 130.6, 132.6, 135.1, 136.9,
141.7.
13C NMR (62.5 MHz, CDCl3): d = 41.5, 55.3, 59.9, 61.4, 65.6,
112.6, 112.8, 117.6, 119.5, 127.2, 127.6, 128.7, 129.5, 135.0, 141.2,
145.4, 159.7.
(R)-2-[(S)-1-Non-1-en-4-ylamino]-(R)-2-phenylethanol (3h)
Pale yellow oil; yield: 61%; [a]D23 –63.8 (c 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 0.83 (t, J = 6.9 Hz, 3 H), 1.20 (m,
8 H), 2.19 (t, J = 6.6 Hz, 2 H), 2.49 (quint, J = 5.3 Hz, 1 H), 3.48
(dd, J = 10.4, 9.0 Hz, 1 H), 3.65 (dd, J = 10.5, 4.4 Hz, 1 H), 3.88
(dd, J = 8.6, 4.4 Hz, 1 H), 5.07 (dm, J = 11.2 Hz, 1 H), 5.08 (dm,
J = 16.9 Hz, 1 H), 5.79 (m, 1 H), 7.30 (m, 5 H).
2-[(R)-1-(4-Fluorophenyl)but-3-enylamino]-(R)-2-phenyl-
ethanol (3d)
Yellow oil; yield: 80%; [a]D23 –38.1 (c 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 2.22 (br s, 2 H), 2.36–2.57 (m, 2
H), 3.52 (dd, J = 10.7, 7.2 Hz, 1 H), 3.62–3.75 (m, 2 H), 3.82 (dd,
J = 7.1, 4.7 Hz, 1 H), 5.01 (dm, J = 10.4 Hz, 1 H), 5.02 (dm,
J = 18.4 Hz, 1 H), 5.63 (ddt, J = 18.4, 10.4, 7.0 Hz, 1 H), 6.93 (t,
J = 8.7 Hz, 2 H), 7.10–7.36 (m, 7 H).
13C NMR (62.5 MHz, CDCl3): d = 14.0, 22.5, 25.4, 31.8, 34.7, 37.9,
53.7, 61.6, 66.8, 117.1, 127.2, 127.5, 128.5, 135.3, 141.3.
HRMS-ESI: m/z [M + H]+ calcd for C17H28NO: 262.2171; found:
262.2179.
Synthesis 2008, No. 1, 61–68 © Thieme Stuttgart · New York

PAPER
Hydrozirconation of Unsaturated Secondary Amines
65
2-[(R)-2-Methylhex-5-en-3-ylamino]-(R)-2-phenylethanol (3i)17
Pale yellow oil; yield: 81%; [a]D23 –120.5 (c 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 0.83 (d, J = 6.8 Hz, 3 H), 0.85 (d,
J = 6.8 Hz, 3 H), 1.63 (m, 1 H), 2.21 (m, 2 H), 2.32 (m, 1 H), 3.50
(dd, J = 10.5, 8.5 Hz, 1 H), 3.68 (dd, J = 10.6, 4.5 Hz, 1 H), 3.92
(dd, J = 9.0, 4.5 Hz, 1 H), 5.05 (m, 2 H), 5.82 (m, 1 H), 7.32 (m, 5
H).
1H NMR (250 MHz, CDCl3): d = 1.60–1.75 (m, 2 H), 1.87–2.12 (m,
2 H), 2.18 (br s, 1 H), 2.88 (dt, J = 8.9, 6.7 Hz, 1 H), 3.25 (ddd,
J = 9.1, 6.4, 2.2 Hz, 1 H), 3.56 (d, J = 6.5 Hz, 2 H), 3.69 (dd, J = 8.3,
5.3 Hz, 1 H), 3.93 (t, J = 6.5 Hz, 1 H), 7.14–7.29 (m, 10 H).
13C NMR (62.5 MHz, CDCl3): d = 23.4, 30.3, 36.2, 53.3, 62.3, 67.0,
126.80, 126.85, 127.5, 128.1, 128.4, 129.1, 137.2, 146.5.
2-[(R)-2-(2-Bromophenyl)pyrrolidin-1-yl]-(R)-2-phenylethanol
13C NMR (62.5 MHz, CDCl3): d = 18.2, 18.8, 30.5, 35.1, 59.5, 61.9,
66.9, 116.8, 127.4, 127.5, 128.5, 136.1, 141.4.
(4b)
Orange oil; yield: 60%; [a]D23 +42.6 (c 1, CH2Cl2).
tert-Butyl {(R)-1-[(R)-2-Hydroxy-1-phenylethylamino]but-3-
enyl}-1H-indole-1-carboxylate (3j)
Yellow oil; yield: 41%.
