Chemo-, regio-, and stereoselective silver-catalyzed aziridination of dienes: Scope, mechanistic studies, and ring-opening reactions

Article abstract of DOI:10.1021/ja412547r

Silver complexes bearing trispyrazolylborate ligands (Tp^x) catalyze the aziridination of 2,4-diene-1-ols in a chemo-, regio-, and stereoselective manner to give vinylaziridines in high yields by means of the metal-mediated transfer of NTs (Ts = p-toluensulfonyl) units from PhI=NTs. The preferential aziridination occurs at the double bond neighboring to the hydroxyl end in ca. 9:1 ratios that assessed a very high degree of regioselectivity. The reaction with the silver-based catalysts proceeds in a stereospecific manner, i.e., the initial configuration of the C=C bond is maintained in the aziridine product (cis or trans). The degree of regioselectivity was explained with the aid of DFT studies, where the directing effect of the OH group of 2,4-diene-1-ols plays a key role. Effective strategies for ring-opening of the new aziridines, deprotection of the Ts group, and subsequent formation of β-amino alcohols have also been developed.

Full text of DOI:10.1021/ja412547r

Article
pubs.acs.org/JACS
Chemo‑, Regio‑, and Stereoselective Silver-Catalyzed Aziridination of
Dienes: Scope, Mechanistic Studies, and Ring-Opening Reactions
∥
‡
†
†
,‡
́
Josep Llaveria, Alvaro Beltran, W. M. C. Sameera, Abel Locati, M. Mar Díaz-Requejo,*
́
M. Isabel Matheu,*,∥ Sergio Castillon,*,∥ Feliu Maseras,*,†,§ and Pedro J. Perez*,‡
∥Departament de Química Analítica i Química Organ
43007 Tarragona, Spain
‡Laboratorio de Catal
Departamento de Química y Ciencia de los Materiales, Universidad de Huelva, Campus de El Carmen 21007 Huelva, Spain
†Institute of Chemical Research of Catalonia, ICIQ, Av. Països Catalans 16, 43007 Tarragona, Spain
§Departament de Química, Universitat Auton
̀
oma de Barcelona, 08193 Bellaterra, Spain
́
́
̀
ica, Facultat de Química, Universitat Rovira i Virgili, C/Marcel·lí Domingo s/n,
isis Homogenea, Unidad Asociada al CSIC, CIQSO-Centro de Investigacion en Química Sostenible and
́ ́ ́
S
* Supporting Information
ABSTRACT: Silver complexes bearing trispyrazolylborate
ligands (Tpx) catalyze the aziridination of 2,4-diene-1-ols in
a chemo-, regio-, and stereoselective manner to give
vinylaziridines in high yields by means of the metal-mediated
transfer of NTs (Ts = p-toluensulfonyl) units from PhINTs.
The preferential aziridination occurs at the double bond
neighboring to the hydroxyl end in ca. 9:1 ratios that assessed
a very high degree of regioselectivity. The reaction with the silver-based catalysts proceeds in a stereospecific manner, i.e., the
initial configuration of the CC bond is maintained in the aziridine product (cis or trans). The degree of regioselectivity was
explained with the aid of DFT studies, where the directing effect of the OH group of 2,4-diene-1-ols plays a key role. Effective
strategies for ring-opening of the new aziridines, deprotection of the Ts group, and subsequent formation of β-amino alcohols
have also been developed.
Scheme 1. Vinylaziridines Reported Synthetic Methods
INTRODUCTION
■
Vinylaziridines are versatile and powerful three-membered
heterocyclic intermediates that allow a direct access to
biologically relevant structural moieties due to their high
reactivity and ability to act as carbon electrophiles.1 With the
appropriate selection of substituents, vinylaziridines can be
opened regio- and stereoselectively by different nucleophiles to
further afford functionalized allyl- and homoallyl-amines.2 They
are also known to provide a wide spectrum of heterocycles, such
as β-lactams,3 pyrrolidines,4 tetrahydropyridines,5 azepines,6a
cyclic ureas,6b oxazolidinones,7a and pyrrolo- and indolo-
piperazinones7b,c through opening/cyclization tandem processes.
Not surprisingly, the above applications of vinylaziridines
have triggered the development of a number of synthetic routes
for their preparation. Most of them are based on stoichiometric
procedures through nucleophilic intramolecular substitutions.
