Asymmetric organocatalytic Strecker-type reactions of aliphatic N,N-dialkylhydrazones

Article abstract of DOI:10.1039/c3ob41437j

The enantioselective organocatalytic Strecker-type reaction of aliphatic N,N-dialkylhydrazones is presented. Using trimethylsilyl cyanide (TMSCN) as the cyanide source, the reaction can be efficiently catalyzed by a tert-leucine-derived bifunctional thiourea to afford the corresponding hydrazino nitriles in good to excellent yields (50-96%) and moderate to good enantioselectivities, up to 86% ee. Further transformations of the nitrile functionality allow access to useful protected hydrazino acids and imidazolidinones. Interestingly, some of the hydrazino nitriles and their derivatives could be recrystallized in high recovery, yielding essentially pure enantiomers.

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ARTICLE TYPE
Asymmetric Organocatalytic Strecker-Type Reactions of Aliphatic N,N-
Dialkylhydrazones
Aurora Martínez-Muñoz,a David Monge,*,a Eloísa Martín-Zamora,a Eugenia Marqués-López,a Eleuterio
Álvarez,b Rosario Fernández,*,a and José M. Lassaletta*,b
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
The enantioselective organocatalytic Strecker-type reaction of aliphatic N,N-dialkylhydrazones is
presented. Using trimethylsilyl cyanide (TMSCN) as the cyanide source, the reaction can be efficiently
catalyzed by a tert-leucine–derived bifunctional thiourea to afford the corresponding hydrazino nitriles in
10 good to excellent yields (50-96%) and moderate to good enantioselectivities, up to 86% ee. Further
tranformations of the nitrile functionality allow access to useful protected hydrazino acids and
imidazolidinones. Interestingly, some of the hydrazino nitriles and their derivatives could be
recrystallized in high recovery, yielding esencially pure enantiomers.
.
30 The L-enantiomer of hexahydropyridazine-3-carboxylic acid
15 Introduction
(piperazic acid) also resides within the bicyclic ring system of
many bioactive synthetic products such as cilazapril,4 a drug
widely used in the treatment of hypertension. Furthermore, α-
hydrazino acids have attracted great interest in recent years as
35 valuable precursors of conformationally restricted,5 protease–
resistant peptidomimetics.6
Hydrazino acids are important bioactive molecules in medicinal
chemistry (Figure 1). Some of their derivatives containing the N-
N-C-C=O fragment have been identified as inhibitors of several
amino acid metabolizing enzymes with potential applications.1
20 For example, L-Carbidopa is an inhibitor of the peripheral
aromatic L-amino acid decarboxylase (DDC), an enzyme
responsible for the metabolism of levodopa to dopamine, and has
improved the efficiency of Parkinson’s treatment in combination
with L-DOPA.2 Additionally, cyclic α-hydrazino acids are
25 present in a variety of natural peptides with remarkable biological
properties (antibacterial, antitumour or even anti-HIV
therapeutics).3
Existing routes to enantioenriched hydrazino acids7 rely generally
on elaboration of amino acid derivatives,8 sporadic catalytic
hydrogenation of hydrazones,9 and electrophilic amination of
40 enolates with azodicarboxylates.10 In this context, the
development of asymmetric catalytic versions of hydrazone
cyanation, which enables direct access to hydrazino acids,
appears as a very challenging task. In contrast to the Strecker-
type reaction of imines,11 approaches involving catalytic
45 hydrocyanation of hydrazone derivatives have received relatively
little attention. The reported few inventions have relied on N-
acylhydrazones as imine surrogates (Eq. 1, Scheme 1).12
O
OH
N
H
N
H
N
Me NH
NH2
R2
O
R2
N
M-Catalysis
HN
R1
N
H
N
HO
(1)
+
"CN
"
or
O
O
O
O
O
OH
R1
Organocatalysis
CN
HO
L!Carbidopa
Cilazapril
R2
R2
N
N
R2
O
R3
R2
Organocatalysis
O
HN
N
H
N
H
N
+
"CN
"
(2)
R1
R1
This work
R1
N
OH
R1
N
N
H
CN
R1
R2
R1
R2
O
Scheme 1 Asymmetric catalytic Strecker-type reactions of hydrazones
Hydrazino acid
Hydrazino peptide
50 The first asymmetric variant of the reaction was reported in 2004
by Jacobsen and co–workers employing lanthanide-PYBOX
Fig. 1 Hydrazino acids in medicinal chemistry
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

Organic & Biomolecular Chemistry
Page 2 of 9
complexes as the catalysts.12a Recently, the group of Tsogoeva
reported an enantioselective organocatalytic hydrazone
hydrocyanation by
O-silylated BINOL-phosphate.12b
Considering that the higher basicity of N,N-dialkylhydrazones
Several alkaloid–derived quaternary ammonium salts (bearing a
free OH group), (S)-BINOL, (S)-BINOL–derived phosphoric acid
View Article Online
a
and N,N'-bis[3,5-bis(trifluoromethyl)]phenyl thiourea (I) were
DOI: 10.1039/C3OB41437J
chosen as model organocatalysts for their ability to establish H–
5
over acyl hydrazones offers different interaction opportunities 45 bonding cooperative networks to activate reagents. Phase transfer
with acidic organocatalysts, we envisioned an alternative
procedure from N,N-dialkylhydrazones (Eq. 2, Scheme 1). To the
best of our knowledge, a catalytic reaction for this system has not
been described to date.13 On the other hand, we have investigated
catalysts (PTCs) showed a moderate catalytic activity in Et2O,
toluene or CHCl3 (40-50% conv. after 72 hours), but afforded 2
in racemic form, whereas (S)-BINOL and phosphoric acid
derivatives were less active (22–30% conv., 72 h, racemic).
10 on the ambiphilic reactivity of aldehyde N,N-dialkylhydrazones.14 50 Thiourea I, however, efficiently accelerated the model reactions
Their imine-type reactivity has been exploited in Mannich-type
additions of ketene silyl acetals and thioacetals,15 in Staudinger-
like cycloadditions16 and cyanosilylations13c employing C2-
symmetric dialkylamino groups as chiral auxiliaries. The
with respect to the background reaction in several solvents
(CHCl3: 46–67%, 72 h; CH2Cl2: 58%, 72 h; toluene: 35–47%, 72
h; CH3CN: 72%, 72 h), thereby opening opportunities for the
development of an asymmetric catalytic version. Aliphatic N,N-
15 development of a catalytic system for this last reaction was 55 dibenzylhydrazones 1B (slightly superior) and piperidin-1-yl
problematic for the tendency of nitrogen-containing reagents to
bind acidic metals and undergo side reactions, decomposition,
dimerization or catalyst deactivation.17 The mild nature of H-
bonding and Brønsted acid organocatalytic activations,18
derivatives 1A proved to be better substrates than other
considered N,N-dialkylhydrazones such as pyrrolidine or N,N-
dimethylamino derivatives 1C and 1D, respectively, while
TMSCN provided the higher reactivities over KCN or
20 however, appears to be more compatible with hydrazones, and 60 CH3COCN. Finally, addition of 2–3 equivalents of PhOH as
applications have been developed in other contexts.19 We now
report on a novel enantioselective Strecker-type reaction of N,N-
dialkylhydrazones using bifunctional H-bonding activation.
protic additive to the reaction mixtures in toluene improved the
catalytic efficiency, leading to the desired hydrazino nitriles rac-2
in full conversions (>95%) and shorter reaction times (48 h).
