Functional-Group-Tolerant, Silver-Catalyzed N-N Bond Formation by Nitrene Transfer to Amines

Article abstract of DOI:10.1021/jacs.6b08219

Silver(I) promotes the highly chemoselective N-amidation of tertiary amines under catalytic conditions to form aminimides by nitrene transfer from PhI NTs. Remarkably, this transformation proceeds in a selective manner in the presence of olefins and other functional groups without formation of the commonly observed aziridines or C-H insertion products. The methodology can be applied not only to rather simple tertiary amines but also to complex natural molecules such as brucine or quinine, where the products derived from N-N bond formation were exclusively formed. Theoretical mechanistic studies have shown that this selective N-amidation reaction proceeds through triplet silver nitrenes.

Full text of DOI:10.1021/jacs.6b08219

Subscriber access provided by UNIV OF CALIFORNIA SAN DIEGO LIBRARIES
Article
Functional-Group-Tolerant, Silver-Catalyzed N-
N Bond Formation by Nitrene Transfer to Amines
Lourdes Maestre, Ruth Dorel, Oscar Pablo, Imma Escofet, W. M. C. Sameera, Eleuterio
Álvarez, Feliu Maseras, M. Mar Diaz-Requejo, Antonio M. Echavarren, and Pedro J. Pérez
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 18 Jan 2017
Downloaded from http://pubs.acs.org on January 18, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 10
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Functional-Group-Tolerant, Silver-Catalyzed N-N Bond For-
mation by Nitrene Transfer to Amines
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Lourdes Maestre,a Ruth Dorel,b Óscar Pablo,b Imma Escofet,b W. M. C. Sameera,b,c Eleuterio Ál-
varez,d Feliu Maseras,b,e,* M. Mar Díaz-Requejo,a,* Antonio M. Echavarren,b,f,* Pedro J. Péreza,*
aLaboratorio de Catálisis Homogénea, Unidad Asociada al CSIC, CIQSO-Centro de Investigación en Química Soste-
nible and Departamento de Química, Universidad de Huelva, 21007 Huelva, Spain
bInstitute of Chemical Research of Catalonia, ICIQ, Av. Països Catalans, 16, Barcelona Institut of Science and Tech-
nology, 43007 Tarragona, Spain
cDepartment of Chemistry, Faculty of Science, Hokkaido University, North-10 West-8, Kita-ku, Sapporo, Hokkaido
060-0810, Japan
dInstituto de Investigaciones Químicas, Centro de Investigaciones Científicas Isla de la Cartuja, CSIC, Av. Américo
Vespucio 49, 41092 Sevilla, Spain
eDepartament de Química, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
fDepartament de Química Orgànica i Analítica, Universitat Rovira i Virgili, C/ Marcel·lí Domingo s/n, 43007 Tarra-
gona, Spain
KEYWORDS : N-N bond formation, aminimides, nitrene transfer, silver catalysis, triplet silver nitrene
ABSTRACT: Silver(I) promotes the highly chemoselective N-amidation of tertiary amines under catalytic con-
ditions to form aminimides by nitrene transfer from PhI=NTs. Remarkably, this transformation proceeds in a
selective manner in the presence of olefins and other functional groups without formation of the commonly
observed aziridines or C-H insertion products. The methodology can be applied not only to rather simple ter-
tiary amines but also to complex natural molecules such as brucine or quinine, where the products derived from
N-N formation were exclusively formed. Theoretical mechanistic studies have shown that this selective N-
amidation reaction proceeds through triplet silver-nitrenes.
INTRODUCTION
The nitrene transfer to amines, pyridines and other aro-
matic N-heterocycles results in the formation of amini-
mides of general formula R3N+-N-R,5,6 which display dis-
tinctive physicochemical properties due to their zwitteri-
onic nature7 and consequently have found a wide range of
applications6 including their use as polymer additives in
adhesives8 and surfactants.9 Aminimides have also been
studied as potential CNS-acting agents,10 antifungals,11
anti-cancer,12 anti-peroxidation agents,13 HIV-1 protease
inhibitors,14 as well as peptidomimetics.15 Furthermore,
amidines have also been used as precursors for the gener-
ation of isocyanates16 and as intermediates for the synthe-
sis of biologically active imidazolidinones.17
Transition metal-catalyzed nitrene transfer reactions
constitute well-established methods for the synthesis of
aziridines by functionalization of unsaturated C=C bonds1
and for the preparation of protected amines by the inser-
tion into saturated C-H bonds.1a-c,2 Most of these methods
rely on the generation of an active metal-nitrene species
from isolated or in situ generated hypervalent iodine
reagents3 or azides4 (Scheme 1).
Scheme 1. General Metal-Catalyzed Nitrene Transfer
to Unsaturated or Saturated bonds
Aminimides can be obtained by the thermal reaction of
sulfonyl azides with pyridines and amines (Scheme 2a),18
by sulfonylation of N-amino pyridium salts (Scheme 2b),19
as well as by quaternization of hydrazine derivatives
(Scheme 2c).20 However, many of these synthetic proto-
cols exhibit low selectivity and therefore show a narrow
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 10
1
2
3
Scheme 3. Silver-Catalyzed Regio- and Stereose-
lective Aziridination of Dienols
Scheme 2. Methods for the Synthesis of Amini-
mides
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
rationale for this highly chemoselective N-N bond for-
mation with the aid of theoretical calculations.
