Divergent Synthesis of Oxa-Cyclic Nitrones through Gold(I)-Catalyzed 1,3-Azaprotio Transfer of Propargylic α-Ketocarboxylate Oximes: Experimental and DFT Studies

Article abstract of DOI:10.1002/chem.201901522

1,3-Azaprotio transfer of propargylic α-ketocarboxylate oximes, a new type of alkynyl oximes featuring an ester tether, has been explored by taking advantage of gold catalysis. The incorporation of an oxygen atom to the chain of alkynyl oximes led to the formation of two different oxa-cyclic nitrones. It was found that internal alkynyl oximes with an E-configuration deliver five-membered nitrones, whereas terminal alkynyl oximes with an E-configuration afford six-membered nitrones. DFT calculations on four possible pathways supported a stepwise formation of C?N and C?H bonds, in which a 1,3-acyloxy-migration competes with the 1,3-azaprotio-transfer, especially in the case of internal alkynyl oximes. The relative nucleophilic properties of oxygen in the carbonyl group and the nitrogen in the oxime, the electronic effects of alkynes, and the influence of the ring system have been investigated computationally.

Full text of DOI:10.1002/chem.201901522

A Journal of
Accepted Article
Title: Divergent Synthesis of Oxa-Cyclic Nitrones via Gold(I)-Catalyzed
1,3-Azaprotio Transfer of Propargylic α-Ketocarboxylate Oximes:
Experimental and DFT Studies
Authors: Chunhong Wang, Qi Cui, Zhixin Zhang, Zhu-Jun Yao,
Shaozhong Wang, and Zhi-Xiang Yu
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Divergent Synthesis of Oxa-Cyclic Nitrones via Gold(I)-Catalyzed
1,3-Azaprotio Transfer of Propargylic -Ketocarboxylate Oximes:
Experimental and DFT Studies
Chunhong Wang#, Qi Cui#, Zhixin Zhang, Zhu-Jun Yao, Shaozhong Wang,* and Zhi-Xiang Yu*
Dedication ((optional))
Abstract: 1,3-Azaprotio transfer of propargylic -ketocarboxylate
oximes, a new type of alkynyl oximes featuring an ester tether, has
been explored by taking advantage of gold catalysis. The
incorporation of oxygen atom to the chain of alkynyl oximes led to
the formation of two different oxa-cyclic nitrones. It was found that
internal alkynyl oximes with E-configuration deliver five-membered
nitrones, while terminal alkynyl oximes with E-configuration afford
six-membered nitrones. DFT calculations on four possible pathways
supported that a stepwise formation of C-N and C-H bonds are
involved, in which a 1,3-acyloxy migration competes with the 1,3-
azaprotio transfer especially in the case of internal alkynyl oximes.
The relative nucleophilic properties of oxygen in carbonyl group and
the nitrogen in oxime, the electronic effects of alkynes as well as the
influence of the ring system have been investigated computationally.
activation of alkynes, we envisioned that Au catalysis could be
applied for 1,3-azaprotio transfer of alkynyl oxime. [10] Meanwhile,
it was reported that Au(I) can catalyze 1,3-acyloxy migration of
propargylic carboxylate to give an allene-Au complex.[11] We
therefore expected the designed substrates, propargylic -
ketocarboxylate oximes, could have such a reaction pattern to
give intermediate I, which then underwent C1-N bond formation
to give five-membered oxa-cyclic nitrones (Scheme 1c, pathway
A). Another possible pathway is the C2-N bond formation to give
six-membered products (Scheme 1c, pathway B). We did not
know which pathway would be preferred before we tested the
reactions experimentally. To our delight, we found by
subsequent experiments that we could tune the reaction
selectivity by choosing different R groups, either to give five-
membered nitrones when R = alkyl or aryl, or six-membered
nitrones when R = H.[12] Here we report the results and explain
the regiochemistry by DFT calculations.
