Towards a catalytic asymmetric version of the [3+2] cycloaddition between hydrazones and cyclopentadiene

Article abstract of DOI:10.1055/s-0030-1260467

A novel and easily accessible metal-free catalytic system, an in situ generated BINOL-phosphate-derived silicon Lewis acid, has been described for the [3+2] cycloaddition of N-benzoylhydrazone to cyclopentadiene to afford a cycloadduct in high diastereomeric ratio of 95:5 (syn/anti) and enantiomeric excess of 89%. These results provide insights in the future design and development of highly active and enantioselective silicon Lewis acids for this and other cycloaddition types. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260467

1988
PAPER
Towards a Catalytic Asymmetric Version of the [3+2] Cycloaddition between
Hydrazones and Cyclopentadiene
[3+2]
C
ycloadditio
l
n
betw
e
e
en
H
ydra
z
x
ones and Cy
a
clopentadie
n
ne dru Zamfir, Svetlana B. Tsogoeva*
Department of Chemistry and Pharmacy, Institute of Organic Chemistry I, University of Erlangen-Nuremberg, Henkestr. 42,
91054 Erlangen, Germany
Fax +49(9131)8526865; E-mail: tsogoeva@chemie.uni-erlangen.de
Received 12 April 2011
metal-free catalysis because of its operational simplicity,
Abstract: A novel and easily accessible metal-free catalytic sys-
mild reaction conditions, and environmental advantages.7
tem, an in situ generated BINOL-phosphate-derived silicon Lewis
acid, has been described for the [3+2] cycloaddition of N-benzoyl-
hydrazone to cyclopentadiene to afford a cycloadduct in high dia-
stereomeric ratio of 95:5 (syn/anti) and enantiomeric excess of
89%. These results provide insights in the future design and devel-
opment of highly active and enantioselective silicon Lewis acids for
this and other cycloaddition types.
Inspired by the work of Kobayashi, which showed that
Lewis acids are potent catalysts for this reaction, our at-
tention was set on silicon compounds,8 as catalytic spe-
cies. The use of silicon-based Lewis acids8e as well as
hydrazones are accompanied by practical advantages,
which motivated our current and previous work.9 Our in-
tention was, first to find a proper achiral silicon-based cat-
alyst that would efficiently promote the reaction, and then
extend the results to the asymmetric reaction, by modify-
ing the catalyst structure to a chiral compound.
Key words: cycloaddition, silicon, hydrazones, Lewis acids, nitro-
gen heterocycles
[3+2] Cycloaddition of hydrazones to olefins is a straight-
forward synthetic route providing direct access to pyrazo-
lidines and pyrazolines. These types of heterocyclic
subunits are found in natural products and bioactive com-
pounds,1 presenting therefore attractive targets for syn-
thetic chemists. The pioneering work in this field was
reported from the groups of Hesse, Hamelin, and Grigg.
Hesse2a obtained pyrazolidines under strong acidic
conditions2 (acetic acid in the presence of a stoichiometric
amount of sulfuric acid) out of a three-component reaction
between an aldehyde, an N-acetylhydrazine, and an olefin.
The addition reaction of acetaldehyde hydrazone with E-
and Z-alkenes in acidic media was reported by Hamelin
and co-wokers2b,c in 1979. In their study, the results were
compatible with a concerted process of the polar [3+2] cy-
cloaddition type. Thermal conditions3 (150 °C) were also
found to activate the reaction between a hydrazone and an
activated olefin by Grigg and co-workers.3a,b Recently
Kobayashi found that Lewis acids also promote this trans-
formation. Pyrazolidine derivatives were isolated, by us-
ing a stoichiometric amount of BF3·OEt2 (1.1 equiv) or a
catalytic amount of Zr(OTf)4 and Hf(OTf)4.4a
The model reaction between ethyl glyoxylate-derived hy-
drazone 1i and freshly distilled cyclopentadiene was in-
vestigated first. Cyclopentadiene was used in excess due
to its tendency to form dimers. By studying different tet-
ravalent silicon compounds10 we found that the cycload-
dition proceeded smoothly in the presence of TMSOTf
(trimethylsilyl triflate) at 10 mol% loading. Adducts of
cyclopentadiene were observed as side products, which
showed no problems of separation from the pyrazolidines.