substrate scope or give aminimides in low yields with the
concomitant formation of side products from competing
reactions.21
RESULTS AND DISCUSSION
We have developed group 11 metal-based catalysts for the
nitrene transfer reactions to saturated and unsaturated
Development of the N-Amidation Reaction and Sub-
strate Scope. We first tried the reaction of allyl amine
with PhI=NTs in the presence of TpBr3Cu(NCMe) or
[Tp*,BrAg]2 as catalysts,27 although complex mixtures of
products were observed. However the use of N,N-
dimethylallylamine (1) as the substrate led to the isolation
of the aminimide product 2 in 65-76 % yield using both
catalysts as the result of the formation of a N-N bond by
transfer of the NTs group from the metal center to the
amine (Scheme 4a). A minor product, which was also
formed in the non-catalyzed reaction of PhI=NTs and 1
under identical conditions, was detected from the crude
reaction mixtures. This product was not stable enough to
be isolated, but in any case its formation was circumvent-
ed by performing the silver-catalyzed reaction at 50 ºC,
which led to the isolation of aminimide 2 in almost quan-
titative yields. It is remarkable that the corresponding
aziridine could not be detected in spite of the well-known
capabilities of the catalysts employed to promote such
C=C functionalization. In fact, when a competition exper-
iment with equimolar mixtures of 1 and styrene was car-
ried out under those optimized conditions, a mixture of 2
and the aziridine derived from styrene was obtained in ca.
9:1 ratio (Scheme 4b). Given the well-known tendency of
styrene to be aziridinated by this methodology, this result
assesses the outstanding selectivity of our catalytic system
toward the formation of the N-N bond.
substrates.22 23 24 Furthermore,
a general mechanistic
,
,
profile for the aziridination of olefins catalyzed by TpxM
systems (M = Cu, Ag) based on experimental data and
theoretical calculations25 has been reported from our
laboratories. Stavropoulos and co-workers have also pro-
vided related mechanistic studies on copper-based
nitrene transfer reactions.26 From those contributions,
the importance of the electronic states of the metal-
nitrene intermediates in the mechanism of these trans-
formations has been demonstrated.
It has also been shown that certain functional groups can
exert a significant effect in the catalytic process. Thus, the
silver-catalyzed aziridination of dienes bearing a terminal
hydroxyl group at the allylic position proceeds in a regio-
and stereospecific manner to form vinylaziridines through
nitrene transfer to the double bond neighboring to the
hydroxyl group (Scheme 3),23 which was applied for the
synthesis of sphingosine. The high regioselectivity was
explained in terms of the directing effect of the hydroxyl
group through hydrogen bond with one of the oxygen
atoms of the tosyl group of the silver-nitrene intermedi-
ate.
With the aim of expanding this methodology, we em-
barked on the use of allylic amines as the substrates for
the metal-catalyzed nitrene transfer reaction. Following
this strategy, we have discovered that the NTs moiety is
selectively transferred to the amine functionality to form
aminimides, even in the presence of a C=C bond. This
unprecedented observation has been expanded to a num-
ber of examples showing a high degree of tolerance with
other functional groups. We also provide a mechanistic
The structure of 2 was unambiguously assigned by X-ray
diffraction (Scheme 4),28 thus confirming the presence of
the aminimide moiety with a N-N bond length of 1.467(1)
Å, which is within the expected range for the dipolar
R3N+-N-SO2R’ nitrogen ylide function.29
ACS Paragon Plus Environment

Page 3 of 10
Journal of the American Chemical Society
Scheme 5. Scope of the Tp*,BrAg-Catalyzed Synthe-
1
2
3
sis of Aminimidesa
Scheme 4. Silver-Catalyzed Selective Formation of
Aminimides
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
a
Reaction conditions: [catalyst]/[PhI=NTs]/[amine] =
1:20:100 with respect to 0.015 mmol of catalyst. NMR
yields. TsNH2 accounted for 100% initial PhINTs not
converted into aminimide 2. b Isolated yields in paren-
theses. The competition reaction was evaluated by
NMR.
The substrate scope of this transformation was next ex-
amined for a series of tertiary amines with a variety of
structural motifs and functional groups (Scheme 5). The
reactions were carried out in the presence of the silver-
[Tp*,BrAg]2 catalyst using an excess of the amine with re-
spect to the nitrene source at room temperature or at 50
ºC. In general, good to excellent isolated yields (44-95%)
were obtained for the diverse array of substrates exam-
ined. The high tendency of this catalytic system to selec-
tively form N-N bonds in the presence of C=C bonds is
highlighted in the reaction of mono-, di-, and tri-allyl
amines that were cleanly converted into their correspond-
ing aminimides 3-7, which were characterized spectro-
scopically as well as by X-ray diffraction.28 It is worth
noting that aminimides 6 and 7 derive from di- and tri-
substituted olefins, respectively, which are more reactive
than terminal olefins towards electrophilic reagents. A
second series of aminimides 8-15 lacking of olefin groups
were also prepared. Significantly, no competing Csp3-H
functionalization was observed even in cases with availa-
ble benzylic positions or reactive C-H bonds adjacent to
ethers or acylamino groups. Nitrogen groups protected as
carboxamide (15) or carbamate (11 and 12) do not react. In
addition, protecting groups such as t-butyloxycarbonyl
(Boc) in 11 and 12 and benzyloxycarbonyl (Cbz) in 15 were
perfectly tolerated. It is important to remark that this
silver complex has been shown to be competent for the
catalytic amidation of alkanes,30 which have Csp3-H bonds
much less reactive than those present in these substrates.
a
Reaction conditions: [catalyst]/[PhI=NTs]/[amine] =
1:20:100 with respect to 0.015 mmol of catalyst (per Ag
unit), 6 mL of CH2Cl2, reaction temperature = 25 ºC.