Given that cyclic nitrones behave as powerful and versatile
N,O-containing building blocks in organic synthesis, a variety of
preparative protocols have been developed in the past
decades.[1] Among them, 1,3-azaprotio transfer of oxime is
supposed to be a highly atom-economical one, which is free of
oxidants and hydroxylamine agents. It involves an addition of an
concerted
or stepwise
O
R
N
O
(a)
(b)
+
R
N
H
H
heat
R
R
N
O
Grigg's work
N
oxime across
a
carbon-carbon multiple bond and the
HO
straightforward formation of C-N and C-H bonds (Scheme 1a).[2]
In fact, the 1,3-azaprotio transfer of alkenyl oximes towards an
electron-deficient alkene, a terminal alkene as well as a styrene
has been explored and carried out successfully under thermal,
acidic and basic conditions, respectively.[3-6] In contrast, the
corresponding alkynyl analogues remain less developed. As
independently reported by Grigg and Beauchemin, only a few
alkynyl oximes tethered by an all-carbon chain took part in a
thermal 1,3-azaprotio transfer to deliver N-vinyl substituted cyclic
nitrones, which tend to further undergo an isomerization or a N-
O bond cleavage.[7-8] Previously Lewis acids were used instead
of Brønsted acids for the 1,3-azaprotio transfer of allenyl oxime
substrates (Scheme 1b).[9] Inspired by recent progresses in Au
H
R = H, alkyl, aryl
acid
Beauchemin's work
Gallagher's work
N
Me
N
N
Me
OH
OH
AgI
n
n
N
O
N
HO
H
n = 1, 2, 3
O
(c)
R
1
R
1
R
R1
N
O
N
1
R1
N
O
R1
[Au+]
R2
2
C1-N bond formation
2
[Au+]
2
O
HO
O
HO
O
R2
R2
O
Pathway A
I
R = alkyl, aryl
Pathway B
R = H
O
1
C2-N bond formation
R1
N
CH2R
R2
2
O
O
[a]
Chunhong Wang, Zhixin Zhang, Prof. Zhu-Jun Yao, Dr. Shaozhong
Wang
Scheme 1. 1,3-azaprotio transfer of oximes
We commenced the study by using alkynyl oxime 1a as a
model substrate, which was prepared from undec-4-yn-3-ol and
2-oxopropanoic acid by two steps. Treatment of 1a with a
catalytic amount of Ph3PAuNTf2 in toluene at room temperature
for 3 hours gave five-membered oxa-cyclic nitrone 2a in 79%
yield (Table 1, entry 1). Solvent testing showed that
dichloromethane is the best one in terms of both yield and
reaction time (Table 1, entries 1-5). The effects of ligand and
counteranion of gold catalyst were further examined (Table 1,
entries 6-9). It was found that the combination of Ph3PAuCl and
AgSbF6 displays the best efficiency, delivering 2a in 96% yield.
State Key Laboratory of Coordination Chemistry, Jiangsu Key
Laboratory of Advanced Organic Materials, School of Chemistry and
Chemical Engineering
Nanjing University, Nanjing 210023, China
E-mail: wangsz@nju.edu.cn
[b]
[#]
Qi Cui, Prof. Zhi-Xiang Yu
Beijing National Laboratory for Molecular Sciences (BNLMS), Key
Laboratory of Bioorganic Chemistry and Molecular Engineering of
Ministry of Education, College of Chemistry
Peking University, Beijing 100871, China
Email: yuzx@pku.edu.cn
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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Control experiments revealed that both the gold catalyst and
silver additive are indispensable for the formation of this cyclic
five-membered cyclic nitrones 2a-2e in yields ranging from 59%
to 96%. Cyclic nitrones 2f-h with cyclohexylidene, gem-dimethyl
vinylidene and vinyl groups can be generated smoothly from the
corresponding E-propargylic -keto carboxylate oximes. The
tert-butyldiphenylsilyl ether substrate is well tolerated, albeit
giving nitrone 2i in 40% yield. It seems like that the electronic
effect of the aromatic substituents on the alkyne terminus
significantly affect the formation of cyclic nitrones 2j-2l. The
electron-donating group (Me) is more favorable than the
electron-withdrawing one (Cl), giving 2k in a yield higher than
that of 2l. The structure of 2k was further confirmed by a series
of NMR studies (H-H COSY, DEPT-135, HSQC, and HMBC).
Oximes derived from 6-(benzyloxy)-2-oxohexanoic acid, 2-
oxoacetic acid as well as 2-phenyl-, 2-cyclohexyl-, 2-(1-(tert-
butoxycarbonyl)piperidin-4-yl)-2-oxoacetic acids proceeded the
gold(I)-catalyzed 1,3-azaprotio transfer as well as their 2-
nitrone.
