Proline-derived aminotriazole ligands: Preparation and use in the ruthenium-catalyzed asymmetric transfer hydrogenation

Article abstract of DOI:10.1002/adsc.201000678

The preparation of 2-triazolyl- and 2-triazolylmethylpyrrolidines from L-proline and L-trans-4-hydroxyproline is described, along with their evaluation as chiral ligands in ruthenium-catalyzed asymmetric transfer hydrogenation. Modular evolution of the ligands by introduction of remote substituents is also presented, showing a surprisingly important effect on the performance of the ligands.

Full text of DOI:10.1002/adsc.201000678

FULL PAPERS
DOI: 10.1002/adsc.201000678
Proline-Derived Aminotriazole Ligands: Preparation and Use in
the Ruthenium-Catalyzed Asymmetric Transfer Hydrogenation
Xacobe C. Cambeiroa,b and Miquel A. Pericꢀsa,b,*
a
Institute of Chemical Research of Catalonia (ICIQ), Av. Paꢁsos Catalans 16, E-43007 Tarragona, Spain
Fax : (+34)-97-792-0222; phone: (+34)-97-792-0200; e-mail: mapericas@iciq.es
Departament de Quꢂmica Orgꢀnica, Universitat de Barcelona, E-08028 Barcelona, Spain
b
Received: August 31, 2010; Published online: December 30, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000678.
Abstract: The preparation of 2-triazolyl- and 2-tri- also presented, showing a surprisingly important
ACHTUNGTRENNUNGazolylmethylpyrrolidines from l-proline and l-trans- effect on the performance of the ligands.
4-hydroxyproline is described, along with their evalu-
ation as chiral ligands in ruthenium-catalyzed asym-
metric transfer hydrogenation. Modular evolution of Keywords: asymmetric catalysis; click chemistry; hy-
the ligands by introduction of remote substituents is drogen transfer; proline; ruthenium; triazoles
Introduction
phines (ClickFerrophos),[12] as well as in organic cata-
lysts.[13]
Since the birth of click chemistry[1] and, more particu-
In all these approaches, the triazole group has been
larly, the discovery of Cu(I)-based catalytic systems exploited just as a structural fragment or as a linker,
for the cycloaddition between azides and alkynes,[2] although it may exert some influence in the final
the triazole group has drawn increasing attention, properties of the materials mainly by polar or steric
finding application in many different research fields.[3] effects, but not for an intrinsic reactivity of the tria-
In biological chemistry, the copper-catalyzed azide- zole itself. However, the ability of the triazole group
alkyne cycloaddition (CuAAC) has been applied for to act as a donor in coordination chemistry is not only
modification of biopolymers by conjugation with apparent from observation of its structure (bearing
small molecules.[4] Also, the development of the Huis- two non-bonding electron pairs, orthogonal to the ar-
gen cycloaddition under physiological conditions omatic p-system) but has also been confirmed by ex-
opened a door for in vivo click chemistry, applicable perimental studies. As an example, in the course of
in imaging of cellular processes.[5] In medicinal the research developed in our group on the immobili-
chemistry it has been used as an effective means for zation of ligands for the catalytic enantioselective ad-
creating molecular diversity in an easy and modular dition of organozinc compounds to aldehydes,[10a] an
manner.[6]
important decrease in the enantioselectivity was regis-
This reaction has reached its great importance in tered when triazole-linked catalysts were used (com-
materials chemistry, as a means for modification of pared to the ether-linked analogue), which was ex-
surfaces by linking different kinds of molecules, prep- plained by a competition of the triazole and the
aration of dendrimers or copolymers, and immobiliza- amino alcohol moieties for complexing the zinc re-
tion of catalysts and other functional units onto poly- agent.
mers.[7] In our group we have been actively engaged
Moreover, other systems containing triazole units
in this field, extensively exploring CuAAC for the im- acting as donors in metal complexes have been re-
mobilization of organic catalysts[8,9] and ligands[10] ported in the last years,[14] including even some appli-
onto polystyrene resins.
cations in catalysis (Figure 1). Namely, the tris-
Finally, also in the field of catalysis, CuAAC
ACHTUNGTREN(NGNU triazole) ligands 1 and 2, described by the Sharpless
has been used as a reliable means for introducing group[15] and by us[16] turned out to be very effective
structural variability in tuneable ligands such as catalysts for the CuAAC reaction. Also, (triazolylme-
monophosphines (ClickPhos)[11] or ferrocenyl diphos- thyl)phosphines (Clickphine, 3)[17] have been applied
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AHCTUNGTRENNUNG
AHCTUNGTREGaNNUN mide, alcohol, thiol, etc.). Most frequently, but not
exclusively, the auxiliary group acts as an anionic
ligand, thus giving place to neutral ruthenium com-
plexes.
With this in mind, aminotriazole ligands 5 and 6
(Scheme 1) were expected to form chelate complexes
with ruthenium coordinated to the triazole moiety
through different nitrogen atoms (Figure 3), both
likely to be active as catalysts for the transfer hydro-
genation of ketones.
Figure 1. Triazole-based ligands used in catalysis.
as ligands for Pd-catalyzed allylic alkylation reactions
and tetradentate bis(triazolylamines) (4) for Mn-cata-
lyzed epoxidation reactions.[18] In some cases, direct
coordination of either the N-2 or N-3 nitrogen atoms
of the triazole group to the metal was demonstrated
by different means including X-ray crystallographic
analysis, as in the case of tristriazole-copper[16] and
phosphinito-triazole-rhodium[19] complexes. Enantio-
selective applications, however, remain completely
unexplored.
In the light of all these data, we envisioned to
assess the applicability of triazoles as donors in metal-
based asymmetric catalysis. With this purpose, we de-
signed ligands 5 and 6 (Scheme 1), constituted by the
conjuction of a well-known, easily accessible chiral
backbone and a triazole group, in two complementary
approaches. Herein we report our studies on the prep-
aration and the initial application in catalysis of such
ligands.
Figure 2. General structure and catalytic cycle of Noyori-
type catalysts for transfer hydrogenation.
As a benchmark reaction for initially testing the
chiral aminotriazole ligands, we chose the ruthenium-
catalyzed transfer hydrogenation of ketones. This re-
action has been extensively studied in the last two de-
cades, since the groundbreaking work by Noyori on
the use of ruthenium-arene complexes with mono-
Figure 3. Putative ruthenium(II) complexes with chiral ami-
notriazole ligands 5 and 6.
Results and Discussion
Synthesis of the Ligands
The preparation of ligands with the targeted struc-
tures from commercially available l-proline was plan-
ned as having its key step in a CuAAC reaction,
either with a proline-derived chiral azide and an
alkyne or with a proline-derived chiral alkyne and an
azide (Scheme 1).
