Asymmetric synthesis of α-(heteroaryl)alkylamines and α-amino acids via nucleophilic 1,2-addition of lithiated heterocycles to aldehyde SAMP-hydrazones

Article abstract of DOI:10.3906/kim-1302-71

The asymmetric synthesis of α-(heteroaryl)alkylamines was accomplished by employing a diastereoselective nucleophilic 1,2-addition of lithiated aromatic heterocycles to aldehyde SAMP-hydrazones, followed by BH ₃·THF or SmI₂ promoted removal of the chiral auxiliary. The CBz or benzoyl-protected amines were obtained in good yields (40%-78%) and excellent enantiomeric excesses (ee = 88%-99%). The methodology can be applied to the synthesis of highly enantioenriched α-amino acids (ee = 90%-99%). TUeBITAK.

Full text of DOI:10.3906/kim-1302-71

Turk J Chem
Turkish Journal of Chemistry
(2013) 37: 492 – 518
¨
http://journals.tubitak.gov.tr/chem/
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c
⃝ TUBITAK
doi:10.3906/kim-1302-71
Research Article
Asymmetric synthesis of α-(heteroaryl)alkylamines and α-amino acids via
nucleophilic 1,2-addition of lithiated heterocycles to aldehyde SAMP-hydrazones
Dieter ENDERS,1,∗ Giuseppe DEL SIGNORE,1,2 Gerhard RAABE1
1Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
2Mercachem BV, Kerkenbos 1013, 6546 BB Nijmegen, the Netherlands
Received: 27.02.2013
•
Accepted: 08.04.2013
•
Published Online: 12.07.2013
•
Printed: 05.08.2013
Abstract: The asymmetric synthesis of α-(heteroaryl)alkylamines was accomplished by employing a diastereoselective
nucleophilic 1,2-addition of lithiated aromatic heterocycles to aldehyde SAMP-hydrazones, followed by BH3·THF or
SmI2 promoted removal of the chiral auxiliary. The CBz or benzoyl-protected amines were obtained in good yields
(40%–78%) and excellent enantiomeric excesses (ee = 88%–99%). The methodology can be applied to the synthesis of
highly enantioenriched α-amino acids (ee = 90%–99%).
Key words: Amines, asymmetric synthesis, SAMP-hydrazone, nucleophilic addition, amino acids
1. Introduction
Highly enantiomerically enriched amines with a stereocenter in the α position are of paramount importance
in organic chemistry.1 In particular, α-(heteroaryl)alkylamines are often characteristic structural features of
biologically active natural products and pharmaceuticals. For example, α-(2-furyl)alkylamines constitute the
backbone of nuphar alkaloids, α-(3-pyridyl)-alkylamines are common subunits in the tobacco alkaloids, and
the potent antineoplastic agents dolastatin 102 and virenamides3 are both linear peptides containing α-(2-
thiazolyl)ethylamine units (Figure 1). From a synthetic point of view, α-(heteroaryl)alkylamines are widely
used as chiral ligands in metal complex catalysis4 and as important starting materials. Particular attention
has been focused on the various synthetic applications of α-(2-furyl)alkylamines. Oxidative cleavage of the
furan ring under mild conditions allows the conversion into α-amino acids.5 Moreover, the aza-Achmatovicz
rearrangement6 represents an easy and unique entry into the piperidine skeleton and has thus been applied in
the synthesis of numerous alkaloids7 and azasugars.8
The broad utility of α-(heteroaryl)alkylamine derivatives has stimulated a relentless pursuit of practical
asymmetric routes to these valuable compounds. Since the pioneering work by Smith and co-workers,9 which
was based on classical resolution of the racemate with an optically active acid, there has been significant growth
in this area and thus many reliable synthetic methods have been devised. To date, most approaches have been
based on a nucleophilic attack of organometallic reagents on imines bearing a stereogenic N -substituent. Savoia
et al. applied valine derivatives as chiral auxiliary in the asymmetric synthesis of (S)-1-(2-pyridyl)alkyl-amines.
Although (S)-valinate10 gave good results, O-trimethylsilyl valinol11 proved to be a superior chiral auxiliary
affording high yields and excellent diastereoselectivity (de = 40%–99%).
∗Correspondence: enders@rwth-aachen.de
In memory of Prof Dr Ayhan S. Demir, an outstanding alumnus and good friend.
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ENDERS et al./Turk J Chem
Figure 1. Typical biologically active compounds containing α-(heteroaryl)alkylamine units.
Zhou et al.12 explored the addition of cerium derivatives to chiral imines derived by condensation of
2-furaldehyde and (1S ,2R)-2-amino-1,2-diphenylethanol or its enantiomer (de = 84%–99%). Harwood and
co-workers13 used (S)-5-phenylmorpholin-2-one in the presence of a range of aliphatic aldehydes to form enan-
tioenriched iminium intermediates, which underwent diastereoselective Mannich reactions with 2-furylboronic
acid to afford the corresponding tertiary amines in moderate to good yields and high diastereoselectivities
(de = 86%–98%). On the other hand, chiral oxime ethers were employed by Moody et al.14 in an asym-
metric synthesis of N -protected 1-(2-thiazolyl)alkylamines (ee = 83%–92%). More recently, a few cases have
been reported using asymmetric catalytic nucleophilic 1,2-additions.15 A conceptually different approach was
presented by Shiori et al.16 investigating the α-alkylation of chiral Schiff bases obtained by condensation of
1-(2-heteroaryl)methylamine and (+)-2-hydroxy-3-pinanone or (–)-3-hydroxy-2-caranone. The method was ex-
tremely efficient when pyridine and furan moieties were used, and after removal of the chiral auxiliary the
corresponding amines were obtained in excellent enantioselectivities (ee = 88%–98%). Demir et al.5a,d studied
the reduction of furyl ketone oxime ethers using chiral boron reagents17 prepared from optically pure amino
alcohol and BH3·THF complex (ee = 87%–95%). Finally enzymatic18 and chemical19 resolution of racemic
amines have been employed as well by different groups.
Scheme 1. Asymmetric synthesis of α-(heteroaryl)alkylamines: a) SAMP, Et2 O, rt; b) HetArLi, THF or Et2 O; c)
BH3·THF, THF, reflux and then CbzCl, K2 CO3 , THF/H2 O; d) DMAP, Et3 N, CH2 Cl2 , PhCOCl, rt, then SmI2 ,
THF, DMPU, rt.
We have briefly reported a very efficient asymmetric synthesis of α-(heteroaryl)alkylamines20 by nucle-
ophilic 1,2-addition of metallated hetarenes to aldehyde-SAMP-hydrazones. Herein we disclose the full account
of this research and further applications of this protocol to the synthesis of α-amino acids.
Our general protocol exploring the use of easily accessible lithium hetarenes is depicted in Scheme 1.
Preliminary studies were conducted treating the simple propanal-SAMP-hydrazone 2a, dissolved in THF or
alternatively in Et2 O, with 11 different lithiated heterocycles21 prepared by modified literature procedures.22
Due to the different nature, basicity, and reactivity of the heteroarenylithium species, optimal reaction conditions
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ENDERS et al./Turk J Chem
had to be determined case by case. We found that either 2- or 3-thienyllithium (Table 1, Entries 1 and 2) reacted
well using Et2 O as solvent. The highest conversions and selectivities were obtained by treating hydrazone 2a
with 3 equiv of organolithium compound at –78 ◦ C for 30 min, after which the reactions were allowed to warm
up to room temperature. The NMR spectra of the crude products showed only the desired hydrazines without
the presence of starting material or eventual side products.
Table 1. Nucleophilic 1,2-addition of lithiated hetarenes to 2a to form the hydrazines 3a–k (Scheme 1).
Yield (%) a
91
de (%) b
95
-
3
Entry
1
Product
Li HetAr
Equivalents
3.2
Solvent
Et2O
Time (h)
2
T (°C)
a
–78 to rt
2
b
3.2
Et2O
–78 to rt
5
86
94
3
4
c
3.2
3.2
Et2O
THF
–78 to rt
–78 to rt
5
90
95
88
d
14
70 c
5
6
e
f
8.0
5.0
Et2O
Et2O
–100
–78
54
14
82
82
95
95
7
g
3.2
THF
–78 to rt
14
75 c
94%
8
9
h
i
3.2
3.2
THF
THF
–78 to rt
–78 to rt
14
14
95
87
95
92
10
11
j
3.2
3.2
THF
Et2O
–78 to rt
–78 to rt
2
2
91
85
95
95
k
a
Yield of crude product (≥95% purity as determined by 1 H and 13 C NMR spectroscopy).
b Determined by 1 H and 13 C NMR spectroscopy.
c
Conversion (determined by 1 H and 13 C NMR spectroscopy).
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ENDERS et al./Turk J Chem
The reactions turned out to be very efficient, even if a chloride atom was carried on the thiophene ring
(Entry 3), affording the corresponding hydrazine in excellent yield as a single product. 2-(Pyridinyl)lithium
and 3-(pyridinyl)litihum (Entries 5 and 6) showed the highest reactivities and thus a relatively high instability.
Therefore, the reactions were carried out at low temperature and 8 and 5 equiv of organolithium species had
to be used, respectively. It was noteworthy that employing THF as solvent in all the previous cases changed
drastically the reactivity of the lithium hetarenes, affording only traces of products. On the other hand,
THF was clearly a superior solvent in the cases of 1-methyl-2-lithiumpyrrole (Entry 4), 1-methyl-2-lithio-indole
(Entry 7), 1-methyl-2-lithio-imidazole (Entry 8), and 1-methyl-2-lithio-benzoimidazole (Entry 9), providing
excellent diastereoselectivities when the reactions were allowed to reach room temperature overnight. Finally,
1,2-nucleophilic addition using 2-(furyl)lithium (Entry 10) and 2-(benzofuryl)litihum (Entry 11) was conducted
in THF for the former and in Et2 O for the latter.
Due to the sensitivity of the obtained hydrazines, cleavage of the chiral auxiliary was performed using
the crude products without any purification. We were pleased to find that the chiral auxiliary group could be
removed smoothly without detectable racemization when hydrazines 3a–d were refluxed with a large excess of
BH3•THF23 complex for 6–18 h. The corresponding polar amines were not isolated but directly treated with
CbzCl to give the corresponding carbamates 4a–d, which could be purified by flash chromatography on silica
gel (Table 2). Unfortunately, when the hydrazines 3e–k were reacted with an excess of BH3•THF only poor
results were obtained. Attempts to overcome the problem using Zn in acetic acid met the same fate. In an effort
to find a suitable method for removing the chiral auxiliary, we decided to examine the SmI2 promoted N-N bond
cleavage.24 For this purpose, the tertiary hydrazines had to be activated by conversion to the corresponding
benzoyl derivatives. The desired reaction was performed treating 3e–k with an excess of benzoyl chloride in
the presence of a stoichiometric amount of Et3 N and a catalytic amount of DMAP. The obtained N-benzoyl
hydrazines could be isolated after purification as a mixture of amide rotamers in high yields. We were delighted
to find that when treating the N -protected hydrazines with 2–3 equiv of SmI2 in the presence of an equimolar
N
O
S
Figure 2. X-ray crystal structure and absolute configuration of 4l and proposed mechanism for the nucleophilic 1,2-
addition of lithiated heteroarenes to the aldehyde-SAMP-hydrazones.
495

ENDERS et al./Turk J Chem
amount of DMPU a smooth cleavage of the chiral auxiliary took place. After purification, the corresponding
benzoyl amines 4–k (Table 2) were obtained in a very good overall yield. Furthermore, determination of the
ee value by HPLC analysis using a chiral stationary phase by comparison with the racemate showed that the
cleavage proceeded without any detectable epimerization or racemization.