1H NMR (250 MHz, CDCl3): d = 1.66 (s, 9 H), 2.28 (br s, 1 H), 2.64
(m, 2 H), 3.53 (dd, J = 10.7, 2.8 Hz, 1 H), 3.74 (dd, J = 6.3, 4.6 Hz,
1 H), 3.96 (dd, J = 7.9, 4.6 Hz, 1 H), 4.00 (t, J = 6.3 Hz, 1 H), 5.00
(dm, J = 9.5 Hz, 1 H), 5.07 (dm, J = 16.0 Hz, 1 H), 5.73 (m, 1 H),
7.15–7.32 (m, 9 H), 7.42 (s, 1 H), 8.10 (br d, J = 8.1 Hz, 1 H).
1H NMR (250 MHz, CDCl3): d = 1.42 (m, 1 H), 1.65 (m, 1 H), 1.93
(m, 3 H), 2.81 (dt, J = 9.0, 6.7 Hz, 1 H), 3.28 (t, J = 6.8 Hz, 1 H),
3.67 (d, J = 6.4 Hz, 2 H), 3.80 (t, J = 6.5 Hz, 1 H), 4.28 (dd, J = 8.9,
3.8 Hz, 1 H), 6.94 (t, J = 7.6 Hz, 1 H), 7.10–7.22 (m, 6 H), 7.32 (d,
J = 7.5 Hz, 1 H), 7.58 (d, J = 7.7 Hz, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 23.6, 34.2, 53.1, 61.9, 63.3, 68.2,
101.1, 101.5, 105.2, 122.4, 127.3, 127.5, 127.7, 128.1, 128.6,
129.0, 132.3, 147.3.
13C NMR (62.5 MHz, CDCl3): d = 28.2, 39.2, 51.8, 61.6, 66.0, 83.6,
115.3, 117.4, 119.5, 122.3, 122.8, 123.0, 124.3, 127.1, 127.5, 128.5,
129.0, 134.9, 135.6, 140.8, 149.6.
MS (ES+): m/z [M + H]+ calcd for C18H21BrNO: 346.0807; found:
346.0800.
2-[(R)-2-(3-Methoxyphenyl)pyrrolidin-1-yl)-(R)-2-phenyl-
ethanol (4c)
HRMS-ESI: m/z [M + H]+ calcd for C25H31N2O3: 407.2335; found:
407.2333.
Yellow oil; yield: 60%; [a]D23 +62.1 (c 1, CH2Cl2).
TBS-Protected Amino Alcohols; (R)-N-[(R)-2-(tert-Butyl-
dimethylsilyloxy)-1-phenylethyl]-4-methylpent-1-en-3-amine
(3i¢); Typical Procedure C
1H NMR (250 MHz, CDCl3): d = 1.59 (m, 2 H), 1.91 (m, 2 H), 2.19
(br s, 1 H), 2.79 (td, J = 9.0, 6.8 Hz, 1 H), 3.16 (m, 1 H), 3.52 (m, 2
H), 3.61 (dd, J = 8.4, 5.0 Hz, 1 H), 3.71 (s, 3 H), 3.86 (t, J = 7.0 Hz,
1 H), 6.67 (ddd, J = 8.2, 2.7, 1.0 Hz, 1 H), 6.75–6.82 (m, 2 H), 7.08–
7.22 (m, 6 H).
13C NMR (62.5 MHz, CDCl3): d = 23.4, 36.0, 53.1, 62.4, 62.6, 66.9,
112.0, 112.4, 119.1, 127.4, 128.0, 129.1, 129.3, 137.3, 148.4, 159.6.
To a solution of the amino alcohol 3i (240 mg, 0.7 mmol), Et3N (1
mL), and DMAP (85 mg, 0.7 mmol) in CH2Cl2 (5 mL) was added
dropwise a solution of TBSCl (545 mg, 3.6 mmol) in CH2Cl2 (5 mL)
at r.t. The mixture was stirred at r.t. overnight and then quenched
with H2O (5 mL). The aqueous layer was extracted with CH2Cl2
(2 × 5 mL). The organic layers were combined, dried (Na2SO4), fil-
tered, and concentrated. The residue was purified by column chro-
matography on silica gel using CH2Cl2 as solvent to give 3i¢;
colorless oil; yield: 219 mg (90%); [a]D23 –45.1 (c 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 0.00 (s, 6 H), 0.79 (d, J = 6.8 Hz,
3 H), 0.83 (d, J = 6.8 Hz, 3 H), 0.87 (s, 9 H), 1.55 (m, 1 H), 1.78 (br
s, 1 H), 2.19 (m, 2 H), 3.47 (dd, J = 9.7, 8.9 Hz, 1 H), 3.59 (dd,
J = 9.7, 3.8 Hz, 1 H), 3.89 (dd, J = 8.9, 3.8 Hz, 1 H), 5.01 (dm,
J = 9.9 Hz, 1 H), 5.06 (dm, J = 16.8 Hz, 1 H), 5.75 (m, 1 H), 7.20–
7.38 (m, 5 H).