Isolated yields in parentheses. TsNH2 accounted for
b
100% initial PhINTs not converted into aminimides.
Reaction carried out at 50 ºC. ORTEP plots (50% ther-
mal ellipsoids) of the X-ray crystal structures of 3, 5-7
are shown. Oxygen atoms are shown in red, sulfur
atoms yellow, hydrogen atoms white, and carbon at-
oms gray.28
With the aim of exploring more complex molecules that
could challenge the selectivity of the formation of N-N
bonds with this catalytic system, we targeted brucine (16)
and quinine (19a) as the substrates (Scheme 6). Indeed,
brucine (16) and cinchonidine (19b), a closer relative of
19a, had been studied before as substrates in a rhodium-
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 10
catalyzed nitrene transfer reaction.21b In that study from
the allylic amine 2 with PhINTs in the presence of
1
2
3
4
5
6
7
8
other laboratories, 16 gave aminimide 17a in low yield,
together with lactam 18 as a result of a competing C-C
bond cleavage, whereas in the case of 19b, the N-
amidation occurred unselectively at the quinoclidine and
quinoline nitrogen atoms to give a mixture of three prod-
ucts 20a-c. In sharp contrast, our silver-catalyzed nitrene
transfer reaction proceeded very cleanly at the tertiary
amines of both brucine (16) and quinine (19a) to give
aminimides 17b and 21 in 83 and 73% yield, respectively,
Rh2(OAc)4 did not induce the formation of aminimides,
decomposition of the nitrene source into unidentified
products being observed.
Scheme 7. Thermal Rearrangement of Amini-
mides 2 and 5.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6. Silver-Catalyzed vs. Reported Rhodium-
catalyzed21b N-N Bond Formation on Complex Natu-
ral Products
Synthesis of Hydrazines by Thermal Rearrangement
of Allylaminimides. Certain allylic and benzylic amini-
mides are known to undergo thermally induced rear-
rangements to afford the thermodynamically more stable
neutral hydrazide derivatives.31 On the basis of these
precedents, and in order to evaluate the thermal stability
of the aminimides prepared through our method, the
rearrangement of 2 was initially examined (Scheme 7).
Interestingly, we obtained hydrazone 22 in an excellent
95% yield instead of product 23 of allylic migration
(Wawzonek rearrangement).31 Presumably, under the
a
reaction conditions, the initial sulfonyl hydrazine 23 elim-
inates p-toluenesulphinic acid to form acrolein N,N-
dimethyl hydrazone (24), which then undergoes a Mi-
chael addition with p-toluenesulphinic acid31 to afford
b
22. Aminimide 5 underwent an analogous rearrangement
to afford crystalline 25, whose structure was confirmed by
X-ray diffraction.28 In contrast, under the same reaction
conditions aminimide 10 gave a complex mixture of prod-
ucts, whereas heating of other aminimides such as 9 or 14
only led to the recovery of unreacted starting materials.
whose structures were confirmed by X-ray diffraction
analysis.28 These two examples underscore the exquisite
chemoselectivity of this silver-catalyzed transformation
which leads selectively to the formation of a N-N bond in
molecules containing C=C bonds, pyridine-type rings,
carboxamides, electron-rich aromatic systems, as well as
activated Csp3-H bonds (tertiary, benzylic or vicinal to
heteroatoms). It is worth mentioning that the reaction of
Computational Study on the Origin of the Chemose-
lectivity. As mentioned above, the reaction described in
this contribution is remarkable both because the amini-
mide is formed and because potential alternative prod-
ucts, namely aziridines or C-H functionalization deriva-
tives, are not. To shed light on the origin of such ob-
servance, we first carried out DFT calculations for the
ACS Paragon Plus Environment

Page 5 of 10
Journal of the American Chemical Society
when starting from 3R. These free energies are clearly
reaction between the parent dimethylallylamine (Sub, 1),
Tp*,BrAg complex, and PhI=NTs (the nitrene source).
Scheme 8 summarizes the calculated free energy profiles
for the N-amidation. Starting from the [Tp*,BrAg]2 system,
the Tp*,BrAg species can be generated with a free energy
cost of 12.6 kcal mol-1, in good agreement with previous
experimental results.27 Then, coordination of PhI=NTs
gives rise to an intermediate, Tp*,BrAg(PhINTs), which is
further 10.8 kcal mol-1 higher in free energy. This
Tp*,BrAg(PhINTs) intermediate is the highest point in the
whole free energy profile, 23.4 kcal mol-1 above the start-
ing species, confirming that once the metal-nitrene com-
plex is formed the reaction proceeds smoothly. After dis-
sociation of PhI, the closed-shell singlet state of the met-
al-nitrene (1R) can be formed, which is 18.5 kcal mol-l
above the entry point of the free energy profile.
affordable under the experimental conditions.