Table 1. Optimization of gold(I)-catalyzed 1,3-azaprotio transfer of 1a[a]
Time
(h)
3
3
12
Yield
(%)[b]
79
76
24
92
94
88
86
Entry
Catalyst
Additive
Solvent
1
2
3
4
5
6
7
8
9
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
Ph3PAuCl
JohnPhosAuCl
NHCAuCl
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgOTf
PhMe
THF
CH3CN
Acetone
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
3
0.25
0.25
0.25
0.25
0.25
Ph3PAuCl
Ph3PAuCl
85
96
oxopropanoic acid counterparts, which enables
a
facile
AgSbF6
installation of diverse substituents (benzyloxybutyl, hydrogen,
cyclohexyl, piperidin-4-yl and phenyl) to the C4-position of oxa-
cyclic nitrones 2m-2r. It is worthy to mention that when a mixture
containing E- and Z-oximes was examined, only one of them
underwent the 1,3-azaprotio transfer. To identify which isomer is
responsible for the reactivity, we attempted parallel experiments
using pure E- and Z-alkynyl oximes. It was revealed that cyclic
nitrones 2q and 2r originate from E-1q and E-1r, respectively.
The Z-isomers of 1q and 1r did not give any cyclic nitrones or
heterocyclic compounds under the identical conditions (see
Supporting Information for more details).
When terminal alkynyl oxime 1s was examined using
Ph3PAuNTf2 as catalyst, a labile N-vinyl nitrone 4 was obtained
in 25% yield (Table 2, entry 1). A more stable cyclic nitrone 3s
was isolated as the major product when the reaction was
performed in toluene at elevated temperature (Table 2, entry 2).
Ligand screening revealed that the sterically hindered and
electron-rich phosphine (JohnPhos) gave a better yield than
triphenylphosphine or N-heterocyclic carbene (Table 2, entries
2-4). An acidic additive was proven to be beneficial for the
[a] Reaction conditions: alkynyl oxime 1a (0.1 mmol), gold catalyst (2.5
mol%), silver additive (2.5 mol%) in 2.0 mL solvent at room temperature. [b]
Isolated yield. JohnPhos = 2-(di-tert-butylphosphino)biphenyl. IPr = 1,3-
bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
After obtaining the optimal reaction conditions, we sought
to investigate the scope of the internal alkynyl oximes (Scheme
2). Substrates containing ethyl, cyclopropyl, cyclohexyl, phenyl,
3-benzyloxypropyl groups at the propargylic position participated
in the gold(I)-catalyzed 1,3-azaprotio transfer reaction, giving
O
N
O
N
5
5
Me
Me
O
O
Ph
O
Et
O
2d, 79%
2a, 96%
O
N
5
Me
O
O
2f, 70%
O
OTBDPS
O
Table 2. Optimization of gold(I)-catalyzed 1,3-azaprotio transfer of 1s[a]
Ph
N
N
Me
Me
O
O
Et
O
Et
O
2j, 94%b
2i, 40%b
Yield[c]
En
try
Time
(h)
Catalyst
Additive
Solvent
3s
4
1[b]
2
3
Ph3PAuCl
Ph3PAuCl
IPrAuCl
JohnPhosAuCl
JohnPhosAuCl
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
MsOH
AgNTf2
MsOH
-
DCM
PhMe
PhMe
PhMe
PhMe
3
3
2
2
0.2
0
25
5
0
0
0
41
43
53
92
O
N
5
Ph
4
5[d]
O
O
2q, 93%b
Et
6[e]
JohnPhosAuCl
PhMe
24
10
0
7
8
JohnPhosAuCl
-
PhMe
PhMe
24
24
0
0
0
0
AgNTf2
Scheme 2. Five-membered oxa-cyclic nitrones. Reaction conditions: internal
alkynyl oxime 1 (0.1 mmol), Ph3PAuCl (2.5 mol%), AgSbF6 (2.5 mol%) in 2.0
mL dichloromethane at room temperature for 15 minutes unless otherwise
specified. [a] Oxime, Ph3PAuCl (10 mol%), AgSbF6 (10 mol%) in DCE (0.05
M) at 80 °C for 2 h. [b] Reaction time = 2 h. [c] A mixture of inseparable E- and
Z-oxime isomers was examined.
[a] Reaction conditions: alkynyl oxime 1s (0.1 mmol), gold catalyst (2.5
mol%), silver additive (2.5 mol%) in 2.0 mL solvent at mentioned
temperature. [b] The reaction temperature is 40 oC. [c] Isolated yield. [d] 10
mol% methanesulfonic acid was employed. [e] At room temperature.
