Diastereoselective synthesis of propargylic N-hydroxylamines via NHC-copper(I) halide-catalyzed reaction of terminal alkynes with chiral nitrones on water

Article abstract of DOI:10.1039/c4cc08742a

The first NHC-copper(I)-halide catalyzed addition of terminal alkynes to enantiomerically pure nitrones on water is described. This reaction provides a straightforward access to propargylic N-hydroxylamines in excellent yield and with excellent stereoselectivity (up to 97%). The presented methodology was applied as a key step in the formal synthesis of (-)-lentiginosine.

Full text of DOI:10.1039/c4cc08742a

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Diastereoselective synthesis of propargylic
N-hydroxylamines via NHC–copper(I)
halide-catalyzed reaction of terminal alkynes
with chiral nitrones on water†
Cite this:DOI: 10.1039/c4cc08742a
Received 3rd November 2014,
Accepted 10th December 2014
Ł. Wozniak, O. Staszewska-Krajewska and M. Michalak*
´
DOI: 10.1039/c4cc08742a
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The first NHC–copper(I)-halide catalyzed addition of terminal
alkynes to enantiomerically pure nitrones on water is described.
This reaction provides a straightforward access to propargylic
N-hydroxylamines in excellent yield and with excellent stereo-
selectivity (up to 97%). The presented methodology was applied
as a key step in the formal synthesis of (ꢀ)-lentiginosine.
The discovery of new catalytic reactions leading to C–C bond
formation as a result of addition to CQO or CQN bonds is of
high importance for the development of efficient methods in Scheme 1 Metal salts used in the alkynylation of nitrone.
organic synthesis.1 A direct stereoselective addition of acety-
lides to the carbonyl or imine2 group would enable the synth-
esis of propargylic alcohols and amines which serve as versatile case of indium salts) and, often, a stoichiometric amount of the
building blocks.3
organometallic reagent is required. On the other hand, it is well
In this respect, the synthesis of propargylic N-hydroxyl- documented that copper acetylides are not sensitive towards
amines in an asymmetric fashion is seldom reported.4 This water, enabling the development of a catalytic process in this
class of propargylic amine derivatives represents an important environmentally benign solvent.14 The most impressive examples
organic scaffold.5 They are easily transformed by exhaustive/ of their utility include widely used alkyne–azide cycloaddition.15
partial reduction into respective amines, allylamines6 or pro-
To the best of our knowledge, copper(I) salts and complexes of
pargylamines,4b b-amino ketones7 or b-amino alcohols7 and copper(I) have not been investigated so far in the alkynylation of
used in subsequent transformations, such as cyclization to 2,3- nitrones, probably due to their low reactivity.11 Herein, we wish
dihydrooxazoles,8 aziridines,9 and lactams4d or rearrangement to report an unprecedented NHC–copper(I) complex-promoted
to b-enaminones.10
reaction between enantiomerically pure nitrones and terminal
Usually, a stoichiometric amount of moisture-sensitive alkynes under mild reaction conditions on water (Scheme 2).
lithium4b–g or magnesium4a compounds has to be used in the
To probe the influence of solvent and catalyst structure on
addition (Scheme 1). Among other metals able to catalyze the the course of the addition reaction, tartaric acid-derived nitrone
addition of terminal alkynes to nitrones, zinc is the most widely 1a and phenylacetylene 2a were selected as model substrates
used in the form of a salt such as Zn(OTf)2/Et3N,11,4h ZnCl2/ (Table 1).
Et3N,4j or Me2Zn.12,4i Direct addition of the respective indi-
When phenylacetylene (2a) was mixed with 2 mol% of
um4n,13 and aluminum4m acetylides has also been reported. SIPrCuCl in the presence of triethylamine, within a second’s
All of the above mentioned methods suffer from the need to time a yellow solid of copper acetylide has formed, which was
protect the reaction mixture from moisture (especially in the allowed to react with nitrone 1a for 16 h.‡ To our dismay, no
product was detected in common organic solvents while the use
of DMF or MeOH led to desired propargylic N-hydroxylamine 3a
in low yield (Table 1, entries 2 and 3). To our delight, the best
result was achieved when water was used as the reaction medium
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52,
01-224 Warsaw, Poland. E-mail: michal.michalak@icho.edu.pl
† Electronic supplementary information (ESI) available: Detailed synthetic
(Table 1, entry 4). The expected product 3a was isolated as a
single diastereomer in 81% yield.
procedures, full characterization data and copies of NMR spectra for all com-
pounds. See DOI: 10.1039/c4cc08742a
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Table 2 Catalyst screening
Scheme 2 Possible reactivity pathways of copper acetylides in the reac-
tion with nitrones.