1
2
3
4
5
6
7
8
Scheme 8. Calculated Free Energy Profiles (kcal·mol-
1) for the N-amidation of 1.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
We will first describe the reaction in the above singlet
electronic state. Starting from the singlet metal-nitrene
intermediate (1R), we located the transition state (TS) for
the N-N bond formation, which has an overall relative
free energy of 20.8 kcal mol-1 (1TSN-N), and leads to the
species Tp*,BrAg(PN-N) (-22.4 kcal mol-1), where the N-N
bond is already formed. Dissociation of the PN-N product
from the catalyst leads to electronic reorganization and a
substantial lowering of the free energy down to -70.8 kcal
mol-1. The catalyst (Tp*,BrAg) can be recovered at this
point for the next catalytic cycle. The highest free energy
point for this singlet path from the nitrene species is 1TSN-
N, with a free energy of 20.8 kcal mol-1. There is however a
lower energy path through the triplet spin state. The
metal-nitrene complex is more stable as a triplet (3R, 11.9
kcal mol-1, <S2> = 2.01), and this state can be reached
through the minimum energy crossing point MECP1 (17.9
kcal mol-1). Spin crossovers in transition metal catalysis
are well-known.32 The spin density distribution of 3R
[ρ(N) = 1.34 an ρ(Ag) = 0.28 ] implies that two unpaired
electrons are localized on the metal-nitrene unit. The
We next explored the free energy profiles for the compet-
ing aziridination process (Scheme 9). There are number
of reports in the literature on the mechanisms of transi-
tion metal catalyzed aziridination, showing concerted or
radical reaction paths.33 The concerted two-electron
transfer from 1R to C=C of the substrate can occur
through the closed-shell singlet TS (1TSN-C, 25.3 kcal mol-
1), giving rise to the Tp*,BrAg(PC-N) complex (-45.2 kcal
mol-1). Despite several attempts, location of the corre-
sponding open-shell form of the TS was not successful,
where calculations ultimately converged to the product
complex, Tp*,BrAg(PC-N). The stepwise two-electron trans-
fer from the thermodynamically stable 3R can occur
through the triplet TS (3TSN-C, 21.2 kcal mol-1), where the
first electron transfer leading to N-C1 bond formation,
3
approach of the substrate to R leads to intermediate (3I,
<S2> = 2.02), which is 4.0 kcal mol-1 higher in free energy.
3
In I, the N-N bond distance is longer (2.45 Å), and the
calculated spin density distribution in 3I [ρ(N) = 1.30,
ρ(Ag) = 0.04, and ρ(N, Sub) = 0.45] implies some spin
density transfer from the metal-nitrene unit to the sub-
strate. Despite several attempts, we were unable to locate
3
and a triplet radical intermediate RI is formed (1.3 kcal
mol-1). We have also located the barrier for the N-C2 bond
formation, which is however 3.4 kcal mol-1 higher than
3
3
a TS connecting from R to I. We confirmed the absence
of a transition state in the potential energy surface by a
scan of the approach between the two fragments (Figure
S1). We explored the eventual existence of an open-shell
3
3TSN-C (not shown in Scheme 9). Before the RI, there is a
MECP between the triplet and singlet surfaces complex
(MECP3, 0.3 kcal mol-1, leading to the Tp*,BrAg(PC-N).
Then, the aziridine product, PC-N (-95.5 kcal mol-1), disso-
ciates from the metal center. The overall picture of the
free energy profiles for the aziridination is consistent with
our previous reports.23b,25
3
singlet state in geometries similar to I, all attempts lead-
ing to the closed-shell species Tp*,BrAg(PN-N). Beyond the
3I intermediate, the triplet potential energy surface is
highly repulsive (see Figure S1, Supporting Information).
The key to the triplet reactivity is the existence of a min-
imum energy crossing point (MECP2, 15.8 kcal mol-1),
The N-N bond formation could start from the triplet met-
al-nitrene intermediate (3R), since this step only requires
3.9 kcal mol-1 barrier (MECP2). The alternative aziridina-
3
which is very close in geometry to I, returning to the
singlet state. By crossing to the triplet state, the product
can be reached through a highest free energy point of 17.9
3
tion pathway from R is less likely to occur, since the
barrier (3TSN-C) for this process is significantly higher (9.3
1
kcal mol-1 (MECP1) when starting from R, or through an
kcal mol-1). This is in agreement with our experimental
even lower free energy point of 15.8 kcal mol-1 (MECP2)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 6 of 10
results. Additionally, NMR studies have shown that there
The efficiency of the formation of the aminimide can be
explained by the combination of two factors: (i) the nitro-
gen lone pair is more nucleophilic than the -electrons of
the C-C double bond and (ii) the aminimide formation
from the high energy metal-nitrene complex is sufficient-
ly exergonic to make the reaction irreversible. The com-
bination of the two factors leads to the exceptional selec-
tivity of this system.
1
2
3
4
5
6
7
8
is no direct interaction between the silver complex and
the amine substrate. The aziridination is certainly favored
thermodynamically, but kinetically disfavored. Similar
conclusions can be made from MO6L and ωB97XD free
energy profiles (Figure S2 and S3), where energy separa-
tion between MECP2 and 3TSN-C are 6.0 kcal mol-1 and 5.0
kcal mol-1, respectively. According to these results, we
conclude that the N-N bond formation is favored over the
aziridination.
π
9
CONCLUSIONS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 9. Calculated Free Energy Profiles (kcal·mol-
1) for the Aziridination of 1.
The chemoselective N-amidation of tertiary amines cata-
lyzed by a Ag(I) complex has been developed using
PhI=NTs as the nitrene source, thus opening a new entry
to the synthesis of functionalized aminimides. This trans-
formation tolerates a range of functionalities including
aromatic N-heterocycles and olefins, which remain unre-
acted under the reaction conditions. Complex natural
products such as brucine and quinine have been selective-
ly functionalized at the tertiary amine site, in spite of the
presence of other functional groups, including olefins or
allylic C-H bonds. The selectivity of the process has been
rationalized by DFT calculations.