Table 2. Asymmetric synthesis of N-protected α-(heteroaryl)alkylamines 4 (Scheme 1).
a
Cleavage
4
a
b
HetAr
Yield (%)
ee (%) b
99
BH3·THF
BH3·THF
83
70
93
c
d
e
f
80
64
71
73
96
88
96
99
BH3·THF
BH3·THF
SmI 2
SmI 2
g
SmI 2
54
94
h
i
SmI 2
SmI 2
82
85
99 c
92
j
SmI 2
SmI 2
68
81
98
97
k
a
b
c
Yield of isolated product over 2 steps.
Determined by HPLC on a chiral stationary phase.
Determined by GC on a chiral stationary phase.
The absolute configuration of the protected amines 4 was determined to be S by single crystal X-ray
analysis (Figure 2, A)25 on the N-acetyl protected 1-(thiophen-2-yl)propan-1-amine synthesized according to an
analogous procedure (see Experimental). This stereochemical outcome is in agreement with the relative topicity
observed for all 1,2-additions of nucleophiles to the CN bond of aldehyde SAMP-hydrazones.26 The preferential
formation of the S isomer can be explained considering an initial complexation of a first equivalent of lithio
hetarene with the chiral auxiliary to give the chelate structure B. This should allow a low-energy pathway for
the subsequent nucleophilic addition and moreover should result in the complete shielding of the Si-face of
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ENDERS et al./Turk J Chem
the imine double bond. The relative topicity of the nucleophilic attack is then directed by steric interactions,
resulting in a Re-face attack by a second equivalent of organometallic reagent.
In order to demonstrate the generality of our approach, we performed the nucleophilic 1,2-additions
on a range of different aldehyde hydrazones. First experiments were conducted using 2-(thienyl)lithium as a
nucleophile.
Scheme 2. Screening of different aldehyde SAMP-hydrazones: a) 2-(thienyl)lithium Et2 O or 1-methyl-2-lithiopyrrole,
THF; b) THF, BH3·THF, reflux; c) CbzCl, K2 CO3 , THF/H2 O.
As depicted in Scheme 2, the application of our established 3-step protocol afforded in all cases the
desired carbamates 5a–f in high overall yields and excellent enantiomeric excesses (Table 3). In particular,
it is remarkable that in the addition steps the rates of formation of the tertiary hydrazines as well as the
selectivities were not significantly altered by the presence of bulky groups on the hydrazone. A second series
of experiments were conducted with 1-methyl-2-lithiopyrrole. In agreement with the observation made in our
trial system, we found that although the desired carbamates 5g–j could be obtained with good to excellent
selectivities, the overall yields were moderate. The decreased level of efficiency was mainly due to the insufficient
conversion obtained in the first step, confirming the lower reactivity of 1-methyl-2-lithiopyrrole compared with
2-(thienyl)lithium.
Having demonstrated the generality and efficiency of our methodology, we turned our attention to explor-
ing possible synthetic applications. For this purpose, as disclosed in the introduction, α-(2-furyl)alkylamines
represented a straightforward entry into the synthesis of α-amino acids as the furan moiety is a synthetic
equivalent of the carboxylic acid functionality. Intrigued by this possibility and confident that our methodology
could provide a flexible solution, we decided to embark on an asymmetric synthesis of α-amino acids.
The reaction sequence to synthesize the benzoyl protected 2-furylalkylamines 7 is outlined in Scheme 3.
The SAMP-hydrazones 2 were treated with 3.2 equiv of 2-(furyl)lithium in THF at –78 ◦ C. NMR analysis of the
crude products showed that the corresponding hydrazines were obtained with perfect stereocontrol. Although
some of them were stable during flash chromatography and hence could be isolated, we found it more practical
and efficient to carry out the protection on the crude hydrazine and to isolate the corresponding N -benzoyl
hydrazines (Table 4).
Surprisingly, hydrazine 6e was obtained in very poor yield. Therefore, we chose to adopt a different
pathway to introduce the methyl group by reacting hydrazone 2k with MeLi. When the reaction was performed
in Et2 O, an excellent diastereoselectivity and high yield was obtained. Moreover, as expected, NMR analysis
showed that (S, S)-6e and (S ,R)-6e are epimers.
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ENDERS et al./Turk J Chem
Table 3. Screening of different aldehyde SAMP-hydrazones 2 using 2-thienyllitihum and 2-lithio-N-methylpyrrole as
nucleophiles to form the amines 5 (see Scheme 2).
ee (%)a
5
a
HetAr
R
Yield (%)
70
n-Bu
94
95
S
b
Ph(CH2)2
83
S
c
d
e
f
t-Bu
i-Pr
93
93
S
S
57
73
Et2CHCH2
Ferrocenyl
78
49
94
S
S
≥95 b
g
n-Bu
Ph(CH2)2
t-Bu
35
36
25
53
92
99
88
90
N
Me
h
N
Me
i
j
N
Me
Et2CHCH2
N
Me
a
Determined by chiral stationary phase HPLC.
bDetermined by 1H and 13C NMR on the corresponding hydrazine.
Scheme 3. Asymmetric synthesis of α-amino acids: a) 2-furyllithium, THF, –78 ◦ C to rt 2–18 h; b) BzCl, CH2 Cl2 ,
Et3 N, DMAP, rt, 12–48 h; c) SmI2 , DMPU, THF, rt, 1 h.
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ENDERS et al./Turk J Chem
Table 4. Asymmetric synthesis of N -protected α-(2-furyl)alkyl-ydrazines 6 (see Scheme 3).
6
a
b
c
d
e
f
R
n-Bu
Ph(CH2)2
t-Bu
Yield (%) de (%)a Confg.
75
75
72
88
30
45
≥ 96
≥ 96
≥ 96
≥ 96
≥ 96
90
S, S
S, S
S, S
S, R, S
S, S
S, S
CH3(CH2)2CH(CH3)
Me
TBDMSO(CH2)3
aDetermined by 1H and 13C NMR spectroscopy.
Scheme 4. Screening of different aldehyde SAMP-hydrazones: a) methyllithium, Et2 O, –78 ◦ C; b) BzCl, CH2 Cl2 ,
Et3 N, DMAP, rt, 12 h; c) SmI2 , DMPU, THF, rt, 1 h.
Thus we were able to confirm that by using only the SAMP chiral auxiliary we have access to both the
enantiomers of α-(2-furyl)alkylamines.The N-N bond cleavage was achieved using the above-reported SmI2 -
method, affording the N-protected amines in good to excellent yield and enantiomeric purity27 greater than
96% (Table 5). It is noteworthy that when compound 6f was used as substrate the corresponding amine 7f was
obtained in 40% yield together with 20% of O-deprotected compound.
Table 5. SmI2 promoted N-N bond cleavage to form 7 (see Scheme 3).
7
a
b
c
d
e
f
R
n-Bu
Ph(CH2)2
t-Bu
Yield (%) ee (%)a Confg.
84
80
76
80
90
40
96
96
98
99
98
90
S
S
S
S, Rb
S
CH3(CH2)2CH(CH3)
Me
TBDMSO(CH2)3
aDetermined by chiral stationary phase HPLC.
S
bde ≥ 96% determined by 1H and 13C NMR spectroscopy.
Finally, conversion into α-amino acids was carried out by treatment of 7a–e, 4j with a catalytic amount
of RuCl3·H2 O in the presence of a large excess of NaIO4 in a mixture of H2 O/CH2 Cl2 /CH3 CN (Scheme 5).5b
Scheme 5. Synthesis of α-amino acids: a) RuCl3·H2 O, NaIO4 , H2 O/CH2 Cl2 /CH3 CN, rt, 2 h.
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ENDERS et al./Turk J Chem
After 2 h at room temperature the reaction was complete. Work-up and subsequent purification either
by recrystallization or flash chromatography provided the α-amino acids as virtually enantiomerically pure
products in excellent overall yields (Table 6).
Table 6. Synthesis of α-amino acids 8 by oxidation with RuCl3·H2 O and NaIO4 (see Scheme 5).
8
a
b
c
d
e
f
R
n-Bu
Yield (%) ee (%)a Confg.
70
90
77
82
86
79
96
96
98
99
98
99
S
S
S
S, R
S
S
Ph(CH2)2
t-Bu
CH3(CH2)2CH(CH3)
Me
Et
aDetermined by chiral stationary phase HPLC.
Notably, product 8d demonstrated that our methodology is compatible with the SAMP-α-alkylation,
allowing us to generate α-amino acids with 2 stereocenters.
A final detail should be addressed: regardless of the extensive experimentation we were not able to
synthesize aromatic α-amino acids. Even by changing the solvent, temperature, and aromatic substituents the
reaction between aromatic hydrazones and 2-furyllithium did not take place.
In summary, we have achieved a highly efficient asymmetric synthesis of α-(heteroaryl)alkylamines based
on the nucleophilic 1,2-addition of lithiated aromatic heterocycles to aldehyde SAMP-/RAMP-hydrazones.28
In addition, oxidative furan to carboxylic acid conversion allowed the asymmetric synthesis of α-amino acids
of high enantiomeric purities.
2. Experimental
Preparative column chromatography: Merck silica gel 60, particle size 0.040–063 mm (230–240 mesh, flash).
Analytical TLC: silica gel 60 F254 plates from Merck, Darmstadt, Germany. Optical rotation values were
measured on a PerkinElmer P241 polarimeter. Microanalyses were obtained with a Vario EL element analyzer.
Mass spectra were acquired on a Finnigan SSQ7000 (CI 100 eV; EI 70 eV) spectrometer. IR spectra were taken
on a PerkinElmer FT/IR 1760. 1 H and 13 C NMR spectra were recorded on Varian Gemini 300 or Inova 400
spectrometers and all measurements were performed with tetramethylsilane as internal standard. Melting points
were determined on a Tottoli melting point apparatus and are uncorrected. Gas chromatography: Lipodex A
(Macherey-Nagel) or Chirasil-L-Val (25 m × 0.25 mm, 1 bar H2 , Chrompak) columns. ee-Determination with
HPLC: Chiralpak AD or OD (250 × 4.4 mm, n-heptane: isopropanol = 95:5).
2.1. General procedure 1 (GP1): preparation of the lithiated heteroarenes
2-(Furyl)lithium: n-(butyl)lithium (6.4 mmol) was added to a solution of furan (462 mg, 6.8 mmol) in 20 mL
of dry THF at 0 ◦ C. The ice bath was removed and the mixture warmed up to 50–60 ◦ C for 60–90 min.
2-(Thienyl)lithium, 2-(benzothienyl)lithium and 2-(benzofuryl)lithium: n-(butyl)lithium (6.4 mmol) was
added to a solution of thiophene, benzothiophene, or benzofuran (6.8 mmol) in dry Et2 O (20 mL) at 0 ◦ C.
After 5 min the ice bath was removed and the mixture was stirred for 1 h at rt (90 min for benzothiophene).
2-Lithio-1-methyl pyrrole and 2-lithio-1-methylindole: n-(butyl)lithium (6.4 mmol) was added to a
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ENDERS et al./Turk J Chem
solution of N -methylpyrrole or N -methylindole (6.8 mmol) in dry THF (20 mL) at rt. The mixture was
warmed up to 60 ◦ C for 1 h or alternatively stirred at rt overnight.
2.2. GP2: synthesis of 1-(2-thienyl)alkylcarbamates
To a solution of 2-(thienyl)lithium in Et2 O cooled to –78 ◦ C was added dropwise hydrazone 2 (2 mmol)
dissolved in dry Et2 O (2 mL). After 30 min the cooling bath was removed, the temperature allowed to warm
to room temperature, and the reaction mixture stirred for an additional 2–9 h. The mixture was quenched with
saturated aqueous NH4 Cl and extracted 3 times with Et2 O. The organic layer was then washed twice with
brine, dried over MgSO4 , and evaporated in vacuo. The crude hydrazine was dissolved in dry THF (10 mL pro
mmol of hydrazine) and heated up to reflux with 10 or 20 equiv of BH3·THF (1.0 mol in THF) for 9–36 h. The
reaction was cooled to room temperature, acidified with aqueous HCl (1N), and stirred for 1 h. The THF was
evaporated under reduced pressure and the aqueous solution was basified with a saturated solution of K2 CO3
and extracted with methylene chloride. The organic layers were concentrated in vacuo and the residue was
dissolved in a mixture of H2 O and THF (1:1). Then 2 equiv of potassium carbonate were added, followed by
1.8 equiv of benzyl chloroformate, and the heterogeneous solution was stirred at room temperature overnight.
