Copper-catalyzed amine-alkyne-alkyne addition reaction: An efficient method for the synthesis of γ,δ-alkynyl-β-amino acid derivatives

Article abstract of DOI:10.1002/chem.200901416

A simple and efficient method for the synthesis of γ,δ-alkynyl- β-amino acid derivatives by a copper-catalyzed three-component amine-alkyne-alkyne addition reaction was developed. Various γ,δ-alkynyl-βamino acid derivatives were synthesized in moderate to

Full text of DOI:10.1002/chem.200901416

DOI: 10.1002/chem.200901416
Copper-Catalyzed Amine–Alkyne–Alkyne Addition Reaction: An Efficient
Method For the Synthesis of g,d-Alkynyl-b-amino Acid Derivatives
Lei Zhou,[a, b] Qi Shuai,[a] Huan-feng Jiang,*[b] and Chao-Jun Li*[a]
Abstract:
method for the synthesis of g,d-alkyn-
yl-b-amino acid derivatives by
copper-catalyzed three-component
amine–alkyne–alkyne addition reaction
was developed. Various g,d-alkynyl-b-
amino acid derivatives were synthe-
sized in moderate to good yields in one
A
simple and efficient
step. With chiral prolinol derivatives
employed as the amine component, ex-
cellent diastereoselectivities (up to
>99:1 diastereomeric ratio (dr)) were
obtained. The scope of the reaction
and further transformations of the re-
sulting amino acid derivatives, such as
deprotection and cyclization are also
described.
a
Keywords: alkynes · amines · ami-
no esters · copper · multicomponent
reactions
Introduction
change the biological properties of some natural amino
acids, but are also the key intermediates of certain designed
drugs, such as Xemilofiban and SC-54701, which are platelet
aggregation inhibitors that can prevent ischemia, heart at-
tacks, and other major adverse cardiac events, (Scheme 1).[8]
Multicomponent reactions are among the most efficient syn-
thetic methods for the construction of organic molecules.[1]
À
À
The ability to form two or more C C and/or C heteroatom
bonds with high levels of stereocontrol and in a single oper-
ation is highly desirable in synthetic chemistry. Such reac-
tions provide the potential methods for the construction of
complex molecular architectures from simple precursors
with high atom economy[2] and without the need for isola-
tion of intermediates.
b-Amino acid derivatives are important building blocks
for the preparation of natural products,[3] pharmaceutical
agents,[4] and polypeptides with unique structural properties.
Free b-amino acids show interesting biological and pharma-
cological properties, such as antiketogenic,[5] antihelminth-
ic,[6] and antitumor properties.[7] Among the various b-amino
acids, g,d-alkynyl-b-amino acid derivatives are a special class
of nonproteinogenic amino acids. It is now recognized that
b-ethynyl-substituted amino acids can not only greatly
Scheme 1. Structure of Xemilofiban and SC-54701.
[a] L. Zhou, Q. Shuai, Prof. Dr. C.-J. Li
Department of Chemistry, McGill University
Montreal, QC, H3A 2K6 (Canada)
Fax : (+1)514-398-3797
Recently, we discovered a new copper-catalyzed amine–
alkyne–alkyne addition reaction, which proceeds via an en-
amine intermediate.[9] In addition, we also reported the dia-
stereoselective synthesis of a-oxyamines through gold-,
silver-, and copper-catalyzed three-component couplings of
a-oxyaldehydes, alkynes, and amines in water.[10] With our
continued interest in synthesizing b-amino acids and propar-
gylamines,[11] we wish to disclose herein our detailed studies
on the different parameters influencing the outcome of this
E-mail: cj.li@mcgill.ca
[b] L. Zhou, H.-f. Jiang
College of Chemistry and Chemical Engineering
South China University of Technology
Guangzhou, 510640 (P.R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901416.
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Chem. Eur. J. 2009, 15, 11668 – 11674

FULL PAPER
reaction. The broad scope and synthetic utility of this reac-
tion were also demonstrated. Furthermore, excellent diaste-
reoselectivity (up to >99:1) was observed when chiral proli-
nol derivatives were employed as the amine component.