Unfortunately, aromatic-substituted hydrazones showed no
65 reactivity under these conditions.
Results and Discussion
25 We started studies on the Strecker–type reactivity enploying
piperidine-containing (1A, R = i-Bu) or N,N-dibenzyl (1B, R = i-
Bu) hydrazones and trimethylsilyl cyanide (TMSCN) as model
reactions. At room temperature, the non-catalyzed reaction hardly
took place after 72 hours in toluene (<5% conv.) or CHCl3 (<15%
30 conv.), while a polar protic solvent like MeOH afforded cleanly
the corresponding hydrazino nitriles rac-2 in excellent yields
(90–95%) in short reaction times (< 4 h),20 suggesting that HCN,
produced in situ, spontaneusly adds to the hydrazone C=N bond.
Preliminary screenings were then performed to identify the best
35 cyanide source, structure of the N,N-dialkylhydrazone 1, catalyst
and solvent for the catalytic enantioselective version (Scheme 2,
see Supplementary Information).
OH
S
S
ArF
N
H
N
H
NH
NMe2
ArF NH
3b
3a
S
ArF
N
H
N
H
S
S
HN ArF
H
N
H
N
NH HN
ArF
ArF NH
S
3c
3d
tBu
S
Me tBu
S
N
R'
N
R'
N
N
ArF
N
H
N
H
Bn
N
H
N
H
O
N
Ph
Me
R'
Cat. (20 mol%)
HN
O
R'
N
+
"CN
"
3e
3f
Solvent, rt
Additive
CN
R
R
Ph
2
1: R = Alkyl, aryl
Me
S
Me tBu
S
ArF
Ph
N
ArF
N
N
H
N
H
N
N
H
H
NR'2
=
Ph
N
Ph
N
Ph
O
Ph
O
N
3h
3g
N
A
B
C
D
ArF: 3,5-(CF3)2C6H3
"CN " = KCN, CH3COCN, TMSCN
S
Fig. 2 Thiourea Organocatalysts tested
ArF
ArF
Catalyst = PTCs, BINOL, BINOL-Phosphoric acid,
N
H
N
H
Previous studies have shown that chiral thiourea-based catalyst
are effective promoters for conducting the activation of imines
70 towards cyanide attack in highly enantioselective Strecker–type
reactions.21 Hence we performed a screening of representative
thiourea catalysts (Figure 2) employing the reaction between (E)-
1,1-dibenzyl-2-(3-methylbutylidene)hydrazine (1a ≡ 1B, R = i-
Bu) and TMSCN/PhOH 3:2, in toluene [0.1M] at 0 °C as the
ArF: 3,5-(CF3)2C6H3
Solvent = H2O, MeOH, Et2O, CHCl3, CH3CN, Toluene
Additive = H2O, MeOH, PhOH
Scheme 2 Preliminary optimization of Strecker-type reactions of
hydrazones 1 (The best choices are marked in blue).
40
2 | Journal Name, [year], [vol], 00–00
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Organic & Biomolecular Chemistry
model system and the results are collected in Table 1.
45 Under the optimized conditions, the reaction was performed on a
0.5 mmol scale for the synthesis of hydrazino nitrile 2a in 93%
View Article Online
Table 1 Screening of catalysts for the enantioselective Strecker-type
reaction of 1a.a
yield and matching the same 72% ee (enDtrOyI:11,0T.1a0b3l9e/2C3),OaBn4d14t3h7eJ
scope of the methodology was explored with a representative set
of aliphatic hydrazones 1b-h. The results summarized in Table 3
50 indicate a uniform behaviour for the synthesis of hydrazino
nitriles 2a-h, obtained in good yields (89-98%) and moderate
enantioselectivities (62–86% ee). As an exception, tert-butyl-
substituted hydrazone 1g required 7 days to afford adduct 2g in
40% yield and 68% ee (entry 7). This result could be slightly
55 improved by making use of the superior reactivity observed in
trifluorotoluene, 50% yield and 68% ee in 4 days (entry 8).
Noteworthy, products 2e and 2f proved to be fairly crystalline,
and this circumstance was exploited to obtain essentially pure
enantiomers (99:1 ee) after a single crystallization.
NBn2
NBn2
3 (20 mol%)
HN
N
+
TMSCN
Toluene, 0 ˚C
PhOH
CN
2a
1a
5
Entry
Catalyst
t (days)
Conv. (%)b
eec
1
2
3
4
5
3a
3b
3c
3d
3e
3f
7
7
7
1
7
3
7
3
3
7
3
48
>95
63
>95
40
71
76
22
75
10
16
16
18
40
40
46
rac
72
44
72
6
7d
8
3f
60
Table 2 Scope of the synthesis of enantioenriched hydrazino nitriles 2.a
3g
3h
3h
3h
9
NBn2
NBn2
10d
11e
79
>95
3h (10 mol%)
N
HN
TMSCN
+
Toluene, 0 °C
R
R
CN
a
PhOH
Unless otherwise stated, reactions were performed with 1a (0.1 mmol),
1
2
TMSCN (0.3 mmol), 3 (20 mol%) and PhOH (0.2 mmol) in toluene (1
1
c
mL) at 0 ºC. b Determined by H NMR. Determined by HPLC on chiral
stationary phases. d Without PhOH. e 10 mol% catalyst.
