Gold-catalyzed synthesis of nitrogen-containing heterocycles from ε-N-protected propargylic esters

Article abstract of DOI:10.1039/c003734f

A mild and efficient gold-catalyzed tandem cyclization to piperidinyl enol esters has been developed with facilely available ε-N-Boc-protected propargylic esters.

Full text of DOI:10.1039/c003734f

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COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Gold-catalyzed synthesis of nitrogen-containing heterocycles from
e-N-protected propargylic esters†
Jianfeng Huang,a Xuan Huanga and Bo Liu*a,b
Received 4th March 2010, Accepted 14th April 2010
First published as an Advance Article on the web 27th April 2010
DOI: 10.1039/c003734f
A mild and efficient gold-catalyzed tandem cyclization to
piperidinyl enol esters has been developed with facilely
available e-N-Boc-protected propargylic esters.
ester, a variation of a-piperidinyl ketone, could be achieved via
tandem [3,3]-rearrangement/allene hydroamination from e-N-
protected propargylic ester (Scheme 1), in an extension of our
interest in gold-catalyzed synthesis.11 Herein we would like to
present our results on this project.
Nitrogen-containing heterocycles are extensively distributed in na-
ture with various biological activities.1 Specifically, a-piperidinyl
ketone is a ubiquitous structure motif in natural alkaloids (Fig. 1).
A variety of synthetic strategies have been advanced to achieve this
substructure, including intra-molecular SN2 aza-cyclization,2 in-
tramolecular aza-Michael addition,3 dearomatization of pyridine4
and nucleophilic addition of cyclic N-acyliminium ions5 etc.
However, there is continuous demanding for developing new
processes to produce such functionalized azacycles.
Scheme 1 Gold-catalyzed synthesis of a-piperidinyl enol ester.
With compound 1a as the test substrate, different catalysts were
investigated to evaluate their activity of catalyzing the desired
tandem rearrangement/azacycle formation (Table 1). Simple
gold salts, both AuCl and AuCl3, prompted this transformation
smoothly in moderate yield (entries 1–2). Although AuCl(PPh3)
or AgOTf did not show any catalytic activity respectively, the
combined use of these two noble metal salts afforded the desired
product in 76% yield (entries 3–5). A comparable yield was
obtained with AuCl/AgOTf (1 : 1), but in a greater reaction rate
(120 min vs. 60 min; entry 5 vs. entry 6), which was exceeded
by AuCl3/AgOTf combination achieving a rather better yield in
shorter time (entry 7).12 The data indicated that polar solvents
should be favorable for this catalytic transformation (entries 7–12).
Interestingly, the catalytic systems including gold(III) chloride,
combined with other silver salts than AgOTf, did not provide
Fig. 1 Structures of selected natural alkaloids.
Gold-catalyzed reactions of alkynes have drawn much attention
from the synthetic community in recent years, mainly rooting from
the interesting p acid property of gold catalysts and the resultant
formidable molecular diversity.6 Although gold-catalyzed carbon–
nitrogen bond formation has been broadly investigated,7 few
examples were reported on piperidine cyclization. Recently, gold-
catalyzed tandem reactions of alkynyl amines were elegantly
explored as effective protocols to achieve a-piperidinyl ketone
structure motifs, via a facile enone-forming and intramolecular
aza-Michael sequence,8 an effective formal [4+2] synthesis,9 or a
formal alkyne aza-Prins cyclization.10 So new catalysts leading to
piperidine formation, which are active in a mild reaction atmo-
sphere, are still worth searching for, especially for synthetically
significant internal alkynes. We envisioned that piperidinyl enol
Table 1 Optimization of reaction conditions toward a-piperidinyl enol
estera
Entry
R
Catalystb
Solvent Time/min Yield (%)c
1
2
3
4
5
6
7
8
Me(1a) AuCl
MeCN 120
MeCN 120
MeCN 60
MeCN 60
69
62
\
Me(1a) AuCl3
Me(1a) AuCl(PPh3)
Me(1a) AgOTf
d
d
\
Me(1a) AuCl(PPh3)/AgOTf MeCN 120
76
78
84
Me(1a) AuCl/AgOTf
Me(1a) AuCl3AgOTf
Me(1a) AuCl3AgOTf
Me(1a) AuCl3/AgOTf
Me(1a) AuCl3/AgOTf
Me(1a) AuCl3/AgOTf
Me(1a) AuCl3/AgOTf
Me(1a) AuCl3/AgBF4
Me(1a) AuCl3/AgSbF6
OEt(1b) AuCl3/AgOTf
tBu(1c) AuCl3/AgOTf
MeCN 60
MeCN 45
DCM
PhMe
THF
Et2O
120
trace
d
9
120
120
120
\
10
11
12
13
14
15
16
17
trace
trace
67
MeNO2 120
MeCN 80
MeCN 120
MeCN 60
MeCN 45
MeCN 30
83
62
72
83
aKey Laboratory of Green Chemistry & Technology of Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, P. R. China.
