Asymmetric Mannich-type addition of ketene silyl acetals and thioacetals to N,N-dialkylhydrazones

Article abstract of DOI:10.1055/s-2006-926283

The choice of the 2,6-diphenylpiperidine moiety as the N,N-dialkylamino auxiliary in simple aliphatic dialkylhydrazones and the use of scandium inflate as the catalyst in aqueous media appear as the key strategies that enable the highly diastereoselective

Full text of DOI:10.1055/s-2006-926283

540
FEATURE ARTICLE
Asymmetric Mannich-Type Addition of Ketene Silyl Acetals and Thioacetals
to N,N-Dialkylhydrazones
A
symmetric Ma
l
nnich-
e
Type
A
ddit
n
ions to
N
,
N
-D
a
ialkylhydrazone
D
s
íez,a Auxiliadora Prieto,a Monika Simon,a Juan Vázquez,a Eleuterio Álvarez,b Rosario Fernández,*a
José María Lassaletta*b
a
Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apdo. de Correos No. 553, 41071 Seville, Spain
Instituto de Investigaciones Químicas, CSIC-USe, c/ Américo Vespucio s/n, Isla de la Cartuja, 41092 Seville, Spain
b
Fax +34954460565; E-mail: jmlassa@iiq.csic.es
Received 1 December 2005; revised 16 December 2005
Dedicated to Prof. Steven V. Ley on the occasion of his 60th birthday
also reported the Ag-catalyzed enantioselective Mannich
Abstract: The choice of the 2,6-diphenylpiperidine moiety as the
reaction of enol ethers to some aliphatic imines.7 Though
N,N-dialkylamino auxiliary in simple aliphatic dialkylhydrazones
these pioneering contributions demonstrated the feasibili-
ty of the reaction, the reported yields (typically 40–60%)
and the use of scandium triflate as the catalyst in aqueous media ap-
pear as the key strategies that enable the highly diastereoselective
nucleophilic addition of ketene silyl acetals and thioacetals. The re- were unfortunately disappointing in most cases.
action proceeds to afford the expected adducts in high yields (88–
During the last years, our research group has been inves-
98%) and diastereomeric ratios of up to 99:1. N–N bond cleavage
tigating the chemistry and use of aldehyde N,N-dialkylhy-
of adducts affords enantiomerically pure b-amino esters.
drazones in asymmetric synthesis. These compounds
exhibit hybrid properties between those presented by
imines and enamines, constituting a singular case of am-
biphilic reactivity with a high synthetic potential. Taking
advantage of such versatility, N,N-dialkylhydrazones
Key words: asymmetric synthesis, hydrazones, ketene silyl acetals,
ketene silyl thioacetals, diastereoselectivity
have been used as nucleophilic, d1 reagents (Scheme 1,
path a) for the enantioselective formylation and cyanation
of a wide range of electrophilic substrates,8 as chiral
ligands in asymmetric catalysis,9 and as stable imines in
asymmetric Staudinger cycloadditions.10 In this last con-
text, the higher stability and lower tendency of hydra-
zones to tautomerize with respect of simple imines were
found to be the key characteristics for a qualitatively bet-
ter performance.
Introduction
The asymmetric Mannich or Mannich-type reactions pro-
vide one of the most efficient methods for the synthesis of
optically enriched b-amino ketones or esters, which are
useful chiral building blocks for the preparation of many
nitrogen-containing, biologically important compounds.1
The Lewis acid mediated addition reaction of silyl eno-
lates to imines is one of the most popular variants of this
reaction that has collected a considerable success in many
cases,2 but there are still limitations to this procedure due
to the poor chemical and thermal stability of some of the
required imine substrates. Thus, while there are a number
of satisfactory methods for the asymmetric addition of
several nucleophiles to aromatic imines3 and to activated
a-imino esters,4 the asymmetric Mannich-type additions
to aliphatic, easily enolizable imines is a more challenging
task due to the poor stability of such substrates, in part as-
sociated to the formation of enamine tautomers and their
subsequent transformations. Nevertheless, a few reports
have appeared on the asymmetric Mannich reactions of al-
iphatic imines. The Zr-catalyzed enantioselective addition
of ketene silyl acetals to o-aminophenol derived imines
developed by Kobayashi and co-workers could be applied
to some aliphatic subtrates.5 The same authors have also
shown that the use of acylhydrazones as stable imine
equivalents can also be exploited in the same reaction.6
Very recently Josephsohn, Snapper and Hoveyda have
Concerning the imine-type electrophilic reactivity
(Scheme 1, path b), N,N-dialkylhydrazones have been
previously used as targets for the nucleophilic attack of
R1
N
R1
N
R1
N
Nu
E
N
R2
N
R2
N
R2
b
a
E
Nu
H
H
R3
H
R3
R3
H
– H
R1
N
R1
N
HN
R3
R2
N
R2
Nu
H
E
R3
R3 = H
CN
E
NH2
O
R3
Nu
H
E
R3
SYNTHESIS 2006, No. 3, pp 0540–0550
x
x
.
x
x
.2
0
0
6
Advanced online publication: 11.01.2006
DOI: 10.1055/s-2006-926283; Art ID: E15005SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 The ambiphilic reactivity and synthetic utility of N,N-di-
alkylhydrazones

FEATURE ARTICLE
Biographical Sketches
Asymmetric Mannich-Type Additions to N,N-Dialkylhydrazones
541
Elena Díez was born in Madrid in 1971.
She studied Chemistry at the University of
Seville (Spain) and received her Ph.D. de-
gree in 1998 under the supervision of Dr.
José M. Lassaletta and Prof. Rosario
Fernández. She spent two and a half years
as a Marie Curie postdoctoral researcher
with Prof. Steven V. Ley at the University
of Cambridge, UK. In 2002 she was ap-
pointed as a ‘Ramón y Cajal’ researcher at
the Department of Organic Chemistry, Uni-
versity of Seville. Her current research in-
terests include the development of new
strategies for homogeneous enantioselec-
tive catalysis.
Auxiliadora Prieto was born in Seville in
1975. She studied Chemistry at the Univer-
sity of Seville, Spain and received her Ph.D.
degree in 2003 under the supervision of Dr.
José M. Lassaletta and Prof. Rosario
Fernández. She spent ten months as a post-
doctoral fellow in Prof. Karl Anker Jør-
gensen’s group at the University of Aarhus,
Denmark. In December 2004, she was ap-
pointed as lecturer at University of Huelva,
Spain. Her research interests include the de-
velopment of new catalysts for enantiose-
lective synthesis.
Monika Simon was born in 1971 in Sighi-
soara, Romania. She graduated in Chemical
Engineering at the ‘Politehnica’ University
of Timisoara, Romania in 1995 and re-
ceived her Ph.D. in Chemistry under the su-
pervision of Professor Carol Csunderlik in
2005. She was a member of Prof. R.
Fernández group with a Marie Curie fel-
lowship (2003–2004). She is now an assis-
tant professor at the Department of Organic
Chemistry and Technologies, ‘Politehnica’
University of Timisoara. Her research inter-
ests include the development of new syn-
thetic methodologies and synthesis of
biologically interesting compounds.
Juan Vázquez was born in Sevilla in 1968.
He studied Chemistry at the University of
Seville and received his Ph.D. degree in
1995 under the supervision of Dr. José M.
Lassaletta and Prof. R. Fernández. He spent
two years as a postdoctoral researcher with
Prof. D. Enders at the University of
Aachen, Germany. In 1999 he returned to
Spain as assistant professor at Huelva Uni-
versity and in 2002 he moved to the Depart-
ment of Organic Chemistry at Seville
University. His current research interests
focus on the development of new strategies
for homogeneous enantioselective cataly-
sis.
Eleuterio Álvarez was born in Tenerife,
Spain in 1955. After receiving his B.S. de-
gree in Organic Chemistry (1980) from La
Laguna University, Spain, he obtained his
Ph.D. in 1987 with Prof. Marc Julia at the
Ecole Normale Supérieure – Paris-VI Uni-
versity. He then joined the group of Prof.
Julio D. Martín at I.U.B.O. (La Laguna
University, Spain), where he was promoted
to Associate Professor in 1990. In 1996 he
accepted a position as Tenured Scientist at
the Instituto de Investigaciones Químicas
(CSIC, Sevilla), where he established and
built up the X-ray department. His main re-
search interests include X-ray diffraction,
organometallic chemistry and the develop-
ment of novel metal-promoted organic re-
actions.
Rosario Fernández was born in 1958 in
Seville, Spain. She received both her B.S.
degree (1980) and her Ph.D. degree (1985)
from the University of Seville, Spain under
the supervision of Prof. Antonio Gómez
Sánchez. She was a NATO postdoctoral
fellow at the University of Paris-Sud, Or-
say, France in the laboratory of Prof. Serge
David from 1986–1987. In 1987 she re-
turned to the University of Seville, where
she was promoted to Associate Professor.
Her current research interests include
asymmetric synthesis, enantioselective ca-
talysis and computational chemistry.
