An investigation of the asymmetric Huisgen 'click' reaction 1

Article abstract of DOI:10.1055/s-0033-1340152

The preparation of a series of new prochiral bis-alkynes is reported. A selection of chiral ligands is examined to gain additional information about the scope of the new asymmetric Huisgen 'click' reaction [the desymmetrisation of bis-alkynes using chiral ligands in conjunction with the widely applied copper-catalysed azide-alkyne cycloaddition (CuAAC) triazole synthesis]. The development of a new chiral assay for (±)-methyl 2-[(1-benzyl-1H-1,2,3- triazol-4-yl)methyl]-2-cyanopent-4-ynoate, and the production of this mono-triazole in up to 18% enantiomeric excess is described. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340152

LETTER
▌2723
lAettner Investigation of the Asymmetric Huisgen ‘Click’ Reaction1
Asymmetric Huisgen ‘Click’ Reaction
G. Richard Stephenson,*a James P. Buttress,a Damien Deschamps,a,b Mélanie Lancelot,a James P. Martin,a Alexander
I. G. Sheldon,a,b Carole Alayrac,b Annie-Claude Gaumont,b Philip C. Bulman Pagea
a
School of Chemistry, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, UK
Fax +44(0)1603592004; E-mail: g.r.stephenson@uea.ac.uk
b
Laboratoire de Chimie Moléculaire et Thio-organique, UMR CNRS 6507, INC3M, FR308, ENSICAEN & Université de Caen Basse-
Normandie, 6 Boulevard du Maréchal Juin, 14050 Caen, France
Received: 31.08.2013; Accepted: 17.09.2013
lipases3 with prochiral diesters, or the Hajos–Parrish reac-
Abstract: The preparation of a series of new prochiral bis-alkynes
tion,4 which distinguishes the two enantiotopic ketones of
is reported. A selection of chiral ligands is examined to gain addi-
a 2,2-disubstituted cyclohexane-1,3-dione. More recently,
tional information about the scope of the new asymmetric Huisgen
‘click’ reaction [the desymmetrisation of bis-alkynes using chiral li-
the development of asymmetric Heck coupling reactions5
gands in conjunction with the widely applied copper-catalysed has transformed the synthetic application of the palladi-
azide–alkyne cycloaddition (CuAAC) triazole synthesis]. The de-
velopment of a new chiral assay for (±)-methyl 2-[(1-benzyl-1H-
1,2,3-triazol-4-yl)methyl]-2-cyanopent-4-ynoate, and the produc-
synthesis because, in contrast to conjugate addition6 with
tion of this mono-triazole in up to 18% enantiomeric excess is de-
scribed.
um-catalysed arylation of α,β-unsaturated esters and relat-
ed substrates. This reaction was originally prized in
diarylcuprates, Heck coupling achieves a comparable
C–C bond formation, but retains the alkene functionality
Key words: chiral ligands, copper, CuAAC reaction, asymmetric
in the product. The valuable reactivity of the alkene is thus
synthesis
still available to be employed again (for example in
epoxidation7 or cycloaddition8 processes). Although valu-
able, however, this conventional use of Heck coupling
Desymmetrisation reactions2 are a powerful tool in enan-
does not produce a new stereogenic centre, and it was 17
tioselective synthesis since they allow access to chiral
years from its first description9 in the literature until the
non-racemic products from bond-formation chemistry
first reports10 of its use with a chiral ligand.
that does not directly introduce chirality at the reaction
centre (Scheme 1). Classic examples are the use of
enantiotopic acetates
OAc
OH
OAc
OAc
lipase from P. putida
N
N
pH 7 buffer
Boc
Boc
>98% ee
enantiotopic ketones
O
MeO
MeO
N
MeO
N
O
N
HO
O
L-proline, then HCl, MeOH
MeO
MeO
MeO
O
O
O
enantiotopic alkenes
OTBS
87% ee
OTBS
(magellanine-type alkaloid core)
[PdCl2(R)-BINAP]
(intermediate for (–)-oppositol)
Ag3PO4, CaCO3, NMP
H
I
86% ee
Scheme 1 Desymmetrisation reactions in synthesis3,4b,5e
SYNLETT 2013, 24, 2723–2729
Advanced online publication: 05.11.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1340152; Art ID: ST-2013-D0839-L
© Georg Thieme Verlag Stuttgart · New York

