In search of diamine analogs of the α,α-diphenyl prolinol privileged chiral organocatalyst. Synthesis of diamine derivatives of α,α-diphenyl-(S)-prolinol and their application as organocatalysts in the asymmetric Michael and Mannich reactions

Article abstract of DOI:10.1016/j.tet.2015.11.032

This paper describes improved reaction conditions for the substitution of the hydroxyl group in (S)-diphenyl(pyrrolidin-2-yl)methanol by the azide group, which was then reduced to the diamine derivative. We examined two protecting groups (N-Bn and N-Boc) on the pyrrolidine nitrogen in order to functionalize the primary amino group into various amide, alkylated amine, sulfonamide, thiourea and triazole derivatives. Notably, carefully controlled conditions were required to generate the desired derivatives from the sterically hindered benzhydrylamine moiety. Unexpectedly, upon removal of the N-protecting group in derivatives containing electrophilic polar double bonds (C=S, C=O) cyclization took place, affording products such as amidines. The target compounds were evaluated as bifunctional organocatalysts in the asymmetric Michael and Mannich addition reactions. (S)-2-(Azidodiphenylmethyl)pyrrolidine (S)-7 was identified as the most efficient organocatalyst among the various diamine derivatives of α,α-diphenyl-(S)-prolinol prepared in this work.

Full text of DOI:10.1016/j.tet.2015.11.032

Tetrahedron 72 (2016) 379e391
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In search of diamine analogs of the
a,a-diphenyl prolinol privileged
chiral organocatalyst. Synthesis of diamine derivatives of
a,a-
diphenyl-(S)-prolinol and their application as organocatalysts in the
asymmetric Michael and Mannich reactions
*
Gloria Reyes-Rangel, Jorge Vargas-Caporali, Eusebio Juaristi
ꢀ
ꢀ
ꢀ
Departamento de Química, Centro de Investigacion y de Estudios Avanzados, Instituto Politecnico Nacional, Apartado Postal 14-740, Mexico D.F., 07000
Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
This paper describes improved reaction conditions for the substitution of the hydroxyl group in (S)-di-
phenyl(pyrrolidin-2-yl)methanol by the azide group, which was then reduced to the diamine derivative.
We examined two protecting groups (N-Bn and N-Boc) on the pyrrolidine nitrogen in order to func-
tionalize the primary amino group into various amide, alkylated amine, sulfonamide, thiourea and tri-
azole derivatives. Notably, carefully controlled conditions were required to generate the desired
derivatives from the sterically hindered benzhydrylamine moiety. Unexpectedly, upon removal of the N-
protecting group in derivatives containing electrophilic polar double bonds (C]S, C]O) cyclization took
place, affording products such as amidines. The target compounds were evaluated as bifunctional or-
ganocatalysts in the asymmetric Michael and Mannich addition reactions. (S)-2-(Azidodiphenylmethyl)
pyrrolidine (S)-7 was identified as the most efficient organocatalyst among the various diamine de-
Received 9 September 2015
Received in revised form 13 November 2015
Accepted 16 November 2015
Available online 23 November 2015
Keywords:
Organocatalysis
Proline derivatives
ThorpeeIngold effect
Asymmetric Michael addition
Asymmetric Mannich reaction
Water effect
rivatives of a,a-diphenyl-(S)-prolinol prepared in this work.
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
which provided the corresponding carbocation precursor of azide
(S)-3 and hence, of diamine (S)-5. Enantiopure diamine (S)-5 was
treated with borane in order to afford the desired diazaborolidine
precatalyst for the asymmetric reduction of carbonyl compounds
(Fig. 1).5 It should be noticed that also in 2008, Ooi et al.6 described
Chiral b-aminoalcohols containing bulky substituents, in par-
ticular the geminal diphenyl segment, constitute an important
group of ligands with diverse applications in asymmetric synthesis
and catalysis. In this regard, oxazaborolidine derivatives prepared
the preparation of several chiral diamines derived from
isoleucine and -tert-leucine via azidation of the corresponding
diarylamino alcohols.
L-valine, L-
from
enantioselective reduction of prochiral ketones.1 Emblematic
organocatalysts containing the -diaryl-(S)-prolinol segment do
not only include free
-amino alcohols as bifunctional molecules,2
a,
a-diphenyl-(S)-prolinol have been extensively applied in the
L
a
,a
In subsequent years, the synthesis and application of analogs of
azide (S)-3 and diamine (S)-5 aroused considerable interests. It can
be appreciated that the key step in the preparation of novel diamine
(S)-5 corresponds to the replacement of the tertiary hydroxyl group
in aminoalcohol (S)-6 by azide, by means of strong Brønsted acids
(Fig. 2). While we initially employed aqueous sulfuric acid to re-
place the hydroxyl group via a SN1 reaction, Zhong and co-workers7
obtained azide (S)-7 by means of TFA instead of H2SO4, and used it
directly as catalyst in a novel asymmetric formally [4þ1] annulation
to generate cis-isoxazoline N-oxides.
b
but also the corresponding silyl ether derivatives.3 As anticipated,
the high stereoinduction achieved by means of these organo-
catalysts originates for the most part from the distinctive geminal
biaryl group.4
In 2008 our research group accomplished the first synthesis of
the N-benzylated (S)-proline-azide (S)-3, by means of the re-
placement of the tertiary hydroxyl group in (S)-2 with azide anion
as nucleophile, via a SN1 type substitution. This substitution re-
action required the use of strongly acidic conditions (aq H2SO4),
In order to synthesize N-protected azide (S)-3, Asami and co-
workers employed a mixture of H2SO4 and CF3CO2H in biphasic
media under reflux.8 These researchers also employed azide (S)-3
as precursor of diamine (S)-5, whose primary amine functionality
* Corresponding author. Tel.: þ52 55 5747 3722; fax: þ52 55 5747 3897; e-mail
address: juaristi@relaq.mx (E. Juaristi).
http://dx.doi.org/10.1016/j.tet.2015.11.032
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

380
G. Reyes-Rangel et al. / Tetrahedron 72 (2016) 379e391
Fig. 3. Azidation reaction of (S)-2 in the preparation of key intermediate (S)-3, and
subsequent reduction to afford diamines (S)-4 and (S)-5.
Fig. 1. Synthesis and application of
eyeBakshieShibata (CBS) oxazaborolidine catalyst.
a diazaborolidine analog of the Cor-
acid and temperatures around 10e15 ꢀC (Fig. 3). Indeed, the
homogeneity of the reaction emulsion was improved at this acid
concentration and slightly higher reaction temperature
(10e15 ꢀC instead of 0 ꢀC, as initially used5a). Under these con-
ditions, agglomeration and precipitation of alkyl ammonium
sulfate is prevented, and this facilitates the subsequent reaction
with hydrazoic acid.
With the desired amino azide (S)-3 at hand, diamine (S)-5 could
be directly obtained through catalytic hydrogenation with Pd(OH)2
at 120 psi H2 and heating to 60 ꢀC. On the other hand, diamine (S)-4
was prepared in good yield by reducing the azido functionality in
(S)-3 with LiAlH4 under THF reflux, as previously described5a
(Fig. 3).
Fig. 2. Azidation reaction of tertiary alcohol (S)-6 via SN1 substitution of the hydroxyl
group by means of strong Brønsted acid.
was N-phenylated to obtain an analog of the diazaborolidine cat-
alyst. On the other hand, Lee and co-workers obtained a series of
chiral aminoazides, including (S)-7, employing a biphasic reaction
media of H2SO4-toluene.9,10
In the initial attempts to functionalize (S)-4, neither alkyl halides
nor p-toluenesulfonyl chloride were sufficiently reactive to afford
the expected N-alkylated or N-sulfonylated products. This lack of
reactivity was observed when bulky amine (S)-4 was treated with
the corresponding reagents either at room temperature, under
conventional heating, or even with microwave activation. By con-
trast, reactions carried out with electrophilic reagents containing
polarized carbon-heteroatom double-bond did give rise to the de-
sired N-functionalization of the sterically hindered exocyclic ni-
trogen. In particular, treatment of (S)-4 with benzoyl chloride
generated amide (S)-8 and thiourea (S)-9 was obtained by means of
Edman’s reagent (Fig. 4).
Recently, Connon and co-workers evaluated N-acylated de-
rivatives of (S)-7 in the kinetic resolution of alcohols,11 while Bez
and co-workers12 examined several Cu(II) complexes of azide (S)-3
and their derivatives as catalysts in the asymmetric Henry reaction,
achieving moderate results. Recently, Kesavan and co-workers13
developed an N-methylated pyrrolidine-thiourea derivative from
(S)-7, which was evaluated as potential catalyst in the Michael
addition of 1,3-dicarbonyl compounds to nitroolefins; however, this
derivative was not effective in this specific reaction.
Nevertheless, it is worth mentioning that there are some im-
portant structural features of this class of pyrrolidine diamine de-
rivatives that have not been properly addressed in the literature.
Indeed, despite the apparent structural similarity of diamine (S)-5
and aminoalcohol (S)-6, particular reactivity patterns decisively
affect the possibility of handling and applying the former diamine
(S)-5 and derivatives thereof in asymmetric organocatalysis.
Hence, we revisited some proline diamine derivatives that were
already described in the literature, and developed several novel
derivatives as well. Nevertheless, in the present work we focused
mainly in the preparation of compounds presenting an unsub-
stituted NeH pyrrolidine nitrogen, so that they could be evaluated
as bifunctional organocatalysts. In this regard, asymmetric orga-
nocatalysis via enamine has proven to be one of the most effective
Fig. 4. Successful functionalization of the sterically hindered primary amino group in
(S)-4.a
methods to carry out enantioselective a-functionalizations on al-
dehydes and ketones. In particular, asymmetric Michael and Man-
nich addition reactions seemed to be attractive applications of our
proline-derived catalysts because of their structural resemblance
with the intensively studied (S)-2-[diphenyl(trimethylsilyloxy)
methyl] pyrrolidine (JørgenseneHayashi catalyst3).
Debenzylation of derivatives (S)-8 and (S)-9 was attempted
under the conditions that previously had been effective in the
hydrogenolysis of (S)-3, i.e. 20% Pd(OH)2/C in AcOH/methanol un-
der hydrogen pressure (Fig. 5). However, instead of obtaining the
desired NeH products, amide (S)-8 generated cyclic amidine (S)-10
by water loss (Fig. 5), while thiourea (S)-9 produced cyclic thiourea
(S)-11 by loss of aniline (Fig. 6). These unanticipated processes are
explained by an intramolecular attack of the free pyrrolidine ni-
trogen towards the electrophilic carbonyl or thiocarbonyl functions.
The formation of cyclic derivatives (S)-10 and (S)-11 was corrobo-
rated by means of X-ray crystallography.
2. Results and discussion
2.1. Synthesis of (S)-(N-benzylpyrrolidin-2-yl)diphenyl-meth-
anamine, (S)-4, and derivatives
Azide (S)-3 was prepared via azidation reaction of tertiary
alcohol (S)-2 using the methodology developed in our group5
with some minor modifications. Specifically, it was found that
best results are obtained when employing 70% aqueous sulfuric
Examination of the X-ray crystallographic structure of thiourea
(S)-9 (Fig. 6) makes evident the proximity between the pyrrolidine

