Kinetic resolution of propargylamines via a highly enantioselective non-enzymatic N-acylation process

Article abstract of DOI:10.1039/c2cc35719d

The non-enzymatic kinetic resolution of diversely substituted primary propargylic amines is reported featuring a highly selective acetyl transfer using (1S,2S)-1 in conjunction with Aliquat^TM 336, affording the corresponding enantio-enriched N-

Full text of DOI:10.1039/c2cc35719d

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Kinetic Resolution of Propargylamines via a Highly Enantioselective
Non-enzymatic N-Acylation Process†
Amandine Kolleth, Sarah Christoph, Stellios Arseniyadis,* and Janine Cossy*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
The non-enzymatic kinetic resolution of diversely substituted
primary propargylic amines is reported featuring a highly selective
acetyl transfer using (1S,2S)-1 in conjunction with AliquatTM 336,
affording the corresponding enantio-enriched N-acetylated
Table 1. Evaluation of the reaction parametersa
10 propargylic amines with unprecedented levels of selectivity (s-factors
up to 193 at 50% conversion).
50
ee (%)b
without AliquatTM 336 with AliquatTM 336
Enantioꢀenriched propargylic amines are particularly useful
building blocks in synthetic organic chemistry finding use in the
preparation of various nitrogenꢀcontaining compounds such as
15 allylamines and pyrrolidines.1 In addition, they are also valuable
intermediates in the synthesis of complex natural products2 as
well as several pharmaceuticals3 and agrochemicals.4 In this
context, a number of synthetic tools have been developed to
access this specific structural motif. These methods generally
20 involve the enantioselective addition of alkyne nucleophiles to
imines and afford the corresponding enantioꢀenriched secondary
amines.5 Another practical approach to optically active
propargylic amines consists of the kinetic resolution (KR) of the
corresponding racemic amines. In this field however, only one
25 example has to the best of our knowledge been reported so far.6
The strategy is based on a particularly elegant dual catalytic
approach involving a chiral thioureaꢀacylpyridinium catalyst
which affords the KR of primary propargylic amines with
sꢀfactors7 up to 56 at –78 °C.
Entry Solvent
1
2
3
4
5
6
7
8
9
THF
46 (Rc)
51 (R)
46 (R)
36 (R)
32 (R)
38 (R)
37 (R)
74 (S)
76 (S)
85 (S) [91d (S)]
80 (S)
Cyclohexane
Toluene
81 (S)
Dioxane
73 (S)
α,α,αꢀTrifluorotoluene
CH2Cl2
77 (S)
80 (S)
CHCl3
61 (S)
NMP
76 (S)
DMPU
78 (S)
a All reactions were carried out on a 0.25 mmol scale using 0.5 equiv of
b
(1S,2S)ꢀ1 at rt with or without AliquatTM 336 [0.7M]. Enantiomeric
c
excess of compound 3a determined by chiral SFC analysis. Absolute
d
configuration of the major enantiomer.
Reaction run at –20 °C.
55 AliquatTM 336 = trioctylmethylammonium chloride. DMPU=1,3ꢀdimetylꢀ
3,4,5,6ꢀtetrahydroꢀ2(1H)ꢀpyrimidinone. NMP = Nꢀmethylꢀ2ꢀpyrrolidone.
30
Interestingly, since the pioneering work of Murakami et al.,8
the development of effective nonꢀenzymatic processes for the KR
of racemic amines has become the focus of tremendous work,9
mostly from the groups of Fu,10 Mioskowski,11 Krasnov12 and,
more recently, by Birman,13 Miller,14 Bode15 and Seidel.6,16,17 In
useful levels of selectivity at room temperature (sꢀfactors
up to 12).11c
In this paper, we wish to report a new benchmark in the KR of
60 primary propargylic amines using (1S,2S)ꢀ1.
On the basis of the previous results,11a we decided to initiate
our study by screening various solvents at room temperature
using (±)ꢀmethylꢀ3ꢀphenylꢀpropꢀ2ꢀynylamine 2a as a model
substrate. The results of this survey are summarized in Table 1.
