Enantioselective Conjugate Azidation of α,β-Unsaturated Ketones under Bifunctional Organocatalysis by Direct Activation of TMSN3

Article abstract of DOI:10.1002/adsc.201900831

An enantioselective organocatalytic conjugate azidation of α,β-unsaturated ketones is presented. A bifunctional organocatalyst activates TMSN₃, triggering the nucleophilic addition of the azido group to enones in absence of external promoters and avoiding the direct use or the pre-formation of highly toxic and explosive hydrazoic acid. This protocol proceeds with excellent enantiocontrol under mild conditions. DFT calculations and mechanistic trials have been performed in order to demonstrate the direct activation performed by the bifunctional organocatalyst. (Figure presented.).

Full text of DOI:10.1002/adsc.201900831

Title: Enantioselective Conjugate Azidation of α,β-Unsaturated Ketones
under Bifunctional Organocatalysis by Direct Activation of TMSN3
Authors: Jorge Humbrias, M. Carmen Perez-Aguilar, Ruben Mas,
Antonella Dentoni Litta, Alessandra Lattanzi, Giorgio Della
Sala, Jose A. Fernandez-Salas, and Jose Julian Aleman Lara
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900831
Link to VoR: http://dx.doi.org/10.1002/adsc.201900831

10.1002/adsc.201900831
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Enantioselective Conjugate Azidation of α,β-Unsaturated
Ketones under Bifunctional Organocatalysis by Direct
Activation of TMSN3
Jorge Humbrías-Martín,a M. Carmen Pérez-Aguilar,a Rubén Mas-Ballesté,b,d Antonella
Dentoni Litta,c Alessandra Lattanzi,c Giorgio Della Sala,c Jose A. Fernández-Salasa*
and José Alemána,d*
a
Organic Chemistry Department, Módulo 1, Universidad Autónoma de Madrid, 28049 Madrid, Spain. e-mail:
j.fernandez@uam.es; jose.aleman@uam.es
Inorganic Chemistry Department, Módulo 7, Universidad Autónoma de Madrid, 28049 Madrid, Spain
Dipartimento di Chimica e Biologia “A. Zambelli” Universitꢀ degli Studi di Salerno, 84084 Fisciano, SA, Italy
Institute for Advanced Research in Chemical Sciences (IAdChem) Universidad Autónoma de Madrid, 28049 Madrid,
b
c
d
Spain
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
their incorporation. Although less explored, electron-
Abstract. An enantioselective organocatalytic conjugate
azidation of α,β-unsaturated ketones is presented. A deficient alkenes have also been described as platforms
bifunctional organocatalyst activates TMSN3, triggering the
for the nucleophilic asymmetric β-azidation.[3b,6]
nucleophilic addition of the azido group to enones in absence
of external promoters and avoiding the direct use or the pre-
formation of highly toxic and explosive hydrazoic acid. This
protocol proceeds with excellent enantiocontrol under mild
conditions. DFT calculations and mechanistic trials have
been performed in order to demonstrate the direct activation
performed by the bifunctional organocatalyst.
In this regard, the azido-Michael reaction to α,β-
unsaturated carbonyl compounds remains a key
transformation in the synthetic chemist’s toolbox, as it
represents a powerful tool for the rapid installation of
molecular complexity.[7] Although asymmetric aza-
Michael reactions have been widely explored,[8] the
corresponding conjugate azidation still stands as an
outstanding challenge in asymmetric catalysis.[3b] Thus,
Jacobsen and coworkers reported the asymmetric
Keywords: organocatalysis • enantioselective azidation •
squaramide • aza-Michael • direct activation
hydroazidation
of
α,β-unsaturated
N-
enoylbenzamides[9] and ketones[10] catalyzed by a salen-
Aluminum complex using hydrazoic acid; a toxic and
explosive reagent which is not easy to handle (eq. A,
Scheme 1). In pursuit of this challenging objective,
other research groups have focused their attention on the
Introduction
The development of efficient and practical strategies for
the stereoselective construction of new bonds is an
ongoing objective and still holds a preferred position in
organic chemistry research.[1] Organic azides have
attracted the attention of organic chemists over the years
as they are interesting and versatile intermediates in
organic synthesis. [2] Azides provide facile and direct
access to valuable functional groups (amines, amides,
etc.) and heterocycles (pyrroles, pyridines, 1,2,3-
triazoles and tetrazoles),[2] which stand as moieties that
are difficult to install in a single operation. Moreover,
the azide functionality is a prevalent structure in
medicinal chemistry and chemical biology.[2]
The singularity and special reactivity of the azide
moiety has led to a variety of synthetic methods
centered on its installation.[3] Considering their
asymmetric synthesis, enantioselective nucleophilic
azidations[3b] (mainly ring opening of meso aziridines[4]
and epoxides[5]) are among the preferred strategies for
1
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900831
Advanced Synthesis & Catalysis
Scheme 1. Scheme 1. Previous works (equations A and B) conditions led to the desired product in low yields (entry
and present work (equation C).
