Gold(I)-Catalyzed Hydroaminaloxylation and Petasis-Ferrier Rearrangement Cascade of Aminaloalkynes

Article abstract of DOI:10.1021/acs.orglett.6b00585

An efficient method has been developed to generate a diverse array of indolizidines and quinolizidines from readily available aminaloalkynes via a gold(I)-catalyzed hydroaminaloxylation and Petasis-Ferrier rearrangement cascade. The method enabled a formal synthesis of (±)-antofine.

Full text of DOI:10.1021/acs.orglett.6b00585

Letter
pubs.acs.org/OrgLett
Gold(I)-Catalyzed Hydroaminaloxylation and Petasis−Ferrier
Rearrangement Cascade of Aminaloalkynes
Amol B. Gade and Nitin T. Patil*
Division of Organic Chemistry, CSIR-National Chemical Laboratory, Dr. Homi Bhabha Road, Pune - 411008, India
Academy of Scientific and Innovative Research (AcSIR), New Delhi 110025, India
S
* Supporting Information
ABSTRACT: An efficient method has been developed to
generate a diverse array of indolizidines and quinolizidines
from readily available aminaloalkynes via a gold(I)-catalyzed
hydroaminaloxylation and Petasis−Ferrier rearrangement
cascade. The method enabled a formal synthesis of
( )-antofine.
Scheme 1. Aza-heterocycles through Gold-Catalyzed Cascade
Reactions Involving Petasis−Ferrier Cyclizations
he indolizidines and quinolizidines are an important
Tstructural motif found in numerous natural products and
pharmaceutically important compounds (Figure 1).1 Accord-
ingly, novel strategies for the stereoselective synthesis of these
“izidine”-type alkaloids continue to gain great attention.
Figure 1. Selected indolizidine and quinolizidine natural products.
During the past decade, gold catalysis has emerged as a
powerful tool in the area of organic synthesis.2 Based on the
intrinsic π-activation property of gold catalysts, a great number of
novel transformations for the synthesis of heterocyclic cores have
appeared in the literature. Recently, gold-catalyzed cascade
reactions, involving Petasis−Ferrier cyclization as one of the
elementary steps, has emerged as a new area. As far as
azaheterocycles are concerned, Rhee and co-workers were the
first one to report a gold(I)-catalyzed Petasis−Ferrier type
cyclization for the synthesis of piperidine enol ethers which after
hydroalysis afforded piperidones (Scheme 1, eq 1).3 A year later,
Zhang and co-workers reported the one-pot synthesis of
piperidin-4-ols by sequential gold(I)-catalyzed cyclization,
chemoselctive reduction, and spontaneous Petasis−Ferrier
rearrangement (Scheme 1, eq 2).4 Subsequently, the same
group successfully developed gold(I)-catalyzed Petasis−Ferrier
Received: March 1, 2016
© XXXX American Chemical Society
A
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cyclization triggered by amide cyclization for the synthesis of
arene-fused hexahydroquinolizinones (Scheme 1, eq 3).5
Recently, Fustero and Pozo reported a slightly different
cyclization cascade of homopropargyl amides for the synthesis
of dihydropyridones (Scheme 1, eq 4).6
the reaction increased to 80 °C, the reaction was faster and 2a
was obtained 90% yield in just 6 h (entry 12). Next, the effect of
catalyst loading on the reaction outcome in terms of yield was
studied (entries 13 and 14). At 80 °C, there was no substantial
effect on product yield when 5 mol % (95%) and 3 mol % (92%)
of catalyst were used. Therefore, we considered the optimal
catalyst loading for further study to be 3 mol %. A significant
decrease in yield was observed when the reaction was carried out
without 5 Å MS (entry 15). It should be noted that substrate 1a
was inert either in the presence of AgOTf or in the absence of a
gold catalyst (entries 16 and 17).
Although a few reports exist on gold-catalyzed cascade
reactions involving Petasis−Ferrier cyclization7 as mentioned
above,3−6 a new approach is necessary because of following
reasons: (a) all the reported methods utilize only terminal
alkynes; (b) all the methods generate piperidines except the work
reported by Zhang and co-workers wherein quinolizidines were
accessible (Scheme 1, eq 3). Although the latter report deals with
quinolizidine synthesis, the appended aromatic ring was
necessary and therefore the method limits it application in the
synthesis of natural products. These pitfalls encouraged us to
initiate a research project oriented toward the development of a
new methodology for the synthesis of indolizidines and
quinolizidines that will allow the rapid assembly of both bicyclic
scaffolds through a common mechanistic pathway. Our approach
is based on the direct utilization of aminaloalkynes as the starting
material, and the details of the work are outlined herein.