Table 1 Screening of solvent
Entry
Catalyst (5 mol%)
Yielda (%)
1
2
3
4
5
6
CuI, CuBr, CuCl or Ph3PCuI
IMesCuCl
IMesCuBr
SIMesCuCl
IMesCuBr
IPrCuCl
N.R.
85
82
86
86
Entry
1
Solvent
Yielda (%)
N.R.
81
7
8
IPrCuBr
IPrCuI
76
63
DCM, DMSO, hexane, MTBE,
MeCN, pyridine, neat
9
SIPrCuCl
SIPrCuBr
SIPrCuI
[IPr]2CuPF6
SIPrAgCl
85
91
2
3
4
DMF
MeOH
Water
16
26
81
10
11
12
13
14
96(97b)
N.R.
58
a
Isolated yield.
IPrAuCl
25
a
b
Isolated yield. 1 mol% of SIPrCuI was used, 48 h; N.R. – no reaction.
It should be noted that the reaction conducted in the
presence of a catalytic amount of copper(I) halide and Et3N,
or without any copper source in the presence of a base or NHC analogs was more effective, where SIPrCuI appeared to be the
salt, did not afford the desired product, unambiguously con- catalyst of choice, enabling the isolation of propargylic N-hydroxyl-
firming the unique effect of water as a solvent in combination amine 3a in a virtually quantitative yield (Table 1, entry 11). The
with the NHC–copper(I) catalyst. The relative configuration desired propargylic N-hydroxylamine 3a can be obtained by using
of the newly formed stereogenic centre of product 3a was 1 mol% SIPrCuI, although the reaction time has to be extended to
confirmed by extensive NMR studies (see ESI†).
48 h (Table 2, entry 8) to maintain a high 97% yield.
It should be pointed out that this is an unprecedented
Notably, further screening of complexes revealed that silver
behaviour of copper(I) acetylide in the reaction with nitrones. and gold NHC complexes are not preparatively attractive as the
Usually, copper(I) halides and complexes of copper(I) act as expected adducts were isolated in lower yield in comparison to
catalysts in Cu(I)-catalyzed Kinugasa reaction between nitrones the case with copper(I) complexes (Table 2, entries 9 vs. 13 and
and terminal alkynes, leading to the b-lactam core (Scheme 2).16 6 vs. 14). Surprisingly, the ionic complex [IPr]2CuPF6 was also
Combining the copper source with the strong s-donor and weak ineffective in this reaction.
p-acceptor NHC ligand (in contrast to phosphine ligands exhibiting
With the optimized conditions in hand, we explored the
strong s-donor and strong p-acceptor properties) results in an substrate scope of nitrones and acetylenes. In order to determine
increase of the nucleophilicity of the acetylide.17 Additional steric the influence of the electronic nature of the alkyne, nitrone 1b
shielding of the metal center by the NHC carbene ligand favors the was chosen as the model substrate (Scheme 3). In the reaction
addition pathway over the dipolar cycloaddition giving exclusively with phenylacetylene and its derivatives, propargylic N-hydroxyl-
the N-hydroxylamine derivative instead of b-lactam.
amines 3b–3e were obtained in high yield (490%). The yield was
This unprecedented reactivity led us to examine the influence slightly decreased to 73% in the reaction with a phenylacetylene
of the electronic and steric nature of the NHC carbene–copper(I) derivative bearing a dimethylamine group in the para position.
complex in more detail. Initially, we were pleased to find that Comparable results were obtained applying a thiophene deriva-
copper(I) complexes bearing IMes or SIMes carbene ligands also tive, providing N-hydroxylamine 3g in 85% yield, whereas
catalyze the addition, providing the product in a good 82–86% sulfonyl-protected 4-hydroxyphenylacetylene and 4-nitrophenyl-
yield (Table 2, entries 2–5). In the series of the more hindered acetylene did not afford the expected product 3, probably due to
unsaturated IPr complexes, the yield of the reaction could be the strong chelation of the copper centre.
improved from 63% to 81% by changing the counterion from
Next, the scope of alkyne substrates was extended to those
iodide to chloride (Table 2, entry 6). The family of saturated bearing an alkyl substituent. When hex-1-yne was reacted with
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Scheme 3 The scope of alkynes.
