Enantio- and Regioselective Palladium(II)-Catalyzed Dioxygenation of (Aza-)Alkenols

Article abstract of DOI:10.1002/anie.202109312

An oxidative Pd-catalyzed intra-intermolecular dioxygenation of (aza-)alkenols has been reported, with total regioselectivity. To study the stereoselectivity, different chiral ligands as well as different hypervalent-iodine compounds have been compared. I

Full text of DOI:10.1002/anie.202109312

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Accepted Article
Title: Enantio- and Regioselective Palladium(II)-Catalyzed
Dioxygenation of (Aza)-Alkenols
Authors: Egle Maria Beccalli, Sabrina Giofrè, Letizia Molteni, Donatella
Nava, and Leonardo Lo Presti
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202109312
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Enantio- and Regioselective Palladium(II)-Catalyzed
Dioxygenation of (Aza)-Alkenols
S. Giofrè,[a] L. Molteni, [a] D. Nava,[a] L. Lo Presti,[b] E. M. Beccalli [a]*
[a]
S. Giofrè, E. M. Beccalli*, L. Molteni, D. Nava
DISFARM, Sezione di Chimica Generale e Organica “A. Marchesini”
Università degli Studi di Milano,
Via Venezian 21, 20133, Milano (Italy)
E-mail: egle.beccalli@unimi.it
[b]
L. Lo Presti
Dipartimento di Chimica
Università degli Studi di Milano,
Via Golgi 19, 20133, Milano (Italy)
Supporting information for this article is given via a link at the end of the document.
Abstract:
An
oxidative
Pd-catalyzed
intra-intermolecular
The enantioselective PdII-catalyzed difunctionalizations of amino
alkenes have been recently reported by Liu.[7] In particular, an
asymmetric 6-endo-aminoacetoxylation has been described as
efficient method to afford enantioenriched 3-acetoxy piperidines
(Scheme 1b).[7a] Also an inter-intermolecular dialkoxylation has
been lately described on terminal alkenes as efficient way to
access various chiral 1,2-diols (Scheme 1c).[4]
dioxygenation of (aza)-alkenols has been reported, with total
regioselectivity. To study the stereoselectivity, different chiral ligands
as well as different hypervalent iodines have been compared. In
particular, by using C-6 modified pyridinyl-oxazoline (Pyox) ligand and
hypervalent iodine bearing an aromatic ring, an excellent enantio- and
diastereoselectivity has been achieved.
The formation of two carbon-heteroatom bonds across an
unsaturated system in one-pot process have gained considerable
importance as a means to achieve structural motifs in a rapid
manner and to provide the main goals of the modern organic
synthesis as efficiency, atom-economy, and sustainability.[1] This
process do not require isolation of intermediates, change of the
reaction conditions, or addition of further reagents to those initially
mixed. To achieve this goal, different methods have been
developed, making use of transition metal catalysts in oxidative
conditions. In particular, the Pd-catalyzed difunctionalization of
alkenes[2] has been widely studied due to high tolerability of
different functional groups and mild reaction conditions required.
In these reactions, the presence of an oxidant, such as copper
salts, quinones and hypervalent iodines, is required in order to
oxidize the Pd-catalyst to its active species. Recently,
difunctionalization of alkenes in transition metal free conditions
have also been reported, making use of the electrophilic nature of
hypervalent iodines, in intramolecular C-N and C-O bond
formations.[3] Nevertheless, the limited substrate scope and the
need in some cases of stoichiometric amount of the chiral iodine
represent still a challenge of this emerging field. Moreover,
despite several studies have been published on enantioselective
intermolecular dialkoxylations,[3c,4] less explored is the field of the
asymmetric intramolecular C-O bond formation of alkenols.
In our interest in developing efficacious Pd-catalyzed alkenes
difunctionalizations,[5] we recently reported the dialkoxylation and
alkoxyarylation,[6] processes, starting from 3-aza-5-alkenols,
using different oxidants species and nucleophiles. (Scheme 1a).
The two reaction typologies involved an intramolecular step with
different regioselectivity, as a result of a 6-exo- or 7-endo-trig
Scheme 1. Recent difunctionalizations of unactivated alkenes.
In the present work, we focused on the development of
enantioselective cyclization of (aza)-alkenols, for the synthesis of
functionalized O-containing heterocycles under mild reaction
conditions and in particular, on the inter-intramolecular
cyclization
step.
Lately,
difunctionalizations
involving
stereocontrol have gained considerable attention, too.