15). By changing the stoichiometry of the reaction and
increasing the catalyst loading (20 mol%), the β-keto
azide (3a) was isolated in 66% yield and 94% ee (entry
development of the asymmetric hydroazidation of 16).
Michael acceptors while trying to elude the use of
metal-based catalysts and avoid the direct use of Table 1. Optimization of the conjugate azidation of enones.a)
hydrazoic acid as nucleophilic azide source (eq. B,
Scheme 1). In this context, different organocatalytic
systems have been described to promote the
enantioselective conjugate addition of the azide group
to
α,β-unsaturated
N-enoylbenzamides[11]
and
nitroalkenes.[12] These methodologies are predicated on
the in situ generation of hydrazoic acid from TMSN3 in
the presence of a carboxylic acid as additive.[13] These
processes can be dramatically affected by the steric and
the electronic nature of the acid.
In spite of these particular achievements, we believe
there is still great room for improvement in the
challenging β-azidation of α,β-unsaturated carbonyl
compounds. Considering our experience in the field,[14]
we envisioned that a neutral coordinate organocatalyst
would be able to directly activate the organosilyl
nucleophile (TMSN3). This would trigger the
enantioselective conjugate addition of the azide group
to the α,β-unsaturated ketone.[15]
Herein, we describe an enantioselective conjugate
azidation of α,β-unsaturated ketones. The asymmetric
process is promoted by a bifunctional organocatalyst
which is able to synergistically activate both the enone
and the TMSN3 in absence of the carboxylic acid
additive (eq. C, Scheme 1), avoiding the pre-formation
of the highly toxic and explosive hydrazoic acid.
Cat. Solvent
T
(ºC)
Conv.b)
ee
c)
1
2
3
4
5
6
7
8
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
HFB
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
4
66
50
90
90
87
80
94
87
93
95
100
100
74
67
5
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
40
20
27
14
47
21
12
11
53
50
70
75
93
9
10
11
12
13
14
15d)
2j
2g
2g
2g
2g
2g
nHexane
HFB
nHexane
nHexane:HFB
Results and Discussion
4
4
54 (32)e)
100(76)e)
(66)g)
Based on our experience in bifunctional catalysis, [14]
we began our investigations by studying the reaction of
α,β-unsaturated ketone 1a as model substrate with
trimethyl silyl azide in the presence of different
bifunctional organocatalysts based on thiourea and
squaramide cores (Table 1) and tertiary amines, which
may act as Lewis base sites. At first, all catalysts were
examined in toluene at room temperature (entries 1-10).
All of them showed the ability to promote the reaction
featuring good levels of reactivity. Squaramide 2g
showed the best result, leading to the desired conjugate
adduct (3a) with the highest enantiomeric excess (47%
ee). Different solvents were then studied, using 2g as
optimal catalyst (entries 11-12 and see Supporting
Information). Only hexafluorobenzene (HFB) and
hexane displayed increased performance, enhancing the
selectivity up to 53% and 50% ee, respectively. These
results were improved at lower temperatures (4 ºC), and
already reasonably high enantioselectivities were
observed (entries 13 and 14), although the reactivity
was diminished and longer reaction times were required.