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formation of 3s. In the presence of a catalytic amount of
methanesulfonic acid (MsOH), the gold(I)-catalyzed 1,3-
azaprotio transfer of 1s was finished in 10 minutes at 110 °C,
giving 3s in 92% yield (Table 2, entry 5). The yield dropped
drastically when the reaction was performed at room
temperature (Table 2, entry 6). No reaction occurred in the
absence of either JohnPhosAuCl or AgNTf2 (Table 2, entries 7-
8).
followed by intramolecular protodemetallation to give six-
membered nitrones. We chose 1h and 1v as the model
substrates for analyzing the Gibbs free energy surfaces of
internal alkynyl oximes and terminal alkynyl oximes, respectively.
In order to simplify the calculation process, we used PMe3 as the
ligand and ignored the counter-anion effect because of the
-
relatively weak coordination ability of SbF6 and Tf2N- (Scheme
4).
Under the cooperative catalysis of JohnPhosAuNTf2 and
MsOH, the scope of the terminal alkynyl oximes was examined
(Scheme 3). Oximes bearing ethyl, cyclopropyl, cyclohexyl
substituents locating at the propargylic position underwent the
1,3-azaprotio transfer smoothly, delivering six-membered oxa-
cyclic nitrones 3s-3u in moderate to good yields. 6-
Unsubstituted nitrone 3v was obtained in 95% yield. The benzyl
ether was kept untouched, giving nitrone 3w in 89% yield. Aryl-
substituted alkynyl oximes 1x-1z engaged in the 1,3-azaprotio
transfer as their alkylated counterparts, affording arylated
nitrones 3x-3z in good yields. Oximes derived from 2-oxoacetic
acid and 2-cyclohexyl-2-oxoacetic acid were converted to
nitrones 3aa, 3ab in moderate yields, respectively. The
incomplete conversion from a mixture containing E- and Z-1ab
isomers to 3ab was observed, further indicating that the
configuration of oxime is essential for the 1,3-azaprotio transfer.
To our disappointment, an attempt to attain 3ac from E- and Z-
1ac failed at this stage.
Scheme 4. Catalytic cycles of Pathways A & B.
We computed the Gibbs free energy surfaces of substrates
1h and 1v of pathways A & B (see Schemes 1c and 4) to
understand why R group can influence the selectivity (Figure 1).
There is an equilibrium between r0-N and r1 due to the different
coordination group. As demonstrated (in red), when R = Me, the
reaction undergoes the 1,3-acyloxy migration via TS1 from the
alkyne coordinated intermediate r1, forming the six-membered
ring intermediate INT1. The following step is a ring-opening
reaction via TS2 (the relative Gibbs free energy of this step is
19.9 kcal/mol), giving rise to Au(I) coordinated allene complex
INT2. After that, through the intramolecular attack of nitrogen
atom towards Au(I) coordinated allene, the five-membered ring
intermediate INT3 is generated. This step needs an activation
Gibbs free energy of 11.5 kcal/mol. The final step is an
intramolecular protonation to break Au-C bond via TS4, which is
relatively easy with an activation Gibbs energy of 12.9 kcal/mol.
O
N
O
N
Me
O
Me
Me
O
Me
O
4-MePh
O
4-ClPh
3z, 72%
3y, 84%
In the competition pathway
B (the 1,3-azaprotio transfer
process), branching from r1, the first step is the C-N bond
formation via TS5, followed by the intramolecular protonation to
give INT6, which is not stable under acidic conditions and
isomerizes to six-membered oxa-cyclic nitrones. TS5 is the rate-
determining transition state in this pathway, which has an overall
activation Gibbs free energy 21.1 kcal/mol. Therefore, pathway
A of forming five-membered nitrones is more favorable for 1h
(19.9 vs 21.1 kcal/mol), which is consistent with experimental
observation. However, for substrate 1v (R = H, Gibbs free
Scheme 3. Six-membered oxa-cyclic nitrones. Reaction conditions: terminal
alkynyl oxime (0.1 mmol), JohnPhosAuCl (2.5 mol%), AgSbF6 (2.5 mol%) and
MsOH (10 mol%) in 2.0 mL PhCH3 at 110 °C for 10 minutes. [a] A mixture of
inseparable E- and Z-oxime isomers was examined.