The suitable solvent for the reaction was dichlo-
romethane. The acidic conditions were found to favor the
isomerization of the E-configured hydrazone to the Z-
form, which showed to be less reactive. Lowering the
temperature from room temperature to –10 °C reduced the
isomerization, so that the product of the cycloaddition
could be obtained in 99% yield and with a diastereoselec-
tivity of 94:6 (Scheme 1).
Next different hydrazones as substrates were investigated
(Table 1) and generally excellent yields and selectivities
were obtained (up to 99% yield, 98:2 dr). Using the 4-ni-
tro or 4-bromo derivatives of the benzoyl protecting group
Regarding an asymmetric version for this kind of reac-
tions, some examples are found in literature, but these are
restricted to intermolecular cyclizations,4b,5 or reactions
with activated olefins.4c,6 Thus, there is still a lot of space
for development and improvement especially for the
[3+2] cycloaddition of hydrazones with nonfunctional-
ized olefins, which lacks a catalytic asymmetric method.
Furthermore, a factor that has gained importance for dif-
ferent organic transformations in recent years is the use of
C6H4(4-NO2)
HN
O
F
N
Me
Me
O
F
F
H
C6H4(4-NO2)
H
Si
S
O
EtO2C
Me
O
O
1i
N
99% yield
(10 mol%)
+
94:6 dr
HN
CH2Cl2, 24 h, –10 °C
(syn/anti)
H
EtO2C
+ enantiomer
2i
SYNTHESIS 2011, No. 12, pp 1988–1992
x
x.
x
x
.
2
0
1
1
Advanced online publication: 17.05.2011
DOI: 10.1055/s-0030-1260467; Art ID: C01111SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 TMSOTf-catalyzed [3+2] cycloaddition of hydrazone 1i
to cyclopentadiene

PAPER
[3+2] Cycloaddition between Hydrazones and Cyclopentadiene
1989
Table 1 Substrate Scope for the Catalytic [3+2] Cycloaddition of Hydrazones and Cyclopentadiene
H
N
R2
N
R2
R2
O
O
O
R1
H
1
H
H
N
N
TMSOTf (10 mol%)
CH2Cl2, 24 h
HN
+
HN
+
H
H
R1
R1
syn-2
anti-2
Entry
1
R1
Ph
R2
Temp (°C)
r.t.
Yield (%)a
dr (syn/anti)
1
2
1a
1b
1c
1d
1e
1f
1g
1h
1i
C6H4(4-NO2)
C6H4(4-NO2)
C6H4(4-NO2)
C6H4(4-Br)
Ph
–
–
PhCH2
PhCH2CH2
PhCH2CH2
PhCH2CH2
Et
r.t.
58
99
88
90
98
99
99
99
88
95:5b
89:11c
97:3c
97:3c
96:4c
96:4c
98:2c
94:6b,d
89:11b,d
3
r.t.
4
r.t.
5
r.t.
6
C6H4(4-NO2)
C6H4(4-Br)
C6H4(4-NO2)
C6H4(4-NO2)
Ph
r.t.
7
Et
r.t.
8
i-Bu
r.t.
9
EtO2C
EtO2C
–10
r.t.
10
1j
a Yield of the isolated product.
b The dr was determined by HPLC.
c The dr was determined by NMR spectroscopy.
d Both isomers were isolated.
a slight improvement of selectivity and yield was found tive (entry 3).11 With TMSOTf, as a suitable catalyst for
(Table 1, compare entries 9 and 10).
this system, an analogue chiral silicon-based catalyst was
envisioned that would share the following feature: it
should contain a tetravalent silicon center, with a leaving
group similar to TfO–.