Et2 O was added to the mixture, the layers were separated and the aqueous layer was washed with 2 further
portions of Et2 O. The combined organic extracts were dried (MgSO4) and evaporated. The crude product was
purified by column chromatography.
2.3. GP3: preparation of furfuryl hydrazines
To a solution of 2-(furyl)lithium (GP1) cooled to –78 ◦ C was added dropwise hydrazone 2 (2 mmol) dissolved
in dry THF (2 mL). After 30 min the cooling bath was removed and the temperature allowed to warm to rt,
followed by stirring for an additional 2–18 h. The mixture was hydrolyzed with saturated aqueous NH4 Cl
and extracted 3 times with Et2 O. The organic layer was then washed twice with brine, dried with MgSO4 ,
and evaporated in vacuo. The crude product was either purified via column chromatography or used as crude
product in the next step.
2.4. GP4: SmI2 promoted cleavage
To a solution of protected hydrazine in dry THF (strict anaerobic conditions are required) (10 mL pro mmol of
hydrazine) were added 2 equiv of DMPU followed by 2–3 equiv of SmI2 . After 2 h at rt the reaction mixture
was quenched with a mixture of NaHCO3 solution and CH2 Cl2 (5:2), extracted with CH2 Cl2 , dried over
MgSO4 , and concentrated in vacuo. The crude product was purified by column chromatography.
2.5. GP5: oxidation of furfuryl amides to N -protected α-amino acids
RuCl3·H2 O (2 mol%) was added to a mixture of NaIO4 (15 equiv) in CH2 Cl2 /MeCN/H2 O (1.0:0.04:0.7) and
the mixture was stirred for 0.5 h. A solution of furfuryl amide in CH2 Cl2 was rapidly added to the mixture
via cannula. Upon completion of the reaction after 2 h, the organic phase was separated and the aqueous phase
was washed with CH2 Cl2 . The collected organic layers were washed with saturated aqueous NaHSO3 and
brine, dried (MgSO4), and concentrated in vacuo. The crude product was purified by column chromatography
or recrystallization.
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2.6. (1S)-(1-Thiophen-2-yl-propyl)-carbamic acid benzyl ester (4a)
Prepared according to GP 2 from 2-lithio-thiophene (6.4 mmol) and hydrazone 2a (340 mg, 2.0 mmol). After
N,N-cleavage and protection purification by column chromatography (Et2 O:pentane 1:2) gave 4a (420 mg, 75%)
as a colorless solid. ee ≥ 99%; mp 69–70 ◦ C; [α]D26 –57.8 (c = 1.4, CHCl3).
IR (KBr): u˜ = 3309, 2971, 2934, 2878, 1685, 1535, 1499, 1467, 1454, 1443, 1327, 1298, 1266, 1238, 1081,
1045, 1029, 974, 752 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 0.96 (t, 3H, J = 7.4 Hz, CH3 CH2), 1.85–1.96 (m, 2H, CH3 CH2),
4.91–5.14 (m, 4H, NH , CH NH, CH2 OC=O), 6.93–6.97 (m, 2H, arom CH), 7.18–7.20 (m, 1H, arom CH),
7.29–7.34 (m, 5H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 10.97 (C H3), 30.49 (CH3C H2), 52.80 (C HN), 67.15 (C H2 OC=O),
124.31, 124.47, 126.98, 128.34, 128.73, (arom C H), 136.58, 146.18 (arom C), 155.83 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 275 (1) [M+• ], 246 (6), 202 (9), 185 (5), 184 (50), 140 (11), 97 (6), 92 (9),
91 (100), 85 (5), 65 (9), 56 (10).
Anal. Calcd for C15 H17 NO2 S: C, 65.43; H, 6.22; N, 5.09; Found: C, 65.50; H, 6.16; N, 4.99.
2.7. (1S)-(1-Thiophen-3-yl-propyl)-carbamic acid benzyl ester (4b)
To a solution of 3-bromothiophene (1.127 g, 7 mmol) in ether (20 mL) was added n-BuLi (6.4 mmol) dropwise
at –78 ◦ C and the obtained mixture was stirred for 90 min. A solution of hydrazone 2a (340 mg, 2.0 mmol) in
Et2 O (4 mL) was added to the mixture according to GP2. After N,N-cleavage and protection purification by
column chromatography (Et2 O:pentane 1:2) gave 4b (385 mg, 70%) as a colorless solid. ee ≥ 93%; mp 76–77
◦ C; [α]2D2 – 47.4 (c = 1.1, CHCl3).
IR (KBr): u˜ = 3341, 1683, 1533, 1268, 1239, 1083, 776 cm−1
.
1 H NMR (300 MHz, CDCl3): δ = 0.87 (t, 3H, J = 7.4 Hz, CH3), 1.70–1.83 (m, 2H, CH3 CH2),
4.68–4.80 (m, 1H, CH NH), 5.02 (d, 1H, J = 12.4 Hz CH HOC=O), 5.08 (d, 1H, J = 12.4 Hz CHH OC=O),
5.35 (d, 1H, J = 8.7 Hz, NH), 6.96 (d, 1H, J = 4.2 Hz, arom CH), 7.03–7.06 (m, 1H, arom CH), 7.20 (dd,
1H, J = 3.0, 5.2 Hz, arom CH), 7.22–7.30 (m, 5H, arom CH) ppm.
13 C NMR (75 MHz, CDCl3): δ = 10.72 (C H3), 29.21 (CH3C H2), 52.70 (C HN), 66.79 (C H2 OC=O),
120.98, 126.15, 126.28, 128.18, 128.62 (arom C H), 136.74, 143.78 (arom C), 156.12 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 275 (7) [M+• ], 246 (24), 202 (15), 184 (16), 140 (6), 97 (5), 92 (8), 91 (100),
65 (6).
Anal. Calcd for C15 H17 NO2 S: C, 65.43; H, 6.22; N, 5.09; Found: C, 65.54; H, 6.09; N, 5.04.
2.8. (1S)-[1-(5-Chloro-thiophen-2-yl-propyl)]-carbamic acid benzyl ester (4c)
To a solution of 2-bromo-5-chloro-thiophene (1.365 g, 7 mmol) in Et2 O (20 mL) was added n-BuLi (6.4 mmol)
dropwise at –78 ◦ C and the obtained mixture was stirred for an additional 90 min. A solution of hydrazone
2a (340 mg, 2.0 mmol) in Et2 O (4 mL) was added to the mixture according to GP2. After N,N-cleavage and
protection purification by column chromatography (Et2 O:pentane 1:2) gave 4c (495 mg, 80%) as a colorless
solid. ee = 96%; mp 65–66 ◦ C; [α]D22 – 49.7 (c 1.4, CHCl3).
IR (CHCl3): u˜ = 3446, 1684, 1536, 1263, 700 cm−1
.
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ENDERS et al./Turk J Chem
1 H NMR (400 MHz, CDCl3): δ = 0.95 (t, 3H, J = 7.4 Hz, CH3), 1.74–1.86 (m, 2H, CH3 CH2),
4.76–4.78 (m, 1H, CH NH), 5.05–5.13 (m, 3H, NH, CH2 CO=O), 6.70–6.73 (m, 2H, arom CH), 7.27–7.36 (m,
5H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 10.71 (C H3), 29.79 (CH3C H2), 52.86 (C HN), 67.09 (C H2 OC=O),
123.61, 125.77, 128.12, 128.21, 128.55 (arom C H), 136.29, 145.14 (arom C), 155.61 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 309 (7) [M+• ], 220 (23), 219 (6), 218 (61), 174 (10), 92 (7), 91 (100), 65
(5), 56 (14).
Anal. Calcd for C15 H16 ClNO2 S: C, 58.15; H, 5.21; N, 4.52. Found: C, 57.84; H, 5.53; N, 4.46
2.9. (1S)-[1-(1-Methyl-1H -pyrrol-2-yl)-propyl]-carbamic acid benzyl ester (4d)
Prepared according to GP2 from 2-lithio-1-methylpyrrole (6.4 mmol) and hydrazone 2a (340 mg, 2.0 mmol).
After N,N-cleavage and protection purification by column chromatography (Et2 O:pentane 1:3) gave 4d (245
mg, 45%) as a colorless solid. ee = 88%; mp 70–71 ◦ C; [α]D22 – 62.4 (c 1.8, CHCl3).
IR (KBr): u˜ = 3309, 1684, 1540, 1305, 1266, 1248, 1077, 718, 696 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 0.98 (t, 3H, J = 7.4 Hz, CH3 CH2), 1.80–1.95 (m, 2H, CH3 CH2),
3.54 (s, 3H, NCH3), 4.67–4.76 (m, 2H, CH N, NH), 5.09 (s, 2H, CH2 OC=O), 6.00–6.49 (m, 2H, arom CH),
6.54–6.55 (m, 1H, arom CH), 7.27–7.35 (m, 5H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 11.36 (C H3 CH2), 28.51 (CH3C H2), 34.15 (NC H3), 48.90 (C HN),
66.98 (C H2 OC=O), 105.89, 106.95, 122.79, 128.22, 128.32, 128.73 (arom C H), 133.19, 136.81, (arom C),
155.86 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 273 (6) [M+•+1], 272 (36) [M+• ], 243 (28), 199 (25), 181 (16), 172 (7),
137 (9), 122 (7), 107 (8), 92 (7), 91 (100), 82 (14), 65 (5).
Anal. Calcd for C16 H20 N2 O2 : C, 70.56; H, 7.41; N, 10.28. Found: C, 70.49; H, 7.35; N, 10.10.
2.10. (1S)-N -(1-pyridin-2-yl-propyl)-benzamide (4e)
A solution of benzoyl protected hydrazine 3e (355 mg, 1 mmol) in THF (10 mL) was treated with 2 equiv
of SmI2 (0.1M in THF) and an equimolar amount of DMPU according to GP4. After work-up and flash
chromatography (Et2 O:pentane 95:5) 4e was obtained as a colorless solid (185 mg, 77%); ee = 96%; mp 69–70
◦ C; [α]2D2 –16.0 (c 1.0, CHCl3).
IR (KBr): u˜ = 3325, 1634, 1588, 1576, 1525, 1487, 1467, 1433, 1309, 695, 664 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 0.76 (t, 3H, J = 7.4 Hz, CH3 CH2), 1.78–1.96 (m, 2H, CH3 CH2),
5.09–5.16 (m, 1H, CH N), 7.07 (ddd, J = 1.4, 4.9, 7.7 Hz, 1H, arom CH), 7.15–7.17 (m, 1H, arom CH),
7.26–7.39 (m, 3H, arom CH), 7.54 (dt, 1H, J = 1.7, 8.7 Hz, arom CH) 7.63 (d, 1H, J = 7.4 Hz, NH),
7.57–7.78 (m, 2H, arom CH), 8.44–8.46 (m, 1H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 10.12 (C H3 CH2), 29.70 (C H2 CHN), 55.52 (C HN), 122.58, 127.28,
128.67, 131.54 (arom C H), 134.92 (arom C), 136.84, 149.32 (arom C H), 160.01 (arom C), 166.93 (C =O)
ppm.
MS (EI, 70 eV): m/z (%) = 240 (12) [M+• ], 212 (13), 211 (44), 135 (13), 120 (6), 118 (6), 107 (7), 106
(8), 105 (100), 78 (5), 77 (40), 51 (9).
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Anal. Calcd for C15 H16 N2 O: C, 74.93; H, 6.71; N, 11.66. Found: C, 74.86; H, 6.88; N, 11.59.