Scheme 1. Proline-derived chiral triazole-based ligands.
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Proline-Derived Aminotriazole Ligands: Preparation and Use
Scheme 2. Preparation of proline-derived chiral aminotriazole ligands 5 and 6.
Compound 5 had already been described as an or- Based on these results, we decided to take the struc-
ganic catalyst for the Michael reaction between ke- ture 6 as the reference one for further development
tones and nitrostyrene derivatives.[13a] It was readily of our ligand family.
prepared for the work presented herein by a modifi-
cation of the previously reported procedures, starting
from enantiopure l-proline (Scheme 2).[24]
Second Generation
On the other hand, ligand 6 was prepared by
CuAAC of the known chiral alkyne 7 and azidotrime- To obtain ligands with improved catalytic behaviour,
thylsilane followed by deprotection (Scheme 2),[24] we planned to introduce structural variability in the
alkyne 7 having been itself obtained also from enan- pyrrolidine ring by testing different substitutions.
tiopure l-proline.[23]
Bearing in mind the availability of trans-4-hydroxy-
proline, we envisioned to use it as the starting point
for the development of new ligands. This strategy was
expected also to help us in assessing whether remote
substituents, far away from the catalytic metal centre,
Preliminary Tests in Catalysis
With enantiopure 2-(4-phenyltriazolyl)methylpyrroli- could exert an influence on the catalytic performance
dine (5) and 2-(5-triazolyl)pyrrolidine (6) in hand, we either by polar effects,[25] by steric effects (by blocking
set out to test their performance as ligands in the Ru- one of the faces of the pyrrolidine ring), or through
catalyzed transfer hydrogenation of acetophenone the simultaneous operation of both factors.
(9a) leading to (S)-1-phenylethanol (10a). Reactions
A simplified procedure[26] entailing reduction of the
were carried out with both ligands, using potassium N-Boc-trans-4-hydroxyproline methyl ester to alde-
hydroxide as the base and isopropyl alcohol as the re- hyde followed, in one pot, by treatment with the Best-
ducing agent (Scheme 3).
Although both ligands represented active catalysts to the enantiopure hydroxyalkyne 11a (Scheme 4).
for the reaction, the results made apparent the superi- With this alkyne in hand, introduction of different
mann–Ohira reagent[27] allowed straightforward access
ority of ligand 6, bearing a free triazole NH group. substituents on the hydroxy group, by well known
Although the use of neutral ligands in this reaction protecting group chemistry allowed preparation of
(giving place to cationic ruthenium catalysts) has various ether and silyl ether derivatives 11b–f. Cu-cat-
been described, it is worth noting that the vast majori- alyzed cycloaddition with trimethylsilyl azide, fol-
ty of the successful ligands in this kind of systems act lowed by deprotection, led uneventfully to the target
as anionic ones (giving place to neutral catalysts). ligands 13a–f (Scheme 5).[23]
Scheme 3. ATH of acetophenone with ligands 5 and 6.
Scheme 4. One-pot preparation of hydroxyalkyne 11a.
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Xacobe C. Cambeiro and Miquel A. Pericꢀs
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sults being those obtained with ligand 13f, bearing the
bulkiest TBDPS group. This contrasting behaviour
may follow polar effects, and be related to the differ-
À
À
ent polarities of C O and Si O bonds.
Taking as a reference ligand 13f, we decided to run
some experiments aimed at determining optimal reac-
tion conditions. As shown by the results on Table 2,
neither the use of different arene ligands or potassium
tert-butoxide as the base resulted in any improvement
(entries 1–4). Contrarily, in fact, with benzene or
hexaACTHNUTRGNEmNUG ethylbenzene as arene ligands, a strong de-
crease in the enantioselectivity of the process, as well
as in the catalytic activity, was observed (entries 2 and
3).
Additionally, the influence of the metal to ligand
ratio was also studied by performing a series of ex-
periments where this ratio was systematically modi-
fied (entries 4–8). With respect to catalytic activity,
the results showed that it reaches a maximum around
a 1:1 ratio, being significantly lower with a two-fold
excess of any of the components. This strongly sug-
gests the active species to be a complex of 1:1 stoichi-
Scheme 5. Preparation of the family of ligands 13a–f.
Catalytic Tests
ATH experiments run with these ligands under the ometry, with the triazolylpiridine acting as a bidentate
same conditions as previously used for 5 and 6 ligand. With respect to enantioselectivity, slightly
showed the results displayed in Table 1.
better results were recorded in the presence of excess
Gratifyingly enough, even the presence of a free ligand, and the conditions of entry 7 were considered
hydroxy group at C-4 on the pyrrolidine ring (ligand to be optimal.
13a) caused a 23% increase in the ee compared to the
Finally, we explored the performance of the catalyst
unsubstituted pyrrolidine (ligand 6), although this was derived from ligand 13f in the transfer hydrogenation
accompanied by an important decrease in catalytic ac- of a family of diversely substituted ketones under the
tivity. With the other ligands, bearing different pro- optimized reaction conditions. The results of this
tecting groups on the oxygen atom (13b–f), better study are summarized in Table 3.
conversions and ees were recorded in all the cases.
Acetophenone derivatives 9b–g with different sub-
For alkyl ethers, ligand 13b, bearing the less bulky stitution patterns on the phenyl ring were first evalu-
methoxy substituent afforded better results, both in ated, with varying results both in terms of catalytic ac-
terms of catalytic activity and enantioselectivity. tivity and enantioselectivity. In all the cases except for
Somewhat intriguingly, in the case of silyloxy substitu- p-methoxyacetophenone (9d, entry 4), good conver-
ents the trend was exactly the opposite, the best re- sions were recorded after four hours. On the other
hand, moderate to good ees were registered, except in
the case of o-methoxyacetophenone (9b, entry 2).
With acetonaphthones 9h, i as substrates (entries 8
Table 1. Tests in ATH of acetophenone with amino triazole
and 9), bearing a larger planar substituent, high con-
versions and ees were observed in both cases. With
rigid cyclic ketones such as 1-tetralone 9j and 1-chro-
manone 9k (entries 10 and 11), excellent ees were
achieved although at expense of a moderate decrease
in the catalytic activity.
Finally, use of propiophenone 9l as the substrate
(entry 12) resulted in moderate decreases both in con-
version and ee, compared to those obtained with ace-
tophenone.
ligands 13a–f.[a]
Ligand Time [h] Conv. [%][b] TOF1/2 [hÀ1][c] % ee[b]
6
7
71
9
2.46
0.08[d]
3.17
2.00
3.48
4.06
7.96
41
64
84
77
70
74
81
13a
13b
13c
13d
13e
13f
18
18
18
18
5
93
71
87
60
93
4
As an approach for obtaining a better understand-
ing of the role played by the ether or silyl ether sub-
stituents in the C-4 position, the enantiodifferentiat-
ing step of the reduction of chromanone (9k) leading
to 10k was studied by theoretical means, using a DFT
approach with the B3LYP functional as implemented
[a]
All reactions performed at room temperature, with 0.1M
concentration of acetophenone and 1:1:10:17 Ru:ligand:
base:substrate ratio.