E-mail: chembliu@scu.edu.cn; Fax: +86 28 8541 3712; Tel: +86 28 8541
3712
Ph(1d)
AuCl3/AgOTf
92
bKey Laboratory of Synthetic Chemistry of Natural Substances, Shanghai
Institute of Organic Chemistry, CAS, 345 Lingling Road, Shanghai 200032,
P. R. China
a All reactions were carried out at room temperature. b 5 mol% of catalyst
loading was used for all entries. As for Au/Ag combined catalyst,
AuI/AgI = 1/1 or AuIII/AgI = 1/3. c Isolated yield. The Z/E ratios range
from 1/1 to 2/3. d No desired product could be detected.
† Electronic supplementary information (ESI) available: Experimental
details and characterization data for the new compounds. See DOI:
10.1039/c003734f
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Table 2 Gold-catalyzed cyclization of e-N-Boc-protected propargylic
esters to afford piperidinyl enol estersa
Product; Yield/%b
Entry Substrate
Time/min (Z : E)c
n
1
2
3
4
5
1d; R1 = Bu
30
30
30
60
60
2d; 92 (2 : 3)
3a; R1 = isopentyl
3b; R1 = (CH2)3Ph
3d; R1 = (CH2)3OBz
3e;
4a; 83 (2 : 3)
4b; 85 (2 : 3)
4d; 55 (3 : 7)d
4e; 81 (2 : 3)
Fig.
2
Tentative mechanism for gold-catalyzed piperidine ring
cyclization.
R1 = (CH2)3OTBDPS
intermediates to the final E- or E/Z- products. Indeed, in view
of the weak nucleophilicity of carbamate, it seems reasonable that
the direct SN2 attack by Boc-protected nitrogen through path a,
affording E-IV stereospecificly, should not be dominant. Thus
the cyclization through gold-activated allenyl ester III might be
considered as the preferred pathway, albeit without a favored
stereochemical bias, which is consistent with the data in Table 2.
Furthermore, 2◦ amine 3m exhibits excellent reactivity as well
in 91% yield, though without any diastereoselectivity. We suspect
that it might be the imperceptible energy difference between
the two respective transition states (A & B) that accounts for
the insignificant selectivity (kA ª kB, Scheme 2).19 To elucidate
the applicability of our methodology, the facile conversion of
piperidinyl enol esters to piperidinyl ketones was confirmed
by transforming compounds 2d and 4m to the corresponding
ketones 5 and 6 smoothly using potassium carbonate in methanol
(Scheme 3).