2.11. (1S)-N -(1-pyridin-3-yl-propyl)-benzamide (4f)
A solution of benzoyl protected hydrazine 3f (355 mg, 1 mmol) in THF (10 mL) was treated with 2 equiv of SmI2
(0.1M in THF) and an equimolar amount of DMPU according to GP4. After work-up and flash chromatography
(Et2 O) 4f was obtained as a colorless solid (200 mg, 83%). ee = 99%; mp 72–73 ◦ C; [α]D22 +11.7 (c 1.4,
CHCl3).
IR (KBr): u˜ = 3319, 2966, 1639, 1603, 1578, 1533, 1480, 1459, 1325, 1334, 1001, 795, 715, 690 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 0.84 (t, 3H, J = 7.3 Hz, CH3 CH2), 1.73–1.86 (m, 2H, CH3 CH2),
4.95 (q, 1H, J = 7.7 Hz, CH N), 7.10 (dd, J = 4.9, 8.0 Hz, 1H, arom CH), 7.21–7.25 (m, 2H, arom CH),
7.31–7.35 (m, 2H, NH , arom CH), 7.54 (dt, 1H, J = 1.7, 8.7 Hz, arom CH) 7.66–7.68 (m, 2H, arom CH),
8.33 (dd, 1H, J = 1.7, 4.8 Hz, arom CH), 8.44 (d, 1H, J = 1.9 Hz, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 11.11 (C H3 CH2), 29.04 (C H2 CHN), 53.66 (C HN), 123.71, 127.35,
128.65, 131.70 (arom C H), 134.52 (arom C), 134.71 (arom C H), 138.37 (arom C), 148.56, 148.59 (arom CH),
167.63 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 240 (15) [M+• ], 211 (17), 106 (8), 105 (100), 77 (33), 51 (7).
Anal. Calcd for C15 H16 N2 O: C, 74.93; H, 6.71; N, 11.66. Found: C, 74.72; H, 6.58; N, 11.46.
2.12. (1S)-N -[1-(1-Methyl-1H-indol-2-yl)-propyl]-benz-amide (4g)
A solution of benzoyl protected hydrazine 3g (405 mg, 1 mmol) in THF (10 mL) was treated with 2 equiv
of SmI2 (0.1 M in THF) and an equimolar amount of DMPU according to GP4. After work-up and flash
chromatography (Et2 O:pentane 3:2) 4g was obtained as a colorless solid (210 mg, 72%). ee = 94%; mp
165–166 ◦ C; [α]2D2 –120.2 (c 1.6, CHCl3).
IR (KBr): u˜ = 3286, 2929, 1632, 1457, 1385, 1338, 1314, 1295, 1272, 1152, 783, 748, 731, 712, 696 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 1.02 (t, 3H, J = 7.4 Hz, CH3 CH2), 1.95–2.12 (m, 2H, CH3 CH2),
3.64 (s, 3H, NCH3), 5.39 (q, 1H, J = 7.4 Hz, CH N), 6.14–6.16 (br, 1H, NH), 6.41 (s, 1H, arom CH), 7.00–
7.04 (m, 1H, arom CH), 7.11–7.42 (m, 5H, arom CH), 7.50 (d, 1H, J = 7.7 Hz, arom CH), 7.49–7.66 (m, 2H,
arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 11.42 (C H3 CH2), 28.10 (C H2 CHN), 30.16 (NC H3), 47.44 (C HN),
99.23, 109.52, 119.88, 120.67, 122.04, 127.10 (arom C H), 127.45 (arom C), 128.83, 131.87 (arom C H), 134.30,
137.83, 140.48 (arom C), 166.61 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 293 (15) [M+•+1], 292 (72) [M+• ], 264 (14), 263 (75), 187 (13), 171 (10),
160 (8), 157 (8), 156 (6), 132 (24), 130 (6), 106 (7), 105 (100), 77 (33).
Anal. Calcd for C19 H20 N2 O: C, 78.05; H, 6.89; N, 9.58. Found: C, 77.71; H, 6.84; N, 9.53.
2.13. (1S)-N -[1-(1-Methyl-1H-imidazol-2-yl)-propyl]-benzamide (4h)
A solution of hydrazine 3h (356 mg, 1 mmol) in THF (10 mL) was treated with 2 equiv of SmI2 (0.1 M in THF)
and an equimolar amount of DMPU according to GP4. After work-up and flash chromatography (AcOEt) 4h
was obtained as a colorless solid (210 mg, 87%). ee = 99%; mp 115–116 ◦ C; [α]D22 –25.0 (c 1.2, CHCl3).
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ENDERS et al./Turk J Chem
IR (KBr): u˜ = 3212, 3042, 2966, 2932, 2873, 1651, 1600, 1577, 1540, 1491, 1458, 1381, 1334, 1295, 750,
715 cm−1
.
1 H NMR (300 MHz, CDCl3): δ = 0.86 (t, 3H, J = 7.4 Hz, CH3 CH2), 1.90–2.00 (m, 2H, CH3 CH2),
3.61 (s, 3H, NCH3), 5.25 (q, 1H, J = 7.2 Hz, CH N), 6.68 (d, 1H, J = 1.1 Hz, CH =CHN), 6.78 (d, 1H, J =
1.1 Hz, CH=CH N), 7.22–7.36 (m, 3H, arom CH), 7.72–7.75 (m, 3H, NH , arom CH) ppm.
13 C NMR (75 MHz, CDCl3): δ = 9.35 (C H3 CH2), 26.86 (C H2 CHN), 31.69 (NC H3), 45.56 (C HN),
119.85, 125.94, 126.18, 127.34, 130.43 (arom C H), 132.85, 147.08 (arom C), 165.73 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 244 (6) [M+•+1], 243 (29) [M+• ], 214 (14), 138 (75), 123 (6), 121 (12),
106 (8), 105 (100), 83 (5), 77 (41), 51 (7).
Anal. Calcd for C14 H17 N3 O: C, 69.11; H, 7.04; N, 17.27. Found: C, 68.81; H, 6.79; N, 17.08.
2.14. (1S)-N -[1-(1-Methyl-1H-benzoimidazol-2-yl)-pro pyl]-benzamide (4i)
A solution of benzoyl protected hydrazine 3i (406 mg, 1 mmol) in THF (10 mL) was treated with 2 equiv of
SmI2 in THF (0.1 in THF) and an equimolar amount of DMPU according to GP4. After work-up and flash
chromatography (AcOEt) 4i was obtained as a colorless solid (230 mg, 78%). ee = 92%; mp 163–164 ◦ C;
[α]2D2 –32.5 (c 1.1, CHCl3).
IR (KBr): u˜ = 3291, 3054, 2966, 2932, 2872, 1654, 1528, 1488, 1332, 1290, 1236, 842, 741, 700, 655
cm−1
.
1 H NMR (300 MHz, CDCl3): δ = 1.02 (t, 3H, J = 7.4 Hz, CH3 CH2), 2.08–2.32 (m, 2H, CH3 CH2),
3.85 (s, 3H, NCH3), 5.58 (dt, 1H, J = 6.9, 8.4 Hz, CH N), 7.21–7.30 (m, 3H, arom CH), 7.39–7.55 (m, 4H,
arom CH , NH), 7.62–7.66 (m, 1H, arom CH), 7.87–7.90 (m, 2H, arom CH) ppm.
13 C NMR (75 MHz, CDCl3): δ = 10.21 (C H3 CH2), 28.03 (C H2 CHN), 29.98 (NC H3), 47.09 (C HN),
109.56, 119.13, 122.31, 122.82, 127.23, 128.58, 131.76 (arom C H), 133.80, 135.50, 139.96 (arom C), 166.85
(C =O) ppm.
MS (EI, 70 eV): m/z (%) = 294 (12) [M+•+1], 293 (59) [M+• ], 278 (8), 264 (8), 189 (12), 188 (100),
171 (5), 160 (7), 133 (8), 131 (6), 106 (6), 105 (75), 77 (40).
Anal. Calcd for C18 H19 N3 O: C, 73.69; H, 6.53; N, 14.32. Found: C, 74.07; H, 6.64; N, 14.31.
2.15. (S)-N -(1-Furan-2-yl-propyl)-benzamide (4j)
A solution of benzoyl protected hydrazine 3j (342 mg, 1 mmol) in THF (10 mL) was treated with 2 equiv of SmI2
(0.1M in THF) and an equimolar amount of DMPU according to GP4. After work-up and flash chromatography
(Et2 O:pentane 1:2) 4j was obtained as a colorless solid (190 mg, 83%). ee = 99%; mp 86–88 ◦ C; [α]D22 –62.4
(c 1.1, CHCl3).
IR (KBr): u˜ = 3291, 2968, 1635, 1534, 1339, 1301, 1153, 1011, 803, 697 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 0.86 (t, 3H, J = 7.4 Hz, CH3 CH2), 1.77–1.94 (m, 2H, CH3 CH2),
5.12–5.18 (m, 1H, CH NH), 6.14 (d, 1H, J = 3.0 Hz, CH CO), 6.23 (dd, 1H, J = 1.6, 3.0 Hz, CH CHO),
6.44–6.48 (br, 1H, NH), 7.25–7.26 (m, 1H, arom CH), 7.29–7.33 (m, 2H, arom CH), 7.37–7.41 (m, 1H, arom
CH), 7.68–7.71 (m, 2H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 10.84 (C H3 CH2), 27.56 (CH3C H2), 49.37 (C HN), 106.79, 110.42,
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ENDERS et al./Turk J Chem
127.22, 128.73, 131.69 (arom C H), 134.64 (arom C), 142.03 (arom C H), 154.38 (arom C), 166.87 (C =O)
ppm.
MS (EI, 70 eV): m/z (%) = 230 (5) [M+•+1], 229 (31) [M+• ], 200 (34), 106 (8), 105 (42), 77 (27).
Anal. Calcd for C14 H15 NO2 : C, 73.34; H, 6.59; N, 6.11. Found: C, 73.11; H, 6.79; N, 6.03.
2.16. (1S)-N -(1-benzofuran-2-yl-propyl)-benzamide (4k)
A solution of benzoyl protected hydrazine 3k (392 mg, 1 mmol) in THF (10 mL) was treated with 2 equiv
of SmI2 (0.1M in THF) and an equimolar amount of DMPU according to GP4. After work-up and flash
chromatography (Et2 O:pentane 1:3) 4k was obtained as a colorless solid (238 mg, 85%). ee = 97%; mp
132–134 ◦ C; [α]D22 − 85.4 (c 0.9, CHCl3).
IR (KBr): u˜ = 3291, 1633, 1600, 1578, 1527, 1487, 1452, 1341, 1290, 1255, 1157, 805, 754, 695 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 0.89 (t, 3H, J = 7.4 Hz, CH3 CH2), 1.83–2.00 (m, 2H, CH3 CH2),
5.23–5.29 (m, 1H, CH N), 6.50 (s, 3H, arom CH), 6.71 (d, 1H, J = 8.8 Hz, NH), 7.07–7.16 (m, 2H, arom
CH), 7.24–7.41 (m, 3H, arom CH) 7.69–7.71 (m, 2H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 10.76 (C H3 CH2), 27.26 (C H2 CHN), 49.73 (C HN), 103.69, 111.36,
121.24, 123.06, 124.27, 127.34 (arom C H), 128.42 (arom C), 128.79, 131.85 (arom C H), 134.52, 155.00, 157.16
(arom C), 167.20 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 280 (7) [M+•+1], 279 (33) [M+• ], 251 (5), 250 (34), 158 (5), 106 (8), 105
(100), 77 (33).
Anal. Calcd for C18 H17 NO2 : C, 77.40; H, 6.13; N, 5.01. Found: C, 77.29; H, 6.08; N, 4.93.
2.17. (1S)-N -(1-Thiophen-2-yl-propyl)-acetamide (4l)
To a solution of 2-lithio-thiophene (6.4 mmol) in Et2 O (20 mL) was added hydrazone 2a (340 mg, 2.0 mmol)
dissolved in Et2 O (4 mL) according to GP2. After cleavage of the chiral auxiliary, the crude amine was dissolved
in CH2 Cl2 (10 mL) in the presence of 2 equiv of Et3 N and a catalytic amount of DMAP. The resulting mixture
was cooled to 0 ◦ C and 2 mmol of acetylchloride was added dropwise and the reaction was allowed to reach rt.