Scheme 1 shows some of those protocols, the aza Darzens-type
reaction being (Scheme 1a), for instance, a well-known method
for the preparation of aziridines with an array of functional groups,
including vinyl substituents.8 The reaction between an allylic
ylide and imines or sulfinimines9 (Scheme 1b) has also been
described as a route to vinylaziridines. These two methods have
usually led to thermodynamically stable cis-vinylaziridines.10
The reaction of benzylsulfonium salts with imines (the so-called
aza Corey−Chaykovzky reaction) constituted an alternative
route for the synthesis of chiral cis-vinylaziridines (Scheme 1c).11
Trans-vinylaziridines have been prepared in a stereoselective
manner, with the latter route driving the reaction under steric
and kinetic control.9j Vinylepoxides have served as precursors to
the aziridine product by means of ring-opening/-closing reactions
Received: December 10, 2013
Published: March 12, 2014
© 2014 American Chemical Society
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with azides12 or ammonia13 (Scheme 1d). Ring-closing of 1,2-
amino halides (Scheme 1e)14 or conjugate addition processes
complete the array of stoichiometric methods toward vinyl-
aziridines.15
The metal-catalyzed nitrene transfer reaction to olefin
constitutes a well-known strategy for the synthesis of aziridines
(Scheme 2a).16 However, in spite of the large number of
allylic position.18b This target was established on the basis of
the importance of β-amino alcohol moieties in biologically
active compounds. However, the tolerance of the catalytic
system to such hydroxyl functionality was unknown, and
therefore we first examined allylic alcohol as a simple substrate
to evaluate this variable. With TpBr3Cu(NCMe) and Tp*,BrAg
as representative catalysts, allylic alcohol was converted into the
corresponding aziridine with 68% and 65% isolated yields
(Scheme 4), respectively, based on initial PhINTs (the
Scheme 2. Aziridination of Olefins or Dienes by
Metal-Catalyzed Nitrene Transfer Reactions
Scheme 4. Aziridination of Allyl Alcohol
remaining of the initial nitrene precursor can be decomposed
into TsNH2). When O-protected derivatives (methyl, benzyl
and silyl ether, acetyl, or carbamate) were employed, the yields
decreased significantly.
catalytic systems described for such purpose, the use of this
methodology with dienes as substrates to yield vinylaziridines
(Scheme 2b) is yet scarce, and regioselectivity remains a
challenge. Also, several copper-, manganese-, and ruthenium-
based catalysts17 were reported for this reaction, where two
general features being observed: mixtures of isomers (derived
from aziridination of one or the other double bond) were
obtained with nonsymmetric dienes (R1 ≠ R2), and the
cis/trans ratios (in each isomer) were low, as the result of the
poor selectivity induced by the metal center.
With the aim of developing a metal-catalyzed route to
vinylaziridines via nitrene transfer methodology, we have
studied the catalytic activity of copper and silver complexes
bearing trispyrazolylborate ligands (Tpx, Scheme 3) in the
After the above experiments, we have carried out a catalyst
screening with several copper- and silver-complexes bearing the
ligands shown in Scheme 3, and (2E,4E)-hexa-2,4-dien-1-ol (1)
as the substrate. A set of four (2−5) different aziridines can be
expected from this dienol, depending on the functionalized
double bond and the geometry of the substituents in the
aziridine. Regioselectivity is therefore provided by 2+3:4+5
ratio, whereas stereoselectivity corresponds to 2:3 and 4:5 in
each case. Under the reaction conditions (1:20:30 ratio of
catalyst:PhINTs:1), high to quantitative yields were observed
(Table 1), even with the catalyst loadings as low as 0.5%
(entries 9 and 11) or using stoichiometric mixtures of PhINTs
and the dienol (entry 11). In all cases a ca. 90:10 regioselectivity
toward the aziridines derived from the functionalization of the
double bond neighboring to the hydroxyl end was found, and no
diaziridination products were observed in all cases. The OH
group was not affected during the catalytic reaction. The main
distinction between the copper- and silver-based catalyst is
observed for the stereoselection, where a certain degree of
inversion of the initial E-configuration of the CC bond leading
to the final E:Z aziridine mixtures within the interval 1:1 to 2:1
was obtained for the copper-based systems, while the silver-based
catalysts give rise to complete stereoretention (within exper-
imental error). Therefore, the first catalyst screening has shown
that (i) both TpxCu and TpxAg complexes catalyze the
aziridination of the probe dienol in an effective manner with
no effect on the hydroxyl group; (ii) the reaction takes place
preferentially in the double bond neighboring to the OH group;
and (iii) full stereoretention is only ensured with the silver
catalysts.
General Aziridination Reaction of 2,4-Dien-1-ols. To
verify the generality of this procedure, a series of 2,4-diene-1-ol
derivatives 6−16 (Scheme 5) were employed as the substrate,
with a certain variability of structural features such as
configuration 2E,4E with several different substituents at the
ω position (6−9) or with substituents at the double bonds
(10−12) as well as configurations 2Z,4E (13), 2Z,4Z (14), and
2E,4Z (15, 16). The previous behavior observed with (2E,4E)-
hexa-2,4-dien-1-ol has been extended to this series of dienols.
Overall, regioselection toward the aziridines derived from
the addition of the nitrene moiety to the double bond vicinal
to the OH group ranged from 72:28 to 93:7, even for C2- or
Scheme 3. Trispyrazolylborate Ligands and the Nitrene
Precursor Employed in This Work
reaction of dienes and PhINTs (Scheme 3) as the nitrene
precursor, taking advantage of our previous studies related to
olefin aziridination.18 In this contribution, we describe the
catalytic properties of a silver-based catalyst for the regio- and
stereoselective aziridination of dienes, particularly those bearing
terminal OH groups,19 with a broad scope. Experimental data
and DFT studies have provided a mechanistic explanation for
this highly selective transformation. In addition, to prove the
validity of this methodology from a synthetic point of view,
selective aziridine ring-opening with N-, O-, and S-nucleophiles
has provided an easy route to allylic and homoallylic amines.