Determined by gas chromatography.
TOF calculated at 50% conversion.
[b]
[c]
[d]
TOF calculated at 9% conversion.
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Proline-Derived Aminotriazole Ligands: Preparation and Use
Table 2. Effect of base, arene ligand and metal to ligand ratio in the ATH of acetophenone with ligand 13f.[a]
Entry
Arene
Base
M:L
Conv. [%][b]
TOF1/2 [hÀ1][c]
% ee[b]
1
2
3
4
5
6
7
8
p-cymene
C6Me6
C6H6
p-cymene
p-cymene
p-cymene
p-cymene
p-cymene
t-BuOK
t-BuOK
t-BuOK
KOH
KOH
KOH
1:1
1:1
1:1
1:1
2:1
3:2
2:3
1:2
86
40
51
93
84
91
91
81
8.20
1.69[d]
2.11
7.96
5.52
8.94
8.03
5.52
81
57
43
81
70
79
82
84
KOH
KOH
[a]
All the reactions run for 4 h under the conditions described in Table 1, changing only the variables indicated in the table.
[b]
[c]
[d]
Determined by gas chromatography.
TOF calculated at 50% conversion
TOF calculated at 40% conversion.
Table 3. Substrate scope of the ATH reaction with ligand
Table 3. (Continued)
13f.a
Entry
Substrate
Conv. [%][b]
% ee[b]
7
97
69
Entry
1
Substrate
Conv. [%][b]
% ee[b]
8
9
79
80
87
90
91
82
2
3
96
85
34
75
10
11
42
67
78
94
>99
70
4
5
24
93
60
71
66
70
12
[a]
All reactions run for 4 h under the conditions described
in Table 2, entry 7.
Determined by gas chromatography.
[b]
in Gaussian 09.[28] The SDD basis set, including SDD
cartesian pseudopotentials for the ruthenium atom,
was employed.
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Figure 4. DFT calculated reaction profile for the ruthenium-catalyzed ATH of chromanone (9k) with ligand 13b.
Figure 5. DFT calculated transition states for the ruthenium-catalyzed ATH of chromanone (9k) with ligand 13b; top left:
(SRu,SN)-pro-R; top right: (SRu,SN)-pro-S; bottom left: (RRu,RN)-pro-S; bottom right: (RRu,RN)-pro-R.
The two possible configurations at the ruthenium
Of the two possible ruthenium hydride catalysts,
and nitrogen atoms, and the two possible approaches the one with the S configuration at the Ru and N cen-
of the ketone undergoing reduction (pro-R and pro-S) tres, was clearly favoured (6.7 kcalmolÀ1) over the
were explored. The results have been summarized in one with the R configuration. This preference was
Figure 4 and Figure 5.
also reproduced in the corresponding transition states,
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Proline-Derived Aminotriazole Ligands: Preparation and Use
was obtained as a colourless oil; yield: 225 mg (55%).
1H NMR (CDCl3, 400 MHz): d=1.48 (s, 9H), 1.92 to 2.34
(br, 4H), 3.40 to 3.62 (br, 2H), 5.07 (br, 1H), 7.55 (s, 1H);
13C NMR (125 MHz, DMSO-d6, 373 K): d=25.6, 28.8, 31.7,
48.3, 55.1, 77.9, 129.3, 150.3, 156.2; IR (ATR): n=3348
(NH), 2975, 1701 (C=O), 1523, 1367, 1166 cmÀ1; HR-MS
the lowest energy one for the (SRu,SN) system being
6.2 kcalmolÀ1 more favourable than the lowest energy
one for the (RRu,RN) system.
Between the two possible approaches of the
ketone, in the (SRu,SN) catalyst, the pro-R one was
favoured by 7.0 kcalmolÀ1, and this is consistent with
the complete enantioselectivity experimentally ob-
served when the reduction of 9k is performed with
the analogous ligand 13f (Table 3, entry 11).
+
(ES+): m/z=239.1499, calcd. for C11H19N4O2 (M+H):
239.1508; [a]2D5: À19.8 (c 1.05, MeOH).
It is interesting to recall that even with the unsub-
stituted ligand 6, the sign of enantioselectivity (prefer-
ential production of the R enantiomer) is preserved.
It thus appears that the more compact (SRu,SN)-pro-S
type transition states are intrinsically less stable than
the (SRu,SN)-pro-R type ones. Interestingly, the critical
region of the transition state where the enantiodiffer-
entiating bond-making process takes place is closer to
the R-oxy substituent at C-4 in the pro-S (Figure 5,
top right) than in the pro-R transition state. Thus, the
effect exerted by the remote C-4 substituent in li-
gands 13 would be that of further destabilizing the
(SRu,SN)-pro-S type transition states.
(S)-5-(Pyrrolidin-2-yl)-1H-1,2,3-triazole (Trifluoro-
acetic Acid Salt) (6·TFA)
Triazole 8 (200 mg, 0.83 mmol) was dissolved in DCM
(4.0 mL) and TFA (4.0 mL) was added. The resulting mix-
ture was stirred for 30 min at room temperature, monitoring
the progress of the reaction by TLC. After this time, the vol-
atile compounds were removed under reduced pressure and
the product was dried for 4 h under high vacuum. The solid
obtained was triturated with diethyl ether to obtain, after fil-
tering and drying again, the title product as a tan solid;
1
yield: 210 mg (99%). H NMR (400 MHz, CD3OD): d=2.15
to 2.41 (m, 4H), 3.36 (ddd, J=12.1, 6.5, 4.6 Hz, 1H), 3.61
(dd, J=12.1, 5.6 Hz, 1H), 5.11 (dd, J=10.9, 6.2 Hz, 1H),
7.79 (s, 1H); 13C NMR (100 MHz, CD3OD, 373 K): d=26.5
(CH2), 32.1 (CH2), 49.2 (CH2), 56.6 (CH), 129.5 (CH), 142.3
(C); 19F NMR (CD3OD, 376 MHz): d=À76.2 (s); IR
(ATR): n=2948, 1662 (C=O TFA), 1191, 836 cmÀ1; HR-MS
Conclusions
+
(ES+): m/z=139.0986, calcd. for C6H11N4 (M+H):
In conclusion, we have demonstrated the applicability
of triazolyl units as donors in metal chelates for asym-
metric catalysis through the development of a new
family of enantiopure 2-(5-triazolyl)pyrrolidines and
their use in the Ru-catalyzed asymmetric transfer hy-
drogenation of ketones. Taking into account that tria-
zoles can be installed in a very controlled manner on
almost every organic molecule containing a singly
bonded functional group through the CuAAC reac-
tion,[2] the present finding will probably give rise to
139.0984; [a]2D5:À23.0 (c 1.05, MeOH); mp 85–888C.