2724
G. R. Stephenson et al.
enantiotopic azides
N3
LETTER
N
N
Ph
Ph
Ph
N
N
N
N
Cl
+
Cl
Cl
ligand L1
CuI, CH2Cl2
N
N3
N3
59% ee
25% yield
N
N
equation 1
60% yield
N
N
N
N
N
N
Bn
Bn
N
Bn
N3
enantiotopic alkynes
+
BnN
BnN
ligand L2
CuCl, 2,5-hexanedione
O
N
O
N
6% yield
95% ee
70% yield
O
N
O
O
N
BnN
O
O
N
N
N
N
N
N
N
N
+
N3
O
O
equation 2
O
BnN
BnN
ligand L2
CuCl, 2,5-hexanedione
N
O
O
N
O
N
98% ee
51% yield
5% yield
Scheme 2 Examples of asymmetric ‘click’ reactions27,28
There are many powerful, generally applicable, high- symmetrisation of prochiral bis-alkynes much greater
yielding C–C bond-forming reactions that have similarly potential, and we therefore focused our attention in that
been overlooked for investigation with chiral ligands for direction. Our initial work has concentrated on simple,
the same reason (that they do not typically form stereo- readily available prochiral bis-alkynes that can easily be
genic centres). Some years ago,11 it occurred to us that the obtained from β-keto esters or cyanoacetate esters by al-
popular copper-catalysed ‘click’ reaction between an al- kylation with two equivalents of propargyl bromide. Very
kyne and an azide [the copper-catalysed azide–alkyne cy- recently, an extremely elegant demonstration of this type
cloaddition (CuAAC)],12 which forms a flat achiral of asymmetric ‘click’ chemistry was reported by Zhou,28
triazole functional group, was just such a case. Sharpless with enantiomeric excesses as high as 98%, working with
introduced the concept of ‘click’ chemistry in 2001,13 em- a different, but structurally related class of prochiral bis-
phasising the strategic power of bond-forming chemistry alkynes obtained from an N-protected oxindole (Scheme
that can be applied in almost any situation. By definition, 2, eq 2 and Figure 1, L2). The publication of this highly
‘click’ reactions are easy to carry out, fast, and high-yield- important paper by Zhou et al. prompts us to disclose our
ing, so the concept of an asymmetric ‘click’ reaction is own results in this area. We describe here the synthesis
highly attractive, promising enantiopure products in al- and characterisation of new examples of cyanoacetate-
most quantitative yield. Indeed, during the last decade, the derived prochiral bis-alkynes, their mono- and bis-triazole
CuAAC reaction has been applied in almost every con- products from the CuAAC reaction, and preliminary
ceivable situation (recent examples are in fields as diverse results with a representative series of chiral ligands.
as electrochemistry,14 polymer science,15 bioimaging,16
Our prochiral starting materials are easily obtained by
heating methyl or tert-butyl cyanoacetate with propargyl
drug delivery,17 metabolic glycoengineering,18 supramo-
lecular organogels,19 neoglycoproteins,20 magnetic21 and
bromide and potassium carbonate at reflux temperature in
electronic22 materials, dendrimers,23 immobilised cyclo-
acetonitrile for 15–70 hours.29 Methyl acetoacetate gave
dextrin derivates,24 fluorescence sensors,25 and
the prochiral methyl 2-acetyl-2-(prop-2-yn-1-yl)pent-
semiconductors26), but, at the start of our work, compared
4-ynoate ester by the same procedure. Unsymmetrical
malonate diesters (e.g., the ethyl, tert-butyl diester 4) can
to these many thousands of CuAAC papers, there was
only one report27 of its use with a chiral ligand (for an ex-
also be used (Scheme 3).30
ample, see Figure 1, L1). This study from Fokin and
The CuAAC reaction with benzyl azide was examined
Finn’s group at the Scripps Institute employed a prochiral
first using copper powder31 for ease of work-up32 (simple
bis-azide reacting with alkynes to form chiral mono-azide
filtration), and also with copper iodide under microwave
derivatives containing triazole functionality (Scheme 2,
conditions33 (using a combination of the ‘one pot’ benzyl
eq 1). For our own investigations, we felt that the synthet-
bromide, sodium azide, alkyne method,34 and the homo-
ic value of alkynes in organic chemistry afforded the de-
Synlett 2013, 24, 2723–2729
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Huisgen ‘Click’ Reaction
2725
O
1: R1 = Me, R2 = CN
O
R2
Br
R1O
2: R1 = t-Bu, R2 = CN
R2
O
O
N
R1O
3: R1 = Me, R2 = Ac
K2CO3, MeCN
reflux, 15–70 h
N
N
4: R1 = t-Bu, R2 = CO2Et
19–71% yield
HN
H
N
L1
N3
O
O
O
O
N
CN
CN
N
N
MeO
MeO
L2
Ph
Ph
N
+
N
N
Me
R1 = Me, R2 = CN
N
N
N
N
N
P
P
methods A, B and C
N
PPh2
Me
Me
PR2
PR2
PPh2
5
6
Me
(R)-BINAP: R = Ph
(R,R)-NORPHOS (9) (S,S)-Me-DUPHOS (10)
Scheme 3 Preparation and CuAAC reactions of prochiral 2,2-diynes
[method A: copper powder; method B: microwave irradiation with
copper powder; method C: chiral ligand with copper iodide and diiso-
propylethylamine (DIPEA)]; see Tables 1–3
(R)-7 tol-BINAP: R = 4-Tol
(R)-8 xyl-BINAP: R = 3,5-Xyl
Ph2P
Ph2P
O
O
i-Pr
t-Bu
N
O
N
S
N
N
nient high-throughput chiral analysis for the investigation
of the asymmetric ‘click’ reaction, using the ratios of peak
areas observed at 229 nm.
