Microwave-assisted or Cu-NHC-catalyzed cycloaddition of azido-disubstituted alkynes: Bifurcation of reaction pathways

Article abstract of DOI:10.1021/jo5011262

Microwave irradiation promoted the intramolecular cycloaddition of 2-azidoacetamides derived from α-chiral propargylic amines, affording 1,4,5-trisubstituted triazoles 4 bearing a chiral aminomethyl side chain at C5. In contrast, for the same substrates 3

Full text of DOI:10.1021/jo5011262

Note
pubs.acs.org/joc
Microwave-Assisted or Cu−NHC-Catalyzed Cycloaddition of Azido-
Disubstituted Alkynes: Bifurcation of Reaction Pathways
†
†
†
,†
,‡,§
Yuyu Xia, Ling-yan Chen, Shang Lv, Zhihua Sun,* and Bing Wang*
†College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620,
China
‡
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
§
Institutes of Biomedical Sciences, Fudan University, 138 Yixueyuan Road, Shanghai 200032, China
*
S Supporting Information
ABSTRACT: Microwave irradiation promoted the intra-
molecular cycloaddition of 2-azidoacetamides derived from
α-chiral propargylic amines, affording 1,4,5-trisubstituted
triazoles 4 bearing a chiral aminomethyl side chain at C5. In
contrast, for the same substrates 3a−k, Cu(I)−NHC
complexes catalyzed the intermolecular cycloaddition in an
unexpected desilylative fashion, leading to 1,4-disubstituted
triazoles 5. This demonstrates that 1-silyl alkynes can be
employed as substrates for CuAAC with a suitable coupling
partner.
1
,2,3-Triazole is a well-known pharmacophore possessing a
azide function and explored their reactivity under both
microwave dielectric heating and Cu−NHC catalysis. This
enabled us to compare the scope and limitations of the two sets
of conditions for unsymmetrically disubstituted alkynes and to
determine whether the 1,5-regioselectivity of 1-silylated alkynes
also holds for CuAAC.
1
wide spectrum of interesting biological activities. The thermal
1,3-dipolar cycloaddition of azides to alkynes to form 1,2,3-
triazoles (Huisgen reaction) was first documented in 1893 and
studied in greater detail in the late 1950s and the 1960s.
However, this reaction in general has low regioselectivities for
even terminal alkynes. The copper-catalyzed variant of this
transformation (CuAAC), first reported in 2002, marked the
emergence of “click chemistry” and has since found wide-
spread applications in medicinal chemistry, materials science,
and chemical biology. A complementary ruthenium-catalyzed
approach (RuAAC) exhibits the opposite regioselectivity. With
the recent advances in N-hetereocyclic carbene (NHC)
chemistry, a few Cu−NHC complexes have been reported
to catalyze azide cycloaddition to terminal alkynes. While the
CuAAC of terminal alkynes enjoys excellent regioselectivity for
the 1,4-disubstituted adducts, unsymmetric internal alkynes
remain difficult substrates because of low reactivity and
problematic regioselectivity control. In this regard, several
groups have recently reported Huisgen reactions of well-
designed internal alkynes with unambiguous regioselectivity by
2
The substrates were based on synthetically versatile α-chiral
13
3
propargylic amines because of their ready availability, high
enantiopurity, and structural diversity. The preparation was
straightforward. After removal of the N-sulfinyl group,
4
14
5
amidation with azidoacetic acid produced the desired azido
alkynes in good yields (Scheme 1). The γ- and α-groups of the
propargylic amines constitute the C4 and C5 substituents of the
triazole.
6
7
8
Substrates 3 were first subjected to Cu-free microwave-
assisted cyclization at 160 °C (power = 200 W, maximum
internal pressure = 200 psi). The Huisgen cycloaddition
proceeded smoothly to form 1,4,5-trisubstituted triazoles 4 in
very good to excellent isolated yields (>85% in most cases;
Scheme 1. Synthesis of Azido Internal Alkynes
9
taking advantage of intramolecular reaction. Additionally,
Schubert and co-workers reported that 1-trimethylsilyl-
substituted alkynes are excellent substrates favoring the formal
1
,5-regioselective intermolecular AAC under thermal con-
1
0
ditions. However, the scope of CuAAC of unsymmetrically
disubstituted alkynes is still limited to 1-halo- and 1-metallo
11
(
Al, Bi)-substituted alkynes. As part our ongoing interest in
1
2
novel Cu−NHC complexes for organic synthesis, we
designed a series of disubstituted alkynes with a pendant
Received: June 11, 2014
©
XXXX American Chemical Society
A
dx.doi.org/10.1021/jo5011262 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1). Conventional heating at the same temperature proved
ineffective, and the starting material was recovered unchanged.