We then explored the scope of the reaction under the op-
timized conditions (Table 2). Treatment of 1a and 3a with
different terminal alkynes 2a–2h furnished the correspond-
ing g,d-alkynyl-b-amino esters 4a–4h in moderate to good
yields (Table 2, entries 1–8). The reaction can tolerate vari-
ous functional groups present in alkyne 2, including halogen,
alkyne, and protected alcohols. In the reaction of 1a, 3a,
and 1,4-diethynylbenzene (2h), a monoaddition adduct was
isolated as the sole product (Table 2, entry 8) in 60% yield.
For these reactions, we chose amines with readily removable
protecting groups as substrates. In fact, only bisalkylated
amines (R1, R2 =alkyl) yielded the b-amino acid derivatives
4, whereas the replacement of alkyl groups by acetyl or
tosyl groups did not give any of the desired product 4. By in-
creasing the steric hindrance of the protecting groups, the
yields of the reaction decreased ((All)2 >(All)Bn>Bn2;
All=allyl). Treatment of 3a and 2a with allylbenzylamine
(1b) or dibenzylamine (1c) gave the corresponding g,d-al-
kynyl-b-amino ester derivatives 4k and 4m in 72 and 70%
yields, respectively (Table 2, entries 11 and 13). It is note-
worthy that the yield of this addition reaction is substantial-
ly affected by the substituents on the alkyne component 3.
For example, 2-butynoate gave a lower yield than 3a
(Table 2, entries 9 and 16) and with the use of diethyl acety-
lenedicarboxylate in place of 3a, the desired product was
not detected (Table 2, entry 10).
Results and Discussion
In our previous investigations, we discovered that heating a
mixture of diallylamine (1a), phenylacetylene (2a), and
ethyl propiolate (3a) with CuBr (5 mol%) as the catalyst at
608C for 24 h generated 4a in a 26% yield (Table 1,
Table 1. The addition reaction of 1a, 2a, and 3a catalyzed by copper.[a]
Catalyst[b]
T [8C]
Solvent
Yield [%][c]
1
2
3
4
5
6
7
8
CuBr
CuBr
CuBr
CuBr/bipyridine
CuBr/phenanthroline
CuCN
60
80
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
NMP
EtOH
1,4-dioxane
xylene
water
26
47
81
trace
<10
<10
40
0
84
77
27
23
15
11
75
69
21
0
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
CuI
Cu
CuBr2
Cu(CF3CO2)2
Cu(OTf)2
A
9
Next, we turned our attention to the Cu-catalyzed amine–
alkyne–alkyne addition reaction with cyclic amines as the
substrates. However, compared with 1a or 1c, the addition
reaction of piperidine (1d) with 3a and 2a gave a lower
yield of the desired product. Recently, Rueping and co-
workers reported the addition of terminal alkynes to a-
amino esters by using a Brønsted acid and silver in dual cat-
alysis.[12] Enlightened by this report, we examined various
Brønsted and Lewis acids, such as HOAc, HCl, ScCl3, and
10
11
12
13
14
15
16
17
18
N
T
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
water/TBAB
[a] All reactions were carried out by using 1a (0.5 mmol), 3a (0.5 mmol),
2a (0.75 mmol), and 5% mol of the copper catalysts in solvent (2 mL)
for 24 h. [b] IMes=1,3-bis(2,4,6-trimethylphenyl)imidazole, OTf=tri-
ScACTHNUGTRENNG(U OTf)3. However, these additives did not affect the reac-
tion favorably. Further studies to optimize the reaction con-
ditions revealed that the yield of the desired product could
be increased to 69% with the addition of 20 mol% of Et3B
(Scheme 2).
1
fluoromethanesulfonate. [c] Measured by H NMR spectroscopy.
entry 1). Increasing the reaction temperature increased the
yield; carrying out the reaction at 80 and 1008C gave the
product in 47 and 81% yield, respectively (Table 1, entries 2
and 3). Adding a ligand, such as bipyridine or phenanthro-
line did not favor the reaction (Table 1, entries 4 and 5).