16f)
4
94
nHexane:HFB
2g
a) All the reactions were performed on a 0.1 mmol scale in
the presence of 2 (10 mol%) in 0.6 mL of solvent with a
determined residual amount of water (250 ppm,
b)
determined by Karl-Fisher titration). The conversion
1
c)
was determined by H-NMR. The enantiomeric excess
(ee) was measured by SFC. d) The reaction was performed
in a mixture of n-hexane:HFB (1:1, 0.17 M) (0.5 equiv.
e)
H2O) for 72 h.
NMR yield in brackets using
f)
trimethoxybenzene as internal standard. The reaction
was performed in the presence of 20 mol% of 2g, 1.2
equiv. of 1a and at 0.04 M concentration (0.5 equiv. H2O)
for 72 h. g) Isolated yield.
Once the reaction conditions had been optimized
(entry 16, Table 1), we studied the scope of the reaction
considering differently substituted α,β-unsaturated
ketones (Table 2). The conjugate azidation embraced a
variety of aromatic α,β-unsaturated ketones bearing
alkyl substituents. The reaction proceeded smoothly
employing enones substituted with a linear aliphatic
chain, achieving excellent enantiocontrol with 3a, 3b
and 3f. Bulkier carbon chain substituents such as iso-
propyl (3c), cyclohexyl (3d) and tert-butyl (3e) were
To our delight,
a
mixture of hexane and
hexafluorobenzene (1:1) significantly improved the
enantioselectivity to 93% ee when the initial amount of
water was controlled and set at 0.5 equiv.[16] However,
the low reactivity observed under such reaction
This article is protected by copyright. All rights reserved.
2

10.1002/adsc.201900831
Advanced Synthesis & Catalysis
very well tolerated, reaching the desired adducts with To our delight, no erosion in the enantiomeric purity
excellent enantioselectivities. The stereoelectronic was observed, despite of reports on the racemization of
nature of the aromatic ring was also studied. Differently enantioenriched azides in the presence of multiple
[17]
substituted electron-rich aromatic rings in para and Lewis acids.
It should be noted that N1–
meta positions led to the desired β-keto azide with very functionalized triazole derivatives are difficult to access
good results in both yield and enantioselectivity (3g, 3h by direct addition of 1,2,3-triazole in a conjugated
and 3j). Electron-deficient systems were not tolerated fashion, as they tend to react through the central
(3i) and low levels of enantioinduction were observed. nitrogen atom (N2) of the heterocycle.[18]
Gratifyingly, the protocol enabled access to the
corresponding β-azido substituted adduct in the
presence of heterocyclic enones with high
enantioselectivities (3k). Aromatic α,β-unsaturated
ketone bearing an aryl substituent was not suitable for
this transformation.
Table 2. Scope of the reaction for the enantioselective
conjugate azidation of enones.
Scheme 2. Derivatization of β-azido ketone 3a.
In order to gain insight into the reaction mechanism,
we performed a series of experiments, including NMR
29
studies (1H and Si NMR) (Scheme 3, see Supporting
Information for full details). The role of water in the
reaction was studied through analysis of the side-
products generated in the reaction, which unequivocally
result from the reaction of enone 1a, TMSN3 and water.
a)
Reaction conditions: To a solution of the catalyst 2g (20
mol%) in n-hexane (1.2 mL), the corresponding enone 1 (1.2
equiv.) was added. The reaction was cooled to 4 oC. Then, the
azidotrimethylsilane (0.075 mmol,
1
equiv.) and
hexafluorobenzene (1.2 mL) were sequentially added. H2O
content was 0.0035 mmol (0.5 equiv.). The reaction was
stirred for 48 hours at 4 oC. Isolated yields are in brackets.
The absolute configuration of product 3a was
assigned by correlation and was determined as S (see
Supporting Information). The same stereochemical
outcome was assumed for the rest of compounds 3.
As stated before, azides are powerful and versatile
building blocks in organic chemistry due to their
inherent and special reactivity.[2] Notably, Pd/C
mediated selective hydrogenation of the azido group
efficiently led to the β-amino ketone derivative 5 with
no significant loss of stereochemical information
(Scheme 2).[9] Moreover, the enantioenriched β-azido
derivative 3a was transformed to triazole derivative 4.