EXPERIMENTAL SECTION
General Methods. Reactions under inert (argon or ni-
trogen) atmosphere were carried out in solvents dried by
passing through an activated alumina column on a Pure-
SolvTM solvent purification system (Innovative Technolo-
gies, Inc., MA). Analytical thin layer chromatography was
carried out using TLC-aluminum sheets with 0.2 mm of
silica gel (Merck GF234) using UV light as the visualizing
agent and an acidic solution of vanillin in ethanol as the
developing agent. Chromatographic purifications were
carried out using flash grade silica gel (SDS Chromatogel
60 ACC, 40-63 μm). Organic solutions were concentrated
under reduced pressure on a Büchi rotary evaporator. All
reagents were used as purchased and used with no further
purification. PhI=NTs35 and TpxM (M = Cu, Ag)30,36 com-
plexes were prepared according to the procedures de-
scribed in the literature.
NMR spectra were recorded at 25 ºC on a Fourier 300,
Bruker Avance 400 Ultrashield or Bruker Avance 500
Ultrashield apparatus. The signals are given as δ (ppm)
downfield from tetramethylsilane, with calibration on the
residual protio-solvent used (δH = 7.26 ppm and δC =
77.00 ppm for CDCl3, δH = 3.31 ppm and δC = 49.00 ppm
for CD3OD, and δH = 7.16 ppm and δC = 128.06 ppm for
C6D6). Mass spectra were recorded on a Waters LCT
Premier Spectrometer (ESI and APCI) or on an Autoflex
Bruker Daltonics (MALDI and LDI). Melting points were
determined using a Büchi melting point apparatus.
The calculations reported above involve a number of
approximations due to the size and complexity of the
system. We comment here two of them that we consider
may affect specific numbers but would not alter the gen-
eral trends. The free energy profiles could be refined to
take into account the presence of diffusion barriers in the
barrierless steps (or those with very low barrier) in the
3
3
potential energy surface (for instance from R to I), a
procedure that has been applied in other cases.34 How-
ever, this would have a similar effect on both competing
pathways, resulting in the same balance. Another issue is
the assumption that the spin flip between different spin
states will take place easily once the MECP is reached. We
suspect this is the case, although we have not proved it
through computationally demanding spin-orbit coupling
calculations. We would like in any case to mention that
the trend would be the same if the systems stayed in the
singlet state throughout the process, as the singlet/triplet
difference is similar for both pathways.
Crystal structure determinations were carried out using a
Bruker-Nonius diffractometer equipped with an APPEX 2
4K CCD area detector, a FR591 rotating anode with MoKa
radiation, Montel mirrors as monochromator and a
Kryoflex low temperature device (T = –173 ºC). Full-sphere
data collection was used with w and j scans. Programs
used: Data collection APEX-2, data reduction Bruker Saint
ACS Paragon Plus Environment

Page 7 of 10
Journal of the American Chemical Society
ing calculations with the MO6L37 and ωB97XD42 function-
V/.60A and absorption correction SADABS. Structure
1
2
3
4
5
6
7
8
Solution and Refinement: Crystal structure solutions were
achieved using direct methods as implemented in
SHELXTL and visualized using the program XP. Missing
atoms were subsequently located from difference Fourier
synthesis and added to the atom list. Least-squares re-
finement on F2 using all measured intensities was carried
out using the program SHELXTL. All non-hydrogen at-
oms were refined including anisotropic displacement
parameters.
als and found very similar results (see Supporting Infor-
mation). The eventual existence of open-shell singlet
electronic states was evaluated through stability calcula-
1
1
1
tions43 on the selected species R, TSN-N, TSN-C. In all
cases it was found that the closed-shell singlet was pre-
ferred.
Supporting Information. All procedures and characteri-
9
zation data for new compounds, computed free energy
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
General Procedure for the Synthesis of Aminimides.
A previously flame-dried Schlenk covered with aluminum
foil was charged with [Tp*BrAg]2 (0.0075 mmol) and a
magnetic stirring bar inside a glovebox before being
equipped with a septum. Dry and degassed CH2Cl2 (6 mL)
was added followed by the corresponding amine (1.5
mmol). After stirring for 5 minutes, PhI=NTs (0.3 mmol)
was added in one portion to the reaction and the mixture
was stirred for 16 h at the desired temperature. Then vola-
tiles were removed under reduced pressure and the re-
sulting crude was purified by silica gel column chroma-
tography unless otherwise stated. See Supporting Infor-
mation for details and full spectroscopic data.
Rearrangement of Allylaminimides. A microwave vial
was charged with the corresponding aminimide (0.1
mmol) and a magnetic stirring bar. The tube was
equipped with a septum and evacuated and backfilled
with Ar (3 times). Then C6D6 (2 mL) was added and the
reaction was heated up to 80 ºC during 4 h (monitored by
1H-NMR) and after cooling down to room temperature,
the volatiles were removed under reduced pressure to
obtain crude hydrazine. See Supporting Information for
purification details and full spectroscopic data.
Computational Details. Solvent phase structure optimi-
zations were performed with the M06 density function-
al,37 as implemented in Gaussian09 program.38 The SMD
implicit solvation model was used with dichloromethane
(ε = 8.93). The SDD basis sets were used for silver, copper,
bromine and iodine.39 The 6-31G(d) basis sets were used
for the remaining atoms.40 Final energies were obtained
by doing single-point energy calculations on the opti-
mized structures, where silver, bromine, and iodine were
still described with SDD, while the remaining atoms were
treated with the 6-311++G(d,p) basis sets. All geometry
optimizations were full with no restrictions, and vibra-
tional frequency calculations were performed to establish
the nature of the stationary points (i.e. minima or transi-
tion states). Connectivity of the transition states was con-
firmed by IRC calculations. Free-energy corrections at
298.15 K and 1 atm pressure were used, including zero-
point energy corrections. Minimum energy crossing
points were calculated by using the MECP program of J.