Entry
R
t (days)
2
Yield (%)b
eec
10
1
2
3
4
5
i-Bu, 1a
i-Pr, 1b
Et, 1c
3
3
3
3
3
3
7
4
3
2a
2b
2c
2d
2e
2f
2g
2g
2h
93
98
89
93
91
96
40
50
90
72
76
62
86
82 (98)
74 (98)
68
Initially we explored the behavior of bifunctional catalysts 3a and
3b for the simultaneous activation of the hydrazone (by the
thiourea as an hydrogen-bond donor moiety) and the cyanide
reagent (by the amino nitrogen in 3a or hydroxyl group in 3b).22
(CH3)3CH2, 1d
CH2Ph, 1e
CH2CH2Ph, 1f
t-Bu, 1g
t-Bu, 1g
C6H11, 1h
6
7
15 Unfortunately, the reaction proceeded with low enantioselectivity
after prolonged reaction times (entries 1,2). Bis–thioureas 3c and
3d also afforded product 2a with poor enantiomeric ratios (entries
3,4). Notably, (R)–BINAM derived bis–thiourea 3d proved to be
the most active catalyst, as a significant shorter reaction time was
20 observed (from 7 days to 1 day); the enhanced reactivity in this
case might be attributed to the superior acidity associated to the
aromatic groups atached to both N atoms.23 Finally, Jacobsen–
type thiourea catalysts 3e-h were tested (entries 5-6, 8-9) and the
results revealed 3h as the best catalyst, reaching conversions of
25 around 75% in 3 days (entry 9) and affording 2a with good
enantioselectivity (72% ee). Control experiments conducted
without PhOH (entries 7,10) revealed the role of this additive as
activator of TMSCN, affording similar conversions in prolonged
reaction times (7 days). Noteworthy, the catalyst loading could be
30 reduced to 10 mol% without compromising the selectivity nor the
reactivity, as shown in entry 11. A further optimization was then
performed to identify best solvent, reaction temperature, and
protic additives (see Supplementary Information). From this
study, reactions performed in toluene at 0 °C in the presence of
35 PhOH (2 equivalents) afforded best results (> 95%, 72% ee).
Substitution of PhOH by different alcohols such as iPrOH (>
95%, 66% ee), HFIP (> 95%, 64% ee) or 1-naphthol (> 95%,
54% ee) in substitution of PhOH, is also possible, whereas
bulkier tBuOH or 2,6-di-tert-butyl-p-cresol are less efficient,
40 affording 2a in 4 days with 22 and 57% conversion, respectively.£
These data are in agreement with a nucleophilic preactivation of
TMSCN to generate HCN;24 the assistance of the dialkylamino
group N atom should not be ruled out, as related N-acyl
hydrazones exhibited no reactivity.‡,25
8d
9
68
72
a
Unless otherwise stated, reactions were performed with 1 (0.5 mmol),
TMSCN (1.5 mmol), 3h (10 mol%) and PhOH (1 mmol) in toluene (5
65 mL) at 0 ºC. b Isolated yield after column chromatography. Determined
c
by HPLC on chiral stationary phases. In parenthesis, ee after a single
crystallization. d Reaction performed in trifluorotoluene.
Furthermore, the cyano group in adducts 2 can be conveniently
70 transformed into
a variety of valuable functional groups.
Attempts to hydrolize directly adducts 2 under acidic or basic
conditions were unsuccessful as a result of a competing retro-
Strecker reaction. Therefore, representative products 2a,b were
transformed into the corresponding formyl hydrazines 4a,b via a
75 “one-pot” Strecker/formylation§ sequence in excelent 86 and 98%
yield, respectively (Scheme 3), and these products were
selectively hydrolized with concentrated sulfuric acid at 45 °C to
afford hydrazino acids 5a,b in excellent yields. Alternatively,
hydrolysis of the cyano and formyl groups of 4a was performed
80 by sequential treatment with sulfuric and hydrochloric acid to
yield hydrazino acid 6a in 60% yield, although with a slight
racemization. Unfortunately, attempts to achieve a selective
removal of the N-benzyl groups were unsuccessful.
This journal is © The Royal Society of Chemistry [year]
Journal Name, [year], [vol], 00–00 | 3

Organic & Biomolecular Chemistry
Page 4 of 9
O
O
NBn2
NBn2
i) "Strecker"
N
i) 4-Br-C6H4COCl
HN
NBn2
CN
Bn2N
H
N
N
View Article Online
CH2Cl2, Et3N, 35 °C
ii) HCO2H/Ac2O
R
DOI: 10.1039/C3OB41437J
CN
Br
CN
R
ii) HPLC
1a,b
4a: R = iBu, 86%, 70% ee
4b: R = iPr, 98%, 78% ee
2b, 76% ee
(S)-8, 45%, >99% ee
i) 65% (w/v) H2SO4
45 °C
ii) HCl (6M), 90 °C
65% (w/v) H2SO4
45 °C
O
NBn2
NBn2
HN
H
N
COOH
R
COOH
6a: 60%, 62% ee
5a: R = iBu, 80%, 82% ee
5b: R = iPr, 66%, >99% ee
20
O
NBn2
HN
Scheme 4 Synthesis and X-Ray structure of (S)-8. H atoms except H8 are
omitted for clarity. Thermal ellipsoids are drawn at 50% probability.
Bn2N
i) AlLiH4, Et2O
N
NH
ii) CO(OCCl3)2, Et3N
R
CN
2a,b
CH2Cl2
Jacobsen and co–workers have performed extensive
computational and experimental studies to elucidate the mode of
R
7a: R = iBu, 67%, 70% ee
7b: R = iPr, 64%, 76% ee
25 action of this class of chiral thiourea catalysts in hydrocyanations
of imines,29 concluding that the tranformation proceeds via anion-
binding catalysis.30 On this basis, a similar mode of activation is
suggested in Figure 3. In the proposed pathway, an initial
catalyst–promoted hydrazone protonation by HCN is believed to
Scheme 3 Synthesis of acids 5, 6a and imidazolidinones 7.
Importantly, single crystallizations made possible to improve the
enantioselectivities (5a: 82% ee; 5b: 99% ee) while slightly
compromising the chemical yields. Alternatively, hydrazino
nitriles 2a,b were subjected to reduction with lithium aluminum
hydride and subsequent condensation with triphosgene leading to
imidazolidinones 7a,b in good overall yields and without
racemization. These are also valuable products containing an
30 generate
a catalyst–bound hydrazonium/cyanide ion pair.
5
Collapse of this ion pair and selective C–C bond formation
leading to (S) hydrazino nitrile 2 then occurs where the preferred
orientation of hydrazonium cation might be additionally
stabilized by π-π interactions between benzhydryl moiety of
35 optimum catalyst 3h and benzyl groups of hydrazone 1.∫,¥
10 unsymmetrical vicinal diamine moiety,26 often present in
biologically active compounds.27
Me
H
CF3
tBu
S
N
Ph
Absolute configuration and stereochemical model
N
O
N
Ph
Ph
H
The absolute configuration of acylated derivative (S)-7 (major
enantiomer isolated by chiral semi-preparative HPLC) was
15 assigned by X-ray diffraction analysis as shown in Scheme 4.28
!-! interactions
H
H
N
N
CF3
?
C
R
N
The absolute configurations of hydrazino nitriles
2 and
derivatives 4-7 were assigned by analogy assuming a uniform
reaction pathway by which the cyanide attacks from the Re face
to the azomethine C=N bond of hydrazone 1 (Figure 3).
