Divergent Reactivity of In Situ Generated Metal Azides: Reaction with N,N-Bis(oxy)enamines as a Case Study

Article abstract of DOI:10.1002/chem.201605390

Metal azides generated in situ by ion exchange exhibit divergent reactivity in reaction with cyclic N-alkoxy,N-siloxy-enamines. Depending on the nature of metal and the [M]/N₃^? ratio, addition of the azide ion to the C,C-double bond proceeds with regioselective cleavage of either exo- or endo-cyclic N?O bond leading to cyclic or open-chain α-azidooxime derivatives, respectively. Mechanistic studies in combination with solvent state FTIR spectroscopy and DFT calculations revealed that covalently bound metal azides (Co, Cu, Zn) transfer N₃^? anion to the C,C-double bond through a Lewis acid-assisted S_N′ substitution of trialkylsilyloxy-group. More ionic metal azides (N1, Mg, Al, Sc, Ni, Yb) tend to react by initial nucleophilic attack of N₃^? anion on the silicon atom generating conjugated nitrosoalkenes. α-Azidooxime derivatives prepared by using the designed protocols were stereoselectively reduced to valuable 1,2-diaminoalcohols bearing up to four contiguous stereogenic centers. By reducing the α-azidooxime fragment in a stepwise manner site-selective protection and reductive amination of each of the emerging primary amino groups was achieved.

Full text of DOI:10.1002/chem.201605390

A Journal of
Accepted Article
Title: Divergent Reactivity of In Situ Generated Metal Azides. Reaction
with N,N-Bis(oxy)enamines as a Case Study
Authors: Petr A. Zhmurov, Yulia Yu. Khoroshutina, Roman Novikov,
Ivan Golovanov, Alexey Yurievich Sukhorukov, and Sema
Ioffe
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Divergent Reactivity of In Situ Generated Metal Azides. Reaction
with N,N-Bis(oxy)enamines as a Case Study
Petr A. Zhmurov,[a] Yulia A. Khoroshutina,[a] Roman A. Novikov,[a] Ivan S. Golovanov,[a]
Alexey Yu. Sukhorukov,[a],* Sema L. Ioffe[a]
Abstract: Metal azides generated in situ by ion exchange exhibit
divergent reactivity in reaction with cyclic N-alkoxy,N-siloxy-
enamines. Depending on the nature of metal and the [M]/N3 ratio,
its dissociation in solution would influence the nucleophilicity of
the azide anion. Moreover, depending on the Lewis acidity the
metal ion can selectively activate specific reactive centers in a
polyelectrophilic substrate for the attack of the azide anion.[7] In
this connection, a comparative study of the reactivity of various
metal azides may lead to the development of new methods and
reagents for the introduction of the azido group in organic
molecules. As we demonstrate here, the problem with safe
handling and storage of p-, d- and f-metal azides can be solved
by their generation in solution from cheap and stable reagents.[9]
-
addition of the azide ion to the С,С-double bond proceeds with
regioselective cleavage of either exo- or endo-cyclic N−O bond
leading to cyclic or open-chain α-azidooxime derivatives,
respectively. Mechanistic studies in combination with solvent state
FTIR spectroscopy and DFT calculations revealed that covalently
bound metal azides (Co, Cu, Zn) transfer N3- to the С,С-double bond
through a Lewis acid-assisted SN’ substitution of silyloxy-group. More
ionic metal azides (Mg, Al, Sc, Ni, Yb) tend to react via initial
-
nucleophilic attack of N3 on the silicon atom generating conjugated
nitrosoalkenes. α-Azidooxime derivatives prepared using the
designed protocols were stereoselectively reduced to valuable 1,2-
diaminoalcohols bearing up to four contiguous stereogenic centers.
By reducing the α-azidooxime fragment in a stepwise manner site-
selective protection and reductive amination of each of the emerging
primary amino groups was achieved.
Introduction
Azide anion is one of the most synthetically useful
nucleophiles owing to the key role of organic azides as
intermediates in target-oriented synthesis and bioconjugation.[1]
In organic synthesis, NaN3 is commonly used as a source of
nucleophilic azide anion.[1a] Azides of other main and transition
group metals are rarely employed because of their less
availability and explosive character in a free state.[2] Only a few
examples of the application of some stable metal azide
complexes and organometal azides in Mitsunobu reaction[3] and
nucleophilic ring opening of some epoxides[4] have been
reported so far.
Scheme 1. Addition of the azide ion to N,N-bis(oxy)enamines 1 and 2.