José María Lassaletta was born in Barce-
lona, Spain in 1961. He received his bache-
lor of chemistry from the University of
Seville, where he also obtained his Ph.D.
degree in 1990 under the supervision of
Professor M. Gómez-Guillén. After two
years of postdoctoral research in the ‘Insti-
tuto de la Grasa y sus Derivados’ (CSIC,
Seville) he joined the research group of
Professor Richard R. Schmidt in Konstanz,
Germany as a Marie Curie fellow. Back in
Spain in 1995 he worked as a postdoctoral
research fellow at the Instituto de Investiga-
ciones Químicas (CSIC-USe) in Seville,
where he was promoted to ‘Científico Titu-
lar’ in 1996. His current research interests
include asymmetric synthesis and catalysis,
development of new synthetic methodolo-
gies, and the synthesis and applications of
new types of chiral N-heterocyclic car-
benes.
Synthesis 2006, No. 3, 540–550 © Thieme Stuttgart · New York

542
E. Díez et al.
FEATURE ARTICLE
strongly basic, non-stabilized organometallic re- A second conclusion from the preliminary screening con-
agents,11,12 but there are no known precedents of the Man- cerns the activation of the hydrazone. Among the set of
nich-type, 1,2-addition of silyl enol ethers and related p- common Lewis acids tested [SiMe3OTf, BF3·OEt2, InCl3,
nucleophiles to these compounds, which, due to n → p SnCl4, ZnCl2, Zn(BF4)2, MgI2], best results were regularly
conjugation, have a more electron-rich C=N bond than re- observed by using Sc(OTf)3 in a 9:1 THF–H2O mixture13
lated imines. We reasoned that reduction of the effective- as the solvent. Starting from hydrazones 5, these condi-
ness of the N–N=C conjugation by tuning their steric and/ tions led to excellent yields of adducts 7 without any hy-
or electronic properties should increase the electrophilic drolysis or decomposition of the starting material
character of the azomethine carbon, while some stabiliz- (Scheme 2).
ing effect could be maintained. We wish to report here our
results collected on the basis of this hypothesis, illustrated
in the stereoselective Sc(OTf)3-catalyzed addition of
ketene silyl acetals and thioacetals to aliphatic aldehyde
N,N-dialkylhydrazones.
"RR'N
OSiMe3
OMe
NR'R"
H
NH
O
Cat.
N
+
R
OMe
R
6
1-5
7
Ph
Et
Addition of Silyl Ketene Acetals to Chiral N,N-Di-
alkylhydrazones. Screening of Auxiliaries and
Conditions
Et
O
O
OMe
N
H
N
H
N
O
N
N
N
R
Ph
Initially, a screening was performed in order to identify
the best combination of catalyst, reaction conditions and
the most appropriate structure of the dialkylamino group.
To this aim, dimethylketene silyl acetal 6 was made to re-
act with hydrazones 1–3 and 5, derived from different
types of N,N-dialkylhydrazines and with sulfonylhydra-
R
O
H
R
1
2
3
Ph
N
N
N
N
zones
4
containing Oppolzer’s sultam auxiliary
S
O
Ph
O
(Scheme 2). As expected, taking into account previous
observations, the electron rich pyrrolidine-derived hydra-
zones 1 and 2 showed a poor reactivity in this context,
leading to decomposition after addition of Lewis acids.
The mannitol-derived hydrazones 3 exhibited better elec-
trophilic reactivity, a fact attributed to the poorer n → p
conjugation imposed by the lack of flexibility that the
condensed dioxane rings confer to the pyrrolidine ring and
to the steric interactions operating in planar conforma-
tions.10d Oppolzer’s sultam derivatives 4 were initially
considered as promising candidates for the reaction, as the
electron-withdrawing sulfonyl group should increase their
electrophilicity. Unexpectedly, however, these deriva-
tives were unreactive against 6, even in the presence of
added Lewis acids. Finally, hydrazones 5 derived from
(S,S)-1-amino-2,6-diphenylpiperidine9 showed the best
reactivity toward 6 under a variety of conditions.
H
R
H
R
5
4
Scheme 2 Mannich addition of ketene silyl acetal 6 to hydrazones
1–5
Diastereoselective Addition of Ketene Silyl Acetals to
Hydrazones Derived from (S,S)-1-Amino-2,6-diphe-
nylpiperidine
Once having established the best structure for the dial-
kylamino group and the conditions for the activation of
the substrate [0.2 equiv of Sc(OTf)3 as catalyst, 9:1 THF–
H2O as the solvent, excess of ketene silyl acetal], the reac-
tion was applied to a series of hydrazones 5a–f derived
from (S,S)-1-amino-2,6-diphenylpiperidine and either
formaldehyde 5a or several enolizable aldehydes 5b–f. In
most cases, the preliminary essays revealed a marked de-
pendence of the diastereoselectivity with the reaction tem-
perature and, therefore, reactions were carried out at low
temperatures in order to achieve highly diastereoselective
additions. As an illustrative example, the simplest
prochiral substrate 5b derived from acetaldehyde afforded
the corresponding addition product 7b in a moderate dia-
stereomeric ratio of 6.3:1 (Table 1, entry 2) when the re-
action was carried out at room temperature, but this result
progressively improved by lowering the reaction temper-
ature, reaching a much better dr of 13:1 for the reaction
performed at –78 °C (entries 3–5). The additions to hydra-
zones from higher, easily enolizable aldehydes such as
The analysis of the structure of these hydrazones suggests
that the reason for the good performance of these com-
pounds is the efficient inhibition of the opposite nucleo-
philic reactivity. Accordingly, the planar conformations
required for the undesired n → p conjugation in the N–
N=C system are efficiently inhibited in this case by the
strain associated with the loss of the preferred chair-like
conformation of the six-membered piperidine ring and by
the steric repulsion by the phenyl groups at positions 2 and
6. Therefore, the C=N bond of 5 is available to behave al-
most as a ‘standard’ imine C=N bond. However, these hy-
drazones still have a higher stability than imine analogues
and can be therefore used in a broadened range of condi-
tions.
Synthesis 2006, No. 3, 540–550 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Mannich-Type Additions to N,N-Dialkylhydrazones
543
propionaldehyde 5c or isovaleraldehye 5d proceeded with The behavior of benzyloxyacetaldehyde hydrazone 5f was
better selectivity at room temperature (entries 6 and 8), also investigated. Interestingly, the reaction was found to
and the corresponding products 7c,d were obtained as sin- be slower than non-functionalized analogues under the
gle diastereomers when the reactions were carried out at same conditions, and the poorer selectivity (dr 4:1) ob-
–40 °C (entries 7 and 9). The moderate dr 12:1 observed served at room temperature (entry 13) could not be sub-
for the reaction of the dihydrocinnamaldehyde derivative stantially improved by applying lower reaction
5e at room temperature (entry 10) could also be improved temperatures: up to 31 days were required to obtain a 5:1
up to a complete >99:1 dr in the reaction performed at mixture of isomers from the reaction performed at –40 °C.
–78 °C (entry 12), but the reaction required as much as 20 This result suggests that coordination of the BnO moiety
days to completion. However, a more convenient result takes place to some extent, thereby modifying the geome-
was observed at –40 °C, still affording an excellent selec- try of the substrate in such a way that results in a more dif-
tivity (dr 78:1) but in a much shorter reaction time (entry ficult and less selective approach of the nucleophile.
11).
Next, we examined the addition to ketene silyl acetal 8 in
On summarizing, an almost complete selectivity can be order to obtain a-unsubstituted b-amino ester derivatives
reached for simple aliphatic derivatives except for the (Scheme 3). Surprisingly, when the reaction was per-
smallest acetaldehyde derivative 7b. Presumably, the formed under previously optimized conditions, only a
lower steric demand confers a higher conformational flex- 44% yield of adduct 9 was observed, along with a 39% of
ibility to the reacting complex, resulting in a slightly poor- hydrazone self-condensation by-product 10 as a mixture
er facial discrimination in this case.
of cis and trans isomers.14 Tentatively, the formation of
Table 1 Asymmetric Mannich-Type Addition of Ketene Silyl Acetal 6 to N,N-Dialkylhydrazones 5a–fa
Ph
Ph
Sc(OTf)3
OSiMe3
THF–H2O (9:1)
N
R
N
H
NH
O
+
N
OMe
Ph
Ph
OMe
R
5a–f
6
7a–f
Entry
1
Hydrazone 5
R
H
Time (d)
0.1
Temp (°C)
r.t.
Product 7
7a
c (mol/L)b
0.2e
Yield (%)c
drd
5a
5b
5b
5b
5b
5c
5c
5d
5d
5e
5e
5e
5f
98
86
90
97
98
98
92
94
96
91
99
91
92
94
–
2
Me
<0.5f
<0.5f
<0.5f
<0.5f
<0.5f
3
r.t.
7b
0.4e
6.3:1
7.5:1
11:1
13:1
12:1
>99:1
21:1
>99:1
12:1
78:1
>99:1
4:1
3
Me
Me
Me
Et
0
7b
0.4e
4
-40
-78
r.t.
7b
0.4e
5
7b
0.4e
6
7c
0.4e
7
Et
–40
r.t.
7c
0.4e
8
i-Bu
i-Bu
2
7d
1.6g
1.6g
1.6g
1.6g
1.6g
1.6g
1.6g
9
5
–40
r.t.
7d
10
11
12
13
14
PhCH2CH2
PhCH2CH2
PhCH2CH2
BnOCH2
<0.5f
5
7e
–40
–78
r.t.