Ph
H
CN
H
N
Ph
R
N
(S)
H
Ph
Figure 3 Activation and stereochemical model
Conclusions
In summary, an enantioselective Strecker-type transformation of
40 aliphatic N,N-dibenzylhydrazones 1 has been developed. The
reaction can be efficiently catalyzed by a tert-leucine derived
bifunctional amide–thiourea to afford the corresponding
hydrazino nitriles 2 in good to excellent yields (50-96%) and
moderate to good enantioselectivities, up to 86% ee. The protocol
45 requires a combination of TMSCN and PhOH for the in situ
generation of HCN as cyanide source. The synthetic potential of
4 | Journal Name, [year], [vol], 00–00
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Page 5 of 9
Organic & Biomolecular Chemistry
adducts 2 has been illustrated by transformations into protected 55 calculated for [C19H23N3]+ 293.1905; found: 293.1894. The
hydrazino acids 5-6 and imidazolidinones 7.
enantiomeric excess was determined by HPLC using a Chiralpak
AD-H column [hexane/i-PrOH (98:2)]; flow rate 1VmieLw/Amrtiincl;eτOmnilninore
DOI: 10.1039/C3OB41437J
= 7.7 min, τmajor = 8.2 min.
General methods.
(S)-2-(2,2-Dibenzylhydrazinyl)butanenitrile (2c): Colourless
5
1H NMR spectra were recorded at 300 MHz or 500 MHz; 13C
NMR spectra were recorded at 75 MHz or 125 MHz, with the
solvent peak used as the internal standard. The following
abbreviations are used to indicate the multiplicity in 1H NMR
spectra: s, singlet; d, doublet; t, triplet; q, quartet; dd, double
25
1
60 oil (89% yield); [α]D −16.6 (c 0.8, CHCl3). (62% ee); H NMR
(300 MHz, CDCl3) δ 7.42-7.27 (m, 10H), 3.93 (d, J = 12.9 Hz,
2H), 3.74 (d, J = 12.9 Hz, 2H), 3.39 (t, J = 6.7 Hz, 1H), 2.82 (s,
1H), 1.66-1.45 (m, 2H), 0.88 (t, J = 7.4 Hz, 3H); 13C NMR (125
MHz, CDCl3) δ 137.5, 129.8, 128.5, 127.6, 121.0, 61.6, 53.4,
65 25.1, 10.0; HRMS (CI): calculated for [C18H21N3]+ 279.1735;
found: 279.1731. The enantiomeric excess was determined by
HPLC using a Chiralpak AD-H column [hexane/i-PrOH (98:2)];
flow rate 1.0 mL/min; τminor = 11.6 min, τmajor = 10.4 min.
10 doublet; m, multiplet; bs, broad signal. Analytical thin layer
chromatography (TLC) was performed on 0.25 mm silica gel 60-
F plates and visualized by ultraviolet irradiation or by dipping the
plates in solutions of Mostain, anisaldehyde or phosphomolibdic
acid stains followed by heating. Optical rotations were measured
15 on a Perkin-Elmer 341 MC polarimeter.
(S)-2-(2,2-Dibenzylhydrazinyl)-4,4-dimethylpentanenitrile
70 (2d): White solid (93% yield); MP: 77-79 °C; [α]D25 −23.1 (c 0.3,
1
CHCl3). (86% ee); H NMR (300 MHz, CDCl3) δ 7.44-7.28 (m,
Materials.
10H), 4.00 (d, J = 12.9 Hz, 2H), 3.67 (d, J = 12.9 Hz, 2H), 3.37
(dd, J = 7.9, 4.6 Hz, 1H), 2.73 (s, 1H), 1.66-1.59 (dd, J = 14.0,
7.7 Hz, 1H), 1.28-1.22 (dd, J = 14.0, 5.8 Hz, 1H), 0.78 (s, 9H);
75 13C NMR (125 MHz, CDCl3) δ 137.7, 129.7, 128.4, 127.6, 122.3,
62.1, 49.2, 45.6, 30.1, 29.5; HRMS (CI): calculated for
[C21H27N3]+ 321.2205; found: 321.2197. The enantiomeric excess
was determined by HPLC using a Chiralpak AD-H column
[hexane/i-PrOH (99:1)]; flow rate 1 mL/min; τminor = 13.9 min,
80 τmajor = 14.7 min.
Unless otherwise noted, analytical grade solvents and
commercially available reagents, or catalysts, were used without
20 further purification. For flash chromatography (FC) silica gel
(0.040-0.063 mm) was used. TMSCN was distilled under Argon.
Not commercially available catalysts 3c,d,g,h31 were synthesized
according to literature. Synthesis and characterization data of
hydrazones 1 are described in the Supplementary Information.
25
(S)-2-(2,2-Dibenzylhydrazinyl)-3-phenylpropanenitrile (2e):
General procedure for the enantioselective addition of
TMSCN to N,N-dibenzylhydrazones 1:
25
Yellow solid (91% yield); MP: 101-103 °C; [α]D −31.2 (c 0.5,
1
CHCl3). (98% ee after a single crystallization from pentane); H
TMSCN (0.2 mL, 1.5 mmol, freshly distilled) was added to a
solution of hydrazone 1 (0.5 mmol), catalyst 3h (29 mg, 0.05
30 mmol) and PhOH (94 mg, 1.0 mmol) in toluene (5 mL) at 0 °C
under an Argon atmosphere. The mixture was stirred for 3-5
days. The enantiomerically enriched products 2 were purified by
FC (Cyclohexane/Et2O, 6:1). Enantiomeric excesses were
determined by HPLC analysis.
NMR (300 MHz, CDCl3) δ 7.32-7.25 (m, 13H), 7.08-7.05 (m,
85 2H), 3.87 (d, J = 13.0 Hz, 2H), 3.64 (d, J = 13.0 Hz, 2H), 3.62
(overlaped signal, 1H), 2.89 (s, 1H), 2.87-2.72 (m, 2H); 13C NMR
(125 MHz, CDCl3) δ 137.4, 135.4, 129.7, 129.3, 128.9, 128.5,
127.6, 127.5, 120.5, 61.5, 53.2, 37.9; HRMS (CI): calculated for
[C23H23N3]+ 341.1892; found: 341.1899. The enantiomeric excess
90 was determined by HPLC using a Chiralpak OD column
[hexane/i-PrOH (98:2)]; flow rate 1.0 mL/min; τminor = 16.5 min,
τmajor = 15.0 min.