The experimental divergent selectivity drove us to further
study the mechanism by DFT calculations. We proposed two
possible pathways, which start from Au(I)-coordinated substrate
(Scheme 4). In pathway A, 1,3-acyloxy migration takes place
first, giving allene-Au intermediate. This is followed by N-OH
group’s nucleophilic attack to activated allene, and form a 5-
membered heterocycle-Au complex, which is then liberated from
the catalytic cycle through intramolecular protodemetallation. In
pathway B, substrate-Au complex directly undergoes 6-exo
cyclization by N-OH group attack to the alkyne-Au moiety,
energy surfaces in blue), pathway
B is more favorable,
considering that this pathway has an activation Gibbs free
energy of 17.0 kcal/mol (TS5 is the rate-determining TS), while
the rate-determining step (via TS1) in pathway A has an
activation free energy of 21.1 kcal/mol. This suggests that
internal alkynyl oximes leads to five-membered nitrones, which
is in agreement with the experiment results.
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Figure 1. (a) Gibbs free energy surfaces for 1h (R = Me) and 1v (R = H); (b) Analysis of regio-chemistry
nitrones, while terminal alkynyl oximes afford six-membered
ones. DFT calculations revealed that in the case of internal
alkynyl oximes, an initial 1,3-acyloxy migration is more favorable
than the 1,3-azaprotio transfer. The factors including the
nucleophilic properties of the oxygen in carbonyl group and the
nitrogen in oxime, as well as the electronic effects of alkynes
were further investigated based on computational analyses.
The above results can be explained by nucleophilicities of
N and O, together with the electrophilicities of C1 and C2 in the
substrates (Figure 1b). N is more nucleophilic than O, because
the activation barrier difference for their attacks to Au-
coordinated alkyne is near
5 kcal/mol (see Supporting
Information). In the intramolecular case, substrate-Au complex
has three resonance forms. II form is favored and C2 is more
electrophilic than C1 for R = H, whereas III form is favored and
C1 is more electrophilic than C2 for R = Me, due to the electron-
donating abilities of Me > E group > H (E group is indicated in
Figure 1b; computational charge and structure analysis for given
in the Supporting Information). For 1v with R = H, N attack is still
favored than O attack (17.0 vs. 21.1 kcal/mol) due to two
reasons: 1, N is more nucleophilic than O; and C2 is more
electrophilic than C1. For 1h with R = Me, C1 is more
electrophilic than C2, O attack to C1 becomes a little easier than
that in 1v (19.9 vs. 21.1 kcal/mol). But the N attack to C2
becomes dramatically sluggish (22.1 vs. 17.0 kcal/mol) due to
the electrophilicity of C2 is reduced dramatically. Therefore, the
above different regioselectivity changes can be attributed to the
Acknowledgements
The authors gratefully thank the National Science Foundation of
China (21572098, 21871132), and the National Key Research
and Development Program of China (2018YFC0310900).
Conflict of interest
The authors declare no conflict of interest.
Keywords: 1,3-azaprotio transfer • oxa-cyclic nitrone • gold
catalysis • DFT calculations • propargylic -ketocarboxylate
oxime
different electrophilicitis of C1 and C2 caused by R group.
To summarize, a gold(I)-catalyzed stepwise 1,3-azaprotio
transfer of propargylic -ketocarboxylate oximes has been
developed. The alkyne substituent effect resulted in the
divergent formation of oxa-cyclic nitrones with different ring sizes.
It was found that internal alkynyl oximes give five-membered
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10.1002/chem.201901522
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Chunhong Wang, Qi Cui, Zhixin Zhang,
Zhu-Jun Yao, Shaozhong Wang*, and
Zhi-Xiang Yu*
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Divergent Synthesis of Oxa-Cyclic
Nitrones via Gold(I)-Catalyzed 1,3-
Azaprotio Transfer of Propargylic -
Ketocarboxylate Oximes:
Experimental and DFT Studies
Regiodivergent C-N bond formation was observed in a gold-catalyzed 1,3-azaprotio transfer of
alkynyl oximes, which makes controllable synthesis of five- and six-membered oxa-cyclic nitrones.
DFT calculations suggested that owing to different electrophilicities of C1 and C2 caused by R group,
the oxime and the ester groups may compete initially as N- and O-nucleophiles.
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