7e
20
3
7e
7f
5f
BnOCH2
31
–40
7f
5:1
a Reactions were performed on a 1 mmol scale in THF–H2O (9:1) using 20 mol% of Sc(OTf)3 as the catalyst.
b Initial concentration of hydrazone 5.
c Yield of isolated product after column chromatography.
d Determined by 1H and 13C NMR analysis of the crude reaction mixtures.
e Reaction was performed with 4 equiv of 6.
f Overnight reaction, was complete by morning.
g Reaction was performed with 8 equiv of 6.
Synthesis 2006, No. 3, 540–550 © Thieme Stuttgart · New York

544
E. Díez et al.
FEATURE ARTICLE
this by-product can be explained as the result of the attack ford the corresponding adducts 14c and 14e in 88 and 90%
by a ‘ene-hydrazine’ tautomer of 5c15 to propionaldehyde, yield, respectively (Table 2, entries 3 and 4). In the first
the latter resulting from the hydrolysis of 5c. A simple de- example, three isomers of adduct 14c were formed in
hydration of the resulting adduct would then yield the ob- 8:2:0.5 ratio (entry 3), while only two isomers of 14e were
served by-product 10.
detected in a 4:1 ratio. Again, the pure (dr >99:1) major
diasteromer could be isolated by medium-pressure liquid
chromatography.
Ph
Sc(OTf)3
OSitBuMe2
OMe
THF–H2O (9:1), r.t.
N
H
+
N
Ph
Release of the Auxiliary: Cleavage of the N–N Bond
8
Several methods were investigated for the cleavage of the
dialkylamino auxiliary. Acyl-protected derivatives offer a
broader range of possibilities for the reductive N–N bond
cleavage, and are additionally suitable substrates for the
oxidative cleavage by peracids recently developed in our
laboratory.16 Therefore, acylation of adducts 7a–f was at-
tempted under several conditions [(CF3CO)2O/Et3N/
CH2Cl2, r.t., ClCO2Me/NaH/HMPA, r.t., n-BuLi/BzCl/
THF, etc.], but, unfortunately, the formation of the desired
products was not observed in any case. Presumably, the
considerable crowding around the NH group and the sta-
bilization by an intramolecular NH–CO hydrogen bond
prevented the desired acylation, and only oxidation of the
hydrazine to products 15 was observed under more forc-
ing conditions (Scheme 4).
5c
Ph
N
Ph
N
N
NH
O
+
Ph
H
Ph
OMe
9: 44%, dr 5:1
10: 39%
Scheme 3 Mannich addition of ketene silyl acetal 8 to hydrazone 5c
Addition of Ketene Silyl Thioacetals
In sharp contrast, the addition to ketene silyl thioacetal 11
to hydrazones 5c,e afforded the corresponding adducts
13c,e in excellent yields and with diastereomeric ratios of
8:1 and 7:1, respectively (Table 2, entries 1 and 2). The
pure major diastereomer of 13e was easily obtained by
medium-pressure liquid chromatography. Interestingly,
no traces of the self-condensed products were observed in
the reaction mixtures.
Alternatively, adduct 7c was treated with in n-BuLi at low
temperature to promote the deprotonation of the hydra-
zine NH group and the subsequent cyclization to b-lac-
tam. Though this reaction has been successfully
performed in closely related systems,6 only reaction with
the carboxylate to yield the tertiary alcohol 16 was ob-
served in our case, again indicating the very depleted re-
activity of this group.
Further investigations were directed to the reaction with
ketene silyl thioacetal 12. Again, the addition to hydra-
zones 5c,e proceeded smoothly at low temperatures to af-
Finally, a direct reductive protocol was applied to achieve
the desired N–N bond cleavage. Thus, compounds 7d,e
Table 2 Mannich-Type Addition of Ketene Silyl Thioacetals to Hydrazones 5c,ea
Ph
Ph
Sc(OTf)3
OSiMe3
N
R
THF–H2O (9:1)
N
H
NH
O
N
+
SR"
Ph
Ph
SR"
R'
R
R'
5c,e
11,12
13c,e–14c,e
Entry
Hydrazone
R
Reagent
R¢
H
R¢¢
Time (d) Temp (°C) Adduct
Yield (%)b drc
1
2
3
4
5c
5e
5c
5e
Et
11
t-Bu
t-Bu
Et
8
–78
–78
–78
–60
13c
13e
14c
14e
88
98
88
90
8:1
PhCH2CH2
Et
11
12
12
H
13
18
7
7:1 (>99:1)d
8:2:0.5
Me
Me
PhCH2CH2
Et
4:1 (>99:1)d
a Reactions were performed in 1 mmol scale in 1.6 M THF–H2O (9:1) using 8 equiv of ketene silyl thioacetal and 20 mol% of Sc(OTf)3.
b Yield of isolated product.
c Determined by 1H and 13C NMR analyses of the crude reaction mixture.
d Values in parenthesis correspond to products purified by medium-pressure column chromatography.
Synthesis 2006, No. 3, 540–550 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Mannich-Type Additions to N,N-Dialkylhydrazones
545
Ph
N
N
R
COR
O
Ph
OMe
XCOR
Base
Ph
Ph
N
N
O
N
R
Ph
NH
O
R
OMe
Ph
OMe
15a,c
Ph
7a–f
N
O
N
Ph
R
n-BuLi, THF
–78 °C
Figure 1 Crystal structures of 16 showing thermal ellipsoids at 30%
probability
Ph
N
NH OH
order to avoid the coexistence of two severe ‘gauche’
C=N/Ph interactions that would be present in case of an
equatorially arranged N–N bond.18 The reactive complex
would then be formed by approach of the bulky scandium
catalyst from the less hindered zone, endo with respect to
the piperidine ring. The selectivity would then be the re-
sult of the shielding of the Si face by the equatorial phenyl
group at C-2, leaving the Re face as the only region avail-
able for the attack of the nucleophile.
Ph
16
Scheme 4 Unsuccessful attempts to protect or cyclize adducts 7
were efficiently hydrogenated in the presence of
HCO2NH4, Pd/C, and Raney-Ni to afford free b-amino es-
ters 17d and 17e in 80 and 78% yield,17 respectively
(Scheme 5).
Ph
Ph
N
H
NH
Nu
Ph
R
NH2
O
HCOONH4/Pd/C
N
R
NH
O
favored
R
OMe
Raney-Ni/H2, 65 °C
78–80%
Ph
OMe
N
si face
N
ScLn
7d: R = i-Bu
7e: R = CH2CH2Ph
17d: R = i-Bu
17e: R = CH2CH2Ph
hindered
Nu
R
Ph
re face
Ph
R
Nu
Scheme 5 Cleavage of the auxiliary
N
Nu
H
NH
Determination of the Absolute Configuration and
Stereochemical Outcome
Figure 2 Proposed model to account for the selectivity and absolute
configuration observed for adducts 7
The S configuration of the newly created stereogenic cen-
ter in adducts 7 was determined by the analysis of the X-
ray structure of the crystalline derivative 16, obtained un-
expectedly in the cyclization experiment from 7c
(Figure 1).
Conclusion
In summary, N,N-dialkylhydrazones behave as a stable
class of enolizable imines in the Mannich-type addition of
ketene silyl acetals and thioacetals. The novel methodolo-
gy developed is based in the efficiency of the chosen com-
bination of the (S,S)-2,6-diphenylpiperidine auxiliary and
scandium triflate as the catalyst, that allows the formation
In order to explain the high inductions effected by the
novel 2,6-diphenylpiperidine auxiliary and the observed
sense of the facial discrimination, a preferred geometry in
the hydrazone-catalyst complex is proposed (Figure 2). In
this model, the N–N bond adopts an axial orientation in
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546
E. Díez et al.
FEATURE ARTICLE
HRMS: m/z calcd for C19H23N2: 279.1861; found: 279.1853.
of the expected b-amino esters in excellent yields and
good-to-excellent diastereoselectivities.
(2S,6S)-1-Propylideneamine-2,6-diphenylpiperidine (5c)
From propionaldehyde (145 mL, 2 mmol). Purification by flash
chromatography (1:35 EtOAc–PE + 1% Et3N) gave 105 mg (36%)
The development of a catalytic, enantioselective version
of the reaction based in the use of chiral lanthanide com-
plexes as the catalysts is currently the subject of study in
our laboratory.
22
of hydrazone 5c as a white solid; mp 55–56 °C; [a]D –99.7 (c =
1.1, CHCl3).
IR (film): 3026, 2932, 2857, 1601, 1494, 1448, 882, 755, 699 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.79 (t, 3 H, J = 7.5 Hz), 1.59–1.69
(m, 2 H), 1.97–2.16 (m, 6 H), 4.87 (t, 2 H, J = 5.7 Hz), 6.73 (t, 1 H,
J = 5.1 Hz), 7.22–7.42 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 11.4, 18.8, 26.4, 30.6, 61.1, 126.1,
127.7, 128.0, 141.7, 143.2.
MS (EI): m/z (%) = 293 (75, [M+ + 1]), 292 (100, [M+]), 263 (74),
236 (11), 215 (25), 117 (37), 104 (23), 91 (21).
Solvents were purified and dried by standard procedures. Petroleum
ether (PE) refers to the fraction boiling at 60–70 °C. Flash chroma-
tography was performed on silica gel Merck 60 (0.063–0.200 mm,
0.040–0.063 mm or 0.015–0.040 mm) or prepacked silica gel col-
umns. Analytical TLC was performed on precoated plates (Merck
Kieselgel 60 F254). Melting points were recorded using a Gallen-
kamp MFB-595 apparatus and are uncorrected. Optical rotations
were measured using a Perkin-Elmer 241 MC polarimeter. IR spec-
tra were recorded for KBr pellets or films on a FT-IR Bomen MB-
HRMS: m/z calcd for C20H24N2: 292.1939; found: 292.1924.