N. Harvey and co-workers.41 Thermal corrections to the
MECP structures were obtained by performing frequency
calculations for the two states, and taking the average
values of the corrections. The MO6 functional applied
here was found in previous works on aziridination by
related systems to perform better than BP86.23b,25 We have
further benchmarked its performance by repeating select-
scan beyond intermediate I and Cartesian coordinates of
the optimized structures. The Supporting Information is
available free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
perez@dqcm.uhu.es (PJP), aechavarren@iciq.es (AME),
mmdiaz@dqcm.uhu.es (MMDR), fmaseras@iciq.es (FM)
Funding Sources
No competing financial interests have been declared.
ACKNOWLEDGMENT
We thank MINECO for Grants CTQ2014-52769-C3-1-R,
CTQ2013-42106-P, CTQ2014-57761-R, Severo Ochoa Excel-
lence Accreditation 2014-2018 (SEV-2013-0319), Red
Intecat (CTQ2014-52974-REDC), FPI fellowship (LM), the
European Research Council (Advanced Grant No. 321066),
the AGAUR (2014 SGR 818), and CERCA Pro-
gram/Generalitat de Catalunya. We also thank Dr. Tania
Jiménez for additional experiments and the ICIQ X-ray
diffraction unit for the crystal structures of compounds 5-
7, 17b, 21 and 25.
REFERENCES
(1) (a) Degennaro, L.; Trinchera, P.; Luisi, R. Chem. Rev. 2014,
114, 7881–7929. (b) Chang, J. W. W.; Ton, T. M. U.; Chan, P.
W. H. Chem. Rec. 2011, 11, 331–357. (c) Pellisier, H. Tetrahe-
dron 2010, 66, 1509–1555. (d) Halfen, J. A. Curr. Org. Chem.
2005, 9, 657–669. (e). Müller, P.; Fruit, C. Chem. Rev. 2003,
103, 2905–2919.
(2) (a) Buendía, J.; Grelier, G.; Dauban, P. Adv. Organomet.
Chem. 2015, 64, 1–123. (b) Dequirez, G.; Pons, V.; Dauban,
P. Angew. Chem., Int. Ed. 2012, 51, 7384−7395. (c) Díaz-
Requejo, M. M.; Caballero A.; Fructos, M. R. Pérez, P. J. Al-
kane C-H Activation by Single-Site Metal Catalysis, Spring-
er, Amsterdam, 2012, Chap. 6. (d) Zalatan, D. N.; Du Bois,
J. Top. Curr. Chem. 2010, 292, 347−378. (f) Díaz-Requejo,
M. M.; Pérez, P. J. Chem. Rev. 2008, 108, 3379–3394.
(3) Sordergren, M. J.; Alonso, D. A.; Bedekar, A. V.; Andersson,
P. G. Tetrahedron Lett. 1997, 38, 6897–6900.
(4) Cenini, S.; La Monica, G. Inorg. Chim. Acta 1976, 18, 279–
293.
(5) (a) Jain, S. L.; Sharma, V. B.; Sain, B. Tetrahedron Lett.
2003, 44, 4385-4387. (b) Ochiai, M.; Kawano, Y.; Kaneaki,
T.; Tada, N.; Miyamoto, K. Org. Lett. 2009, 11, 281-284. (c)
Ochiai, M.; Miyamoto, K.; Hayashi, S.; Nakanishi, W.
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 8 of 10
1
2
Chem. Commun. 2010, 46, 511-521. (d) Pujari, S. A.; Guénée,
C.; Locati, A.; Díaz-Requejo, M. M.; Matheu, M. I.; Casti-
3
4
5
6
7
8
9
L.; Lacour, J. Org. Lett. 2013, 15, 3930-3933.
llón, S.; Maseras, F.; Pérez, P. J. J. Am. Chem. Soc. 2014, 136,
5342–5350.
(24) (a) Fructos, M. R.; Álvarez, E.; Díaz-Requejo, M. M.; Pérez,
P. J. J. Am. Chem. Soc. 2010, 132, 4600–4607. (b) Maestre,
L.; Fructos, M. R.; Díaz-Requejo, M. M.; Pérez, P. J. Orga-
nometallics 2012, 31, 7839−7843
(25) Maestre, L.; Sameera, W. M. C.; Díaz-Requejo, M. M.;
Maseras, F.; Pérez, P. J. J. Am. Chem. Soc. 2013, 135, 1338–
1348.
(26) Bagchi, V.; Paraskevopoulou, P.; Das, P.; Chi, L.; Wang, Q.;
Choudhury, A.; Mathieson, J. S.; Cronin, L.; Pardue, D. B.;
Cundari, T. R.; Mitrikas, G.; Sanakis, Y.; Stavropoulos, P. J.
Am. Chem. Soc. 2014, 136, 11362–11381.
(27) The dinuclear structure of complex [Tp*,BrAg]2 in the solid
state dissociates in solution, as demonstrated by stduies of
molecular weight in solution. See: Urbano, J.; Braga, A.
A.C.; Maseras, F.; Álvarez, E.; Díaz-Requejo, M. M.; Pérez,
P. J. Organometallics 2009, 28, 5968–5981.
(28) See Supporting Information for cif files of X-ray structures.
(29) Morris, D. G.; Ryder, K. S.; Muir, K. W. Cryst. Growth Des.
2005, 5, 361–364.
(30) Gómez-Emeterio, B. P.; Urbano, J.; Díaz-Requejo, M. M.;
Pérez, P. J. Organometallics 2008, 27, 4126–4130.