6
7
8
9
10
11
12
3f; eR2 = H, R3 = H
3g; eR2 = Ph, R3 = H
3h; R2 = Me, R3 = H
3i; R2 = Me, R3 = Me
3j; R2 = OMe, R3 = H
60
60
60
60
60
4f; 50 (1 : 1)
4g; 53 (1 : 1)
4h; 64 (1 : 2)
4i; 75 (1 : 2)
4j; 61 (3 : 2)
4k; 65 (1 : 1)
4l; trace
3k; R2 = OTBDPS, R3 = H 60
3l; R2 = CO2Et, R3 = H
60
a All reactions were carried out at 0.2 mmol scale in acetonitrile (2 ml)
with AuCl3 (5 mol%) and AgOTf (15 mol%) as the combined catalyst at
room temperature. b Isolated yield. c The Z/E ratios were determined by
1H NMR spectra. d The Z/E ratio is based on the isolated yields of two
isomers. e PG = Bz.
superior results (entries 13–14). Taking the efficiency and the
expense into account, we selected AuCl3/AgOTf as the preferred
catalyst combination. Other propargylic esters were also tested to
acquire the optimal reaction result. To our delight, the benzoate 1d,
as an excellent substrate, affords the top yield, while the pivaloate
1c behaves as well as the acetate 1a (entries 15–17).13
To explore the scope of this catalytic tandem transformation, a
variety of propargylic esters were surveyed in the optimized con-
ditions (Table 2). Acyclic aliphatic alkynes were firstly examined
and internal alkynes (1d, 3a and 3b), are found to be suitable
substrates in satisfactory yields (entries 1–3).14 A distal TBDPS
ether in compound 3e was found to be compatible with the catalyst
very well, while the benzoate at g position of the triple bond in
3d seemingly affects the reaction efficiency unfavorably (entries
4 and 5). Aromatic alkynes were also tested to be appropriate
substrates. Compounds 3f and 3g produce comparable yields,
indicating that a phenyl substitution at para position has minute
influence (entries 6 and 7).15 However, the pivaloates 3h–3k, with
electron-donating groups, such as alkyl, methoxyl and TBDPS
ether at the para position of the benzene ring, show better reactivity
than compound 3l with electron-withdrawing group (entries 7–13).
Based on the yields and stereoselectivities listed above, we
speculate a mechanism as illustrated in Fig. 2. At first, the gold
catalyst acts as a p-acid to activate the triple bond in substrates
and then initiates an intramolecular rearrangement to afford
intermediates II and III, which coexist in a fast equilibrium.16,17
Secondly, the corresponding reactive sites in intermediates II
and III are captured by Boc-protected nitrogen atom, providing
intermediate E-IV and E/Z-V respectively via path a and path b.18
The following protonation of carbon–gold bond converts these
Scheme 2 Transition states to compound 4m.
Scheme 3 Conversion to piperidinyl ketone.
In summary, we have developed an efficient method achieving
piperidinyl enol esters and piperidinyl ketones in mild reac-
tion conditions. Compared to intermolecular catalyzed propar-
gylic substitution20 and nucleophilic addition to propargyl
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carboxylates,21 this intramolecular piperidine cyclization method-
ology shows different reactivity and different substrate applicabil-
ity. The tandem cyclization is potentially useful and its application
in total synthesis of natural product is under way in our laboratory.
12 Other catalytic systems, such as InCl3, Hg(OTf)2, PtCl2, Zeise’s dimer,
PtCl2(PPh3)2, afforded trace of the desiredproduct or complex mixtures.
13 It is interesting to note that different substituents on nitrogen, ranging
from Boc to Ac, Ms, Ts, Cbz and methyl carbamate, appear to have
different influence on the reaction, but N-Boc-protected substrate
behaves best. For the detail, please see the following scheme.
Acknowledgements
We appreciate the financial support from the National Natural
Science Foundation of China (20702032, 20872098), the Ministry
of Education of China (NCET-08-0365), and National Basic
Research Program of China (973 Program, 2010CB833200). We
also thank Analytical & Testing Center of Sichuan University
for NMR recording and State Key Laboratory of Biotherapy for
HRMS determination.
14 No reaction occurs with terminal alkyne 3c in the standard condition
within an hour. Prolonged reaction time or heating the reaction mixture
makes no improvement.
15 For entries 6 and 7 in Table 2, the benzoates 3f and 3g were found to
offer better yields than the corresponding pivaloates.
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This journal is
The Royal Society of Chemistry 2010
Org. Biomol. Chem., 2010, 8, 2697–2699 | 2699
©