N,N-Bis(oxy)enamines 1 and 2 (Scheme 1), which have been
extensively studied in our group,[10] were proposed to be
convenient bielectrophilic models to study the effect of metal
counterion on the nucleophilic addition of the azide anion. These
electrophilic reagents are easily accessible by silylation of
aliphatic nitro compounds[11] or readily available cyclic
nitronates.[12] Owing to the pyramidality of nitrogen and strong
π→σ*N-O, nO→σ*N-O interactions,[13] bis(oxy)enamines 1 and 2 can
enter SN’ reactions at β-carbon atom with the breakage of one of
two weak nitrogen-oxygen bonds (Scheme 1).[10c, 10d, 14] Another
electrophilic center in their structure is silicon atom. The attack
of strong nucleophiles on silicon results in cleavage of
nitrosoacetal unit to give conjugated nitrosoalkenes.[10b] The
latter are Michael acceptors and readily react with
nucleophiles.[15] In the case of cyclic N-alkoxy,N-siloxyenamines
2 possessing two non-equivalent N−O bonds these processes
would lead to two different nucleophilic addition products
(Scheme 1). Evidently, both pathways may be affected by a
metal ion, which can bind to oxygen atoms of the N−O bonds.[16]
The nature of metal ion often plays a key role in nucleophilic
substitution and addition reactions.[5]
A
counterion may
dramatically affect the reactivity of nucleophile,[6] and the
electrophilic substrate,[7] as well as change the mechanism of
the process (for example, switching from SN2 to SN1).[8] In the
case of metal azides, the nature of M−N3 bond and the ease of
[a]
Mr. Petr A. Zhmurov, Dr. Yulia A. Khoroshutina, Dr. Roman A.
Novikov, Mr. Ivan S. Golovanov, Dr. Alexey Yu. Sukhorukov, Dr.
Prof. Sema L. Ioffe
Laboratory of Functional Organic Compounds
N. D. Zelinsky Institute of Organic Chemistry
119991, Leninsky prospect, 47, Moscow, Russia
sukhorukov@ioc.ac.ru
Supporting information for this article is given via a link at the end of
the document.
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In this report we demonstrate, that depending on the nature
of metal cation, the addition of the azide anion to
bis(oxy)enamines 2 may selectively produce open-chain or
cyclic α-azidooxime derivatives (products 3 and 4, respectively).
The formation of one or another product correlates with the
Lewis acidic properties of the metal ion and the coordination
state of the azide anion in solution (free or bound to metal),
which can be determined by the solvent state FTIR
spectroscopy.
α-Azidooxime products 3 and 4 can serve as useful platforms
for the preparation of synthetically challenging 1,2-
diaminoalcohols (Scheme 1). Such fragment is present in
natural molecules and pharmaceutically relevant compounds
(some are shown in Figure 1).[17] Since azido and oxime
functions are reduced under different conditions, successive
modification of the emerging primary amino groups can be
performed, thus allowing to access unsymmetrically substituted
1,2-diamines. These vast synthetic opportunities of α-
azidooxime derivatives 3 and 4 have been also demonstrated
here.
Scheme 2. Reaction of N,N-bis(oxy)enamines 1a and 2a with sodium azide.
Based on our prior studies on reactions of bis(oxy)enamines
2 with metal halides,[10c] we speculated, that the presence of
Lewis acidic metal cations may direct the attack of the azide
anion on the C,C double bond by activating the cleavage of the
weak exocyclic N−O bond. Since most of metal azides are not
available in a free state, we attempted to generate these species
in situ by the ion exchange between NaN3 and the
corresponding metal salt containing
a
non-nucleophilic
counterion (triflate or perchlorate). In our experiments, a mixture
of NaN3 with a metal salt was vigorously stirred for 1h in DMF (or
other solvent indicated in Table 1) for the ion exchange to take
place followed by the addition of the solution of model
bis(oxy)enamine 2a in dichloromethane.[18] Prior the analysis,
reaction mixtures were subjected to acidic aqueous work-up
(diethyl ether/NaHSO4 aqueous solution) to decompose
inorganic azides and to desilylate products. Table 1 summarizes
the results of these experiments.
Indeed, in reactions of enamine 2a with in situ generated p-,
d- and f-metal azides we observed the formation of azide-anion
addition cyclic product 4a, as well as the unexpected open-chain
α-azidooxime 3a arising from the cleavage of the endo-cyclic
N−O bond. Furthermore, along with these products the
aforementioned 2-pyranone oxime 6a, 3-hydroxymethyl-
substituted 1,2-oxazine 7a and its silyl ether 8a were identified
(Table 1). In all cases, the initial enamine 2a was consumed
completely. The distribution of products strongly depended on
the nature of metal salt additive used as well as on the
conditions. Thus, interaction of model enamine 2a with
NaN3/Mg(OTf)2 mixture afforded a mixture of α-azidooxime 3a
and pyranone oxime 6a in comparable amounts (Table 1, entry
1). When Mg(ClO4)2 was used instead of Mg(OTf)2, α-
azidooxime 3a was formed as the only product and no by-
product 6a was detected (yield: 89%, Table 1, entry 2).