After stirring for 12 h at rt, the reaction mixture was poured in water (10 mL) and extracted with CH2 Cl2 (3
times); the organic layer was dried over MgSO4 and evaporated under reduced pressure. Crystallization from
Et2 O afforded 4l (275 mg, 75%) as a colorless solid. ee = 99%; mp 126–127 ◦ C; [α]D22 –149.8 (c 0.2, CHCl3),
lit.15d [α]D22 –148.0 (c 0.14, CHCl3). The rest of the analytical data are in agreement with those reported in
the literature.15d
2.18. (1S)-(1-Thiophen-2-yl-pentyl)-carbamic acid benzyl ester (5a)
To a solution of 2-lithio-thiophene (6.4 mmol) in Et2 O (20 mL) was added hydrazone 2b (396 mg, 2.0 mmol)
dissolved in Et2 O (4 mL) according to GP2. After cleavage of the chiral auxiliary, purification by column
chromatography (Et2 O:pentane 1:4) gave 5a (425 mg, 70%) as a colorless solid. ee = 94%; mp 56–57 ◦ C;
[α]2D2 –48.0 (c 2.1, CHCl3).
IR (KBr): u˜ = 3336, 2951, 2936, 2885, 2857, 1688, 1527, 1465, 1455, 1433, 1333, 1300, 1286, 1248, 1225,
1140, 1123, 1102, 1045, 1028, 1011, 749, 701, 650 cm−1
506
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1 H NMR (400 MHz, CDCl3): δ = 1.12 (t, 3H, J = 7.0 Hz, CH3 CH2), 1.50–1.66 (m, 4H, CH3 CH2 CH2),
2.08–2.13 (m, 2H, CH2 CH), 5.21–5.39 (m, 4H, CH N, NH , CH2 OC=O), 7.16–7.19 (m, 2H, arom CH), 7.42–
7.44 (m, 1H, arom CH), 7.51–7.57 (m, 5H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 14.46 (C H3), 22.84 (CH3 CH2), 28.71 (CH3 CH2C H2), 37.37
(C H2 CH), 51.53 (C HN), 67.35 (C H2 OC=O), 124.57, 124.70, 127.28, 128.64, 129.03, (arom C H), 136.92,
147.17 (arom C), 156.14 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 303 (1) [M+• ], 246 (12), 212 (65), 202 (20), 168 (11), 97 (7), 92 (8), 91
(100), 84 (5), 65 (6).
Anal. Calcd for C17 H21 NO2 S: C, 67.29; H, 6.97; N, 4.61. Found: C, 67.21; H, 6.82; N, 4.56.
2.19. (1S)-(3-Phenyl-1-thiophen-2-yl-propyl)-carbamic acid benzyl ester (5b)
To a solution of 2-lithio-thiophene (6.4 mmol) in Et2 O (20 mL) was added hydrazone 2c (492 mg, 2.0 mmol)
dissolved in Et2 O (4 mL) according to GP2. After cleavage of the chiral auxiliary purification by column
chromatography (Et2 O:pentane 1:2) gave 5b (585 mg, 83%) as a colorless solid. ee = 95%; mp 56–57 ◦ C;
[α]2D2 –36.5 (c 1.4, CHCl3).
IR (KBr): u˜ = 3312, 3029, 2944, 1684, 1538, 1497, 1453, 1436, 1326, 1282, 1261, 1250, 1134, 1051, 1028,
750, 698, 657, 575 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 2.10–2.22 (m, 2H, CH2 CH2), 2.60–2.73 (m, 2H, PhCH2), 5.03–5.28
(m, 4H, NH , CH NH, CH2 OC=O), 6.93–6.96 (m, 2H, arom CH), 7.14–7.35 (m, 11H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 32.78 (PhC H2), 39.13 (CH2C H2), 51.09 (C HN), 67.23 (C H2 OC=O),
124.56, 124.74, 126.32, 127.09, 128.40, 128.61, 128.71, 128.76 (arom C H), 136.54, 141.23, 146.02 (arom C),
155.74 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 351 (1) [M+• ], 260 (28), 202 (7), 199 (14), 156 (6), 92 (8), 91 (100), 65 (6).
Anal. Calcd for C21 H21 NO2 S: C, 71.76; H, 6.03; N, 3.99. Found: C, 71.72; H, 6.00; N, 3.76.
2.20. (1S)-(2,2-Dimethyl-1-thiophen-2-yl-propyl)-carbamic acid benzyl ester (5c)
To a solution of 2-lithio-thiophene (6.4 mmol) in Et2 O (20 mL) was added hydrazone 2d (396 mg, 2.0 mmol)
dissolved in Et2 O (4 mL) according to GP2. After cleavage of the chiral auxiliary purification by column
chromatography (Et2 O:pentane 1:3) gave 5c (345 mg, 57%) as a colorless solid. ee = 93%; mp 59–60 ◦ C;
[α]2D2 –8.1 (c 1.5, CHCl3).
IR (KBr): u˜ = 3331, 2965, 2869, 1707, 1526, 1510, 1477, 1465, 1455, 1398, 1367, 1332, 1239, 1110, 1055,
1007, 777, 736, 697 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 1.23 (s, 9H, CH3 C), 5.10 (d, 1H, J = 9.9 Hz, CH NH), 5.28 (d, 1H,
J = 12 Hz CHH OC=O), 5.35 (d, 1H, J = 12 Hz CH HOC=O), 5.45–5.48 (br, 1H, NH), 7.15–7.20 (m, 2H,
arom. CH), 7.42 (dd, 1H, J = 1.4, 5.0 Hz, arom CH), 7.57–7.69 (m, 5H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 27.13 (C H3), 35.67 (CH3C), 60.71 (C HN), 67.49 (C H2 OC=O),
124.27, 126.45, 126.85, 128.74, 129.06, (arom C H), 136.84, 144.09 (arom C), 156.41 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 303 (4) [M+• ], 247 (7), 246 (46), 202 (23), 92 (8), 91 (100), 65 (5).
Anal. Calcd for C17 H21 NO2 S: C, 67.29; H, 6.97; N, 4.61. Found: C, 67.29; H, 7.16; N, 4.59.
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2.21. (1S)-(2-Methyl-1-thiophen-2-yl-propyl)-carbamic acid benzyl ester (5d)
To a solution of 2-lithio-thiophene (6.4 mmol) in Et2 O (20 mL) was added hydrazone 2e (368 mg, 2.0 mmol)
dissolved in Et2 O (4 mL) according to GP2. After cleavage of the chiral auxiliary purification by column
chromatography (Et2 O:pentane 1:2) gave 5d (422 mg, 73%) as a colorless oil. ee = 93%; [α]2D2 –43.3 (c 1.2,
CHCl3).
IR (KBr): u˜ = 3321, 2957, 2934, 2870, 1688, 1540, 1466, 1455, 1331, 1309, 1273, 1242, 1024, 747, 697
cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 1.19 (t, 6H, J = 7.7 Hz, CH3 CH), 2.29–2.35 (m, 1H, CH3 CH),
5.06–5.11 (m, 1H, CH N), 5.30–5.41 (m, 3H, NH , CH2 OC=O), 7.15–7.20 (m, 2H, arom CH), 7.43 (dd, 1H,
J = 1.1, 5.0 Hz, arom CH), 7.51–7.58 (m, 5H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 18.78, 20.17 (C H3), 34.87 (CH3C H), 57.41 (C HN), 67.43
(C H2 OC=O), 124.42, 125.02, 127.23, 128.67, 129.05, (arom C H), 136.92, 146.12 (arom C), 156.45 (C =O)
ppm.
MS (EI, 70 eV): m/z (%) = 289 (3) [M+• ], 246 (53), 202 (27), 198 (9), 92 (8), 91 (100).
Anal. Calcd for C16 H19 NO2 S: C, 66.41; H, 6.62; N, 4.84. Found: C, 66.16; H, 6.98; N, 4.77.
2.22. (1S)-(2-Ethyl-1-thiophen-2-yl-butyl)-carbamic acid benzyl ester (5e)
To a solution of 2-lithio-thiophene (6.4 mmol) in Et2 O (20 mL) was added hydrazone 2f (424 mg, 2.0 mmol)
dissolved in Et2 O (4 mL) according to GP2. After cleavage of the chiral auxiliary purification by column
chromatography (Et2 O:pentane 3:7) gave 5e (495 mg, 78%) as a colorless solid. ee = 94%; mp 59–60 ◦ C;
[α]2D2 –43.7 (c 2.0, CHCl3).
IR (KBr): u˜ = 3361, 2965, 2939, 2875, 1690, 1522, 1456, 1316, 1267, 1252, 1227, 1134, 1022, 746, 712,
699 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 0.86–0.95 (m, 6H, CH3 CH2), 1.19–1.49 (m, 4H, CH3 CH2), 1.58–
1.63 (m, 1H, CH CHN), 5.00–5.17 (m, 4H, NH , CH NH, CH2 OC=O), 6.90–6.93 (m, 1H, arom CH), 6.94 (dd,
1H, J = 3.5, 5.0 Hz, arom CH), 7.18 (dd, 1H, J = 1.1, 5.0 Hz, arom CH) 7.26–7.35 (m, 5H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 11.67, 11.70 (C H3), 21.93, 22.74 (CH3C H2), 47.43 (C HCHN),
53.40 (C HN), 67.13 (C H2 OC=O), 124.12, 126.63, 127.02, 128.37, 128.78, (arom C H), 136.82, 146.62 (arom
C), 156.30 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 317 (4) [M+• ], 247 (5), 246 (32), 226 (6), 202 (24), 92 (8), 91 (100).
Anal. Calcd for C18 H23 NO2 S: C, 68.10; H, 7.30; N, 4.41. Found: C, 67.96; H, 7.45; N, 4.45.
2.23. (1S)-(Ferrocenyl-thiophen-2-yl-methyl)-carbamic acid benzyl ester (5f)
To a solution of 2-lithio-thiophene (3.2 mmol) in Et2 O (10 mL) was added hydrazone 2g (326 mg, 1.0 mmol)
dissolved in Et2 O (2 mL) according to GP2. After cleavage of the chiral auxiliary purification by column
chromatography (Et2 O:pentane 1:6) gave 5f (210 mg, 49%) as an orange solid. ee ≥ 95% (based on 1 H NMR
of the corresponding hydrazine); mp 85–87 ◦ C; [α]D22 –38.8 (c 1.1, CHCl3).
IR (KBr): u˜ = 3355, 1693, 1514, 1227, 1019, 819, 751, 698, 485 cm−1
1 H NMR (300 MHz, CDCl3): δ = 4.10–4.56 (m, 9H, CH Fc), 5.16 (d, 1H, J = 12.3 Hz, CHH OC=O),
.
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5.24 (d, 1H, J = 12.3 Hz CHH OC=O), 5.56–5.59 (br 1H, CH N), 5.97–6.00 (br, 1H, NH), 6.95–6.98 (m, 2H,
arom CH), 7.23–7.28 (m, 1H, arom CH), 7.38–7.42 (m, 5H, arom CH) ppm.
13 C NMR (75 MHz, CDCl3): δ = 50.26 (C HN), 66.89 (C H, Fc), 67.13 (C H2 O), 67.29, 68.10, 68.16,
69.03 (C H, Fc), 90.34 (C , Fc), 124.31, 125.05, 126.43, 128.17, 128.54 (arom C H), 136.45, 146.15 (arom C),
155.25 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 433 (9) [M+•+2], 432 [M+•+1], 431 (100) [M+• ], 429 (7), 296 (12), 230
(8), 226 (11), 217 (9), 212 (19), 160 (7), 121 (11), 91 (13), 56 (6).
Anal. Calcd for C23 H21 FeNO2 S: C, 64.04; H, 4.91; N, 3.25. Found: C, 64.34; H, 5.21; N, 3.16.