35
(S)-2-(2,2-Dibenzylhydrazinyl)-4-methylpentanenitrile (2a):
25
Colourless oil (93% yield); [α]D –8.7 (c 1.3, CHCl3). (72% ee);
(S)-2-(2,2-Dibenzylhydrazinyl)-4-phenylbutanenitrile
White solid (96% yield); MP: 65-67 °C; [α]D −7.2 (c 0.3,
95 CHCl3). (98% ee after a single crystallization from pentane); H
(2f):
1H NMR (300 MHz, CDCl3) δ 7.33-7.17 (m, 10H), 3.86 (d, J =
12.9 Hz, 2H), 3.60 (d, J = 12.9 Hz, 2H), 3.33 (t, J = 7.5 Hz 1H),
40 2.67 (bs, 1H), 1.57-1.47 (m, 1H), 1.40-1.31 (m, 1H), 1.23-1.13
(m, 1H), 0.65 (d, J = 6.7 Hz, 3H), 0.62 (d, J = 6.6 Hz, 3H); 13C
NMR (125 MHz, CDCl3) δ 137.6, 129.7, 128.5, 127.6, 121.4,
61.9, 50.6, 40.7, 24.8, 22.3, 22.1; HRMS (CI): calculated for
[C20H25N3]+ 307.2048; found: 307.2050. The enantiomeric excess
45 was determined by HPLC using a Chiralpak AD-H column
[hexane/i-PrOH (98:2)]; flow rate 1.0 mL/min; τminor = 10.3 min,
τmajor = 9.4 min.
25
1
NMR (500 MHz, CDCl3) δ 7.28-7.15 (m, 12H), 7.12-7.09 (m,
1H), 6.94-6.93 (m, 2H), 3.80 (d, J= 12.9 Hz, 2H), 3.64 (d, J =
12.9 Hz, 2H), 3.33 (t, J = 6.9 Hz, 1H), 2.74 (s, 1H), 2.53-2.44 (m,
2H), 1.81-1.74 (m, 1H), 1.71-1.64 (m, 1H); 13C NMR (125 MHz,
100 CDCl3) δ 140.2, 137.5, 129.8, 128.7, 128.5, 128.4, 127.6, 126.4,
120.8, 61.7, 51.2, 33.3, 31.6; HRMS (CI): calculated for
[C24H25N3]+ 355.2048; found: 355.2052. The enantiomeric excess
was determined by HPLC using a Chiralpak AD-H column
[hexane/i-PrOH (98:2)]; flow rate 1.0 mL/min; τminor = 16.8 min,
105 τmajor = 15.0 min.
(S)-2-(2,2-Dibenzylhydrazinyl)-3-methylbutanenitrile
(2b):
Colourless oil (98% yield); [α]D25 −14.5 (c 0.9, CHCl3). (76% ee);
50 1H NMR (500 MHz, CDCl3) δ 7.42-7.29 (m, 10H), 3.96 (d, J =
12.9 Hz, 2H), 3.72 (d, J = 12.9 Hz, 2H), 3.29 (d, J = 5.1 Hz, 1H),
2.80 (bs, 1H), 1.83-1.73 (m, 1H), 0.92 (d, J = 6.7 Hz, 3H), 0.87
(d, J = 6.7 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 137.5, 129.8,
128.4, 127.6, 120.1, 61.6, 58.7, 30.2, 19.3, 18.2; HRMS (CI)
(S)-2-(2,2-Dibenzylhydrazinyl)-3,3-dimethylbutanenitrile
(2g): Reaction performed in trifluorotoluene. White solid (50%
25
1
yield); MP: 78-80 °C; [α]D –18.1 (c 1.1, CHCl3). (68% ee); H
NMR (300 MHz, CDCl3) δ 7.43-7.27 (m, 10H), 4.04 (d, J = 12.9
110 Hz, 2H), 3.67 (d, J = 12.9 Hz, 2H), 3.19 (s, 1H), 2.81(s, 1H), 0.88
This journal is © The Royal Society of Chemistry [year]
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Organic & Biomolecular Chemistry
Page 6 of 9
(s, 9H); 13C NMR (75 MHz, CDCl3) δ 137.6, 129.8, 128.3, 127.5,
DMSO, 363K) δ 165.2, 162.8, 137.6, 137.3, 136.9, 136.2, 129.3,
120.6, 63.1, 61.5, 34.0, 26.3; HRMS (CI): calculated for
[C20H25N3]+ 307.2048; found: 307.2040. The enantiomeric excess
129.2, 129.0, 128.6, 128.4, 128.3, 128.1, 127.7, 117.6, 117.5,
59.8, 58.3, 58.5, 57.9, 56.6, 49.9, 29.4, 19.3, 18.8,Vi1e8w.4A,rti1cl8e.O1n;line
DOI: 10.1039/C3OB41437J
was determined by HPLC using a Chiralpak AD-H column 60 HRMS (CI): calculated for [C20H24N3O]+ 322.1919; found:
5
[hexane/i-PrOH (99:1)]; flow rate 1.0 mL/min; τminor = 7.6 min,
τmajor = 8.7 min.
322.1915. The enantiomeric excess was determined by HPLC
using a Chiralpak OJ-H column [hexane/i-PrOH (96:4)]; flow
rate 1 mL/min; τminor = 25.5 min, τmajor = 35.7 min.
(S)-2-Cyclohexyl-2-(2,2-dibenzylhydrazinyl)acetonitrile (2h):
25
White solid (90% yield); MP: 63-65 °C; [α]D −7.8 (c 0.3,
1
CHCl3). (72% ee); H NMR (300 MHz, CDCl3) δ 7.39-7.27 (m,
65 General procedure for the transformation of 4 into acids 5:
10 10H), 3.93 (d, J = 12.9 Hz, 2H), 3.68 (d, J = 12.9 Hz, 2H), 3.27
(d, J = 6.1 Hz, 1H), 1.68-1.58 (m, 4H), 1.48-1.36 (m, 2H), 1.15-
0.98 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 137.6, 129.8, 128.4,
127.6, 120.3, 61.5, 57.9, 39.4, 29.7, 28.8, 26.1, 25.8, 25.7; HRMS
(CI): calculated for [C22H27N3]+ 333.2205; found: 333.2208. The
15 enantiomeric excess was determined by HPLC using a Chiralpak
AD-H column [hexane/i-PrOH (98:2)]; flow rate 1.0 mL/min;
τminor = 9.3 min, τmajor = 11.5 min.
Sulfuric acid (65% w/v, 17.5 mL) was added to a solution of 4
(0.5 mmol) in the minimal ammount of CH2Cl2. The reaction was
stirred at 45 °C for 24 h, followed by pouring into ice/water and
extracted with Et2O (3 x 15 mL). The organic extracts were dried
70 over Na2SO4 and the solvents were removed in vacuo.
Crystallization from pentane afforded the corresponding acids 5.