Table 2. Screening of Cu(I)−NHC Catalysts
Table 1. Intramolecular Cycloaddition of Azido Alkynes 3
under Microwave Irradiation
a
entry
NHC precursor
yield (%)
1
2
3
4
5
6
7
none
6
11
40
45
38
81
30
10
NR
66
a
entry
1
R′
2-propyl
R
product
yield (%)
7
8
TMS
4a
4a
4b
4c
4d
4e
4f
95
NR
97
96
85
90
87
93
94
b
9
2
2-propyl
TMS
10
11
9
3
4
5
6
7
8
9
cyclohexyl
TMS
cyclopropyl
1-adamantyl
benzyl
TMS
b
8
TMS
c
9
9
TMS
a
b
c
(E)-PhCHCH
4-Me-phenyl
4-MeO-phenyl
pyridin-3-yl
furan-2-yl
TMS
Isolated yields. In MeCN. In 1:1 t-BuOH/H
2
O.
TMS
4g
4h
4i
TMS
c
10
11
12
13
14
TMS
75
TMS
4j
88
85
80
75
d
e
N-Boc-indol-3-yl
4-MeO-phenyl
TMS
4k
4l
phenyl
cyclopropyl
e
4-MeO-phenyl
4m
a
b
Isolated yields. Upon oil bath heating to 160 °C for 4 h, 3a was
c
d
recovered (>90%). Yield after desilylation. The indole N-Boc
protection was simultaneously removed because of its lability. The
e
reaction time was 3 h.
Very bulky 1-adamantyl or heterocyclic R′ groups were all
tolerated, except in the case of 3i, where the silyl group was
partially cleaved because of its decreased stability in the
presence of the basic pyridine ring (entry 10). It is notable that
substrates 3a−k required only 1 h of microwave irradiation,
while the reaction time for the azido alkynes used in Taddei’s
study was three times longer. This suggests that placement of
a substituent at the α-carbon of the propargylic amine rather
than at the α-position of the carbonyl resulted in a more
favorable conformation placing the azido group and the alkyne
in proximity of each other to facilitate the cyclization. Replacing
the silyl group with either an aromatic group (phenyl) or an
alkyl group (cyclopropyl) still afforded satisfactory yields,
although a longer reaction time was necessary (entries 13 and
Figure 1. NHC precursors screened for the cycloaddition reaction.
Other mixed solvent systems such as 1:1 t-BuOH/H O
2
9a
afforded lower yields (entry 9). Under the optimal conditions,
a single isolable product was obtained in a satisfactory yield of
81% after 24 h at rt. NMR and MS analysis revealed that the
isolated product 5g was formed via an intermolecular reaction
with formal 1,4-regioselectivity (as confirmed by HMBC
experiments), opposite to that of the thermal AAC of silyl
10
alkynes. Furthermore, it is interesting that the TMS group
supposed to be on the heterocycle was absent, while the
terminal TMS of the unreacted alkyne was intact. The
spontaneous loss of TMS during an AAC reaction, without
the assistance of desilylation reagents, has not been reported to
date. In all cases with Cu−NHC catalysis, no intramolecular
reaction product was detected by either TLC or LC−MS. It is
also notable that further reaction of 5g, which possesses both
azide and alkyne functions, to form oligomers or polymers was
minimal without resorting to high-dilution conditions. Un-
14). Products 4 have the potential for further modifications
such as hydrolytic ring opening, reduction of the lactam, and
stereoselective α-alkylation. Moreover, the TMS group on the
triazole ring can be easily converted to halides and used for
15
subsequent cross-coupling.
Then the reaction of azido alkynes 3 using Cu−NHC
catalysis was examined at room temperature (Table 2).
Different types of NHC precursors, including those widely
represented in the literature (6−8; Figure 1) and the
benzoimidazole-based compounds recently reported by our
group (9−11), were screened using 3g as a model substrate. It
was found that the complex formed by the NHC derived from
16
fortunately, the accelerating effect of carboxylic acids in
CuAAC cannot be exploited in the present protocol, as HOAc
could decompose the Cu−NHC catalyst. The use of a Lewis
acid (ZnCl ) alone or with an NHC was also unproductive.
2
9
exhibited the highest catalytic activity in 50% aqueous
This protocol was then extended to other azido alkynes 3,
and the results are summarized in Table 3. A series of 1,4-
disubstituted 1,2,3-triazoles 5 carrying alkyne and azide
functions on the side chains were obtained (Table 3, entries
acetonitrile (Table 2, entry 5), while other Cu−NHC
complexes were less effective. In anhydrous solvents such as
MeCN, THF, tert-butanol, and DMF, no product was formed.