RESULTS AND DISCUSSION
Catalyst Screening. We aimed at developing a catalytic
system for the aziridination of dienes bearing OH groups at the
■
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Table 1. Aziridination of (2E,4E)-hexa-2,4-dien-1-ol (1) with
TpxM (M = Cu, Ag) Catalysts Using PhINTs As Nitrene
Table 2. Aziridination of Dienols 6−16 using Tp*,BrAg as the
a
Catalyst
a
Source
yield
trans:cis
bc
b
b
,
entry
1
dienols
(%) PhINTs:dienol regiosel.
ratio
R1 = R2 = R3 =
>99
>99
>99
>99
>99
>99
>99
>99
1:1
17/24, 88:12 >98:<2
18/25, 85:15 >98:<2
19/26, 93:7 >98:<2
20/27, 86:14 >98:<2
21/28, 86:14 >98:<2
31/33,90:10 <2:>98
32/34, 87:13 <2:>98
35/37, 86:14 >98:<2
36/38, 72:28 >98:<2
R4 = H (6)
2
3
4
5
6
7
8
9
R1 = R2 = R4 = H,
1:1
R3 = Et (7)
R1 = R2 = R4 = H,
1:1
R3 = Ph (8)
b
b
b
entry
catalyst
yield (%)
regiosel. (2+3):(4+5) ratio 2:3
R1 = R2 = R4 = H,
1:1
R3 = C13H27 (9)
1
2
TpPh,4EtCu
Tpp‑ClPh,Br2Cu
TpMe2Cu
60
80
83:17
81:19
82:18
86:14
90:10
90:10
90:10
88:12
89:11
89:11
88:12
60:40
51:49
R1 = R3 = Me,
1:1
R2 = R4 = H (10)
3
67
66:34
R1 = R2 = R4 = H,
1:1
4
TpBr3Cu
>99
>95
>99
>99
>99
>99
80
66:34
R3 = C13H27 (13)
c
5
TpMe2Ag
Tp*,BrAg
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
>98:<2
R1 = R2 = R3 = H,
1:1.5
1:1.5
1:1.5
c
c
c
c
c
c
R4 = Me (14)
6
d
Tp*,BrAg
R1 = R3 = H,
7
R2 = R4 = Me (15)
d
8
Tp*,BrAg
R1 = R2 = R3 = H = >99
d
9
Tp*,BrAg
R4 = Me (16)
d
10
11
Tp*,BrAg
a
de
,
Tp*,BrAg
>99
0.0125 mmol of catalyst, 5% with respect to PhINTs in all cases, 8 h,
b
rt. Determined by 1H NMR, as initial PhINTs converted into
aziridines. The minor isomer was not detected by H NMR.
a
[catalyst]:[PhINTs]:[1] = 1:20:30, referred to 0.0125 mmol of
c
1
catalyst, 5% mol catalyst loading. Reaction time 8 h, rt. TsNH2
accounted for 100% initial PhINTs not converted into aziridines.
b
c
1
1
allylic position with respect to one of the CC bonds, we have
performed further experiments to assess the role of each
particular element. First, the homoallyldiene 39 (R = H) was
investigated as the substrate (eq 1) in the reaction with PhINTs
Determined by H NMR. cis isomer was not detected by H NMR.
d
Catalyst loading 7.5%, 1.25%, 0.5%, 0.1%, and 0.5%, respectively, for
e
entries 7−11. [PhINTs]:[1] = 1:1.
C3-substituted substrates (Table 2, entries 9 and 3). The
exception was found with trisubtitution at the distal double
bond (additional substitutent at C4 or C5, substrates 11 and
12), and in spite of the complete consumption of the starting
material, an unextractable mixture of compounds was obtained.
We have observed that when the dienol is less reactive, PhI
NTs decomposition into TsNH2 takes place, and this amine
provides a basic medium in which aziridine decomposition
takes place. Actually, the more reactive dienols 6−10 and 13
can be converted into aziridines using a 1:1 mixture with
PhINTs, whereas for the less reactive 14−16 a 1:1.5 ratio of
PhINTs and dienol was employed.
using Tp*,BrAg as the catalyst. Compound 40 was obtained
with a high yield (92%) and high regioselectivity (>98:<2), as
the result of the preferential aziridination at the distal double
bond. It is clear that the loss of the allylic relative position of
the OH with respect to the CC double bond dramatically
affects the reaction outcome. The methyl homologue did not
provide similar results, since major decomposition was
observed, probably due to the aforementioned effect of a
lower reactivity of this substrate and formation of TsNH2 that
triggers aziridine decomposition.