Scheme 3. Mechanistic investigation. Reactions carried out
in presence of different amounts of H2O (i). NMR studies
showing silicon species detected (ii, iii and iv).
This article is protected by copyright. All rights reserved.
3

10.1002/adsc.201900831
Advanced Synthesis & Catalysis
TSI
TSI
TSI’
TSI’
TSI’ (24.3)
25
20
15
10
5
TSII’ (18.6)
TSI (14.6)
8
10.6
TSII (10.8)
20.8
II (7.3)
3.5
6.4
14.6
3.5
III (5.7)
I
IV (-0.2)
0
-5.7
-5
Figure 1. DFT M062x/6-3111G** reaction energy (ΔG in Kcal/mol) profile in the addition of TMSN3 to 1a.
Thus, after a catalytic run, even if water is not
explicitly added to the system, two new silylated
species were observed in the reaction mixture by
means of 2D-HMBC{1H,29Si} (Scheme 3, eq. iii), that
showed signals clearly identified as trimethyl silanol
(29Si-NMR shift 15.82 ppm) and its corresponding
siloxane (29Si-NMR shift 6.57 ppm) (Scheme 3, eq.
iii.). Therefore, water – even at low concentrations –
seems to play a crucial role in the reaction. To further
support such feature, subsequent experiments in the
presence of an excess of water resulted in an increase
of the reaction kinetics and, as a result, a decrease in
the enantioselectivity (Scheme 3, eq. i). This
observation suggests that the activation of reagent 1a
proceeds via hydrolysis. A positive KIE value (see
Supporting Information) when monitoring the reaction
in presence of H2O or D2O confirms that water is
involved in the rate determining step. Previous
observations described in the literature[19] suggest the
spontaneous reaction of TMSN3 with water,
generating HN3 in solution. In contrast, under our
reaction conditions, water itself is not capable of
activating TMSN3 in the absence of the catalyst
(Scheme 3, eq. ii), which is in accordance with the high
enantiocontrol achieved in the organocatalyzed
conjugate azidation of enones.
Taking all the experimental evidence presented
above as starting point, we carried out a series of DFT
calculations at the M06-2X/6311G** level[20] in order
to define a plausible mechanism (Figure 1). First, with
the aim of determining the most feasible initial species,
we calculated an initial complex that includes a water
molecule, TMSN3, enone 1a and the catalyst. Enone
1a interacts with the squaramide moiety through two
practically equal H···O=C hydrogen bonds (O···H =
1.88-1.99 Å), while the water molecule does it with the
tertiary nitrogen atom of the quinuclidine moiety of the
cinchona fragment (N···H = 1.90-1.94 Å). Thus,
TMSN3 is allocated between the water and the enone
molecules, favouring the overall reaction. In the initial
structure, a hydrogen bond interaction is found
between the water molecule and the amine group
(N···H = 1.90-1.94 Å). Further evolution of this
system implies at first, a proton transfer from the water
molecule to the nitrogen atom of the quinuclidine
moiety followed by a nucleophilic attack of the
resulting hydroxide to the silicon atom that results in
the N-Si bond cleavage (II). Exhaustive exploration of
the potential energy surface indicates that these
4
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900831
Advanced Synthesis & Catalysis
processes take place in an asynchronous concerted
manner, and only a transition state (TSI) has been
found that connects species I to species II. TSI, which
is depicted in Figure 1, could be described as a
pentacoordinated N3···Si(OH)(CH3)3 silicon species,
found in the pro-R and pro-S dispositions. This
transition state results from the cleavage of an O-H
bond of the water molecule, which is compensated by
the formation of a N-H bond (N···H = 1.07-1.06 Å)
and Si-O bond (Si-O = 1.78-1.77 Å), and is
concomitant to the elongation of Si-N bond to 2.45-
2.47 Å. On this overall process, any minimum can be
observed, and therefore it can be described as an uphill
path up to TSI that costs 16.0 kcal/mol (pro-R) and
14.6 kcal/mol (pro-S). This is the greatest kinetic
barrier found in the reaction profile, indicating that the
proton transfer is involved in the rate determining step
(in good agreement with experimental kinetic data).