B
dx.doi.org/10.1021/jo5011262 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 3. Intermolecular CuAAC of 1-Silylated Alkynes 3
a
b
entry
R′
2-propyl
R
conversion (%)
product
yield (%)
1
2
3
4
5
6
7
8
9
TMS
73
5a
69
65
68
72
81
79
75
−
cyclohexyl
TMS
70
5b
5e
benzyl
TMS
70
(E)-PhCHCH
4-Me-phenyl
4-MeO-phenyl
furan-2-yl
TMS
75
5f
TMS
85
5g
TMS
84
5h
5j
TMS
78
4-MeO-phenyl
4-MeO-phenyl
phenyl
cyclopropyl
H
NR
NR
100
−
−
−
−
10
4-Me-phenyl
b
polymer
a
Based on recovered 3. Isolated yields.
1
−7). Although the reaction did not go to completion in 24 h
using 2-azidoacetamide. This could occur because the
corresponding transition states became slack and less favorable.
Therefore, we speculate that a cyclic transition state was
involved as a result of the dative interaction of the amide
carbonyl with the silyl group (eq 6). Without this neighboring
group, the formation of copper acetylide species could rely only
on the assistance of water, and this process is apparently not
efficient.
Compounds 4 were converted to unnatural amino acids 13
in very good yields upon microwave-assisted acid hydrolysis
(Scheme 3). These products may find application in the study
of conformationally constrained peptides and medicinal
chemistry.
In summary, the [3 + 2] cycloaddition of a series of
azidoacetamides derived from α-chiral propargylic amines was
investigated. Microwave irradiation promoted intramolecular
cycloaddition to afford 1,4,5-trisubstituted triazoles bearing a
chiral aminomethyl side chain at C5, while Cu(I)−NHC
complexes catalyzed intermolecular desilylative AAC of azido 1-
silyl alkynes at rt, leading to 1,4-disubstituted triazoles 5
without the heterocyclic TMS group. Intramolecular reaction
products were not detected under the present CuAAC
protocol, while analogous terminal alkynes underwent facile
polymerization. The controllable reaction pathways offer good
opportunities for building molecular diversity from readily
available chiral propargylic amines. The use of 1-silyl alkynes as
substrates for CuAAC will also enhance the application of this
reaction in organic synthesis.
(65−85% conversion), the yields based on reacted starting
material were excellent (>90%). In all cases, the triazole ring
did not bear a TMS group. Unfortunately, when the terminal
silyl group was replaced by a carbogenic group, the cyclo-
addition did not proceed, and the starting material was
recovered (entries 8 and 9). Interestingly, for an analogous
terminal alkyne substrate (desilylated 3g), polymer formation
17
was observed immediately (entry 10). Therefore, compound
represents a class of triazole-based bifunctional molecules that
5
is not readily accessible via the conventional AAC of terminal
alkynes.
In order to gain some insight into the mechanism for the
CuAAC of 1-silyl alkynes, several control experiments were
carried out (Scheme 2). When 1 equiv of benzyl azide was
reacted with 3g, only 5% of the product was 1-benzyl triazole
1
2, while 95% was the normal product 5g (eq 1). In view of the
fact that the intrinsic reactivities of azidoacetamide and benzyl
azide toward a terminal alkyne under Cu−NHC catalysis are
virtually the same (eq 2), this and the polymerization of
terminal alkyne (Table 3, entry 10) essentially ruled out free
terminal alkyne (formed by either Cu-catalyzed or simple base-
induced hydrolysis) as the key intermediate as well as the
presence of a desilylation step prior to CuAAC. Another
possible mechanism is that the amide carbonyl group may
participate in the reaction to facilitate removal of the TMS
group for the formation of copper acetylide species without
involving a free terminal alkyne. In order to test this possibility,
reactions 3 and 4 were conducted. The results showed that the
reaction between benzyl azide and 1-(trimethylsilyl)-
phenylacetylene was very sluggish under our CuAAC
conditions. However, the reaction of N-benzyl-2-azidoaceta-
mide with the same alkyne afforded the triazole in a good yield
EXPERIMENTAL SECTION
■
General Methods. All commercially available reagents were used
without purification unless otherwise noted. Acetonitrile was refluxed
with sodium under argon before use. Column chromatography was
performed using silica gel (300−400 mesh). Visualization of the
(
70%) in 24 h. Moreover, when the very bulky and
1
compounds was accomplished with UV light (254 nm) and iodine. H
hydrolytically stable 1-triisopropylsilyl group was employed to
cap the alkyne, a moderate yield of 58% could still be achieved.