t-Bu
(S)-t-Bu-BOX (13)
t-Bu
(S)-i-Pr-PHOX (11) (S)-t-Bu-Thia-PHOX (12)
Figure 1 Structures of L1 and L2 and chiral ligands tested in our
work (7–13)
The reaction was examined next in the presence of (R)-
and (S)-tol-BINAP (7), in toluene, employing a 1:1 ratio
of the bis-alkyne 1 and benzyl azide and 10 mol% of cop-
per(I) iodide. The reaction was stopped after 18 hours
(21% conversion) and analysed by chiral HPLC. With
(R)-7, the faster eluting peak was larger than the second
peak, showing a modest enantiomeric excess of about
13% (calculated from the areas of the two peaks). The re-
action employing (S)-7, was again stopped before comple-
tion (38% conversion). In this experiment, the second
(slower eluting) peak was the larger. A similar enantio-
meric excess (15%), favouring the opposite enantiomer,
was observed (Table 2).
geneous tert-butanol–water procedure35). The bis-alkyne
1 was reactive under both of these conditions, and, de-
pending upon the concentration of reagents and the excess
of the azide, mixtures of the starting material 1 and the
mono- and bis-triazoles36,37 (538 and 639) were produced
(Table 1). An authentic racemic sample of 5 obtained in
this way was separated by analytical HPLC using a
Chiralpak IC column with heptane–isopropyl alcohol (80:20
v/v) as the mobile phase (1 mL·min–1). The two enantio-
mers were eluted separately with retention times of 67 and
75 minutes. Shorter elution times are possible using
hexane–isopropyl alcohol (70:30 v/v at 1 mL·min–1; reten-
tion times of 31 and 34 minutes), establishing a conve-
Based on this protocol, we next performed a preliminary
survey of a range of chiral ligands, but obtained the mono-
Table 1 CuAAC Reactions of the Bis-Alkyne 1 with Benzyl Azidea
Method
Time (h)
BnN3 (equiv)
Concn (M)
Recovered 1 (%)
Mono-triazole 5 (%) Bis-triazole 6 (%)
A
A
A
B
B
C
C
C
40
1b
0.06
0.05
0.04
0.24
0.4
57
59
16
71
19
94
38
32
30
37
28
28
54
5
13
4
16
1b
16
2.5b
1c
56
1
16
16
1c
27
1
0.17
0.25
0.33
1d
0.14
0.14
0.14
1d
26
30
36
38
1d
a Reactions in t-BuOH–H2O for method A, in DMSO for method B, and in toluene for method C; see Scheme 3 and citations in the text.
b Added as benzyl azide.
c Generated in situ40 before the ‘click’ reaction, using benzyl bromide and sodium azide.