To evaluate such role of the OH group, we carried out the
aziridination of O-protected (2E,4E)-hexa-2,4-dien-1-ol with
both copper and silver catalysts (Table 3). As shown in Table 3,
yields and regioselectivities decreased with both metals compared
with the parent dienol. The observed loss of regioselectivity
The retention of the stereochemistry was also observed along
the series of dienes studied that were converted into the
corresponding aziridines maintaining the initial geometry of the
double bond in the final aziridine (i.e., cis or trans double bonds
were stereospecifically transformed into cis or trans aziridines,
respectively).
The Role of the Hydroxyl Group and Diene
Conjugation. In order to check the effect of the structure of
the starting dienol, in which the hydroxyl group occupies the
Scheme 5. Dienols 6−16 Tested in Nitrene Transfer Reactions with Tp*,BrAg as the Catalyst
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Table 3. Conversions and Selectivities of the Reaction of
Scheme 6. Directing Effect of the OH Group in the
Aziridination Reaction
a
1-O-Protected-(2E,4E)-hexa-2,4-dien-1-ols 41 and 42 with
a
TpxM Catalysts using PhINTs as Nitrene Source
b
b
b
entry
catalyst
diene
yield (%)
regiosel.
trans:cis ratio
c
f
1
2
3
4
5
6
TpBr3Cu
Tp*,BrAg
TpBr3Cu
Tp*,BrAg
TpBr3Cu
Tp*,BrAg
41
41
77
80
80
66
67
68
78:22
62:38
c
f g
53:47
>98:<2 ,
d
g
42a
42a
42b
42b
65:35
58:42
d
h,g
60:40
>98:<2
58:42
ig
a
e
(a) The stoichiometric reaction by Atkinson and co-workers. (b) A
plausible related explanation for the metal-catalyzed aziridination.
58:42
e
54:46
>98:<2 ,
a
[cat]:[PhINTs]:[diene] = 1:20:30, referred to 0.0125 mmol of
shown in Scheme 5, such behavior must be related to the loss
of conjugation. Moreover, the use of the O-protected geranyl-
derivative 57 (eq 4) led to the formation of aziridine 59 as the
catalyst, 5% mol catalyst loading. Reaction time is 8 h in all cases, rt.
TsNH2 accounted for 100% initial PhINTs not converted into
b
c
1
aziridines. Determined by H NMR of the major regioisomer. As
d
e
(43+45):(47+49). As (44a+46a):(48a+50a). As (44b+46b):
(48b+50b). As 43:45. cis isomer was not detected by H NMR.
As 48a:50a. As 48b:50b.
f
g
1
h
i
seems to be independent of the nature of the protecting group
since Ac, Bn, or even the less sterically demanding Me
substituents provided the same negative effect in the reaction
outcome. However, the silver catalyst induced the same
excellent stereoselectivity with only trans aziridines being
observed. Therefore, the presence of the hydroxyl functionality
at the allylic position seems to be crucial in the aziridination
reaction. Atkinson and co-workers have proposed20 that the
stoichiometric aziridination of allyl alcohols with (3-(acetoxy-
amino)-2-ethylquinazolin-4-(3H)-one takes place in a prefer-
ential manner due to the formation of a hydrogen bond
between the OH group and −CO unit that directs the CC
bond in the vicinity of the nitrogen atom (Scheme 6a). On the
basis of this, it could be possible that in the case of our copper-
or silver-catalyzed aziridination, the OH bond may support for
the nitrene transfer toward the CC double bond proximal to
the hydroxyl group (Scheme 6b). This proposal will be
discussed in the computational part of this work.
major product, which is in good agreement with the above
results that evidence the allylic OH groups significantly enhance
the aziridination of the proximal CC bond.
An additional experiment has been carried out in which
conjugated dienes lacking of hydroxyl groups were employed.
As shown in eq 5, when R = H only aziridination at terminal
double bond was observed, in line with the reactivity observed
for the related dienol 8. In the former, the aziridination takes
place in the double bond remote to the aryl ring. When R =
Me, the aziridination of double bond farthest of phenyl group
takes also place. The phenyl substituent of the dienic system
provides additional stabilization of the radical intermediate
generated during the reaction.
The effect of conjugation of both double bonds was
evaluated with geraniol (51) and nerol (54) as the starting
dienes (eqs 2 and 3) that only differ in the stereochemistry of
Overall, the collected data in this section indicated that the
highly selective aziridination of dienols in Table 2 seems to be
favored by the presence of the −OH group in the allylic
position, in a clear example of substrate-directed aziridination.21
In the case of the silver-based catalyst, the aziridination takes
place with very high regioselection and complete stereo-
selection. In order to collect additional information to explain
such behavior, we have in silico studied these aziridination
reactions, with the results described below.
Computational Study on the Origin of Regioselectiv-
ity. We have carried out DFT calculations on the reaction
between the parent molecule (2E,4E)-hexa-2,4-dien-1-ol (1)
and the Tp*,BrAg complex. Experimental data reported above
the CC bond (E or Z, respectively) close to the hydroxyl
functionality. Regioselectivity decreased in both cases when
compared with the values obtained with the conjugated dienes.