AHCTUNGTREG(NNNU 2S,4R)-tert-Butyl 2-Ethynyl-4-methoxypyrrolidine-1-
carboxylate (11b)
Over a suspension of sodium hydride (32.9 mg, 1.30 mmol)
in dry DMF (3.0 mL) under an inert atmosphere, at À208C,
a solution containing 11a (250 mg, 1.18 mmol) in DMF
(3.0 mL) was added. The mixture was stirred at the same
new ligand designs for many types of catalytic pro- temperature for 1 h. After this time, methyl iodide (89 mL,
1.4 mmol) was added and the mixture was allowed to reach
room temperature while stirring for further 5 h. Finally, the
reaction was quenched with aqueous ammonium chloride
solution, the product was extracted with diethyl ether and
the organic layer was washed several times with ammonium
chloride and water, it was dried with anhydrous sodium sul-
phate, filtered and concentrated under reduced pressure.
The crude material was then purified by flash chromatogra-
phy through deactivated silica, eluting with hexane-ethyl
acetate mixtures. After removal of the solvents, the title
product was obtained as a pale-yellow oil; yield: 201 mg
(75%). 1H NMR (500 MHz, DMSO-d6, 373 K): d=1.44 (s,
9H), 2.09 (ddd, J=13.1, 6.1, 5.3 Hz, 1H), 2.25 (ddd, J=13.0,
7.9, 4.4 Hz, 1H), 2.95 (d, J=2.2 Hz, 1H), 3.40 (d, J=4.2 Hz,
2H), 4.01 (quintuplet, J=4.5 Hz, 1H), 4.42 (ddd, J=8.0, 5.9,
2.1 Hz, 1H); 13C NMR (125 MHz, DMSO-d6, 373 K): d=
27.8 (CH3), 38.3 (CH2), 46.0 (CH), 50.1 (CH2), 55.5 (CH),
71.9 (CH), 77.4 (CH3), 78.8 (C), 84.0 (C), 153.1 (C); IR
(ATR): n=3264 (CH), 2977 (CH MeO), 1692 (C=O), 1393,
cesses. Further work in this direction is in progress in
our laboratories and will be reported in due course.
Experimental Section
(S)-tert-Butyl 2-(1H-1,2,3-Triazol-5-yl)pyrrolidine-1-
carboxylate (8)
Alkyne 7 (332 mg, 1.70 mmol) was placed together with
CuSO4·5H2O (12 mg, 34 mmol) and sodium ascorbate
(34 mg, 0.17 mmol) in a flask. A 1:1 tert-butyl alcohol-water
mixture (5 mL) was added, followed by trimethylsilyl azide
(247 mL, 1.79 mmol), and the resulting mixture was stirred
overnight at room temperature. Then, water was added and
the organics were extracted with diethyl ether. The resulting
solution was dried with anhydrous sodium sulphate and con-
centrated under reduced pressure to give a pale yellow oil.
The crude material was purified by flash chromatography
through deactivated silica, eluting with hexane-ethyl acetate
mixtures. After removal of the solvents, the title product
1367, 1156, 1096 cmÀ1
; HR-MS (ES+): m/z=226.1435,
+
calcd. for C12H20NO3 (M+H): 226.1443; [a]2D5:À25.7 (c 1.13,
MeOH).
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Xacobe C. Cambeiro and Miquel A. Pericꢀs
FULL PAPERS
46.2 (CH), 54.0 (CH2), 69.2 (CH), 71.8 (CH), 78.7 (C), 83.7
(C), 153.2 (C); IR (ATR): n=3301 (CH), 2793, 1702 (C=O),
1392, 1109 cmÀ1; HR-MS (ES+): m/z=368.2633, calcd. for
C20H38NO3Si+ (M+H): 368.2621; [a]2D5: +23 (c 1.11,
MeOH).
ACHTUNGTRENNUNG
idine-1-carboxylate (11c)
The same method described for 11b was applied, employing
sodium hydride (34.2 mg, 1.35 mmol), 11a (260 mg,
1.23 mmol) and benzyl bromide (180 mL, 1.48 mmol) in
DMF (6 mL). After purification, the title product was ob-
AHCTUNGTREG(NNNU 2S,4R)-tert-Butyl 4-(tert-Butyldiphenylsilyloxy)-2-
ethynylpyrrolidine-1-carboxylate (11f)
1
tained as a pale yellow oil; yield: 274 mg (74%). H NMR
(400 MHz, CDCl3): d=1.48 (s, 9H), 2.20 (dt, J=12.9,
5.5 Hz, 1H), 2.24 to 2.39 (br, 2H), 3.43 to 3.68 (br, 2H),
4.23 (br, 1H), 4.47 to 4.65 (br, 3H), 7.27 to 7.37 (m, 5H);
13C NMR (100 MHz, CDCl3): d=28.4 (CH3), 38.8 and 39.8
(CH2, br, rotamers), 46.6 (CH, br), 50.4 and 51.1 (CH2, br,
rotamers), 71.3 (CH2), 75.9 (CH, br), 80.2 (C), 84.5 (C),
127.6 (CH), 127.8 (CH), 128.5 (CH), 137.8 (C), 154.1 (C);
IR (ATR): n=3276 (CH), 2978, 1696 (C=O), 1395,
The same method described for 11d was applied, employing
11a (285 mg, 1.35 mmol), imidazole (115 mg, 1.62 mmol)
and TBDPSCl (430 mL, 1.62 mmol) in DMF (7 mL). After
purification, the title product was obtained as a pale-yellow
oil; yield: 606 mg (quantitative). 1H NMR (500 MHz,
DMSO-d6, 373 K): d=1.06 (s, 9H), 1.45 (s, 9H), 2.02 (ddd,
J=12.8, 6.3, 4.9 Hz, 1H), 2.25 (dddd, J=12.8, 7.7, 4.5,
1.5 Hz, 1H), 2.85 (d, J=2.1 Hz, 1H), 3.31 (dd, J=11.3,
4.7 Hz, 1H), 3.40 (ddd, J=11.3, 3.2, 1.5 Hz, 1H), 4.52 to
4.57 (m, 2H), 7.41 to 7.47 (m, 6H), 7.62 to 7.65 (m, 4H);
13C NMR (125 MHz, DMSO-d6, 373 K): d=18.2 (C), 26.3
(CH3), 27.7 (CH3), 41.6 (CH2), 46.0 (CH), 53.2 (CH2), 70.7
(CH), 71.8 (CH), 78.7 (C), 83.7 (C), 127.3 (CH), 129.4 (CH),
134.7 (CH), 136.3 (C), 153.2 (C); IR (ATR): n=3281 (CH),
2930, 2857, 1699 (C=O), 1392, 1159, 1111, 703 (doop Ar CH)
1156 cmÀ1
; HR-MS (ES+): m/z=302.1749, calcd. for
C18H23NO3 (M+H): 302.1756; [a]2D5: À63.0 (c 1.18, MeOH).