1
120 spectrometer. H NMR spectra were recorded at 300 MHz or
500 MHz on a Bruker AMX 300 or Bruker AMX 500 instruments,
respectively. 13C NMR spectra were recorded at 75.5 MHz or
125.5 MHz on a Bruker AMX 300 or Bruker AMX 500 instru-
ments, respectively. Mass spectra were obtained on a Kratos MS 80
RFA or Micromass AutoSpecQ spectrometers.
(2S,6S)-1-(3¢-Methylbutylideneamine)-2,6-diphenylpiperidine
(5d)
From isovaleraldehyde (151 mL, 1.5 mmol). Purification by flash
chromatography (1:50 Et2O–PE + 1% Et3N) gave 246 mg (77%) of
hydrazone 5d as a white solid; mp 57–58 °C; [a]D22 –80.4 (c = 1.0,
CHCl3).
tert-Butyl trimethylsilyl ketene thioacetal and (Z)-ethyl trimethyl-
silyl methylketene thioacetal were synthesized following proce-
dures described in literature.19
IR (film): 3028, 2947, 2866, 1601, 1491, 1451, 1364, 1113, 752,
698 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.64 (d, 3 H, J = 6.6 Hz), 0.65 (d,
3 H, J = 6.6 Hz), 1.48 (m, 1 H, J = 6.6 Hz), 1.55–1.63 (m, 2 H),
1.81–1.85 (m, 2 H), 1.92–2.03 (m, 2 H), 2.09–2.17 (m, 2 H), 4.86 (t,
2 H, J = 5.7 Hz), 6.66 (t, 1 H, J = 5.6 Hz), 7.18–7.37 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 18.7, 22.1, 22.3, 27.2, 31.3, 42.1,
61.4, 126.4, 127.8, 128.1, 140.4, 143.6.
MS (EI): m/z (%) = 321 (26, [M+ + 1]), 320 (100, [M+]), 305 (5),
277 (16), 263 (60), 243 (44), 189 (25), 131 (30), 117 (85), 104 (52),
91 (51).
Hydrazones 5a–f Derived from 1-Amino[(2S,6S)-diphenyl]pi-
peridine; General Procedure
To a stirred solution of 1-amino-[(2S,6S)-diphenyl]piperidine (252
mg, 1 mmol) in CH2Cl2 (1.3 mL) was added the corresponding al-
dehyde (1.5–2.0 mmol) and anhyd Na2SO4. The reaction was stirred
at room temperature overnight, dried (Na2SO4), concentrated, and
the residue was purified by flash chromatography.
(2S,6S)-1-Methylideneamine-2,6-diphenylpiperidine (5a)
From paraformaldehyde (64 mg, 2 mmol) and a catalytic amount of
p-TsOH. Purification by flash chromatography (1:20 EtOAc–PE +
1% Et3N) gave 169 mg (64%) of hydrazone 5a as a white solid; mp
60–61 °C; [a]D22 –131.9 (c = 1.0, CHCl3).
HRMS: m/z calcd for C22H28N2: 320.2252; found: 320.2255.
Anal. Calcd for C22H28N2: C, 82.45; H, 8.81; N, 8.74. Found: C,
82.02; H, 9.02; N, 8.60.
IR (film): 3059, 2936, 2858, 1586, 1491, 1445, 1360, 1113, 978,
872, 750, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.51–1.57 (m, 2 H), 1.90–2.05 (m,
2 H), 2.10–2.20 (m, 2 H), 4.98 (t, 2 H, J = 5.8 Hz), 5.99 (d, 1 H,
J = 11.0 Hz), 6.10 (d, 1 H, J = 11.0 Hz), 7.15–7.40 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 18.4, 32.7, 60.7, 123.1, 126.5,
127.6, 128.4, 142.5.
(2S,6S)-1-(3¢-Phenylpropylideneamine)-2,6-diphenylpiperidine
(5e)
From dihydrocinnamaldehyde (145 mL, 1.1 mmol). Purification by
flash chromatography (1:30 EtOAc–PE + 1% Et3N) gave 273 mg
(74%) of hydrazone 5e as a white solid; mp 69–70 °C; [a]D22 –97.7
(c = 1.1, CHCl3).
IR (film): 3085, 3060, 3026, 2936, 2858, 1602, 1495, 1451, 754,
699 cm–1.
MS (EI): m/z (%) = 264 (62, [M+]), 187 (21), 145 (21), 131 (27), 117
1H NMR (500 MHz, CDCl3): d = 1.55–1.58 (m, 2 H), 1.92–2.02 (m,
2 H), 2.05–2.12 (m, 2 H), 2.27–2.32 (m, 2 H), 2.44–2.54 (m, 2 H),
4.84 (dd, 2 H, J = 3.9, 3.0 Hz), 6.65 (t, 1 H, J = 5.0 Hz), 6.94–6.96
(m, 2 H), 7.11–7.34 (m, 13 H).
13C NMR (100 MHz, CDCl3): d = 18.6, 31.0, 33.3, 34.6, 61.1,
125.6, 126.3, 127.8, 128.2, 128.5, 138.0, 141.8, 143.1.
(55), 104 (56), 91 (100), 77 (16).
HRMS: m/z calcd for C18H20N2: 264.1626; found: 264.1623.
(2S,6S)-1-Ethylideneamine-2,6-diphenylpiperidine (5b)
From acetaldehyde (113 mL, 2 mmol). Purification by flash chroma-
tography (1:20 EtOAc–PE + 1% Et3N) gave 167 mg (60%) of hy-
drazone 5b as an oil; [a]D22 –153.2 (c = 0.4, CHCl3).
MS (CI): m/z (%) = 369 (100, [M+ + 1]), 368 (34, [M+]), 291 (6),
277 (6).
IR (film): 3057, 2936, 2859, 1450, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.57–1.65 (m, 2 H), 1.67 (d, 3 H,
J = 5.2 Hz), 1.98–2.16 (m, 4 H), 4.86 (t, 2 H, J = 5.7 Hz), 6.72 (q, 1
H, J = 5.2 Hz), 7.22–7.40 (m, 10 H).
13C NMR (100 MHz, CDCl3): d = 18.7, 19.2, 30.8, 61.2, 126.2,
127.7, 128.1, 136.1, 143.3.
MS (EI): m/z (%) = 279 (100, [M+ + 1]), 278 (61, [M+]), 263 (10),
236 (10), 201 (20).
HRMS: m/z calcd for C26H29N2: 369.2331; found: 369.2332.
Anal. Calcd for C26H28N2: C, 84.74; H, 7.66; N, 7.60. Found: C,
84.35; H, 7.66; N, 7.42.
(2S,6S)-1-(2¢-Benzyloxyethylidene)-2,6-diphenylpiperidine (5f)
From benzyloxyacetaldehyde (281 mL, 2 mmol). Purification by
flash chromatography (1:20 EtOAc–PE + 1% Et3N) gave 188 mg
Synthesis 2006, No. 3, 540–550 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Mannich-Type Additions to N,N-Dialkylhydrazones
547
(49%) of hydrazone 5f as a white solid; mp 68–69 °C; [a]D22 –121.0
(c = 1.4, CHCl3).
MS (EI): m/z (%) = 381 (100, [M+ + 1]), 380 (50, [M+]), 379 (10),
349 (4), 279 (74), 117 (20).
IR (film): 3028, 2938, 2859, 1599, 1493, 1449, 1113, 1065, 750,
700 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.54–1.62 (m, 2 H), 1.95–2.06 (m,
2 H), 2.12–2.22 (m, 2 H), 3.86 (d, 2 H, J = 5.3 Hz), 4.16 (d, 1 H,
J = 11.7 Hz), 4.24 (d, 1 H, J = 11.7 Hz), 5.0 (t, 2 H, J = 5.8 Hz), 6.58
(t, 1 H, J = 5.3 Hz), 7.10–7.42 (m, 15 H).
HRMS: m/z calcd for C24H33N2O2: 381.2542; found 381.2548.
Anal. Calcd for C24H32N2O2: C, 75.75; H, 8.48; N, 7.36. Found: C,
75.29; H, 8.78; N, 6.93.
7c
From hydrazone 5c (292 mg, 1 mmol) and ketene acetal 6 (1.62 mL,
8 mmol). Purification by flash chromatography (1:30 Et2O–PE)
gave 366 mg (93%) of 7c as an oil; [a]D22 –17.2 (c = 0.9, CHCl3).
13C NMR (75 MHz, CDCl3): d = 18.1, 32.2, 61.3, 70.1, 70.8, 126.4,
127.4, 128.1, 132.1, 138.2, 142.7.
IR (film): 2933, 2869, 1733, 1545, 1382, 1270, 1096, 985, 869, 800
cm–1.
MS (EI): m/z (%) = 407 (87, [M+ + Na]), 385 (27, [M+ + 1]), 293
(10), 277 (100), 263 (21).