Changing DMF to DMSO did not affect the reaction outcome.
However, the use of THF as solvent resulted in a complete
change of the reaction pathway and the formation of cyclic azide
4a as major product accompanied by hydroxyoxazine derivative
7a (cf. entries 3 and 4 in Table 1). Interestingly, in the last
reaction, the acyclic α-azidooxime 3a was not detected even in
trace amounts by 1H NMR.
Figure 1. Bioactive and natural 1,2-diaminoalcohols.
Process optimization and substrate scope
studies
In our initial studies we reacted two different N,N-
bis(oxy)enamines 1a and 2a with sodium azide in DMF aiming to
achieve nucleophilic addition of the azide-anion to the C,C-
double bond. With acyclic derivative 1a the desired α-
azidooxime 5a was formed only in 29% yield, while with 2a no
azide addition products were observed with the major product
being pyranone oxime 6a (95% yield). Same result was obtained
when Bu4NN3 was used instead of NaN3. The formation of cyclic
oxime 6a is likely to proceed through the nucleophilic attack of
N3- on the silicon atom of enamine 2a followed by ring opening
and recyclization (vide infra).
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generated from transition metal salts (Co, Cu, Zn) led to
Table 1. Interaction of bis(oxy)enamine 1a with in situ generated metal azides
cyclic azide 4a accompanied by hydroxy-1,2-oxazine 7a in
some cases (Table 1, entries 8, 10-13).
A surprising
exception was nickel azide system (NaN3/Ni(ClO4)2), which
reacted with enamine 2a in analogous fashion to in situ
generated p-metal azides affording oximes 3a and 6a (Table
1, entry 9). Combinations of NaN3 with CuOTf (Table 1, entry
11) provided 1,2-oxazine 4a as the major product even with
a two-fold excess of azide anion relative to copper (Table 1,
entry 12). The highest yield of cyclic azide 4a was observed
with a NaN3/Zn(OTf)2 mixture in DMF (Table 1, entry 13).
In view of our interest in products of type 4a, the
interaction of in situ generated zinc azide with
bis(oxy)enamine 2a was studied in a more detail. Variation
of solvent did not result in improvement of the product yield,
yet increased the amount of the by-product 7a (Table 1,
Yields of products, %[a]
#
Metal salt (MXn)
(equiv.)
NaN3
Solvent
(equiv.)
3a[b]
4a
-
6a[b]
7a[c]
-
1
Mg(OTf)2 (2)
4
4
4
4
6
6
6
4
4
4
2
4
4
4
4
4
4
8
4
2
1
DMF
DMF
DMSO
THF
41
89
81
-
52
-
2
Mg(ClO4)2 (2)
Mg(ClO4)2 (2)
Mg(ClO4)2 (2)
Al(OTf)3 (2)
-
-
3
-
-
-
4
49
23
13
25
60
-
-
19
-
entries 14-16). Addition of triethylamine as
a proton
scavenger did not influence the products distribution (Table
5
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
THF
68
63
64
-
-
-
1, entry 17). Surprisingly, the use of [Zn]/N3 ratio 1 : 4
(instead of 1 : 2) led to an almost complete switch of
selectivity towards the open-chain oxime 3a (Table 1, entry
18).
Zinc sulfate (heptahydrate) could be employed instead of
expensive zinc triflate with only a slight decrease in the yield
of product 4a (Table 1, entry 19). Notably, the amount of
ZnSO4/NaN3 mixture could be decreased twice without any
lowering of the product yield (Table 1, entry 20). Further
decrease of ZnSO4/NaN3 loading resulted in somewhat
reduced yield of cyclic azide 4a (Table 1, entry 21).
These results demonstrate that in situ generated
magnesium and nickel azide species undergo addition to
enamine 2a with selective breakage of endo-cyclic N−O
bond, while zinc, cobalt and copper azides favor the
cleavage of exo-cyclic N−O bond. Since both azido
6
Sc(OTf)3 (2)
-
10
-
7
Yb(OTf)3•H2O (2)
Co(ClO4)2•6H2O (2)
Ni(ClO4)2 (2)
-
8
-
-
9
47
-
51
-
-
10
11
12
13
14
15
16
17
18
19
20
21
Cu(OTf)2 (2)
46
69
68
71
65
61
56
66
23
65
65
62
34
-
CuOTf•PhH (2)
CuOTf•PhH (2)
Zn(OTf)2 (2)
-
-
-
15
-
-
-
25
29
33
39[d]
25
6
Zn(OTf)2 (2)
-
-
Zn(OTf)2 (2)
-
-
derivatives
3
and
4
can be considered as useful
intermediates in the synthesis of functionalized 1,2-diamine
derivatives, the substrate scope of both reactions was
studied.