d Generated in situ during the ‘click’ reaction, using benzyl bromide and sodium azide.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2723–2729

2726
G. R. Stephenson et al.
LETTER
Table 3 Asymmetric ‘Click’ Reactions at –40 °C with 20 mol% Cat-
alyst Loading (2:3 Ratio of Copper Iodide and Chiral Ligand) in Tol-
uene
Table 2 Asymmetric ‘Click’ Reactions at –40 °C with 10 mol% Cat-
alyst Loading (2:3 Ratio of Copper Iodide and Chiral Ligand)
Liganda
Solvent
Time SM/
ee
erc
Liganda
Time SM/mono/bisb ee (%) erc
mono/bisb (%)
(R,R)-NORPHOS (9)
(S,S)-Me-DUPHOS (10)
(S)-i-Pr-PHOX (11)
18 h
4 h
66:34:0
92:8:0
16
5
42:58
53:47
48:52
49:51
48:52
41:59
(R)-tol-BINAP
toluene
toluene
toluene
toluene
toluene
Et2O
18 h 79:19:2
18 h 62:35:3
5 d 74:24:2
5 d 61:35:4
18 h 72:25:3
18 h 70:27:3
5 d 71:25:4
18 h 68:28:4
18 h 61:35:4
5 d 49:43:8
5 d 45:48:7
13 56:44
15 42:58
(S)-tol-BINAP
18 h
60:35:5
60:35:5
53:31:15
94:6:0
3
(R)-xyl-BINAP
(S)-xyl-BINAP
5
6
9
7
53:47
47:53
46:54
46:54
(S)-t-Bu-Thia-PHOX (12) 18 h
2
(S)-t-Bu-BOX (13)
(S)-tol-BINAP (7)
18 h
18 h
3
(R,R)-NORPHOS
(R,R)-NORPHOS
(R,R)-NORPHOS
(R,R)-NORPHOS
(R,R)-NORPHOS
(R,R)-NORPHOS
(R,R)-NORPHOS
18
a (R,R)-NORPHOS = (2R,3R)-(–)-2,3-bis(diphenylphosphino)bicy-
clo[2.2.1]hept-5-ene; (S,S)-Me-DUPHOS = 1,2-bis[(2S,5S)-2,5-di-
methylphospholano]benzene; (S)-i-Pr-PHOX = (S)-2-(2-diphenyl-
phosphinophenyl)-4-iso-propyl-4,5-dihydrooxazole; (S)-t-Bu-Thia-
PHOX = (S)-2-(2-diphenylphosphinophenyl)-4-tert-butyl-4,5-dihy-
drothiazole; (S)-t-Bu-BOX = 2,2′-iso-propylidene-bis(4-tert-butyl-
oxazoline); (S)-tol-BINAP = 1,1′-binaphthalene-2,2′-diylbis[bis-
(4-methylphenyl)phosphine].
EtOH
10 45:55
MeOH
EtOAc
EtOAc
Et2O
7
6
3
4
46:54
47:53
48:52
48:52
b Ratio of starting material to mono- and bis-triazoles.
a tol-BINAP = 1,1′-binaphthalene-2,2′-diylbis[bis(4-methylphe-
nyl)phosphine]; xyl-BINAP = 1,1′-Binaphthalene-2,2′-diyl-
bis[bis(3,5-dimethylphenyl)phosphine]; (R,R)-NORPHOS =
(2R,3R)-(–)-2,3-Bis(diphenylphosphino)bicyclo[2.2.1]hept-5-ene.
b Ratio of starting material to mono- and bis-triazoles.
c HPLC ratios of peak areas eluting at 31 min and 34 min using a 4.6
mm × 250 mm, 5 μm Daicel Chiralpak IC column with hexane–
i-PrOH (70:30 v/v) at 1 mL·min–1 [or at 67 and 75 min eluting at 1
mL·min–1 with heptane–i-PrOH (80:20 v/v)].
c HPLC ratios of peak areas eluting at 31 min and 34 min using a 4.6
mm × 250 mm, 5 μm Daicel Chiralpak IC column with hexane–
i-PrOH (70:30 v/v) at 1 mL·min–1 [or at 67 and 75 min eluting at 1
mL·min–1 with heptane–i-PrOH (80:20 v/v)].
The best result with (R,R)-NORPHOS (9) was obtained in
toluene by increasing the quantities of copper(I) iodide
and ligand 9 and keeping the reaction time as 18 hours
(Table 3). Under these conditions, at 34% conversion,
none of the bis-triazole was observed and the chiral dis-
crimination was improved to give the mono-triazole 5 in
16% enantiomeric excess.41 With this higher catalyst
loading (20 mol% CuI and 30 mol% chiral ligand), the
range of chiral auxiliaries tested in this study was expand-
ed to include (S,S)-Me-DUPHOS (10), (S)-i-Pr-PHOX li-
gand (11)42 and the (S)-t-Bu-Thia-PHOX ligand (12)43
(Figure 1), as well as an example of a non-phosphorus bi-
dentate ligand [(S)-t-Bu-BOX (13)], but all four gave low
enantiomeric excesses in the range 2–5%. (S)-Tol-BINAP
was also studied with the higher catalyst loading, giving
the mono-triazole product in 18% enantiomeric excess at
a low conversion.