This provides strong evidence that the adjacent functional
group of the azide plays an important role in promoting the
cleavage of the terminal silyl group regardless of its size. To
further illustrate this possibility, eq 5 showed that when the
azide and the carbonyl group were separated with more
methylene units, the reaction was significantly less efficient than
and 13C NMR spectra were recorded in CDCl operating at 400 and
3
1
00 MHz, respectively. Proton chemical shifts are reported relative to
the residual proton signals of the deuterated solvent [CDCl (7.26
3
ppm) or DMSO-d (2.50 and 3.33 ppm)] or TMS. Carbon chemical
6
shifts were internally referenced to the deuterated solvent signals in
CDCl (77.00 ppm) or DMSO-d (40.0 ppm). Data are represented as
3
6
follows: chemical shift (multiplicity, coupling constant in hertz,
integration). Multiplicities are denoted as follows: bs = broad singlet, s
C
dx.doi.org/10.1021/jo5011262 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Scheme 2. Control Experiments and a Plausible Mechanism for the Desilylative CuAAC
Scheme 3. Hydrolysis of 4 to Amino Acids
M HCl solution in dioxane (2 equiv) was added dropwise at 0 °C. The
solution was maintained at 0 °C for 1 h, and the solvent was removed
under vacuum. The residue was washed with 2:1 hexane/ether, and the
resulting solid was filtered and used directly for the next step without
further purification. Crude 2a (650 mg, 3.8 mmol) and DMAP (235
mg, 1.9 mmol) were mixed in methylene chloride in a flask, and the
mixture was cooled to 0 °C. HOBt (520 mg, 3.8 mmol) and
azidoacetic acid (390 mg, 3.8 mmol) were added, and the mixture was
allowed to warm to rt and maintained for 1 h. DCC (950 mg, 4.6
mmol) was added, and the reaction mixture was stirred at rt overnight.
The solvent was removed under vacuum, and the crude product was
purified by silica gel chromatography (eluent: 15:1 hexane/ethyl
=
singlet, d = doublet, t = triplet, m = multiplet. High-resolution mass
spectra were recorded on a liquid chromatograph−mass spectrometer
LCMS-IT-TOF). Microwave-assisted reactions were carried out using
(
a focused microwave unit (Biotage Initiator). The reaction temper-
atures during microwave heating were measured with an internal
infrared sensor.
Synthetic Procedures. General Procedure for the Synthesis of
Azido Alkynes 3: (S)-2-Azido-N-(4-methyl-1-(trimethylsilyl)pent-1-
yn-3-yl)acetamide (3a). In a dry flask, compound 1 (1 equiv) was
dissolved in a small amount of dioxane and methanol (10 equiv). A 2
1
acetate) to give 3a as a colorless oil (700 mg, 72.3%). H NMR (400
MHz, DMSO-d ) δ 8.56 (d, J = 8.8 Hz, 1H), 4.49−4.45 (m, 1H),
6
3
(
.89−3.79 (m, 2H), 1.82−1.77 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.90
d, J = 6.8 Hz, 3H), 0.15 (s, 9H). 13C NMR (100 MHz, DMSO-d ) δ
6
167.2, 105.0, 87.8, 50.8, 47.4, 32.9,19.2, 18.4, 0.4. HRMS (ESI-TOF)
+
calcd for C H N NaOSi [M + Na] 275.1299, found 275.1297.
11
20
4
D
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The Journal of Organic Chemistry
Note
(
S)-2-Azido-N-(1-cyclohexyl-3-(trimethylsilyl)prop-2-yn-1-yl)-
1H), 7.30−7.26 (m, 1H), 6.10 (d, J = 8.0 Hz, 1H), 3.94−3.81 (m,
1
13
acetamide (3b). A colorless oil (800 mg, 71%). H NMR (400 MHz,
DMSO-d ) δ 8.54 (d, J = 8.4 Hz, 1H), 4.49−4.45 (m, 1H), 3.88−3.79
2H), 1.63 (s, 9H), 0.20 (s, 9H). C NMR (100 MHz, DMSO-d ) δ
6
6
167.2, 149.2, 135.7, 128.0, 125.4, 124.6, 123.3, 120.1, 119.1, 115.4,
(
0
5
m, 2H), 1.83−1.6 (m, 5H), 1.46−1.42 (m, 1H), 1.26−0.96 (m, 5H),
1
03.9, 88.2, 84.6, 50.9, 37.6, 28.1, 0.2. HRMS (ESI-TOF) calcd for
.15 (s, 9H). 13C NMR (100 MHz, DMSO-d ) δ 167.1, 105.3, 87.7,
+
6
C H N NaO Si [M + Na] 448.1775, found 448.1766.