As expected, a solventꢀinduced reversal of selectivity was
observed when switching from solvents such as THF,
cyclohexane, toluene, dioxane, trifluorotoluene, dichloromethane
or chloroform (Table 1, entries 1ꢀ7) to solvents exhibiting a
higher relative permittivity such as NMP and DMPU (Table 1,
70 entries 8 and 9). Interestingly, we also observed a particularly
important salt effect similar to the one witnessed when
performing the KR of primary benzylic amines, leading to an
increase in both reactivity and selectivity in conjunction with a
reversal of the overall stereoselectivity. Hence, by performing the
35 this context, Arseniyadis, Mioskowski and coꢀworkers
established that (1S,2S)ꢀNꢀacetylꢀ1,2ꢀbisꢀtrifluoromethanesulfonꢀ
amidocyclohexane (1S,2S)ꢀ1 could be used as a highly selective
acetylating agent for the KR of primary benzylic amines
affording the corresponding acetamides with up to 84% ee at
40 room temperature (sꢀfactor up to 30 at 50% conv.) and displaying
65
a
unique solventꢀinduced reversal of stereoselectivity.11a
Following these initial results, a spectacular salt effect was also
reported, allowing to increase both the reactivity and the
selectivity of the reagent an afford the KR of primary benzylic
45 amines with sꢀfactors up to 115 (up to 94% ee at –20 °C and 50%
conv.).11b Finally, a fully recyclable and particularly effective
solidꢀsupported version of the reagent was developed capable of
resolving primary benzylicꢀ and homobenzylic amines with
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reaction in the presence of AliquatTM 336 under otherwise
identical conditions, we were able to isolate acetamide 3a in
quantitative yield and 85% ee (s = 33, Table 1, entry 1).
Optimizing the reaction conditions by simply reducing the
temperature to −20 °C produced an additional increase in
selectivity affording the desired acetamide in 91% ee (s = 67,
Table 1, entry 1) which compared favourably with the result
obtained by Seidel et al. (s = 39 at 48% conv.) on the same
substrate.6
5
10
With this set of conditions in hand, we next examined the
scope and limitations of the reaction (Scheme 1). A number of
racemic propargylic amines were therefore prepared and resolved
under our optimized conditions [(1S,2S)ꢀ1 (0.5 equiv),
AliquatTM 336 (0.7M in THF) at −20 °C] affording the
15 corresponding acetamides with good to excellent selectivities.
Hence, whereas an exchange of the methyl for an ethyl in the
parent substrate led to a small increase in selectivity from s = 67
to s = 79, substrates bearing a bulkier substituent such as an
isopropyl (2c, s = 58), an isobutyl (2d, s = 51) or a benzyl (2e,
20 s = 33) were resolved with slightly lower s-factors. Aryl
propargylic amines bearing substituents on different positions
(2i-n) of the aryl ring were also effectively resolved regardless of
the electronic nature of the substituents on the aromatic ring
(s-factors ranging from 45 to 94) and with pꢀmethoxyꢀsubstituted
25 arylpropargylic amine 3j giving rise to the highest selectivity
(s = 94). Remarkably, introducing the propargylamine on either
the C1ꢀ (2g) or the C2ꢀposition (2h) of a naphthalene ring had a
profound impact on the selectivity as sꢀfactors ranged from s = 13
(C1: 73% ee at 50% conv.) to s = 193 (C2: 96% ee at 50% conv.).
30 In addition, substrates with extended πꢀsystems such as enyne 2p
or heteroaryl propargylic amines such as 2o were also effectively
resolved with sꢀfactors of 45 and 67, respectively. Finally,
propargylic amines with two aliphatic residues such as
compounds 2q and 2r proved to be viable substrates as well, as
35 the corresponding acetamides were obtained in 90% ee (s = 49 at
48% conv.) and 91% ee (s = 78 at 51% conv.), respectively.
Unfortunately, our system was not capable of distinguishing
between two different πꢀsystems, as exemplified by the resolution
of substrate 2f. Indeed, the corresponding acetamide 3f was
40 obtained in only 7% ee (s = 1) albeit in quantitative yield. Our
concern was that the enantioꢀenriched product could undergo
epimerization under the reaction conditions or during the
purification step. We therefore ran a few control experiments to
test for this possibility. The enantioꢀenriched acetamide 3f was
45 thus reꢀsubjected to the same reaction conditions, but no
racemization could be detected even after stirring for 48 h at
temperatures ranging from +20 °C to +60 °C. Compound 3f was
also exposed to (1S,2S)ꢀ1,2ꢀbisꢀtrifluoromethanesulfonamidoꢀ
cyclohexane, which is the byꢀproduct formed during the reaction,
50 but once again no erosion of the ee was observed. Likewise,
treating 3f with silica gel did not modify the ee thus indicating the
considerable configurational stability of the product and therefore
confirming the lack of selectivity of our reagent in front of such
compounds.