The procedure employing in situ generated magnesium
azide (procedure i) proved to be well-applicable to both
Zn(OTf)2 (2)
CH3CN
DMF
DMF
DMF
DMF
DMF
-
-
Zn(OTf)2 + Et3N
Zn(OTf)2 (2)
-
-
56
-
5
3
-
ZnSO4•7H2O (2)
ZnSO4•7H2O (1)
ZnSO4•7H2O (0.5)
27
22
26
acyclic bis(siloxy)enamines
1
and cyclic N-alkoxy,N-
siloxyenamines (Table 2). In case of acyclic N,N-
2
-
bis(siloxy)enamines 1a-f the corresponding α-azidooximes
5a-f were prepared in high yields. This procedure brings a
significant advantage to the previous method for preparation
of azides of type 5, which employs a large excess of
expensive and toxic azidotrimethylsilylane.[10a]
-
-
Ph
[a] Yields were determined by 1H NMR with internal
standard. [b] Yield for sum of E and Z isomers (E-3a/Z-3a =
8.5 : 1.0; E-6a/Z-6a = 5 : 1). [c] Structure of by-product 7a:
[d] Additionally, 5% of O-trimethylsilyl ether of 7a
(compound 8a) was detected in reaction mixture.
OH
N
H3C
O
Reaction of NaN3/Mg(ClO4)2 system with cyclic analogs
2a-g afforded in good to high yields previously unknown α-
azidooximes 3a-g bearing a hydroxy-group in the side chain
(Table 2). In none of these cases, the formation of cyclic oxime
ethers 4 was detected. Unfortunately, we did not succeed in
CH3
7a
Combinations of sodium azide with aluminium, scandium or
ytterbium triflates in reaction with 2а exhibited similar
performance to NaN3/Mg(ClO4)2 system in DMF delivering α-
azidooxime 3a as the main product (Table 1, entries 5-7).
However, in these cases, the cyclic 3-azidomethyl-substituted
1,2-oxazine 4a was also observed as a by-product. On the
contrary, interaction of enamine 2a with azide systems
preparing oximes of type
3 from five-membered cyclic
bis(oxy)enamines 2, which delivered only complex mixtures of
indecipherable products.
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Table 2. Synthesis of α-azidooximes from bis(oxy)enamines 1 and 2
Zinc sulfate/NaN3 system was chosen as a source of zinc
azide to study the substrate scope of the reaction leading to
cyclic azides 4 (procedure ii). Employing this procedure, a series
of 3-azidomethyl-substituted isoxazolines and 5,6-dihydro-4H-
1,2-oxazines 4a-l were prepared in moderate to good yields
from corresponding five- and six-membered bis(oxy)enamines
2a-l (Table 3). The procedure ii proved to be poorly applicable to
acyclic bis(siloxy)enamines 1. In the corresponding experiment
with enamine 1a the desired oxime 5a was obtained only in 32%
yield.
FTIR and DFT studies of metal-azide systems
As demonstrated by our experiments, the reactivity of NaN3
can be efficiently altered by the addition of р-, d- or f-metal salts.
The behavior of metal-azide systems depends not only on the
nature of metal, but also on the metal/azide ratio and the solvent
used. Evidently, insights into the fundamental difference in the
reactivity of these systems are not impossible without
understanding of the nature of in situ generated metal azide
species and the relationship between their structure and
reactivity with bis(oxy)enamines. Though the structure of many
metal azides in solid state is well-studied,[19] there is not much
information about their structures in solution.[20]
Table 3. Synthesis of 3-azidomethyl-substituted cyclic oxime ethers 4 from N-
alkoxy,N-siloxyenamines 2
It is logical to assume that in NaN3/MXn (X – OTf, ClO4)
mixtures an ion exchange takes place and corresponding azides
M(N3)n or other metal-azide species are generated. Upon mixing
a triflate or perchlorate of a non-alkali metal with sodium azide in
DMF, dissolution of both salts was usually observed (in the
absence of metal salt additive, NaN3 did not dissolve completely
in a same concentration). The only case, when complete
dissolution of NaN3 did not happen, was the reaction with
magnesium triflate. Apparently, in this system the generation of
magnesium azide is complicated because of stronger
magnesium-triflate interaction. Experiments with specially
prepared pyridine complexes of zinc and cobalt azides
[19g]
[21]
Zn(N3)2(py)2
and Co(N3)2(py)2
led to same results as the
reactions of 2a with NaN3/Zn(OTf)2 and NaN3/Co(ClO4)2 systems
(see Supporting information). This confirms the participation of
metal azides as reactive species in reaction of bis(oxy)enamines
1,2 with NaN3/MXn systems.