(31) (a) Wawzonek, S.; Yeakey, E. J. Am. Chem. Soc. 1960, 82,
5718–5721. (b) Baldwin, J. E.; Brown, J. E. J. Org. Chem. 1971,
36, 3642–3644.
(32) (a) Meunier, P.; de Visser, S. P.; Shaik, S. Chem. Rev. 2004,
104, 3947-3980. (b) Shaik, S.; Kumar, D.; de Visser, S. P.; Al-
tun, A.; Thiel, W. Chem. Rev. 2005, 105, 2279-2328. (c)
Schröder, D.; Shaik, S; Schwarz, H. Acc. Chem. Res. 2000,
33, 139-145. (c) Linde, C.; Akermark, B.; Norrby, P-O.;
Svensson, M. J. Am. Chem. Soc. 1999, 121, 5083-5084. (d)
Cavallo, L.; Jacobsen, H. Angew. Chem. Int. Ed. Engl. 2000,
39, 589-592. (e) Cavallo, L.; Jacobsen, H. Eur. J. Inorg.
Chem. 2003, 892-902. (f) Cavallo, L.; Jacobsen, H. J. Phys.
Chem. A, 2003, 107, 5466-5471. (g) Cavallo, L.; Jacobsen, H.
J. Org. Chem. 2003, 68, 6202-6207. (h) Jacobsen, H; Caval-
lo, L. Chem. Eur. J. 2001, 20, 1533-1544.
(33) (a) Comba, P.; Haaf, C.; Lienke, A.; Muruganantham, A.;
Wadepohl, H. Chem.-Eur. J. 2009, 15, 10880-10887. (b)
Comba, P.; Lang, C.; López de Laorden, C.; Muruganant-
ham, A.; Rajaraman, G.; Wadepohl, H.; Zajaczkowski, M.
Chem.-Eur. J. 2008, 14, 5313-5328. (c) Gillespie, K. M.; Crust,
E. J.; Deeth, R. J.; Scott, P. Chem. Commun. 2001, 785-786.
(d) Brandt, P.; Södergren, M. J.; Andersson, P. G.; Norrby,
P.-O. J. Am. Chem. Soc. 2000, 122, 8013-8020. (e) Lin, X.;
Che, C.-M.; Phillips, D. L. J. Org. Chem. 2008, 73, 529-537.
(f) Suárez, A. I. O.; Jiang, H.; Zhang, X. P.; de Bruin, B. Dal-
ton Trans. 2011, 40, 5697-5705. (g) Cundari, T. R.; Dinescu,
A.; Kazi, A. B. Inorg. Chem. 2008, 47, 10067-10072. (h)
Hopmann, K. H.; Ghosh, A. ACS Catal. 2011, 1, 597-600. (i)
Kundu, S.; Miceli, E.; Farquhar, E.; Pfaff, F. F.; Kuhlmann,
U.; Hildebrandt, P.; Braun, B.; Greco, C.; Ray, C. J. Am.
Chem. Soc. 2012, 134, 14710-14713. (j) Lyaskovskyy, V.; Sua-
rez, A. I. O.; Lu, H.; Jiang, H.; Zhang, X. P.; de Bruin, B. J.
Am. Chem. Soc. 2011, 133, 12264-12273. (k) Klotz, K. L.;
Slominski, L. M.; Riemer, M. E.; Phillips, J. A.; Halfen, J. A.
(6) (a) McKillip, W. J.; Sedor, E. A.; Culbertson, B. M.;
Wawzonek, S. Chem. Rev. 1973, 73, 255–281. (b) Rade-
macher, P. Science of Synthesis 2008, 40b, 1133–1210.
(7) (a) Illien, B.; Berthelot, M.; Morris, D. G.; Laurence, C. J.
Phys. Org. Chem. 2000, 13, 293–299. (b) Chardin, A.; Lau-
rence, C.; Berthelot, M.; Morris, D. G. J. Chem. Soc., Perkin
Trans. 2 1996, 1047–1051.
(8) Throckmorton, P. E.; Luckman, E. R. Rubber Chem Tech.
1980, 53, 270–284.
(9) (a) Morris, D. G.; Ryder, K. S.; Muir, K. W. Crystal Growth
Des. 2005, 5, 361–364. (b) Oba, G.; Coleman, B. E.; Hart, D.
J.; Zakin, J.; Zhang, Y.; Kawaguchi, Y.; Talmon, Y. Tetrahe-
dron 2006, 62, 10193–10201.
(10) Capuano, B.; Crosby, I. T.; Lloyd, E. J.; Neve, J. E.; Tylor, D.
A. Aust. J. Chem. 2008, 61, 422–431.
(11) Abel, M. D.; Hewgill, R. T.; Malczyk, K. J.; Micetich, R. G.;
Daneshtalab, M. J. Heteocycl. Chem. 1998, 35, 193–199.
(12) Gangapuram, M.; Redda, K. K. J. Heterocycl. Chem. 2009,
46, 309–316.
(13) Grisar, J. M.; Marciniak, G.; Bolkenius, F. N.; Verne.Misner,
J.; Wagner, E. R. J. Med. Chem. 1995, 38, 2880–2886.
(14) Rutenber, E. E.; McPhee, F.; Kaplan, A. P.; Gallion, S. L.;
Hogan, J. C. Jr.; Craik, C. S.; Stoud, R. M. Bioorg. Med.
Chem. 1996, 4, 1545–1558.
(15) Peisach, E.; Casbier, D.; Gallion, S. L.; Furth, P.; Petsko, G.;
Hogan, J. C. Jr.; Ringe, D. Science 1995, 269, 66–69.