triazole product in lower enantiomeric excesses. Using
(R)-xyl-BINAP (8) gave the same sense of asymmetric
induction as (R)-tol-BINAP, but only 5% enantiomeric
excess. Because of the very low enantiomeric excess, S
order of large/small peaks was reversed, which proved to
be the case (6% ee). Perhaps because of the more bulky li-
gand, the xyl-BINAP reaction was much slower than the
tol-BINAP alternative, and these reactions required five
days to reach comparable levels of consumption of the
azide (26–39% conversions). (R,R)-NORPHOS (9) has
also been examined, and after 18 hours gave only 9% en-
antiomeric excess. In all of these reactions (see Table 2),
small amounts of the achiral bis-triazole 6 were also ob-
served. Using (R,R)-NORPHOS, a selection of reaction
solvents (methanol, ethanol, ethyl acetate and diethyl
ether) were tested, but gave similar results (3–10% ee).
The reaction in ethanol required five days to achieve 29%
conversion. The enantiomeric excess obtained in ethanol
at 29% conversion (10%) was very similar to the enantio-
meric excess obtained after 18 hours in our initial
NORPHOS experiment (28% conversion, 9% ee). The lowest
enantiomeric excesses in the NORPHOS experiments
were encountered in ethyl acetate and diethyl ether when
the reactions were allowed to proceed to about 50–55%
conversion. In these examples, because of the longer reac-
tion times, noticeably more of the bis-triazole product 6
was present.
In conclusion, the development of asymmetric ‘click’
chemistry is still at a very early stage, but it is clear from
our results and those of Zhou et al.28 that the efficiency of
asymmetric induction is sensitive to the structure of the
prochiral bis-alkyne and the choice of solvent, as well as
the nature of the ligand class itself. The examples reported
here include chelating diphosphines, chelating ‘P–N’ mo-
nophosphine ligands, and a BOX-type non-phosphine
chelating ligand, but with our cyanoacetate series of pro-
chiral bis-alkynes, all significantly underperform the
PYBOX ligand employed initially by Meng, Fokin and
Finn,27 and now optimised by Zhou et al.28
Synlett 2013, 24, 2723–2729
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Huisgen ‘Click’ Reaction
2727
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Acknowledgment
We thank EU Interreg IVA (project 4061) for financial support and
the EPSRC Mass Spectrometry Centre at the University of Wales,
Swansea for high-resolution mass spectrometric measurements. We
thank Dr Mihaela Gulea (LCMT) for a sample of (S)-2-(2-diphenyl-
phosphinophenyl)-4-tert-butyl-4,5-dihydrothiazole (12) and Mr
Fabien Le Cavelier (LCMT) for the separation of the enantiomers
of 5 by chiral HPLC.
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Typical Procedure
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MeCN (600 mL). K2CO3 (69.7 g, 505 mmol) was added and
the mixture was cooled in an ice bath. Propargyl bromide
(49.5 mL, 444 mmol) was added, and the resulting orange
suspension was heated at reflux temperature overnight. The
deep yellow suspension was allowed to cool and worked up
with H2O (400 mL). The deep brown organic layer was
separated, and the brown aqueous layer was extracted with
EtOAc (3 × 250 mL). The combined organic layers were
washed with H2O (250 mL) and brine (250 mL), and dried
over anhydrous MgSO4. After evaporating the solvents, the
resulting brown oil was purified by vacuum distillation at
115–125 °C to give methyl 2-cyano-2-(prop-2-yn-1-yl)pent-
4-ynoate (1) as a colourless oil, which solidified to a white
solid (25.1 g, 143 mmol, 71%). IR (neat): 3275, 2249
(nitrile), 1740 (C=O) cm–1. 1H NMR (400 MHz, CDCl3):
δ = 3.89 (s, 3 H), 2.94 (d, J = 2.6 Hz, 4 H), 2.24 (t, J = 2.6
Hz, 2 H). 13C NMR (75 MHz, CDCl3): δ = 166.6, 117.0,
76.0, 73.7, 54.1, 47.1, 25.6. HRMS (NSI): m/z [M + NH4]+
calcd for C10H13O2N2: 193.0972; found: 193.0971.
tert-Butyl 2-Cyano-2-(prop-2-yn-1-yl)pent-4-ynoate (2)
Yield: 4.0 g (53%); pale solid. IR (neat): 3289, 2989, 2979,
1728 (C=O) cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.86 (d,
(9) For the first examples using aryl and alkenyl halides, see:
(a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn.