Depending on the affinity of metal cation to DMF and the
azide anion, the latter can be present in a free state, in a contact
ion pair or covalently bonded to a metal. The nature of the
-
interaction between N3 and metal cations was studied by
solvent state FTIR spectroscopy in DMF (Figure 2).
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Figure 2. Solvent state FTIR spectra of in situ generated metal azides (0.06 M
solutions of NaN3 in DMF were used in all experiments).
coordinated form, as can be seen from the spectra shown in
Figure 2, C. This should account for the fact that nickel system
reacts with cyclic bis(oxy)enamine 2a in a same manner as
magnesium azide species do. A small band at above 2100 cm-1
attributed to coordinated azide is also present. Its intensity
increases in time (72 h) or upon heating (60−80oC) reaching
about the same intensity as the non-coordinated N3 (see
Supporting information). This may be explained by a slow
formation of 1 : 1 Ni−N3 complex in DMF solution.
M(N3)n
+
n NaX
n NaN3
+
MXn
-
100
80
100
80
(A)
(B)
60
60
For copper and zinc triflates, even with a 2-fold and a 4-fold
-
excess of NaN3 most of N3 remains in a coordinated state,
40
20
0
40
20
0
definitely in a form of anionic metal-azide complexes (Figure 2,
D). However, in both cases a small band corresponding to the
non-coordinated azide anion is present in FTIR spectra,
indicating the reversibility of extensive azide binding.
For a further understanding of the structure of metal-azide
species DFT calculations (rm06l/Def2TZVP/W06) were
performed. In our model, the geometry of the metal-azide pair
with six DMF molecules was optimized and anharmonic
vibrational analysis was carried out (Figure 3).
1900
1900
2100 2050 2000 1950
2100 2050 2000 1950
2150
2150
Wavenumber, cm-1
Wavenumber, cm-1
100
80
100
80
(C)
(D)
60
60
Figure 3. DFT-optimized structures of metal-azide pairs in DMF.
40
20
0
40
20
0
(B)
(A)
1900
1900
2150 2100 2050 2000 1950
2150 2100 2050 2000 1950
-
-
Wavenumber, cm-1
Wavenumber, cm-1
N3
N3
Zn2+
Bu4NN3 in DMF
Bu4NN3 in DMF
NaN3 in DMF
NaN3/CuOTf (1 : 1) in DMF
Mg2+
NaN3/Zn(OTf)2 (2 : 1) in DMF
NaN3/CuOTf (ratio 2 : 1) in DMF
NaN3/Zn(OTf)2 (4 : 1) in DMF
NaN3/Mg(ClO4)2 (2 : 1) in DMF
NaN3/Ni(ClO4)2 (2 : 1) in DMF
NaN3/Co(ClO4)2 6H2O (2 : 1) in DMF
-
The asymmetric stretching band (ν3) of free N3 (solution of
Bu4NN3 in DMF) appears at 1996 cm-1 (in covalently bound
organoazides ν3(N3) is usually observed at c.a. 2100 cm-1). The
presence of metal ion shifts the ν3 band to a lower wavenumber
[Zn(DMF)5N3]+(DMF)
[Mg(DMF)5N3]+(DMF)
d(Zn-N3) = 2.07 Å
3 = 2099 cm-1
d(Mg-N3) = 2.11 Å
3 = 2121 cm-1
-
value due to the formation of contact ion pairs and binding of N3
(C)
(D)
to a metal.[20],[22] Furthermore, splitting and widening of the band
is observed attributed to the presence of different metal-azide
species in solution[23] and/or several azido-groups coordinated to
a metal center. Thus, in solution of NaN3 in DMF two bands are
present in IR spectra (1999 cm-1 and 2030 cm-1), which
-
N3
-
N3
Na+
-
correspond to the free N3 and the ion pair (Figure 2, A).[20]
Na+
Somewhat similar picture is observed for NaN3/Mg(ClO4)2
mixture (2 : 1) in DMF. In addition to these two bands, a band at
2060 cm-1 appears relating to N3- coordinated to metal (Figure 2,
A) (no changes in IR spectra after 24h). In situ generated zinc
(II), copper (I) and cobalt (II) azides show only bands at
-
[Na(DMF)6]+ N3
d(Na-N3) = 5.93 Å
3 = 2048 cm-1
[Na(DMF)5N3](DMF)
-
2050−2090 cm-1 demonstrating that N3 is covalently bonded to
d(Na-N3) = 2.40 Å
3 = 2063 cm-1
the metal ion (cf. with IR spectra of solid complexes[24]) and is
not present in a free form in solution (Figure 2, B, C). The IR
wavelength and the splitting character of azido-group in the
NaN3/Zn(OTf)2 solution is very similar to that previously
In all cases, complex [M(DMF)5N3]n+ with an inner-sphere N3
and one outer-sphere DMF molecule was found as a local
minima. The M−N3 distance increases in row ZnN3 < MgN3
NaN3 that reflects the relative strength of the metal-azide
-
reported[19g] for Zn(N3)2(py)2 complex in solid state.