G. Reyes-Rangel et al. / Tetrahedron 72 (2016) 379e391
381
Fig. 7. X-ray crystallographic structure of azide (S)-7 (30% probability ellipsoids). The
ellipsoid that describes C(4) was divided into two positions owing to disorder in the
organization of molecules in the crystal lattice.
protected amino azide (S)-12, which turned out to be more stable
than the starting material so it could be stored during longer pe-
riods before its use. The azido functionality in (S)-12 was reduced
selectively by catalytic hydrogenation (Pd/C, 10%-w) at 1 Atm
pressure, and this methodology resulted in clean formation of
amine (S)-13, in 77% yield (Fig. 8).
Fig. 5. a) Proposed mechanism for the cyclization reaction. b) X-ray crystallographic
structure of the resulting amidine (S)-10 (thermal ellipsoids at 30% probability).
Fig. 8. Synthesis of amine (S)-13 from azide (S)-7.a
N-Sulfonylation of amine (S)-13 with p-toluenesulfonyl chloride
under SchotteneBauman reaction conditions proved fruitless.
Nevertheless, N-sulfonylation of (S)-13 was achieved by means of
a stronger sulfamoylating reagent. Indeed, formation of 1-tosyl-3-
methylimidazolium triflate from 1-tosyl-1H-imidazole and
CF3SO3CH3,15 followed by treatment with amine (S)-13 in anhy-
drous THF, afforded sulfonamide (S)-14 in moderate yield (Fig. 9).
Amine (S)-13 was the substrate for reaction with benzoyl chlo-
ride and acetyl chloride, providing amides (S)-15 and (S)-16, re-
spectively. These derivatives turned out to be crystalline and it was
Fig. 6. a) Proposed mechanism for the formation of thiourea (S)-11. b) X-ray
crystallographic structures of thioureas (S)-9 and (S)-11 (thermal ellipsoids at 30%
probability).
nitrogen N(1) and the thiocarbonyl carbon C(8), which apparently
facilitates the formation of cyclic thiourea (S)-11.
The unexpected rearrangements leading to the formation of
cyclized amidine (S)-10 and thiourea (S)-11 (Figs. 5 and 6) pre-
vented at this point the synthesis of the required pyrrolidine NeH
derivatives, the desired chiral organocatalysts.
2.2. Synthesis of pyrrolidine derivatives containing the carbo-
tert-butoxy (N-Boc) protecting group
In order to allow for the functionalization of diamine (S)-5,
while simultaneously facilitating the removal of the N-protecting
group needed afterward, the carbo-t-butoxy (N-Boc) group was
deemed more convenient than the N-benzyl group. Therefore, we
synthesized amino alcohol (S)-6 following the methodology de-
scribed by Bhaskar Kanth and Periasamy.14 Subsequently,
a,a-
diphenyl-(S)-prolinol (S)-6 was treated with NaN3 and TFA at room
temperature as previously reported by Zhong et al.7 generating
amino azide (S)-7 in good yield (Cf. Fig. 2).
Suitable crystals for X-ray diffraction analysis of amino azide (S)-
7 were obtained by crystallization from a saturated hexane solution
(Fig. 7). The ellipsoid describing C(4) was divided into two positions
due to disorder in the organization of molecules in the crystal lat-
tice. Azide (S)-7 was then protected with Boc2O to give the N-Boc
Fig. 9. Sulfamoylation of amine (S)-13 using a tosyl-imidazolium triflate.a

382
G. Reyes-Rangel et al. / Tetrahedron 72 (2016) 379e391
than 7.0 accelerate the cyclization reaction. In this way, amide (S)-
20 generates amidine (S)-10, and similarly, amide (S)-21 forms the
corresponding amidine (S)-24, whose X-ray structures are shown in
Fig. 11. The ease with which amidines are produced corroborates
that the tendency of the NeH compounds to cyclize is related to the
intrinsic nature of these amino amides, specifically by the Thor-
peeIngold effect induced by the gem-diphenyl fragment.17
Fig. 10. X-ray crystallographic structures of the acylated products (S)-15 and (S)-16
(ellipsoids at 30% probability). A pyrrolidine carbon in amide (S)-15 is refined in two
positions because of disorder.
possible to collect crystallographic data, the resulting structures
can be appreciated in Fig. 10.
Amides (S)-15 and (S)-16 were reduced to the corresponding
alkylated amines (S)-17 and (S)-18 by means of AlH3, which was
generated from anhydrous aluminum trichloride combined with
LiAlH4 in THF at room temperature.16
Fig. 11. X-ray crystallographic structure of amidine (S)-24 with ellipsoids at 30%
Diluted TFA was used to remove the N-Boc protecting group in
derivatives 13e18 (Table 1). Reactions were carried out at 0 ꢀC, by
dropwise addition of the acid solution to a solution of the corre-
sponding N-Boc substrate. Although these conditions worked quite
well for the majority of the derivatives, the use of formic acid at
room temperature (stirring during prolonged periods of time)
afforded better results in the case of sulfonamide (S)-14 (entry 2 in
Table 1).
probability.
2.3. Synthesis of chiral triazol (S)-25
The azide substituent present in (S)-7 gave the opportunity to
try out a ‘click’ reaction with phenyl acetylene, using CuSO4$5H2O
as catalyst, methanolewater (9:1) as solvent, and stirring at room
temperature during 18 h (Fig. 12) according to the procedure de-
scribed by Kosmrlj and co-workers.18 Although triazole (S)-25 was
ꢁ
Table 1
obtained from azide (S)-7 in a relatively low yield (45%), it is re-
markable that this direct click reaction took place without the need
of protection/deprotection steps.
Conditions for N-Boc deprotection of compounds (S)-13e18, and yields of the cor-
responding products (S)-5 and (S)-19e23
Entry
1
R
Conditions
Product
Yielda (%)
99
(S)-13
-H
CF3CO2H 1 mL/g
CH2Cl2
(S)-5
0
ꢀC / rt, 18 h
2
3
(S)-14
(S)-15
-Ts
-Bz
HCO2H 4 mL/g
rt, 18e20 h
CF3CO2H 1 mL/g
CH2Cl2
(S)-19
(S)-20
85
96a
0
ꢀC / rt, 18 h
4
5
6
(S)-16
(S)-17
(S)-18
-Ac
-Bn
-Et
CF3CO2H 1 mL/g
CH2Cl2
(S)-21
(S)-22
(S)-23
99a
71
Fig. 12. Click reaction for azide (S)-7a.
0
ꢀC / rt, 18 h
CF3CO2H 8 mL/g
CH2Cl2
In this regard, Lee and co-workers10 recently reported alterna-
tive reaction conditions for the preparation of triazole (S)-25, which
consisted in the use of sodium ascorbate as additive, com-
plementing copper catalysis, and using MeCNeH2O (1:1) as solvent,
achieving up to 80% yield.
0
ꢀC / rt, 4 h
CF3CO2H 5 mL/g
CH2Cl2
80
0
ꢀC / rt, 4 h
a
Determined yields are based on the corresponding triflate salt.
2.4. Evaluation of the NeH pyrrolidine derivatives (S)-5, (S)-7,
(S)-19e23 and (S)-25 as organocatalysts in the asymmetric
Michael addition
It is important to point out that the isolation and preservation of
deprotected diamines (S)-20 and (S)-21 was only possible by
keeping them as trifluoroacetate salts, since the release of free di-
amine at neutral pH promotes their cyclization.
This cyclization process is retarded but not totally prevented
when the products are extracted at pH 5e6, since pH values higher
trans-b-Nitrostyrene was selected as electrophilic olefin and
isobutyraldehyde as the enamine precursor in the model reaction
to test pyrrolidine derivatives (S)-5, (S)-7, (S)-19e23 and (S)-25 as

G. Reyes-Rangel et al. / Tetrahedron 72 (2016) 379e391
383
Fig. 14. Plausible transition state in the formation of the CeC bond, where the tra-
jectory of the approaching enamine/olefin trigonal centers is emphasized.
azide and trimethylsilyl groups are not directly involved in the
transition state of the reaction. Stereocontrol should then originate
from the steric effect of the gem-diphenyl segment (Fig. 14).
Regarding the amino amide salts (S)-20 and (S)-21, the pro-
tonated amino group in the pyrrolidine ring prevented the forma-
tion of the enamine nucleophile, indispensable for the Michael
addition to take place.
On the other hand, triazol (S)-25 promoted the Michael addition
reaction with relatively good enantioinduction; however, the yield
of the reaction was quite low. Similarly, sulfonamide (S)-19
exhibited extremely limited catalytic function. It is likely that in
Fig. 13. Chiral proline derivatives evaluated as organocatalysts in the Michael addition
reaction between trans- -nitrostyrene and isobutyraldehyde.
b
organocatalysts in the asymmetric Michael addition reaction
(Fig. 13). Isobutyraldehyde was chosen in order to avoid the for-
mation of a new enamine from the Michael adduct.19 In addition,
we decided to use PhCO2H as additive, since this simple carboxylic
acid has exhibited significant efficiency as olefin activator in pre-
vious reports of organocatalyzed Michael reactions.20 Finally,
aqueous media were preferred since water in combination with
acidic additives attenuates the formation of species identified as
‘resting states’ in the catalytic cycle.19
For amino azide (S)-7 or triazole derivative (S)-25 it seems
reasonable that stereoinduction is mainly dictated by steric hin-
drance from the bulky gem-diphenyl fragment. By contrast, with
diamines (S)-5, (S)-22 and (S)-23, sulfonamide (S)-19, and the
amino amide salts (S)-20 and (S)-21 intermolecular hydrogen
bonding could intervene in the transition state, being partly re-
sponsible of the observed stereoinduction. Table 2 summarizes the
results of Michael additions organocatalyzed by the NeH pyrroli-
dine derivatives prepared in this work.
both cases the corresponding a-pyrrolidine fragments are sterically
too demanding, preventing the formation of the required enamine.
In this sense, Schmid, Zeitler, and Gschwind21 recently suggested
that from a thermodynamic standpoint, the relative stability of
pyrrolidine enamines decreases as the size of the
increases.
a-substituent
Once azide (S)-7 was identified as the best organocatalyst
among the series of chiral NeH pyrrolidine derivatives prepared in
this work, we proceeded to study its efficiency in the asymmetric
Michael addition reaction, evaluating as well the impact of catalyst
concentration, the potential effect of Brønsted acids as additive,
and solvent influence (Table 3). At this stage, best results were
obtained with a relatively high concentration of the organo-
catalyst, 20%, and in water solvent. Indeed, the enantioselectivity
of the reaction diminished slightly when the amount of catalyst
was reduced to 10%-mol, although the yield was essentially un-
affected (entry 2 in Table 3). However, when the quantity of cat-
alyst was reduced to 5%-mol or less (entries 3 and 4 in Table 3),
product formation was totally inhibited. On the other hand, the
presence of half equivalent of benzoic acid as additive was es-
sential (compare entries 1 and 2 with entries 6 and 7 in Table 3).
Nevertheless, with 2 equiv of benzoic acid a slight increase of ee
was accompanied by a considerable decrease in yield (entry 5 in
Table 3).
Most relevant is the effect of water in the Michael addition re-
actions catalyzed by (S)-7. Indeed, no product is observed when
anhydrous isopropanol, toluene, or methylene chloride are used as
solvent (entries 7e9 in Table 3).
On the other hand, although recent studies conclude that an
acidic additive may influence the rate and in some instances the
reaction diastereoselectivity but not the enantioselectivity,19 we
were interested in evaluating the potential effect of chiral organic
acids as additives. In the event, the use of either enantiomer of
mandelic acid as additive (entries 11 and 12 in Table 3) afforded
essentially the same enantioselectivity relative to the use of achiral
benzoic acid (entry 13 in Table 3).
Table 2
Asymmetric Michael addition reaction organocatalyzed by NeH derivatives of (S)-
proline containing the gem-diphenyl segment
Entry Catalyst Solvent
Additive Yield (%) (er)a [% ee] Configurationb
1
2
3
4
5
6
7
8
(S)-5
(S)-5
(S)-5
(S)-7
(S)-7
(S)-19 H2O
(S)-20 H2O
(S)-21 H2O
(S)-22 H2O
(S)-23 H2O
(S)-25 H2O
H2O
PhCO2H 98
(80:20) [60] (S)
(84:16) [68] (S)
IPA:H2O (3:1) PhCO2H 57
H2O
H2O
CF3CO2H
d
d
d
PhCO2H 70
(95:5) [90] (R)
(94:6) [88] (R)
(83:17) [66] (R)
IPA:H2O (3:1) PhCO2H 87
PhCO2H
PhCO2H
PhCO2H
7
d
d
d
d
d
d
9
PhCO2H 50
PhCO2H 32
PhCO2H 14
(94:6) [88] (R)
(93:6) [86] (R)
(83:17) [66] (R)
(88:12) [76] (R)
10
11
12
(S)-25 IPA:H2O (3:1) PhCO2H
7
Salient results are highlighted in bold
a
Determined by HPLC with a chiral column OD-H.
Configurations were assigned with base on previous literature reports.
b
Upon consideration of these observations, the following condi-
tions were selected as most convenient: 20%-mol catalyst (S)-7,
0.5 equiv of acidic additive, and isopropanolewater (3:1) as solvent.
This solvent mixture was preferred because it enhanced the ho-
mogeneity of the reaction medium, especially in tests carried out at
lower temperature (Table 4). Examination of Table 4 shows that
Examination of Table 2 indicates that azide (S)-7 affords the
highest yields and stereoselectivities, especially when employing
a mixture isopropanolewater (3:1) as solvent (Table 2, entry 5).
This stereoselectivity is essentially similar to that promoted by (S)-
diphenyl prolinol trimethylsilylether, (S)-60,3 corroborating that the