1971, 44, 581. (b) Heck, R. F.; Nolley, J. P. Jr. J. Org. Chem.
1972, 37, 2320. (c) See also: Heck, R. F. J. Am. Chem. Soc.
1968, 90, 5518.
(10) (a) Sato, Y.; Sodeoka, M.; Shibasaki, M. J. Org. Chem.
1989, 54, 4738. (b) Carpenter, N. E.; Kucera, D. J.;
Overman, L. E. J. Org. Chem. 1989, 54, 5846.
(11) Sheldon, A.; Deschamps, D.; Buttress, J. M.; Alayrac, C.;
Gaumont, A.-C.; Stephenson, G. R.; Page, P. C. B. Poster
Abstract, Eleventh Anglo-Norman Organic Chemistry
Colloquium (ANORCQ XI), Caen, France, 15–17 April,
2012, P24.
(12) (a) Liang, L.; Astruc, D. Coord. Chem. Rev. 2011, 255,
2933. (b) Tornoe, C. W.; Christensen, C.; Medal, M. J. Org.
Chem. 2002, 67, 3057. (c) Huisgen, R. Angew. Chem., Int.
Ed. Engl. 1963, 2, 565. (d) Huisgen, R. Proc. Chem. Soc.
1961, 357. (e) See also: Huisgen, R.; Knorr, R.
Naturwissenschaften 1961, 48, 716. (f) For the
cycloaddition reaction between phenyl azide and an
acetylenic ester, see: Michael, A. J. Prakt. Chem. 1893, 48,
94.
(13) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int.
Ed. 2001, 40, 2004.
J = 2.7 Hz, 4 H), 2.19 (t, J = 2.7 Hz, 2 H), 1.50 (s, 9 H). 13
C
NMR (100 MHz, CDCl3): δ = 164.8, 117.7, 85.5, 76.6, 73.6,
47.8, 27.9, 25.8. HRMS (NSI): m/z [M + NH4]+ calcd for
C13H19O2N2: 235.1441; found: 235.1444.
(14) (a) Cernat, A.; Griveau, S.; Richard, C.; Bedioui, F.;
Sandulescu, R. Electroanal. 2013, 25, 1369. (b) Ripert, M.;
Farre, C.; Chaix, C. Electrochim. Acta 2013, 91, 82.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2723–2729

2728
G. R. Stephenson et al.
LETTER
Methyl 2-Acetyl-2-(prop-2-yn-1-yl)pent-4-ynoate (3)
Yield: 550 mg (31%); white solid. IR (neat): 3277, 2967,
1747 (C=O), 1712 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 3.75 (s, 3 H), 2.90–2.95 (m, 4 H), 2.18 (s, 3 H), 2.00 (t, J
= 2.7 Hz, 2 H). 13C NMR (101 MHz, CDCl3): δ = 200.9,
169.9, 78.6, 72.2, 62.6, 53.4, 26.3, 22.0. HRMS (NSI): m/z
[M + H]+ calcd for C11H13O3: 193.0859; found: 193.0859.
products were isolated by column chromatography, eluting
with hexane–EtOAc (2:1), see references 38 and 39. .
(34) Appukkuttan, P.; Dehaen, W.; Fokin, V. V.; Van der
Eycken, E. Org. Lett. 2004, 6, 4223.
(35) Cravotto, G.; Mendicuti, F.; Martina, K.; Tagliapietra, S.;
Robaldo, B.; Barge, A. Synlett 2008, 2642.
(36) Simple diynes are known to form bis-triazoles by double
CuAAC reactions, see: (a) Park, I. S.; Kwon, M. S.; Kim, Y.;
Lee, J. S.; Park, J. Org. Lett. 2008, 10, 497. (b) Monkowius,
U.; Ritter, S.; König, B.; Zabel, M.; Yersin, H. Eur. J. Inorg.
Chem. 2007, 4597. (c) Lee, B.-H.; Wu, C.-C.; Fang, X.; Liu,
C. W.; Zhu, J.-L. Catal. Lett. 2013, 143, 572. (d) Chan, T.
R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett.
2004, 6, 2853. (e) The control of mono- and bis-products
from 1,3-butadiene has been studied: Aizpurua, J. M.;
Azcune, I.; Fratila, R. M.; Balentova, E.; Sagartzazu-
Aizpurua, M.; Miranda, J. I. Org. Lett. 2010, 12, 1584.
