Silver(i)-mediated highly enantioselective synthesis of axially chiral allenes under thermal and microwave-assisted conditions

Article abstract of DOI:10.1039/b914516h

Silver(i) salts mediated stereospecific transformation of optically active propargylamines to axially chiral allenes with excellent enantioselectivities (17 examples with 96-99% ee; one substrate with 91% ee) without subsequent racemization.

Full text of DOI:10.1039/b914516h

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Chemical Communications
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Volume 46 | Number 2 | 14 January 2010 | Pages 165–344
ISSN 1359-7345
COMMUNICATION
Man-Kin Wong, Chi-Ming Che et al.
Silver(I)-mediated highly
enantioselective synthesis of axially
chiral allenes
FEATURE ARTICLE
Michael P. Coogan et al.
Application of d6 transition metal
complexes in fluorescence cell imaging
1359-7345(2010)46:2;1-I

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Silver(I)-mediated highly enantioselective synthesis of axially chiral
allenes under thermal and microwave-assisted conditionswz
Vanessa Kar-Yan Lo,a Cong-Ying Zhou,a Man-Kin Wong*b and Chi-Ming Che*a
Received (in College Park, MD, USA) 20th July 2009, Accepted 4th September 2009
First published as an Advance Article on the web 16th September 2009
DOI: 10.1039/b914516h
Silver(I) salts mediated stereospecific transformation of optically
active propargylamines to axially chiral allenes with excellent
enantioselectivities (17 examples with 96–99% ee; one substrate
with 91% ee) without subsequent racemization.
silver compounds in highly enantioselective organic synthesis
are sparse. Among them, a notable example is enantioselective
allylation and Mukaiyama aldol reaction catalyzed by
Yamamoto and Yanagisawa’s BINAP–Ag(I) system.7
At the outset, we examined the catalytic activities of different
silver(I) salts towards the transformation of propargylamine 1a to
allene 2a, and the results are depicted in Table 1.
Axially chiral allenes are important structural motifs present
in biologically active natural products,1 and are versatile
synthons featuring excellent axis-to-center chirality transfer.1b,2
The synthesis of chiral allenes mainly relies on SN20 displacement
reactions of chiral propargylic compounds by organometallic
reagents, 3,3-sigmatropic rearrangement of propargyl alcohols,
and asymmetric catalysis with chiral metal complexes as
catalysts.1b,3 Recently, we reported a gold-catalyzed synthesis
of axially chiral allenes from optically active propargylamines.4
Although this method is tolerant to a variety of functional
groups, the substrate scope was confined to 1,3-diarylallenes,
and the enantiomeric excess of the allene products was found
to be dependent on the electronic effect of substrates
(Scheme 1); for example, electron-rich propargylamines led
to corresponding allenes with low enantioselectivities. This
result was explained by coordination of the gold catalyst to
axially chiral allenes that subsequently leads to racemization.5
Thus there is a need to search for other metal catalysts for
highly enantioselective synthesis of axially chiral allenes from
optically active propargylamines. The criterion is that such a
metal catalyst is active for the transformation (Scheme 1) but
would not racemize allenes.
The initial experiment was conducted with AgNO3. Treatment
of propargylamine 1a (99% ee)8 with AgNO3 (10 mol%) in
CH3CN (2 mL) at 40 oC for 24 h in the dark led to (R)-1,3-
diphenylpropa-1,2-diene 2a in 90% yield and 98% ee based on
39% substrate conversion (entry 1); no racemization of the
resulting allene was observed. Increasing the silver(I) loading
could improve the substrate conversion. When 50 mol% of
AgNO3 was used, the substrate conversion reached 91%
(entry 3), while no further significant improvement was observed
when a stoichiometric amount of AgNO3 was used (entry 4). The
substrate conversion was reduced to 50% when the reaction was
performed in the presence of light (entry 5), and this is attributed
to the fact that most silver(I) compounds are light-sensitive.
The activities of other silver(I) salts were examined. AgBF4
was also effective to convert propargylamine 1a to allene 2a
with 99% ee and with substrate conversion and product yield
comparable to those of the reaction mediated by AgNO3
(entry 6). AgOTf, Ag(OOCCF3) and Ag(OOCCH3) can
also mediate this transformation with lower product yields
(entries 7–9). AgCl, AgBr and AgI were found to be inactive
under similar conditions (entries 10–12). Since AgNO3 is
non-hygroscopic, air-stable and inexpensive, the protocol with
50 mol% of AgNO3 and reaction time of 24 h under 40 1C was
employed for subsequent studies.
We are attracted to silver(I) compounds that are known to
activate alkynes for nucleophilic attack, and there are many
examples revealing that the chirality of allenes could be
preserved in silver(I)-mediated organic transformations.6 Here
we report a silver(I)-mediated reaction of optically active
propargylamines to form a wide range of axially chiral allenes
with enantiomeric excess values, with the exception of one
example, being 96–99%. To our knowledge, applications of
With the optimized conditions, a variety of axially chiral
allenes were synthesized in high product yields (up to 95%)
and high enantioselectivities (98–99% ee with the exception of
product 2e being obtained in 91% ee). In all cases, no
racemization of the resulting allenes was observed. The results
are listed in Table 2. This protocol allows the synthesis of a
variety of 1,3-diarylallenes having different aryl moieties from
corresponding propargylamines in a stereospecific manner
(entries 1–9).
a Department of Chemistry and Open Laboratory of Chemical Biology
of the Institute of Molecular Technology for Drug Discovery and
Synthesis, The University of Hong Kong, Pokfulam Road,
Hong Kong, China. E-mail: cmche@hku.hk; Fax: +852-2857-1586;
Tel: +852-2859-2154
b Department of Applied Biology and Chemical Technology,
The Hong Kong Polytechnic University, Hung Hom, Kowloon,
Hong Kong, China. E-mail: bcmkwong@inet.polyu.edu.hk;
Fax: +852-2364-9932; Tel: +852-3400-8701
w This article is part of a ChemComm ‘Catalysis in Organic Synthesis’
web-theme issue showcasing high quality research in organic
chemistry. Please see our website (http://www.rsc.org/chemcomm/
organicwebtheme2009) to access the other papers in this issue.
z Electronic supplementary information (ESI) available: Experimental
procedures, compound characterization data and supports for
mechanistic studies. See DOI: 10.1039/b914516h
Scheme 1 Electronic effect on enantiomeric excess of allenes from
gold-catalyzed reaction of optically active propargylamines.
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 213–215 | 213