1H NMR (500 MHz, CDCl3): d = 0.6 (t, 3 H, J = 7.5 Hz), 0.84–0.90
(m, 1 H), 0.97 (s, 3 H), 1.02 (s, 3 H), 1.03–1.06 (m, 1 H), 1.73–1.77
(m, 2 H), 1.79–1.89 (m, 2 H), 2.05–2.12 (m, 2 H), 2.68 (t, 1 H,
J = 4.7 Hz), 2.98 (s, 1 H), 3.64 (s, 3 H), 4.11 (br s, 2 H), 7.24–7.51
(m, 10 H).
13C NMR (125 MHz, CDCl3): d = 13.0, 20.0, 20.4, 22.6, 23.1, 46.0,
51.6, 60.2, 63.8, 126.4, 127.8, 128.7, 142.6, 178.4.
HRMS: m/z calcd for C26H28N2O: 384.2201; found: 384.2204.
Anal. Calcd for C26H28N2O: C, 81.21; H, 7.34; N, 7.28. Found: C,
80.78; H, 7.32; N, 7.01.
Addition of Ketene Silyl Acetals/Thioacetals 6, 8, 11 or 12 to
Hydrazones 5; General Procedure
Sc(OTf)3 (98 mg, 20 mol%) and ketene silyl acetal or thioacetal 6,
8, 11 or 12 (4–8 mmol) were added to a solution of hydrazones 5a–
f (1 mmol) in THF–H2O (9:1) under argon. The mixture was stirred
until TLC indicated total consumption of the starting material. The
mixture was then diluted with CH2Cl2 (5 mL), washed with aq sat.
NaHCO3 (10 mL) and the aqueous layer was extracted with CH2Cl2
(2 × 10 mL). The combined organic layers were dried (Na2SO4),
concentrated, and the residue was purified by flash chromatogra-
phy.
MS (EI): m/z (%) = 417 (2, [M+ + Na]), 394 (25, [M+]), 293 (100).
HRMS: m/z calcd for C25H34N2O2: 394.2626; found: 394.2620.
Anal. Calcd for C25H34N2O2: C, 76.10; H, 8.69; N, 7.10. Found: C,
76.38; H, 8.61; N, 7.03.
7d
From hydrazone 5d (320 mg, 1 mmol) and ketene acetal 6 (1.62 mL,
8 mmol). Purification by flash chromatography (1:30 Et2O–PE)
gave 405 mg (96%) of 7d as an oil; [a]D22 –34.7 (c = 1.0, CHCl3).
IR (film): 2943, 2872, 1736, 1548, 1267, 1140, 750, 703 cm–1.
1H NMR (500 MHz, CDCl3): d = 0.61–0.73 (m, 2 H), 0.67 (d, 3 H,
J = 4.1 Hz), 0.68 (d, 3 H, J = 4.1 Hz), 0.95 (s, 3 H), 0.97 (s, 3 H),
1.53–1.59 (m, 1 H), 1.69–1.72 (m, 2 H), 1.83–1.85 (m, 2 H), 2.04–
2.10 (m, 2 H), 2.83 (dd, 1 H, J = 5.9, 3.5 Hz), 2.93 (br s, 1 H), 3.64
(s, 3 H), 4.14 (br s, 2 H), 7.24–7.51 (m, 10 H).
13C NMR (125 MHz, CDCl3): d = 19.9, 20.0, 22.4, 22.9, 23.6, 26.3,
40.3, 46.3, 51.5, 59.4, 60.6, 126.5, 127.8, 128.7, 142.5, 178.4.
MS (FAB): m/z (%) = 422 (8, [M+]), 321 (60), 320 (24), 236 (14),
131 (37), 117 (100), 104 (47), 91 (44).
7a
From hydrazone 5a (264 mg, 1 mmol) and ketene acetal 6 (0.8 mL,
4 mmol). Purification by flash chromatography (1:8 Et2O–PE) gave
359 mg (98%) of 7a as an oil; [a]D22 –76.6 (c = 1.2, CHCl3).
IR (film): 3031, 2936, 2856, 1736, 1450, 1363, 1148, 997, 878, 759,
703 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.77 (s, 3 H), 0.80 (s, 3 H), 1.68–
1.76 (m, 2 H), 1.91–1.98 (m, 4 H), 2.51 (d, 1 H, J = 11.0 Hz), 2.68
(d, 1 H, J = 11.0 Hz), 2.84 (br s, 1 H), 3.31 (s, 3 H), 4.24 (t, 2 H,
J = 5.6 Hz), 7.19–7.47 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 19.4, 23.2, 23.5, 28.6, 42.2, 51.4,
58.3, 62.0, 126.4, 127.9, 128.3, 143.4, 177.7.
HRMS: m/z calcd for C27H38N2O2: 422.2933; found: 422.2907.
MS (CI): m/z (%) = 367 (73, [M+ + 1]), 366 (64, [M+]), 365 (100),
305 (16), 287 (11), 265 (17), 117 (16), 104 (15).
7e
From hydrazone 5e (368 mg, 1 mmol) and ketene acetal 6 (1.62 mL,
8 mmol). Purification by flash chromatography (1:30 Et2O–PE)
gave 428 mg (91%) of 7e as an oil; [a]D22 –32.5 (c = 1.0, CHCl3).
HRMS: m/z calcd for C23H30N2O2: 366.2307; found 366.2282.
7b
From hydrazone 5b (278 mg, 1 mmol) and ketene acetal 6 (0.8 mL,
4 mmol). Purification by flash chromatography (1:15 Et2O–PE)
gave 373 mg (98%) of 7b as an oil.
IR (film): 3055, 2959, 2880, 1740, 1494, 1454, 1265, 1132, 754,
615 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.92 (s, 3 H), 0.95 (s, 3 H), 0.97–
1.24 (m, 2 H), 1.64–2.09 (m, 6 H), 2.22 (td, 1 H, J = 13.4, 5.4 Hz),
2.56 (td, 1 H, J = 13.4, 5.4 Hz), 2.75 (t, 1 H, J = 4.5 Hz), 2.97 (br s,
1 H), 3.56 (s, 3 H), 4.06 (br s, 2 H), 6.87–7.44 (m, 15 H).
13C NMR (125 MHz, CDCl3): d = 20.2, 23.2, 32.4, 35.8, 46.3, 51.7,
60.3, 62.5, 125.5, 126.7, 128.0, 128.1, 128.3, 128.7, 142.5, 143.1,
178.2.
IR (film): 3031, 2943, 2872, 1728, 1458, 1371, 1267, 1148, 989,
870, 751, 711 cm–1.
1H NMR (500 MHz, CDCl3): d (major isomer) = 0.45 (d, 3 H,
J = 6.4 Hz), 0.96 (s, 3 H), 0.99 (s, 3 H), 1.72–2.11 (m, 6 H), 2.83 (q,
1 H, J = 6.4 Hz), 2.92 (br s, 1 H), 3.62 (s, 3 H), 4.03 (br s, 2 H), 7.25
(t, 2 H, J = 7.3 Hz), 7.34 (t, 4 H, J = 7.4 Hz), 7.48–7.53 (m, 4 H).
13C NMR (125 MHz, CDCl3): d (major isomer) = 13.5, 19.5, 20.2,
22.4, 23.2, 45.7, 51.6, 58.2, 60.2, 126.4, 127.7, 127.8, 128.6, 128.6,
142.6, 178.2.
MS (FAB): m/z (%) = 470 (20, [M+]), 369 (100), 251 (18), 132 (18).
HRMS: m/z calcd for C31H39N2O2: 471.3011; found: 471.3032.
1H NMR (500 MHz, CDCl3): d (minor isomer) = 0.73 (s, 3 H), 0.78
(s, 3 H), 0.84 (d, 3 H, J = 6.5 Hz), 1.72–2.11 (m, 6 H), 2.64 (q, 1 H,
J = 6.5 Hz), 2.92 (br s, 1 H), 3.40 (s, 3 H), 4.16–4.18 (m, 2 H), 7.23–
7.53 (m, 10 H).
7f
From hydrazone 5f (384 mg, 1 mmol) and ketene acetal 6 (1.62 mL,
8 mmol). Purification by flash chromatography (1:8 Et2O–PE) gave
457 mg (94%) of 7f as an oil.
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E. Díez et al.
FEATURE ARTICLE
IR (film): 3323, 3036, 2932, 2868, 1960, 1728, 1601, 1457, 1370,
1138, 875, 748, 700 cm–1.
IR (film): 3296, 3082, 3059, 2957, 2930, 2866, 1676, 1491, 1452,
1364, 1161, 752, 700 cm–1.
1H NMR (500 MHz, CDCl3): d (major isomer) = 1.04 (s, 3 H), 1.06
(s, 3 H), 1.74–1.77 (m, 2 H), 2.06–2.10 (m, 4 H), 2.86–2.92 (m, 2
H), 3.05 (dd, 1 H, J = 10.0, 2.5 Hz), 3.14 (br s, 1 H), 3.50 (s, 3 H),
4.08 (br, 2 H), 4.18–4.24 (m, 2 H), 7.22–7.52 (m, 15 H).
1H NMR (300 MHz, CDCl3): d = 0.33 (t, 3 H, J = 7.5 Hz), 0.91–1.11
(m, 2 H), 1.45 (s, 9 H), 1.74–1.80 (m, 2 H), 1.83–2.10 (m, 4 H), 2.20
(dd, 1 H, J = 14.7, 5.0 Hz), 2.46 (dd, 1 H, J = 14.7, 7.6 Hz), 2.80–
2.86 (m, 1 H), 3.11 (br s, 1 H), 4.10 (br s, 2 H), 7.21–7.51 (m, 10 H).
