Organocatalytic asymmetric syntheses of functionalized tetrahydropyridazines

Article abstract of DOI:10.1016/j.tetasy.2010.07.030

Four tetrahydropyridazines, respectively, substituted at the C-3 position with hydroxymethyl, a silyloxymethyl, a carboxylic acid, and a methyl ester have been prepared in good yields and high enantiomeric purities using organocatalytic α-amination of aldehydes as the key step. These compounds have then been tested as organocatalysts for the same reaction.

Full text of DOI:10.1016/j.tetasy.2010.07.030

Tetrahedron: Asymmetry 21 (2010) 2302–2306
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Organocatalytic asymmetric syntheses of functionalized tetrahydropyridazines
⇑
Delphine Kalch, Ramzi Ait Youcef, Xavier Moreau, Christine Thomassigny, Christine Greck
Institut Lavoisier de Versailles, UMR CNRS 8180, Université de Versailles St-Quentin-en-Yvelines 45, Av. des Etats-Unis, 78035 Versailles Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Four tetrahydropyridazines, respectively, substituted at the C-3 position with hydroxymethyl, a silyl-
oxymethyl, a carboxylic acid, and a methyl ester have been prepared in good yields and high enantio-
Received 12 July 2010
Accepted 26 July 2010
Available online 9 September 2010
meric purities using organocatalytic
a-amination of aldehydes as the key step. These compounds have
then been tested as organocatalysts for the same reaction.
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
report the synthesis of these four cyclic hydrazones, and their
use as catalysts for the reaction of a-amination of aldehydes.
The unsaturated variant of piperazic acid, namely 2,3,4,5-tetra-
hydropyridazine 3-carboxylic acid (‘PCA’),1 is an interesting struc-
ture, which has been found in several bioactive peptides.2 These
peptides have been used in the development of antagonists of bio-
active molecules3 and can be regarded as a conformationally fixed
proline equivalent, with the potential to favor a b-turn in a peptide
chain.4 Furthermore, their interest can be explained by their anal-
ogy with the parent piperazic acid, a basic structure for bioactive
molecule, in which they can be easily reduced.5–7
2. Results and discussion
Organocatalytic electrophilic
a-amination of carbonyl com-
pounds is usually performed at room temperature using 10–
20 mol% of proline.19 The syntheses of piperazic acid, pipecolic acid,
and proline have been reported starting from functionalized alde-
hydes.20,18b We recently described that 4-trans-t-butoxy-
L-proline
could be a useful catalyst for the electrophilic
a-amination of car-
bonyl compounds: the reaction could be run at 0 °C using a low load-
For their preparation, in addition to the possible direct oxidation
of saturated to unsaturated piperazic acids when the N-2 position is
acylated,1,3 access to the PCA subunit can also be achieved by the
ing of catalyst (5%).18c
The 3-tert-butyldiphenylsiloxymethyl- and the 3-hydroxy-
methyltetrahydropyridazine, respectively, 4 and 5, were prepared
using these conditions for the electrophilic amination step
(Scheme 1). The amination of 5,5-dimethoxypentanal 121 with
di-t-butyl azodicarboxylate (DTBAD) in the presence of 5 mol% of
cyclization of an a-hydrazino acid or ester intermediate, itself ob-
tained from chiral7 or prochiral sources.4,8–14 In these cases, the C-
3 stereocenter is introduced by the amination of enolates derived
from Evans’ chiral auxiliaries,4,8–11 or by the asymmetric hydrogena-
4-trans-t-butoxy- -proline at 0 °C followed by a reduction in situ
L
tion of an a,b-insaturated a
-amino ester.12
led to the expected hydrazinoalcohol 2 with a yield of 69%. Alcohol
2 was protected as its t-butyldiphenylsilyl ether to give 3 with a
good yield of 89%. At this stage, the enantiomeric excess was mea-
sured by HPLC analysis using a Chiralpak AD-H column (ee = 97%).
Compound 3 was transformed into the hydrazone 4 upon treat-
ment with trifluoroacetic acid in dichloromethane and cyclization
of the intermediate hydrazine in an aqueous medium: 4 was then
isolated in 70% yield. The treatment of 4 with tetra-n-butylammo-
nium fluoride removed the silyl ether to give 3-hydroxymethyl
tetrahydropyridazine 5 in 96% yield.