Generally, aliphatic aldehyde-derived N-benzoylhydra-
zones performed well in this cycloaddition reaction (en-
tries 3–8). Phenylacetaldehyde-derived hydrazone gives a
product with 58% yield (entry 2) while the benzaldehyde- Structure 3 (Figure 1) was proposed as a candidate. As a
derived hydrazone did not react (entry 1), showing that the chirality source a BINOL phosphate derivative was con-
reaction is drastically influenced by the steric demand of sidered, because of the rigid qualities of the BINOL-scaf-
the substituent on the aldehyde unit of hydrazone (PhCH2 fold. The use of phosphates is also practical from a
→ Ph). For the 3-phenylpropionaldehyde-derived hydra- synthetic point of view: due to their higher acidity (pKa =
zones, the presence of 4-bromobenzoyl- (entry 4) and ~1) compared to BINOL’s (pKa = ~17)12 they react direct-
benzoyl-protecting groups (entry 5), shows better selec- ly with silicon compounds that contain leaving groups.
tivities but lower yields than their 4-nitrobenzoyl deriva- This is an advantage, because such silicon-based catalysts
could be obtained in situ from the corresponding BINOL
phosphates.
Based on our recent DFT studies of the reaction mecha-
nism, considering TMSOTf as a catalyst and 1i as a sub-
strate,10 two plausible TS structures of a closely related
reaction of hydrazone 1f and cyclopentadiene with both
achiral and chiral catalysts are proposed (TS 1 and TS 2,
respectively, Figure 2). In accordance with the proposed
TS 2, the use of newly designed catalyst 3 is expected to
induce enantioselectivity.
O
O
O
O
Me
Si
Ph
P
Me
Me
tetravalent
silicon
Si
Ph
O
Cl
leaving group
Tf
The system of BINOL phosphate 3¢ and SiCl2Ph2 that
would bind by exchanging one of its chlorine groups was
used to give the catalyst 3 in situ by stirring for one hour
3
Figure 1 Rationalizing a chiral catalyst
Synthesis 2011, No. 12, 1988–1992 © Thieme Stuttgart · New York

1990
A. Zamfir, S. B. Tsogoeva
PAPER
In summary, we have developed a novel and practical cy-
cloaddition of aliphatic aldehyde-derived N-acylhydra-
zones with cyclopentadiene using catalytic amounts of
readily available TMSOTf (trimethylsilyl triflate) as a
Lewis acid. This method has been expanded to the asym-
metric reaction, delivering the product with high enantio-
selectivity, but in low yield. With these novel insights in
the development of enantioselective silicon-based Lewis
acidic catalysts, further investigations are currently in
progress in our laboratory.
∗
O
Me
Me
Si
Ph
Si
O
P
O
O
Me
O
Ph O
H
H
Et
N
Et
N
N
R
N
R
+ TfO–
+ Cl–
TS 2
TS 1
Figure 2 Proposed transition state structures for [3+2] cycloaddi-
tions catalyzed by TMSOTf (TS 1) and chiral BINOL-phosphate-
derived silicon Lewis acid (TS 2); R = C6H4(4-NO2)
Commercial products were used without further purification. Hy-
drazones were synthesized from commercial available hydrazines
and aldehydes, purchased from Sigma-Aldrich Co. or Acros Organ-
ics. Cyclopentadiene was obtained from commercially available di-
cyclopentadiene (Merck KGaA) through heating and distillation at
205 °C at atmospheric pressure. All solvents used were previously
dried using appropriate methods. Petroleum ether (PE) used refers
to the fraction boiling in the range 40–65 °C. Column chromatogra-
phy was performed on Acros silica gel 60A and TLC on Macherey-
at room temperature; 15 mol% of BINOL phosphate was
used to ensure the full complexation of silicon. The reac-
tion was first carried out with BINOL phosphate 3¢ with-
out the use of silicon additives as a reference. The syn
(dr = 99:1) product was obtained in 13% yield and 47% ee
(Table 2, entry 1). Running the reaction for three days at
–20 °C, and using SiCl2Ph2 as an additive (entry 2), the
syn product (dr = 96:4) was obtained in 18% yield, but in
higher enantioselectivity (80% ee). Addition of 4 Å MS to
the reaction mixture raised the selectivity of the reaction
to 89% ee (entry 3).
