An easily removable stereo-dictating group for enantioselective synthesis of propargylic amines

Article abstract of DOI:10.1039/c3cc45118f

We report herein a CuBr-catalyzed three-component coupling of 2-methylbut-3-yn-2-ol, aldehydes and pyrrolidine or 1,2,3,4- tetrahydroisoquinoline leading to the corresponding chiral propargylamines in excellent enantiomeric excess (91 to >99% ee) and high yields (79-95% yield). The dimethylcarbinol unit in 2-methylbut-3-yn-2-ol, which may be easily removed at the later stage to regenerate a terminal alkyne unit for further elaboration, plays a very important role in ensuring high enantioselectivity. This protocol provides easy and very general access to different terminal and non-terminal tertiary propargylic amines. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc45118f

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An easily removable stereo-dictating group for
enantioselective synthesis of propargylic amines†
Wu Fana and Shengming Ma*ab
Cite this: Chem. Commun., 2013,
49, 10175
Received 8th July 2013,
Accepted 30th August 2013
DOI: 10.1039/c3cc45118f
www.rsc.org/chemcomm
We report herein a CuBr-catalyzed three-component coupling of a catalyst resulting in shortened reaction times with excellent
2-methylbut-3-yn-2-ol, aldehydes and pyrrolidine or 1,2,3,4-tetra- yields (up to 99%) and enantiomeric excesses (up to 99%).7c
hydroisoquinoline leading to the corresponding chiral propargylamines However, alkyl-substituted alkynes afforded propargylic amines
in excellent enantiomeric excess (91 to >99% ee) and high yields with lower ee’s and reaction was also sluggish compared to
(79–95% yield). The dimethylcarbinol unit in 2-methylbut-3-yn-2-ol, aryl-substituted alkynes. Chan and co-workers employed ethyl
which may be easily removed at the later stage to regenerate a glyoxylate instead of an aromatic aldehyde using the CuOTf/
terminal alkyne unit for further elaboration, plays a very important Pybox-type ligand as a catalyst to prepare b,g-alkynyl a-amino acid
role in ensuring high enantioselectivity. This protocol provides easy ethyl esters in good yields (61–80%) and enantiomeric excesses
and very general access to different terminal and non-terminal (66–74%).7d Recently, Nakamura and co-workers employed bis-
tertiary propargylic amines.
(oxazolinyl)pyridine instead of the bis(imidazoline)pyridine
ligand. Improved yields and enantiomeric excesses (81–98%) were
Optically active propargylic amines are important building blocks obtained with aliphatic alkynes under CuOTf/pybim-catalyzed
for synthesis of biologically active materials,1 pharmaceuticals,2 conditions as compared to the earlier report by Li,7b yet with too
natural products,3 plant pesticides,4 etc.5 Many synthetic methods long reaction time.7e However, the asymmetric three-component
have been developed for preparing these useful intermediates.6 reaction with aliphatic aldehydes for preparing secondary
Among them, the copper-catalyzed asymmetric one-pot three- propargylic amines remains unsolved, probably due to the
component reaction of easily available aldehydes, alkynes and low steric hindrance and oligomerization side reaction.
amines became one of the most widely used tools since it is atom
For tertiary propargylic amines, Knochel and co-workers
economic and efficient as compared to the classical stepwise described a CuBr/Quinap-catalyzed asymmetric three-component
synthetic routes. For the syntheses of secondary propargylic coupling of secondary amines with good yields (43–99%) and
amines, the first asymmetric three-component coupling of alde- enantioselectivities (32–96% ee) in 1–6 days.7f Trimethylsilylacetylene
hydes, alkynes and amines was described by Li in 2002.7a The was observed to show highest enantioselectivities.7f–l Unfortunately,
reaction with aromatic aldehydes, anilines and phenyl acetylene however, the enantioselectivity of reactions using aromatic
could perform well in both toluene and water using a Cu(I) complex aldehydes is largely inferior to ee values in the range of 32–82%.