MS (ES+): m/z [M + H]+ calcd for C19H24NO2: 298.1807; found:
298.1806.
2-[(R)-2-(4-Fluorophenyl)pyrrolidin-1-yl]-(R)-2-phenylethanol
(4d)
Yellow oil; yield: 62%; [a]D23 +15.8 (c 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 1.66 (m, 1 H), 1.80 (m, 1 H), 2.07
(m, 2 H), 2.92 (dt, J = 9.0, 8.2 Hz, 1 H), 3.16 (td, J = 6.7, 3.0 Hz, 1
H), 3.66 (d, J = 6.7 Hz, 2 H), 3.59 (t, J = 6.7 Hz, 1 H), 3.77 (t,
J = 6.7 Hz, 1 H), 7.16 (t, J = 8.7 Hz, 2 H), 7.34–7.49 (m, 7 H).
13C NMR (62.5 MHz, CDCl3): d = 23.4, 36.1, 53.2, 62.60, 62.65,
67.3, 115.0 (d, J = 21.2 Hz), 127.5, 128.0, 128.2 (d, J = 7.9 Hz),
129.0, 137.6, 142.2 (d, J = 2.8 Hz), 161.6 (d, J = 244 Hz).
19F NMR (235 MHz, CDCl3): d = –117.0.
13C NMR (62.5 MHz, CDCl3): d = –5.5, –5.4, 18.1, 18.3, 19.3, 25.9,
30.6, 34.3, 59.2, 62.4, 68.7, 116.8, 127.1, 128.0, 128.1, 136.0,
141.9.
HRMS-ESI: m/z [M + H]+ calcd for C21H38NOSi: 348.2723; found:
348.2718.
MS (ES+): m/z [M + H]+ calcd for C18H21FNO: 286.1607; found:
286.1606.
Pyrrolidines 4; General Procedure D
To a solution of homoallylamine 3 (1 mmol) in CH2Cl2 (2 mL) was
added Cp2Zr(H)Cl (309 mg, 2.2 mmol) in one portion and the mix-
ture was stirred until complete dissolution (ca. 30 min to 1 h). Et3N
(150 mL) and I2 (254 mg, 1 mmol) were added and the stirring was
continued for 1 h at r.t. H2O (2 mL) was added, and the mixture was
vigorously stirred for 30 min. The layers were separated and the
aqueous layer was extracted with CH2Cl2 (4 × 2 mL). The organic
layers were combined, washed with aq sat. Na2CO3 (2 mL), dried
(Na2SO4), filtered, and concentrated under vacuum. Purification of
the residue by column chromatography on silica gel using a mixture
of PE–EtOAc gave the pyrrolidines 4 (Table 1).
2-[(R)-2-(3-Furyl)pyrrolidin-1-yl)-(R)-2-phenylethanol (4e)
Yellow oil; yield: 45%; [a]D23 +10.1 (c 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 1.72 (m, 2 H), 1.94 (m, 2 H), 2.12
(br s, 1 H), 2.81 (td, J = 8.9, 7.5 Hz, 1 H), 3.03 (td, J = 9.3, 3.6 Hz,
1 H), 3.66 (dd, J = 10.3, 5.8 Hz, 1 H), 3.70–3.80 (m, 3 H), 6.36 (s,
1 H), 7.21–7.37 (m, 7 H).
13C NMR (62.5 MHz, CDCl3): d = 22.0, 32.7, 44.8, 55.2, 61.2, 61.6,
108.9, 127.1, 127.7, 128.1, 129.4, 134.7, 140.2, 143.8.
HRMS-ESI: m/z [M + H]+ calcd for C16H20NO2: 258.1494; found:
258.1497.
(R)-2-Phenyl-2-[(R)-2-phenylpyrrolidin-1-yl]ethanol (4a)18
Pale yellow oil; yield: 68%; [a]D23 +62.9 (c 1, CH2Cl2).
(R)-2-Phenyl-2-[(R)-2-(2-thienyl)pyrrolidin-1-yl]ethanol (4f)18
Yellow oil; yield: 67%; [a]D23 +34.6 (c 1, CH2Cl2).