13C NMR (125 MHz, CDCl3): d (major isomer) = 20.1, 21.7, 22.4,
23.5, 44.6, 51.5, 60.5, 62.7, 68.8, 72.7, 126.3, 126.5, 127.2, 127.4,
127.6, 127.7, 127.8, 128.1, 128.5, 128.7, 128.8, 142.4, 177.8.
1H NMR (500 MHz, CDCl3): d (minor isomer) = 0.75 (s, 3 H), 0.81
(s, 3 H), 1.63 (br s, 2 H), 2.06–2.10 (m, 4 H), 2.77–2.79 (m, 1 H),
3.14 (br s, 1 H), 3.38–3.47 (m, 2 H), 3.41 (s, 3 H), 4.13 (br s, 2 H),
4.37 (s, 2 H), 7.22–7.52 (m, 15 H).
13C NMR (125 MHz, CDCl3): d (minor isomer) = 19.8, 21.7, 22.4,
23.5, 44.6, 51.4, 61.0, 63.7, 68.5, 77.0, 126.2, 127.4, 127.9, 128.0,
128.2, 128.5, 129.1, 129.2, 129.3, 129.4, 129.5, 129.6, 129.7, 129.8,
129.9, 138.6, 177.8.
13C NMR (75 MHz, CDCl3): d = 8.9, 19.9, 24.3, 25.4, 29.8, 47.3,
47.9, 55.7, 60.6, 126.4, 127.9, 128.5, 142.8, 200.3.
MS (CI): m/z (%) = 425 (100, [M+ + 1]), 424 (99, [M+]), 395 (10),
335 (12), 293 (71), 251 (17), 236 (13), 117 (55), 57 (41).
HRMS: m/z calcd for C26H36N2OS: 424.2548; found: 424.2554.
Anal. Calcd for C26H36N2OS: C, 73.54; H, 8.54; N, 6.60. Found: C,
73.33; H, 8.27; N, 6.32.
13e
From hydrazone 5e (368 mg, 1 mmol) and ketene thioacetal 11 (1.6
mL, 8 mmol). Purification by flash chromatography (1:2 toluene–
PE) gave 491 mg (98%) of 13e as an oil. This compound was further
purified by medium pressure liquid chromatography (1:1 toluene–
PE) for the isolation of pure diastereomers.
MS (FAB): m/z (%) = 487 (M+ + 1, 100), 486 (M+, 89), 455 (6), 409
(4), 385 (51), 365 (64).
HRMS: m/z calcd for C31H39N2O3: 487.2961; found: 487.2956.
Major Isomer
9
[a]D22 –50.2 (c = 0.9, CHCl3).
From hydrazone 5c (292 mg, 1 mmol) and ketene acetal 8 (1.7 mL,
8 mmol). Purification by flash chromatography (1:50 Et2O–PE)
gave 161.3 mg (44%) of 9 and 129 mg (39%) of by-product 10 as a
4:1 mixture of isomers.
IR (film): 3065, 3030, 2937, 2866, 1682, 1497, 1457, 1369, 1163,
996, 750, 702 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.19–1.25 (m, 1 H), 1.34–1.40 (m,
1 H), 1.47 (s, 9 H), 1.76–1.79 (m, 2 H), 1.9 (br s, 2 H), 2.06–2.14
(m, 2 H), 2.17–2.21 (m, 2 H), 2.32 (dd, 1 H, J = 14.7, 5.0 Hz), 2.53
(dd, 1 H, J = 14.7, 7.5 Hz), 2.94–2.97 (m, 1 H), 3.15 (br s, 1 H), 4.10
(br s, 2 H), 6.95–7.48 (m, 15 H).
13C NMR (125 MHz, CDCl3): d = 19.9, 24.2, 29.7, 31.1, 34.1, 47.6,
47.9, 54.7, 60.6, 125.4, 126.5, 127.9, 128.0, 128.2, 128.5, 142.4,
142.6, 199.9.
9
IR (film): 3295, 3059, 3028, 2934, 2866, 1734, 1493, 1452, 1369,
1190 cm–1.
1H NMR (300 MHz, CDCl3): d (major isomer) = 0.37 (t, 3 H, J = 7.5
Hz), 0.92–0.98 (m, 1 H), 1.00–1.13 (m, 1 H), 1.74–2.10 (m, 7 H),
2.30 (dd, 1 H, J = 15.5, 7.5 Hz), 2.78–2.86 (m, 1 H), 3.66 (s, 3 H),
4.14–4.18 (m, 2 H), 7.24–7.51 (m, 10 H).
13C NMR (75 MHz, CDCl3): d (major isomer) = 9.1, 19.8, 25.2,
25.5, 37.1, 51.3, 54.9, 60.9, 126.5, 127.9, 128.6, 142.8, 173.8.
1H NMR (300 MHz, CDCl3): d (minor isomer) = 0.72 (t, 3 H,
J = 7.5 Hz), 0.83–0.91 (m, 1 H), 1.26–1.34 (m, 1 H), 1.57–1.62 (m,
1 H), 1.74–2.10 (m, 6 H), 2.15–2.19 (m, 1 H), 2.67–2.71 (m, 1 H),
3.54 (s, 3 H), 4.06–4.08 (m, 2 H), 7.24–7.51 (m, 10 H).
13C NMR (75 MHz, CDCl3): d (minor isomer) = 9.8, 20.1, 23.1,
29.7, 37.9, 51.2, 56.2, 126.5, 127.9, 128.6, 142.4, 173.5.
MS (FAB): m/z (%) = 523 (18, [M+ + Na]), 500 (92, [M+ + 1]), 369
(100).
HRMS: m/z calcd for C32H41N2O5: 501.2939; found: 501.2918.
Minor Isomer
[a]D22 –29.3 (c = 0.9, CHCl3).
1H NMR (500 MHz, CDCl3): d = 1.43 (s, 9 H), 1.56–1.65 (m, 2 H),
1.74–1.84 (m, 5 H), 2.05–2.11 (m, 2 H), 2.43–2.50 (m, 3 H), 2.83–
2.86 (m, 1 H), 3.12 (br s, 1 H), 4.05 (br s, 2 H), 7.11–7.49 (m, 15 H).
13C NMR (125 MHz, CDCl3): d = 20.1, 23.2, 29.8, 31.8, 33.9, 47.7,
48.4, 55.5, 61.1, 125.7, 126.6, 127.9, 128.3, 128.5, 142.2, 142.3,
199.7.
MS (CI): m/z (%) = 367 (100, [M+ + 1]), 366 (91, [M+]), 337 (24),
293 (40), 251 (18), 236 (15), 146 (25), 145 (22), 117 (55), 91 (28).
HRMS: m/z calcd for C23H30N2O2: 366.2307; found: 366.2309.
By-product 10
14c
1H NMR (300 MHz, CDCl3): d (major isomer) = 0.91 (t, 3 H, J = 7.5
Hz), 1.49 (d, 3 H, J = 1.0 Hz), 1.60–1.69 (m, 2 H), 2.02–2.17 (m, 6
H), 4.91 (t, 2 H, J = 5.7 Hz), 5.25 (td, 1 H, J = 7.2, 0.9 Hz), 7.06 (s,
1 H), 7.22–7.42 (m, 10 H).
From hydrazone 5c (292 mg, 1 mmol) and Z-ketene thioacetal 12
(1.74 mL, 8 mmol). Purification by flash chromatography (1:50 →
1:30 Et2O–PE) gave 361 mg (88%) of 14c as an oil.
IR (film): 3318, 3033, 2936, 2876, 1686, 1461, 959, 757, 705 cm–1.
1H NMR (300 MHz, CDCl3): d (major isomer) = 0.20 (d, 3 H,
J = 7.5 Hz), 0.67 (d, 3 H, J = 6.9 Hz), 0.80–0.90 (m, 1 H), 1.18 (dq,
1 H, J = 7.5, 3.3 Hz), 1.28 (t, 3 H, J = 7.5 Hz), 1.73–1.79 (m, 2 H),
1.91–2.19 (m, 4 H), 2.82–2.95 (m, 4 H), 4.05 (br s, 1 H), 4.23–4.27
(m, 2 H), 7.24–7.55 (m, 10 H).
13C NMR (75 MHz, CDCl3): d (major isomer) = 9.2, 10.6, 14.8,
19.4, 21.0, 23.0, 26.5, 49.2, 59.8, 61.5, 126.6, 128.0, 128.6, 143.0,
203.6.
13C NMR (75 MHz, CDCl3): d (major isomer) = 11.2, 13.9, 19.2,
21.3, 29.9, 60.6, 126.3, 127.9, 128.0, 133.8, 139.2, 142.4.
MS (CI): m/z (%) = 333 (90, [M+ + 1]), 332 (100, [M+]), 303 (10),
236 (11), 131 (10), 117 (21), 104 (17), 91 (10).
HRMS: m/z calcd for C23H28N2: 332.2252; found: 332.2255.
13c
From hydrazone 5c (292 mg, 1 mmol) and ketene thioacetal 11 (1.6
mL, 8 mmol). Purification by flash chromatography (1:50 Et2O–
PE) gave 374 mg (88%) of 13c as an oil.