+
ACHTUNGTRENNUNG(2S,4R)-tert-Butyl 4-(tert-Butyldimethylsilyloxy)-2-
ethynylpyrrolidine-1-carboxylate (11d)
Over a solution of 11a (251 mg, 1.19 mmol) and imidazole
(98.9 mg, 1.43 mmol) in DMF (4.0 mL), at 08C, another so-
lution containing tert-butylchlorodimethylsilane (221 mg,
1.43 mmol) in DMF (2.0 mL) was added dropwise. The mix-
ture was allowed to warm up to room temperature and
stirred overnight. After this time, the reaction was quenched
with aqueous ammonium chloride solution and the product
was extracted with diethyl ether. The organic layer was
washed several times with ammonium chloride in order to
remove the DMF and, then, dried with anhydrous sodium
sulphate, filtered and concentrated under reduced pressure.
The product thus obtained was purified by flash chromatog-
raphy through deactivated silica eluting with hexane-ethyl
acetate mixtures to obtain, after removal of the solvents, the
title product as a pale-yellow oil; yield: 216 mg (56%).
1H NMR (400 MHz, CDCl3): d=0.07 (two signals, 6H), 0.87
(s, 9H), 1.48 (s, 9H), 2.13 (br, 2H), 2.26 (br, 1H), 3.28 (br,
1H), 3.52 (br, 1H), 4.46 (m, 1H), 4.57 (br, 1H); 13C NMR
(100 MHz, CDCl3): d=À4.9 (CH3), 17.9 (C), 25.7 (CH3),
28.4 (CH3), 41.9 and 42.6 (CH2, br, rotamers), 46.4 (CH, br),
53.5 and 54.0 (CH2, br, rotamers), 69.6 and 70.3 (CH, br, ro-
tamers), 80.0 (C), 84.3 (C); IR (ATR): n=3291 (CH), 2978,
1677 (C=O), 1394, 1251 (ds Si-CH3) cmÀ1; HR-MS (ES+):
m/z=326.2146, calcd. for C17H32NO3Si+ (M+H): 326.2151;
[a]2D5: +8.3 (c 1.07, MeOH).
cmÀ1
;
HR-MS (ES+): m/z=450.2458, calcd. for
C27H36NO3Si+ (M+H): 450.2464; [a]2D5: +17 (c 0.996,
MeOH).
AHCTUNGTREG(NNNU 2S,4R)-tert-Butyl 4-Hydroxy-2-(1H-1,2,3-triazol-5-
yl)pyrrolidine-1-carboxylate (12a)
Under inert atmosphere, 11a (50.0 mg, 0.237 mmol) and cop-
per(I) iodide (2.3 mg, 12 mmol) were dissolved in a degassed
9:1 DMF-MeOH mixture (2.4 mL). DIPEA (62 mL,
0.36 mmol) was added, with the reaction mixture turning im-
mediately red, followed by azidotrimethylsilane (49 mL,
0.36 mmol), and the mixture was warmed up to 1008C
(reflux) and stirred at this temperature for 12 h. After this
time, the reaction mixture was allowed to cool down to
room temperature, diluted with ethyl acetate and washed
several times with aqueous ammonium chloride solution.
The organic layer was dried with anhydrous sodium sul-
phate, filtered and concentrated under reduced pressure.
The crude material was then purified by flash chromatogra-
phy through deactivated silica eluting with hexane-ethyl ace-
tate mixtures. After removal of the solvents the title product
was obtained as a pale-yellow oil; yield: 44.6 mg (74%).
1H NMR (500 MHz, DMSO-d6, 373 K): d=1.31 (s, 9H), 2.10
to 2.22 (m, 2H), 3.37 (ddd, J=11.1, 3.4, 1.1 Hz, 1H), 3.52
(dd, J=11.2, 5.1 Hz, 1H), 4.37 (quin, J=4.5 Hz, 1H), 4.70
(br, 1H), 5.02 (t, J=7.0 Hz, 1H), 7.55 (s, 1H); 13C NMR
(125 MHz, DMSO-d6, 373 K): d=27.7 (CH3), 41.3 (CH2, br),
51.2 (CH, br), 54.1 (CH2), 67.8 (CH), 78.1 (C), 126.4 (CH),
147.1 (C), 153.5 (C); IR (ATR): n=3144, 2977, 1671 (n C=
O), 1397, 1160 cmÀ1; HR-MS (ES+): m/z=255.1450, calcd.
ACHTUNGTRENNUNG(2S,4R)-tert-Butyl 2-Ethynyl-4-(triisopropylsilyloxy)-
pyrrolidine-1-carboxylate (11e)
The same method described for 11d was applied, employing
11a (124 mg, 0.586 mmol), imidazole (50.1 mg, 0.703 mmol)
and triisopropylsilyl trifluoromethanesulphonate (195 mL,
0.703 mmol) in DMF (3.0 mL). After purification, the title
product was obtained as a pale-yellow oil; yield: 117 mg
+
for C11H19N4O3 (M+H): 255.1457; [a]2D5: +5.5 (c 1.10,
1
(54%). H NMR (500 MHz, DMSO-d6, 373 K): d=1.02 (d,
MeOH).