of pyridyl-bisoxazoline, leading to the corresponding propargylic Carreira and co-workers developed an atropisomeric P,N ligand
amines in up to 93% yield and 78–96% ee, and the reaction is (N-Pinap), for the same reaction described by Knochel,7f generally
slow (2–4 days). Later the catalytic system was extended to affording products with higher ee values.7m Next, the same
various aliphatic alkynes with lower enantioselectivity.7b Singh reaction was conducted using 4-piperidinone hydrochloride
and co-workers further optimized the enantioselectivities of hydrate instead of dibenzylamine, and the resulting propargylic
these coupling reactions by employing iPr-pybox-diPh-CuPF6 as amines were obtained in good yields with up to 95% ee.7n
However, the use of aromatic aldehydes, i.e., benzaldehyde, did
not give satisfactory results providing the desired product in
only 22% yield. Therefore, the development of such a catalytic
asymmetric three-component reaction with a very general scope
is still highly desirable. Herein, we wish to report a CuBr-
catalyzed highly enantioselective three-component reaction of
aromatic and aliphatic aldehydes, amines and alkynes using
(R,R)-N-Pinap as the ligand,7m pyrrolidine or 1,2,3,4-tetrahydro-
isoquinoline as the secondary amine, and 2-hydroxy-2-propyl as
a Shanghai Key Laboratory of Green Chemistry and Chemical Process,
Department of Chemistry East, China Normal University,
3663 North Zhongshan Road, Shanghai 200062, P. R. China.
E-mail: masm@sioc.ac.cn; Fax: +86-21-6260-9305
b State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, P. R. China
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc45118f
c
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Chem. Commun., 2013, 49, 10175--10177 10175

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the enantioselectivity-dictating group for preparing the corre-
sponding highly optically active tertiary propargylic amines.
At the beginning, based on our recent observation,5c we
chose pyrrolidine as the amine to ensure a fast reaction and
envisioned that a sterically bulky yet easily removable R group
of the alkyne for such a reaction will be crucial (eqn (1),
Scheme 1).7f,l After some trials, commercially available and
cheap 2-methylbut-3-yn-2-ol 1a was identified. Then we examined
the reaction of benzaldehyde, pyrrolidine, 1a and 4 Å MS in
toluene with various Cu(I) catalysts of chiral ligands such as
Cu(I)-Pybox, Cu(I)-Quinap and Cu(I)-Pinap. Fortunately, we were
pleased to find that the desired product 4aa was obtained in
93% yield with 98% ee using 5 mol% of CuBr and 5.5 mol% of
(R,R)-N-Pinap 3 within 19 h (eqn (2), Scheme 1).
Scheme 2 Coupling with other amines.
(99% ee, Table 1, entry 7). Then various aliphatic aldehydes were
tested: linear alkyl-substituted aldehydes afforded the corre-
sponding propargylic amines 4ah–4aj in good yield (89–95%) and
excellent enantioselectivity (98 to >99% ee, Table 1, entries 8–10);
aldehydes containing an i-alkyl or a cyclic substituent also provided
the desired products 4ak–4am with similar results (91–95% yield,
98 to >99% ee, Table 1, entries 11–13).
In addition, 1,2,3,4-tetrahydroisoquinoline, which often
showed a low reactivity,8 could also perform well affording the
corresponding propargylic amine in 96% ee (eqn (1), Scheme 2),
which may be used for the synthesis of allene at a much lower
temperature.9 However, p-methoxyaniline, as a primary amine,
reacted with the benzaldehyde and 2-methybut-3-yn-2-ol only
giving N-benzylidene-4-methoxyaniline (eqn (2), Scheme 2).