The PCAs with asymmetric carbon atoms at C-3 and C-4 have
also been prepared by this methodology: the two consecutive ste-
reocenters are then controlled by a reduction or catalytic hydroge-
nation of a b-ketoester/electrophilic amination6,13 tandem reaction,
or again by the opening of an epoxide by hydrazine.14 Stoodley
reported an asymmetric hetero Diels–Alder reaction, followed by
hydrogenation and then trifluoroacetolysis, leading to PCA with
an excellent diastereoselectivity.15,16 A route to 3-hydroxymethyl-
4-hydroxy-2,3,4,5-tetrahydropyridazine, which relies on the aza-
Achmatowicz methodology, has also been reported.17
We then obtained carboxylic acid 8 and its methyl ester deriv-
ative 9 (Scheme 2). The hydrazinoaldehyde 6 was prepared from 1
as previously reported and engaged in two different ways. In the
first one, the oxidation of 6 with potassium permanganate fol-
lowed by the cyclization of the intermediate afforded tetrahydro-
pyridazine carboxylic acid 8 in very good yield (95% for the two
steps). In the second method, aldehyde 6 was oxidized, and the
intermediate was esterified to give compound 7 in 89% yield.
Deprotection of the t-butylcarbamates, and cyclization in water
In our studies to enlarge upon the range of organocatalysts for
the electrophilic
prepared via an organocatalytic way, PCA and three derivatives;
the 2,3,4,5-tetrahydropyridazines bearing a 3-hydroxymethyl, a
3-silyloxymethyl, and a 3-methyl ester functionality. Herein, we
a
-amination of aldehydes and ketones,18 we
⇑
Corresponding author. Tel.: +33 (0)1 39 25 44 05; fax: +33 (0)1 39 25 44 72.
E-mail address: greck@chimie.uvsq.fr (C. Greck).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.07.030

D. Kalch et al. / Tetrahedron: Asymmetry 21 (2010) 2302–2306
2303
NHBoc
BocN
iii
i
O
MeO
MeO
ii
OR
N
OR
N
H
OMe
OMe
2 R = H
1
4 R = TBDPS
5 R = H
iv
3 R = TBDPS
Scheme 1. Synthesis of compounds 4 and 5. Reagents and conditions: (i) (a) trans-4-tert-butoxy-
L-proline (5 mol%), DTBAD, DCM, 0 °C; (b) NaBH4, EtOH, 0 °C; 69%; (ii)
TBDPSCl, Im., DMF, 50 °C; 89%, ee = 97%; (iii) (a) TFA/DCM (1/1), 40 °C; (b) H2O/MeOH (1/1); 70%; (iv) TBAF, THF; 96%.
product. The use of 3-hydroxymethyl tetrahydropyridazine 5 led
NHBoc
BocN
to the same major enantiomer with a poor yield and with no signif-
icant enantioselectivity (entry 2). We attempted to reverse the
enantiomeric ratio to obtain 11b as the major enantiomer using
the catalyst bearing a carboxylic acid 8. In this case, the selectivity
should be controlled by the formation of a hydrogen bond between
the carboxylic acid and the electrophile.22 The reaction was run for
3 h in dichloromethane (entry 3). The yield was moderate (45%)
and a weak inversion of the enantiomeric ratio was observed
(11a/11b: 46/54). No significant improvement was observed when
changing the solvent. Finally, catalyst 9 led mainly to compound
11a with an acceptable yield and an enantiomeric ratio of 71/29
(entry 4).
i
MeO
O
R
N
1
N
H
CO2R
OMe
ii,iv
iv
6 R = H
7 R = OMe
8 R = H
ii,iii
9 R = Me
Scheme 2. Synthesis of compounds 8 and 9. Reagents and conditions: (i) trans- 4-
tert-butoxyproline (5 mol%), DBAD, DCM, 0 °C; 80%; (ii) NaH2PO4 1 M, KMnO4 1 M,
t-BuOH; (iii) TMSCHN2, Tol/MeOH (3/1); 89% (2 steps); (iv) (a) TFA, 40 °C; (b) H2O;
8: 95% (2 steps); 9: 72%.