Synthesis 2008, No. 1, 61–68 © Thieme Stuttgart · New York

66
M. Ahari et al.
PAPER
(R)-2-Phenyl-[(1R,2R)-1-(2-thienyl)-2-phenylbut-3-enyl-
1H NMR (250 MHz, CDCl3): d = 1.73 (m, 2 H), 2.00 (m, 2 H), 2.38
(br s, 1 H), 2.84 (dt, J = 8.5, 7.0 Hz, 1 H), 3.13 (td, J = 8.0, 3.4 Hz,
1 H), 3.71 (m, 2 H), 3.89 (t, J = 6.5 Hz, 1 H), 4.20 (dd, J = 7.2, 2.7
Hz, 1 H), 6.79 (d, J = 3.3 Hz, 1 H), 6.88 (m, 1 H), 7.16–7.32 (m, 5
H).
13C NMR (62.5 MHz, CDCl3): d = 23.1, 36.1, 52.2, 58.2, 59.9, 62.8,
66.3, 123.3, 123.9, 125.4, 126.8, 127.6, 128.2, 128.6, 138.0, 151.5.
amino]ethanol (5)
To a mixture of (R)-2-phenyl-(2-thienylmethylamino)ethanol (0.69 g,
3 mmol), Zn dust (0.49 g, 7.5 mmol) and CeCl3·7H2O (0.12 g, 0.5
mmol) in THF (15 mL) was added dropwise cinnamyl bromide (7.5
mmol) at 0 °C. The resulting mixture was stirred for 2 h and
quenched with H2O (15 mL). The layers were separated and the
aqueous layer was extracted with Et2O (3 × 10 mL). The organic
layers were combined, dried (Na2SO4), filtered, and concentrated.
The residue was purified by column chromatography on silica gel
using a mixture of PE–EtOAc as solvent to give 5; yellow oil; yield:
0.45 g (43%).
1H NMR (250 MHz, CDCl3): d = 3.48 (dd, J = 10.7, 5.9 Hz, 1 H),
3.62 (d, J = 4.3 Hz, 1 H), 3.65–3.72 (m, 2 H), 4.26 (d, J = 8.0 Hz,
1 H), 4.99 (dm, J = 17.2 Hz, 1 H), 5.04 (dm, J = 10.5 Hz, 1 H), 5.99
(m, 1 H), 6.67 (m, 1 H), 6.84 (m, 1 H), 7.10–7.38 (m, 11 H).
HRMS-ESI: m/z [M + H]+ calcd for C16H20NOS: 274.1266; found:
274.1263.
2-[(R)-2-(Cinnamyl)pyrrolidin-1-yl]-(R)-2-phenylethanol (4g)
Pale yellow oil; yield: 57%; [a]D23 +60.2 (c 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 1.68 (m, 2 H), 1.88 (m, 2 H), 2.23
(br s, 1 H), 2.76 (dt, J = 8.7, 7.9 Hz, 1 H), 3.01 (td, J = 8.2, 3.7 Hz,
1 H), 3.31 (d, J = 7.2 Hz, 1 H), 3.73 (d, J = 8.6, 4.5 Hz, 1 H), 3.94
(m, 2 H), 6.11 (dd, J = 15.8, 8.5 Hz, 1 H), 6.33 (d, J = 15.8 Hz, 1
H), 7.27 (m, 10 H).
13C NMR (62.5 MHz, CDCl3): d = 22.5, 32.9, 52.2, 62.3, 62.9, 66.8,
126.4, 127.4, 127.5, 127.9, 128.3, 128.4, 128.65, 128.70, 129.4,
129.7, 133.2, 137.2, 137.5.
(1R,2R)-N-[(R)-2-(tert-Butyldimethylsilyloxy)-1-phenylethyl]-
2-phenyl-1-(2-thienyl)but-3-en-1-amine (5¢)
Prepared according to Procedure C; yellow oil; yield: 88%; [a]D
–33.5 (c 1, CH2Cl2).
23
1H NMR (250 MHz, CDCl3): d = 0.00 (s, 6 H), 0.91 (s, 9 H), 2.60
(br s, 1 H), 3.61 (dd, J = 9.6, 7.8 Hz, 1 H), 3.74 (dd, J = 9.9, 3.5 Hz,
1 H), 3.84 (dd, J = 7.8, 7.4 Hz, 1 H), 3.94 (dd, J = 7.3, 3.8 Hz, 1 H),
4.41 (d, J = 6.8 Hz, 1 H), 5.08 (dm, J = 16.9 Hz, 1 H), 5.14 (dm,
J = 9.4 Hz, 1 H), 6.02 (ddd, J = 16.9, 9.4, 7.6 Hz, 1 H), 6.59 (d,
J = 3.0 Hz, 1 H), 6.83 (ddd, J = 4.5, 3.7, 0.8 Hz 1 H), 7.15 (d,
J = 5.0 Hz, 1 H), 7.14–7.36 (m, 10 H).