Similar bis-triazole formation is possible in the CuAAC
reactions of mono-alkynes though competing Glaser-type
alkyne coupling processes: (f) Angell, Y.; Burgess, K.
Angew. Chem. Int. Ed. 2007, 46, 3649. (g) González, J.;
Pérez, V. M.; Jiménez, D. O.; Lopez-Valdez, G.; Corona, D.;
Cuevas-Yañez, E. Tetrahedron Lett. 2011, 52, 3514.
(37) (a) For an example of the formation of a bis-triazole from a
glycine-derived meso bis-alkyne, see: Struthers, H.; Mindt,
T. L.; Schibli, R. Dalton Trans. 2010, 39, 675. (b) Statistical
mixtures of mono- and bis-triazoles have been reported
previously for a ‘click’ reaction of a meso-diyne performed
in the absence of a chiral ligand, see: Rodionov, V. O.;
Fokin, V. V.; Finn, M. G. Angew. Chem. Int. Ed. 2005, 44,
2210.
(30) tert-Butyl ethyl malonate (1 mL, 0.994 g, 5.28 mmol),
propargyl bromide (2.1 mL, 18.85 mmol) and K2CO3 (2.82
g, 20.39 mmol) were combined in MeCN (20 mL). The
yellow suspension was heated at reflux temperature
overnight. The cooled reaction mixture was worked up with
H2O (15 mL) and extracted with EtOAc (3 × 20 mL). The
combined organic layers were washed with H2O (20 mL)
and brine (20 mL), dried over anhydrous MgSO4 and the
solvents evaporated. Crystallisation of the residue from
EtOH gave crystals of the pure product, 1-tert-butyl 4-ethyl
2,2-di(prop-2-yn-1-yl)malonate (4) (262 mg, 0.99 mmol,
19%). IR (neat): 3284, 3262, 2983, 1728 (C=O) cm–1. 1H
NMR (400 MHz, CDCl3): δ = 4.19 (q, J = 7.1 Hz, 2 H), 2.90
(d, J = 2.6 Hz, 4 H), 1.99 (t, J = 2.6 Hz, 2 H), 1.41 (s, 9 H),
1.23 (t, J = 7.1 Hz, 3 H). 13C NMR (101 MHz, CDCl3):
δ = 169.1, 167.7, 82.9, 78.9, 71.7, 62.0, 56.8, 27.9, 22.6,
14.3. HRMS (NSI): m/z [M + Na]+ calcd for C15H20O4Na:
287.1254; found: 287.1259.
(31) (a) Gommermann, N.; Gehrig, A.; Knochel, P. Synlett 2005,
2796. (b) For an example with copper nanoparticles, see:
Orgueira, H. A.; Fokas, D.; Isome, Y.; Chan, P. C.-M.;
Baldino, C. M. Tetrahedron Lett. 2005, 46, 2911. (c) For an
example with copper turnings, see: David, O.; Maisonneuve,
S.; Xie, J. Tetrahedron Lett. 2007, 48, 6527.
(32) General procedure for method A: benzyl azide (1–2.5 equiv)
and methyl 2-cyano-2-(prop-2-yn-1-yl)pent-4-ynoate (1) (1
g, 5.71 mmol) were dissolved in t-BuOH–H2O (2:1 v/v) (for
concentrations, see Table 1) and Cu powder (2 equiv) was
added. The mixture was stirred at r.t. overnight and then
diluted with H2O. After filtration through Celite to remove
the Cu powder, the resulting liquid was extracted with
EtOAc (3 × 30 mL). The combined organic layers were
washed with H2O and brine and then dried over anhydrous
MgSO4. The solvents were removed under reduced pressure.
Representative procedure for method B with in situ
generation of the benzyl azide: NaN3 (0.412 g, 6.34 mmol)
was dissolved in DMSO (25 mL) with vigorous stirring.
Benzyl bromide (0.830 mL, 6.98 mmol) was added, and the
mixture stirred for 2 h. Methyl 2-cyano-2-(prop-2-yn-1-
yl)pent-4-ynoate (1) (1 g, 5.71 mmol) and Cu powder (0.605
g, 9.51 mmol) were added, and the mixture stirred at r.t.
overnight. The mixture was diluted with H2O. After
filtration through Celite to remove the Cu powder, the
resulting liquid was extracted with EtOAc (3 × 30 mL). The
combined organic layers were washed with H2O and brine,
and then dried over anhydrous MgSO4. The solvents were
removed under reduced pressure.