Since steric and/or electronic factors are similar to the dienes
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showed a regioselectivity of 90:10 for this system in favor of
aziridination on the double bond closer to the hydroxyl
substituent, and it is a representative example of the systems
experimentally studied. First, we have analyzed the overall
energy profile for reaction between the silver-nitrene complex
and the diene. The results, summarized in Figure 1, show a
Figure 2. The two lowest energy transition states leading to aziridine
products of (2E,4E)-hexa-2,4-dien-1-ol catalyzed by Tp*,BrAg. Selected
distances (Å) in black. Selected atomic spin populations in red.
The structures for the two most stable conformers of this
triplet transition state are presented in Figure 2, where selected
interatomic distances and atomic spin densities are included. It
is clear from the overall view of the structure that the diene
ligand places itself in a parallel orientation along the side of the
Tp*,Br ligand. The two transition states in Figure 2 differ in the
position of the terminal groups of the diene. The upper
position is occupied by the hydroxyl in TS1 or by the methyl in
TS8. It is worth noting that in this triplet transition state only
one N−C bond is being formed, and the second N−C bond
will be formed further down in the energy profile, as the system
moves to the singlet electronic state.
Figure 1. Calculated free energy profiles (kcal mol−1) for aziridination
of (2E,4E)-hexa-2,4-dien-1-ol catalyzed by Tp*,BrAg. Spin population
(atomic units) is indicated for key atoms.
The translation of transition state relative energies to product
populations can be made through a similar scheme to that used
in enantioselectivity studies.23,24 First, we need to analyze
different conformations of this transition state. If we assume
that the probability of crossing a given transition state follows a
Boltzmann distribution, their relative energies will give the ratio
of the different products. In order to make a systematic
conformational search, we followed two criteria: (i) identify the
carbon making the first bond to nitrogen and (ii) orientation of
the diene molecule with respect to the Tp−Ag−N axis. There
are four carbons available for the first bond to nitrogen (two
per double bond), and there are two possible orientations for
the diene (hydroxyl-up or methyl-up). This results in the eight
isomers shown in Scheme 7 and Figure S1. We carried out
transition state searches starting from each of these eight
similar picture to that previously reported by us on the reaction
of silver-nitrene complexes with more simple olefins,22 although
the more complex nature of the dienols employed in this work
have added certain clues that need to be explained. It is first
important to recognize the electronic complexity of the systems
that was discussed at length in the previous publication.22 The
reaction is formally simple as the catalyst reacts with the
PhINTs nitrene source, resulting in a nitrene complex that can
transfer the nitrene function to an olefin, resulting in an
aziridine. The detailed picture is however more subtle, because
the resting state of the nitrene complex is a triplet (see Figure 1 for
spin localization), which reacts with the singlet diene to produce
two singlet molecules (the product and the metal catalyst).
Therefore, a spin-crossing through a minimum energy crossing
point (MECP) must take place in the course of the reaction. The
behavior of the silver and copper catalysts differs on the placement
of this MECP in the free energy profile. In the case of silver, it is
before the open ring intermediate, which results in a stereo-
selective process (see Figure 1). For copper, stereoselectivity is
lower because the spin crossing takes place later in the free energy
profile, which allows for scrambling. We will report here our
results for the silver species and comment briefly on how these
results could be modified in the case of copper.
Scheme 7. Schematic View of the Possible Isomers
Considered As Starting Geometry for the Transition State of
the Aziridination of (2E,4E)-Hexa-2,4-dien-1-ol catalyzed by
Tp*,BrAg
For the silver catalyzed process, starting from the stable triplet
metal-nitrene intermediate (3R), the first N−C bond formation
has a barrier of only 1.6 kcal mol−1 (3TS1), while the
corresponding singlet transition state is further, 5.2 kcal mol−1
3
higher in energy. Beyond TS, there is a MECP between the
triplet and closed-shell singlet profiles. Therefore, the singlet
product 1P (same as compound 2, Table 1) can be formed with a
complete retention of the stereochemistry of the olefin, and 3TS1
becomes the selectivity determining transition state. This means
that we can concentrate on the study of regioselectivity on this
triplet transition state.
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delocalization effect that directs the nitrene attack toward
the “terminal” carbons of the dien-1-ol 39. The attack on the
carbon further away from the phenyl substituent places the
unpaired electron in the adjacent carbon, with a favorable
delocalization toward the other double bond and the phenyl
ring. If the nitrene attack takes place on the carbon closest to
the phenyl ring, delocalization can only take place toward the
other double bond. The key factor for the systems shown in eq
5 is thus purely electronic and is simpler than that computed
above, where there is a combination of electronic and
hydrogen-bond effects.