1
Nagel ALUGram® SIL G/UV254 plates. H NMR and 13C NMR
spectra were recorded on Bruker Avance 400 (400 MHz; 2001) or
Bruker Avance 300 (300 MHz; 2001) using the solvent as internal
standard. Mass spectra [m/z, relative intensity (%)] were obtained
with a Shimadzu AXIMA Confidence - MALDI Time of Flight
(TOF) or Micromass ZabSpec FAB mass spectrometer; DCTB =
2-[(2E)-3-(4-tert-butylphenyl)-2-methylprop-2-enylidene]maloni-
trile; DHB = 2,5-dihydroxybenzoic acid; w/o m = without matrix.
HPLC measurements were recorded on Agilent 1200 Series system.
Table 2 Asymmetric [3+2] Cycloaddition of Hydrazones and Cy-
clopentadiene
Ar
O
O
O
TMSOTf-Catalyzed [3+2] Cyloaddition of Cyclopentadiene to
Hydrazones; Typical Procedure
P
OH
To a solution of TMSOTf (1.9 mL, 0.0113 mmol, 10 mol%) in
CH2Cl2 (2 mL) were added hydrazone 1i (30 mg, 0.113 mmol) and
freshly distilled cyclopentadiene (200–300 mL). After stirring for 24
h at r.t., the reaction mixture was quenched by the addition of sat.
aq NaHCO3 (10 mL) and extracted with CH2Cl2 (3 × 20 mL). The
combined organic layers were dried (MgSO4), the solvent was re-
moved under reduced pressure, and the residue purified by silica gel
column chromatography (EtOAc–PE, 1:1) to afford product 2i.
Ar =
Ar
3'
C6H4(4-NO2)
O
C6H4(4-NO2)
3' (15 mol%)
additive (10 mol%)
HN
N
O
+
N
HN
toluene, –20 °C
3 d
H
∗
Et
Et
2b
1f
syn-2f
13C NMR (100 MHz, CDCl3): d = 30.89, 33.88, 43.90, 64.62, 69.55,
122.15, 126.17, 127.63, 128.10, 128.36, 128.43, 129.61, 134.92,
137.53, 140.86, 147.95, 165.61.
Entry
Additive
–
Yield (%)a drb
ee (%) (syn)b
MALDI-MS (DCTB): m/z = 350 [M + H]+, 390 [M + K]+.
1
13
18
13
–
99:1
47
80
89
–
1H NMR (400 MHz, CDCl3): d = 2.34 (m, 1 H), 2.54 (d, J = 16 Hz,
1 H), 2.66 (m, 1 H), 2.84 (m, 1 H), 3.09 (m, 1 H), 3.40 (m, 1 H), 4.01
(d, J = 13 Hz, 1 H), 5.50 (d, J = 7 Hz, 1 H), 5.82 (m, 1 H), 5.95 (m,
1 H), 7.10–7.29 (m, 5 H), 7.79 (d, J = 9 Hz, 2 H), 8.10 (d, J = 9 Hz,
2 H).
2
SiPh2Cl2
SiPh2Cl2
SiPh3Cl
96:4
95:5
–
3c
4
a Yield of the isolated product.
b Determined by HPLC.
2c
1H NMR (400 MHz, CDCl3): d = 1.75 (m, 2 H), 2.40 (m, 2 H), 2.63
(m, 2 H), 3.10 (m, 2 H), 3.73 (d, J = 12 Hz, 1 H), 5.57 (m, 1 H), 5.80
(m, 1 H), 5.96 (m, 1 H), 7.0–7.4 (m, 5 H), 7.81 (d, J = 9 Hz, 2 H),
8.19 (d, J = 9 Hz, 2 H).
c MS 4 Å were added to the reaction mixture.
Lastly, SiPh3Cl was used as an additive (entry 4). In this
case the reaction did not take place, suggesting that the
proposed TS 2 is plausible: however, the lack of a leaving
group hinders the binding with the hydrazone. The low
13C NMR (100 MHz, CDCl3): d = 14.65, 21.49, 30.46, 31.45, 33.66,
44.58, 60.82, 63.54, 70.22, 123.09, 126.64, 128.71, 128.91, 130.39,
135.76, 141.32, 142.00, 148.84, 166.82.
yields may suggest that there is a problem with the regen- MALDI-MS (DHB): m/z = 364 [M]+.
eration of the catalyst after the product is formed.