(16) Kirino, M.; Tomita, I. Macromolecules 2010, 43, 8821–8827.
(17) (a) Aelony, D.; McKillip, W. J. J. Heterocycl. Chem. 1972, 9,
687–690. (b) Wright, W.; Brabander, H.; Hardy, R.; Oster-
berg, A. J. Med. Chem. 1966, 9, 852–857.
(18) (a) Hafner, K.; Zinser, D.; Moritz, K.-L. Tetrahedron Lett.
1964, 5, 1733–1737. (b) Abramovitch, R. A.; Takaya, T. J. Org.
Chem. 1972, 37, 2022–2029.
(19) (a) Slagel, R. C. J. Org. Chem. 1968, 33, 1374–1378. (b) Gan-
gapuram, M.; Redda, K. K. J. Heterocycl. Chem. 2009, 46,
309–316. (c) Gangapuram, M.; Mazzio, E.; Eyunni, S.; Soli-
man, K. F. A.; Redda, K. K. Arch. Pharm. Chem. Life Sci.
2014, 347, 360–369.
(20) For selected examples see: (a) Wawzonek, S.; Meyer, D. J.
Am. Chem. Soc. 1954, 76, 2918–2920. (b) McKillip, W. J.;
Clemens, L. M.; Haugland, R. Can. J. Chem. 1967, 45, 2613–
2617. (c) McKillip, W. J.; Slagel, R. C. Can. J. Chem. 1967, 45,
2619–2623. (d) Slagel, R. C.; Bloomquist, A. E. Can. J. Chem.
1967, 45, 2625–2628.
(21) (a) Trost, B. M.; Boyle, O.; Torres, W.; Ameriks, M. K.
Chem. Eur. J. 2011, 17, 7890–7903. (b) Li, J.; Cisar, J. S.;
Zhou, C.-Y.; Vera, B.; Williams, H.; Rodríguez, A. D.; Cra-
vatt, B. F.; Romo, D. Nat. Chem. 2013, 5, 510–517.
(22) (a) Pérez, P. J.; Brookhart, M.; Templeton, J. L. Organome-
tallics 1993, 12, 261–262. (b) Díaz-Requejo, M. M.; Pérez, P.
J.; Brookhart, M.; Templeton, J. L. Organometallics 1997, 16,
4399–4402. (c) Díaz-Requejo, M. M.; Belderraín, T. R.; Ni-
casio, M. C.; Trofimenko, S.; Pérez, P. J. J. Am. Chem. Soc.
2003, 125, 12078–12079. (d) Mairena, M. A.; Díaz-Requejo,
M. M.; Belderraín, T.; Nicasio, M. C.; Trofimenko, S.; Pérez,
P. J. Organometallics 2004, 23, 253–256. (e) Arenas, I.;
Fuentes, M. Á.; Álvarez, E.; Díaz, Y.; Caballero, A.; Casti-
llón, S.; Pérez, P. J. Inorg. Chem. 2014, 53, 3991–3999.
(23) (a) Llavería, J.; Beltrán, A.; Díaz-Requejo, M. M.; Matheu,
M. I.; Castillón, S.; Pérez, P. J. Angew. Chem. Int. Ed. 2010,
49, 7092–7095. (b) Llavería, J.; Beltrán, A.; Sameera, W. M.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Inorg. Chem. 2008, 48, 801-803
.
(34) (a) Rush, L. E.; Pringle, P. G.; Harvey, J. N. Angew. Chem.,
Int. Ed. 2014, 53, 8672−8676. (b) Goehry, C.; Besora, M.;
Maseras, F. ACS Catal. 2015, 5, 2445−2451. (c) Fernández-
ACS Paragon Plus Environment

Page 9 of 10
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Alvarez, V. M.; Nappi, M.; Melchiorre, P.; Maseras, F. Org.
Lett. 2015, 17, 2676-2679.
(35) Yamada, Y.; Yamamoto, T.; Okawara, M. Chem. Lett. 1975,
4, 361–362.
(36) Caballero, A.; Díaz-Requejo, M. M.; Belderrain, T. R.; Nica-
sio, M. C.; Trofimenko, S.; Pérez, P. J. J. Am. Chem. Soc.
2003, 125, 1446–1447.
(37) Zhao, Y.; Truhlar, D. G. J. Chem. Phys. 2006, 125, 194101–
194118.
(38) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G. ; Barone, V.;
Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.;
Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng,
G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fu-
kuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers,
E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Nor-
mand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.;
Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, J. M.;
Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Mar-
tin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.;
Farkas, Ö.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox,
D. J. Gaussian 09, revision B.1; Gaussian, Inc.: Wallingford,
CT, 2009.
(39) Andrae, D.; Häussermann, U.; Dolg, M.; Stoll, H.; Preuss,
H. Theor. Chim. Acta 1990, 77, 123–141.
(40) (a) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys.
1972, 56, 2257–2261. (b) Hariharan, P. C.; Pople, J. A. Theor.
Chim. Acta 1973, 28, 213–222. (c) Gordon, M. S. Chem. Phys.
1980, 76, 163–168.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(41)
Harvey, J. N.; Aschi, M.; Schwarz, H.; Koch, W. Theor.
Chem. Acc. 1998, 99, 95–99
.
(42) Chai, J.-D.; Head-Gordon, M. Phys. Chem. Chem. Phys.
2008, 10, 6615-6620.
(43) Bauernschmitt, R.; Ahlrichs, R. J. Chem. Phys. 1996, 104,
9047-9052)
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 10 of 10
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
10
ACS Paragon Plus Environment