(S)-2-(2,2-Dibenzyl-1-formylhydrazinyl)-4-methylpentanoic
25
acid (5a): White solid (80% yield); MP: 148-150 °C; [α]D
1
+55.1 (c 1.0, CHCl3). (82% ee); mixture of rotamers: H NMR
General procedure for the one pot Strecker/formylation
75 (300 MHz, CDCl3) δ 8.30 (s, 0.1H), 8.04 (s, 0.9H), 7.36-7.25 (m,
10H), 5.24 (s, 1H), 4.47-4.18 (m, 0.4H), 4.12-3.93 (m, 4.6H),
2.41-2.32 (m, 1H), 1.75-1.57 (m, 1H), 1.36-1.26 (m, 1H), 1.04 (d,
J = 6.6 Hz, 2.7H), 0.95 (d, J = 6.6 Hz, 2.7H), 0.70 (d, J = 6.6 Hz,
0.3H), 0.63 (d, J = 6.6 Hz, 0.3H); 13C NMR (75 MHz, CDCl3) δ
80 174.4, 167.7, 136.1, 129.7, 129.4, 129.2, 128.8, 128.6, 128.3,
128.0, 59.7, 58.6, 58.5, 38.8, 25.6, 23.4, 22.0; HRMS (FAB):
calculated for [C21H26N2NaO3]+ 377.1841; found: 377.1849. The
enantiomeric excess was determined by HPLC using a Chiralpak
OJ-H column [hexane/i-PrOH (90:10)]; flow rate 1.0 mL/min;
85 τminor = 7.2 min, τmajor = 10.2 min.
20 protocol:
Mixed acetic formic anhydride, prepared from acetic anhydride
(1.5 mL) and formic acid (0.6 mL) by heating at 60 °C for 2
hours, was cooled to 0 °C and added to the crude Strecker
reaction described above (0.5 mmol scale). The reaction mixture
25 was allowed to stir for 1 hour and poured into ice/water (15 mL)
and extracted with dichloromethane (3 x 10 mL). Combined
organic extracts were washed with 10% aqueous solution of
sodium bicarbonate (2 x 10 mL) and brine (10 mL). The organic
extracts were dried over Na2SO4 and the solvents were removed
30 in vacuo. Flash chromatography (Cyclohexane/Et2O, 4:1)
afforded the corresponding formamide derivatives 4.
(S)-2-(2,2-Dibenzyl-1-formylhydrazinyl)-3-methylbutanoic
25
acid (5b): White solid (66% yield); MP: 118-120 °C; [α]D
1
(S)-N',N'-Dibenzyl-N-(1-cyano-3-methylbutyl)formo-
hydrazide (4a): Colourless oil (86% yield); [α]D −7.4 (c 1.0,
+42.7 (c 1.0, CHCl3). (99.8% ee); mixture of rotamers: H NMR
25
(300 MHz, CDCl3) δ 8.23 (s, 1H), 7.43-7.24 (m, 10H), 5.17 (s,
90 1H), 4.10-3.83 (m, 4H), 3.55 (d, J = 11.5 Hz, 1H), 2.96-2.78 (m,
1H), 1.07 (d, J = 6.6 Hz, 3H), 0.90 (d, J= 6.6 Hz, 3H); 13C NMR
(125 MHz, CDCl3) δ 174.5, 167.5, 136.5, 136.1, 129.3, 129.1,
129.0, 128.9, 128.5, 128.2, 127.9, 69.1, 59.5, 56.9, 27.2, 20.7,
19.7; HRMS (FAB): calculated for [C20H24N2NaO3]+ 363.1685;
95 found: 363.1692. The enantiomeric excess was determined by
HPLC using a Chiralpak AD-H column [hexane/i-PrOH (95:5)];
flow rate 1.0 mL/min; τminor = 30.7 min, τmajor = 26.1 min.
CHCl3). (70% ee); mixture of rotamers: 1H NMR (300 MHz,
35 CDCl3) δ 8.26 (s, 0.3H), 8.10 (s, 0.7H), 7.45-7.30 (m, 10H), 4.80
(dd, J = 10.1, 5.5 Hz, 0.7H), 4.52-4.36 (m, 1H), 4.24-3.97 (m,
3H), 3.87 (dd, J = 10.1, 5.5 Hz, 0.3H), 1.91-1.82 (m, 0.7H), 1.77-
1.64 (m, 0.7H), 1.51-1.39 (m, 0.3H), 1.37-1.29 (m, 0.3H), 1.15-
1.01 (m, 0.7H), 0.89 (dd, J = 6.6, 1.8 Hz, 5H), 0.72 (d, J = 6.6
40 Hz, 0.4H), 0.61 (d, J = 6.6 Hz, 0.6H), 0.59-0.49 (m, 0.3H); 13C
NMR (125 MHz, (CDCl3) δ 163.8, 161.3, 137.5, 137.4, 135.7,
135.6, 130.1, 129.8, 129.7, 129.5, 129.0, 128.9, 128.8, 128.7,
128.5, 128.4, 128.1, 128.0, 117.1, 60.5, 59.5, 59.2, 57.4, 52.3,
43.9, 41.1, 39.4, 25.2, 24.6, 22.8, 22.7, 21.4, 20.9; HRMS (CI):
45 calculated for [C21H26N3O]+ 336.2076; found: 336.2065. The
enantiomeric excess was determined by HPLC using a Chiralpak
(S)-2-(2,2-Dibenzylhydrazinyl)-4-methylpentanoic acid (6a).
Sulfuric acid (65% w/v, 17.5 mL) was added to a solution of 4a
100 (168 mg, 0.5 mmol) in the minimal ammount of CH2Cl2. The
reaction was stirred at 45 °C for 24 h, followed by pouring into
ice/water and extracted with Et2O (3 x 15 mL). The organic
extracts were removed in-vacuo and the crude acid 5a was treated
with 6M HClaq (15 mL) and stirred at 90 ºC for 12 h. The solvent
105 was removed in-vacuo and a solution of crude acid 6a, re-
disolved in CH2Cl2, was treated with NaHCO3 sat. until pH ~ 8,
and extracted with CH2Cl2 (2 x 10 mL) and Et2O (2 x 10 mL).
The organic extracts were dried over Na2SO4 and the solvents
were removed in-vacuo. Crystallization from pentane afforded
110 the corresponding acid 6a as a white solid (103 mg, 63%); MP:
OD column [hexane/i-PrOH (98:2)]; flow rate 1 mL/min; τminor
22.2 min, τmajor = 25.7 min.