Table 4. Relative Energies of the Different Isomers for the
Transition States and Their Reaction Path Ratios for
Aziridination of (2E,4E)-Hexa-2,4-dien-1-ol Catalyzed by
Tp*,BrAg
attacked C
atom
diene
orient.
energy
reaction path
(%)
label
(kcal mol−1
)
3TS1
3TS2
3TS3
3TS4
3TS5
3TS6
3TS7
3TS8
2
3
4
5
2
3
4
5
OH-up
OH-up
OH-up
OH-up
Me-up
Me-up
Me-up
Me-up
1.6
9.6
12.8
5.7
4.4
6.9
5.0
2.5
80.1
0.0
0.0
0.1
0.7
A second experimental result worth commenting is the lower
selectivity observed when silver is replaced by copper in the
catalyst (Table 1). We think that the origin of the difference is
in the electronic differences between the copper and silver-
catalyzed processes discussed in our previous computational
study work with more simple olefins.22 For the copper system,
the free energy profile described in Figure 1 is no longer valid,
as the crossing between the triplet and singlet surfaces takes
0.0
0.3
18.9
conformations. The results are summarized in Table 4 (see
Table S1 for further details).
Transition states TS1, TS2, TS5, and TS6 lead to the major
product 2, with the aziridination of the double bond closer to
the OH group. The other four transition states lead to the
minor product 4, where aziridination occurs at the other double
bond. The main result in Table 4 is in good agreement of
the computed regioselectivity of 81:19 for product 2, with
the experimental value of 90:10 for the same product. The
comparison of the energies of the eight transition states also
allows the understanding of the origin of selectivity. There are
three trends that can be easily identified. First, the transition
states with the nitrene attacking one “terminal” carbon of the
diene (carbons 2 or 5) are in general lower in energy. This
happens in TS1, TS4, TS5, and TS8. This can be understood
by checking the atomic spin populations in Figure 2 (and also
in Figure S1). This has an electronic origin. When the nitrene
attacks a terminal carbon, the spin is delocalized on the whole
chain, and the barrier is lowered. When the nitrene attacks a
“central” carbon (carbons 3 or 4), there is no spin
delocalization into the other double bond, but only into the
next carbon of the same double bond, and this results a higher
barrier. The second trend is that the most stable structures, TS1
and TS8, place the diene chain parallel alongside the Tp*,Br
ligand. There seems to be a favorable dispersion interaction
between the diene chain and the ligand. The third and decisive
factor for regioselectivity is the presence of a hydrogen bond
between the terminal OH group and one of the oxygen atoms
of the OTs ligand. Therefore, the hydrogen bond plays a critical
role in deciding between the two most stable transition states,
TS1 and TS8, leading each to one regioisomer, but this
becomes critical only when the electronic and dispersion effects
are also playing their role.
3
place after the triplet intermediate RI. Therefore, regioselec-
tivity is not exclusively decided in transition state 1TS, as
scrambling in the triplet intermediate is still possible. This will
surely reduce selectivity and make the directing effect of the
OH groups less efficient in the copper case.
Ring-Opening Reactions. As mentioned in the Introduc-
tion, ring-opening reactions of vinylaziridines1a,2 through SN2
or SN2′ processes constitute a tool for the synthesis of a variety
of functionalized amine derivatives such as sphingosines,13,25
allyl amines,26 (E)-alkene dipeptide isosteres,27 or boron
derivatives (Scheme 8).28 Different strategies have been studied
Scheme 8. Ring-Opening Reactions to Vinylaziridines
since aziridines are valuable building blocks in organic
chemistry.29 Both SN2 and SN2′ processes afford a set of
products that can be transformed in highly functionalized
synthons by functionalization of the double bond.
The vinylaziridine 2 was employed as a model substrate for
ring-opening reactions using different S, N, and O nucleophiles.
Under basic conditions (Scheme 9) such as KOH, the amino
Scheme 9. Ring-Opening of Vinylaziridine 2 by SN2
Reactions
We further confirmed the importance of the hydrogen bond
by carrying an additional set of calculations on a system where
this was precluded by replacing OH by OAc. The detailed
results on the study of the aziridination of (2E,4E)-hexa-2,4-
dien-1-yl acetate are provided in Table S2, but the key result
was that the most stable transition states were still TS1 and
TS8. However, the energy difference between them was so
small that the predicted regioselectivity ratio decreased to
53:47, in agreement with experimental results.
The rationale emerging from our calculations on (2E,4E)-
hexa-2,4-dien-1-ol (1) and the Tp*,BrAg complex can be also
applied to other experimental systems reported above. The
regioselectivity of the systems with a phenyl group (see eq 5;
98% of the terminal aziridine) is associated to the same
diol 61 was obtained in a 68% yield over two consecutive steps,
namely aziridination and ring-opening. The use of NH3 or
PhSNa as nucleophiles provided the 1-hydroxy-2,3-diamino
derivative 60 or the 1-hydroxy-2-amino-3-thio derivative 62 in
64% and 46% yield, respectively. Ring-opening has also been
achieved under acid conditions (Scheme 10). Vinylaziridine 2
i
reacted with PrOH, BnSH, and TsNH2 in the presence of
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Nearly quantitative yields (based on the nitrene source) with
very high regioselection (ca. 9:1) toward the double bond
vicinal to the hydroxyl group have been obtained, the latter
remaining unreacted as an additional feature of this system. In
addition, this process is stereospecific regarding the initial
geometry of the double bond, that is maintained in the aziridine
product (Z or E olefins gave cis or trans aziridines, respectively).