2.24. (1S)-[1-(1-Methyl-1H -pyrrol-2-yl)-pentyl]-carbamic acid benzyl ester (5g)
To a solution of 2-lithio-1-methylpyrrole (6.4 mmol) in THF (20 mL) was added hydrazone 2b (396 mg, 2.0
mmol) dissolved in THF (4 mL) according to GP2. After cleavage of the chiral auxiliary purification by column
chromatography (Et2 O:pentane 1:2) gave 5g (210 mg, 35%) as a colorless solid. ee = 92%; mp 67–68 ◦ C;
[α]2D2 –65.3 (c 1.0, CHCl3).
IR (KBr): u˜ = 3313, 2950, 2925, 2869, 2858, 1682, 1532, 1466, 1412, 1335, 1298, 1247, 1231, 1100, 1047,
1009, 750, 721, 697, 669 cm−1
.
1 H NMR (300 MHz, CDCl3): δ = 0.89 (t, 3H, J = 7.4 Hz, CH3 CH2), 1.32–1.40 (m, 4H, CH3 CH2 CH2),
1.78–1.95 (m, 2H, CH2 CHN), 3.55 (s, 3H, NCH3), 4.69–4.82 (m, 2H, CH N, NH), 5.09 (s, 2H, CH2 OC=O),
6.02–6.05 (m, 2H, arom CH ,), 6.56–6.57 (m, 1H, arom CH), 7.27–7.33 (m, 5H, arom CH) ppm.
13 C NMR (75 MHz, CDCl3): δ = 14.28 (C H3 CH2), 22.76 (CH3C H2), 28.73 (CH3 CH2C H2), 34.07
(NC H3), 35.14 (C H2 CHN), 47.27 (C HN), 66.92 (C H2 OC=O), 105.86, 106.93, 122.79, 128.26, 128.36, 128.76
(arom C H), 133.45, 136.85, (arom C), 155.90 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 301 (7) [M+•+1], 300 (36) [M+• ], 244 (6), 243 (40), 209 (13), 199 (30),
165 (12), 107 (8), 94 (8), 92 (8), 91 (100), 82 (15).
Anal. Calcd for C18 H24 N2 O2 : C, 71.97; H, 8.05; N, 9.32. Found: C, 71.72; H, 7.69; N, 9.08.
2.25. (1S)-[1-(1-Methyl-1H -pyrrol-2-yl)-3-phenyl-propyl]-carbamic acid benzylester (5h)
To a solution of 2-lithio-1-methylpyrrole (6.4 mmol) in THF (20 mL) was added hydrazone 2c (492 mg, 2.0
mmol) dissolved in THF (4 mL) according to GP2. After cleavage of the chiral auxiliary purification by column
chromatography (Et2 O:pentane 1:2) gave 5h (250 mg, 36%) as a colorless solid. ee = 99%; mp 92–93 ◦ C;
[α]2D2 –48.1 (c 2.0, CHCl3).
IR (KBr): u˜ = 3309, 1681, 1535, 1495, 1454, 1331, 1297, 1255, 1244, 1045, 1029, 754, 720, 699 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 2.12–2.29 (m, 2H, CH2 CH2 CH), 2.80 (t, 2H, J = 8.3 Hz, PhCH2),
3.57 (s, 3H, NCH3), 4.89–4.93 (m, 2H, CH N, NH), 5.19 (s, 2H, CH2 OC=O), 6.13–6.15 (m, 2H, arom CH),
6.63–6.64 (m, 1H, arom CH), 7.18–7.44 (m, 10 H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 33.13 (PhC H2), 34.19 (NC H3), 37.26 (C H2 CH), 47.14 (C HN),
67.11 (C H2 OC=O), 106.14, 107.16, 122.95, 126.28, 128.33, 128.44, 128.73, 128.82 (arom C H), 132.92, 136.83,
141.76 (arom C), 155.84 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 349 (11) [M+•+1], 348 (46) [M+• ], 257 (11), 243 (33), 213 (11), 199 (29),
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107 (6), 92 (7), 91 (100), 82 (8), 65 (5).
Anal. Calcd for C22 H24 N2 O2 : C, 75.83; H, 6.94; N, 8.04. Found: C, 75.41; H, 6.72; N, 7.86.
2.26. (1S)-[2,2-Dimethyl-1-(1-methyl-1H -Pyrrol-2-yl)-propyl]-carbamic acid benzyl ester (5i)
To a solution of 2-lithio-1-methylpyrrole (6.4 mmol) in THF (20 mL) was added hydrazone 2d (396 mg, 2.0
mmol) dissolved THF (in 4 mL) according to GP2. After cleavage of the chiral auxiliary purification by column
chromatography (Et2 O:pentane 1:2) gave 5i (150 mg, 25%) as a colorless oil. ee = 88%; [α]2D2 –18.6 (c 1.0,
CHCl3).
IR (KBr): u˜ = 3332, 3032, 2958, 2871, 1713, 1511, 1455, 1419, 1394, 1365, 1325, 1304, 1234, 1125, 1091,
1050, 1028, 1007, 915, 774, 753, 698, 678, 610 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 0.96 (s, 9H, (CH3)3 C), 3.64 (s, 3H, NCH3), 4.65 (d, 1H, J = 9.6
Hz, CH N), 5.01–5.15 (m, 3H, NH , CH2 OC=O), 5.97 (dd, 1H, J = 1.6, 3.6 Hz, arom CH ,), 6.06 (t, 1H, J =
3.6 Hz arom CH), 6.50–6.52 (m, 1H, arom CH), 7.27–7.33 (m, 5H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 26.79 (C H3 C), 34.79 (NC H3), 36.57 (C CHN), 55.50 (C HN), 67.19
(C H2 OC=O), 106.14, 106.95, 121.59, 128.37, 128.41, 128.75 (arom C H), 132.92, 136.61, (arom C), 156.33
(C =O) ppm.
MS (EI, 70 eV): m/z (%) = 300 (10) [M+• ], 244 (14), 243 (90), 200 (5), 199 (39), 172 (12), 135 (7), 107
(7), 92 (9), 91 (100).
Anal. Calcd for C18 H24 N2 O2 : C, 71.97; H, 8.05; N, 9.32. Found: C, 71.74; H, 8.16; N, 9.01.
2.27. (1S)-[2-Ethyl-1-(1-methyl-1H -pyrrol-2-yl)-butyl]-carbamic acid benzyl ester (5j)
To a solution of 2-lithio-1-methylpyrrole (6.4 mmol) in THF (20 mL) was added hydrazone 2e (424 mg, 2.0
mmol) dissolved in THF (4 mL) according to GP2. After cleavage of the chiral auxiliary purification by column
chromatography (Et2 O:pentane 1:2) gave 5j (333 mg, 53%) as a colorless oil. ee = 90%; [α]2D2 –27.7 (c 1.5,
CHCl3).
IR (KBr): u˜ = 3338, 2961, 2933, 2875, 1702, 1530, 1456, 1329, 1298, 1253, 1136, 1092, 1021, 736, 698
cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 0.89 (t, 6H, J = 7.4 Hz, CH3 CH2), 1.69–1.86 (m, 4H, CH3 CH2),
3.44 (s, 3H, NCH3), 4.58–4.72 (m, 2H, CH N, NH), 4.99 (s, 2H, CH2 OC=O), 5.91–5.95 (m, 2H, arom CH),
6.44–6.45 (m, 1H, arom CH), 7.17–7.26 (m, 5H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 11.40 (C H3 CH2), 28.51 (CH3C H2), 34.16 (NC H3), 48.91 (C HN),
66.98 (C H2 OC=O), 105.94, 106.97, 122.80, 128.24, 128.33, 128.74 (arom C H), 133.17, 136.86, (arom C),
155.92 (C =O) ppm.
MS (EI, 70 eV): m/z (%) = 314 (14) [M+• ], 244 (16), 243 (99), 199 (41), 172 (10), 107 (7), 94 (5), 92
(8), 91 (100).
Anal. Calcd for C19 H26 N2 O2 : C, 72.58; H, 8.33; N, 8.91. Found: C, 73.03; H, 8.55; N, 8.90.
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2.28. (S)-N -(1-Furan-2-yl-pentyl)-benzamide (7a)
A solution of hydrazine 6a (370 mg, 1 mmol) in THF (10 mL) was treated with 2 equiv of SmI2 (0.1 M in THF)
and an equimolar amount of DMPU according to GP4. After work-up and flash chromatography (Et2 O:pentane
2:3) 7a was obtained as a colorless solid (215 mg, 84%). ee = 96%; mp 95–96 ◦ C; [α]D22 –60.0 (c 1.2, CHCl3).
IR (KBr): u˜ = 3297, 2954, 2932, 2856, 1635, 1579, 1537, 1465, 1382, 1340, 1308, 1222, 1183, 1151, 1077,
1008, 802, 731, 696 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 0.81 (t, 3H, J = 7.0 Hz, CH3 CH2), 1.21–1.31 (m, 4H, CH3 CH2 CH2),
1.81–1.89 (CH2 CHN), 5.20–5.27 (m, 1H, CH N), 6.10 (dt, 1H, J = 0.8, 3.0 Hz, CH CHCO), 6.21 (dd, 1H, J =
1.6, 3.0 Hz, CH CHO), 6.40–6.44 (br, 1H, NH), 7.27 (dd, 1H, J = 0.8, 1.6 Hz, arom CH), 7.31–7.36 (m, 2H,
arom CH), 7.39–7.43 (m, 1H, arom CH), 7.69–7.71 (m, 2H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 14.33 (C H3 CH2), 22.74 (CH3C H2), 28.44 (CH3 CH2C H2), 34.16
(C H2 CHN), 47.96 (C HN), 106.55, 110.41, 127.20, 128.72, 131.69 (arom C H), 134.64 (arom C), 141.97 (arom
C H), 154.63 (arom C), 166.74 (C =O) ppm.
MS (EI, 70 eV)m/z (%) = 257 (7) [M+• ], 200 (14), 106 (8), 105 (100), 77 (28).
Anal. Calcd for C16 H19 NO2 : C, 74.68; H, 7.44; N, 5.44. Found: C, 74.41; H, 7.42; N, 5.42.
2.29. (S)-N -(1-Furan-2-yl-3-phenyl-propyl)-benzamide (7b)
A solution of hydrazine 6b (420 mg, 1 mmol) in THF (10 mL) was treated with 2 equiv of SmI2 (0.1M in THF)
and an equimolar amount of DMPU according to GP4. After work-up and flash chromatography (Et2 O:pentane
1:2) 7b was obtained as a colorless solid (245 mg, 80%). ee = 96%; mp 120–121 ◦ C; [α]D22 –34.8 (c 1.2, CHCl3).
IR (KBr): u˜ = 3309, 1631, 1577, 1523, 1488, 1341, 1283, 744, 697 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 2.12–2.20 (m, 2H, CH2 CHN), 2.50–2.63 (m, 2H, PhCH2), 5.24–5.31
(m, 1H, CH NH), 6.12 (d, 1H, J = 3.3 Hz, CH CHCO), 6.21 (dd, 1H, J = 1.9, 3.3 Hz, CH CHO), 6.60–6.63
(br, 1H, NH), 7.05–7.08 (m, 3H, arom CH), 7.14–7.17 (m, 2H, arom CH), 7.22–7.28 (m, 3H, arom CH),
7.33–7.37 (m, 1H, arom CH), 7.61–7.63 (m, 2H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 32.68 (PhC H2 CH2), 35.88 (CH2C H2), 47.88 (C HN), 106.86,
110.51, 126.24, 127.29, 128.62, 128.69, 128.71, 131.72 (arom C H), 134.52, 141.50 (arom C), 142.13 (arom C H),
154.31 (arom C), 166.88 (C =O) ppm.
MS (EI, 70 eV)m/z (%) = 306 (8) [M+•+1], 305 (37) [M+• ], 214 (18), 201 (12), 200 (16), 184 (5), 105
(100), 91 (8), 77 (24).