Synthesis 2011, No. 12, 1988–1992 © Thieme Stuttgart · New York

PAPER
[3+2] Cycloaddition between Hydrazones and Cyclopentadiene
1991
2d
J = 7.1 Hz, 2 H), 4.53 (d, J = 13.2 Hz, 1 H), 5.67 (m, 3 H), 5.95 (m,
1 H), 7.84 (d, J = 8.9 Hz, 2 H), 8.20 (d, J = 9 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 14.12, 33.96, 43.98, 61.55, 65.28,
68.98, 122.77, 127.47, 129.89, 135.06, 140.81, 148.57, 167.09,
169.18.
1H NMR (400 MHz, CDCl3): d = 1.67–1.82 (m, 2 H), 2.37 (m, 2 H),
2.65 (m, 2 H), 3.06 (m, 2 H), 3.73 (d, J = 12 Hz, 1 H), 5.72 (br s, 1
H), 5.79 (br s, 1 H), 5.93 (m, 1 H), 7.00–7.30 (m, 5 H), 7.48 (d, J = 9
Hz, 2 H), 7.62 (d, J = 9 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 29.71, 30.57, 32.84, 43.54, 62.56,
69.28, 124.20, 125.73, 127.89, 127.92, 127.98, 128.04, 130.19,
130.50, 133.65, 134.46, 134.46, 140.57, 166.88.
FAB-MS: m/z = 332 [M + H]+.
anti-Diastereomer
1H NMR (400 MHz, CDCl3): d = 1.18 (t, J = 7.1 Hz, 3 H), 2.41 (d,
J = 18 Hz, 1 H), 2.82 (m, 1 H), 3.27 (m, 1 H), 3.58 (m, 1 H), 4.08
(q, J = 7 Hz, 2 H), 4.59 (d, J = 6.6 Hz, 1 H), 5.64 (d, J = 7.6 Hz, 1
H), 5.8 (s, 1 H), 5.96 (m, 1 H), 7.92 (d, J = 8.7 Hz, 2 H), 8.19 (d,
J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 14.00, 38.35, 46.15, 60.31, 68.11,
68.57, 122.64, 128.07, 129.89, 134.19, 141.62, 148.36, 167.44,
170.75.
MALDI-MS (DCTB): m/z = 397 [M]+, 398 [M + H]+.
2e
1H NMR (400 MHz, CDCl3): d = 1.76 (m, 2 H), 2.38 (m, 2 H), 2.68
(m, 2 H), 3.07 (m, 2 H), 3.70 (m, 1 H), 5.61 (br s, 1 H), 5.82 (br s, 1
H), 5.94 (m, 1 H), 7.00–7.30 (m, 5 H), 7.30–7.48 (m, 3 H), 7.60–
7.75 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 21.50, 33.72, 44.47, 70.09,
126.55, 127.79, 128.89, 135.81, 141.55.
MALDI-MS (DCTB): m/z = 319 [M + H]+, 341 [M + Na]+.
FAB-MS: m/z = 332 [M + H]+.
2j
syn-Diastereomer
2f
1H NMR (400 MHz, CDCl3): d = 1.25 (t, J = 7 Hz, 3 H), 2.13–2.19
(m, 1 H), 2.45–2.52 (m, 1 H), 3.34–3.41 (m, 1 H), 3.83 (dd,
J = 12, 8 Hz, 1 H), 4.18 (q, J = 7 Hz, 2 H), 4.63 (d, J = 12 Hz, 1 H),
5.75 (m, 2 H), 5.90 (m, 1 H), 7.31–7.40 (m, 3 H), 7.68 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 14.64, 31.35, 34.49, 44.50, 61.80,
65.81, 128.02, 128.52, 129.43, 130.88, 135.25, 169.97.