60 Scheme 1. Scope and limitations of the reaction
The synthesis began with the benzylation of 3ꢀbutynꢀ1ꢀol 4
under standard conditions (BnBr, NaH, DMF, 0 °C) (Scheme 2).
The corresponding benzyl ether was then treated with n-BuLi and
the resulting propargyl lithium species was added to butanal to
65 afford propargyl alcohol 5 as a racemic mixture in 78% overall
yield. The latter was then engaged in a twoꢀstep sequence
featuring a Mitsunobu reaction with phthalimide (DEAD, PPh3,
THF, rt) followed by a hydrazineꢀmediated cleavage to afford the
corresponding propargyl amine 6 in 62% yield over two steps.
70 The resulting propargyl amine was eventually engaged in the KR
process under our optimized conditions [(1S,2S)ꢀ1 (0.5 equiv),
AliquatTM 336 (0.7M in THF) at −20 °C] to afford the
corresponding acetamide 7 in 94% ee and 50% yield. Reduction
of the alkyne moiety concomitantly with the cleavage of the
75 benzyl ether was possible under hydrogenation conditions (H2,
Pd/C, EtOH, rt), affording the corresponding hydroxyamide 8 in
quantitative yield. Tosylation of the primary alcohol (TsCl, Et3N,
DMAP, CH2Cl2, rt) followed by ringꢀclosure through
a
nucleophilic substitution (NaH, THF, 0 °C) finally afforded the
80 piperidine ring. To facilitate productꢀisolation due to the inherent
volatility of coniine, and considering the fact that N-acetyl
coniine had already been reported in the literature,19 we decided
to stop the synthesis at this stage. Gratifyingly, the spectroscopic
and physical data of 9 were identical with those reported in the
55
In order to confirm the absolute configuration of the acetylated
product obtained through the KR process and also demonstrate
the synthetic utility of this method, we undertook the synthesis of
coniine,18,19 a toxic alkaloid present in poison hemlock.
85 literature for N-acetyl (S)ꢀconiine {[α]20 +46.0 (c 0.65, CHCl3);
D
lit. [α]22 +46.9 (c 0.4, CHCl3)}19b confirming that under our
D
optimized conditions (1S,2S)ꢀ1 reacts preferentially on the
2
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55
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60
65
Scheme 2. Application of the KR to the synthesis of N-acetyl (S)ꢀ
coniine 9.
6
7
70
75
S-enantiomer, which is consistent with the results previously
obtained in the KR of primary benzylic amines.11
In summary, we have described a highly selective process for
the KR of propargylic amines. The reaction itself is operationally
simple, proceeds under mild conditions and affords enantioꢀ
enriched propargylic amines with unprecedented levels of
10 selectivity (sꢀfactor up to 193) setting a new benchmarck in the
field of nonꢀenzymatic amine KR. Further applications of this
method are currently under investigation and will be reported in
due course.
This communication is dedicated to the memory of Dr. Charles
15 Mioskowski.
5
8
9
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80
85
Notes and references
Laboratoire de Chimie Organique, ESPCI ParisTech, CNRS, 10 rue
Vauquelin, 75231 Paris Cedex 05, France. Fax: +33 (0)1 40 79 46 60;
Tel: +33 (0)1 40 79 46 62; E-mail: stellios.arseniyadis@espci.fr;
20 E-mail: janine.cossy@espci.fr
† Electronic Supplementary Information (ESI) available: [details of
experimental procedures and 1H NMR, 13C NMR spectra for all new
compounds. This material is available free of charge via the internet at
http://pubs.rsc.org]. See DOI: 10.1039/b000000x/
90
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Abstract
COMMUNICATION
The nonꢀenzymatic kinetic resolution of diversely substituted primary propargylic amines is reported featuring a highly selective acetyl transfer using
(1S,2S)ꢀ1 in conjunction with AliquatTM 336, affording the corresponding enantioꢀenriched Nꢀacetylated propargylic amines with unprecedented
levels of selectivity (sꢀfactors up to 193 at 50% conversion).
5
O
O
S
CF3
NH
(1S,2S)-1
(1S,2S)-1
O
NHAc
R2
NH2
R2
NHAc
R2
(0.5 molar equiv.)
(0.5 molar equiv.)
N
S
CF3
THF, RT
THF/AliquatTM 336
–20 °C
O
O
R1
up to 46% ee (R)
R1
R1
up to 96% ee (S)
racemic
(1S,2S)-1
50% conversion in 1-3 hours at room temperature
up to 96% ee (S) in a THF/AliquatTM 336 mixture using 0.5 equiv. of (1S,2S)-1 at –20 °C
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 4