384
G. Reyes-Rangel et al. / Tetrahedron 72 (2016) 379e391
Table 3
Examination of the effect of the concentration of organocatalyst (S)-7, influence of the reaction media, and impact of Brønsted acids as additives in the asymmetric Michael
addition reaction between isobutyraldehyde and (E)- -nitrostyrene
b
Entry
%-mol (S)-7
Additive
Equiv. Additive
Solvent
Yield (%)
(er)a [% ee]
1
2
3
4
5
6
7
8
20
10
5
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
d
0.5
0.5
0.5
0.5
2.0
d
H2O
H2O
H2O
H2O
80
79
d
d
54
32
d
d
d
88
85
86
93
(95:5) [90]
(93:7) [86]
d
3
d
20
20
20
20
20
20
20
20
20
H2O
(96:4) [92]
(70:30) [40]
d
IPA:H2O (3:1)
d
d
IPAb
PhCO2H
PhCO2H
p-Chlorobenzoic acid
(R)-Mandelic acid
(S)-Mandelic acid
PhCO2H
0.5
0.5
0.5
0.5
0.5
0.5
Tolueneb
d
b
9
CH2Cl2
d
10c
11c
12c
13c
IPA:H2O (3:1)
IPA:H2O (3:1)
IPA:H2O (3:1)
IPA:H2O (3:1)
(94:6) [88]
(94:6) [88]
(94:6) [88]
(93:7) [86]
Salient results are highlighted in bold
a
Determined by HPLC with a chiral column OD-H.
Under stirring during 6e8 days.
Under stirring during 3 days.
b
c
Table 4
Evaluation of temperature effect in the asymmetric Michael addition reaction between isobutyraldehyde and (E)-
b
-nitrostyrene
Entry
Catalyst
Additive
Temperature (ꢀC)
Yield (%)
(er)a [% ee]
Configurationb
1
2
3
4
5
6
(S)-7
(S)-7
(S)-5
(S)-25
(S)-7
(S)-7
PhCO2H
PhCO2H
PhCO2H
PhCO2H
(R)-Mandelic acid
(S)-Mandelic acid
10
50c
10
74
57
14
7
37
19
(97:3) [94]
(84:16) [68]
(85:15) [70]
(77:24) [53]
(94:6) [88]
(92:8) [84]
(R)
(R)
(S)
(R)
(R)
(R)
10d
10
10
Salient results are highlighted in bold
a
Determined by HPLC with a chiral column OD-H.
Configuration assigned with base on previous literature reports.
Under stirring for 10 h.
b
c
d
Under stirring for 8 days.
product (R)-26 can be obtained in good yield and 94% ee at 10 ꢀC,
which represents an improvement in comparison with room tem-
perature experiments (entry 1).
stereoselectivity than those presenting electron attracting groups.
The majority of the electrophilic nitroolefins gave rise to the
corresponding Michael adducts in good yield and with high
enantioselectivity at ambient temperature, although ee values
improved at 10 ꢀC for some nitrostyrenesethis effect being more
pronounced when the substituents were located at the ortho
position.
Experiments carried out at 10 ꢀC when using diamine (S)-5
(entry 3 in Table 4) led to a significant decrease in yield, although ee
values remained practically constant. With triazole (S)-25 as
organocatalyst the yield and ee were low (entry 4). Employment of
either enantiomer of mandelic acid as additive (entries 5 and 6 in
Table 4), resulted in high enantioselectivity of the product, but re-
action yields were somewhat lower.
2.5. Detection of reaction intermediates by ESI-MS TOF mass
spectrometry and 1H and 13C NMR spectroscopy
The scope of the asymmetric Michael addition reaction between
isobutyraldehyde and diverse aryl-substituted nitroolefins with
chiral organocatalyst (S)-7 was then evaluated, and the results are
summarized in Table 5. The previously optimized conditions (with
regard to catalyst concentration, solvent, and amount of PhCO2H)
were used, both at 10 ꢀC and at ambient temperature.
In spite of the fact that a thorough mechanistic study is beyond
the scope of this paper, we did perform some experiments that
shed some light in the process of the Michael addition reaction
catalyzed by (S)-7. In particular, ESI-MS TOF experiments were
carried out in order to detect some of the species that intervene in
the mechanism of the Michael reaction between isobutyraldehyde
In summary, azide (S)-7 has proven to be a good organo-
catalyst for the asymmetric Michael addition reaction between
and b-nitrostyrene in aqueous medium, with benzoic acid as ad-
isobutyraldehyde and a range of aryl-substituted
both at ambient temperature and in aqueous media.
styrenes containing electron donor groups exhibited better
b
-nitrostyrenes,
ditive. First, an aliquot of a mixture of azide (S)-7 and iso-
butyraldehyde in aqueous media was directly introduced into the
electrospray source. Ion [m/z 333.207] corresponding to the
b
-Nitro-

G. Reyes-Rangel et al. / Tetrahedron 72 (2016) 379e391
385
Table 5
Scope of the use of azide (S)-7 as organocatalyst in the Michael addition reaction, employing various aryl-substituted nitroolefins as the electrophilic substrate
~
T (10 ꢀC), t ¼ 12 days
Room temperature, t ¼ 3 days
Product
R
Entry
Yield (%)
era
ee (%)
Entry
Yield(%)
era
ee (%)
Phe
1eI
2eI
3eI
4eI
5eI
6eI
7eI
8eI
89
94
95
63
d
97:3
96:4
85:15
95:5
d
94
92
70
90
d
1eII
2eII
3eII
4eII
5eII
6eII
7eII
8eII
93
98
82
79
83
Traces
88
80
75
80
97
77
74
93:7
92:8
71:29
90:10
81:19
n. d.
78:22
95:5
95:5
95:5
77:23
94:6
94:6
96:4
86
84
42
80
62
n. d.
56
90
90
90
54
88
88
92
(R)-26
p-CH3-C6H4e
o-CH3O-C6H4e
p-CH3O-C6H4e
2,3-CH3O,CH3O-C6H3e
p-BnO-C6H4e
o-Cl-C6H4e
m-Cl-C6H4e
p-Cl-C6H4e
2,3-Cl,Cl-C6H3e
o-Br-C6H4e
(R)-26a
(R)-26b
(R)-26c
(R)-26d
(R)-26e
(S)-26f
(R)-26g
(R)-26h
(R)-26i
(S)-26j
(R)-26k
(R)-26l
(R)-26m
d
d
d
92
81
58
33
51
d
84:16
97:3
97:3
97:3
81:19
d
68
94
94
94
62
d
9eI
9eII
10eI
11eI
12eI
13eI
14eI
10eII
11eII
12eII
13eII
14eII
p-Br-C6H4e
p-F-C6H4e
p-NO2-C6H4e
77
16
96:4
89:11
92
78
80
a
Determined by HPLC using chiral columns.
anticipated protonated enamine could be detected in the mass
spectrum. Subsequently, -nitrostyrene was added to the reaction
b
mixture and this was monitored by ESI-MS after stirring for 15 min.
A species with m/z¼482.257 uma was detected, which can be
assigned most securely to the dihydro-1,2-oxazine N-oxide (S)-7-II0
(Fig. 15), arising from the addition of the enamine to b-nitrostyrene.
Fig. 16. Proposed mechanism for the Michael addition reaction, organocatalyzed by
(S)-7.
these species might exist since the three of them present the same
m/z value.
Thus, we carried out 13C NMR experiments where an equimolar
mixture of proline azide (S)-7 and isobutyraldehyde in anhydrous
methanol-d4 showed signals corresponding to product A, resulting
from the addition of methoxide-d3 to the initial iminium ion. The
analogous species B and 7-I00 were respectively observed in the
presence of D2O and PhCO2H (Table 6). Species B and (S)-7-I00 might
suggest that the acidic additives (water, benzoic acid) play a more
determining role in the formation of the key enamine intermediate
(Fig. 15).
Fig. 15. Nucleophilic attack on the iminium double bond. Hemiaminal A0 was identified
by 13C NMR in the presence of water. Interestingly, enamine (S)-7-I was only barely
detected by ESI-MS TOF, which could suggest that this enamine is quickly consumed
once it is generated. The occurrence of Michael adduct only in aqueous media (see main
text) reinforces the importance of water for this catalytic system.
Based on precedent available in the literature,19,21e24 an equi-
librium involving the zwitterionic intermediate (S)-7-II as well as
the corresponding dihydro-1,2-oxazine N-oxide (S)-7-II0, in addi-
tion to a nitro-cyclobutane derivative can be advanced. Neverthe-
less, it is not possible to determine by ESI-MS the ratio in which
A 13C NMR experiment was run in anhydrous toluene-d8 seeking
to corroborate the existence of cyclobutane species as ‘resting state’
in the reaction pathway; however, the expected signals were not
observed. By contrast, we were able to confirm the formation of the

386
G. Reyes-Rangel et al. / Tetrahedron 72 (2016) 379e391
Table 6
Table 8
13C NMR chemical shifts for the products of addition to iminium intermediate
Evaluation of conditions in the a-aminomethylation of isovaleraldehyde catalyzed
by (S)-7
Entry Solvent
Additive
PhCO2H
Time (h) Yield (%)
era
ee (%)
13C NMRa (CD3OD, ppm)
A
B
(S)-7-I00
1
2
3
4
DMSO-H2O
86
65:35 30
66:34 32
67:33 34
78:22 56
24
54
24
80
4
1
4
5
6
7
47.95
65.82
103.85
35.09
17.65
18.00
77.53
47.88
47.60
67.81
103.75
34.86
17.82
17.44
74.32
d
47.81
67.40
96.96
33.76
17.85
17.58
73.62
171.75
DMSO
DMF
PhCO2H
PhCO2H
LiCl 1M, DMF PhCO2HeH2O
75
2
8
9
a
Determined by HPLC in chiral column OD-H with phase Hex:IPA (95:5).
a
Determined at 68 MHz.
Table 9
Evaluation of co-solvent and additive in the low-temperature (ꢁ20 ꢀC)
a-amino-
Table 7
methylation of isovaleraldehyde
13C NMR chemical shifts for main intermediates in the Michael addition reaction
between isobutyraldehyde and b-nitrostyrene
Entry
Solvent
Additive
Time (h)
Yield (%)
era
ee (%)
1
2
3
4
5
6
7
LiCl 1M, DMF
LiCl 1M, DMF
DMF
PhCO2H
PhCO2H
PhCO2H
PhCO2H
MeCO2H
MeCO2H
MeCO2H
24
2
83
38
82
85
66
65
90
80:20
84:16
67:33
71:29
78:22
76:24
65:35
60
68
34
42
56
52
30
24
24
24
48
24
d
13C NMRa (toluene-d8, ppm)
(S)-7-II00
(S)-7-III
LiCl 1M, DMF
LiCl 1M, DMF
DMF
1
4
5
6
7
8
9
10
47.21
71.00
94.85
54.74
17.71
78.33
40.88
132.03
48.48
71.72
87.67
43.72
18.28
76.53
41.25
75.97
a
Determined by HPLC in chiral column OD-H with phase Hex:IPA (95:5).
Although the reaction yields were usually good, not so the ob-
served enantioinduction, as ee values are quite moderate (entries 3
and 4 in Table 9). Aiming to improve the stereoselectivity, LiCl 1M in
DMF was selected as the reaction medium for the following tests.
Furthermore, the reactions were cooled to ꢁ20 ꢀC. The results are
collected in Table 9, and the relevance of lithium chloride is evident
as the enantioselectivity was doubled in comparison with tests
without this additive (Cf. entries 1 vs 3, 6 vs 7 in Table 9). The
presence of benzoic acid afforded slightly better results, compared
to the ones obtained with acetic acid. On the other hand, a decrease
of the reaction time resulted in a slight increase of the enantiomeric
excess but with a significant reduction in yield (entries 1 and 2 in
Table 9).
a
Determined at 68 MHz.
dihydro-1,2-oxazine N-oxide (S)-7-II0 (Table 7). In the presence of
toluene-d8þD2O, it was possible to observe species (S)-7-II0 as well
as (S)-7-III, arising from nucleophilic attack of water (Fig. 15). The
occurrence of the Michael adduct (R)-26 at this point also supports
the role of water in the hydrolysis of intermediate (S)-7-II and the
subsequent reincorporation of (S)-7 in the catalytic cycle.
Therefore, based on our spectroscopic observations as well as
literature precedent, we propose the mechanism depicted in Fig. 16
for the Michael reaction catalyzed by the azide (S)-7.
3. Conclusions
The asymmetric Michael addition reaction has become a refer-
ence reaction for the evaluation of the effectiveness of potential
organocatalysts. In addition, the appropriate choice of the reaction
media and/or the use of additives (among other variables) can help
optimize the reaction of interest.
2.6. Evaluation of pyrrolidine azide (S)-7 as organocatalyst in
the asymmetric Mannich addition reaction
In order to expand the scope of application, proline azide (S)-7
was evaluated as catalyst in the Mannich type reaction developed
by Gellman et al.25 Thus, N-benzyl-N-(methoxymethyl) (phenyl)-
methanamine C (imine precursor) was prepared in quantitative
yield according to the procedure described by Stewart and Brad-
ley.26 Initially, experiments were carried out at room temperature
and employing benzoic acid as additive instead of acetic acid. For
the rest of the experiments, the conditions employed by Gellman
Fig. 17. Use of chiral proline-azide (S)-7 as organocatalyst in the asymmetric Michael
addition reaction of isobutyraldehyde and b-nitrostyrenes.
and Cordova were followed.25,27 The results are gathered in Table 8.
ꢀ