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Table 1 Conditions for optimization
Table 2 AgNO3-mediated synthesis of axially chiral allenes from
propargylaminesa
Entry
Catalyst
mol%
Conv. (%)a
Yield (%)b
Eec
Conv. Yield ee
(%)c
1
2
3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgBF4
10
30
50
100
50
50
50
50
50
50
50
50
39
55
91
90
50
92
96
96
38
0
90
99
74
73
84
79
61
67
95
—
—
—
98
99
99
98
99
99
99
99
85
—
—
—
Entry Substrate
Product
(%)b
(%)d
4
5d
6
7
8
9
10
11
12
AgOTf
1
2
3
4
5
X = H, 1a
2a
2c
2d
2f
91
68
80
87
71
74
91
78
73
84
99
98
98
99
91
Ag(OOCCF3)
Ag(OOCCH3)
AgCl
AgBr
AgI
X = Br, 1c
X = t-Bu, 1d
X = Me, 1f
X = OMe, 1e
0
0
2e
a
Determined by 1H NMR analysis of the crude reaction mixture.
6
92
75
99
b
c
Isolated yield based on conversion. Determined by HPLC using
d
Chiralcel-OD column. Reaction performed in the presence of light.
Vinylallenes are versatile intermediates for the construction
of organic compounds with complexity through [4+2]
cycloaddition.9 In this work, axially chiral vinylallenes can
be synthesized stereospecifically via silver(I)-mediated trans-
formation of optically active propargylamines bearing an
alkene moiety at a terminal or a position of the alkyne (entries
10–13). As an example, the reaction of propargylamine 1k
bearing a cyclohexenyl group led to vinylallene 2k in 80%
yield with 99% ee (entry 10). However, when KAuCl4 was
used as the catalyst, 2k was obtained with 50% ee under the
same conditions. Propargylamine 1n having a cinnamyl moiety
at the a position of the alkyne gave the corresponding
vinylallene 2n in 74% yield based on 95% conversion and
with 99% ee (entry 13).
7
49
95
98
8
9
86
70
70
61
99
98
10
100
77
80
64
99
99
It is well-known that microwave irradiation can accelerate
transition metal-catalyzed reactions.10 Recently, we reported that
the reaction time of gold-catalyzed hydroamination and hydro-
arylation of alkenes could be significantly shortened by microwave
irradiation.11 In this work, we also investigated microwave-
assisted silver(I)-mediated transformation of propargylamines
to allenes.
11
12
70
95
90
74
98
99
It was found that considerably shorter reaction times
of around 20 min were achieved for the AgNO3-mediated
transformation of propargylamines to allenes, affording
corresponding products in good yields and with excellent
enantioselectivities. The results are depicted in Table 3. As
an example, the reaction of propargylamine 1a mediated by
AgNO3 was completed under microwave irradiation in 20 min,
leading to 2a in 80% yield based on 100% conversion and with
99% ee (entry 1). This protocol is useful for the synthesis
of axially chiral 1,3-alkylarylallenes from corresponding
propargylamines, affording products in high yields (up to
85%) with almost complete chirality transfer (entries 2–5).
In contrast, when using the conventional thermal conditions a
long reaction time was needed, resulting in products in low
yields.4 This protocol under microwave irradition also allowed
the synthesis of 1,3-dialkylallene in high enantioselectivity
(entry 6).
13
a
b
Substrate : AgNO3 = 1 : 0.5, ee of substrates = 99%. Determined by
1H NMR analysis of the crude reaction mixture. Isolated yield based on
c
d
conversion. Determined by HPLC using Chiralcel-OD column.
A proposed reaction mechanism is depicted in Scheme 2.
Silver(I) ion coordinates to the alkyne moiety of the propargyl-
amine to give intermediate I. An intramolecular hydride transfer
converting intermediate I to intermediate II, followed by
b-elimination gives the allene product in a stereospecific manner.
ESI-MS analysis of a reaction mixture of 1a and AgNO3
(50 mol%) after stirring for
1 h in CH3CN at room
temperature showed peaks centered at m/z 398, which is
attributed to the adduct between 1a and silver(I) ion (see
supporting informationz). The isotopic pattern of the adduct
ꢀc
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214 | Chem. Commun., 2010, 46, 213–215