gave tetrahydropyridazine methyl ester 9 in 72% yield. The physi-
cal properties of compounds 8 and 9 are in agreement with those
described in the literature of their enantiomers.8–11,15,16
Next, we tested the four tetrahydropyridazines as catalysts for
the electrophilic amination reaction. To the best of our knowledge,
only the use of amines has been reported and hydrazones have
never been tried due to the poor nucleophilicity of the secondary
nitrogen atom.1 However, the structure of the tetrahydropyrid-
azine ring could be interesting in a catalytic mechanism.
MeO
OH
1) Cat*
OMe
CbzN
NHCbz
(10% mol),
DBAD, 25°C
MeO
11a
O
OMe
+
2) NaBH4,
EtOH, 0°C.
10
MeO
OH
The compounds 4, 5, 8, and 9 were screened as catalysts for the
enantioselective
OMe
CbzN
a-amination of two aldehydes; 6,6-dimethoxy-
NHCbz
hexanal 10 and the 5,5-dimethoxypentanal 1. In all cases, the alde-
hydes were treated with DBAD in the presence of 10 mol % of
catalyst in dichloromethane and at room temperature and were di-
rectly reduced in situ with sodium borohydride in ethanol at 0 °C.
After purification by chromatography on silica gel, the enantio-
meric ratios were determined by chiral HPLC analysis.
11b
NHCbz
OH
CbzN
MeO
The four chiral tetrahydropyridazines were initially screened as
catalysts for the amination–reduction of aldehyde 10, leading to
the hydrazino derivatives (R)-11a and/or (S)-11b (Scheme 3).18b
The results are summarized in the Table 1.
OMe
OMe
1) Cat*
12a
(10% mol),
DBAD, 25°C
1
+
2) NaBH4,
EtOH, 0°C.
NHCbz
OH
CbzN
MeO
Table 1
Formation of the hydrazino alcohols 11a and 11b from 10
12b
Entry
Catalyst
Time (h)
Yield
11a/11ba
ee (%)
1
2
3
4
4
5
8
9
2.5
21
3
55
11
45
53
82/18
64.5/35.5
46/54
64
29
8
Scheme 3.
21
71/29
42
From these first assays, silyloxymethyl tetrahydropyridazine 4
was shown to be an efficient catalyst. We tested it for the electro-
philic amination of 1 with DBAD, followed by the in situ reduction,
giving (R)-12a and/or its enantiomer (S)-12b (Scheme 4). The main
results with catalyst 4 are summarized in Table 2.
a
Determined by HPLC in
(90:10) + 0.2% TFA; flow 0.5 mL/min; k = 260 nm; T = 25 °C; tr(11b) = 52.07 min;
tr(11a) = 55.31 min.
a Chiralpak AD-H column. Eluant heptane/i-PrOH
The use of tetrahydropyridazine 4 led mainly to 11a with 55%
yield and an enantiomeric ratio of 82/18 for 11a/11b after 2.5 h
(entry 1). It is interesting to note that a longer reaction time
(21 h) gave similar values. The selectivity could be explained with
the model described by Houk, where steric hindrance is the main
promoter of the stereoselectivity.22 In this case, the bulky t-butyl-
diphenylsilyl ether group prevents the approach of the electrophile
DBAD on the same face and the new C–N bond is formed on the
opposite face to preferentially induce an (R)-configuration for the
Table 2
a-Amination of 1 in the presence of the catalyst 4
Entry
Time (h)
Yield
12a/12ba
ee (%)
1
2
3
2.5
6.5
24
7
44
69
93/7
85/15
85/15
86
70
70
a
Determined by HPLC in
a Chiralpak AS-H column. Eluant heptane/i-PrOH
(90:10); flow 0.8 mL/min; k = 260 nm; tr(12b) = 20.9 min; tr(12a) = 53.6 min.