G. Reyes-Rangel et al. / Tetrahedron 72 (2016) 379e391
387
In the specific case of the NeH amines derived from (S)-proline
and containing a gem-diphenyl fragment that were examined in
this work [(S)-5, (S)-7, (S)-19e23, (S)-25], derivative (S)-7 turned
out to be the best organocatalyst for the asymmetric Michael ad-
dition reaction. Furthermore, benzoic acid was identified as a con-
venient Brønsted acid additive (co-catalyst) (Fig. 17).
TOF [MþH]þ (m/z) calcd for [C31H30N2OþH]þ: 447. 24,309; found:
447.24307.
4.1.2. (S)-1-[(1-Benzylpyrrolidin-2-yl)diphenylmethyl]-3-
phenylthiourea, (S)-9. Diamine (S)-4 (0.455 g, 1.33 mmol) was
placed in a 50-mL round bottomed flask provided with magnetic
stirring bar and under N2 atmosphere before the addition of 15 mL
of anhydrous THF via cannula. The resulting solution was cooled to
The use of water and isopropanolewater (3:1) as solvent (at-
tractive from an ecological point of view28) proved suitable for the
Michael reaction between isobutyraldehyde and
b
-nitrostyrene. It
0
ꢀC before the dropwise addition of 0.41 mL (0.288 g, 2.1 mmol,
is indeed remarkable that amino azide (S)-7 tolerates quite well
aqueous media in the promotion of Michael reactions. In this
regard, isopropanol and water are considered innocuous solvents;
by contrast, the JørgenseneHayashi catalyst3 usually requires the
use of potentially toxic solvents such as hexane,3b toluene,
CH2Cl2,29 PhCF330 and even benzene.19 Furthermore, by comparison
with other proline derivatives, where the diphenylsilylether is
replaced by fluorine,31 azide (S)-7 is remarkably stable, suppressing
the possibility of an undesirable acid hydrolysis.
1.6 equiv) of phenyl isothiocyanate. The reaction mixture was
stirred during 3 days at room temperature under inert atmosphere.
The THF was evaporated under reduced pressure, and the crude
product was redissolved in 10 mL of warm CH2Cl2. Hexane (10 mL)
was then added to induce the precipitation of the product. Re-
crystallization from hexane:CH2Cl2 (1:1) afforded 0.584 g (92%
yield) of the N-benzylated thiourea (S)-9. Rf 0.4 (hexane:CH2Cl2,
25
1:1), mp 152 ꢀC, [
a]
¼ þ153 (c¼1.0, CHCl3); dH (CDCl3, 270 MHz):
D
1.57e1.93 (m, 2H, CH2CH2CH2), 2.02e2.17 (m, 1H, CH2CH2CH), 2.28
*
With regard to the Mannich type addition reaction, proline
azide (S)-7 resulted less efficient than its silylether counterpart.
(ddd, 1H, J¼17.7, 13.1, 9.2 Hz, CH2CH2CH), 2.56 (td, 1H, J¼9.9, 6.6 Hz,
*
CH2CH2N), 2.89 (ddd, 1H, J¼9.9, 5.5, 4.5 Hz, CH2CH2N), 3.36 (d, 1H,
J¼12.1 Hz, NeCH2Ph), 3.97 (d, 1H, J¼12.1 Hz, NeCH2Ph), 4.50 (dd,
1H, J¼9.2, 3.4 Hz, CH2CH2
*
CHe), 6.59e6.66 (m, 2H, ArH), 6.86e6.98
4. Experimental section
4.1. General
(m, 5H, ArH), 7.00e7.16 (m, 4H, ArH), 7.18e7.43 (m, 5H, ArH),
7.46e7.53 (m, 2H, ArH), 7.62e7.70 (m, 2H, ArH), 11.7e12.6 (a, 1H,
NH); dC (CDCl3, 68 MHz): 24.07 (CH2CH2CH2), 30.37 (CH2CH2CH),
*
54.92 (CH2CH2N), 62.87 (NeCH2Ph), 70.80 (N*CHCH2), 74.04
[-C(Ph2)-NH(C]S)], ArC: 125.15, 125.41, 126.64, 127.30, 127.56,
128.22, 128.26, 128.31, 128.45, 129.03, 137.46 (C-ipso), 139.37 (C-
ipso), 140.92 (C-ipso), 145.38 (C-ipso), 182.00 [NH(C]S)eNHPh]. IR
ṽmax (KBr) cmꢁ1: 3421, 3061, 2952, 2825, 2656, 1953, 1888, 1813,
1562, 1488, 1447, 1360, 1265, 1200, 1076, 1031, 863, 742, 703. MS (IE)
m/z (%): 326 (2), 161 (15), 160 (100), 135 (14), 91 (29). HR-ESI-TOF
[MþH]þ (m/z) calcd for [C31H31N3SþH]þ: 478. 23,115; found:
478.23101. Crystal data for (S)-9: C31H31N3S, monoclinic, space
For general information, optimized synthetic protocols and de-
tailed characterization data in the preparation of compounds pre-
viously reported in the literature, 1H and 13C NMR spectra, and
HPLC chromatograms, see the Supplementary data.
X-ray crystallographic analysis was carried out in an Enraf-
Nonius Kappa CCD diffractometer. Programs SHELX-97,32 and
WinGX,33 were used for solving and refining, while graphics were
obtained with the Diamond 2.1 software. The collected structures
(atomic coordinates) were deposited in the database of the Cam-
bridge Crystallographic Data Centre (http://www.ccdc.cam.ac.uk/).
ꢂ
ꢂ
ꢂ
group P 21, Z¼4, a¼10.0814(3) A, b¼15.4528(5) A, c¼17.4317(6) A,
3
ꢀ
ꢂ
a
¼90ꢀ,
b
¼105.2970(10)ꢀ,
g
¼90 , V¼2619.38(0) A , crystal size:
0.3ꢂ0.2ꢂ0.1 mm3, R1¼0.084 (wR2¼0.2496). CCDC 1440766 con-
tains supplementary crystallographic data for this paper. These
data can be obtained free of charge from the Cambridge Crystal-
lographic Data Centre.
4.1.1. (S)-N-[(1-Benzylpyrrolidin-2-yl)diphenylmethyl]
benzamide,
(S)-8. In a round bottomed flask provided with a magnetic stirring
bar was added 0.7 g (2 mmol) of diamine (S)-4, and 0.5 equiv of
DMAP. The flask was purged with nitrogen before the addition of
25 mL of anhyd. THF and the resulting solution was cooled to 0 ꢀC.
Et3N (0.27 g, 0.37 mL, 2.7 mmol,1.3 equiv) and BzCl (0.35 g, 0.29 mL,
2.5 mmol, 1.2 equiv) were added simultaneously, and the reaction
mixture was stirred during 3 days at rt. The reaction mixture was
concentrated and the crude product was extracted twice with brine
and ethyl acetate. The combined organic phase was dried with
anhyd. Na2SO4, the solvent was evaporated, and the concentrate
was purified by flash chromatography, with CH2Cl2:EtOAc (9:1) as
eluent, obtaining benzamide (S)-8 in 78% yield (0.713 g) as a foam.
dH (CDCl3, 500 MHz): 0.48e0.59 (m, 1H, CH2CH2CH2), 1.34e1.42 (m,
4.1.3. (S)-1,1-Diphenyl-hexahydropyrrolo[1,2-e]imidazole-3-thione,
(S)-11. A glass vessel for hydrogenation containing 0.5 g of phen-
ylthiourea (S)-9, 120 mL of methanol:CH2Cl2 (5:1) and a catalytic
amount of acetic acid was purged with nitrogen before the addition
of Pd(OH)2/C 20%-w (0.1 g). The container was pressurized to 120
psi of hydrogen and the reaction mixture was mechanically stirred
during 20 h at 60 ꢀC. The reactor was cooled to room temperature
and depressurized. The palladium catalyst was filtered over Celite,
washing the paste with MeOH and CH2Cl2. The filtrate was con-
centrated, dried under reduced pressure, and purified by CC,
1H, CH2CH2CH2), 1.80e1.88 (m, 1H, CH2CH2
CH2CH2
CH), 2.31 (ddd, 1H, J¼9.5, 6.7, 0.3 Hz, CH2CH2N), 2.76 (ddd,
1H, J¼9.5, 6.7, 2.8 Hz, CH2CH2N), 3.46 (d, 1H, J¼13.4 Hz, NCH2Ph),
CHN),
*
CH), 1.94e2.05 (m, 1H,
employing CH2Cl2:EtOAc (8:2) as eluent. Cyclic thiourea (S)-11 was
*
25
obtained as a white powder (0.133 g, 43% yield), mp 178 ꢀC, [
a]
¼
D
ꢁ478 (c¼1.03, CHCl3); dH (CDCl3, 270 MHz): 1.07 (dtd, 1H, J¼12.4,
10.7, 8.7 Hz, CH2CH2
CH), 1.58 (dtd, 1H, J¼12.4, 6.1, 2.4 Hz,
CH2CH2
CH), 1.83e2.09 (m, 2H, CH2CH2CH2), 3.47 (ddd, 1H, J¼11.5,
8.8, 4.0 Hz, CH2CH2N), 3.98 (ddd, 1H, J¼11.4, 8.4, 8.2 Hz, CH2CH2N),
4.76 (dd 10.6, 5.8 Hz, CH2CH2CH-), 6.67e6.82 [a, 1H, NH(C]S)],
7.18e7.24 (m, 2H, ArH), 7.25e7.4 (m, 8H, ArH); dC (CDCl3, 68 MHz):
3.94 (d, 1H, J¼13.4 Hz, NCH2Ph), 4.53 (dd, 1H, J¼9.2, 3.3 CH2
*
*
7.16e7.41 (m, 13H, ArH), 7.44e7.52 (m, 3H, ArH), 7.58e7.61 (m, 2H,
ArH), 7.63 (b, 1H, NH), 7.74e7.78 (m, 2H, ArH); dC (CDCl3, 125 MHz):
*
23.88 (CH2CH2CH2), 30.42 (CH2CH2CH), 55.57 (CH2CH2N), 62.08
*
(NeCH2Ph), 68.57 [-C(Ph2)NHPh], 68.66 (N*CHCH2), ArC: 126.65,
126.97, 127.21, 127.57, 127.89, 128.25, 128.5, 128.69, 128.77, 128.94,
131.41, 135.65 [NH(C]O)eC6H5, C-ipso], 140.68 (NCH2Ph, C-ipso),
142.57, 143.9 [ꢁC(C6H5)2NHe,C-ipso], 166.61 [NH(C]O)Ph]. IR ṽmax
*
25.33 (CH2eCH2eCH2-), 28.65 (CH2CH2CH), 47.26 (CH2CH2N), 70.68
*
[-C(Ph2)-NH(C]S)], 73.48 (N*CHCH2), ArC: 126.56, 126.95, 127.68,
127.97, 128.35, 128.76, 140.66 (C-ipso), 144.41 (C-ipso), 184.41
[NH(C]S)eNe]. IR ṽmax (ATR) cmꢁ1: 3171 (a), 2941, 1898, 1808,
1681, 1600, 1476, 1447, 1269, 1230, 1159, 1095, 1018, 994, 915, 878,
(KBr) cmꢁ1: 3310 (NeH,
n), 2960, 2794, 1884, 1821, 1666 (29% T, C]
O), 1580, 1482, 1282, 1116, 1070, 1030, 918, 758, 702, 622. MS (IE) m/
z (%): 288 (1), 287 (3), 161 (16), 160 (100), 105 (9), 91 (30). HR-ESI-