1
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alkoxyacyloxylation process (Scheme 1d). To the best of our
knowledge, only few examples of enantioselective cyclization
involving the oxygen atom in PdII-catalyzed difunctionalizations
has been reported so far.[8] Indeed, enantioselective
hydroalkoxylation have been mainly described as way to access
hindered ligands L2 to the most congested L4 (entries 5,7-9,
Table 1). Changing the solvent, we observed that, while the
mixture of dichloromethane with polar solvents, such as
acetonitrile, had a detrimental effect on both enantioselectivity
and reactivity (entries 11,14), the mixture with the xylene (entry
12) was advantageous on both the aspects. Using the classic
commercially available Pyox ligand (HPyOxtBu), no reaction was
observed.
chiral O-containing heterocycles (through CuII-catalysis[9], TiIV-
[10]
catalysis
CoII-catalysis[11] NiII-catalysis[12] or Brᴓnsted acid-
,
catalysis[13]).
Thus, in order to test the efficiency of different ligands in
intramolecular C-O bond formation, we synthetized the already
described ligands (L1, L3)[7a] and the new ones (L2, L4), where
specifically the steric hindrance given by the biphenyl
disubstitution on C-6 position of the L4 may result in an increase
Pd-complex reactivity.
Table 1. Optimization of the Pd-catalyzed enantioselective dialkoxylation
En
try
Lig
.
Solvent (0.3 M)
Time
(h)
T°C
3aa
%Yie
ld
e.r.
(S:R)
1
2
-
DCM
PhCF3
24 h
24 h
30 h
30 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
48 h
rt
61%
50:50
54:46
70:30
77:23
80:20
81:19
17:83
85:15
86:14
71:29
74:26
88:12
-
L1
L1
L1
L1
L1
L2
L3
L4
L4
L4
L4
L5
L4
rt
78%
75%
69%
71%
49%
62%
73%
77%
82%
55%
79%
-
3
PhCF3
10 °C
10 °C
0 °C
-20 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
0 °C
4
DCM
5
DCM
6
DCM
7
DCM
8
DCM
9
DCM
10
11
12
13
14
ClPh
CH3CN/DCM 1:1
DCM/xylene 1:2
DCM/xylene 1:2
CH3CN/toluene 1:3
64%
77:23
2a = PhI(mcba)2; L5 = HPyOxtBu
Using the N-allyl,N-Ts-aminoethanol 1a as starting material, the
difunctionalization process was performed in the presence of
Pd(OAc)2 as catalyst and a modified hypervalent iodine,[14]
PhI(mcba)2 2a, able to act both as oxidant and nucleophilic source,
in DCM as solvent (entry 1, Table 1). The process was completely
regioselective, affording the 2-substituted N-Ts-morpholine 3aa,
in 61% yield, as result of 6-exo-cyclization. The reaction carried
out in the presence of L1 at room temperature in
trifluoromethylbenzene afforded the product 3aa in good yields
(78%), but really low enantioselectivity (entry 2, Table 1). A
significant improvement of the enantioselectivity was observed,
decreasing the temperature from 10° C to 0° and to -20° C, with
an enantiomeric ratio from 77:23 to 81:19 (entries 4-6, Table 1).
The employment of the different ligands, L1-L4, influenced
slightly the enantioselectivity but it significantly increased the
yields of 3aa, from 62% to 77%, changing from the less sterically-
Scheme 2. Investigations on the effect of different hypervlant iodines 2a-d on
the different reactivity and enatioselectivity observed: a) products 3aa-3ad; b)
hypervalent iodines effect on reaction rate; c) 1H NMR spectra regarding the
complexation of L4 given by Pd(OAc)2 in the presence of PhI(mcba)2 or
PhI(OAc)2; d) proposed complexes IIIAc and IIImcba.