Anal. Calcd for C20 H19 NO2 : C, 78.66; H, 6.27; N, 4.58. Found: C, 78.56; H, 6.11; N, 4.50.
2.30. (S)-N -(1-Furan-2-yl-2,2-dimethyl-propyl)-benzami de (7c)
A solution of hydrazine 6c (370 mg, 1 mmol) in THF (5 mL) was treated with 2 equiv of SmI2 (0.1 M in THF)
and an equimolar amount of DMPU according to GP4. After work-up and flash chromatography (Et2 O:pentane
1:3) 7c was obtained as a colorless solid (195 mg, 76%). ee = 99%, mp 87–89 ◦ C; [α]D22 –43.1 (c 1.3, CHCl3).
IR (KBr): u˜ = 3325, 2966, 1638, 1603, 1578, 1544, 1503, 1448, 1473, 1334, 1148, 1010, 725, 691, 658
cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 0.92 (s, 9H, CH3 C), 5.08 (d, J = 9.9 Hz, 1H, CH N), 6.10 (d, 1H,
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J = 3.3 Hz, CH CHCO), 6.21 (dd, 1H, J = 1.9, 3.3 Hz, CH CHO), 6.62–6.64 (br, 1H, NH), 7.23–7.24 (m, 1H,
arom CH), 7.29–7.33 (m, 2H, arom CH), 7.35–7.40 (m, 1H, arom CH), 7.67–7.70 (m, 2H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 27.07 (C H3 C), 36.27 (CH3C), 56.04 (C HN), 107.80, 110.28, 127.19,
128.78, 131.69 (arom C H), 134.90 (arom C), 141.61 (arom C H), 153.28 (arom C), 166.86 (C =O) ppm.
MS (EI, 70 eV)m/z (%) = 257 (8) [M+• ], 201 (22), 200 (87), 106 (7), 105 (100), 77 (22), 50 (5).
Anal. Calcd for C16 H19 NO2 : C, 74.68; H, 7.44; N, 5.44. Found: C, 74.54; H, 7.67; N, 5.42.
2.31. (1S,2R)-N -(1-Furan-2-yl-2-methyl-pentyl)-benzami de (7d)
A solution of hydrazine 6d (384 mg, 1.0 mmol) in THF (10 mL) was treated with 2 equiv of SmI2 (0.1 M
in THF) and an equimolar amount of DMPU according to GP4. After work-up and flash chromatography
(Et2 O:pentane 1:4) 7d was obtained as a colorless solid (217 mg, 80%). ee = 99%, de ≥ 96%; mp 95–96 ◦ C;
[α]2D2 –45.3 (c 1.0, CHCl3).
IR (KBr): u˜ = 3350, 2957, 2930, 2871, 1634, 1579, 1524, 1487, 1463, 1329, 1289, 1148, 1013, 805, 736,
716, 691 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 0.79 (t, 3H, J = 6.9 Hz, CH3 CH2), 0.90 (d, 2H, J = 6.9 Hz,
CH3 CH), 1.00–1.35 (m, 4H, CH3 CH2 CH2), 2.01–2.08 (m, 1H, CH CH3), 5.23 (dd, 1H, J = 6.7, 9.4 Hz,
CH N), 6.12 (dt, 1H, J = 0.7, 3.2 Hz, CH CHCO), 6.23 (dd, 1H, J = 1.7, 3.2 Hz, CH CHO), 6.39 (d, 1H, J =
9.4 Hz, NH), 7.26 (dd, 1H, J = 0.7, 1.7 Hz, arom CH), 7.32–7.44 (m, 3H, arom CH), 7.69–7.72 (m, 2H, arom
CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 14.62 (C H3 CH2), 16.03 (C H3 CH), 20.59 (CH3C H2), 35.89
(CH3 CH2C H2), 37.25 (C HCH3), 52.34 (C HN), 106.93, 110.02, 127.17, 128.81, 131.74 (arom C H), 134.80
(arom C), 141.80 (arom C H), 154.06 (arom C), 166.88 (C =O) ppm.
MS (EI, 70 eV)m/z (%) = 271 (11) [M+• ], 233 (10), 201 (10), 200 (77), 106 (7), 105 (100), 77 (23).
Anal. Calcd for C17 H21 NO2 : C, 75.25; H, 7.80; N, 5.16. Found: C, 75.00; H, 7.99; N, 5.07.
2.32. (1S)-N -(1-Furan-2-yl-ethyl)-benzamide (7e)
A solution of hydrazine 6e (328 mg, 1 mmol) in THF (10 mL) was treated with 2 equiv of SmI2 (0.1 M in THF)
and an equimolar amount of DMPU according to GP4. After work-up and flash chromatography (Et2 O:pentane
1:1) 7e was obtained as a colorless solid (195 mg, 90 %). ee = 98%; mp 105–106; [α]2D2 –53.4 (c 1.3, CHCl3).
IR (KBr): u˜ = 3339, 1636, 1578, 1520, 1485, 1316, 1151, 1008, 925, 813, 740, 720, 695 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 1.51 (d, 3H, J = 6.9 Hz, CH3 CH), 5.30–5.42 (m, 1H, CH N), 6.16
(dt, 1H, J = 0.7, 3.2 Hz, CH CHCO), 6.25 (dd, 1H, J = 1.7, 3.2 Hz, CH CHO), 6.31–6.34 (br, 1H, NH), 7.29
(dd, 1H, J = 0.7, 1.7 Hz, arom CH), 7.30–7.44 (m, 3H, arom CH), 7.68–7.71 (m, 2H, arom CH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 20.10 (C H3 CH), 43.78 (C HN), 106.05, 110.50, 127.18, 128.76,
131.74 (arom C H), 134.59 (arom C), 142.18 (arom C H), 155.45 (arom C), 166.40 (C =O) ppm.
MS (EI, 70 eV)m/z (%) = 216 (6) [M+•+1], 215 (40) [M+• ], 189 (5), 106 (8), 105 (100), 95 (11), 94
(10), 77 (29), 50 (12).
Anal. Calcd for C13 H13 NO2 : C, 72.54; H, 6.09; N, 6.51. Found: C, 72.54; H, 6.26; N, 6.46.
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2.33. (S)-N -[4-(tert-Butyl-dimethyl-silanyloxy)-1-furan-2-yl-butyl]-benzamide (7f)
A solution of hydrazine 6f (486 mg, 1 mmol) in THF (10 mL) was treated with 2 equiv of SmI2 (0.1 M in THF)
and an equimolar amount of DMPU according to GP4. After work-up and flash chromatography (Et2 O:pentane
3:7, then AcOEt) 2 products were obtained: 7f (150 mg, 40%) and 7f1 (52 mg, 20%) as colorless solids. ee =
90%; mp 102–104 ◦ C; [α]D22 –40.0 (c 1.1, CHCl3).
IR (KBr): u˜ = 3316, 2953, 2931, 2886, 2859, 1635, 1604, 1580, 1538, 1492, 1470, 1304, 1254, 1098, 1008,
838, 776, 733, 695 cm−1
.
1 H NMR (300 MHz, CDCl3): δ = 0.01 (s, 6H, CH3 Si), 0.89 (s, 9H, (CH3)3 CSi), 1.53–1.71 (m, 2H,
CH2 CH2 OSi), 1.95–2.07 (m, 2H. CH2 CHNH), 3.66 (dt, 2H, J = 1.4, 6.3 Hz, CH2 OSi), 5.30–5.38 (m, 1H,
CH N), 6.25 (d, 1H, J = 3.3 Hz, CH CHCO), 6.30 (dd, 1H, J = 1.9, 3.3 Hz, CH CHO), 6.49 (d, 1H, J = 8.2
Hz, NH), 7.36–7.52 (m, 4H, arom CH), 7.76–7.79 (m, 2H, arom CH) ppm.
13 C NMR (75 MHz, CDCl3): δ = –5.29, –5.27 (C H3 Si), 18.35 (C Si), 25.98 (C H3 CSi), 29.17
(C H2 CH2 OSi), 30.55 (C H2 CHNH), 47.52 (C HN), 62.69 (C H2 OSi), 106.39, 110.23, 127.02, 128.56, 131.51
(arom C H), 134.55 (arom C), 141.86 (arom C H), 154.44 (arom C), 166.65 (C =O) ppm.
MS (EI, 70 eV)m/z (%) = 373 (2) [M+• ], 316 (19), 269 (12), 268 (59), 195 (12), 180 (5), 179 (15), 178
(100), 165 (13), 136 (30), 135 (7), 121 (8), 105 (40), 77 (17), 75 (18).
Anal. Calcd for C21 H31 NO3 Si: C, 67.52; H, 8.36; N, 3.75. Found: C, 67.63; H, 8.36; N, 3.77.
2.34. (S)-N -(1-Furan-2-yl-4-hydroxy-butyl)-benzamide (7f1)
ee = 90%; mp 100–102 ◦ C; [α]D22 –48.8 (c 0.8, CHCl3).
IR (KBr): u˜ = 3292, 3058, 2946, 2924, 1632, 1530, 1488, 1055, 1007 741, 700 cm−1
.
1 H NMR (300 MHz, CDCl3): δ = 1.55–1.68 (m, 2H, CH2 CH2 OH), 2.01 (q, 2H, J = 7.4 Hz,
CH2 CHNH), 2.80–2.90 (br, 1H, OH), 3.64 (t, 2H, J = 6.2 Hz, CH2 OH), 5.28–5.37 (m, 1H, CH N), 6.21
(d, 1H, J = 3.2 Hz, CH CHCO), 6.29 (dd, 1H, J = 2.0, 3.2 Hz, CH CHO), 6.90–6.95 (br, 1H, NH), 7.32–7.48
(m, 4H, arom CH), 7.74–7.78 (m, 2H, arom CH) ppm.
13 C NMR (75 MHz, CDCl3): δ = 28.67 (C H2 CH2 OH), 30.52 (C H2 CHNH), 47.49 (C HN), 62.06
(C H2 OSi), 106.46, 110.25, 127.08, 128.51, 131.57 (arom C H), 134.22 (arom C), 141.89 (arom C H), 154.23
(arom C), 167.04 (C =O) ppm.
MS (EI, 70 eV)m/z (%) = 259 (4) [M+• ], 200 (16), 155 (5), 154 (60), 138 (6), 106 (8), 105 (100), 77
(26).
Anal. Calcd for C15 H17 NO3 : C, 69.48; H, 6.61; N, 5.40. Found: C, 69.11; H, 6.57; N, 5.40.
2.35. (1R)-N -(1-Furan-2-yl-ethyl)-benzamide [(R)-7e]
A solution of hydrazine 6g (328 mg, 1 mmol) in THF (10 mL) was treated with 2 equiv of SmI2 (0.1 M in THF)
and an equimolar amount of DMPU according to GP4. After work-up and flash chromatography (Et2 O:pentane
1:1) 7g was obtained as a colorless solid (175 mg, 81%). ee = 98%; mp 105–106 ◦ C; [α]D22 –52.9 (c 0.8, CHCl3).
Anal. Calcd for C13 H13 NO2 : C, 72.54; H, 6.09; N, 6.51. Found: C, 72.36; H, 6.18; N, 6.45.
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2.36. (S)-2-Benzoylamino-hexanoic acid (8a)
Benzamide 7a (150 mg, 0.58 mmol) was added to a stirred solution of RuCl3·H2 O (2.6 mg, 2 mol %) and
NaIO4 (1.87 g, 8.75 mmol) in 20 mL of a CH2 Cl2 /MeCN/H2 O (1.0:0.04:0.7) mixture, according to GP5.
After work-up and purification by flash chromatography (CH2 Cl2 :MeOH 9:1), 8a (96 mg, 70%) was obtained
as a colorless solid. ee = 96%; mp 95–96; [α]2D2 –26.3 (c 1.4, CHCl3).
IR (KBr): u˜ = 3427, 3322, 3065, 2974, 1727, 1647, 1577, 1531, 1489, 1345, 1215, 1161, 1074, 758, 714,
692, 667 cm−1
.