2304
D. Kalch et al. / Tetrahedron: Asymmetry 21 (2010) 2302–2306
was quenched with aqueous saturated NH4Cl (2 mL), and extracted
NHCbz
OH
CbzN
with EtOAc (3 ꢀ 5 mL). The combined organic layers were washed
with brine, dried with Na2SO4, filtered, and concentrated in vacuo.
The resulting residue was purified by column chromatography on
MeO
MeO
OMe
1) Cat*
12a
silica gel to provide the a-hydrazino alcohol. For physical analysis
(10% mol),
DBAD, 25°C
of derivatives 11 and 12, see the literature.18b,c
1
+
2) NaBH4,
EtOH, 0°C.
NHCbz
OH
4.3. (R)-2-(N,N0-Di-tert-butoxycarbonylhydrazino) 50,50-
dimethoxypentanol 2
CbzN
OMe
The general procedure of the
dimethoxypentanal22 (100 mg, 0.68 mmol) in the presence of
trans-4-t-butoxy- -proline (5 mol %), and DTBAD followed by the
classical treatment and a purification with (CH2Cl2/EtOAc: 5:1) as
a-amination was applied to 5,5-
12b
Scheme 4.
L
After 2.5 h of reaction, derivative 12a was obtained as the major
enantiomer (12a/12b: 93/7, entry 1). Nevertheless, the yield was
very low (7%). Increasing the reaction time increased the yield to
69% with a small decrease in the enantiomeric ratio (12a/12b:
85/15, entries 2 and 3).
eluant gave the a-hydrazino alcohol 2 as a white solid in 69% iso-
lated yield. mp: 124 °C; Rf = 0.14 (CH2Cl2/EtOAc: 5:1); ½a D25
¼ ꢂ4 (c
ꢁ
~
1.1, MeOH); IR (KBr): mmax = 3396, 2980, 2935, 2832, 2520, 2366,
1706 cmꢂ1 1H NMR (300 MHz, CD3OD, 25 °C): d = 1.18–1.74 (m,
;
22 H, 30-H, 40-H and tBu), 3.28–3.35 (m, 6 H, 2 OCH3), 3.36–3.51
(m, 2 H, 10-H), 4.16 (br s, 1 H, 20-H), 4.37 (t, 1 H, J = 5.6 Hz, 50-H)
ppm; 13C NMR (75 MHz, CD3OD, 25 °C): d = 23.9 (30-C), 28.5
(C(CH3)3), 30.0 (40-C), 49.0 and 49.6 (OCH3), 59.1 (20-C), 63.1 (10-
C), 82.3 and 82.6 (C(CH3)3), 106.0 (50-C), 157.4 (CO) ppm; MS
(ESI): m/z 401 [M+Na]+; Calcd for C17H34N2O7 (378.46): C, 53.95;
H, 9.06; N, 7.40. Found: C, 54.02; H, 9.11; N, 7.05.
3. Conclusion
In conclusion, we have prepared four 3-functionalized tetrahyd-
ropyridazines 4, 5, 8, and 9 in very good overall yields with short
stereoselective synthetic sequences. The organocatalytic
a-hydra-
zination of the aldehyde in the presence of trans-4-t-butoxy-
L
-pro-
line allowed the control of the newly created stereogenic
aminated center. The obtained tetrahydropyridazine derivatives
4.4. (R)-1-tert-Butyldiphenylsilyl-2-(N,N0-di-tert-but-
oxycarbonylhydrazino) 50,50-dimethoxypentanol 3
have been screened as organocatalysts for the electrophilic
nation of aldehydes. In particular, the 3-silyloxymethyl tetrahydro-
pyridazine 4 promoted the direct asymmetric -amination of
a-ami-
To a solution of alcohol 2 (155 mg, 0.41 mmol) in DMF (2 mL)
were added imidazole (84 mg, 1.23 mmol) and t-butylchlorodi-
phenylsilane (133 lL, 0.51 mmol). The reaction mixture was
a
aldehydeswith azodicarboxylatewith good yields and enantioselec-
tivities. Further developments are currently in progress.