13C NMR (62.5 MHz, CDCl3): d = –5.55, –5.50, 18.4, 26.0, 55.9,
60.6, 62.4, 67.6, 117.6, 123.9, 124.8, 125.8, 126.6, 127.0, 127.7,
128.0, 128.3, 128.5, 137.4, 141.3, 141.4, 147.2.
HRMS (ES+): m/z [M + H]+ calcd for C20H24NO: 294.1858; found:
294.1856.
[(R)-2-Pentyl)pyrrolidin-1-yl]-(R)-2-phenylethanol (4h)
Colorless oil; yield: 66%; [a]D23 +8.6 (c 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 0.78 (t, J = 6.4 Hz, 3 H), 0.94–
1.70 (m, 12 H), 2.64 (q, J = 8.2 Hz, 1 H), 2.88 (m, 1 H), 3.71 (dd,
J = 7.7, 5.5 Hz, 2 H), 3.83 (t, J = 7.8 Hz, 1 H), 7.20–7.34 (m, 5 H).
13C NMR (62.5 MHz, CDCl3): d = 14.0, 22.6, 23.1, 26.3, 30.1, 31.8,
35.0, 52.5, 59.4, 63.3, 67.5, 127.6, 128.2, 128.9, 139.2.
HRMS-ESI: m/z [M + H]+ calcd for C17H28NO: 262.2171; found:
262.2166.
[(2R,3R)-1-[(R)-2-tert-Butyldimethylsilyloxy)-1-phenylethyl-2-
(2-thienyl)pyrrolidine (6)
Prepared according to Procedure D; yellow oil; yield: 60%; [a]D
+10.2 (c 1, CH2Cl2).
23
(R)-1-[(R)-2(tert-Butyldimethylsilyloxy)-1-phenylethyl-2-iso-
propylpyrrolidine (4i)
Prepared according to Procedure D using 1.2 equiv of the Schwartz
1H NMR (250 MHz, CDCl3): d = –0.02 (s, 3 H), 0.00 (s, 3 H), 0.91
(s, 9 H), 2.12 (m, 1 H), 2.40 (m, 1 H), 3.11 (dt, J = 9.2, 6.4 Hz, 1 H),
3.22 (td, J = 9.2, 1.6 Hz, 1 H), 3.63 (dt, J = 11.6, 7.1 Hz, 1 H), 3.95
(dd, J = 9.3, 5.9 Hz, 1 H), 4.02 (t, J = 5.9 Hz, 1 H), 4.19 (dd,
J = 9.3, 5.9 Hz, 1 H), 4.91 (d, J = 8.1 Hz, 1 H), 6.24 (d, J = 3.5 Hz,
1 H), 6.69 (dd, J = 5.0, 3.5 Hz, 1 H), 6.94–7.42 (m, 11 H).
13C NMR (62.5 MHz, CDCl3): d = –5.55, –5.50, 18.2, 25.9, 28.5,
48.4, 50.1, 64.5, 65.6, 65.7, 123.5, 124.3, 126.0, 126.1, 126.7,
127.5, 127.7, 128.4, 128.5, 140.2, 141.0, 147.6.
reagent.
Colorless oil; yield: 64%; [a]D23 +3.1 (c 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 0.00 (s, 3 H), 0.12 (s, 3 H), 0.77
(d, J = 6.5 Hz, 3 H), 0.79 (d, J = 6.9 Hz, 3 H), 0.85 (s, 9 H), 1.50–
1.70 (m, 5 H), 2.77 (td, J = 7.6, 5.7 Hz, 1 H), 2.90 (m, 1 H), 2.97
(m, 1H), 3.85–3.99 (m, 2 H), 4.09 (dd, J = 9.0, 5.6 Hz, 1 H), 7.18–
7.32 (m, 3 H), 7.39 (d, J = 7.9 Hz, 2 H).
13C NMR (62.5 MHz, CDCl3): d = –5.5, 15.8, 18.1, 20.3, 24.2, 24.9,
25.8, 30.0, 48.5, 63.6, 64.8, 67.2, 126.4, 127.8, 128.1, 142.8.