In order to demonstrate the role of the 2-hydroxy-2-propyl
group, control experiments were performed to show that a
dramatic decrease in selectivity was observed when primary
proparyl alcohol 1b was used (Table 2, entry 2); even with
trimethylsilylacetylene, which was reported to give the chiral
propargylic amines with highest enantioselectivities in
the presence of copper-chiral ligands such as quinap7f,k and
N-pinap,7l,m the corresponding propargylic amine 4cm was
obtained only in 91% ee under the current optimized reaction
conditions with pyrrolidine (Table 2, entry 3). Here the possible
coordination of the hydroxyl oxygen with Cu may be respon-
sible for the enantioselectivity observed.
Scheme 1 The initial proposal and trial.
The scope of aldehydes is quite general: the presence of
either an electron-withdrawing or an electron-donating substi-
tuent in the para or the meta position of the benzaldehyde has
almost no influence on the enantioselectivity of the reaction
(Table 1, entries 2–5). Furthermore, the presence of an ortho
substituent such as a methyl group in the benzaldehyde gave
rise to the corresponding propargylic amine 4af in slightly
lower yet high ee (Table 1, entry 6). Heterocyclic aldehyde
such as 2-furaldehyde also gave an excellent enantioselectivity
Table 1 Three-component coupling using tertiary proparylic alcohol 1a and
pyrrolidinea
Table 2 Effects of substituent R in the terminal alkynesa
Entry
R1
Time (h)
Yield of 4b (%)
eec (%)
1
2
3
4
5
6
7
8
Ph (2a)
19
22
22
22
19
21
28
20
20
20
20
23
14
93 (4aa)
90 (4ab)
88 (4ac)
80 (4ad)
95 (4ae)
84 (4af)
79 (4ag)
89 (4ah)
95 (4ai)
89 (4aj)
91 (4ak)
92 (4al)
95 (4am)
98
98
98
98
99
91
99
99
499
98
p-BrC6H4 (2b)
p-ClC6H4 (2c)
p-BnOC6H4 (2d)
m-MeC6H4 (2e)
o-MeC6H4 (2f)
2-Furyl (2g)
n-Bu (2h)
n-C6H13 (2i)
n-C7H15 (2j)
i-Pr (2k)
Entry
1
Time (h)
14
Yield of 4b (%)
eec (%)
98
Alkyne R
4am
95
9
2
4bm
4cm
22
24
90
89
84
10
11
12
13
499
Z99
98
3
91d
i-Bu (2l)
c-Hex (2m)
a
b
a
b
The reactions were carried out on the 2.0 mmol scale of 1a. Isolated
The reactions were carried out on the 2.0 mmol scale of 1. Isolated
c d
c
yield. Determined by HPLC.
yield. Determined by HPLC. Determined after transformation to 6.
c
10176 Chem. Commun., 2013, 49, 10175--10177
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The reaction may be easily conducted on a gram scale of of China (2009CB825300) is greatly appreciated. We thank
substrate 1a using aldehyde 2m. After removal of Cu(I) by simple Qiankun Li in this group for reproducing the results of the
filtration, the 2-hydroxy-2-propyl group in 4am was easily removed preparation of 4af, 4ai in Table 1 and 4bm in Scheme 3.
by its treatment with 3 equivalents of NaOH in refluxing toluene10
affording terminal propargylic amine 5 in 77% combined yield
Notes and references
starting from 1a. Sonogashira cross-coupling11a,b of 5 with aryl
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Scheme 3 The gram-scale reaction of 1a with 2m and transformations of
propargylic amine 5.
In summary, we have developed a highly enantioselective
general synthesis of chiral propargylic amines using 2-methybut-
3-yn-2-ol, a variety of different aldehydes and pyrrolidine in the
presence of CuBr and the (R,R)-N-Pinap ligand. The tertiary
alcohol unit in the terminal alkyne plays a unique role in
ensuring high enantioselectivities. Following a facile fragmenta-
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propargylic amines obtained could be further functionalized to
give the corresponding propargylic amine derivatives in good
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Financial support from the National Natural Science Founda-
tion of China (21232006) and the National Basic Research Program
2001, 3, 2883.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 10175--10177 10177