Synthesis 2006, No. 3, 540–550 © Thieme Stuttgart · New York

FEATURE ARTICLE
Asymmetric Mannich-Type Additions to N,N-Dialkylhydrazones
549
1H NMR (300 MHz, CDCl3): d (minor isomer) = 0.28 (d, 3 H,
J = 6.9 Hz), 0.80–0.90 (m, 3 H), 1.24 (t, 3 H, J = 7.5 Hz), 2.70–2.78
(m, 1 H), 2.82–2.95 (m, 3 H).
13C NMR (75 MHz, CDCl3): d (minor isomer) = 8.3, 11.3, 14.7,
20.3, 20.4, 22.9, 50.4, 59.3, 61.5, 126.5, 127.9, 142.4, 203.4.
MS (EI): m/z (%) = 411 (M+ + 1, 9), 410 (M+, 29), 381 (4), 293
(100).
mmol) and the mixture stirred under reflux overnight. The mixture
was diluted with CH2Cl2 (5 mL) and the organic layer was washed
with pH 7 buffer (2 × 10 mL) and brine (10 mL). The organic layer
was dried (Na2SO4), concentrated, and the residue was purified by
flash chromatography (1:50 → 1:25 Et2O–PE) gave 55 mg (56%) of
15c as an oil.
1H NMR (300 MHz, CDCl3): d = 0.83 (t, 3 H, J = 7.6 Hz), 1.27 (s,
3 H), 1.30 (s, 3 H), 1.80–1.88 (m, 2 H), 1.90–2.02 (m, 2 H), 2.10–
2.30 (m, 2 H), 2.33–2.44 (m, 2 H), 3.62 (s, 3 H), 4.08–4.12 (m, 2 H),
7.25–7.53 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 11.1, 20.7, 21.6, 23.3, 23.4, 23.7,
51.0, 51.7, 62.1, 126.3, 127.9, 128.0, 142.4, 174.1, 176.3.
MS (EI): m/z (%) = 393 (39, [M+ + 1]), 392 (73, [M+]), 293 (100),
236 (40), 117 (77), 104 (78), 91 (69), 78 (36).
HRMS: m/z calcd for C25H34N2OS: 410.2392; found: 410.2398.
14e
From hydrazone 5e (368 mg, 1 mmol) and Z-ketene thioacetal 12
(1.74 mL, 8 mmol). Purification by flash chromatography (1:50
Et2O–PE) gave 438 mg (90%) of 14e as an oil. This compound was
further purified by medium pressure liquid chromatography (1:1
toluene–PE) for the isolation of the pure major diastereomer.
HRMS: m/z calcd for C25H32N2O2: 392.2464; found: 392.2475.
Major Isomer
Alcohol 16
[a]D22 –65.3 (c = 0.8, CHCl3).
To a solution of hydrazine 7c (100 mg, 0.25 mmol) in anhyd THF
(0.4 mL) at 0 °C was added n-BuLi (1.6 M in hexane, 350 mL, 0.56
mmol) and the mixture stirred at 0 °C until TLC indicated total con-
sumption of the starting material. Then, pH 7 buffer was added and
the aqueous layer was extracted with CH2Cl2 (3 × 10 mL) and
i-PrOH–CHCl3 (1:3, 2 × 10 mL). The combined organic layer was
dried (Na2SO4), concentrated, and the residue was purified by flash
chromatography (1:25 Et2O–PE) to give 78 mg (65%) of 16 as a
crystalline solid. The product was recrystallized from petroleum
ether at low temperature; [a]D22 +6.0 (c = 0.8, CHCl3).
IR (film): 2932, 2864, 1680, 1452, 960, 750, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.68 (d, 3 H, J = 6.7 Hz), 1.04–
1.15 (m, 1 H), 1.28 (t, 3 H, J = 7.4 Hz), 1.40–1.51 (m, 1 H), 1.72–
1.79 (m, 2 H), 1.80–2.11 (m, 6 H), 2.89 (q, 2 H, J = 7.4 Hz), 2.99–
3.06 (m, 3 H), 4.28–4.32 (m, 2 H), 6.89–7.57 (m, 15 H).
13C NMR (125 MHz, CDCl3): d = 10.2, 14.8, 19.3, 23.1, 27.1, 30.1,
31.8, 49.4, 58.9, 61.8, 125.5, 126.7, 128.1, 128.2, 128.6, 142.4,
143.0, 203.3.
MS (EI): m/z (%) = 487 (14, [M+ + 1]), 486 (37, [M+]), 369 (100).
IR (film): 3293, 3057, 2951, 2870, 1453, 1369, 1125, 988, 870, 750,
700 cm–1.
HRMS: m/z calcd for C31H38N2OS: 486.2705; found: 486.2699.
1H NMR (300 MHz, DMSO-d6, 90 °C): d = 0.69 (t, 3 H, J = 7.5 Hz),
0.72 (s, 3 H), 0.73 (s, 3 H), 0.83 (t, 3 H, J = 7.1 Hz), 0.88 (t, 3 H,
J = 7.0 Hz), 0.96–1.05 (m, 2 H), 1.20–1.51 (m, 12 H), 1.68–1.84 (m,
4 H), 2.02–2.12 (m, 2 H), 2.62 (br s, 1 H), 4.02–4.05 (m, 2 H), 4.1
(br s, 1 H), 4.71 (br s, 1 H), 7.20–7.49 (m, 10 H).
13C NMR (300 MHz, DMSO-d6, 90 °C): d = 18.7, 18.8, 19.8, 22.3,
25.2, 27.0, 27.7, 28.2, 31.5, 31.9, 40.6, 40.7, 49.6, 64.1, 69.2, 83.1,
131.4, 132.8, 133.2, 147.4.
Minor Isomer
1H NMR (300 MHz, CDCl3): d = 0.27 (d, 3 H, J = 6.9 Hz), 1.22 (t,
3 H, J = 7.4 Hz), 1.24–1.26 (m, 1 H), 1.61–2.20 (m, 7 H), 2.45–2.51
(m, 2 H), 2.82 (q, 2 H, J = 7.5 Hz), 2.82–2.84 (m, 1 H), 3.98–4.04
(m, 2 H), 4.28–4.31 (m, 2 H), 6.88–7.57 (m, 15 H).
13C NMR (75 MHz, CDCl3): d = 8.1, 14.8, 20.2, 23.0, 27.0, 29.1,
33.3, 50.2, 59.6, 61.6, 125.5, 125.9, 126.5, 126.7, 128.0, 128.1,
128.2, 128.4, 128.6, 142.2, 203.4.
MS (CI): m/z (%) = 479 (14, [M+ + 1], 478 (10, [M+]), 421 (10), 294
(28), 293 (100), 252 (17), 236 (9), 117 (23).
15a
To a solution of hydrazine 7a (366 mg, 1 mmol) in pyridine was
added benzoyl chloride (290 mL, 2.5 mmol) and a catalytic amount
of DMAP and the mixture stirred at r.t. overnight. Then, aq sat.
CuSO4 (1 mL) was added and the mixture stirred for 10 min. H2O
was added (2 mL) and the aqueous layer was extracted with Et2O (3
× 5 mL). The combined organic layers were dried (Na2SO4), con-
centrated, and the residue was purified by flash chromatography
(1:4 Et2O–PE) to afford 385 mg (84%) of 15a as a foam; [a]D
–131.4 (c = 0.5, CHCl3).
IR (film): 2936, 2856, 1740, 1454, 1263, 1101, 874, 707 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.97 (s, 3 H), 1.00 (s, 3 H), 1.52–
1.60 (m, 2 H), 1.95–2.10 (m, 4 H), 3.34 (s, 3 H), 4.83–4.87 (m, 2 H),
6.53 (s, 1 H), 7.16–7.33 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 19.0, 23.4, 23.6, 31.5, 46.1, 51.6,
61.1, 126.2, 127.9, 138.7, 142.4, 176.4.
MS (CI): m/z (%) = 365 (100, [M+ + 1]), 364 (34, [M+]), 305 (12),
287 (6), 263 (7).
HRMS: m/z calcd for C32H51N2O: 479.4001; found: 479.4013.
Crystal Data for 16
C32H50N2O, Mw = 478.74, colorless block (0.24 × 0.24 × 0.16 mm3)
from petroleum ether. Triclinic, space group P1 (no. 1), a =
9.7315(6) Å, b = 12.3950(6) Å, c = 12.4509(8) Å, a = 75.566(2)°,
b = 78.310(2)°, g = 88.110(2)°, V = 1423.86(14) Å3, Z = 2,
r
calcd = 1.117 gcm–3, l(Mo Ka1) = 0.71073 Å, F(000) = 528, m =
22
0.066 mm–1, T = 100(2) K. Reflections (29739) were collected with
a Bruker-Nonius X8Kappa Apex II CCD diffractometer in the range
5.52 < 2Q < 61.32° and 8566 independent reflections [R(int) =
0.0332] were used in the structural analysis. Reflections were cor-
rected for Lorentz polarization effects and absorption applied by
(SADABS).20 The structure was solved by direct methods
(SIR2002)21 and refined against all F2 data by full-matrix least-
squares techniques (SHELXTL-6.12)22 to final R1 = 0.0392 [I >
2s(I)], and to wR2 = 0.1044 for all data, with a Goodness-of-fit on
F2 = 1.037 and 643 parameters.23
HRMS: m/z calcd for C23H28N2O2: 364.2151; found: 364.2161.