388
G. Reyes-Rangel et al. / Tetrahedron 72 (2016) 379e391
750, 699, 655. HR-ESI-TOF [MþH]þ (m/z) calcd for [C18H18N2SþH]þ:
295.12635; found: 295.12686. Crystal data for (S)-11: C18H18N2S,
becomes colorless). 40 mL of water was added and the resulting
mixture was extracted with EtOAc (2ꢂ50 mL). The combined or-
ganic extracts were washed with 0.5 M H3PO4, with a saturated
solution of NaHCO3 and brine, dried with anhyd. Na2SO4, filtered,
and concentrated. The crude product was purified by chromatog-
ꢂ
ꢂ
monoclinic, space group P21, Z¼4; a¼8.4350(17) A, b¼21.406(4) A,
3
ꢂ
ꢀ
ꢂ
c¼9.6470(19) A,
a
¼90ꢀ,
b
¼113.423(0)ꢀ,
g
¼90 , V¼1598.38(0) A ,
crystal size: 0.4ꢂ0.4ꢂ0.25 mm3, R1¼0.0737 (wR2¼0.1769). CCDC
1440768 contains supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cam-
bridge Crystallographic Data Centre.
raphy using hexane-EtOAc (90:10) as eluent, to give 366.24 mg (51%
25
yield) of the desired sulfonamide (S)-14 as a pale yellow oil. [
a
]
¼
D
ꢁ161 (c¼1.03, CHCl3); dH (DMSO-d6, 120 ꢀC, 500 MHz): 1.23e1.39
(m, 2H, CH2CH2CH2), 1.51 [s, 9H, eC(CH3)3], 1.60 (dddd, 1H, J¼13.9,
4.1.4. t-Butyl (S)-2-(azidodiphenylmethyl)pyrrolidine-1-carboxylate,
(S)-12. In a 500-mL round bottomed flask provided with magnetic
stirrer, 2.11 g of azide (S)-7 (7. 58 mmol) was flushed with Ar, before
the addition of 150 mL of anhyd. CH2Cl2 via cannula. The resulting
solution was cooled to 0 ꢀC, before the addition by means of a sy-
ringe of 1.1 mL (0.77 g, 7.58 mmol, 1 equiv) of Et3N, and the reaction
mixture was stirred during 10 min at 0 ꢀC. Separately, 1.65 g of di-t-
butyl carbonate (7.58 mmol, 1 equiv) was dissolved in 3 mL of an-
hydrous CH2Cl2 and added to the flask, stirring the resulting re-
action mixture for 1 h at 0 ꢀC and for 12 h at rt. The resulting
mixture was treated with 100 mL of saturated aqueous NH4Cl, and
the aqueous phase was extracted twice with CH2Cl2. The combined
organic phase was washed with water until neutral pH. The com-
bined organic phase was dried with anhyd. Na2SO4, filtered and
concentrated. The crude product was purified by CC [hexane:EtOAc
8.9, 6.3, 4.4 Hz, CH2CH2
*
CH), 1.67 (dt, 1H, J¼11.0, 8.0 Hz, CH2CH2N),
2.05 (dtd, 1H, J¼14.2, 9.5, 6.1, CH2CH2
CH3), 3.25 (ddd, 1H, J¼10.9, 8.9, 4.7 Hz, CH2CH2N), 5.08 (dd, 1H,
J¼9.3, 4.3 Hz, CH2CHN), ArH: 6.92e7.0 (m, 4H), 7.02e7.07 (m, 2H),
7.08e7.13 (m, 1H); 8.98 (a, 1H, NH); dC (DMSO-d6, 120 ꢀC, 125 MHz):
20.30 (C6H4-pCH3), 22.10 (CH2CH2CH2), 27.46 (CH2CH2CH), 27.74
[eC(CH3)3], 46.91 (CH2CH2N), 65.93 (N CHCH2), 71.78 [eC(Ph2)e
*
CH), 2.27 (s, 3H, eC6H4ep-
*
*
*
NHTs], 80.47 [(H3C)3CeO], ArC: 125.11,126.45,126.65,126.83,128.10,
129.16, 129.93, C-ipso: 137.57, 138.76, 140.18, 140.66; 156.71 [eN(C]
O)OtBu]. IR ṽmax (ATR) cmꢁ1: 1653 (C]O), 1443, 1412, 1381, 1329,
1154, 1117, 1092, 1056, 895, 858, 812, 772, 698, 658. HR-ESI-TOF
[MþH]þ (m/z) calcd for [C29H34N2O4SþNa]þ: 529.2132; found:
529.2131.
4.1.6. (S)-t-Butyl 2-(benzamidodiphenylmethyl)pyrrolidine-1-
carboxylate, (S)-15. In a round bottom flask (100 mL) conditioned
with nitrogen atmosphere, 4 g (11.3 mmol) of diphenylmethan-
amine (S)-13 was dissolved in 35 mL of anhyd. THF and 4.11 mL of
Et3N (2.98 g, 29.5 mmol, 2.6 equiv). The reaction flask was cooled in
an ice bath before the addition of 3.16 mL (3.83 g, 27.2 mmol,
2.4 equiv) of benzoyl chloride. The reaction mixture was allowed to
warm up to rt and then stirred for 3 days. The THF was evaporated
and the residue was extracted with CH2Cl2, the organic phase was
concentrated under reduced pressure and the crude product was
purified by CC with hexane:CH2Cl2:EtOAc (5:4:1) as eluent. The
(95:5)], obtaining 2.62 g (91% yield) of N-Boc azide (S)-12 as a pale
25
yellow oil. [
a
]
¼ þ13 (c¼1.0, CHCl3); dH (DMSO-d6, 120 ꢀC,
D
500 MHz): 1.11e1.21 (m, 1H, CH2CH2CH2), 1.30 [s, 9H, eC(CH3)3],
1.56 (ddtd, 1H, J¼13.1, 12.2, 6.0, 3.9 Hz, CH2CH2CH2), 1.80 (dddd, 1H,
J¼13.1, 9.0, 3.7, 2.2 Hz, CH2CH2CH), 2.16 (dddd, 1H, J¼18.7, 13.3, 8.9,
*
1.1 Hz, CH2CH2
3.46 (ddd, 1H, J¼10.7, 9.0, 6.3 Hz, CH2CH2N), 5.07 (dd, 1H, J¼8.9,
2.2 Hz, CH
2CHN), 7.25e7.39 (m, 10H, ArH); dC (DMSO-d6, 120 ꢀC,
125 MHz): 22.10 (CH2CH2CH2), 27.45 [eC(CH3)3], 27.61
(CH2CH2CH), 46.82 (CH2CH2N), 62.11 (N CHCH2), 76.09 [eC(Ph2)e
N3], 78.18 [(H3C)3CeO], ArC: 127.51,127.16,127.32,127.75,139.79 (C-
*
CH), 2.76 (ddd, 1H, J¼10.7, 9.0, 5.7 Hz, CH2CH2N),
*
*
*
product (4.86 g, 94% yield) was obtained as a solid, mp 153 ꢀC,
25
ipso), 140.10 (C-ipso); 154.16 [eN(C]O)OtBu]. IR ṽmax (ATR) cmꢁ1
:
[a
]
¼ þ30 (c¼1.02, CHCl3); dH (DMSO-d6, 120 ꢀC, 500 MHz): 0.76
D
2975, 2927, 2103 (eN]Nþ¼Nꢁ), 1692 (C]O), 1447, 1384, 1363,
1254, 1163, 1116, 959, 901, 870, 761, 700. HR-ESI-TOF [MþH]þ (m/z)
calcd for [C22H26N4O2þH]þ: 379.2129, found: 379.2129; (m/z) calcd
for [C22H26N4O2þNa]þ: 401.1948, found: 401.1946.
(ddtd, 1H, J¼12.6, 8.3, 8.0, 6.0 Hz, CH2CH2CH2), 1.34e1.45 (m, 1H,
CH2CH2CH2), 1.48 [s, 9H, eC(CH3)3], 1.74 (dddd, 1H, J¼12.6, 10.0, 4.9,
3.9 Hz, CH2CH2
*
CH), 2.01 (ddd, 1H, J¼10.9, 8.3, 6.6 Hz, CH2CH2N),
*
2.14 (dtd, 1H, J¼13.8, 9.6, 7.7 Hz, CH2CH2
CH), 3.32 (ddd, 1H, J¼10.9,
CHN), ArH:
8.7, 5.9 Hz, CH2CH2N), 5.34 (dd, 1H, J¼9.5, 3.4 Hz, CH2
*
4.1.5. (S)-t-Butyl 2-[(4-methylphenylsulfonamido)diphenyl methyl]
pyrrolidine-1-carboxylate, (S)-14. (a) In a three-necked round bot-
tom flask equipped with addition funnel, oil trap, magnetic stirring
bar and argon atmosphere, imidazole (5.502 g, 0.081 mol) was
dissolved in 25 mL of anhyd. CH2Cl2. The solution was cooled to 0 ꢀC
and then 6.78 g (0.036 mol) of p-toluenesulfonyl chloride dissolved
in 25 mL of anhydrous methylene chloride was added dropwise. The
resulting mixture was stirred during 2 h at rt and then filtered over
silica, and the remnant solid was washed with 50 mL of a hex-
aneeEtOAc (1:1). The filtrate was concentrated in the rotary evap-
orator, redissolved in 6 mL of EtOAc, and induced to precipitate upon
addition of 60 mL of hexane. The resulting white solid was filtered
and dried to give 7.12 g of 1-tosyl-1H-imidazol (0.032 mol, 89%
yield).34 (b) In a round-bottomed flask provided with magnetic
stirring bar and under argon atmosphere, 378.4 mg (1.702 mmol,
1.2 equiv) of 1-tosyl-1H-imidazol was dissolved in 50 mL of anhyd.
THF. The resulting solution was cooled to 0 ꢀC before the slow ad-
dition of 0.186 mL of methyl trifluoromethanesulfonate (0.279 g,
1.702 mmol,1.2 equiv) to produce a milky solution of the sulfonating
agent [triflate of 1-(p-toluenesulfonyl)-3-methylimidazolium].15
Meanwhile, 500 mg (1.419 mmol, 1.0 equiv) of amine (S)-13 was
dissolved in 10 mL of anhydrous THF, the resulting solution was
cooled to 0 ꢀC and treated (slow addition) with the sulfamoylating
agent. The reaction mixture was stirred at 0 ꢀC for 30 min and for
76 h at room temperature (during this time the reaction mixture
7.24e7.29 (m, 1H), 7.3e7.38 (m, 7H), 7.38e7.44 (m, 2H), 7.46e7.51
(m, 1H), 7.8e7.86 (m, 4H); 9.68 (b, 1H, NH). dC (DMSO-d6, 120 ꢀC,
125 MHz): 22.00 (CH2CH2CH2), 26.75 (CH2CH2
*
CH), 27.59
[eC(CH3)3], 46.96 (CH2CH2N), 64.08 (N CHCH2), 68.91 [C(Ph2)
*
NHBz], 79.97 [(H3C)3CeO], ArC: 126.17, 126.42, 126.46, 127.49,
128.23, 128.90, 130.24, C-ipso: 134.83, 137.16, 141.23; [eN(C]O)
OtBu] 157.07, 163.40 [eNH(C]O)Ph]. IR ṽmax (ATR) cmꢁ1: 3307 (a),
3057, 2976, 1662 (C]O), 1579, 1539, 1490, 1448, 1391, 1365, 1298,
1246, 1158, 1127, 1100, 1032, 983, 897, 856, 771, 734, 698. HR-ESI-
TOF [MþH]þ (m/z) calcd for [C29H32N2O3þH]þ: 457.2486; found:
457.2489. Elemental Analysis calcd for C29H32N2O3 (456.24): C
76.29, H 7.06, N 6.14; found: C 76.26, H 7.25, N 6.04. Crystal data for
(S)-15:
C
29H32N2O3, monoclinic, space group
P
21, Z¼2;
ꢂ
ꢂ
ꢂ
a¼8.3110(0) A, b¼15.6870(0) A, c¼10.6000(0) A,
a
¼90ꢀ,
3
ꢂ
b
¼111.040(0)ꢀ,
g
¼90ꢀ,
V¼1289.84(0)
A ,
crystal
size:
0.75ꢂ0.35ꢂ0.25 mm3, R1¼0.0574 (wR2¼0.1560). CCDC 1440769
contains supplementary crystallographic data for this paper. These
data can be obtained free of charge from the Cambridge Crystal-
lographic Data Centre.
4.1.7. (S)-t-Butyl 2-(acetamidodiphenylmethyl)pyrrolidine-1-
carboxylate, (S)-16. The procedure employed for the preparation
of (S)-15 was followed, with 0.647 g (1.84 mmol) of (S)-13, 0.7 mL
(2.6 equiv, 4.6 mmol, 0.483 g) of Et3N, and 0.3 mL (2.4 equiv,
4.41 mmol, 0.346 g) of acetyl chloride, obtaining 0.622 g of product