HPLC: Chiralpak IA, n-hexane: propan-2-ol (95:5), flow rate = 1
mL/min, l = 254 nm, tsyn1 = 31.8 min, tsyn2 = 35.9 min, tanti = 19.01
min (unseparated).
1H NMR (400 MHz, CDCl3): d = 0.93 (t, J = 8 Hz, 3 H), 1.35 (m, 1
H), 1.54 (m, 1 H), 2.38 (m, 2 H), 3.02 (m, 1 H), 3.12 (m, 1 H), 3.68
(d, J = 13 Hz, 1 H), 5.56 (d, J = 8 Hz, 1 H), 5.79 (m, 1 H), 5.94 (m,
1 H), 7.83 (d, J = 9 Hz, 2 H), 8.18 (d, J = 9 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 11.83, 21.81, 31.11, 44.20, 65.99,
70.19, 123.09, 128.47, 130.33, 135.70, 141.94, 148.82, 166.59.
MALDI-MS (DCTB): m/z = 288 [M + H]+, 310 [M + Na]+.
MALDI-MS (DCTB): m/z = 286 [M]+, 287 [M + H]+.
anti-Diastereomer
1H NMR (400 MHz, CDCl3): d = 1.11 (t, J = 6 Hz, 3 H), 2.35 (d,
J = 17 Hz, 1 H), 2.70 (dd, J = 8, 17 Hz, 1 H), 3.15–3.23 (m, 1 H),
3.52 (s, 1 H), 4.03 (q, J = 6 Hz, 2 H), 4.70 (br s, 1 H), 5.58 (br s, 1
H), 5.85–5.87 (m, 1 H), 7.23–7.34 (m, 3 H), 7.63–7.71 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 13.59, 37.66, 45.52, 60.88, 68.26,
127.09, 128.26, 129.72, 133.14, 135.00, 170.60.
2g
1H NMR (400 MHz, CDCl3): d = 0.92 (t, J = 7 Hz, 3 H), 1.32 (m, 1
H), 1.54 (m, 1 H), 2.33 (m, 2 H), 3.04 (m, 1 H), 3.67 (d, J = 12 Hz,
1 H), 5.52 (br s, 1 H), 5.76 (br s, 1 H), 5.89 (m, 1 H), 7.42 (d, J = 8
Hz, 2 H), 7.60 (d, J = 8 Hz, 2 H).
MALDI-MS (DCTB): m/z = 286 [M]+, 287 [M + H]+.
13C NMR (100 MHz, CDCl3): d = 11.89, 21.86, 31.15, 44.11, 65.90,
125.01, 128.78, 131.02, 131.34, 134.52, 135.26, 135.29, 135.31,
167.33.
Asymmetric [3+2] Cyloaddition of Cyclopentadiene to Hydra-
zones; Typical Procedure
To solution of BINOL-phosphate 3¢ (15 mg, 0.0199 mmol, 15
mol%) in toluene (1 mL) was added SiCl2Ph2 (2.8 mL, 0.00136
mmol, 10 mol%) and the mixture was stirred for 1 h at r.t. The mix-
ture was then cooled to –20 °C, and hydrazone 1f (30 mg, 0.1356
mmol) and freshly distilled cyclopentadiene (200 mL) were added.
After stirring for 3 d at –20 °C, the reaction mixture was quenched
by the addition of sat. aq NaHCO3 (10 mL) and extracted with
CH2Cl2 (3 × 20 mL). The combined organic layers were dried
(MgSO4), the solvent was removed under reduced pressure, and the
residue purified by silica gel column chromatography (EtOAc–PE,
1:1) to afford product 2f.
MALDI-MS (DCTB): m/z = 322 [M + H]+.
2h
1H NMR (400 MHz, CDCl3): d = 0.80–0.90 (m, 6 H), 1.28 (t, J = 7
Hz, 2 H), 1.59 (m, 1 H), 2.35 (m, 2 H), 3.11 (m, 2 H), 3.66 (d, J = 12
Hz, 1 H), 5.54 (d, J = 6 Hz, 1 H), 5.79 (m, 1 H), 5.93 (m, 1 H), 7.82
(d, J = 9 Hz, 2 H), 8.16 (d, J = 9 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 22.99, 23.45, 26.69, 31.49, 37.77,
44.84, 62.64, 70.07, 123.06, 128.48, 130.32, 135.71, 141.95,
148.81, 166.65.