21
27
5
3
0.9, 46.6, 42.2, 29.2, 28.8, 26.3, 25.8, 25.7, 0.4. HRMS (ESI-TOF)
calcd for C H N NaOSi [M + Na] 315.1612, found 315.1607.
(
S)-2-Azido-N-(1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-yl)-
+
1
14
24
4
acetamide (3l). A white solid (860 mg, 70%). H NMR (400 MHz,
(
S)-2-Azido-N-(1-cyclopropyl-3-(trimethylsilyl)prop-2-yn-1-yl)-
DMSO-d ) δ 9.16 (d, J = 8.4 Hz, 1H), 7.49−7.40 (m, 7H), 6.97 (d, J =
6
1
acetamide (3c). A colorless oil (660 mg, 69%). H NMR (400 MHz,
8
3
1
.8 Hz, 2H), 6.03 (d, J = 8.4 Hz, 1H), 3.94−3.84 (m, 2H), 3.76 (s,
DMSO-d ) δ 8.70 (d, J = 8.4 Hz, 1H), 4.50−4.46 (m, 1H), 3.88−3.78
13
6
H). C NMR (100 MHz, DMSO-d ) δ 167.0, 159.4, 131.9, 131.6,
13
6
(
m, 2H), 1.15−1.06 (m, 1H), 0.51−0.29 (m, 4H), 0.14 (s, 9H). C
29.3, 129.2, 128.7, 122.4, 114.5, 88.8, 84.0, 55.7, 51.0, 44.2. HRMS
NMR (100 MHz, DMSO-d ) δ 167.0, 104.4, 86.9, 50.9, 44.3, 15.5, 3.3,
+
6
(ESI-TOF) calcd for C H N NaO [M + Na] 343.1165, found
+
18 16
4
2
2
2
.6, 0.4. HRMS (ESI-TOF) calcd for C H N NaOSi [M + Na]
73.1142, found 273.1130.
N-((S)-1-((3S,5S,7S)-Adamantan-1-yl)-3-(trimethylsilyl)prop-2-yn-
-yl)-2-azidoacetamide (3d). A colorless oil (800 mg, 61%). H NMR
400 MHz, DMSO-d ) δ 8.41 (d, J = 9.2 Hz, 1H), 4.35 (d, J = 9.6 Hz,
H), 3.86 (s, 2H), 1.97 (s, 3H), 1.68−1.50 (m, 12H), 0.16 (s, 9H).
C NMR (100 MHz, DMSO-d ) δ 167.5, 104.4, 88.4, 51.1, 50.9, 38.3,
11 18 4
3
43.1154.
(
S)-2-Azido-N-(3-cyclopropyl-1-(4-methoxyphenyl)prop-2-yn-1-
1
yl)acetamide (3m). A white solid (760 mg, 70%). H NMR (400
1
1
(
MHz, DMSO-d ) δ 8.95 (d, J = 8.4 Hz, 1H), 7.32 (d, J = 8.8 Hz, 2H),
6
6
6
.92 (d, J = 8.8 Hz, 2H), 5.72−5.69 (m, 1H), 3.88−3.77 (m, 2H), 3.74
1
1
3
(s, 3H), 1.40−1.34 (m, 1H), 0.82−0.77 (m, 2H), 0.63−0.59 (m, 2H).
6
13
C NMR (100 MHz, DMSO-d ) δ 166.7, 159.3, 132.2, 128.5, 114.3,
6
3
+
7.1, 36.8, 28.1, 0.1. HRMS (ESI-TOF) calcd for C H N NaOSi [M
18
28
4
+
87.8, 74.5, 55.6, 50.9, 43.8, 8.3. HRMS (ESI-TOF) calcd for
Na] 367.1925, found 367.1929.
S)-2-Azido-N-(1-phenyl-4-(trimethylsilyl)but-3-yn-2-yl)acetamide
+
C H N NaO [M + Na] 307.1165, found 307.1167.