With the optimized reaction conditions (Table 1, entry 14) in
hand, the scope of the reaction was examined with various
aminaloalkynes. As shown in Table 2, the reaction is applicable to
ab
,
Table 2. Access to Indolizidines
At the onset of our investigation, we tested our hypothesis
using 1-(but-3-yn-1-yl)-5-hydroxypyrrolidin-2-one 1a as starting
material (Table 1). Initially, the planned reaction was performed
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
AuCl
solvent
toluene
time (h)
yield
1
12
12
12
12
12
12
12
12
12
12
12
6
−
−
2
Ph3PAuOTf
JohnPhosAuOTf
IPrAuOTf
IPrAuNTf2
IPrAuOTf
IPrAuOTf
IPrAuOTf
IPrAuOTf
IPrAuOTf
IPrAuOTf
IPrAuOTf
IPrAuOTf
IPrAuOTf
IPrAuOTf
AgOTf
toluene
toluene
toluene
toluene
1,4-dioxane
THF
3
22
80
72
67
83
trace
77
87
93
90
95
92
75
−
4
5
6
7
a
Reaction conditions: 0.2 mmol of 1, 3 mol % IPrAuOTf, DCE (1
8
CH3CN
CHCl3
DCM
DCE
b
c
mL), 80 °C, 45 mg of 5 Å MS, 12 h. Isolated yields. Reaction time 6
h. 5 mol % catalyst was used. Reaction time 24 h. Inseparable
mixture of diasteriomers (d.r. determined by H NMR).
9
d
e
f
1
10
11
c
12
DCE
cd
,
a range of aminaloalkynes giving indolizidines in excellent yields.
The reaction proceeds smoothly to furnish various 8-arylhexa-
hydroindolizine-3,7-diones, as single diastereomer. For instance,
8-phenylhexahydroindolizine-3,7-dione (2b) was obtained in
94% yield. Similarly para- and meta-substituted 8-arylhexahydro-
indolizine-3,7-diones (2c−2g) were obtained in excellent yields
(87−97%). Even in the case of a highly electron-withdrawing
group such as −NO2 on the aryl ring (2e), the product was
isolated in high yield (96%). 8-(o-Bromophenyl)hexahydro-
indolizine-3,7-dione (2h) was obtained in 66% yield; however,
the reaction required 24 h to complete even when 5 mol % of
catalyst was used. In the case of 8-hexylhexahydroindolizine-3,7-
dione (2i), the product was isolated in 85% yield; however, the
diastereoselectivity was found to be poor (d.r. = 10:3).8
Interestingly, the introduction of a methyl substitution at the
hemiaminal carbon increased the rate of reaction and 2j was
isolated in 83% yield. Unfortunately the reaction did not work
with α-aryl aminaloalkyne to produce 2k. The relative stereo-
chemistry of 2f was established by X-ray crystallographic
analysis,8 and other indolizidines were assigned by analogy.
13
DCE
12
12
12
12
12
ce
,
14
DCE
cf
,
15
16
17
DCE
DCE
−
DCE
−
a
Reaction conditions: 0.2 mmol of 1a, 10 mol % catalyst, solvent (1
b
c
mL), rt, 5 Å MS (45 mg). Isolated yields. Reaction was carried out at
d
e
80 °C. 5 mol % of catalyst was used. 3 mol % of catalyst was used.
f
Reaction performed without 5 Å MS.
in toluene using various gold(I) complexes (10 mol %). Initial
screening of AuCl and PPh3AuOTf catalysts did not lead to the
formation of product (entries 1 and 2). However, to our delight,
desired product 2a was obtained in 22% yield with the use of
JohnPhosAuOTf as a catalyst (entry 3). When NHC gold
complexes such as IPrAuOTf and IPrAuNTf2 were employed, 2a
was obtained in 80% and 72% yields, respectively (entries 4 and
5). Further extensive screening of solvents revealed that DCE is
the solvent of choice (entries 6−11). When the temperature of
B
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We next examined the scope of the reaction to access
quinolizidine scaffolds (Table 3) by treating 1-(but-3-yn-1-yl)-6-
mol %) resulted in the gold catalyzed aza-Petasis−Ferrier
rearrangement to obtain requisite products 4d and 4e in 70% and
75% yields, respectively. This observation clearly indicated that
the oxazinanes are the potential intermediate for the reaction.