Further evolution of TSI leads to the rupture of the
Si−N bond to produce the silanol byproduct and
vacuum line) and the crude was purified on a Biotage
Isolera Prime using SNAP Cartridge KP-SIL 10g
charged with Geduran® Si 60 or IATROBEADs®
6RS-8060 (see each case).
(S)-3-Azido-1-phenylhexan-1-one (3a). Following
the general procedure, enone 1a (17 µL, 0.1 mmol) and
TMSN3 (10.5 µL, 0.075 mmol) gave the product 3a as
a colorless oil (14.3 mg, 66% yield). Purification was
performed on a Biotage Isolera Prime using SNAP
Cartridge KP-SIL 10g charged with Geduran® Si 60.
Eluent: hexane: dichloromethane; 12%, 3 CV; 12% -
19%; 6 CV; 19%, 5 CV; 19% - 27%, 2.7 CV; 24%, 4.2
CV. TLC in hexane: dichloromethane; 1:1; Rf product
=
0.34 and Rf enone = 0.31. [α]20D= -43 (c 0.02, CHCl3).
1H-NMR (300 MHz, CDCl3) δ 8.01 – 7.93 (m, 2H),
7.63 – 7.55 (m, 1H), 7.48 (ddt, J = 8.3, 6.6, 1.2 Hz,
2H), 4.18 – 4.01 (m, 1H), 3.25 (dd, J = 17.2, 8.0 Hz,
1H), 3.04 (dd, J = 17.2, 4.8 Hz, 1H), 1.68 – 1.50 (m,
2H), 0.98 (t, J = 7.1 Hz, 3H). 13C-NMR (76 MHz,
CDCl3) δ 197.5, 136.9, 133.6, 128.9, 128.3, 58.6, 43.5,
37.0, 19.5, 13.9. HRMS (ESI): calculated for
C12H16N3O+ [M+H]+: 218.1288; found 218.1290. The
enantiomeric ratio was determined by SFC using a
Chiralpak IC column [CO2/MeOH 98:2 in 10 min,
flow rate 3.0 mL/min], major = 5.38 min, minor = 5.04
min (e.r. = 97:3).
−
generating the nucleophile (N3 ). The latter species is
enclosed within the chiral pocket of the pre-organized
system, reacting then with the enone 1a. Thus, such
pre-organization of the two fragments directs the
geometry of the system to specifically generate the
new C−N bond: this nucleophilic attack proceeds
though a low kinetic barrier (3.5-8.0 kcal/mol) to
generate the slightly endothermic enolate intermediate
III. Final proton transfer leads to the
thermodynamically stable ketone IV (-0.2 and -5.1
kcal/mol).
Acknowledgements
We are grateful to the Spanish Government (CTQ2015-64561-R
and RTI2018-095038-B-I00) and “Comunidad de Madrid” and
European Structural Funds (S2018/NMT-4367). J. A. F.-S. thanks
the Spanish Government for a Juan de la Cierva Contract. We
acknowledge the generous allocation of computing time at the
Centro de Computación Científica of the Universidad Autónoma
de Madrid (CCC-UAM). University of Salerno is also
acknowledged for the financial support (FARB).
Conclusion
In conclusion, we have described a highly
enantioselective organocatalyzed 1,4 addition of an
azido group to α,β-unsaturated ketones. This system
avoids the use or pre-formation of dangerous and
highly explosive hydrazoic acid; TMSN3 is used as
nucleophile in the absence of carboxylic acid as
additive. In addition, the mechanistic investigations
and DFT calculations carried out show how the
organocatalyst is able to activate the organosilyl
species directly through a molecule of water, allowing
the asymmetric synthesis of challenging and versatile
β-azido ketones.
References
[1] a) V. Farina, J. T. Reeves, C. H. Senanayake, J. J. Song,
Chem Rev. 2006, 106, 2734-2793; b) M. Breuer, K.
Ditrich, T. Habicher, B. Hauer, M. Keßeler, R. Stꢁrmer,
T. Zelinski, Angew. Chem., Int. Ed. 2004, 43, 788-824.
[2]For selected reviews, see: a) S. Brase, C. Gil, K. Knepper,
V. Zimmermann, Angew. Chem., Int. Ed. 2005, 44,
5188-5240; b) J. Waser, E. M. Carreira in Organic
Azides: Syntheses and Applications; (Eds: S. Brase, K.