heated to 50 °C for 14 h. After cooling, the solution was hydrolyzed
with aqueous saturated NH4Cl (2 mL) and extracted with Et2O
(3 ꢀ 5 mL). The combined organic layers were washed with brine,
dried with Na2SO4, filtered, and concentrated in vacuo. The result-
ing residue was purified by column chromatography on silica gel
(CH2Cl2/EtOAc: 5:1) to give 3 as a yellow oil in 89% isolated yield
4. Experimental
4.1. General
and 97% ee. Rf = 0.71 (CH2Cl2/EtOAc: 5:1); ½a D25
¼ þ11 (c 1.2,
ꢁ
Solvents were distilled according to Purification of Laboratory
Chemicals, 4th Ed., W.L.F. Aramarego and D.D. Perrin, Butterwoth
Heinemann, 1996. Flash chromatography was performed on silica
~
MeOH); IR (NaCl): mmax = 3355, 3068, 2970, 2919, 2377, 1962,
1890, 1747, 1710, 1588 cmꢂ1 1H NMR (200 MHz, CDCl3, 25 °C):
;
d = 1.05 (s, 9H, tBu), 1.15–2.00 (m, 22H, 30-H, 40-H and tBu), 3.29
(s, 6H, 2OCH3), 3.45–3.69 (m, 2H, 10-H), 4.03–4.47 (m, 2H, 20-H
and 50-H), 5.63 (br s, 1H, NH), 7.32–7.50 (m, 6H, Ar), 7.58–7.71
(m, 4H, Ar) ppm; 13C NMR (75 MHz, CD3OD, 25 °C): d = 20.0
(SiC(CH3)3), 24.3 (30-C), 27.4 and 28.6 (C(CH3)3 and SiC(CH3)3),
30.2 (40-C), 53.4 (OCH3), 59.3 (20-C), 65.4 (10-C), 81.4 and 82.0
(C(CH3)3), 106.1 (50-C), 128.8, 131.0, 134.6 and 136.7 (Ar), 157.1,
158.0 (CO) ppm; MS (ESI): m/z 639 [M+Na]+; Calcd for C33H52N2O7-
Si (616.86): C, 64.25; H, 8.50; N, 4.54. Found: C 63.46; H, 8.59; N,
4.43; the ee was determined by chiral HPLC using Chiralpak AD-
H column (heptane/i-PrOH = 96:4 + TFA 0.3%, flow rate 0.2 mL/
min; k = 260 nm), tr [(R)-2] = 67.0 min; tr [(S)-2] = 55.0 min.
gel chromagel 60 ACC 35–70 lm. Analytical TLC was performed
using aluminum-backed silica gel Merck 60 F254 and was visualized
by UV radiation (254 nm) and/or a solution of phosphomolybdic
acid in MeOH and heating. Optical rotations were measured at
25 °C on a Perkin-Elmer 241 polarimeter (1 dm cell) using a sodium
lamp as the light source (589 nm). NMR spectra were recorded on a
Brucker AC 200 or Avance 300 apparatus with chemical shift values
(d) in ppm downfield from tetramethylsilane. Infrared spectra were
recorded on a Nicolet OPUS IR (impact 400D) spectrophotometer.
Melting points were performed with a Büchi B-545 apparatus. Mass
spectra were obtained on a HP MS 5989B spectrometer. Analytical
HPLC was performed on a Jasco LC-NetII/ADC with Chiralpak AD-
H, AS-H, or OD-H columns (0.46 ꢀ 25 cm). Microanalyses were per-
formed by the Service de Microanalyse of ICSN, Gif-sur-Yvette,
France. HRMS were performed by the Service de Spectrométrie de
Masse of ICSN, Gif-sur-Yvette, France.