15
16
4
2
(
1
General Procedure for Cu-Free Microwave-Assisted AAC: (S)-4-
(
8
3
3e). A yellow oil (800 mg, 69%). H NMR (400 MHz, DMSO-d ) δ
6
Isopropyl-3-(trimethylsilyl)-4,5-dihydro[1,2,3]triazolo[1,5-a]pyrazin-
6(7H)-one (4a). Compound 3a (126 mg, 0.5 mmol) was dissolved in
acetonitrile (20 mL) and water (5 mL). This solution was heated by
microwave irradiation to 160 °C and maintained at this temperature
for 1 h. The solvent was removed under vacuum. This gave sufficiently
.67 (d, J = 8.4 Hz, 1H), 7.31−7.23 (m, 5H), 4.78−4.73 (m, 1H),
13
.85−3.72 (m, 2H), 2.90−2.88 (m, 2H), 0.1 (s, 9H). C NMR (100
MHz, DMSO-d ) δ 167.0, 137.4, 130.0, 128.5, 127.1, 105.9, 88.0, 51.0,
6
4
3.2, 41.4, 0.2. HRMS (ESI-TOF) calcd for C H N NaOSi [M +
15 20 4
+
Na] 323.1299, found 323.1284.
S,E)-2-Azido-N-(1-phenyl-5-(trimethylsilyl)pent-1-en-4-yn-3-yl)-
2
5
pure 4a as a white solid (120 mg, 95%). Mp 176−177 °C. [α]
=
(
D
1
1
+
68.3 (c 0.23, MeOH). H NMR (400 MHz, DMSO-d ) δ 8.81 (d, J =
acetamide (3f). An orange-yellow solid (800 mg, 67%). H NMR
6
(
400 MHz, DMSO-d ) δ 8.91 (d, J = 8.0 Hz, 1H), 7.47−7.27 (m, 5H),
3.2 Hz, 1H), 5.15−5.00 (m, 2H), 4.59−4.58 (m, 1H), 1.99−1.95 (m,
6
6
3
1
.73−6.69 (m, 1H), 6.27−6.22 (m, 1H), 5.45−5.41 (m, 1H), 3.94−
1H), 1.01 (d, J = 7.2 Hz, 3H), 0.62 (d, J = 6.8 Hz, 3H), 0.30 (s, 9H).
.84 (m, 2H), 0.19 (s, 9H). 13C NMR (100 MHz, DMSO-d ) δ 167.0,
13
C NMR (100 MHz, DMSO-d ) δ 165.3, 139.6, 137.9, 53.5, 48.7,
6
6
+
36.1, 131.5, 129.2, 128.6, 127.1, 126.6, 104.0, 88.9, 50.9, 43.0, 0.3.
HRMS (ESI-TOF) calcd for C H N NaOSi [M + Na] 335.1299,
37.0, 19.8, 15.8, −0.4. MS (ESI) m/z 253.1 [M + H] . HRMS (ESI-
TOF) calcd for C H N OSi [M + H] 253.1479, found 253.1470.
+
+
16
20
4
11 21
4
found 335.1294.
(
(S)-4-Cyclohexyl-3-(trimethylsilyl)-4,5-dihydro-[1,2,3]triazolo[1,5-
S)-2-Azido-N-(1-(p-tolyl)-3-(trimethylsilyl)prop-2-yn-1-yl)-
a]pyrazin-6(7H)-one (4b). A white solid (142 mg, 97%). Mp 213−214
1
25
1
acetamide (3g). A light-yellow oil (850 mg, 74%). H NMR (400
°C. [α]D = +61.8 (c 0.17, MeOH). H NMR (400 MHz, DMSO-d ) δ
6
MHz, DMSO-d ) δ 9.09 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H),
6
8.81 (d, J = 3.2 Hz, 1H), 5.12−4.99 (m, 2H), 4.54 (s, 1H), 1.77−1.59
1
3
7
2
1
(
3
.20 (d, J = 8.0 Hz, 2H), 5.84 (d, J = 8.4 Hz, 1H), 3.92−3.80 (m, 2H),
(
m, 5H), 1.32−0.92 (m, 6H), 0.31 (s, 9H). C NMR (100 MHz,
.30 (s, 3H), 0.17 (s, 9H). 13C NMR (100 MHz, DMSO-d ) δ 167.0,
6
DMSO-d ) δ 165.2, 139.6, 137.6, 53.2, 48.8, 46.9, 29.9, 26.3, 26.1,
6
37.6, 136.4, 129.6, 127.2, 105.0, 88.6, 50.8, 44.5, 21.1, 0.3. HRMS
ESI-TOF) calcd for C H N NaOSi [M + Na] 323.1299, found
+
2
6.0, 25.8, −0.4. MS (ESI) m/z 293.2 [M + H] . HRMS (ESI-TOF)
+
+
15
20
4
calcd for C H N OSi [M + H] 293.1792, found 293.1785.