J=6.4 Hz, 18H), 1.07 (s, 9H), 1.19 (m, 3H), 2.05 (ddd, J=
13.0, 6.1, 4.7 Hz, 1H), 2.25 (ddd, J=13.0, 7.7, 4.4 Hz, 1H),
2.87 (d, J=2.1 Hz, 1H), 3.29 (dd, J=11.1, 4.6 Hz, 1H), 3.41
(ddd, J=11.1, 3.4, 1.6 Hz, 1H), 4.55 (m, 1H), 4.61 (t, J=
4.5 Hz, 1H), 7.47 (s, 1H); 13C NMR (125 MHz, DMSO-d6,
373 K): d=12.3 (CH), 18.1 (CH3), 26.2 (CH3), 37.6 (CH2),
AHCTUNGTREG(NNNU 2S,4R)-tert-Butyl 4-Methoxy-2-(1H-1,2,3-triazol-5-
yl)pyrrolidine-1-carboxylate (12b)
The same method described for 12a was applied, employing
11b (144 mg, 0.638 mmol), copper(I) iodide (6.2 mg, 32
120
asc.wiley-vch.de
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 113 – 124

Proline-Derived Aminotriazole Ligands: Preparation and Use
mmol), DIPEA (168 mL, 0.958 mmol) and azidotrimethylsi-
lane (133 mL, 0.958 mmol) in a 9:1 DMF-methanol mixture
(1.3 mL). After purification, the title product was obtained
lane (66 mL, 0.48 mmol) in a 9:1 DMF-methanol mixture
(1 mL). After purification, the title product was obtained as
1
a pale-yellow oil; yield: 126 mg (96%). H NMR (500 MHz,
as
a
pale-yellow oil; yield:123 mg (72%). 1H NMR
DMSO-d6, 373 K): d=1.01 (d, J=6.4 Hz, 18H), 1.06 (s,
9H), 1.29 (m, 3H), 2.23 (m, 1H), 2.30 (m, 1H), 3.46 (dd, J=
11.3, 4.6 Hz, 1H), 3.55 (dd, J=11.3, 2.8 Hz, 1H), 4.57 (m,
J=4.0 Hz, 1H), 5.17 (t, J=6.9 Hz, 1H), 7.48 (s, 1H);
13C NMR (500 MHz, DMSO-d6, 373 K): d=12.5 (CH), 18.2
(CH3), 27.7 (CH3), 41.3 (CH2), 51.2 (CH), 54.0 (CH2), 70.9
(CH), 78.4 (C), 129.7 (CH), 145.4 (C), 153.7 (C); IR (ATR):
n=3208 (NH), 2795, 1701 (C=O), 1394, 1096 cmÀ1; HR-MS
(ES+): m/z=411.2799, calcd. for C20H39N4O3Si+ (M+H):
411.2791; [a]2D5: +17.3 (c 1.09, MeOH).
(500 MHz, DMSO-d6, 373 K): d=1.31 (s, 9H), 2.17 to 2.22
(m, 1H), 2.32 (ddd, J=13.1, 7.8, 4.4 Hz, 1H), 3.28 (s, 3H),
3.53 (d, 4.1 Hz, 2H), 4.07 (quintuplet, J=4.4 Hz, 1H), 4.99
(t, 6.98 Hz, 1H), 7.57 (s, 1H); 13C NMR (125 MHz, DMSO-
d6, 373 K): d=27.7 (CH3), 38.0 (CH2), 50.3 (CH2), 50.7
(CH), 55.5 (CH3), 77.6 (CH), 78.4 (C), 127.9 (CH), 142.3
(C), 153.4 (C); IR (ATR): n=3139 (NH), 2978, 1685 (C=O),
1393, 1153 cmÀ1; HR-MS (ES+): m/z=269.1621, calcd. for
+
C21H21N4O3 (M+H): 269.1614; [a]2D5: +138 (c 1.05, MeOH).
A
ACHTUNGTREN(NUGN 2S,4R)-tert-Butyl 4-(tert-Butyldiphenylsilyloxy)-2-
(1H-1,2,3-triazol-5-yl)pyrrolidine-1-carboxylate (12f)
yl)pyrrolidine-1-carboxylate (12c)
The same method described for 12a was applied, employing
11c (254 mg, 0.842 mmol), copper(I) iodide (8.2 mg,
42 mmol), DIPEA (221 mL, 1.26 mmol) and azidotrimethylsi-
lane (175 mL, 1.26 mmol) in a 9:1 DMF-methanol mixture
(2.2 mL). After purification, the title product was obtained
The same method described for 12a was applied, employing
11f (400 mg, 0.890 mmol), copper(I) iodide (8.6 mg, 45
mmol), DIPEA (234 mL, 1.33 mmol) and azidotrimethylsi-
lane (185 mL, 1.33 mmol) in a 9:1 DMF-methanol mixture
(2 mL). After purification, the title product was obtained as
1
as
a
pale-yellow oil; yield: 230 mg (79%). 1H NMR
a pale-yellow oil; yield: 277 mg (63%). H NMR (500 MHz,
(500 MHz, DMSO-d6, 373 K): d=1.32 (s, 9H), 2.25 (bm,
1H), 2.39 (ddd, J=13.0, 7.9, 4.4 Hz, 1H), 3.55 (dd, J=11.6,
4.9 Hz, 1H), 3.60 (ddd, J=11.5, 3.2, 0.5 Hz, 1H), 4.30
(quintuplet, J=4.4 Hz, 1H), 4.52 (d, J=12.1 Hz, 1H), 4.55
(d, J=12.1 Hz, 1H), 5.04 (dd, J=7.7, 6.3 Hz, 1H), 7.26 to
7.39 (m, 5H), 7.58 (b, 1H); 13C NMR (125 MHz, DMSO-d6,
373 K): d=27.7 (CH3), 38.4 (CH2), 51.1 (CH2), 51.4 (CH),
70.0 (CH2), 76.1 (CH), 78.4 (C), 126.9 (CH), 127.0 (CH),
127.8 (CH), 138.2 (C), 153.4 (C); IR (ATR): n=3140 (NH),
2977, 1671 (C=O), 1393, 1156 cmÀ1; HR-MS (ES+): m/z=
DMSO-d6, 373 K): d=1.06 (s, 9H), 1.33 (s, 9H), 2.13 (m,
1H), 2.31 (m, 1H), 3.40 (dd, J=11.4, 4.5 Hz, 1H), 3.51 (dd,
J=11.3, 3.0 Hz, 1H), 4.60 (quintuplet, J=4.0 Hz, 1H), 5.10
(t, J=7.2 Hz, 1H), 7.41 to 7.47, m, 6H), 7.53 (s, 1H), 7.63
(dd, J=8.1, 1.5 Hz, 4H); 13C NMR (500 MHz, DMSO-d6,
373 K): d=18.3 (C), 26.4 (CH3), 27.7 (CH3), 41.3 (CH2),
51.2 (CH), 54.0 (CH2), 70.9 (CH), 78.4 (C), 127.4 (CH),
129.4 (CH, two peaks), 133.2 (C, rotamers), 134.7 (CH, two
peaks), 153.6 (C); IR (ATR): n=3136 (NH), 2960, 1693 (C=
O), 1391, 1106, 701 (doop Ar CH) cmÀ1; HR-MS (ES+):
m/z=493.2639, calcd. for C27H37N4O3Si+ (M+H): 493.2635;
[a]2D5: +9.1 (c 1.03, MeOH).
+
345.1922, calcd for C18H25N4O3 (M+H): 345.1927; [a]2D5:
À11.2 (c 1.02, MeOH).