Cleavage of the N–N Bond in Hydrazines 7d,e to b-Amino
Esters 17d,e; General Procedure
To a solution of hydrazine 7d,e (1 mmol) in MeOH (15 mL) were
added HCO2NH4 (600 mg, 9.5 mmol), Pd/C (600 mg) and Raney Ni
(600 mg). The mixture was hydrogenated (500–700 psi, 65 °C, 4 d)
and filtered through a pad of Celite. The solvent was evaporated un-
15c
To a solution of hydrazine 7c (100 mg, 0.25 mmol) in anhyd THF
(2 mL) at r.t. was added NaH (20 mg, 60% in mineral oil, 0.5
mmol), acetyl chloride (20 mL, 0.27 mmol) and HMPA (87 mL, 0.5
Synthesis 2006, No. 3, 540–550 © Thieme Stuttgart · New York

550
E. Díez et al.
FEATURE ARTICLE
(9) Lassaletta, J. M.; Alcarazo, M.; Fernández, R. Chem.
der reduced pressure and the residue was dissolved in H2O (10 mL)
and washed with PE (3 × 10 mL) to remove organic impurities. The
aqueous layer was then extracted with CHCl3–i-PrOH (4:1, 3 × 8
mL), dried (Na2SO4) and concentrated to yield products 17d,e.
Commun. 2004, 298.
(10) (a) Fernández, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.;
Monge, A. Angew. Chem. Int. Ed. 2000, 39, 2893.
(b) Fernández, R.; Ferrete, A.; Lassaletta, J. M.; Llera, J. M.;
Martín-Zamora, E. Angew. Chem. Int. Ed. 2002, 114, 859.
(c) Díez, E.; Fernández, R.; Marqués-López, E.; Martín-
Zamora, E.; Lassaletta, J. M. Org. Lett. 2004, 6, 2749.
(d) Martín-Zamora, E.; Ferrete, A.; Llera, J. M.; Muñoz, J.
M.; Pappalardo, R. R.; Fernández, R.; Lassaletta, J. M.
Chem. Eur. J. 2004, 10, 6111.
(11) For a comprehensive review on asymmetric addition of
organometallics to the CN double bond of hydrazones, see:
Enders, D.; Reinhold, U. Tetrahedron: Asymmetry 1997, 8,
1895.
(12) (a) Enders, D.; Schubert, H.; Nübling, C. Angew. Chem., Int.
Ed. Engl. 1986, 25, 1109. (b) Denmark, S. E.; Weber, T.;
Piotrowski, D. W. J. Am. Chem. Soc. 1987, 109, 2224.
(c) Molander, G. A. Chem. Rev. 1992, 29. (d) Enders, D.;
Tiebes, J. Liebigs Ann. Chem. 1993, 173. (e) Denmark, S.
E.; Edwards, J. P.; Nicaise, O. J. Org. Chem. 1993, 58, 569.
(f) Nicaise, O.; Denmark, S. E. Bull. Soc. Chim. Fr. 1997,
134, 395. (g) Enders, D.; Nübling, C.; Schubert, H. Liebigs
Ann./Recl. 1997, 1089.
(S)-3-Amino-2,2,5-trimethylhexanoic Acid Methyl Ester (17d)
From hydrazine 7d (1 mmol, 422 mg); white solid; yield: 149 mg
(80%); mp 108–109 °C; [a]D22 –25.3 (c = 0.8, CHCl3).
IR (film): 2955, 2868, 1732, 1589, 1549, 1398, 1344, 1279, 1196,
1136 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.92 (d, 3 H, J = 6.4 Hz), 0.96 (d,
3 H, J = 6.5 Hz), 1.12–1.22 (m, 1 H), 1.26 (s, 3 H), 1.28 (s, 3 H),
1.43–1.52 (m, 1 H), 1.80–1.90 (m, 1 H), 3.26 (dd, 1 H, J = 10.3, 1.7
Hz), 3.73 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 21.0, 21.4, 21.6, 23.8, 24.6, 39.8,
46.0, 52.2, 55.3, 176.7.
MS (CI): m/z (%) = 187 (9, [M+]), 186 (20, [M+ – 1]), 185 (11), 173
(6), 172 (91), 167 (37), 157 (12), 156 (30), 155 (52).
HRMS: m/z calcd for C10H21NO2: 187.1572; found: 187.1574.
(S)-3-Amino-2,2-dimethyl-5-phenylpentanoic Acid Methyl
Ester (17e)
From hydrazine 7e (1 mmol, 470 mg); amorphous solid; yield: 183
mg (78%).
(13) Review: Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002,
35, 209.
(14) Yield of compound 10 increases to 81% when 4 equivalents
of 8 and 0.4 M THF–H2O (9:1) were used.
IR (film): 3026, 2922, 2851, 1738, 1603, 1528, 1452, 1379, 1273,
1140, 739 cm–1.
(15) Recently we have found out that N,N-dialkylhydrazones
from enolizable aldehydes react with nitroalkenes, through
the tautomeric ‘ene-hydrazine’ form, in the presence of
thioureas as H-bonding catalysts: Pettersen, D.; Herrera, R.
P.; Bernardi, L.; Fini, F.; Sgarzani, V.; Fernández, R.;
Lassaletta, J. M.; Ricci, A., Synlett 2006, in press.
(16) Fernández, R.; Ferrete, A.; Llera, J. M.; Magriz, A.; Martín-
Zamora, E.; Díez, E.; Lassaletta, J. M. Chem. Eur. J. 2004,
10, 737.
1H NMR (300 MHz, CDCl3): d = 1.23 (s, 3 H), 1.26 (s, 3 H), 1.67–
1.78 (m, 2 H), 2.65–2.75 (m, 1 H), 3.00–3.10 (m, 1 H), 3.14–3.17
(m, 1 H), 3.66 (s, 3 H), 7.17–7.28 (m, 5 H).
13C NMR (75 MHz, CDCl3): d = 21.2, 21.8, 31.4, 32.9, 52.1, 57.5,
126.0, 128.3, 128.5, 141.4, 176.7.
MS (CI): m/z (%) = 236 (34, [M+ + 1]), 140 (16), 134 (100), 130
(11), 117 (22), 91 (80), 81 (9).
(17) These compounds proved to be rather unstable and did not
resist purification by column chromatography but the crude
products were obtained with a high degree of purity.
(18) It is worth noting that compound 16 exhibits an axial N–N
bond in the solid state. This characteristic has also been
observed in other structures of compounds containing the
2,6-diphenylpiperidine auxiliary: Alcarazo, M. Ph.D.
Thesis; University of Seville: Seville, 2005.
References
(1) Enantioselective Synthesis of b-Amino Acids; Juaristi, E.;
Soloshonok, V. A., Eds.; Wiley-VCH: New York, 2005, 2nd
edition.
(2) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069.
(3) Selected examples: (a) Ishitani, H.; Ueno, M.; Kobayashi, S.
J. Am. Chem. Soc. 1997, 119, 7153. (b) Kobayashi, S.;
Ishitani, H.; Ueno, M. J. Am. Chem. Soc. 1998, 120, 431.
(c) Müller, R.; Goesmann, H.; Waldmann, H. Angew. Chem.
Int. Ed. 1999, 38, 184. (d) Akiyama, T.; Itoh, J.; Yokota, K.;
Fuchibe, K. Angew. Chem. Int. Ed. 2004, 43, 1566.
(4) (a) Kobayashi, S.; Hamada, T.; Manabe, K. J. Am. Chem.
Soc. 2002, 124, 5640. (b) Kobayashi, S.; Matsubara, R.;
Nakamura, Y.; Kitagawa, H.; Sugiura, M. J. Am. Chem. Soc.
2003, 125, 2507. (c) Hamada, T.; Manabe, K.; Kobayashi,
S. J. Am. Chem. Soc. 2004, 126, 7768.
(19) Evans, D. A.; Kozlowski, M. C.; Murry, J. A.; Burgey, C. S.;
Campos, K. R.; Connell, B. T.; Staples, R. J. J. Am. Chem.
Soc. 1999, 121, 669.
(20) Sheldrick, G. SADABS; Bruker AXS, Inc.: Madison,
Wisconsin, 1999.
(21) SIR2002: The Program, see: Burla, M. C.; Camalli, B.;
Carrozzini, M.; Cascarano, G. L.; G iacovazzo, C.; Polidori,
G.; Spagna, R. J. Appl. Cryst. 2003, 36, 1103.
(22) SHELXTL 6.14; Bruker AXS, Inc.: Madison, Wisconsin,
2000-2003.
(5) Ishitani, H.; Ueno, M.; Kobayashi, S. J. Am. Chem. Soc.
2000, 122, 8180.
(6) Kobayashi, S.; Hasegawa, Y.; Ishitani, H. Chem. Lett. 1998,
1131.
(7) Josephsohn, N. S.; Snapper, M. L.; Hoveyda, A. H. J. Am.
Chem. Soc. 2004, 126, 3734.
(23) CCDC 289555 contains the supplementary crystallographic
data for 16. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB21EZ, UK; fax: +44(1223)336033; or
deposit@ccdc.cam.ac.uk].
(8) (a) Review: Fernández, R.; Lassaletta, J. M. Synlett 2000,
1228. (b) See also: Lassaletta, J. M.; Vázquez, J.; Prieto, A.;
Fernández, R.; Raabe, G.; Enders, D. J. Org. Chem. 2003,
68, 2698.
Synthesis 2006, No. 3, 540–550 © Thieme Stuttgart · New York