4.5. (R)-3-((tert-Butyldiphenylsilyloxy) methyl)-2,3,4,5-tetr-
ahydropyridazine 4
Trifluoroacetic acid (2 mL) was added dropwise to a solution of
silyl ether 3 (88 mg, 0.14 mmol) in CH2Cl2 at 0 °C. After 15 min at
40 °C, the excess trifluoroacetic acid and solvent were removed un-
der reduced pressure. The obtained residue was dissolved in a 1:1
mixture of MeOH/H2O (4 mL). After 15 min at room temperature,
the solution was adjusted to pH 9 with aqueous ammonia. The
mixture was then extracted with Et2O (3 ꢀ 2 mL). The combined
organic layer was washed with brine, dried with Na2SO4, filtered,
4.2. General procedure for the a-amination of aldehydes
To a solution of aldehyde (0.68 mmol, 1.5 equiv) and catalyst (5%
or 10 mol %) in CH2Cl2 (2 mL) was added di-t-butyl azodicarboxylate
(1.0 equiv) or dibenzylazodicarboxylate (1.0 equiv) at 0 °C. After
14 h at 0 °C, the mixture was treated with EtOH (2 mL) and NaBH4
(26 mg, 0.68 mg) and was stirred for 15 min at 0 °C. The reaction

D. Kalch et al. / Tetrahedron: Asymmetry 21 (2010) 2302–2306
2305
and concentrated in vacuo. The crude product was purified by col-
umn chromatography on silica gel (CH2Cl2/EtOAc: 5:1) to provide 4
as a yellow oil in 70% isolated yield. Rf = 0.31 (CH2Cl2/EtOAc: 5:1);
~
raphy on silica gel (CH2Cl2/EtOAc: 5:2) to give hydrazino ester 7 as a
colorless oil in 89% isolated yield. Rf = 0.77 (CH2Cl2/EtOAc: 2:1);
~
½
a 2D5
ꢁ
¼ þ26 (c 1.0, MeOH); IR (NaCl): mmax = 3319, 2980, 2930,
½
a 2D5
ꢁ
¼ ꢂ13 (c 1.2, MeOH); IR (NaCl): mmax = 3380, 3334, 3068,
2827, 2351, 1742, 1706 cmꢂ1 1H NMR (200 MHz, CDCl3, 25 °C):
;
2976, 2930, 2853, 1962, 1890, 1824, 1624, 1588 cmꢂ1
;
1H NMR
d = 1.44 (s, 18H, tBu), 1.60–2.07 (m, 4H, 30-H and 40-H), 3.29 (s, 6H,
2OCH3), 3.69 (s, 3H, CO2CH3), 4.22–4.43 (m, 1H, 50-H), 4.46–4.94
(m, 1H, 20-H), 6.31 (br s, 1H, NH) ppm; 13C NMR (75 MHz, CD3OD,
25 °C): d = 23.7 (30-C), 28.1 (C(CH3)3), 29.0 (40-C), 52.3 and 52.7
(OCH3), 52.7 (CO2CH3), 59.5 (20-C), 80.7 and 82.0 (C(CH3)3), 104.3
(50-C), 154.9 and 155.6 (CO), 172.4 (CO2CH3) ppm; MS (ESI): m/z
429 [M+Na]+; Calcd C18H34N2O8 (406.47): C, 53.19; H, 8.43; N,
6.89. Found: C, 53.67; H, 8.47; N, 6.52.
(200 MHz, CDCl3, 25 °C): d = 1.07 (s, 9H, tBu), 1.33–1.83 (m, 2H,
4-H), 1.97–2.40 (m, 2H, 5-H), 3.10–3.32 (m, 1H, 3-H), 3.55–3.69
(m, 2H, CH2OSi), 6.77 (br s, 1H, 6-H), 7.32–7.43 (m, 6H, Ar), 7.56–
7.83 (m, 4H, Ar) ppm; 13C NMR (75 MHz, CDCl3, 25 °C): d = 19.2
(C(CH3)3), 21.5 and 23.0 (4-C and 5-C), 26.8 (C(CH3)3), 52.8 (3-C),
66.3 (CH2OSi), 127.8, 129.8, 133.2 and 135.5 (Ar), 140.5 (6-C)
ppm; MS (ESI): m/z 375 [M+Na]+; HRMS (ESI) Calcd for C21H28N2O-
Si, 375.1869; found, 375.1880.