Among the various copper catalysts examined, aside from
CuBr (Table 1, entries 6–11), CuBr2 gave better results than
other copper salts. The use of different solvents also affected
the reaction. Toluene is the best choice for the reaction; the
use of which resulted in high conversions to the desired
product. The use of polar solvents, such as DMF, N-methyl-
pyrrolidinone (NMP), and ethanol, gave lower yields of the
product than the less polar 1,4-dioxane and xylene (Table 1,
entries 12–16). The use of pure water as a solvent also re-
sulted in 21% yield, whereas no product was obtained when
tetrabutylammonium bromide (TBAB) was added as a
phase transfer reagent (Table 1, entries 17 and 18).
With these results obtained, we then examined the reac-
tion with various amines and alkynes (Table 3). The addition
reaction of 1d, 3a, and 1-ethynyl-3-fluorobenzene led to the
formation of b-amino ester 5b in 75% yield (Table 3,
entry 2). A high yield (77%) was also observed for the addi-
tion reaction of the phenyl-substituted piperidine 1e
Scheme 2. Copper-catalyzed three-component addition reaction of 2a,
3a, and 1d.
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C.-J. Li, H.-f. Jiang et al.
Table 2. Copper-catalyzed amine–alkyne–alkyne addition reaction in toluene.[a]
1
2
R4
Product
Yield
[%][b]
1
2
R4
Product
Yield
[%][b]
1
2
3
1a
1a
1a
2a
2b
2c
H
H
H
77
82
75
9
1a
1a
1b
2a
2a
2a
CH3
CO2Et
H
51
0
10
11
n.d.[c]
72
4
5
6
7
1a
1a
1a
1a
2d
2e
2 f
2g
H
H
H
H
66
57
62
71
12
13
14
15
1b
1c
1c
1c
2d
2a
2b
2 f
H
H
H
H
61
70
74
48
8
1a
2h
H
60
16
1c
2d
CH3
46
[a] All the reactions were carried out by using amine (0.5 mmol), alkyne (0.5 mmol), and terminal alkyne (0.75 mmol) with CuBr2 (5 mol%) as the cata-
lyst in toluene (2 mL) at 1008C for 24 h. [b] Yield of the isolated product. [c] n.d.=not detected, only the hydroamination product of 3 was obtained.
(Table 3, entry 3). Morpholine (1 f) appeared to be slightly
less reactive and a 51% yield of the desired product was ob-
tained upon treatment with 3a and 2a (Table 3, entry 4).
When optically pure methyl prolinoate (1g) was used as the
amine component, compound 5e was obtained in 82% yield
as a mixture of diastereomers (81:19 diastereomeric ratio
(dr)) (Table 3, entry 5). Replacement of 2a with 1-ethynyl-3-
fluorobenzene, gave amino ester 5 f in 80% yield with a
68:32 dr (Table 3, entry 6). With prolinol methyl ether (1h),
compound 5g was obtained with an improved diastereose-
lectivity (95:5 dr), but in a slightly lower yield of 64%
(Table 3, entry 7). Of special interest is the reaction of proli-
namide (1i), which resulted in the introduction of an amide
moiety directly into the b-amino ester without the need for
functional group protection and deprotection (Table 3,
entry 8). An excellent diastereoselectivity (>99:1 dr) was
obtained in the reaction of (S)-prolinol (1j) with methyl
propiolate to give 5i in 75% yield (Table 3, entry 9). To fur-
ther demonstrate the effects of 1j on the diastereoselectivity
of the reaction, (R)-prolinol (1k) was employed in a reac-
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Chem. Eur. J. 2009, 15, 11668 – 11674

Cu-Catalyzed Amine–Alkyne–Alkyne Addition Reaction
Table 3. Three-component addition reaction catalyzed by CuBr.[a]
FULL PAPER
kynes with different substitu-
ents, such as alkyl, phenyl,
fluoro, and naphthyl, all pro-
ceeded smoothly with 1j and
3a to afford the desired three-
component addition products