G. Reyes-Rangel et al. / Tetrahedron 72 (2016) 379e391
389
25
(S)-16 as a white solid (86% yield), mp 147 ꢀC, [
a]
¼ ꢁ74 (c¼1.09,
0.676 g (5.07 mmol, 4 equiv) of AlCl3 in 35 mL of anhydrous THF,
D
CHCl3); dH (DMSO-d6, 120 ꢀC, 500 MHz): 0.5e0.63 y 1.26e1.40 (m,
2H, CH2CH2CH2), 1.51 [s, 9H, eC(CH3)3], 1.69 (td, 1H, J¼8.2, 3.9 Hz,
and 0.607 g (15.21 mmol, 12 equiv) of LiAlH4. Product (S)-18 was
25
obtained in 64% yield (0.308 g), [
a
]
¼ꢁ6 (c¼1.04, CHCl3); dH
D
CH2CH2
*
CH), 1.77 [s, 3H, eNH(C]O)CH3], 2.03e2.16 (m, 2H,
CH, CH2CH2N), 3.28 (ddd, 1H, J¼10.7, 8.6, 6.6 Hz, CH2CH2N),
(DMSO-d6, 100 ꢀC, 500 MHz): 0.64 (dtdd, 1H, J¼12.1, 8.7, 8.6, 5.8 Hz,
CH2CH2CH2), 0.89 (t, 3H, J¼7.0 Hz, eNH-CH2CH3), 1.25e1.38 (m, 1H,
CH2CH2CH2),1.44 [s, 9H, eC(CH3)3],1.77 (dtd,1H, J¼13.5, 4.4, 3.2 Hz,
CH2CH2
*
5.17 (dd, 1H, J¼9.2, 3.0 Hz, CH
*
2CHN), ArH: 7.21e7.33 (m, 8H),
7.67e7.71 (m, 2H); 8.91 (a, 1H, NH). dC (DMSO-d6, 120 ꢀC, 125 MHz):
21.74 (CH2CH2CH2), 23.09 [eNH(C]O)CH3], 26.72 (CH2CH2CH),
27.57 [eC(CH3)3], 47.05 (CH2CH2N), 63.69 (N CHCH2), 68.45
CH2CH2
*
CH), 1.95e2.10 (m, 4H, eNH-CH2CH3, CH2CH2CH, CH2CH2N),
*
*
3.24 (ddd, 1H, J¼10.7, 9.2, 5.9 Hz, CH2CH2N), 5.03 (dd, 1H, J¼9.2,
2.9 Hz, CH2CHN), ArH: 7.21e7.36 (m, 8H), 7.39e7.44 (m, 2H). dC
(DMSO-d6, 100 ꢀC, 125 MHz): 15.03 (eNH-CH2CH3), 22.12
(CH2CH2CH2), 27.34 (CH2CH2CH), 27.82 [eC(CH3)3], 36.57
(NHCH2CH3), 47.01 (CH2CH2N), 62.83 (N CHCH2), 70.18 [eC(Ph2)e
*
*
[eC(Ph2)eNHAc], 69.75 [(H3C)3CeO], ArC: 126.05, 126.31, 126.46,
128.26, 128.66, C-ipso: 137.68, 141.85; [eN(C]O)OtBu] 156.89,
165.78 [eNH(C]O)CH3]. IR ṽmax (ATR) cmꢁ1: 3298, 3051, 2978,
2926, 2894, 1676 (C]O), 1663 (C]O), 1547, 1476, 1452, 1380, 1363,
1295, 1249, 1159, 1129, 1092, 917, 859, 774, 743, 715, 701, 643. HR-
ESI-TOF [MþH]þ (m/z) calcd for [C24H30N2O3þH]þ: 395.2329;
found: 395.2330. Elemental analysis calcd for C29H32N2O3 (394.23):
C 73.07, H 7.66, N 7.10; found: C 73.47, H 8.04, N 7.18. Crystal data for
*
*
NHeEt], 78.31 [(H3C)3CeO], ArC: 125.80, 126.22, 126.62, 126.98,
128.55, 129.34, C-ipso: 141.08, 142.60; 155.30 [eN(C]O)OtBu]. IR
ṽmax (ATR) cmꢁ1: 3344, 2971, 1665 (C]O), 1456, 1388, 1363, 1290,
1253, 1163, 1120, 1032, 985, 907, 866, 766, 703. HR-ESI-TOF [MþH]þ
(m/z) calcd for [C24H32N2O2þH]þ: 381.2537; found: 381.2544.
(S)-16:
C
24H30N2O3, monoclinic, space group P21, Z¼2;
a¼7.2485(2) A, b¼15.0589(5) A, c¼10.5499(3) A,
a
¼90ꢀ,
4.3. (S)-N-[Diphenyl(pyrrolidin-2-yl)methyl]-4-
methylbenzene sulfonamide, (S)-19
ꢂ ꢂ ꢂ
3
ꢂ
b
¼95.930(2)ꢀ,
g
¼90ꢀ,
V¼1145.35(0)
A ,
crystal
size:
0.25ꢂ0.25ꢂ0.125 mm3, R1¼0.0434 (wR2¼0.1155). CCDC 1440770
contains supplementary crystallographic data for this paper. These
data can be obtained free of charge from the Cambridge Crystal-
lographic Data Centre.
In a 25-mL round bottom flask provided with magnetic stirrer,
was placed 246 mg (0.48 mmol) of sulfonamide (S)-14. The flask
was cooled in an ice bath before the slow addition of 1.0 mL of
formic acid, and the resulting mixture was stirred at room tem-
perature during 18 h. The reaction mixture was neutralized with
ammonium hydroxide at 0 ꢀC, extracted with EtOAc, the combined
organic phase was washed with brine and dried with Na2SO4. The
organic phase was concentrated under vacuum and the crude
product was purified by silica gel column chromatography using
4.2. General procedure 1. Reduction of the amide carbonyl
group with AlH3
A round bottom flask provided with magnetic stirrer and con-
taining anhyd. THF was cooled under N2 atmosphere to 0 ꢀC before
the addition of AlCl3. The resulting suspension was treated with
3 equiv of LiAlH4 and the resulting mixture was stirred during
30 min at room temperature. A THF solution of the corresponding
amide was added and the resulting mixture was stirred for 18 h at
room temperature before it was slowly poured onto crushed ice.
Acetic acid was added to this mixture in order to maintain a slightly
acidic pH. The resulting emulsion was diluted with EtOAc, filtered
over Celite and the biphasic mixture was separated, extracting the
aqueous phase with two portions of EtOAc. The combined organic
phase was dried with anhyd. Na2SO4, filtered and concentrated. The
residue was purified by silica gel column chromatography, using
hexane-EtOAc (90:10) as eluent.
a gradient CH2Cl2 / [CH2Cl2eMeOH (95:5)]. The expected product
25
(S)-19 (167 mg, 85% yield) was obtained as a colorless oil. [
a
]
¼
D
ꢁ28 (c¼1.03, CHCl3); dH (CDCl3, 500 MHz): 1.23e1.34 (m, 1H,
CH2CH2CH2), 1.51e1.68 (m, 2H, CH2CH2CH), 1.72e1.82 (m, 1H,
CH2CH2CH), 2.31 (s, 3H, Ph-CH3), 2.68e2.74 (m, 1H, NeCH2CH2),
CH),
*
*
2.77e2.84 (m,1H, NCH2CH2), 4.21 (dd,1H, J¼7.5, 7.2 Hz, CH2CH2
*
6.47 (a, 1H, NHSO2pTol), 6.92e6.97 (d, 2H, J¼8.0 Hz, ArH), 7.05e7.27
(m, 12H, ArH). dC (CDCl3, 125 MHz): 21.35 (Ph-CH3), 25.58
(CH2CH2CH2), 28.48 (CH2CH2
*
CH), 46.36 (CH2CH2N), 65.66
(N CHCH2), 69.94 [C(Ph2)NHTs], ArC: 126.62, 127.02, 127.09, 127.39,
*
128.68, 129.27, 129.71, C-ipso: 139.37, 140.78, 141.81, 141.94. IR ṽmax
(ATR) cmꢁ1: 3351, 3258, 2923, 1749, 1522, 1385, 1303, 1154, 1095,
1052, 900, 812, 703, 664. HR-ESI-TOF [MþH]þ (m/z) calcd for
[C24H26N2O2SþH]þ: 407.1788; found: 407.1791.
4.2.1. (S)-t-Butyl 2-[(benzylamino)diphenylmethyl]pyrrolidine-1-
carboxylate, (S)-17. The general procedure was followed with
1.04 gof amide (S)-15 (2.28 mmol,1 equiv),1.22 gofAlCl3 (9.11 mmol,
4.4. General procedure 2. Removal of the N-Boc group with
4 equiv) and 1.10 g of LiAlH4 (27.33 mmol, 12 equiv). The reduced
CF3CO2H
25
product (S)-17 was obtained in 50% yield (0.504 g), [
a
]
¼ þ13
D
(c¼1.03, CHCl3); dH (DMSO-d6, 100 ꢀC, 500 MHz): 0.62 (ddtd, 1H,
J¼12.4, 8.6, 8.5, 6.0 Hz, CH2CH2CH2), 1.29e1.4 (m, 1H, CH2CH2CH2),
1.36 [s, 9H, eC(CH3)3], 1.79 (dddd, 1H, J¼13.3, 8.8, 4.5, 3.6 Hz,
In a round bottom flask conditioned with inert atmosphere was
placed the N-Boc protected substrate and dissolved in a small
quantity of dry CH2Cl2 (w13.5 mL/g). TFA (1e8 mL/g) was added at
CH2CH2
*
CH), 2.02e2.14 (m, 2H, CH2CH2
*
CH, CH2CH2N), 2.65 (b, 1H,
0
ꢀC and the reaction mixture was stirred at this temperature
eNHBn), 3.11e3.21 (m, 1H, eNHCH2Ph), 3.21e3.3 (m, 2H, CH2CH2N,
eNHCH2Ph), 5.13 (dd, 1H, J¼9.2, 2.7 Hz, CH2CHN), ArH: 7.1e7.6 (m,
15H). dC (DMSO-d6, 100 ꢀC, 125 MHz): 22.15 (CH2CH2CH2), 27.35
(CH2CH2CH), 27.72 [eC(CH3)3], 46.61 (NHCH2Ph) 47.07 (CH2CH2N),
63.11 (N CHCH2), 70.36 [eC(Ph2)eNHBn], 78.45 [(H3C)3CeO], ArC:
125.88, 126.03, 126.46, 126.78, 127.18, 127.46, 128.50, 129.48, C-ipso:
140.28, 140.69, 142.17; 155.44 [eN(C]O)OtBu]. IR ṽmax (ATR) cmꢁ1
during 10 min and then overnight at rt. The resulting solution was
treated with 1 M NaOH and extracted twice with CH2Cl2. The or-
ganic phase was washed with brine, dried with anhyd. Na2SO4 and
concentrated. The crude product was purified by column chroma-
tography employing a gradient of CH2Cl2:MeOH (100:0 / 95:5).
*
*
*
:
4.4.1. (S)-N-[Diphenyl(pyrrolidin-2-yl)methyl]benzamide,
(S)-
2976,1683 (C]O),1493,1453,1388,1363,1169,1106,1030, 918, 866,
766, 738, 703. HR-ESI-TOF [MþH]þ (m/z) calcd for
[C29H34N2O2þH]þ: 443.2693; found: 443.2697.
20. General procedure two was followed with 3.86 g (8.45 mmol)
of amide (S)-15 in 8 mL of CH2Cl2 and 5 mL of TFA. Trifluoroacetate
(S)-20 was obtained in >95% yield (3.78 g, 8.03 mmol) as a colorless
25
oil, [a
]
¼ ꢁ6 (c¼1.04, CHCl3). dH (CDCl3, 500 MHz): 2.04e2.26 (m,
D
4.2.2. t-Butyl (S)-2-[(ethylamino)diphenylmethyl]pyrrolidine-1-
carboxylate, (S)-18. The general procedure was followed, with
0.5 g (1.27 mmol, 1 equiv) of amide (S)-13 in 10 mL of anhyd. THF,
3H, CH2CH2CH2), 2.41e2.59 (m, 1H, CH2CH2
3.47e3.56 (m, 2H, CH2CH2N), 5.28 (ddd, 1H, J¼14.4, 8.6, 7.0 Hz,
CH2CH2CH), ArH: 7.29e7.45 (m, 9H), 7.54e7.60 (m, 2H), 7.66e7.7
*
CH), 3.22e3.32,
*