4.9. (R)-2,3,4,5-Tetrahydropyridazine-3-carboxylic acid 8
4.6. (R)-3-Hydroxymethyl-2,3,4,5-tetrahydropyridazine 5
To a solution of hydrazino aldehyde 6 (56 mg, 0.15 mmol) in t-
butanol (1 mL) was added an aqueous solution of NaH2PO4 (1 M,
0.8 mL, 0.80 mmol) followed by an aqueous solution of KMnO4
(1 M, 0.8 mL, 0.80 mmol). After stirring for 1 min, the excess of
KMnO4 was quenched with an aqueous solution of Na2SO3 (1 mL).
The reaction mixture was then cooled to 0 °C, and the solution was
adjusted to pH 3 with aqueous HCl (1 M). The mixture was then ex-
tracted with EtOAc (3 ꢀ 5 mL). The combined organic layers were
successively washed with water and brine, dried over Na2SO4, fil-
tered, and concentrated in vacuo. The obtained crude product was
dissolved in CH2Cl2 (1 mL) at 0 °C and trifluoroacetic acid (1 mL)
was added dropwise. After 15 min at 40 °C, the excess trifluoroacetic
acid and the solvent were removed under reduced pressure. The ob-
tained residue was dissolved in H2O (1 mL). After 15 min at room
temperature, the solvent was removed under reduced pressure.
To a solution of 4 (31 mg, 0.09 mmol) in THF (1 mL) at 0 °C was
added TBAF 1 M in THF (0.26 mL, 0.26 mmol). After 1 h at room tem-
perature, the solvent was removed under reduced pressure. The
crude product was purified by column chromatography on silica
gel (EtOAc/MeOH: 9:1) to give 5 as a yellow oil in 96% isolated yield.
Rf = 0.45 (EtOAc/MeOH: 1:1); ½a D25
ꢁ
¼ ꢂ127 (c 1.0, MeOH); IR (NaCl):
mmax = 3329, 2930, 2853, 1665, 1634 cmꢂ1
;
1H NMR (200 MHz,
~
CDCl3, 25 °C): d = 1.57–1.93 (m, 2H, 4-H), 1.97–2.40 (m, 2H, 5-H),
3.03–3.24 (m, 1H, 3-H), 3.28–3.78 (m, 3H, CH2OH), 6.77 (br s, 1H,
6-H) ppm; 13C NMR (75 MHz, CDCl3, 25 °C): d = 21.3 and 23.0 (4-C
and 5-C), 52.7 (3-C), 64.6 (CH2OSi), 141.0 (6-C) ppm; MS (ESI): m/z
137 [M+Na]+; HRMS (ESI) calcd for C5H10N2O, 137.0691; found,
137.0686.
½
a 2D5
ꢁ
¼ ꢂ59 (c 1.0, MeOH), lit15,16: +62 (0.3%; MeOH; enantiomer).
4.7. (R)-2-(N,N0-Di-tert-butoxycarbonylhydrazino) 50,50-dimeth-
oxypentanal 6
The resulting salt was eluted on Dowex 50W-X4 ion exchange col-
umn (NH4OH 1M) to give 8 as a yellow oil in 95% isolated yield; IR
(KBr): mmax = 3365, 2935, 1593 cmꢂ1
;
1H NMR (200 MHz, D2O,
~
To a solution of 5,5-dimethoxypentanal22 1 (100 mg, 0.68 mmol)
and trans-4-t-butoxy-L-proline (4 mg, 0.02 mmol) in CH2Cl2 (2 mL)
was added di-t-butyl azodicarboxylate (105 mg, 0.46 mmol) at
0 °C. After 14 h at 0 °C, the solvent was removed under reduced pres-
sure. The crude product was purified by column chromatography on
25 °C): d = 1.79–2.44 (m, 4H, 4-H and 5-H), 3.63 (dd, 1H, J = 8.0 Hz
and J = 3.8 Hz, 3-H), 7.04 (s, 1H, 6-H) ppm; 13C NMR (75 MHz, D2O,
25 °C): d = 20.3 and 20.4 (4-C and 5-C), 54.8 (3-C), 149.9 (6-C),
177.2 (CO) ppm; MS (ESI): m/z 151 [M+Na]+; HRMS (ESI) calcd for
C5H8N2O2, 151.0483; found, 151.0490.