A
+
+
<
substantially different picture is observed for NaN3/Ni(ClO4)2
system. Here, most of the azide anion is present in a non-
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interaction. Thus, for sodium the calculated distance is 2.40Å
(Figure 3, C), which is close to a contact ion pair[20] (in crystalline
sodium azide ionic Na−N distance is 2.44-2.50Å[25]). For zinc,
much shorter M−N3 bond (c.a. 2.07Å) is indicative of a covalent
bonding (Figure 3, A). The structure of a solvent-shared ion pair
(complex С, Scheme 4). Subsequent transfer of the azido-group
from metal to the β-carbon atom with breakage of the N−O bond
leads to cyclic products 4 (LA-promoted SN2’ process), which
cannot form from nitrosoalkenes В. This process may also occur
in a stepwise manner through the generation of putative N-vinyl-
-
[Na(DMF)6]+N3 was also optimized (Figure 3, D). Calculated
N-alkoxynitrenium cations D and subsequent nucleophilic
-
frequencies of ν3 vibrations of free and coordinated azide appear
to be overestimated, yet the trend is in agreement with
experiment and generally correlates with the calculated M−N3
bond length. The shorter is the bond, the higher is the ν3
vibration frequency (the lowest calculated ν3 value was for the
addition of N3 to these highly electrophilic Michael acceptors
(SN1’ process).
Scheme 3. Mechanism for ionic (“nucleophilic”) metal azides.
-
solvent-shared [M(DMF)6](n+1)+ N3 ion pair). Thus, quantum-
Nucleophilic metal azides (M - Na, Mg, Ni):
chemical modeling suggests that zinc and magnesium ions give
-
a stronger interaction with N3 in DMF than sodium ion. The latter
-
+ + N3
forms an contact ion pair, which should dissociate easier.
A strong correlation between the coordination state of azide
anion and the reactivity of metal-azide system can be seen
when comparing experimental data in Table 1 and spectra in
Figure 2. Thus, metal-azide systems possessing non-
coordinated azide anion (even in a small amount) in reaction
with cyclic bis(oxy)enamines 2 afford acyclic azidooximes 3 or
pyranone oximes 6. On the other hand, strongly bound metal
azides tend to form cyclic ethers of azidooximes 4.
[M(N3)n-1
]
M(N3)n
(N3)n-1
M
N
N
-
O
O
O
O
N3
Si(CH3)3
Si(CH3)3
2
- (CH3)3SiN3
M - Na
-Na+
N
N
O
N
O
O
O
O
O
M(N3)n-1
M(N3)n-1
Mechanism studies
B
A
-
N3
M - Mg, Ni
The following mechanistic model was suggested to explain
the difference in the reactivity of in situ generated metal azides
(Schemes
3 and 4). Ionic metal azide species (NaN3,
N
N3
H2O
N3
OH
OH
NaN3/Mg(ClO4)2 and NaN3/Ni(ClO4)2 systems) are more
nucleophilic compared to covalent d-metal azides. In reaction of
these reagents with bis(oxy)enamines 2, the free azide anion
attacks silicon atom (Scheme 3). This leads to the generation of
semiacetals A, which undergo cleavage of the nitrosoacetal unit
producing conjugated nitrosoalkenes B. Intramolecular Michael-
type cyclization of oxy-anion on the C,C-double bond affords
pyranone oximes 6,[10e] which are major products in reaction of
2a with NaN3 without any metal salt additives (Scheme 2). If the
oxy-group is strongly bound to a Lewis acidic metal ion (M − Mg,
Ni), the cyclization to pyranone oximes 6 cannot not occur.
Instead, the nitrosoalkene intermediate B is attacked by the
azide anion (free or from the contact ion pair) producing α-
azidooximes 3. Hence, the metal ion serves as a protective
group, which blocks the nucleophilic oxy-anion in intermediate B.
Such a process occurs with NaN3/MXn systems possessing non-
coordinated azide anion even in a small concentration, in
particular, with in situ generated magnesium and nickel azides in
N
N
O
O
(work-up)
OH
O
6
M(N3)n-1
3
Scheme 4. Mechanism for covalent (“Lewis acidic”) metal azides.