MALDI-MS (w/o m): m/z = 316 [M + H]+.
Acknowledgment
2i
syn-Diastereomer
1H NMR (400 MHz, CDCl3): d = 1.27 (t, J = 7.1 Hz, 3 H), 2.1–2.24
(m, 1 H), 2.48–2.6 (m, 1 H), 3.42 (m, 1 H), 3.84 (m, 1 H), 4.21 (q,
The authors gratefully acknowledge generous financial support
from the Deutsche Forschungsgemeinschaft (Schwerpunktpro-
gramm 1179 ‘Organokatalyse’) and the Bundesministerium für Bil-
dung und Forschung (DLR, Project MDA 08/010).
Synthesis 2011, No. 12, 1988–1992 © Thieme Stuttgart · New York

1992
A. Zamfir, S. B. Tsogoeva
PAPER
(5) (a) Müller, S.; List, B. Angew. Chem. Int. Ed. 2009, 48,
References
9975; Angew. Chem. 2009, 121, 10160. (b) Müller, S.; List,
(1) (a) Rajendra Prasad, Y.; Lakshmana Rao, A.; Prasoona, L.;
Murali, K.; Ravi Kumar, P. Bioorg. Med. Chem. Lett. 2005,
15, 5030. (b) Jeong, T.-S.; Kim, K. S.; An, S.-J.; Cho, K.-H.;
Lee, S.; Lee, W. S. Bioorg. Med. Chem. Lett. 2004, 14,
2715. (c) Gürsoy, A.; Demirayak, Ş.; Capan, G.; Erol, K.;
Vural, K. Eur. J. Med. Chem. 2000, 35. (d) Özdemir, A.;
Turan-Zitouni, G.; Kaplancikli, Z. A.; Revial, G.; Güven, K.
Eur. J. Med. Chem. 2007, 42, 403. (e) Brozozowski, Z.;
Sączewski, F.; Gdaniec, M. Eur. J. Med. Chem. 2000, 35,
1053. (f) Kornet, M. J.; Garrett, R. J. J. Pharm. Sci. 1979, 68,
377. (g) Özdemir, Z.; Kandilici, H. B.; Gümüşel, B.; Caliş,
Ü.; Bilgin, A. A. Eur. J. Med. Chem. 2007, 42, 373.
(h) Harrison, C. R.; Lahm, G. P. Patent WO 91/11438, 1991;
Chem. Abstr. 1991, 115, 207988.
(2) For examples of [3+2] cycloaddition of hydrazones with
olefins under acidic conditions, see: (a) Hesse, K.-D.
Liebigs Ann. Chem. 1970, 743, 50. (b) Fevre, G. L.;
Sinbandhit, S.; Hamelin, J. Tetrahedron 1979, 35, 1821.
(c) Fouchet, B.; Joucla, M.; Hamelin, J. Tetrahedron Lett.
1981, 22, 1333. (d) Shimizu, T.; Hayashi, Y.; Ishikawa, S.;
Teramura, K. Bull. Chem. Soc. Jpn. 1982, 55, 2450.
(e) Shimizu, T.; Hayashi, Y.; Miki, M.; Teramura, K. J. Org.
Chem. 1987, 52, 2277.
(3) For examples of [3+2] cycloaddition of hydrazones with
olefins under thermal conditions, see: (a) Grigg, R.; Kemp,
J.; Thompson, N. Tetrahedron Lett. 1978, 2827. (b) Grigg,
R.; Dowling, M.; Jordan, M. W.; Sridharan, V. Tetrahedron
1987, 43, 5873. (c) Snider, B. B.; Conn, R. S. E.; Sealfon, S.
J. Org. Chem. 1979, 44, 218. (d) Le Fevre, G.; Hamelin, J.
Tetrahedron Lett. 1979, 20, 1757. (e) Ibrahim, Y. A.;
Abdou, S. E.; Selim, S. Heterocycles 1982, 19, 819.