The synthetized vinylaziridines can be selectively opened with
oxygen, nitrogen, or sulfur nucleophiles through selective SN2
or SN2′ processes to afford a variety of unsaturated amino-
alcohols. Mechanistic studies, based on experimental data and
DFT calculations, have shown the directing effect of the OH
bond that through hydrogen bond with an oxygen atom of the
tosyl group favors a given geometry that drives the reaction
toward the observed outcome. The development of the chiral
version of this catalytic system is currently underway in our
laboratories.
Scheme 10. Ring-Opening of Vinylaziridine 2 by SN2′
Reactions
BF3·OEt2 through a SN2′ process affording compounds 63−65
in 70%, 78%, and 55% yields, respectively, over two steps but in
a one-pot procedure. We have not been able to isolate nor de-
tect the products derived from the less abundant vinylaziridines
obtained in <10% yield.
A Practical Case: Synthesis of ( )-Sphingosine. As a
proof of the concept for the overall strategy developed in this
contribution, we have applied the methodology of aziridination
of 2,4-hexadien-1-ols and further ring-opening to the
preparation of racemic sphingosine, the most representative
member of the sphingolipid family.30,31 As described in our
preliminary work, this aminodiol could be prepared by the
selective opening of aziridine 20, that would be obtained via
aziridination of the dienol 9 (Scheme 11). The latter reaction
EXPERIMENTAL SECTION
■
General. All chemicals used in this work were reagent grade and
used as supplied unless otherwise specified. HPLC grade dichloro-
methane (CH2Cl2), tetrahydrofuran (THF), and dimethylformamide
(DMF) were dried using a solvent purification system (Pure SOLV
1
system-4). H and 13C NMR spectra were recorded on a Mercury VX
400 or Varian 400-MR spectrometer in CDCl3 as solvent, with
chemical shifts referenced to internal standards. ESI MS were run on
an Agilent 1100 Series LC/MSD instrument. Melting points were
determined with Reichert apparatus. Reactions were monitored by
TLC carried out on 0.25 mm E. Merck silica gel 60 F254 glass or
aluminum plates. Developed TLC plates were checked with a short-
wave UV lamp (250 nm) after heating plates previously treated with
ethanol/H2SO4 (15:1), a basic solution of potassium permanganate
and cerium molybdate. Flash column chromatography was carried out
using forced flow of the indicated solvent on silica gel 60 (230−400
mesh) using a solvent polarity correlated with TLC mobility. Radial
chromatography was performed on 1 or 2 mm plates of Kieselgel
60 PF254 silica gel, depending on the amount of product. All the dienes
employed as reactants were prepared according with literature methods.
See Supporting Information for the complete description of their
preparation, literature reference, and spectroscopic characterization.
General Procedure for Aziridination of 2,4-dien-1-ols. A
Schlenk tube containing a magnetic stirring bar was charged with
catalyst and the dienol. The flask was cooled in an acetone dry ice bath
and flushed three times with nitrogen, and then anhydrous
dichloromethane (5 mL) was added. Freshly prepared PhINTs was
added in 3−4 portions over 2 h, and the mixture was stirred for an
additional hour after the last addition. For the exact amounts of
reactants see Supporting Information. Finally, the solvent was removed
under vacuum, and the resulting crude was characterized by NMR
without purification given the low stability of the vinylaziridines
toward silica gel or neutral alumina. See the Supporting Information
for full spectroscopic description of the vinylaziridines synthesized in
this work.
Scheme 11. Retrosynthetic Analysis of Sphingosine
has already been discussed (see Table 2, entry 4), providing
aziridine 20 as a 86:14 mixture with aziridine 27 and complete
retention of stereochemistry. Ring-opening of 20 can be carried
out in a one-pot manner by treating the resulting mixture with
KOH in DMSO to give the N-protected sphingosine 66 in 72%
yield for the two steps. Deprotection was performed with
sodium/naphthalene to give racemic sphingosine in 65% overall
yield (Scheme 12). This result demonstrates that the above
Scheme 12. Synthesis of ( )-Sphingosine from Dienol 9
General Aziridination of Dienols 51, 54, and 57. Tp*,BrAg
(3.2 mg, 0.05 mmol) was dissolved in dichloromethane (10 mL),
along with the corresponding terpene (1 mmol). PhINTs (407 mg,
1.1 mmol) was added in four portions over 4 h. The reaction mixture
was stirred for additional 3 h at room temperature before volatiles
were removed under vacuum. The residue was purified by flash
chromatography using hexanes:ethyl acetate (7:3 to 1:1) to afford the
desired products. See Supporting Information for details and
characterization.