-
DMF and also with zinc azide species with [Zn]/N3 ratio 1 : 4
(see data in Table 1).
In covalently bound metal azides (cobalt, copper and zinc
azides), the nucleophilicity of the azide anion is reduced and,
hence, its direct nucleophilic attack on silicon atom is not
possible. However, the metal center in such azides has marked
Lewis acidity (“Lewis acidic azides”) and may induce the
heterolytic cleavage of weak exocyclic N−O bond in
Besides the azide transfer, intermediates С can suffer the
intramolecular 1,3-migration of OSi(CH3)3 group leading to oxy-
substituted derivatives 7 and 8 (Scheme 4).[26] These by-
bis(oxy)enamines
2
by coordination with oxygen atom[10c]
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products usually accompany the formation of cyclic azides 4
(see entries 10, 13-21 in Table 1). In the absence of sodium
azide, the hydroxy-substituted 1,2-oxazine 7а was detected as
the major product (80% yield) in reaction of bis(oxy)enamine 2а
with zinc triflate in DMF.
Aditional evidence in support of these mechanisms were
obtained from experiments on the interaction of in situ generated
magnesium and zinc azides with bis(oxy)enamine 2n bearing a
sterically hindered triisopropylsilyl group (Scheme 5).
demonstrates the dual reactivity of magnesium azide system
due to the presence of both free azide anion and metal-bound
azide species in solution (see Figure 2, A and discussion).
Solvent influences the reactivity of in situ generated metal
azide species. As can be seen from data in Table 1 (entries 2-4
and 13-16), the most pronounced solvent effect is observed for
the reaction of bis(oxy)enamine 2a with magnesium-azide
species. Thus, switching from DMF to THF results in change of
mechanism from nucleophile-promoted to Lewis acid-promoted
(cf. experiments 2 and 4 in Table 1). Apparently, in less
solvating THF most of the azide anion remains bonded to
magnesium cation in form of Mg(N3)2, which reacts with
bis(oxy)enamine 2а as a “Lewis acidic” metal azide according to
the mechanism shown in Scheme 4.
Scheme 5. Reactions of bulky bis(oxy)enamine 2n with zinc and magnesium
azide systems.
Thus, open-chain products 3 are formed employing metal
azides which dissociate in DMF (or reversibly form by ion
exchange with NaN3) and strongly coordinate oxy-anion in the
nitrosoalkene intermediate В (“nucleophilic metal azides”). The
magnesium azide system in DMF has the best
nucleophilicity/Lewis acidity balance to meet these criteria. The
-
formation of cyclic products 4 requires metal azides, in which N3
is covalently bound to a metal center, and the metal exhibits
marked Lewis acidity (“Lewis acidic metal azides”, Zn, Co, Cu).
Azides of some metals (aluminium, scandium and ytterbium) are
borderline cases and react both via nucleophilic and Lewis acid-
promoted pathways.
Unlike the analogous experiments with TMS-enamine 2a,
both reactions led to a same result, i.e. the formation of cyclic
azide 4a and silyl ether 8n together with some unreacted
starting material. The open-chain oxime 3a was not detected
among the products. Evidently, three bulky isopropyl groups
Synthesis of diamino alcohols from
azidooxime derivatives 3 and 4
To demonstrate the synthetic potential of α-azidooxime
derivatives 3 and 4, their transformation to diaminoalcohols was
studied. Direct catalytic hydrogenation of model azidooximes 3a
and 4a with Raney nickel catalyst gave the desired diamine 9a,
which, however, was obtained as an equimolar mixture of
diastereomers and could not be separated from by-products.
-
hamper the attack of N3 on the silicon atom, thus blocking the
nucleophilic pathway leading to oxime 3a (Schemes 3 and 5).
On the other hand, the formation of products 4 and 8 by the LA-
mediated pathway (Scheme 4) is much less sensitive to the size
of substituents at silicon. Interestingly, when the nucleophilic
pathway is hampered, magnesium azide reacts via the LA-
mediated pathway in a same manner as zinc azide does. This
Scheme 6. Stereodivergent synthesis of 1,2-diaminoalcohols 9a.
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In order to improve chemo- and stereoselectivity of 1,2-
oxazine reduction, we probed a two-step procedure, which
includes the hydride addition to C,N double bond and catalytic
hydrogenolysis of N−O bond (see refs.[27] and review[28]).