in good yields and with excel-
Amine
R1
Ph
R2
Et
Product
Yield
[%][b]
dr[c]
lent
diastereoselectivities
(Table 4, entries 1–6). With the
use of diyne 2h as a substrate,
a monoaddition adduct 5q was
obtained as the major product
(Table 4, entry 7). The absolute
configuration was assigned by
analogy to the literature.[13]
Free b-amino esters can be
obtained selectively by the re-
moval of the diallyl or dibenzyl
groups according to known
methods.[14,15] Treatment of the
g,d-alkynyl-b-amino acid deriv-
ative 4a with thiosalicylic acid
(6) in the presence of the pal-
1
2
69
75
–
–
m-FC6H4
Et
Et
3
Ph
77
–
–
4
5
6
Ph
Et
Et
Et
51
82
80
ladium(0) catalyst [PdACHTUNGTRENNUNG(dba)2]
(dba=dibenzylideneacetone;
5 mol%) and 1,4-bis(diphenyl-
phosphino)butane (DPPB; 10
mol%) at room temperature
for 1 h led to the formation of
the monoallylated b-amino
Ph
81:19
68:32
m-FC6H4
ester
7
in
85%
yield
(Scheme 3a). The free b-amino
ester 8 can be obtained in 68%
yield by increasing the temper-
ature and the loading of 6
(Scheme 3a). Primary amines
can also be obtained by hydro-
genation of the g,d-alkynyl-b-
amino acid derivatives 4. For
example, hydrogenation of 4m
in the presence of Pd/C in
methanol under a hydrogen at-
mosphere (1 bar) gave b-amino
7
8
9
Ph
Ph
Ph
Et
64
55
75
95:5
97:3
Et
Me
>99:1
10
Ph
Et
55
98:2
ester
9
in
55%
yield
[a] All of the reactions were carried out by using amine (0.2 mmol), propiolate (0.2 mmol), and terminal
(Scheme 3b). To demonstrate
further the synthetic applica-
tions of this methodology,
allyl-protected amino ester 4a
was employed in a cyclization
alkyne (0.5 mmol) with CuBr (20 mol%) as the catalyst in toluene (1 mL) at 1008C for 30 h. [b] Yield of the
1
isolated product. [c] The dr was determined by LC–MS and/or H NMR spectroscopy.
tion with 3a and 2a, which gave the desired product 5j in
55% yield with a 98:2 dr (Table 3, entry 10). These results
indicated that the chiral carbon atom and a substituents on
the prolinol substrates play key roles in the diastereoselec-
tivity of the reaction.
reaction to produce the a-chloromethylene pyrrolidine de-
rivative, 10. In the presence of [PdCl2A(PhCN)2], CuCl2, and
CTHUNGTRENNUNG
LiCl, the cyclic compound 10 was obtained as the sole prod-
uct in 92% yield (Scheme 3c).[16]
Recently, we reported a method for site-specific carbon
Encouraged by these results, we then examined the scope
of the reaction with 1j, 3a, and various terminal alkynes
(Table 4). It was shown that the reactions of aromatic al-
functionalization of peptides and glycine derivatives by
[17]
À
direct C H bond functionalization. Using this method, we
introduced a phenylethynyl group into a simple peptide, 11,
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C.-J. Li, H.-f. Jiang et al.
Table 4. Highly diastereoselective addition of 1j and 3a with various ter-
minal alkynes.[a]
2
Product
Yield
[%][b]
dr[c]
1
2
2a
70
68
95:5
2d
93:7
97:3
Scheme 3. Selective transformations of g,d-alkynyl-b-amino acid deriva-
tives: i) [Pd
1.2 equiv), THF, RT, 1 h; ii) [Pd
(4 equiv), THF, 608C, 24 h; iii) Pd/C (10%), H2 (1 atm), MeOH, RT,
24 h; iv) [PdCl2A(PhCN)2] (5 mol%), CuCl2 (5 equiv), LiCl (2 equiv),
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
3
4
5
6
77
65
51
60
CTHUNGTRENNUNG
CH3CN, RT, 48 h.
iminium intermediate C.[19] Subsequently, an intramolecular
transfer of the alkyne moiety to the iminium ion produces
the g,d-alkynyl-b-amino ester 4 and regenerates the copper
catalyst.