Banert), Wiley-VCH: Weinheim, 2010, pp. 95-111; c) S.
Chiba, Synlett 2012, 21-44.
Experimental Section
General procedure for the Azidation of α,β
Unsaturated Ketones
[3] For a general review, see: a) M. Goswami, B. de Bruin,
Eur. J. Org. Chem. 2017, 1152-1176; b) P. -G. Ding, X.
-S. Hu, F. Zhou, J. Zhou, Org. Chem. Front., 2018, 5,
1542-1559.
To a solution of the catalyst 2g (9 mg, 0.015 mmol,
0.15 equiv.) in hexane (1.2 mL), the corresponding
enone (0.1 mmol, 1 equiv.) was added. The reaction
was cooled to 4 ᵒC. Then, the azidotrimethylsilane
(0.075 mmol, 10.5 µL, 0.75 equiv.) and
hexafluorobenzene (1.2 mL) were sequentially added.
H2O content was 0.0035 mmol (0.5 equiv.). The
reaction was stirred for 48 hours at 4 ᵒC. Then, the
solvents were evaporated under reduced pressure (high
[4] For selected examples, see: a) B. Wu, J. C. Gallucci, J.
R. Parquette, T. V. RajanBabu, Chem. Sci. 2014, 5,
1102-1117; b) B. Wu, J. C. Gallucci, J. R. Parquette, T.
V. RajanBabu, Angew. Chem., Int. Ed. 2009, 48, 1126-
1129; c) Y. Fukuta, T. Mita, N. Fukuda, M. Kanai, M.
Shibasaki, J. Am. Chem. Soc. 2006, 128, 6312-6313; d)
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900831
Advanced Synthesis & Catalysis
E. B. Rowland, G. B. Rowland, E. Rivera-Otero, J. C.
Rodríguez, S. Díaz-Tendero, J. A. Fernández-Salas, J.
Alemán, Chem. Commun. 2018, 54, 13941-13944; d)
M. Frías, R. Mas-Ballesté, S. Arias, C. Alvarado, J.
Alemán, J. Am. Chem. Soc. 2017, 139, 672-679.
Antilla, J. Am. Chem. Soc. 2007, 129, 12084-12085; e)
G. Della Sala, Tetrahedron 2013, 69, 50-56; f) Z. Li, M.
Fernández, E. N. Jacobsen, Org. Lett. 1999, 1, 1611-
1613.
[15] An enantioselective protonation of the enolate formed
by the conjugated azidation of α-substituted vinyl
ketones has been reported: Z.-K. Xue, N.-K. Fu, S.-Z.
Luo, Chinese Chemical Letters, 2017, 28, 1083-1086.
[5] a) N. C. Gianneschi, S. -H. Cho, S. T. Nguyen, C. A.
Mirkin, Angew. Chem., Int. Ed. 2004, 43, 5503-5507; b)
L. E. Martinez, J. L. Leighton, D. H. Carsten, E. N.
Jacobsen, J. Am. Chem. Soc. 1995, 117, 5897-5898; c)
E. N. Jacobsen, Acc. Chem. Res. 2000, 33, 421-431; d)
B. W. McCleland, W. A. Nugent, M. G. Finn, J. Org.
Chem. 1998, 63, 6656-6666.
[16] A controlled initial amount of water was set in order to
avoid reproducibility issues. The best results regarding
both yield and enantioselectivity were obtained in the
presence of 0.5 equiv. of water.
[6] For selected examples of haloazidation: a) P. K. Shyam,
H.-Y. Jang, Eur. J. Org. Chem. 2014, 1817-1822; b) P.-
F. Zhou, L.-L. Lin, L. Chen, X. Zhong, X.-H. Liu, X.-M.
Feng, J. Am. Chem. Soc. 2017, 139, 13414-13419.
[17] A. A. Ott, J. J. Topczewski, Org. Lett. 2018, 20, 7253-
7256.
[18] U. K. Bhagat, R. K. Peddinti, J. Org. Chem. 2018, 83,
793-804.