Scheme 5 (a) 8 (2 eq.), 10 mol% SIPrCuI, H2O (0.2 M), 50 1C, 16 h, 66%,
dr = 9.2 : 1; (b) 5 mol% Pd/C, H2 (60 bar), EtOH, 16 h; (c) PPh3 (polymer
a
supported), CCl4, DCM, 16 h, 65% (two steps); diastereomer ratio was
nitrone 1b under optimized conditions (5 mol% SIPrCuI, 1 eq.
of Et3N–water), propargylic N-hydroxylamine 3h was isolated in
49% yield after 16 h at rt. The lower reactivity of hex-1-yne can
be correlated to its lower acidity relative to phenylacetylene. As
we anticipated, exchanging Et3N for the more basic N,N,N0,N0-
tetramethylguanidine (TMG) allowed to increase the yield up to
82%. The same conditions appeared to be suitable for reactions
of other alkynes (Scheme 4, product 3i–l).
Further investigation was directed to establish the influence
of the structure of the nitrone on the reaction’s outcome. To
our delight, cyclic nitrones provided respective propargylic
N-hydroxylamines 3k–m in high yield (Scheme 4). The level of
1,2- or 1,3-stereoinduction was high, allowing to isolate adducts
determined by 1H NMR, see ESI,† b diastereomer ratio was not determined.
3h–m with a diastereomer ratio of more than 95 : 5. Equally
excellent results in terms of yield and stereoselectivity were
achieved in the case of an acyclic glyceric aldehyde–derived
nitrone (Scheme 4, 3n).
Having recognized nitrone 1a as a convenient precursor of
(ꢀ)-lengitinosine (7) (Scheme 5), an indolizidine alkaloid exhi-
biting amyloglucosidase inhibition activity,18 we proceeded to
utilize it in a formal synthesis of the compound. The synthetic
sequence involved the addition of a protected homopropargyl
alcohol, one-step multi-site reduction and cyclisation.
An attempt at the addition of a homopropargylic alcohol,
also protected as a tosyl ester or silyl ether, failed. However,
when a benzyl-protected alcohol was used, the product was
isolated in 66% yield under optimized conditions as a mixture
of diastereomers in the ratio of 89 : 11 (2 eq. of 8, 10 mol%
SIPrCuI, H2O, 50 1C, 16 h, see ESI†). Next, N-hydroxyl propar-
gylamine 4 was subjected to hydrogenolysis to reduce the triple
bond, and simultaneously to deprotect the amine and hydroxyl
functions. The resulting alcohol 5 underwent a spontaneous
cyclisation to the indolizidone skeleton 6 when subjected to
Appel’s conditions. To omit the tedious separation of the
product from the triphenylphosphine oxide byproduct, PPh3
supported on a Merrifield resin was used. The key azabicyclic
intermediate 6 was synthesized in three steps in excellent 43%
overall yield, starting from nitrone 1a, thus completing the
formal synthesis of (ꢀ)-lengitinosine.
In conclusion, we have developed the first case of addition of
terminal acetylenes to enantiomerically pure nitrones on water.
The above-mentioned transformation is catalyzed by well-
defined NHC–copper(I) halide complexes, affording the respec-
tive adducts with high diastereoselectivity and good to excellent
yield. The described approach opens an easy access to highly
functionalized propargylic N-hydroxylamine in an experimentally
simple and practical manner, complementing the existing
methods. The developed methodology was applied in the formal
a
b
Scheme 4 The scope of nitrones;
1 eq. of TMG,
1 eq. of Et3N,
diastereomer ratio was estimated based on HPLC or 1H NMR, see ESI;†
single diastereomer formed, configuration was not determined; TMG –
c
d
N0,N0,N,N-tetramethylguanidine.
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‡ Representative procedure: To a solution of nitrone 1a (229.3 mg,
1.0 mmol) in degassed water (5 mL), PhCRCH (130 mL, 1.2 mmol),
SIPrCuI (29.1 mg, 0.05 mmol, 5 mol%) and Et3N (130 mL, 1.0 mmol) were
added sequentially and the biphasic mixture was stirred for 16 h at rt. The
reaction mixture was diluted with EtOAc (15 mL), and the aqueous phase
was separated and extracted with EtOAc (2 ꢁ 10 mL). The combined
organic extracts were washed with brine (1 ꢁ 20 mL), dried over Na2SO4,
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´
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;
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3.95 (m, 1H), 3.73 (br s, 1H), 3.23–3.17 (m, 2H), 1.26 (s, 9H), 1.18 (s, 9H);
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77.2, 77.0, 76.8, 76.0, 74.6, 74.0, 66.4, 62.9, 28.8, 28.5; HRMS (ESI) m/z calcd
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