>99:1
98:2
Conclusion
We have developed a simple and efficient method for syn-
thesizing g,d-alkynyl-b-amino acid derivatives by a new
copper-catalyzed amine–alkyne–alkyne addition reaction.
Various g,d-alkynyl-b-amino acid derivatives were obtained
in moderate to good yields in one step. With chiral prolinol
derivatives as the amine component, excellent diastereose-
lectivities (up to >99:1) have been observed. The resulting
amino ester derivatives can undergo further transformations
readily, such as deprotection and cyclization. This copper-
catalyzed three-component addition reaction also provides a
new approach for synthesizing g,d-alkynyl peptide deriva-
tives.
2 f
>99:1
7
2h
62
>99:1
[a] All the reactions were carried out by using 1j (0.2 mmol), 3a
(0.2 mmol), and terminal alkyne (0.5 mmol) with CuBr (20 mol%) as the
catalyst in toluene (1 mL) at 1008C for 30 h. [b] Yield of the isolated
product. [c] The dr was determined by LC–MS and 1H NMR spectrosco-
py.
À
À
by an oxidative C H/C H coupling (Scheme 4a). Comple-
mentary to the earlier report, g,d-alkynyl peptide 13 could
easily be formed by the present copper-catalyzed three-com-
ponent addition of 2a, 1a, and ynamide 12. The addition re-
action proceeded at 1008C in toluene for 24 h, affording the
addition product 13 in 82% yield (Scheme 4b).
Experimental Section
General: Propynoylaminoacetic acid ethyl ester[20] (12) and allylbenzyl-
AHCTUNGTRENNUNG
amine[21] (1b) were prepared according to published procedures. Other
chemicals were purchased from Aldrich Chemicals and Acros Chemicals,
and were used without further purification. All experiments were carried
out under an atmosphere of nitrogen. Flash column chromatography was
1
performed over SORBENT silica gel 30–60 mm. H and 13C NMR spectra
A plausible mechanism for the copper-catalyzed three-
component amine–alkyne–alkyne addition reaction is shown
in Scheme 5. A copper-catalyzed hydroamination[18] of the
electron-deficient propiolate 3 by amine 1 generates inter-
mediate A. Reaction of A with alkyne 2 results in the for-
mation of intermediate B, which is protonated to give an
were acquired with Varian 400 and 100 MHz, or 300 and 75 MHz spec-
trometers, respectively. Some of the anisidic protons could not be ob-
served in 1H NMR spectra with CDCl3 as the solvent. MS data were ob-
tained by using an Agilent 6890N Network GC System/Agilent 5973
Mass Selective Detector. HRMS (ESI) measurements were performed at
McGill University.
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Cu-Catalyzed Amine–Alkyne–Alkyne Addition Reaction
FULL PAPER
room temperature under nitrogen for
15 min. The preformed catalyst and
thiosalicylic acid (1.2 or 4 equiv) were
added to a solution of 4a in THF and
the reaction mixture was stirred
under argon at 20 or 608C. After
completion of the reaction (the reac-
tion was monitored by TLC and GC–
MS), the mixture was treated with a
10% aqueous solution of HCl and
the byproduct and the catalyst were
extracted into the organic layer with
AcOEt. The aqueous layer containing
the protonated amine was basified
with lm NaOH and extracted with
AcOEt. The organic layer was dried
over MgSO4 and concentrated in
vacuo, affording clean crude products.
Further purification was performed
by flash chromatography on silica gel
with hexane/AcOEt (3:1) as the
À
À
Scheme 4. Copper-catalyzed oxidative C H/C H coupling and three-component addition reaction. TBHP=
tert-butylhydroperoxide, DCE=1,2-dichloroethane.
eluent.