=
(S)-N',N'-Dibenzyl-N-(1-cyano-2-methylpropyl)formo-
50 hydrazide (4b): White solid (98% yield); MP: 110-112 °C; [α]D
25
1
−13.8 (c 1.0, CHCl3). (76% ee); mixture of rotamers: H NMR
(300 MHz, DMSO, 363K) δ 8.26 (s, 0.8H), 8.20 (s, 0.2H), 7.51-
7.16 (m, 10H), 4.73 (d, J = 9.6 Hz, 0.8H), 4.56-4.29 (m, 0.8H),
4.16-3.95 (m, 3.4H), 2.41-2.24 (m, 0.8H), 1.56-1.42 (m, 0.2H),
55 1.00 (d, J = 6.7 Hz, 2.3H), 0.86 (d, J = 6.7 Hz, 0.7H), 0.71 (d, J
= 6.7 Hz, 2.3H), 0.41 (d, J = 6.7 Hz, 0.7H); 13C NMR (75 MHz,
25
1
140-142 °C; [α]D −3.6 (c 0.5, CHCl3) (62% ee); H NMR (300
6 | Journal Name, [year], [vol], 00–00
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Page 7 of 9
Organic & Biomolecular Chemistry
MHz, DMSO-d6) δ 7.35-7.21 (m, 10H), 3.83 (d, J = 13.0 Hz,
mmol) were sequentially added to a solution of 2b (150 mg, 0.5
2H), 3.56 (d, J = 13.0 Hz, 2H), 3.14 (t, J = 6.9 Hz, 1H), 1.51-
1.39 (m, 1H), 1.16 (t, J = 6.9 Hz, 2H), 0.71 (d, J = 6.7 Hz, 3H),
mmol) in anhydrous CH2Cl2 (2.5 mL). The reaction was stirred at
reflux for 48 h, neutralized with a saturated solutioVnieowfANrtaicHleCOnOli3n,e
DOI: 10.1039/C3OB41437J
0.60 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 177.0, 60 and extracted with dichloromethane (3 x 10 mL). Combined
5
139.3, 129.7, 128.6, 127.4, 61.5, 40.5, 24.6, 23.1, 22.6; HRMS
(CI): calculated for [C20H27N2O2]+ 327.2073; found: 327.2081.
The enantiomeric ratio was determined by HPLC using a
Chiralpak AD-H column [hexane/i-PrOH (95:5)]; flow rate 1.0
mL/min; τminor = 8.7 min, τmajor = 9.4 min.
organic extracts were dried over Na2SO4 and the solvent removed
in-vacuo. Flash chromatography (Cyclohexane/Et2O, 6:1)
1
afforded 8 as a yellow solid (73 mg, 70 %, 70% ee). H NMR
(300 MHz, DMSO 333K) δ 7.88-7.84 (m, 1H), 7.72-7.67 (m,
65 1H), 7.51-7.46 (m, 2H), 7.38-7.15 (m, 5H) 7.08-7.03 (m, 2H),
7.00-6.96 (m, 2H), 6.82 (d, J = 7.2 Hz, 2H), 4.73 (d, J = 9.6 Hz,
1H), 4.33 (d, J = 12.5 Hz, 1H), 4.20 (d, J = 12.5 Hz, 1H), 3.83
(d, J = 14.0 Hz, 1H), 3.60 (d, J = 14.0 Hz, 1H), 2.67-2.55 (m,
1H), 1.21 (d, J = 6.6 Hz, 3H), 1.06 (d, J = 6.6 Hz, 3H); 13C NMR
70 (125 MHz, DMSO, 333K) δ 171.6, 167.2, 137.1, 136.0, 135.4,
132.1, 131.7, 130.8, 129,9, 129.8, 129.6, 128.9, 128.3, 127.8,
123.6, 118.8, 59.6, 55.2, 29.6, 20.1, 19.8; HRMS (CI): calculated
for [C26H26BrN3O]+ 476.1337; found: 476.1340. The
enantioenriched mixture was resolved by semipreparative HPLC
75 on a Chiralpak OJ-H column, [hexane/i-PrOH (80:20)], 6
mL/min. Analytical OJ-H, [hexane/i-PrOH (80:20)], 1 mL/min.
10 General procedure for the transformation of
2 into
imidazolidinones 7:
A solution of Strecker adduct 2 (0.5 mmol) in anhydrous Et2O
(1.0 mL) was added to a suspension of LiALH4 (2.1 mmol, 78
mg) in anhydrous Et2O (10.0 mL) at 0 ºC. The reaction mixture
15 was allowed to warm to room temperature and stirred overnight.
AcOEt (5 mL) and water (0.2 mL) were sequentially, dropwise
added to the reaction until a white solid was formed. The mixture
was filtered through Celite and the solvent was removed in
vacuo. The crude amine was taken in anhydrous CH2Cl2 (4.0
20 mL), and DIPEA (0.3 mL, 1.5 mmol) was added dropwise at 0
°C. After 15 minutes, a solution of triphosgene (178 mg, 0.6
mmol) in anhydrous CH2Cl2 (2 mL) was added dropwise and the
mixture reaction was allowed to warm to room temperature and
stirred overnight. The reaction was diluted with CH2Cl2 (2 mL),
25 washed with water (5 mL), brine (5 mL), dried over Na2SO4 and
the solvent was removed in vacuo. Flash chromatography
(S)-8: tR = 10.7 min (47 mg, 45%). X-ray quality crystals were
obtained by crystallization in Hexane/AcOEt at room
25
temperature. MP: 172-174°C. [α]D −14.3 (c 1.0, CHCl3).
80 (99.8% ee).
25
(R)-8: tR = 21.3 min (10 mg, 11%). [α]D +12.6 (c 0.7, CHCl3).
(99.8% ee).
(Cyclohexane/Et2O,
2:1)
afforded
the
corresponding
imidazolidinones 6.
Acknowledgements
(S)-1-(Dibenzylamino)-5-isobutylimidazolidin-2-one
30 White solid (67% yield); MP: 129-131 °C; [α]D +17.2 (c 0.2,
CHCl3). (70% ee). H NMR (500 MHz, CDCl3) δ 7.31-7.16 (m,
(7a):
85
25
We thank the Spanish ‘Ministerio de Ciencia e Innovación’
(grants CTQ2010-15297 and CTQ2010-14974), predoctoral
fellowship to A. M.-M and “Juan de la Cierva” contract to D.M.),
European FEDER funds and the Junta de Andalucía (grants
90 2008/FQM-3833 and 2009/FQM-4537) for financial support.
Membership in the COST Action CM0905 is also acknowledged.
1
10H), 4.33-3.94 (m, 4H), 3.03 (t, J = 7.9 Hz, 1H), 2.80-2.74 (m,
1H), 2.63-2.59 (m, 1H), 1.42-1.37 (m, 1H), 1.26-1.19 (m, 1H),
0.66 (d, J = 6.6 Hz, 3H), 0.58 (d, J = 6.6 Hz, 3H), 0.55-0.49 (m,
35 1H); 13C NMR (125 MHz, CDCl3) δ 162.0, 138.8, 138.6, 129.7,
128.4, 128.2, 127.3, 61.4, 56.7, 56.3, 44.7, 41.7, 24.5, 23.8, 21.7;
HRMS (CI): calculated for [C21H28N3O]+ 338.2232; found:
338.2230. The enantiomeric excess was determined by HPLC
using a Chiralpak AD-H column [hexane/i-PrOH (90:10)]; flow
40 rate 1.0 mL/min; τminor = 5.0 min, τmajor = 4.8 min.