A
ACHTUNGTREN(NUGN 3R,5S)-5-(1H-1,2,3-Triazol-5-yl)pyrrolidin-3-ol
triazol-5-yl)pyrrolidine-1-carboxylate (12d)
Trifluoroacetic Acid Salt (13a·TFA)
The same method described for 12a was applied, employing
11d (196 mg, 0.602 mmol), copper(I) iodide (5.8 mg, 30
mmol), DIPEA (158 mL, 0.904 mmol) and azidotrimethylsi-
lane (125 mL, 0.904 mmol) in a 9:1 DMF-methanol mixture
(1.6 mL). After purification, the title product was obtained
Boc-protected aminotriazole 12a (120 mg, 0.472 mmol) was
dissolved in DCM (2.5 mL) and TFA (2.5 mL) was added.
The mixture was stirred at room temperature for 30 min and
then the volatile materials were removed under vacuum.
The solid residue was triturated with diethyl ether and fil-
tered several times and finally it was dried under reduced
pressure, to obtain the title product as a tan solid; yield:
121 mg (96%). 1H NMR (400 MHz, CD3CN): d=2.42 (m,
2H), 3.34 (d, J=12.6 Hz, 1H), 3.60 (dd, J=12.6, 4.6 Hz,
1H), 4.64 (m, 1H), 5.16 (dd, J=10.1, 7.7 Hz, 1H), 7.84 (s,
1H); 13C NMR (100 MHz, CD3CN): d=40.0 (CH2), 52.6
(CH), 55.1 (CH2), 69.7 (CH), 126.9 (CH), 147.8 (C); IR
(ATR): n=2961, 1671 (C=O TFA), 1198, 1135 cmÀ1; HR-
MS (ES+): m/z=155.0936, calcd. for C6H11N4O+ (M+H):
155.0933; [a]2D5: +26.3 (c 0.956, MeOH); mp 110–1138C.
as
a
pale-yellow oil; yield: 77.0 mg (34%). 1H NMR
(500 MHz, DMSO-d6, 373 K): d=0.09 and 0.10 (s, 6H to-
gether), 0.90 (s, 9H), 1.32 (s, 9H), 2.20 (dd, J=6.6, 4.8 Hz,
2H), 3.40 (dd, J=11.2, 3.3 Hz, 1H), 3.53 (dd, J=11.0,
4.8 Hz, 1H), 4.55 (quintuplet, J=4.4 Hz, 1H), 5.03 (t, J=
7.2 Hz, 1H), 7.58 (s, 1H); 13C NMR (125 MHz, DMSO-d6,
373 K): d=À4.7 (CH3), 17.8 (C), 25.6 (CH3), 27.9 (CH3),
40.1 (CH2), 54.1 (CH), 54.9 (CH2), 73.2 (CH), 78.6 (C),
129.5 (CH), 146.3 (C), 153.7 (C); IR (ATR): n=3346 (NH),
2929, 1671 (C=O), 1367, 1153, 835 cmÀ1; HR-MS (ES+):
m/z=369.2324, calcd. for C17H33N4O3Si+ (M+H): 369.2322;
[a]2D5:+9.8 (c 0.983, MeOH).
5-[(2S,4R)-4-Methoxypyrrolidin-2-yl]-1H-1,2,3-
triazole Trifluoroacetic Acid Salt (13b·TFA)
ACHTUNGTRENNUNG(2S,4R)-tert-Butyl 4-(Triisopropylsilyloxy)-2-(1H-
1,2,3-triazol-5-yl)pyrrolidine-1-carboxylate (12e)
The same procedure described for 13a was applied, employ-
ing 12b (93 mg, 0.35 mmol) in DCM (2 mL) and TFA
(2 mL). The title product was obtained as a tan solid; yield:
The same method described for 12a was applied, employing
11e (117 mg, 0.319 mmol), copper(I) iodide (3.1 mg,
16 mmol), DIPEA (84 mL, 0.48 mmol) and azidotrimethylsi-
1
71.0 mg (72%); H NMR (400 MHz, CD3CN): d=2.38 (ddd,
J=13.9, 11.6, 4.7 Hz, 1H), 2.56 (ddt, J=14.0, 6.3, 1.4 Hz,
Adv. Synth. Catal. 2011, 353, 113 – 124
ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
121

Xacobe C. Cambeiro and Miquel A. Pericꢀs
FULL PAPERS
1H), 3.32 (s, 3H), 3.44 (dt, J=12.8, 1.4 Hz, 1H), 3.63 (dd,
J=12.8, 4.8 Hz, 1H), 4.25 (t, J=4.6 Hz, 1H), 5.02 (dd, J=
11.5, 6.4 Hz, 1H), 7.84 (s, 1H); 13C NMR (100 MHz,
CD3CN): d=36.7 (CH2), 51.3 (CH2), 54.2 (CH), 56.9 (CH3),
79.5 (CH), 117.9 (C, q, JC,F =294 Hz), 129.3 (CH), 141.8 (C),
161.9 (C, q, JC,F =34 Hz); 19F NMR (376 MHz, CD3CN): d=
À76.1 (s); IR (ATR): n=3137, 2948, 2784, 1662 (C=O
TFA), 1187, 1061, 836, 721 cmÀ1; HR-MS (ES+): m/z=
169.1088, calcd. for C7H13N4O+ (M+H): 169.1089; [a]D25:
+31.9 (c 1.14, MeOH); mp 98–998C.
(CH), 17.9 (CH3), 42.8 (CH2), 52.7 (CH), 55.7 (CH2), 73.0
(CH), 128.4 (CH), 146.8 (C); IR (ATR): n=2940, 2864,
1461, 1084, 821, 678 cmÀ1; HR-MS (ES+): m/z=311.2261,
calcd. for C15H31N4OSi+ (M+H): 311.2267; [a]2D5: +44.2 (c
1.03, MeOH).
5-[(2S,4R)-4-(tert-Butyldiphenylsilyloxy)pyrrolidin-2-
yl]-1H-1,2,3-triazole (13f)
The same procedure described for 13c was applied, employ-
ing 12f (230 mg, 0.467 mmol) in DCM (2.5 mL) and TFA
(2.5 mL). The title product was obtained as a white solid;
5-[(2S,4R)-4-Benzyloxypyrrolidin-2-yl)-1H-1,2,3-
triazole (13c)
1
yield: 164 mg (89%). H NMR (400 MHz, CDCl3): d=1.06
(s, 9H), 1.93 (ddd, J=12.7, 9.5, 5.7 Hz, 1H), 2.24 (dd, J=
13.1, 6.7 Hz, 1H), 3.02 (d, J=11.7 Hz, 1H), 3.11 (dd, J=
11.8, 4.5 Hz, 1H), 4.52 (br, 1H), 4.73 (dd, J=8.9, 7.1 Hz,
1H), 7.35 to 7.42 (m, 7H), 7.55 (br, 2H), 7.64 (t, J=7.3 Hz);
13C NMR (100 MHz, CDCl3): d=19.0 (C), 26.9 (CH3), 42.5
(CH2), 52.7 (CH), 55.4 (CH2), 74.1 (CH), 127.7 (CH), 128.6
(CH), 129.7 (CH), 133.8 (C), 135.6 (CH, two signals), 147.6
(C); IR (ATR): n=2855, 1427, 1107, 699 cmÀ1; HR-MS
(ES+): m/z=393.2108, calcd. for C22H29N4OSi+ (M+H):
393.2111; [a]2D5: +17.34 (c 1.14, MeOH); mp 139–1418C.