Both the reaction, i.e. oxazinane formation, and its trans-
formation into products are catalyzed by the gold catalysts in a
relay manner.10
a b
,
Table 3. Access to Quinolizidines
Since in one of the cases (Table 3, 4b) cyclic enamines 6 was
isolated, we were curious to know the intermediacy of 6 as a
potential intermediate. Accordingly, when cyclic enamines 6
were subjected to standard reaction conditions, the formation of
product 4b was not observed at all even with heat for 24 h. This
observation clearly ruled out the intermediacy of cyclic enamines.
However, when 6 was subjected to gold-catalyzed reactions using
a catalytic amount of pyridine, the reaction proceeded and
product 4b was isolated in 40% yield (Scheme 3). This results
account for the involvement of gold−acetonyl complex 711 as an
intermediate.
Scheme 3. Control Experiments: Proof for Intermediacy of
Gold−Acetonyl Complex
a
Reaction conditions: 0.2 mmol of 3, 3 mol % IPrAuOTf, DCE (1
b
c
mL), 80 °C, 45 mg 5 Å MS, 8−12 h. Isolated yields. Cyclic enamine
6 was isolated in 33% yield. 5 mol % catalyst was used. Reaction time
d
e
24 h.
hydroxypiperidin-2-ones under the optimized reaction con-
ditions. As expected, quinolizidine 4a was obtained in 82% yield.
Note that compound 4a is synthetically important, as it can be
transformed into natural products such as Matrine and
Leontine.9 Similarly, 4b was obtained, albeit, in a slightly lower
yield (63%) because in this case cyclic enamine 6 was obtained as
a side product in 33% yield (vide infra). Likewise, 1-
arylhexahydro-2H-quinolizine-2,6(1H)-diones (4c−i) were ob-
tained in 71−94% yield as a single diastereomer. The relative
stereochemistry of 4e was established by X-ray crystallographic
analysis,8 and that of others were assigned by analogy.
Based on these observations and previous reports for gold-
mediated Petasis−Ferrier rearrangement, the mechanism has
been proposed as outlined in Scheme 4. In catalytic cycle A, the
Scheme 4. A Plausible Reaction Mechanism
Interestingly, we found that when aminaloalkynes 3d and 3e
were treated with IPrAuOTf under a very low catalyst loading
(0.5 mol %), oxazinanes 5a and 5b were isolated in 79% and 76%
yields, respectively (Scheme 2). Further treatment of these
oxazinanes under standard reaction conditions (IPrAuOTf, 3
Scheme 2. Control Experiments: Isolation of Oxazinane
intramolecular hydroalkoxylation of aminaloalkynes would occur
to generate oxazinanes (8) via protodeauration of transient
intermediate I. The isolable intermediate 8 would then undergo
Petasis−Ferrier rearrangement12 via π-intermediate13 II and
gold−acetonyl complexes11 III to form products with the
regeneration of the gold catalyst.
Next, the utility of the reaction was demonstrated in the formal
synthesis of ( )-antofine (Scheme 5). The requisite precursor, 2-
C
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Scheme 5. Formal Synthesis of ( )-Antofine
ACKNOWLEDGMENTS
■
Generous financial support by the Department of Science and
Technology (DST), New Delhi (Grant No. SB/S1/OC-17/
2013) and the Council of Scientific and Industrial Research
(CSIR), New Delhi (Grant Nos. CSC0108 and CSC0130) is
gratefully acknowledged. We thank Dr. Rajesh. G. Gonnade and
Mr. Shridhar H. Thorat (Center for Materials Characterization,
CSIR-NCL) for assistance with X-ray crystallography. A.B.G.
thanks CSIR for the award of Junior Research Fellowship (JRF).
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* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00585.
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All experimental procedure, analytical data, and copies of
1H, 13C NMR spectra for all newly synthesized products
(PDF)
X-ray data for 2f (CIF)
X-ray data for 4e (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: n.patil@ncl.res.in.
Notes
The authors declare no competing financial interest.
D
DOI: 10.1021/acs.orglett.6b00585
Org. Lett. XXXX, XXX, XXX−XXX