14 25 4
23.1292.
(
(
S)-4-Cyclopropyl-3-(trimethylsilyl)-4,5-dihydro-[1,2,3]triazolo-
S)-2-Azido-N-(1-(4-methoxyphenyl)-3-(trimethylsilyl)prop-2-yn-
[
1
1,5-a]pyrazin-6(7H)-one (4c). A white solid (120 mg, 96%). Mp
1
1
-yl)acetamide (3h). A light-yellow oil (800 mg, 69%). H NMR (400
25
1
51−152 °C. [α]D = +50.2 (c 0.20, MeOH). H NMR (400 MHz,
MHz, DMSO-d ) δ 9.07 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H),
6
DMSO-d ) δ 8.79 (d, J = 3.6 Hz, 1H), 5.23−5.00 (m, 2H), 4.49−4.47
6
6
3
1
(
3
.95 (d, J = 8.4 Hz, 2H), 5.82 (d, J = 8.4 Hz, 1H), 3.91−3.75 (m, 2H),
13
(
m, 1H), 1.26−1.19 (m, 1H), 0.51−0.49 (m, 4H), 0.46 (s, 9H).
C
.35 (s, 3H), 0.17 (s, 9H). 13C NMR (100 MHz, DMSO-d ) δ 166.9,
6
NMR (100 MHz, DMSO-d ) δ 165.2, 139.7, 137.6, 50.0, 48.8, 19.0,
6
59.4, 131.3, 128.6, 114.4, 105.1, 88.5, 55.6, 50.8, 44.2, 0.3. HRMS
ESI-TOF) calcd for C H N NaO Si [M + Na] 339.1248, found
+
2
.8, 2.3, −0.3. MS (ESI) m/z 251.1 [M + H] . HRMS (ESI-TOF)
calcd for C H N OSi [M + H] 251.1323, found 251.1318.
+
15
20
4
2
+
11
19
4
39.1237.
(
(
4S)-4-((1R,3R,5S)-Adamantan-1-yl)-3-(trimethylsilyl)-4,5-dihy-
S)-2-Azido-N-(1-(pyridin-3-yl)-3-(trimethylsilyl)prop-2-yn-1-yl)-
1
dro-[1,2,3]triazolo[1,5-a]pyrazin-6(7H)-one (4d). This was further
acetamide (3i). A white solid (600 mg, 54%). H NMR (400 MHz,
purified by silica gel chromatography (eluent: 5:1 hexane/acetone) to
DMSO-d ) δ 9.25 (d, J = 8.0 Hz, 1H), 8.65 (d, J = 0.2 Hz, 1H), 8.55−
6
25
give a white solid (152 mg, 85%). Mp 297−298 °C. [α] = +78.4 ( c
D
8
=
.53 (m, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.46−7.43 (m, 1H), 5.97 (d, J
1
13
0.18, MeOH). H NMR (400 MHz, DMSO-d
6
) δ 8.85 (d, J = 4.0 Hz,
8.4 Hz, 1H), 3.96−3.85 (m, 2H), 0.18 (s, 9H). C NMR (100
1
1
H), 5.13−4.96 (m, 2H), 4.07 (d, J = 4.4 Hz, 1H), 1.96 (s, 3H), 1.65−
MHz, DMSO-d ) δ 167.2, 149.5, 148.7, 135.1, 135.0, 124.1, 103.8,
6
13
.44 (m, 12H), 0.33 (s, 9H). C NMR (100 MHz, DMSO-d ) δ
5
0.9, 42.9, 31.1, 0.2. HRMS (ESI-TOF) calcd for C H N NaO [M +
Na] 238.0699, found 238.0686.
6
10
9
5
+
165.8, 141.4, 135.2, 57.7, 49.9, 38.4, 36.5, 28.0, 0.1. MS (ESI) m/z
+
+
3
45.2 [M + H] . HRMS (ESI-TOF) calcd for C H N OSi [M + H]
(
R)-2-Azido-N-(1-(furan-2-yl)-3-(trimethylsilyl)prop-2-yn-1-yl)-
18 29 4
1
acetamide (3j). A yellow oil (700 mg, 66%). H NMR (400 MHz,
345.2105, found 345.2106.