In order to further investigate and confirm the advantages of
this protocol (Table 1, entry 12), a comparison with the classic
acetoxylation conditions,[7a] involving the commercially available
PhI(OAc)2, was carried out, together with other hypervalent
iodines (Scheme 2a-b). By using PhI(OAc)2, both
enantioselectivity and yields were compromised, the product 3ab
was obtained in er 67:33 and 57% yields. Switching to the bi-o-
fluoro-benzoic derivative, PhI(ofba)2 2c, with similar feature to
2
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PhI(mcba)2 2a, the corresponding morpholine derivative 2ac was
obtained in satisfying yield, with complete consumption of the
starting material after 24 h, even if with lower er. In the case of the
bi-N-acetyl-alaninate, PhI(N-acetyl-Ala)2 2d, the results were
unsatisfactory, with almost no reactivity at 0° C and no
diastereoselectivity at room temperature. We tried to explain the
influence of the different hypervalent iodines on the outcome of
the reaction through 1H NMR studies (Scheme 2c). Thus, by
mixing the ligand L4, Pd(OAc)2, and PhI(OAc)2 2b or PhI(mcba)2
2a in a 1:1:2 stoichiometric ratios, we analyzed the corresponding
1H NMR at time 0 (5 min) and after 2 h. Interestingly, while in the
NMR spectra regarding PhI(OAc)2 the signals relative to L4
(circle) were never disappearing, even after 24 h, in the NMR
related to PhI(mcba)2, the L4 signals completely disappeared
after 2 h and a new stable complex was formed, characterized by
a shift of the proton 6-PyH(Ar)2 from 6.03 to 6.82 ppm, which was
even stable after 24 h, at 0° C. As a consequence, the not
complete complexation of the palladium in the first case could
explain the low enantioselectivity observed with PhI(OAc)2, while
it is possible to hypothesize that the new species formed with
PhI(mcba)2 2a might be stabilized by π-π interactions between the
benzoate of the hypervalent iodine and the aromatic ring of the
ligand, improving its performance in the asymmetric
difunctionalization.[15]
Taking the reaction conditions reported in entry 12, Table 1,
as the optimized ones, different class of (aza)-alkenyl alcohols
were investigated in order to check the applicability of the method
(Scheme 3). Replacing the Ts-protecting group on the
aminoethanol with the Boc-group (1b) resulted in a slightly loss of
both reactivity and enantioselectivity, while the Ns-derivative
3da[16] was obtained in higher yields and comparable er. The
substrate 1c, bearing the di-substitution on the α-position to the
amino group, gave the best result, in accordance with the recent
contributions,[7] where the Thorpe-Ingold effect given by the di-
substitution favored both cyclization and enantioselectivity. Then,
starting from simple alkenols 1e-i, we observed a ligand-induced
enhanced reactivity. Indeed, the reaction performed in the
absence of the ligand furnished the alkoxyacyloxylated product in
really low yields and in a mixture with other undesired products.
Thus, with the protocol in our hand (entry 12, Table 1), we were
able to achieve the functionalized pyrans 3ea-na in moderate
yields and satisfying enantioselectivity, as exclusively exo-
products (confirmed by 1H-NOESY NMR, n.O.e between the two
protons, CH and CH2, bonded to the oxygen of the 6-membered
ring). Due to the geometry of the system, the 2,5-trans
diastereoselectivity was preferred in the case of compounds 3ja-
3la (trans/cis > 2.5:1). On the other hand, when the substituent
was located on the carbon bonded to the oxygen, only the 2,6-cis
diastereoisomers were isolated, as demonstrated by compound
3ma-na (trans/cis > 1:10). When the reaction was applied on
chiral N-allyl aminoethanols 1o-s, the chiral center located on the
substrates was the main driver of the stereoselectivity (Scheme
3b). For this reason, the alkoxyacyloxylation was carried out in the
presence the racemic ligand, which led to the formation of the cis-
products as single diastereoisomers.[17] The structures of the 2,5-
cis disubstitued morpholines 3oa-sa have been confirmed by 1H-
NOESY NMR.
Scheme 3. Scope of the enantioselective Pd-catalyzed alkoxyacyloxylation on
(aza)-alkenols
To justify the results observed, a possible mechanism of the
process was proposed (Scheme 4). After the formation of Pd/L*
complex, the activation of the double bond mediated by the
palladium leads to the oxygen nucleophile addition with formation
of the corresponding alkoxypalladated species I.[18] The
interaction of the oxidant agent with the ligand and simultaneous
complexation with metal directly affects stereoselectivity
observed (as elucidated above through NMR studies). The
subsequent reductive elimination affords the alkoxyacyloxylated
compound as exclusive exo-product.
3
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Keywords: Pd-catalysis • alkenes difunctionalizations•
hypervalent iodine • dioxygenation • enantioselectivity • alkenols
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obtained,
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Conflict of interest
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4
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COMMUNICATION
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Entry for the Table of Contents
Keywords: Pd-catalysis • alkenes
difunctionalizations• hypervalent iodine •
dioxygenation • enantioselectivity •
alkenols
Sabrina Giofrè, Letizia Molteni, Donatella
Nava, Leonardo Lo Presti, Egle Maria
Beccalli
Page No. – Page No.
A
palladium-catalyzed intramolecular difunctionalization of (aza)-alkenols with excellent
Enantio- and Regioselective
Palladium(II)-Catalyzed Dioxygenation of
(Aza)-Alkenols
regioselectivity is reported. A new generation of C-6-modified Pyox ligands together with the use of
unusual hypervalent iodine reagents as oxidants enabled the generation of acyloxy-functionalized
heterocycles in excellent enantio- and diastereoselectivity.
6
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