(33) Representative procedure for method C: methyl 2-cyano-2-
(prop-2-yn-1-yl)pent-4-ynoate (1) (100 mg, 0.57 mmol),
copper(I) iodide (16 mg, 0.064 mmol) and NaN3 (46 mg,
0.705 mmol) were combined in a 5 mL microwave reactor
vial. The solvent (t-BuOH–H2O, 1:1, 4 mL) was added and
the vial sealed. Benzyl bromide (0.076 mL, 0.64 mmol) was
added through the septum, and the vessel was heated in a
microwave reactor at 125 °C, 100 W, for 20 min. The cooled
mixture was worked up with H2O, and extracted with
EtOAc. The combined organic layers were washed with H2O
and brine, and then dried over anhydrous MgSO4. The
solvents were removed under reduced pressure. The
(38) Methyl 2-[(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl]-2-
cyanopent-4-ynoate (5)
For yields, see Table 1; mp 71–72 °C. IR (neat): 2249
(nitrile), 1748 (C=O), 1497 (C=C aromatic), 1455 (N=N),
1436 (C-H alkyne) cm–1. 1H NMR (500 MHz, CDCl3):
δ = 7.49 (s, 1 H), 7.41–7.32 (m, 3 H), 7.26–7.21 (m, 2 H),
5.52 (s, 2 H), 3.80 (s, 3 H), 3.39 (s, 2 H), 2.93 (dd, J = 16.9,
2.6 Hz, 1 H), 2.81 (dd, J = 16.9, 2.6 Hz, 1 H), 2.22 (t, J = 2.6
Hz, 1 H). 13C NMR (101 MHz, CDCl3): δ = 167.2, 134.6,
129.1, 128.7, 128.2, 127.9, 123.3, 117.7, 76.7, 73.6, 54.1,
49.1, 32.2, 26.3. HRMS (NSI): m/z [M + H]+ calcd for
C17H17N4O2: 309.1346; found: 309.1345.
(39) Methyl 3-(1-Benzyl-1H-1,2,3-triazol-4-yl)-2-[(1-benzyl-
1H-1,2,3-triazol-4-yl)methyl]-2-cyanopropanoate (6)
For yields, see Table 1. IR (neat): 3132, 3065, 3035, 2997,
2962, 2246 (nitrile), 1740 (C=O) cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.53 (s, 2 H), 7.28–7.20 (m, 6 H), 7.09–7.15 (m,
4 H), 5.39 (s, 4 H), 3.58 (s, 3 H), 3.24–3.20 (m, 4 H). 13
C
NMR (101 MHz, CDCl3): δ = 168.1, 134.9, 129.2, 128.8,
128.4, 128.1, 123.6, 118.5, 54.2, 53.9, 50.4, 32.4. HRMS
(NSI): m/z [M + H]+ calcd for C24H24N7O2: 442.1986; found:
442.1984.
(40) Alvarez, S. G.; Alvarez, M. T. Synthesis 1997, 413.
(41) (R,R)-NORPHOS (0.017 g, 0.038 mmol) and copper(I)
iodide (4.76 mg, 0.025 mmol) were combined in toluene (5
mL). DIPEA (0.13 mL, 0.750 mmol) was added, and the
mixture was allowed to stir at r.t. to allow the complex to
form. The mixture was then cooled to –40 °C and methyl 2-
cyano-2-(prop-2-yn-1-yl)pent-4-ynoate (1) (0.044 g, 0.250
mmol) and benzyl azide (0.031 mL, 0.25 mmol) were added,
and the mixture stirred at –40 °C for 18 h. The mixture was
filtered through silica while still cold, to prevent any further
reaction occurring, and the silica pad was washed through
with CH2Cl2 (5 mL). The solvents were evaporated, and the
residue was analysed by NMR spectroscopy.
(42) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336.
Synlett 2013, 24, 2723–2729
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Huisgen ‘Click’ Reaction
2729
(43) (a) Gaumont, A.-C.; Gulea, M.; Masson, S. unpublished
results. (b) For the isopropyl example of this ligand series,
see: Abrunhosa, I.; Delain-Bioton, L.; Gaumont, A.-C.;
Gulea, M.; Masson, S. Tetrahedron 2004, 60, 9263. (c) See
also: Gaumont, A.-C.; Gulea, M.; Levillain, J. Chem. Rev.
2009, 109, 1371.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2723–2729

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