silica gel (CH2Cl2/EtOAc: 5:1) to provide the a-hydrazino aldehyde 6
as an oil in 80% isolated yield. Rf = 0.27 (CH2Cl2/EtOAc: 9:1); IR
(NaCl): mmax = 3283, 2970, 2930, 2832, 1736 cmꢂ1
;
1H NMR
4.10. (R)-Methyl 2,3,4,5-tetrahydropyridazine-3-carboxylate 9
~
(200 MHz, CDCl3, 25 °C): d = 1.42 (s, 18H, tBu), 1.54–2.13 (m, 4H,
30-H and 40-H), 3.28 (s, 6H, 2OCH3), 4.12–4.62 (m, 2H, 20-H and 50-
H), 6.58 (br s, 1H, NH), 9.63 (br s, 1H, CHO) ppm; MS (ESI): m/z 399
[M+Na]+.
Trifluoroacetic acid (2 mL) was added dropwise to a solution of
hydrazino ester 7 (84 mg, 0.21 mmol) in CH2Cl2 (2 mL) at 0 °C. After
15 min at 40 °C, the excess trifluoroacetic acid and solvent were re-
moved under reduced pressure. The obtained residue was dissolved
in H2O (2 mL). After 15 min at room temperature, the reaction mix-
ture was concentrated in vacuo. The crude product was purified by
column chromatography on silica gel with EtOAc in the presence
of triethylamine (2%) to provide 9 as a yellow oil in 72% isolated
4.8. (R)-Methyl 2-(N,N0-di-tert-butoxycarbonylhydrazino) 50,50-
dimethoxypentanoate 7
To a solution of hydrazino aldehyde 6 (265 mg, 0.71 mmol) in t-
butanol (4 mL) was added an aqueous solution of NaH2PO4 (1 M,
4.0 mL, 0.40 mmol) followed by an aqueous solution of KMnO4
(1 M, 4.0 mL, 0.40 mmol). After stirring for 1 min, the excess KMnO4
was quenched with an aqueous solution of Na2SO3 (4 mL). The reac-
tion mixture was then cooled to 0 °C, and the solution was adjusted
to pH 3 with aqueous HCl 1 M. The mixture was then extracted with
EtOAc (3 ꢀ 20 mL). The combined organic layers were successively
washed with water and brine, dried with Na2SO4, filtered, and con-
centrated in vacuo. The obtained crude hydrazino acid was dissolved
in a 3:1mixture ofTol/MeOH (8 mL), and (trimethylsilyl)diazometh-
yield. Rf = 0.40 (EtOAc); ½a D25
ꢁ
¼ ꢂ67 (c 0.9, MeOH), lit8,9: +139 (c
0.8, MeOH; enantiomer), lit16: +86 to +124 (MeOH; enantiomer):
the authors established the complete dissociation between the spe-
~
cific rotation and enantiomeric purity; IR (NaCl): mmax = 3370, 2971,
2930, 2863, 1742 cmꢂ1; 1H NMR (200 MHz, CD3OD, 25 °C): d = 1.90–
2.37 (m, 4H, 4-H and 5-H), 3.74 (s, 3H, CO2CH3), 3.78–3.91 (m, 1H, 3-
H), 6.69 (s, 1H, 6-H) ppm; 13C NMR (75 MHz, CD3OD, 25 °C): d = 22.2
and 22.8 (4-C and 5-C), 52.7 and 54.5 (3-C and CO2CH3), 141.6 (6-C),
173.7 (CO) ppm; MS (ESI): m/z 165 [M+Na]+; HRMS (ESI) calcd for
C6H10N2O2, 165.0640; found, 165.0644.
ane was added (668
l
L, 1.34 mmol). After stirringfor 10 min at room
Acknowledgements
temperature, acetic acid was added until no more gas formation was
observed. The solvent was then removed under reduced pressure,
and the obtained crude product was purified by column chromatog-
We thank the Ministère de la Recherche for a grant to D.K. and
the ANR CP2D for financial support.

2306
D. Kalch et al. / Tetrahedron: Asymmetry 21 (2010) 2302–2306
13. Greck, C.; Bischoff, L.; Genêt, J. P. Tetrahedron: Asymmetry 1995, 6, 1989–1994.
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