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Table 3 Microwave-assisted AgNO3-mediated synthesis of axially
chiral allenesa
Conv. Yield
(%)b
Entry Substrate
Product
(%)c
ee (%)d
99
1
100
80
Scheme 3 Deuterium-labeling experiment.
2
74
100
65
69
78
85
77
98
96e
97
of the reaction in a much shorter time than that required under
conventional thermal conditions.
We are grateful for the financial support of The University
of Hong Kong (University Development Fund), Hong Kong
Research Grant Council (HKU 7052/07P), and the Areas of
Excellence Scheme established under the University Grants
Committee of the Hong Kong Special Administrative Region,
China (AoE/P-10/01).
3
4
5f
100
63
97
97
Notes and references
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Academic Press, London, 1982; (b) Modern Allene Chemistry,
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6
63
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¨
a
b
Substrate : AgNO3 = 1 : 0.5, ee of substrates = 99%. Determined
by 1H NMR analysis of the crude reaction mixture. Isolated yield
c
d
based on conversion. Unless otherwise specified, determined by
e
HPLC using Chiralcel-OD column. Determined by GC using
f
3 Reviews: (a) A. Hoffmann-Roder and N. Krause, Angew. Chem.,
¨
Int. Ed., 2002, 41, 2933; (b) N. Krause and A. Hoffmann-Roder,
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Cyclodex-b column. Substrate : AgNO3 = 1 : 1.
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N. Krause, Synlett, 2007, 1790; (c) Z. Zhang and
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Scheme 2 Tentative mechanism for silver-mediated synthesis of
´
2008, 108, 3149; (c) M. Alvarez-Corral, M. Munoz-Dorado and
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´ ´
axially chiral allenes from optically active propargylamines.
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is in accordance with the formulation of silver(I)-coordinated
intermediate I.
The reaction of deuterium-labeled propargylamine 1t (79%
deuterium incorporation) in the presence of AgNO3 in
CH3CN under N2 at 40 1C for 24 h gave deuterium-labeled
2t in 79% yield with 79% deuterium incorporation (Scheme 3,
eqn (1)). As no crossover of deuterium was observed in the
allenes by GC-MS analysis of the reaction mixture using a 1 : 1
ratio of 1t and 1u (eqn (2)), the proposed hydride transfer from
I to II could occur in an intramolecular manner.
In summary, we have developed a silver(I)-mediated highly
enantioselective synthesis of a wide range of axially chiral
allenes from optically active propargylamines under mild
conditions. The use of microwave irradiation allows completion
ꢀc
This journal is The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 213–215 | 215