HRMS-ESI: m/z [M + H]+ calcd for C28H38NOSSi: 464.2443;
found: 464.2438.
HRMS-ESI: m/z [M + H]+ calcd for C15H24NO: 234.1858; found:
234.1854.
(R)-2-Phenyl-2-[(R)-1-phenylallylamino]ethanol (7)19
To a solution of (R)-2-benzylideneamino-2-phenylethanol (2.25 g,
10 mmol) in Et2O (30 mL) was added dropwise a solution of vinyl-
magnesium bromide in THF (1 M, 30 mL) at 0 °C. The mixture was
stirred at r.t. for 6 h. H2O (20 mL) was slowly added at 0 °C and the
aqueous layer was extracted with Et2O (3 × 25 mL): The combined
organic layers were combined, concentrated to 50 mL and extracted
with aq 1 M HCl (2 × 25 mL). The aqueous layer was neutralized
with aq sat. Na2CO3 and extracted with Et2O (3 × 25 mL). The or-
ganic layers were combined, dried (Na2SO4), filtered, and concen-
trated to give the title compound; pale yellow oil; yield: 2.02 g
(80%); [a]D23 –16.0 (c 1, CH2Cl2).
tert-Butyl 2-{(R)-1-[(R)-2-Hydroxy-1-phenylethyl)]pyrrolidin-
2-yl}-1H-indole-1-carboxylate (4j)
Yellow oil; yield: 40%; [a]D23 +10.8 (c 1, CH2Cl2).
1H NMR (250 MHz, CDCl3): d = 1.59 (s, 9 H), 1.60–2.00 (m, 4 H),
2.16 (br s, 1 H), 2.76 (q, J = 8.1 Hz, 1 H), 3.17 (t, J = 7.1 Hz, 1 H),
3.57 (dd, J = 10.8, 6.1 Hz, 1 H), 3.69 (dd, J = 10.7, 7.5 Hz, 1 H),
3.83 (t, J = 6.7 Hz, 1 H), 3.93 (dd, J = 7.5, 5.5 Hz, 1 H), 7.16 (m, 8
H), 7.62 (d, J = 7.8 Hz, 1 H), 8.02 (d, J = 7.9 Hz, 1 H).
13C NMR (62.5 MHz, CDCl3): d = 23.3, 28.2, 33.0, 52.5, 55.8, 62.9,
67.1, 83.4, 115.4, 119.8, 122.3, 122.6, 124.2, 124.4, 127.4, 127.9,
129.0, 135.9, 137.7, 149.7 (1 C is missing).
1H NMR (250 MHz, CDCl3): d = 2.23 (br s, 2 H), 3.55 (dd,
J = 10.7, 8.7 Hz, 1 H), 3.41 (dd, J = 10.7, 4.5 Hz, 1 H), 3.98 (dd,
J = 8.7, 4.5 Hz, 1 H), 4.07 (d, J = 8.0 Hz, 1 H), 5.11–5.19 (m, 2 H),
5.86 (ddd, J = 17.0, 10.2, 8.0 Hz, 1 H), 7.19–7.28 (m, 10 H).
HRMS-ESI: m/z [M + H]+ calcd for C25H30N2O3: 406.23; found:
407.2217.
Synthesis 2008, No. 1, 61–68 © Thieme Stuttgart · New York

PAPER
Hydrozirconation of Unsaturated Secondary Amines
67
13C NMR (62.5 MHz, CDCl3): d = 61.4, 62.6, 66.9, 116.5, 127.2,
127.4, 127.5, 127.7, 128.7, 128.8, 140.1, 140.7, 143.2.
J = 9.9, 2.7 Hz, 1 H), 3.83 (t, J = 6.5 Hz, 1 H), 4.04 (dd, J = 6.6, 1.3
Hz, 2 H), 7.20–7.42 (m, 10 H).
MS-ESI: m/z = 254 ([M + H]+).
13C NMR (62.5 MHz, CDCl3): d = 25.1, 26.4, 37.0, 47.7, 59.7, 62.8,
65.8, 126.7, 127.1, 127.7, 128.1 (2 C), 128.5, 140.5, 144.6.
(R)-N-[(R)-2-[(tert-Butyldimethylsilyloxy)-1-phenylethyl]-1-
phenylprop-2-en-1-amine (7¢)
Prepared according to Procedure C; colorless oil; yield: 91%.
HRMS-ESI: m/z [M + H]+ calcd for C19H24NO: 282.1858; found:
282.1866.