Treatment of azidooximes 3a and 4a with NaBH3CN in acetic
acid afforded acyclic and cyclic hydroxylamines 10a and 11a,
respectively, in high yields (Scheme 6). Importantly, in the
course of oxime reduction the azido group remained intact.
conversion of starting material was observed[31]). Fortunately,
screening of catalytic hydrogenation conditions and catalysts
revealed that 3-azidomethyl-substituted isoxazoline 4m could be
reduced using Adams catalyst (Scheme 7). The protected
diaminoalcohol 12m was obtained in reasonable yield and d.r.
6.1 : 1 (stereochemistry was not determined). Product 12m
resembles the core structure of known protein kinase Bα inhibitor
shown in Figure 1.[17c]
Azidohydroxylamine 10a was obtained as
diastereomers with predominance of syn-isomer (d.r. 3.6 : 1.0),
while the cyclic hydroxylamine 11a formed as single
a mixture of
Scheme 7. Stereoselective reduction of azide 4m.
a
diastereomer with 3,4-trans-arrangement of substituents.
Hydrogenolysis of N−O bond in each of these products furnished
the corresponding syn- or anti-diastereomers of diamine 9a
(isolated as hydrochlorides).
In view of higher stereoselectivity of the two-stage reduction
method, it was used to convert azido-substituted 5,6-dihydro-4H-
1,2-oxazines 4b-g to the corresponding diaminoalcohols 9b-g
(Table 4). In all cases the addition of hydride proceeded with
exceptional stereoselectivity and afforded only 3,4-trans-isomers
of 1,2-oxazines 11 (on the stereochemistry of hydride reduction
of 5,6-dihydro-4Н-1,2-oxazines see refs.[28],[29]). Catalytic
hydrogenation of intermediates 11 followed by treatment with
HCl gave hydrochlorides of the desired diastereomerically pure
diamines 9•2HCl bearing up to four contiguous stereogenic
centers. Products 9f and 9g possess a structural motif of known
renin inhibitors (see Figure 1),[17b] diamine 9с has structural
similarity with potent PDE 4 inhibitors (Rolipram analogues[30]).
The possibility of the stepwise reduction of α-azidooxime
fragment makes it a convenient platform for the synthesis of 1,2-
diamines bearing different substituents at the amino groups. In
particular, reduction of azido group in hydroxylamine 10а with
PPh3 in wet THF and subsequent treatment with Boc2O gave a
protected 1,2-diamine 13a with a hydroxyl substituent at one of
the amino groups (Scheme 8).
Scheme 8. Synthesis of aminohydroxylamine 13a.
Table 4. Stereoselective reduction of azidomethyl-substituted 1,2-oxazines 4
to 1,2-diaminoalcohols 9
Another important advantage of the α-azidooxime platform is
the possibility of selective modification of each of the primary
amino groups arising from the reduction of azido and oxime
groups. This was illustrated by the synthesis of unsymmetrically
substituted 1,2-diamine 14a from azido-substituted 1,2-oxazine
4a (Scheme 9). On the first stage, azido group was selectively
reduced under mild catalytic hydrogenation conditions with
Raney nickel catalyst (5 bar H2, r.t.). The resulting primary amine
was trapped with Boc2O to form 15a. Subsequent hydride
reduction of oxime group afforded stereoselectively the
protected aminohydroxylamine 16a. Hydrogenolysis of the N−O
bond liberated the second amino-group, which was immediately
involved
in
reductive
amination
with
3-
methylbutanal/NaBH(OAc)3 system to give target 1,2-
diaminoalcohol 14a.
Attempts to achieve hydride reduction of C,N double bond in
isoxazoline 4m with NaBH3CN were not successful (no
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Scheme 9. Synthesis of unsymmetrically substituted 1,2-diamine 14a.
Acknowledgements
This work was supported by Russian Science Foundation (Grant
14-50-00126). We thank Dr. Maxim A. Novikov for performing
29Si NMR and Mrs. Irina Borisova for taking FTIR spectra.
Keywords: organic azides • metal azides • nitrogen-oxygen
bond • 1,2-diamines • Lewis acids
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synthesis
of
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-
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FULL PAPER
In situ generated metal azides as
reagents. The nature of counterion
allows controlling the regioselectivity
of the addition of the azide anion to
bielectrophilic substrates. As
P. A. Zhmurov, Y. A. Khoroshutina, R. A.
Novikov, I. S. Golovanov, A. Yu.
Sukhorukov,* S. L. Ioffe
Page No. – Page No.
demonstrated here ionic metal azides
(Na, Mg, Ni) react through the initial
attack of N3 on silicon atom
Divergent Reactivity of In Situ
Generated Metal Azides. Reaction
with N,N-Bis(oxy)enamines as a Case
Study
-
generating conjugated nitrosoalkenes,
while strongly bound metal azides (Zn,
-
Co and Cu) directly transfer N3 to the
β-carbon atom via a LA-assisted SN’
substitution of silyloxy-group.
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