(f) Badawy, M. A.; El-Bahaie, S. A.; Kadry, A. M.; Ibrahim,
Y. A. Heterocycles 1988, 27, 7. (g) Khau, V. V.; Martinelli,
M. J. Tetrahedron Lett. 1996, 37, 4323. (h)Sun, B.; Adachi,
K.; Noguchi, M. Tetrahedron 1996, 52, 901.
B. Synthesis 2010, 2171.
(6) (a) Shirakawa, S.; Lombardi, P. J.; Leighton, J. L. J. Am.
Chem. Soc. 2005, 127, 9974. (b) Leighton, J. L.; Berger, R.;
Shirakawa, S. PCT Int. Appl. WO 2006062901, 2006;
Chem. Abstr. 2006, 145, 46186.
(7) For general reviews, see: (a) Dalko, P. I.; Moisan, L. Angew.
Chem. Int. Ed. 2001, 40, 3726; Angew. Chem. 2001, 113,
3840. (b) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed.
2004, 43, 5138; Angew. Chem. 2004, 116, 5248. (c) Houk,
K. N.; List, B. Acc. Chem. Res. 2004, 37, 487.
(d) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis;
Wiley-VCH: Weinheim, 2005. (e) List, B.; Yang, J. W.
Science 2006, 313, 1584. (f) Enantioselective
Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim,
2007. (g) Pellissier, H. Tetrahedron 2007, 63, 9267.
(h) Dondoni, A.; Massi, A. Angew. Chem. Int. Ed. 2008, 47,
4638; Angew. Chem. 2008, 120, 4716. (i) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem. Int. Ed.
2008, 47, 6138; Angew. Chem. 2008, 120, 6232.
(8) (a) Chuit, C.; Corriu, R. J. P.; Reye, C.; Young, J. C. Chem.
Rev. 1993, 93, 1371. (b) Uhlig, W. Chem. Ber. 1996, 129,
733. (c) Holmes, R. R. Chem. Rev. 1996, 96, 927.
(d) Rendler, S.; Oestreich, M. Synthesis 2005, 1727.
(e) Sereda, O.; Tabassum, S.; Wilhelm, R. Top. Curr. Chem.
2009, 291, 349.
(9) (a) Yalalov, D. A.; Tsogoeva, S. B.; Shubina, T. E.;
Martynova, I. M.; Clark, T. Angew. Chem. Int. Ed. 2008, 47,
6624; Angew. Chem. 2008, 120, 6726. (b) Tsogoeva, S. B.;
Wei, S.-W.; Freund, M.; Mauksch, M. Angew. Chem. Int.
Ed. 2009, 48, 590; Angew. Chem. 2009, 121, 598.
(c) Zamfir, A.; Tsogoeva, S. B. Org. Lett. 2010, 12, 188.
(d) For an excellent review on the chemistry of N-acyl-
hydrazones, see: Sugiura, M.; Kobayashi, S. Angew. Chem.
Int. Ed. 2005, 44, 5176; Angew. Chem. 2005, 117, 5306.
(10) Zamfir, A.; Schenker, S.; Bauer, W.; Clark, T.; Tsogoeva, S.
B. Eur. J. Org. Chem. 2011, DOI: 10.1002/ejoc.201100206.
(11) 3-Phenylpropionaldehyde derived hydrazones with other
protecting groups like BOC (tert-butyloxycarbonyl) or
Ac(acetyl) showed no or little reactivity.
(4) (a) Kobayashi, S.; Hirabaysahi, R.; Shimizu, H.; Ishitani, H.;
Yamashita, Y. Tetrahedron Lett. 2003, 44, 3351.
(b) Kobayashi, S.; Shimizu, H.; Yamashita, Y.; Ishitani, H.;
Kobayashi, J. J. Am. Chem. Soc. 2002, 124, 13678.
(c) Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2004,
126, 11279.
(12) Schenker, S.; Zamfir, A.; Freund, M.; Tsogoeva, S. B. Eur.
J. Org. Chem. 2011, 2209.
Synthesis 2011, No. 12, 1988–1992 © Thieme Stuttgart · New York