1H NMR (250 MHz, CDCl3): d = –0.01 (s, 3 H), 0.00 (s, 3 H), 0.86
(s, 9 H), 3.59 (dd, J = 9.9, 8.7 Hz, 1 H), 3.69 (dd, J = 9.9, 4.1 Hz, 1
H), 3.97 (dd, J = 8.6, 3.8 Hz, 1 H), 5.07 (dm, J = 17.1 Hz, 1 H), 5.19
(dd, J = 10.1, 1.2 Hz, 1 H), 5.75 (ddd, J = 17.1, 10.1, 8.1 Hz, 1 H),
7.19–7.38 (m, 10 H).
13C NMR (62.5 MHz, CDCl3): d = –5.45, –5.35, 18.2, 25.9, 61.65,
61.70, 68.3, 115.9, 126.8, 127.0, 127.3, 127.9, 128.25, 128.30,
139.7, 141.1, 143.5.
Acknowledgment
Financial support of this work by the CNRS and the Ministère de
l’Education Nationale et de la Recherche is gratefully acknowled-
ged.
References
(1) Reviews: (a) Wipf, P.; Jahn, H. Tetrahedron 1996, 52,
12853. (b) Lipshutz, B. H.; Pfeiffer, S. S.; Noson, K.;
Tomioka, T. In Titanium and Zirconium in Organic
Synthesis; Marek, I., Ed.; Wiley-VCH: Weinheim, 2002,
110. (c) Wipf, P.; Kendall, C. In Topics in Organometallic
Chemistry, Vol. 8; Takahashi, T., Ed.; Springer-Verlag:
Berlin, 2005, 1.
(2) For the preparation of Cp2Zr(H)Cl, see: Buchwald, S. L.;
La Maire, S. J.; Nielsen, R. B.; Watson, B. T.; King, S. M.
Org. Synth. 1993, 71, 77.
(R)-1-[(R)-2-(tert-Butyldimethylsilyloxy)-1-phenylethyl]-2-phe-
nylazetidine (8)
Prepared according to Procedure D; colorless oil; yield: 54%; [a]D
+55 (c 1, CH2Cl2).
23
1H NMR (250 MHz, CDCl3): d = –0.11 (s, 3 H), –0.07 (s, 3 H), 0.83
(s, 9 H), 2.14–2.34 (m, 2 H), 3.24 (q, J = 8.3 Hz, 1 H), 3.48 (t,
J = 6.2 Hz, 1 H), 3.58 (dd, J = 9.9, 6.0 Hz, 1 H), 3.68 (td, J = 7.5,
2.4 Hz, 1 H), 3.86 (dd, J = 9.9, 6.5 Hz, 1 H), 3.95 (t, J = 8.2 Hz, 1
H), 6.86–7.07 (m, 10 H).
13C NMR (62.5 MHz, CDCl3): d = –5.6, –5.5, 18.2, 25.8, 27.7, 52.6,
67.2, 69.2, 75.5, 126.4, 126.9, 127.2, 127.3, 127.4, 129.1, 138.5,
143.5.
HRMS-ESI: m/z [M + H]+ calcd for C23H34NOSi: 368.2410; found:
368.2408.
(3) (a) Titanium and Zirconium in Organic Synthesis; Marek, I.,
Ed.; Wiley-VCH: Weinheim, 2002. (b) New Aspects of
Zirconium-Containing Compounds: Topics in
Organometallic Chemistry; Marek, I., Ed.; Springer-Verlag:
Berlin, 2005, Vol. 10.
(4) (a) Williams, D. R.; Kissel, W. S. J. Am. Chem. Soc. 1998,
120, 11198. (b) Zheng, B. Z.; Maeda, H.; Mori, M.; Kusaka,
S.; Yonemitsu, O.; Matsushima, T.; Nakajima, N.; Uenishi,
J. Chem. Pharm. Bull. 1999, 47, 1288. (c) Nicolaou, K. C.;
Jung, J. K.; Yoon, W. H.; He, Y.; Zhong, Y. L.; Baran, P. S.
Angew. Chem. Int. Ed. 2000, 39, 1829.
(5) Diederich, F.; Stang, P. J. Metal-Catalyzed Cross-Coupling
Reactions; Wiley-VCH: Weinheim, 1998.
(6) (a) Bertus, P.; Gandon, V.; Szymoniak, J. Chem. Commun.
2000, 709. (b) Gandon, V.; Szymoniak, J. Chem. Commun.