The same procedure described for 13a was applied, employ-
ing 12c (150 mg, 0.436 mmol) in DCM (2.5 mL) and TFA
(2.5 mL). In this case the crude product, after removal of
the volatile materials, was dissolved again in DCM and
treated with aqueous sodium bicarbonate solution. The mix-
ture was stirred for 30 min and then the layers were separat-
ed and the organic one was washed with brine and water,
dried with anhydrous sodium sulphate, filtered and concen-
trated under reduced pressure, to obtain the title product as
1
a pale-yellow oil; yield: 26 mg (24%). H NMR (400 MHz,
CD3CN): d=2.09 (ddd, J=13.2, 9.0, 5.8 Hz, 1H), 2.40 (dd,
J=13.4, 6.7 Hz, 1H), 3.18 (d, J=12.3 Hz, 1H), 3.27 (dd, J=
12.3, 4.2 Hz, 1H), 4.25 (b, 1H), 4.47 (d, J=12.0 Hz, 1H),
4.51 (d, J=12.0 Hz, 1H), 4.65 (t, J=7.9 Hz, 1H), 6.56 (b,
2H), 7.27 to 7.34 (m, 5H), 7.50 (s, 1H); 13C NMR
(100 MHz, CD3CN): d=39.1 (CH2), 52.3 (CH2), 52.9 (CH),
71.1 (CH2), 79.5 (CH), 127.8 (CH), 127.9 (CH), 128.6 (CH),
128.9 (CH), 138.1 (C), 146.9 (C); IR (ATR): n=2854, 1437,
1175, 1026 cmÀ1; HR-MS (ES+): m/z=245.1399, calcd. for
C13H17N4O+ (M+H): 245.1402; [a]2D5: +13 (c 0.98, MeOH).
General Procedure for Asymmetric Transfer
Hydrogenation of Prochiral Ketones
In a typical experiment, under an inert atmosphere, a solu-
tion containing ligand 13f (3.53 mg, 9.00 mmol) in dry and
degassed isopropyl alcohol (1 mL) was added onto dichloro-
AHCTUNGTREG(NNNU p-cymene)ruthenium(II) dimer (1.84 mg, 3.00 mmol), and
the resulting mixture was stirred at room temperature for
40 min. After this time, a solution containing potassium hy-
droxide (1.85 mg, 33.0 mmol) in isopropyl alcohol (0.5 mL)
was added, and the mixture was stirred for further 20 min.
Finally, another solution containing acetophenone (12.0 mg,
100 mmol) in isopropyl alcohol (0.5 mL) was added, this
moment being considered as the starting time of the reac-
tion. Samples were extracted at different times, passed
through a short column of silica and diluted with DCM to a
concentration of approximately 1 mgmLÀ1, and then ana-
lyzed directly by GC (see Supporting Information for condi-
tions). In 4 h, a conversion of 91% was obtained, with 82%
enantiomeric excess.
Alternatively, the same procedure excluding the extrac-
tion of samples and with a final work-up consisting in addi-
tion of saturated NH4Cl aqueous solution, extraction with
DCM and drying with anhydrous sodium sulphate afforded,
after purification by flash chromatography through silica,
the reduced product in pure form; yield: 11.0 mg (90%).
5-[(2S,4R)-4-(tert-Butyldimethylsilyloxy)pyrrolidin-2-
yl)-1H-1,2,3-triazole (13d)
The same procedure described for 13c was applied, employ-
ing 12d (55 mg, 0.15 mmol) in DCM (0.7 mL) and TFA
(0.7 mL). The title product were obtained as a pale-yellow
oil; yield: 39 mg (98%). 1H NMR (400 MHz, CDCl3): d=
0.07 and 0.08 (s, 6H), 0.88 (s, 9H), 2.09 to 2.22 (m, 2H),
2.98 (d, J=11.4 Hz, 1H), 3.30 (d, J=11.3 Hz, 1H), 4.53 (br,
1H), 4.71 (t, J=8.3 Hz, 1H), 7.49 (s, 1H), 8.27 (b, 2H);
13C NMR (100 MHz, CDCl3): d=À4.8 (CH3, two signals),
18.0 (C), 25.8 (CH3), 42.4 (CH2), 52.6 (CH), 55.3 (CH2), 72.8
(CH), 128.3 (CH), 146.6 (C); IR (ATR): n=2928, 2855,
1462, 1254, 1078, 832, 744 cmÀ1; HRMS (ES+): m/z=
269.1802, calcd. for C12H25N4OSi+ (M+H): 269.1798; [a]D25:
+60.0 (c 1.12, MeOH).
5-[(2S,4R)-4-(Triisopropylsilyloxy)pyrrolidin-2-yl]-
1H-1,2,3-triazole (13e)
Acknowledgements
The same procedure described for 13c was applied, employ-
ing 12e (100 mg, 0.244 mmol) in DCM (1.2 mL) and TFA
(1.2 mL). The title product was obtained as a pale-yellow
This work was funded by MICINN (Grant No. CTQ2008-
00947/BQU), DIUE (Grant No. 2009SGR623), Consolider
Ingenio 2010 (Grant No. CSD2006-0003), and the ICIQ
Foundation. We thank Ataualpa Braga for enriching discus-
sion and help with computational techniques. X.C.C. thanks
MEC for an FPU fellowship.
1
oil; yield: 42.8 mg (57%). H NMR (400 MHz, CDCl3): d=
1.05 to 1.08 (m, 21H), 2.11 to 2.18 (m, 1H), 2.25 (dd, J=
13.0, 6.7 Hz, 1H), 3.04 (d, J=11.3 Hz, 1H), 3.15 (dd, J=
11.3, 6.4 Hz, 1H), 4.49 (m, 1H), 4.79 (dd, J=8.6, 6.5 Hz,
1H), 7.48 (s, 1H); 13C NMR (100 MHz, CDCl3): d=12.0
122
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ꢃ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 113 – 124

Proline-Derived Aminotriazole Ligands: Preparation and Use
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