1 H NMR (300 MHz, CDCl3): δ = 0.88 (t, 3H, J = 7.1 Hz, CH3 CH2), 1.30–1.43 (m, 4H, CH3 CH2 CH2),
1.76–1.86 (m, 1H, CH HCHN), 1.95–2.06 (m, 1H, CHH CHN), 4.79 (dt, 1H, J = 5.2, 7.4 Hz, CH N), 7.03 (d,
1H, J = 7.4 Hz, NH), 7.38–7.47 (m, 2H, arom CH), 7.47–7.51 (m, 1H, arom CH), 7.77–7.80 (m, 2H, arom
CH), 9.75–9.85 (br, 1H, OH) ppm.
13 C NMR (75 MHz, CDCl3): δ = 14.23 (C H3 CH2), 22.69 (CH3C H2), 27.71 (CH3 CH2C H2), 32.21
(C H2 CHN), 53.18 (C HN), 127.41, 128.83, 132.20 (arom C H), 133.67 (arom C), 168.24 (C =O), 175.99
(C OOH) ppm.
MS (EI, 70 eV)m/z (%) = 235 (2) [M+• ], 190 (15), 179 (26), 161 (11), 148 (5), 106 (8), 105 (100), 77
(29), 51 (10), 45 (6).
HRMS: m/z calcd for C13 H17 NO3 : 235.1208. Found: 235.1299.
2.37. (S)-2-Benzoylamino-4-phenyl-butyric acid (8b)
Benzamide 7b (200 mg, 0.65 mmol) was added to a stirred solution of RuCl3·H2 O (2.9 mg, 2 mol %) and
NaIO4 (2.0 g, 9.75 mmol) in 20 mL of a CH2 Cl2 /MeCN/H2 O (1.0:0.04:0.7) mixture according to GP5. After
work-up and crystallization (CH2 Cl2), 8b was obtained as a colorless solid (167 mg, 90%). ee = 96%; mp
160–161 ◦ C; [α]D22 +29.5 (c 1.8, CHCl3).
IR (KBr): u˜ = 3395, 1742, 1634, 1577, 1526, 1452, 1397, 1246, 1206, 753, 695 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 2.04–2.33 (m, 2H, CH2 CHN), 2.67 (t, 2H, J = 8.0 Hz, PhCH2),
4.75–4.82 (m, 1H, CH NH), 6.78 (d, 1H, J = 7.7 Hz, NH), 7.09–7.43 (m, 8H, arom CH), 7.54–7.60 (m, 2H,
arom CH), 9.90–10.21 (br, 1H, OH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 32.00 (PhC H2 CH2), 33.71 (CH2C H2), 53.08 (C HN), 126.53,
127.43, 128.72, 128.89, 133.82 (arom C H), 133.55, 140.91 (arom C), 168.25 (C =O), 176.02 (C OOH) ppm.
MS (EI, 70 eV)m/z (%) = 283 (2) [M+• ], 180 (8), 179 (78), 162 (6), 161 (59), 148 (5), 133 (8), 122 (6),
106 (9), 105 (100), 91 (10), 77 (39), 57 (6), 51 (13).
HRMS: m/z calcd for C17 H17 NO3 (M+): 283.1208. Found: 283.1208.
2.38. (S)-2-Benzoylamino-3,3-dimethyl-butyric acid (8c)
Benzamide 7c (150 mg, 0.58 mmol) was added to a stirred solution of RuCl3·H2 O (2.6 mg, 2 mol %) and
NaIO4 (1.87 g, 8.75 mmol) in 20 mL of a CH2 Cl2 /MeCN/H2 O (1.0:0.04:0.7) mixture, according to GP5.
After work-up and crystallization (CH2 Cl2), 8c was obtained as a colorless solid (105 mg, 77%). ee = 98%;
mp 128–130 ◦ C; [α]D22 +32.0 (c 1.4, CHCl3).
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IR (KBr): u˜ = 3425, 3361, 3065, 2967, 1724, 1643, 1578, 1527, 1488, 1371, 1337, 1218, 1174, 1088, 757,
714, 693 cm−1
.
1 H NMR (300 MHz, CDCl3): δ = 1.01 (s, 9H, CH3 C), 4.64 (d, 1H, J = 9.3 Hz, CH N), 6.71 (d, 1H,
J = 9.3 Hz, NH), 7.34–7.38 (m, 2H, arom CH), 7.42–7.46 (m, 1H, arom CH), 7.70–7.73 (m, 2H, arom CH),
8.24–8.44 (br, 1H, OH) ppm.
13 C NMR (75 MHz, CDCl3): δ = 26.88 (C H3 C), 35.28 (CH3C), 60.67 (C HN), 127.35, 128.93, 132.18
(arom C H), 134.11 (arom C), 168.15 (C =O), 175.37 (C OOH) ppm.
MS (EI, 70 eV)m/z (%) = 220 (1) [M+• –CH3 ], 180 (9), 179 (89), 162 (10), 161 (100), 133 (10), 106
(9), 105 (91), 77 (29), 57 (20), 51 (7).
HRMS: m/z calcd for C12 H14 NO3 (M+ –CH3): 220.0974. Found: 220.0973.
2.39. (2S,3R)-2-Benzoylamino-3-methyl-hexanoic-acid (8d)
Benzamide 7d (180 mg, 0.66 mmol) was added to a stirred solution of RuCl3·H2 O (3 mg, 2 mol %) and NaIO4
(2.13 g, 9.96 mmol) in 20 mL of a CH2 Cl2 /MeCN/H2 O (1.0:0.04:0.7) mixture, according to GP5. After work-
up and crystallization (CH2 Cl2), 8d (135 mg, 82%) was obtained as a colorless solid. ee = 99%, de ≥ 96%;
mp 117–119 ◦ C; [α]D22 +39.5 (c 1.3, CHCl3).
IR (KBr): u˜ = 3314, 3228, 3065, 2960, 2928, 2871, 1729, 1642, 1603, 1543, 1352, 1232, 1199, 1075, 862,
836, 737, 722, 691 cm−1
.
1 H NMR (300 MHz, CDCl3): δ = 0.82 (t, 3H, J = 7.1 Hz, CH3 CH2), 0.90 (d, 2H, J = 6.9 Hz,
CH3 CH), 1.08–1.45 (m, 4H, CH3 CH2 CH2), 2.11–2.24 (m, 1H, CH CH3), 4.82 (dd, 1H, J = 3.9, 8.7 Hz,
CH N), 6.63 (d, 1H, J = 8.7 Hz, NH), 7.34–7.47 (m, 3H, arom CH), 7.70–7.74 (m, 2H, arom CH), 8.31–8.49
(br, 1H, OH) ppm.
13 C NMR (75 MHz, CDCl3): δ = 14.30 (C H3 CH2), 15.26 (C H3 CH), 20.52 (CH3C H2), 35.78
(CH3 CH2C H2), 35.96 (C HCH3), 56.48 (C HN), 127.38, 128.89, 132.11 (arom C H), 134.26 (arom C), 168.19
(C =O), 176.35 (C OOH) ppm.
MS (EI, 70 eV)m/z (%) = 249 (3) [M+• ], 204 (15), 179 (37), 162 (8), 161 (42), 133 (5), 122 (16), 106
(8), 105 (100), 77 (35), 57 (7), 55 (5), 51 (15).
HRMS: m/z calcd for C14 H19 NO3 : 249.1364. Found: 249.1365.
2.40. (S)-N-Benzoylalanine (8e)
Benzamide 7e (140 mg, 0.65 mmol) was added to a stirred solution of RuCl3·H2 O (2.9 mg, 2 mol %) and
NaIO4 (2.09 g, 9.76 mmol) in 20 mL of CH2 Cl2 /MeCN/H2 O (1.0:0.04:0.7) according to GP5. After work-up
and crystallization (CH2 Cl2), 8e (108 mg, 86%) was obtained as a colorless solid. ee = 98%; mp 148–149 ◦ C,
[α]2D2 +29.1 (c 1.0, CHCl3).
IR (KBr u˜ = 3409, 1727, 1632, 1576, 1550, 1491, 1460, 1411, 1338, 1218, 1171, 1129, 904, 707, 689, 624
cm−1
.
1 H NMR (300 MHz, CDCl3): δ = 1.54 (d, 3H, J = 7.1 Hz, CH3 CH), 4.72–4.79 (m, 1H, CH N), 6.91
(d, 1H, J = 6.9 Hz, NH), 7.38–7.53 (m, 3H, arom CH), 7.75–7.78 (m, 2H, arom CH), 8.42–8.50 (br, 1H,
OH) ppm.
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13 C NMR (75 MHz, CDCl3): δ = 18.43 (C H3 CH), 48.96 (C HN), 127.40, 128.92, 132.30 (arom C H),
133.62 (arom C), 168.04 (C =O), 176.56 (C OOH) ppm.
MS (EI, 70 eV)m/z (%) = 193 (8) [M+• ], 149 (15), 148 (44), 106 (8), 105 (100), 77 (37), 51 (15), 45
(5).
HRMS: m/z calcd for C10 H11 NO3 : 193.0739. Found: 193.0739.
2.41. (S)-2-Benzoylamino-butyric acid (8f)
Benzamide 4j (150 mg, 0.65 mmol) was added to a stirred solution of RuCl3·H2 O (2.9 mg, 2 mol %) and
NaIO4 (2.0 g, 9.75 mmol) in 20 mL of a CH2 Cl2 /MeCN/H2 O (1.0:0.04:0.7) mixture according to GP5. After
work-up and flash chromatography (CH2 Cl2 :MeOH 9:1), 8f was obtained as a colorless solid (117 mg, 86%).
ee = 99%; mp 140–142 ◦ C; [α]D22 +20.5 (c 1.1, CHCl3).
IR (KBr): u˜ = 3340, 2959, 2931, 2864, 1726, 1643, 1536, 1489, 758, 715 cm−1
.
1 H NMR (400 MHz, CDCl3): δ = 0.98 (t, 3H, J = 7.4 Hz, CH3 CH2), 1.80–1.93 (m, 1H, CH3 CHH),
2.00–2.09 (m, 1H, CH3 CH H), 4.74–4.79 (m, 1H, CH NH), 6.99 (d, 1H, J = 7.7 Hz, NH), 7.39–7.43 (m, 2H,
arom CH), 7.48–7.52 (m, 1H, arom CH), 7.78–7.80 (m, 2H, arom CH), 8.90–9.16 (br, 1H, OH) ppm.
13 C NMR (100 MHz, CDCl3): δ = 9.92 (C H3 CH2), 25.68 (CH3C H2), 54.22 (C HN), 127.38 128.85,
132.22 (arom C H), 133.68 (arom C), 168.24 (NHC =O), 175.72 (C OOH).
MS (EI, 70 eV)m/z (%) = 207 (7) [M+• ], 179 (8), 163 (5), 162 (19), 106 (8), 105 (100), 77 (32), 51
(14), 45 (10).
HRMS: m/z calcd for C11 H13 NO3 (M+): 207.0895. Found: 207.0896.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft (SFB 380, Graduiertenkolleg 440) and the
Fonds der Chemischen Industrie. We thank the former Degussa AG, BASF SE, and Bayer AG for the donation
of chemicals.
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25. The crystallographic data of 4l have been deposited as supplementary publication no. CCDC 925048 at the Cam-
bridge Crystallographic Data Centre. These data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data request/cif or on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK [fax: +44-1223-336033; e-mail: deposit@ccdc.cam.ac.uk].
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26. a) Enders, D.; Schubert, H.; Nu¨bling, C. Angew. Chem. Int. Ed. Engl. 1986, 25, 1109. b) Enders, D.; Tiebes, J.
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Synthesis 2002, 2542.
27. In order to determine the ee of the (S)-furyl amines by chiral stationary phase HPLC, the R-enantiomers were
prepared using RAMP-aldehyde hydrazones.
28. For contributions of Prof AS Demir to the development of the SAMP/RAMP-hydrazone methodology, see: a)
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