2002, 1308. (c) Szymoniak, J.; Bertus, P. In New Aspects of
Zirconium-Containing Compounds: Topics in
(R)-2-Phenyl-2[(R)-1-phenylpent-4-enylamino]ethanol (9)
To a suspension of Mg turnings (0.59 g, 24.5 mmol) in THF (2 mL)
was added a few drops of 1-bromobut-3-ene and the mixture was
stirred vigorously for 15 min. Then a solution of 1-bromobut-3-ene
(3.3 g, 24.5 mmol) in THF (35 mL) was added dropwise over 30
min. The resulting mixture was refluxed for 1 h, cooled to 0 °C and
then added to a solution of (R)-2-benzylideneamino-2-phenyleth-
anol (1.80 g, 8 mmol) in THF (15 mL) via a cannula at 0 °C. The
mixture was stirred overnight at r.t. The reaction was quenched by
adding dropwise aq sat. NH4Cl (10 mL). The aqueous layer was ex-
tracted with Et2O (3 × 5 mL). The organic layers were combined,
dried (Na2SO4), filtered, and concentrated. The residue was purified
by column chromatography using a mixture of PE–EtOAc as eluent
to give 9 as an 8:1 mixture of diastereomers; yellow oil; yield: 0.88
g (39%); [a]D23 –14.5 (c 1, CH2Cl2).
Organometallic Chemistry, Vol. 10; Marek, I., Ed.;
Springer-Verlag: Berlin, 2005, 107.
(7) Vasse, J.-L.; Joosten, A.; Denhez, C.; Szymoniak, J. Org.
Lett. 2005, 7, 4887.
(8) (a) Vilaivan, T.; Winotapan, C.; Banphavichit, V.; Shinada,
T.; Ohfune, Y. J. Org. Chem. 2005, 70, 3464. (b) Yanada,
R.; Okaniwa, M.; Kaieda, A.; Ibuka, T.; Takemoto, Y. J.
Org. Chem. 2001, 66, 1283. (c) Agami, C.; Couty, F.;
Evano, G. Tetrahedron: Asymmetry 2000, 11, 4639.
(9) Several other methods are known for an efficient
deprotection of the similarly substituted N-pyrrolidines, see:
(a) Katrizky, A. R.; Cui, X.-L.; Yang, B.; Steel, P. J.
Tetrahedron Lett. 1998, 39, 1697. (b) Higashiyama, K.;
Inoue, H.; Takahashi, H. Tetrahedron 1994, 50, 1083.
(10) (a) O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435; and
references cited therein. (b) Daly, J. W.; Spende, T. F.In
Alkaloids: Chemical and Biological Perspectives, Vol. 4;
Pelletier, S. W., Ed.; Wiley: New York, 1986, Chap. 1.
(11) (a) Aggarwal, V. K.; Lopin, C.; Sandrinelli, F. J. Am. Chem.
Soc. 2003, 125, 7596. (b) Zhang, F.; Peng, Y.; Liao, S.;
Gong, Y. Tetrahedron 2007, 63, 4636. (c)Enders, D.;Hüttl,
M. R. M.; Rusink, J.; Raabe, G.; Wendt, B. Angew. Chem.
Int. Ed. 2007, 46, 467. (d) Li, H.; Wang, J.; Xie, H.; Zu, L.;
Jiang, W.; Duesler, E. N.; Wang, W. Org. Lett. 2007, 9, 965.
Major Isomer
1H NMR (250 MHz, CDCl3): d = 1.76 (m, 1 H), 1.95 (m, 3 H), 2.46
(br s, 2 H), 3.52 (dd, J = 10.5, 7.1 Hz, 1 H), 3.65 (dd, J = 8.1, 4.9
Hz, 1 H), 3.72–3.84 (m, 2 H), 4.91–5.02 (m, 2 H), 5.77 (ddd,
J = 10.2, 6.2 Hz, 1 H), 7.18–7.30 (m, 10 H).
13C NMR (62.5 MHz, CDCl3): d = 30.2, 35.8, 59.7, 61.2, 65.4,
114.7, 127.0, 127.1, 127.2, 127.4, 128.4, 128.5, 138.2, 141.2, 143.7.
HRMS-ESI: m/z [M + H]+ calcd for C19H24NO: 282.1858; found:
282.1563.
(R)-2-Phenyl-2[(R)-1-phenylpiperidin-1-yl]ethanol (10)20
Prepared according to Procedure D and obtained as an 8:1 mixture
of diastereomers; yellow oil; yield: 62%.
Major Diastereomer
1H NMR (250 MHz, CDCl3): d = 1.25–1.80 (m, 7 H), 2.51 (td,
J = 11.3, 2.6 Hz, 1 H), 2.93 (dm, J = 11.3 Hz, 1 H), 3.76 (dd,
Synthesis 2008, No. 1, 61–68 © Thieme Stuttgart · New York

68
M. Ahari et al.
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