390
G. Reyes-Rangel et al. / Tetrahedron 72 (2016) 379e391
(m, 1H); NH, NHþ2 : 9.21 (b, 1H), 9.77 (b, 1H), 10.86 (b, 2H, CF3CO2H).
dC (CDCl3, 125 MHz): 24.78 (CH2CH2CH2), 27.19 (CH2CH2CH), 46.07
(CH2CH2N), 65.16 (CH2CH2CH), 69.18 [C(Ph2)NHPh], 115.46 (c,
10.3, 9.2 Hz, CH2CH2
*
CH), 1.39 (dtd, 1H, J¼12.5, 6.1, 3.2 Hz,
*
CH2CH2CH), 1.73e1.85 (m, 2H, CH2CH2CH2), 2.02 [s, 3H, eN]
*
*
CeCH3], 3.28 (ddd, 1H, J¼11.1, 8.0, 4.9 Hz, CH2CH2N), 3.41 (ddd, 1H,
J¼11.2, 7.9, 7.7 Hz, CH2CH2N), 4.51 (dd, 1H, J¼10.3, 6.0 Hz,
CF3CO2H, JCeF¼285.34 Hz), ArC: 125.86, 126.41, 127.36, 128.65,
128.95, 129.17, 129.46, 129.79, 129.92, 130.38, 132.02, C-ipso: 133.65,
138.25, 142.43; 160.73 [O(C]O)CF3, JCeF¼40.3 Hz], 170.24
[eNH(C]O)Ph]. IR ṽmax (ATR) cmꢁ1: 3334, 3057, 2941, 2867, 1665
(C]O), 1477, 1288, 1187, 1099, 760, 699, 606. MS (IE) m/z (%): 356
(2), 252 (9), 160 (6), 132 (9), 131 (25), 120 (15), 118 (12), 117 (18), 115
(6), 106 (12), 104 (8), 103 (6), 92 (9), 91 (100), 65 (7), 55 (5). HR-ESI-
TOF [MþH]þ (m/z) calcd for [C24H24N2OþH]þ: 357.1961; found:
357.1963.
CH2CH2CH), ArH: 7.15e7.23 (m, 2H), 7.23e7.31 (m, 4H), 7.38e7.44
*
(m, 4H). dC (CDCl3, 125 MHz): 14.92 [eN]CeCH3], 25.22
(CH2CH2CH2), 28.81 (CH2CH2CH), 47.05 (CH2CH2N), 72.98
(CH2CH2CH), 77.78 [eC(Ph2)eN], ArC: 126.24, 126.57, 126.83,
*
*
127.59, 127.68, 128.08, C-ipso: 144.65, 148.23; 164.10 [eN]
CeCH3]. IR ṽmax (ATR) cmꢁ1: 3057, 2981, 2957, 2162, 1980, 1743,
1614, 1485, 1444, 1386, 1342, 1270, 1224, 1127, 1065, 1023, 978, 887,
758, 698, 661. HR-ESI-TOF [MþH]þ (m/z) calcd for [C19H20N2þH]þ:
277.1699; found: 277.1799. Crystal data for (S)-24: C19H20N2,
ꢂ
4.4.2. (S)-N-[Diphenyl(pyrrolidin-2-yl)methyl]acetamide,
(S)-
monoclinic, space group
P
21, Z¼2; a¼6.01114(3) A,
ꢂ
3
ꢂ
ꢂ
21. General procedure two was followed, with 0.50 g (1.27 mmol)
of amide (S)-16 in 2 mL of CH2Cl2 and 0.5 mL of TFA. Tri-
b¼14.7387(10) A, c¼8.5476(6) A,
a
¼90ꢀ,
b
¼96.516(5)ꢀ,
g
¼90ꢀ,
V¼752.43(0) A , crystal size: 0.4ꢂ0.3ꢂ0.2 mm3, R1¼0.0490
(wR2¼0.1355). CCDC 1440771 contains supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre.
fluoroacetate (S)-21 was obtained with greater than 95% yield
25
(1.21 mmol, 0.493 g) as a colorless oil, [
a]
¼ꢁ43 (c¼1.0, CHCl3). dH
D
(CDCl3, 500 MHz): 1.95e2.11 (m, 3H), 2.13e2.21 (m, 1H), 2.25 (s,
3H), 2.99 (a, 1H), 3.25e3.4 (m, 1H), 4.9e5.1 (m, 1H), 7.19e7.44 (m,
10H), 8.40 (a, 1H), 9.29 (a, 1H), 10.39 (a, 1H). dC (CDCl3, 125 MHz):
23.62, 24.85, 27.30, 46.00, 64.94, 68.82, 126.14, 126.64, 128.58,
128.77, 129.32, 129.53, 139.07, 141.75, 174.24 [eNH(C]O)CH3]. IR
ṽmax (ATR) cmꢁ1: 3317, 3057, 3028, 2970, 2871, 1663 (C]O), 1600,
1578, 1508, 1476, 1446, 1289, 1201, 1127, 1075, 1030, 800, 761, 698.
HR-ESI-TOF [MþH]þ (m/z) calcd for [C19H22N2OþH]þ: 295.1805;
found: 295.1807.
4.4.5. (S)-N-Benzyldiphenyl(pyrrolidin-2-yl)methanamine,
(S)-
22. General procedure two was followed with 170 mg of amine (S)-
17 (0.383 mmol) dissolved in CH2Cl2 (3 mL) and using 2 mL of TFA
dissolved in 2 mL of dichloromethane, stirring at 0 ꢀC during 30 min
and 4 h at rt. 109 mg (0.404 mmol, 83% yield) of the expected di-
amine were obtained. [
25
a]
¼ ꢁ8 (c¼1.04, CHCl3); dH (CDCl3,
D
500 MHz): 1.03 (tt, 1H, J¼13.2, 6.6 Hz, CH2CH2CH2), 1.52 (tt, 1H,
J¼13.2, 7.0 Hz, CH2CH2CH2), 1.73 (dt, 1H, J¼13.9, 7.2 Hz, CH2CH2CH),
CH), 2.50 (dt, 1H,
*
4.4.3. (S)-1,1,3-Triphenyl-5,6,7,7a-tetrahydro-1H-pyrrolo[1,2-e]imid-
azole, (S)-10. In a round bottomed flask provided with a magnetic
stirrer and condenser, 2.91 g (8.2 mmol) of amide (S)-15 and
652 mg (16.4 mmol, 2 equiv) of NaOH were dissolved in 10 mL of
water and 100 mL of MeOH. The resulting mixture was heated to
reflux for 6 h, and then concentrated to dryness. The residue was
diluted with ethyl acetate and the resulting suspension was washed
with water. The organic phase was dried with Na2SO4, concentrated
and the crude product was purified by column chromatography
1.92 (dddd, 1H, J¼13.6, 7.4, 6.8, 6.3 Hz, CH2CH2
*
J¼10.2, 6.6 Hz, CH2CH2N), 2.81 (dt, 1H, J¼10.2, 6.9 Hz, CH2CH2N),
3.36, 3.48 (d, 2H, J¼12.3 Hz, eNHCH2Ph), 4.23 (dd, 1H, J¼7.5, 7.0 Hz,
CH2CH2CH), ArH: 7.18e7.36 (m, 11H), 7.41e7.47 (m, 4H). dC (CDCl3,
*
125 MHz): 25.43 (CH2CH2CH2), 27.84 (CH2CH2
(CH2NH CH), 47.30 (eNHCH2Ph), 62.92 (CH2CH2CH), 68.77
[eC(Ph2)eNHBn], ArC: 126.75,126.78,127.64, 127.68, 128.13,128.27,
129.01, 129.15, C-ipso: 140.88, 143.79, 144.03. IR ṽmax (ATR) cmꢁ1
*
CH), 46.85
*
*
:
3026, 2959, 2869, 1493, 1451, 1070, 1029, 906, 729, 700. HR-ESI-TOF
with EtOAc eluent, obtaining 2.57 g (93% yield) of amidine (S)-10 as
[MþH]þ (m/z) calcd for [C24H26N2þH]þ: 343.2169; found: 343.2177.
25
a white solid, mp 113 ꢀC, [
a
]
D
¼ ꢁ456 (c¼1.0, CHCl3); dH (CDCl3,
270 MHz): 0.98 (dddd, 1H, J¼12.4, 10.8, 10.4, 8.7 Hz, CH2CH2
*
CH),
4.4.6. (S)-N-[Diphenyl(pyrrolidin-2-yl)methyl]ethanamine,
23. General procedure two was followed with 192 mg
(0.505 mmol) of amine (S)-18 in 5 mL of CH2Cl2 and 1 mL of TFA in
2 mL of CH2Cl2. The expected diamine (S)-23 was obtained in 80%
yield (113.2 mg) as a colorless oil, [
(S)-
1.46 (dddd, 1H, J¼12.4, 6.2, 5.7, 2.9 Hz, CH2CH2
*
CH), 1.69e1.88 (m,
2H, CH2CH2CH2), 3.27 (ddd, 1H, J¼10.6, 8.4, 8.2 Hz, CH2CH2N), 3.45
(ddd, 1H, J¼10.8, 7.7, 4.2 Hz, CH2CH2N), 4.73 (dd, 1H, J¼10.4, 5.7 Hz,
25
CH2CH2
*
CH), ArH: 7.11e7.59 (m, 13H), 7.83e7.92 (m, 2H). dC (CDCl3,
a]
¼ ꢁ35 (c¼1.02, CHCl3). dH
D
68 MHz): 25.70 (CH2CH2CH2), 29.53 (CH2CH2
*
CH), 49.73 (CH2CH2N),
(CDCl3, 500 MHz): 0.94e1.07 (m, 1H, CH2CH2CH2), 1.02 (t, 1H,
J¼7.1 Hz, eNH-CH2CH3), 1.44e1.54 (m, 1H, CH2CH2CH2), 1.63 (tdd,
74.14 (CH2CH2CH), 78.41 [eC(Ph2)eNHAc], ArC: 126.33, 126.62,
*
127.11, 127.65, 127.81, 128.10, 128.21, 128.95, 130.27 C-ipso: 131.49,
144.68, 148.49; 166.45 [eNH(C]O)Ph]. IR ṽmax (ATR) cmꢁ1: 3056,
2965,1596,1569,1493,1446,1359,1028,1007, 750, 695. HR-ESI-TOF
[MþH]þ (m/z) calcd for [C24H22N2þH]þ: 339.1856; found: 339.1857.
Elemental analysis calculated for C24H22N2 (338.45): C 85.17, H 6.55,
1H, J¼9.9, 8.1, 6.9 Hz, CH2CH2CH), 1.87 (dtd, 1H, J¼13.2, 7.9, 5.6 Hz,
*
CH2CH2
(dt, 1H, J¼10.0, 6.7 Hz, CH2CH2N), 2.77 (dt, 1H, J¼10.2, 6.9 Hz,
CH2CH2N), 4.11 (t, 1H, J¼7.3 Hz, CH2CHN), ArH: 7.22e7.33 (m, 6H),
7.34e7.41 (m, 4H). dH (CDCl3, 125 MHz): 15.75 (eNH-CH2CH3),
25.47 (CH2CH2CH2), 27.81 (CH2CH2CH), 37.18 (eNH-CH2CH3), 46.73
(CH2CH2N CH), 63.07 (N CHCH2), 68.74 [C(Ph2)NHEt], ArC: 126.53,
126.61, 127.50, 129.08, 129.10, C-ipso: 144.05. IR ṽmax (ATR) cmꢁ1
*
CH), 2.21, 2.29 (dc, 2H, J¼10.8, 7.1 Hz, eNH-CH2CH3), 2.47
*
N 8.28; found: C 84.91, H 6.94, N 8.14. Crystal data for (S)-10:
*
ꢂ
C
24H22N2, orthorhombic, space group P212121, Z¼4; a¼8.0139(2) A,
*
*
ꢂ
ꢂ
b¼8.6034(2) A, c¼27.2822(8) A,
a
¼90ꢀ,
b
¼90ꢀ,
g
¼90ꢀ,
:
3
3
ꢂ
V¼1880.94(0) A , crystal size: 0.275ꢂ0.175ꢂ0.15 mm , R1¼0.0767
(wR2¼0.2022). CCDC 1440767 contains supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from the Cambridge Crystallographic Data Centre.
2959, 2885,1598, 1492, 1445, 1076, 1032, 908, 759, 731, 701. HR-ESI-
TOF [MþH]þ (m/z) calcd for [C19H24N2þH]þ: 281.2012; found:
281.2013.
4.5. (S)-1-[Diphenyl(pyrrolidin-2-yl)methyl]-4-phenyl-1H-
1,2,3-triazol, (S)-25
4.4.4. (S)-3-Methyl-1,1-diphenyl-5,6,7,7a-tetrahydro-1H-pyrrolo
[1,2-e]imidazole, (S)-24. The experimental procedure described for
the preparation of (S)-10 was followed with 0.444 g (1.09 mmol) of
(S)-21 dissolved in 20 mL of MeOH and 86.9 mg of NaOH (2 equiv,
In a round bottomed flask provided with magnetic stirrer was
placed 365 mg (1.31 mmol) of azide (S)-7, phenyl acetylene
(0.144 mL, 0.134 g, 1.0 equiv), 13.1 mg of CuSO4$5H2O (4%-mol) and
5 mL of a mixture of methanolewater (9:1). The reaction mixture
was stirred at rt during 18 h before dilution with 5 mL of
2.17 mmol) dissolved in water (1 mL). Amidine (S)-24 was ob-
25
tained in 74% yield (221 mg, 0.807 mmol); mp 173 ꢀC, [
a]
¼ ꢁ635
D
(c¼1.01, CHCl3); dH (CDCl3, 500 MHz): 0.93 (dddd, 1H, J¼12.3, 10.6,