Representative experimental procedure: synthesis of 5k: A mixture of
CuBr (20 mol%), 1j (20.2 mg, 0.2 mmol), and 3a (19.8 mg, 0.2 mmol) in
toluene (1 mL) was stirred at 608C (the temperature fluctuated slightly
during the reaction) for 2 h under an atmosphere of nitrogen. Then tri-
AHCTUNGTREGeNNNU thylborane (1m solution in THF, 40 ml, 20 mol%) and 2a (51 mg,
0.5 mmol) were added and the resulting solution was stirred at 1008C for
30 h. After cooling to room temperature, the resulting mixture was fil-
tered through a short path of silica gel in a pipette, eluting with ethyl ace-
tate. The volatile compounds were removed in vacuo and the residue was
purified by column chromatography on silica gel (eluent: hexane/ethyl
acetate 3:1 to 1:1). 1H NMR (CDCl3, 400 MHz): d=7.42–7.39 (m, 2H),
7.32–7.26 (m, 3H), 4.38 (t, J=8.0 Hz, 1H), 4.24–4.14 (m, 2H), 3.71 (dd,
J=10.8, 3.2 Hz, 1H), 3.38 (dd, J=10.8, 3.6 Hz, 1H), 3.05–2.95 (m, 2H),
2.89–2.83 (m, 1H), 2.76–2.72 (m, 2H), 1.88–1.72 (m, 4H), 1.27 ppm (t, J=
6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz): d=171.4, 132.0, 128.6, 128.5,
122.9, 86.0, 85.9, 62.8, 62.5, 61.1, 49.5, 47.4, 40.2, 27.7, 24.0, 14.4 ppm; MS
(70 eV): m/z (%): 301 [M+], 216, 188 (100), 173, 145, 128, 115; HRMS
(EI): m/z calcd for C18H23NO3 [M+]: 301.1678, found: 301.1672.
The experiments in Tables 3 and 4 were carried out analogously. All
products were purified by column chromatography and characterized by
NMR spectroscopy and standard/high-resolution mass spectrometry.
Scheme 5. Tentative mechanism for the copper-catalyzed amine–alkyne–
alkyne addition reaction.
Representative experimental procedure: synthesis of 4a: CuBr2 (6 mg,
0.025 mmol, 5 mol%) was suspended in toluene (2 mL) in a 10 mL
Schlenk tube under nitrogen. Then 1a (49 mg, 0.5 mmol), 3a (49 mg,
0.5 mmol), and 2a (76.5 mg, 0.75 mmol) were added. The resulting solu-
tion was stirred at 1008C for 24 h. After cooling to room temperature,
the resulting mixture was filtered through a short path of silica gel in a
pipette, eluting with ethyl acetate. The volatile compounds were removed
in vacuo and the residue was purified by column chromatography (SiO2,
hexane/ethyl acetate 10:1) to give 4a as a pale yellow oil (114 mg, 77%).
1H NMR (400 MHz, CDCl3): d=7.44–7.40 (m, 2H), 7.31–7.29 (m, 3H),
5.86–5.77 (m, 2H), 5.23 (d, J=17.2 Hz, 2H), 5.14 (d, J=10.0 Hz, 2H),
4.31 (t, J=8.4 Hz, 1H), 4.17 (q, J=7.6 Hz, 2H), 3.33 (dt, J=14.0, 2.4 Hz,
2H), 2.98 (dd, J=14.0, 8.0 Hz, 2H); 2.74–2.68 (m, 2H), 1.26 ppm (t, J=
6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=170.8, 136.5, 132.0, 128.5,
128.3, 123.2, 117.5, 86.2, 85.8, 60.7, 54.2, 50.0, 39.9, 14.4 ppm; MS (70 eV):
m/z (%): 296 [M+], 256, 210 (100); HRMS (EI): m/z calcd for
C19H23NO2: 296.1651 [M+]; found: 296.1643.
Acknowledgements
We are grateful to the Canada Research Chair (Tier I) foundation (to C.-
J.L.), the CFI, NSERC, ACS-GCI Green Chemistry Pharmaceutical
Roundtable, and McGill University for supporting our research. L.Z.
thanks the China Scholarship Council for a visiting scholarship.
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The experiments in Table 2 were carried out analogously. All products
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Received: May 27, 2009
Published online: September 23, 2009
11674
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Chem. Eur. J. 2009, 15, 11668 – 11674