General Procedure for Ring-Opening Aziridines with KOH,
Ammonia, or Sodium Thiophenolate. KOH. Vinylaziridine 2
(0.25 mmol) was dissolved in DMSO (0.75 mL), and an aqueous
solution of KOH (10%, 0.75 mL) was added. The solution was stirred
for 1 h at 40 °C. The crude was neutralized with a saturated NH4Cl
aqueous solution. The aqueous solution was extracted with diethyl
route opens a new area in which the design of chiral catalysts
for the aziridination reaction would provide the final product
enantiomerically enriched.
CONCLUSIONS
■
The selective (mono)aziridination of 2,4-dien-1-ols have been
achieved in a chemo-, regio-, and stereoselective manner by
means of silver-catalyzed nitrene transfer from PhINTs.
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ether (3 × 25 mL), and the combined organic layers were washed with
brine and dried over anhydrous MgSO4. The solvent was removed
under vacuum and purified by radial chromatography using 4:6
hexanes:ethyl acetate to afford 56 mg of 61 as a white solid (68%). See
Supporting Information for spectroscopic and analytical characterization.
NH3. Vinylaziridine 2 (5 mmol) and yterbium triflate were dissolved
into an amonia solution (8 mL, 30%), and the mixture was stirred at
95 °C for 8 h. The crude was extracted with three portions of ethyl
acetate. The combined organic layers were washed with a HCl aqueous
solution (5%) and brine and dried over magnesium sulfate. The crude
was purified by radial chromatography using 4:6 hexanes:ethyl acetate
to afford 188 mg of 60 as a colorless oil (64%). See Supporting
Information for spectroscopic and analytical characterization.
Sodium phenolate. Aziridine 2 (0.25 mmol) was dissolved in dry
THF (4 mL), and sodium thiophenolate (0.28 mmol, 36 mg) was
added. The mixture was stirred for 12 h at room temperature. Water
was then added to the mixture, and the aqueous layer was extracted
with dichloromethane. The combined organic layers were washed with
a NaHCO3 aqueous solution and later with water and brine. The
organic layers were dried over anhydrous MgSO4, and the solvent was
removed under vacuum. The crude was purified by radial
chromatography using 7:3 to 6:4 hexanes:ethyl acetate to afford
74 mg of compound 62 as a yellow solid (46%). See Supporting
Information for spectroscopic and analytical characterization.
General Procedure for Ring-Opening of Aziridines with BF3·
OEt2. The nucleophile (10 equiv, 2.5 mmol) was added to a solution
of the vinylaziridine (0.25 mmol) in dichloromethane (4−6 mL). The
stirred mixture was cooled at 0 °C, and the acid (10 mol %, 0.025 mmol)
was added over 30 min. Smooth warming to room temperature and
additional stirring for 3h led to a solution that was diluted with
dichloromethane and washed with water. The organic layer was dried over
MgSO4 before the solvent was removed under vacuum. The residue was
purified by flash or radial chromatography to give the corresponding
products. See Supporting Information for details and characterization.
Computational Details. Gas-phase structure optimizations were
performed using DFT with the M06 functional32 as implemented in
Gaussian09 program.33 Silver was treated with the SDD basis set,34
and the 6-31G(d) basis sets were used for the remaining atoms.35 Final
potential energies were obtained by performing single-point
calculations on the optimized structures, where silver was still
described with SDD, and the remaining atoms were treated with
the 6-311++G(d,p) basis sets. Free energy corrections at 298.15 K and
105 Pa pressure were applied, including zero point energy corrections.
Vibrational frequency calculations were performed to understand the
nature of the stationary points (i.e., minima or transition states).
Connectivity of the transition states was confirmed by relaxing the
transition-state structure to both reactant and the product. MECP was
calculated by using the MECP program of Harvey and co-workers.36
Energy differences between transition states were translated to product
populations by assuming a Boltzmann distribution of transition states
at 298.15 K.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank MINECO (Grants CTQ2011-28942-CO2-01,
CTQ2011-27033, CTQ2011-22872-BQU and Consolider
Ingenio 2010 CSD2006-0003), Fondos FEDER, Junta de
́
Andalucıa (Proyecto P10-FQM-06292), and the ICIQ
Foundation. J.L. thanks MICINN and AB Universidad de
Huelva for fellowships. We also thank Miriam Dıaz de los
Bernardos and Sebastien Soriano for additional experimental
work. This paper is dedicated to the memory of Prof. Gregory
L. Hillhouse (1955-2014).
́
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ASSOCIATED CONTENT
* Supporting Information
́
, J. M.; Rodriguez-Solla, H.; Simal, C. Org. Lett. 2008,
, J. M.; Rodríguez-Solla, H.; Bernad, P.
■
́
S
Detailed experimental catalytic and mechanistic procedures,
including substrates preparation and characterization of
products. Computational data including transition states
geometries and Cartesian coordinates and energies of all
stationary points reported in the text. This information is
available free of charge via the Internet at http://pubs.acs.org
AUTHOR INFORMATION
Corresponding Authors
perez@dqcm.uhu.es
■
sergio.castillon@urv.cat
fmaseras@iciq.es
mmdiaz@dqcm.uhu.es
maribel.matheu@urv.cat
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