G. Reyes-Rangel et al. / Tetrahedron 72 (2016) 379e391
391
H2OeNH4OH(aq) (9:1) and extraction with CH2Cl2 (3ꢂ10 mL). The
Supplementary data
combined organic phase was washed with brine (10 mL), dried
with Na2SO4 and concentrated under vacuum. The residue was
purified by silica gel column chromatography, and two consecutive
eluting procedures, first a gradient hexane:EtOAc (90:10 / 80:20)
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.11.032.
and then a gradient EtOAc:MeOH (100:0 / 95:5). Triazol (S)-25
25
(213 mg, 47% yield) was isolated as a colorless oil. [
a]
¼ þ36
D
References and notes
(c¼1.0, CHCl3). dH (DMSO-d6, 500 MHz): 0.67e0.81 (m, 1H,
CH2CH2CH2), 1.37e1.46 (m, 1H, CH2CH2CH2), 1.46e1.54 (m, 1H,
1. (a) Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551e5553;
(b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986e2012.
2. Lattanzi, A. Chem. Commun. 2009, 1452e1463.
CH2CH2
J¼10.1, 5.9, 5.2 Hz, CH2CH2N), 2.72 (dt, 1H, J¼9.1, 7.2 Hz, CH2CH2N),
CH), ArH: 7.27e7.37 (m, 11H),
*
CH), 2.14 (dc, 1H, J¼12.9, 8.0 Hz, CH2CH2
*
CH), 2.31 (ddd, 1H,
ꢀ
3. (a) Franzen, J.; Marigo, M.; Fielenbach, D.; Wabnitz, T. C.; Kjærsgaard, A.;
5.14 (dd, 1H, J¼8.5, 5.4 Hz, CH2CH2
*
Jørgensen, K. A. J. Am. Chem. Soc. 2005, 127, 18296e18304; (b) Hayashi, Y.;
Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212e4215.
4. Braun, M. Angew. Chem., Int. Ed. 2012, 51, 2550e2562.
7.40 (t, 2H, J¼7.7 Hz), 7.85 (d, 2H, J¼7.3 Hz), 8.43 (s, 1H, N]
NeNeCHC); dC (DMSO-d6, 125 MHz): 25.57 (CH2CH2CH2), 28.77
5. (a) Olivares-Romero, J. L.; Juaristi, E. Tetrahedron 2008, 64, 9992e9998; (b) For
other diamine derivatives of (S)-proline synthesized in our group, see: Vargas-
(CH2CH2CH), 46.50 (CH2CH2N), 62.03 (N CHCH2), 76.93 [eC(Ph2)e
*
ꢀ
N], ArC: 122.71,125.33,127.64, 127.70,127.94,128.03,128.47,128.93,
129.52, C-ipso: 130.76, 145.27. IR ṽmax (ATR) cmꢁ1: 1493, 1447, 1400,
1072, 1035, 972, 848, 761, 694. HR-ESI-TOF [MþH]þ (m/z) calcd for
[C25H24N4þH]þ: 381.2074; found: 381.2074.
Caporali, J.; Cruz-Hernandez, C.; Juaristi, E. Heterocycles 2012, 86, 1275e1300;
(c) See, also: Juaristi, E. J. Org. Chem. 2012, 77, 4861e4884.
6. Uraguchi, D.; Sakaki, S.; Ueki, Y.; Ito, T.; Ooi, T. Heterocycles 2008, 76,
1081e1085.
7. Shi, Z.; Tan, B.; Leong, W. W. Y.; Zeng, X.; Lu, M.; Zhong, G. Org. Lett. 2010, 12,
5402e5405.
8. Hosoda, N.; Kamito, H.; Takano, M.; Takebe, Y.; Yamaguchi, Y.; Asami, M. Tet-
rahedron 2013, 69, 1739e1746.
9. Roy, H. H.; Pitchaiah, A.; Kim, M.; Hwang, I. T.; Lee, K.-I. RSC Adv. 2013, 3,
3526e3530.
4.6. General procedure 3. Asymmetric organocatalytic Mi-
chael reaction
10. Sadu, V. S.; Roy, H. N.; Arigala, P.; Hwang, I.-T.; Lee, K.-I. Bull. Korean Chem. Soc.
2014, 35, 1605e1612.
Organocatalyst (S)-7 (0.2 equiv relative to the corresponding
nitrostyrene) andw0.036 mL of IPA:H2O (3:1) per milligram of
catalyst was placed in a vial provided with a magnetic bar. The
resulting suspension was cooled to 10 ꢀC and 3.0 equiv of iso-
butyraldehyde was added via syringe. Stirring was continued for
30 min, before the addition of 0.5 equiv of benzoic acid and 1 equiv
of nitrostyrene. The resulting reaction mixture was stirred during
12 days at 10 ꢀC. Saturated solution of NaHCO3 (w4 mL) was then
added and the mixture was extracted with EtOAc (2ꢂ5 mL). The
combined organic phase was dried with Na2SO4 and concentrated.
The crude product was purified by silica gel column chromatogra-
phy, with hexane:EtOAc (9:1) eluent.
11. Gleeson, O.; Gun’ko, Y. K.; Connon, S. J. Synlett 2013, 1728e1734.
12. Sema, H. A.; Bez, G.; Karmakar, S. Appl. Organometal. Chem. 2014, 28, 290e297.
13. (a) Vinayagam, P.; Vishwanath, M.; Kesavan, K. Tetrahedron Asymmetry 2014, 25,
568e577; (b) Correction Vinayagam, P.; Vishwanath, M.; Kesavan, K. Tetrahe-
dron Asymmetry 2014, 25, 1252.
14. Bhaskar Kanth, J. V.; Periasamy, M. Tetrahedron 1993, 49, 5127e5132.
15. O’Connell, J. F.; Rapoport, H. J. Org. Chem. 1992, 57, 4775e4777.
16. (a) Brower, F. M.; Matzek, N. E.; Reigler, P. F.; Rinn, H. E.; Roberts, C. B.; Schmidt,
D. L.; Snover, J. A.; Terada, T. J. Am. Chem. Soc. 1976, 98, 2450e2453; (b) Yoon, N.
M.; Brown, H. C. J. Am. Chem. Soc. 1968, 90, 2927e2938; (c) Claesson, A.; Olsson,
L.-I. J. Am. Chem. Soc. 1979, 101, 7302e7311.
17. Jung, M. E.; Piizzi, G. Chem. Rev. 2005, 105, 1735e1766.
€
ꢁ
18. Urankar, D.; Steinbucher, M.; Kosjek, J.; Kosmrlj, J. Tetrahedron 2010, 66,
2602e2613.
19. (a) Patora-Komisarska, K.; Benohoud, M.; Ishikawa, H.; Seebach, D.; Hayashi, Y.
Helv. Chim. Acta 2011, 94, 719e745; (b) Seebach, D.; Sun, X.; Ebert, M.-O.;
ꢀ
Schweizer, W. B.; Purkayastha, N.; Beck, A. K.; Duschmale, J.; Wennemers, H.
Helv. Chim. Acta 2013, 96, 799e852; (c) Seebach, D.; Sun, X.; Sparr, C.; Ebert, M.-
O.; Schweizer, W. B.; Beck, A. K. Helv. Chim. Acta 2012, 95, 1064e1078.
20. (a) Wang, L.; Zhang, X.; Ma, D. Tetrahedron 2012, 68, 7675e7679; (b) Zheng, Z.;
Perkins, B. L.; Ni, B. J. Am. Chem. Soc. 2010, 132, 50e51.
4.7. General procedure 4. Asymmetric organocatalytic Man-
nich reaction
21. Schmid, M. B.; Zeitler, K.; Gschwind, R. M. J. Am. Chem. Soc. 2011, 133,
Organocatalyst (S)-7 (0.2 equiv, 1 mmol) and 1 mL of LiCl 1 M in
DMF were placed in a vial provided with a magnetic bar. The so-
lution was cooled to ꢁ20 ꢀC and 0.11 mL of isovaleraldehyde
(2 equiv, 1 mmol, 86.2 mg) and 12.2 mg of benzoic acid (0.1 mmol,
0.2 equiv) dissolved in 2 mL of DMF were incorporated. The re-
action mixture was stirred for 15 min, then 0.127 mL (1 equiv,
0.5 mmol, 0.121 g) of the N,O-acetal C were added and the resulting
reaction mixture was stirred during 24 h. Later, NaBH4 (56.7 mg)
and MeOH (1 mL) were aggregated, the suspension was set at 0 ꢀC
and stirred during 20 min. The tube content was poured onto
a saturated solution of NH4Cl (at 0 ꢀC), the mixture was extracted
with petroleum ether (2ꢂ10 mL) and brine, the combined organic
phase was dried with Na2SO4 and concentrated in the rotary
evaporator. The residue was purified by silica gel column chroma-
tography, with hexane:EtOAc (95:5) eluent.
7065e7074.
ꢀ
22. See, however (a) Bures, J.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc.
ꢀ
2011, 133, 8822e8825; (b) Bures, J.; Armstrong, A.; Blackmond, D. G. J. Am.
Chem. Soc. 2012, 134, 6741e6750.
23. Moberg, C. Angew. Chem., Int. Ed. 2013, 52, 2160e2162.
ꢀ
ꢀ
ꢀ
24. Sahoo, G.; Rahaman, H.; Madarasz, A.; Papai, I.; Melarto, M.; Valkonen, A.;
Pihko, P. M. Angew. Chem., Int. Ed. 2012, 51, 13144e13148.
25. Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804e6805.
26. Stewart, T. D.; Bradley, W. E. J. Am. Chem. Soc. 1932, 54, 4172e4183.
ꢀ
27. (a) Ibrahem, I.; Dziedzic, P.; Cordova, A. Synthesis 2006, 4060e4064; (b) Ibra-
ꢀ
hem, I.; Zhao, G.-L.; Cordova, A. Chem.dEur. J. 2007, 13, 683e688.
ꢀ
28. Hernandez, J. G.; Juaristi, E. Chem. Commun. 2012, 5396e5409.
29. (a) Chi, Y.; Guo, L.; Kopf, N. A.; Gellman, S. H. J. Am. Chem. Soc. 2008, 130,
5608e5609.
30. Zu, L.; Li, H.; Wang, J.; Yu, X.; Wang, W. Tetrahedron Lett. 2006, 47, 5131e5134.
31. (a) Sparr, C.; Tanzer, E.-M.; Bachmann, J.; Gilmour, R. Synthesis 2010,
1394e1397; (b) Ho, C.-Y.; Chen, Y.-C.; Wong, M.-K.; Yang, D. J. Org. Chem. 2005,
70, 898e906; (c) Sparr, C.; Schweizer, W. B.; Senn, H. M.; Gilmour, R. Angew.
Chem., Int. Ed. 2009, 48, 3065e3068.
32. (a) SHELX-97 Sheldrick, G. M. Programs for Crystal Structure Analysis; University
€
of Gottingen: Germany, 1997; (b) Sheldrick, G. M. Acta Crystallogr. 2008, A64,
112e122.
Acknowledgements
33. (a) WinGX and ORTEP for Windows: an update Farrugia, L. J. J. Appl. Cryst. 2012,
45, 849e854; (b) WinGX suite for small molecule single-crystal crystallography
Farrugia, L. J. J. Appl. Cryst. 1999, 32, 837e838.
We are grateful to Consejo Nacional de Ciencia y Tecnología
(CONACYT) Mexico for financial support via grant 220945.
34. Byun, H.-S.; Zhong, N.; Bittman, R. Org. Synth. 2000, 77, 225e230.