Notes and references
a
Departamento de Química Orgánica, Universidad de Sevilla, C/ Prof.
García González, 1, 41012 Sevilla, Spain; Fax: +34 954624960; Tel:
95 +34 954551518; E-mail: dmonge@us.es, ffernan@us.es
b
Instituto de Investigaciones Químicas (CSIC-US, Américo Vespucio 49,
(S)-1-(Dibenzylamino)-5-isopropylimidazolidin-2-one
White solid (64% yield); MP: 98-100 °C; [α]D −57.8 (c 0.9,
CHCl3). (76% ee). H NMR (300 MHz, CDCl3) δ 7.43-7.32 (m,
(7b):
E-41092 Sevilla, Spain; Fax: +34 954460565; Tel: +34 954489563;
E-mail: jmlassa@iiq.csic.es
25
1
† Electronic Supplementary Information (ESI) available: experimental
100 procedures, characterization data, NMR spectra for new compounds,
HPLC traces and CIF data for (S)-8. CCDC 945611. See
DOI: 10.1039/b000000x/.
£ Interestingly, reaction performed with bulkier tert–butyl dimethylsilyl
cyanide (TBDMSCN), under optimized conditions, afforded no product
105 after 4 days.
10H), 4.58 (d, J = 11.1 Hz, 1H), 4.35 (d, J = 11.1 Hz, 2H), 3.88
45 (d, J = 11.8 Hz, 1H), 3.43-3.28 (m, 2H), 2.57-2.51 (m, 1H), 2.16-
2.06 (m, 1H), 0.73 (d, J = 7.2 Hz, 3H), 0.65 (d, J = 7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 151.4, 144.8, 137.7, 137.1, 129.8,
129.0, 128.6, 128.1, 127.9, 60.5, 59.6, 55.5, 43.8, 27.4, 18.4,
14.4; HRMS (CI): calculated for [C20H26N3O]+ 324.2076; found:
50 324.2070. The enantiomeric excess was determined by HPLC
using a Chiralpak AD-H column [hexane/i-PrOH (90:10)]; flow
rate 1.0 mL/min; τminor = 5.6 min, τmajor = 5.1 min.
‡ Reactions performed with acyl hydrazones I-III (0.1 mmol), TMSCN
(0.15 mmol), 3h (10 mol%) and PhOH (0.1 mmol) in toluene (1 mL)
afforded no product after 4 days at rt.
Determination of absolute configuration (Scheme 5):
Synthesis of (S)-4-bromo-N-(1-cyano-2-methylpropyl)-N-(1,3-
55 diphenylpropan-2-yl)benzamide (8).
Et3N (0.7 mL, 5 mmol) and 4-bromobenzoyl chloride (1 g, 5
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Organic & Biomolecular Chemistry
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NO2
Enders and M. Moser, Tetrahedron Lett. 2003, 44, 8479; (c) A. Ros,
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Iglesias-Sigüenza, R. R. Pappalardo, E. Álvarez, J. M. Lassaletta and
65
70
75
O
N
OtBu
Ph
O
N
OtBu
O
N
View Article Online
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R. Fernández, Tetrahedron: Asymmetry 2008, 19, 998.
N
H
NH
H
NH
H
14 For general reviews on reactivity of N,N-dialkylhydrazones, see: (a)
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II
I
III
§ Employing in situ generated acetic formic anhydride under solvent free
conditions. R. Edwards, J. Am. Chem. Soc. 1942, 64, 1583.
∫ In the X-ray structure of compound 7 a π-π stabilizing interaction
5 between one phenyl ring and other p-bromo phenyl ring is also observed
(see scheme 4).
¥ Supporting this hypothesis, substitution of the N,N-dibenzylamino by
the piperidino group of 1A, (R = i-Bu) resulted in a lower reactivity (70%
conversion after 4 days) and enantioselectivity (20% ee) under the
10 conditions described in Table 2. No reactivity was observed using 1D.
1
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2
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M. R. Attwood, C. H. Hassall, A. Kröhn, G. Lawton and S. Redshaw,
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6
7
8
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M. J. Burk, J. P. Martínez, J. E. Feaster and N. Cosford, Tetrahedron,
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8 | Journal Name, [year], [vol], 00–00
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Organic & Biomolecular Chemistry
23 For discussions on hydrogen-bond donating ability, see: (a) A.
Wittkopp and P. R. Schreiner, Chem. Eur. J. 2003, 9, 407; (b) S. J.
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5 24 Alkylsilyl cyanides as silylating agents: (a) K. Mai, and G. Patil, J.
Org. Chem. 1986, 51, 3545. Interesting examples of improved
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10
Shibasaki, Tetrahedron Lett. 2004, 45, 3147; (d) Y.-L. Liu, T.-D. Shi,
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3826.
25 For interesting NMR control experiments where generation of HCN
from iPrOH and TMSCN (under diluted conditions) is strongly
accelerated by the presence of basic nitrogens, see: J. Wang, W.
Wang, W. Li, X. Hu, K. Shen, C. Tan, X. Liu, and X. Feng, Chem.
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15
26 D. Lucet, T. L. Gall and C. Mioskowski, Angew. Chem., Int. Ed.
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20 27 S. R. S. S. Kotti, C. Timmons and G. Li, Chem. Biol. Drug Des.
2006, 67, 101.
28 Crystal data for (S)-7: C26H26BrN3O, M = 476.41, tetragonal, a =
10.8070(4) Å, b = 10.8070(4) Å, c = 40.306(3) Å, α = 90.00°, β =
90.00°, γ = 90.00°, V = 4707.3(4) Å3, T = 173(2) K, space group
25
30
35
P41212, Z = 8, µ(MoKα) = 1.769 mm-1, 96964 reflections measured,
7175 independent reflections (Rint = 0.0579). The final R1 values were
0.0314 (I > 2σ(I)). The final wR(F2) values were 0.0680 (I > 2σ(I)).
The final R1 values were 0.0492 (all data). The final wR(F2) values
were 0.0741 (all data). The goodness of fit on F2 was 1.008. Flack
parameter = 0.004(5).
29 S. J. Zuend and E. N. Jacobsen, J. Am. Chem. Soc. 2009, 131, 15358.
30 Recent review: K. Brak, and E. N. Jacobsen, Angew. Chem., Int. Ed.
2013, 52, 534.
31 For catalyst 3c: (a) Y. Sohtome, A. Tanatani, Y. Hashimoto and K.
Nagasawa, Tetrahedron Lett. 2004, 45, 5589; For catalyst 3d: (b) X.
G. Liu, J. J. Jiang and M. Shi, Tetrahedron Lett. 2007, 18, 2773; For
catalyst 3g: (c) S. E. Reisman, A. G. Doyle and E. N. Jacobsen, J.
Am. Chem. Soc. 2008, 130, 7198. For catalyst 3h: (d) reference 21d.
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