[7] a) M. Mauduit, O. Baslé, H. Clavier, C. Crévisy, A.
Denicourt-Nowicki, in Comprehensive Organic
Synthesis, 2nd ed.; (Eds: G. A. Molander, P. Knochel),
Elsevier: Oxford, 2014, Vol. 4, pp. 189-341; b) A.
Alexakis, J. E. Bäckvall, N. Krause, O. Pàmines, M.
Diéguez, Chem. Rev. 2008, 108, 2796-2823; c) R.
Ballini, G. Bosica, D. Fiorini, A. Palmieri, M. Petrini,
Chem. Rev. 2005, 105, 933-972.
[19] K. B. Hansen, J. L. Leighton, E. N. Jacobsen, J. Am.
Chem. Soc. 1996, 118, 10924-10925.
[20] a) Y. Zhao, D.G. Truhlar, Theor. Chem. Account, 2008,
120, 215-241; b) A. V. Marenich, C. J. Cramer, D. G.
Truhlar, J. Phys. Chem. B, 2009, 113, 6378−6396; c) M.
J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone,
B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato,
X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G.
Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota,
R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Jr.
Montgomery, J. E. Peralta, F. Ogliaro, M. Bearpark, J. J.
Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R.
Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.
C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega,
N. J. Millam, M. Klene, J. E. Knox, J. B. Cross, V.
Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E.
Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C.
Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma,
V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J.
Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas, J. B.
Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian
09, Revision A.1; Gaussian, Inc.: Wallingford, CT, 2009.
[8] For selected reviews, see: a) D. Enders, C. Wang, J. X.
Liebich, Chem. Eur. J. 2009, 15, 11058-11076; b) J.
Wang, P. Li, P. Y. Choy, A. S. C. Chan, F. Y. Kwong,
ChemCatChem 2012, 4, 917-925; c) J. L. Vicario, D.
Badfa, L. Canillo, J. Etxebarria, E. Reyes, N. Ruiz, Org.
Prep. Proc. Int. 2005, 37, 513-538.
[9] J. K. Myers, E. N. Jacobsen, J. Am. Chem. Soc. 1999,
121, 8959-8960.
[10] M. S. Taylor, D. N. Zalatan, A. M. Lerchner, E. N.
Jacobsen, J. Am. Chem. Soc. 2005, 127, 1313-1317.
[11] a) T. E. Horstmann, D. J. Guerin, S. J. Miller, Angew.
Chem., Int. Ed. 2000, 39, 3635-3638. b) D. J. Guerin, S.
J. Miller, J. Am. Chem. Soc. 2002, 124, 2134-2136.
[12] a) M. Nielsen, W. Zhuang, K. A. Jørgensen,
Tetrahedron 2007, 63, 5849-5854; b) T. Bellavista, S.
Meninno, A. Lattanzi, G. Della Sala, Adv. Synth. Catal.
2015, 357, 3365-3373.
[13] D. J. Guerin, T. E. Horstmann, S. J. Miller, Org. Lett.
1999, 1, 1107-1109.
[14] a) F. Esteban, W. Ciesꢂik, E. M. Arpa, A. Guerrero-
Corella, S. Díaz-Tendero, J. Perles, J. A. Fernꢃndez-
Salas, A. Fraile, J. Alemꢃn, ACS Catal. 2018, 8,
1884−1890; b) V. Laina-Martín, J. Humbrías-Martín,
J. A. Fernández-Salas, J. Alemán, Chem. Commun.
2018, 54, 2781-2784; c) V. Laina-Martín, R. del Río-
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201900831
Advanced Synthesis & Catalysis
FULL PAPER
Enantioselective Conjugate Azidation of α,β-
Unsaturated Ketones under Bifunctional
Organocatalysis by Direct Activation of TMSN3
Adv. Synth. Catal. Year, Volume, Page – Page
Jorge Humbrías-Martín,a M. Carmen Pérez-
Aguilar,a Rubén Mas-Ballesté,b,d Antonella Dentoni
Litta,c Alessandra Lattanzi,c Giorgio Della Sala,c
Jose A. Fernández-Salasa* and José Alemána,d*
7
This article is protected by copyright. All rights reserved.