DMSO-d ) δ 9.18 (d, J = 8.4 Hz, 1H), 7.67 (s, 1H), 6.45−6.40 (m,
(S)-4-Benzyl-3-(trimethylsilyl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]-
pyrazin-6(7H)-one (4e). This was further purified by silica gel
chromatography (eluent: 5:1 hexane/acetone) to give a light-yellow
6
13
2
H), 5.94 (d, J = 8.0 Hz, 1H), 3.92−3.82 (m, 2H), 0.17 (s, 9H). C
NMR (100 MHz, DMSO-d ) δ 167.1, 150.9, 143.8, 111.0, 108.1,
6
2
5
solid (135 mg, 90%). Mp 206−207 °C. [α] = +169.1 ( c 0.15,
1
02.2, 88.1, 50.7, 39.0, 0.2. HRMS (ESI-TOF) calcd for
D
+
1
C H N NaO Si [M + Na] 299.0935, found 299.0928.
MeOH). H NMR (400 MHz, DMSO-d ) δ 8.75 (d, J = 3.6 Hz, 1H),
6
1
2
(
16
4
2
S)-tert-Butyl 3-(1-(2-Azidoacetamido)-3-(trimethylsilyl)prop-2-
7.28−7.19 (m, 3H), 6.74−6.72 (m, 2H), 5.14−5.11 (m, 1H), 4.70 (d, J
yn-1-yl)-1H-indole-1-carboxylate (3k). A yellow oil (1.036 g, 60%).
= 17.2 Hz, 1H), 3.29 (d, J = 17.6 Hz, 1H), 3.15−3.10 (m, 1H), 2.99−
1
13
H NMR (400 MHz, DMSO-d ) δ 9.11 (d, J = 8.4 Hz, 1H), 8.10 (d, J
2.95 (m, 1H), 0.37 (s, 9H). C NMR (100 MHz, DMSO-d ) δ 164.8,
6
6
=
8.4 Hz, 1H), 7.69 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.40−7.36 (m,
139.7, 137.1, 134.9, 130.5, 128.7, 127.6, 49.0, 48.0, 43.8, −0.4. MS
E
dx.doi.org/10.1021/jo5011262 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
+
+
+
(
ESI) m/z 301.1 [M + H] . HRMS (ESI-TOF) calcd for
[M + H] . HRMS (ESI-TOF) calcd for C H N O [M + H]
18 17 4 2
+
C H N OSi [M + H] 301.1479, found 301.1483.
321.1346, found 321.1344.
15
21
4
(
S,E)-4-Styryl-3-(trimethylsilyl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]-
(S)-3-Cyclopropyl-4-(4-methoxyphenyl)-4,5-dihydro-[1,2,3]-
triazolo[1,5-a]pyrazin-6(7H)-one (4m). Reaction time: 3 h. This was
pyrazin-6(7H)-one (4f). This was further purified by silica gel
chromatography (eluent: 5:1 hexane/acetone) to give an orange-
further purified by silica gel chromatography (eluent: 5:1 hexane/
25
25
yellow solid (136 mg, 87%). Mp 197−198 °C. [α] = +94.3 ( c 0.21,
acetone) to give a white solid (107 mg, 75%). Mp 118−119 °C. [α]
D
D
1
1
MeOH). H NMR (400 MHz, DMSO-d ) δ 8.96 (d, J = 3.2 Hz, 1H),
= +31.1 ( c 0.30, MeOH). H NMR (400 MHz, DMSO-d ) δ 9.06 (d,
6
6
7
.46−7.29 (m, 5H), 6.65 (d, J = 15.6 Hz, 1H), 6.35−6.29 (m, 1H),
J = 2.4 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H),
5.90 (s, 1H), 5.26−5.02 (m, 2H), 3.75 (s, 3H), 0.77−0.73 (m, 1H),
13
5
.43−5.40 (m, 1H), 5.17−5.06 (m, 2H), 0.25 (s, 9H). C NMR (100
13
MHz, DMSO-d ) δ 164.3, 140.5, 136.7, 136.0, 132.2, 129.3, 128.8,
0.63−0.56 (m, 2H), 0.53−0.48 (m, 2H). C NMR (100 MHz,
6
+
1
28.1, 127.1, 51.0, 48.5, −0.5. MS (ESI) m/z 313.1 [M + H] . HRMS
DMSO-d
) δ 164.0, 159.6, 143.1, 132.5, 129.1, 128.8, 114.6, 55.7, 51.4,
6
+
+
(
ESI-TOF) calcd for C H N OSi [M + H] 313.1479, found
48.6, 7.4, 7.0, 6.0. MS (ESI) m/z 285.1 [M + H] . HRMS (ESI-TOF)
calcd for C15H N O [M + H] 285.1346, found 285.1347.
17 4 2
16 21 4
+
3
01.1466.
S)-4-(p-Tolyl)-3-(trimethylsilyl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]-
pyrazin-6(7H)-one (4g). A white solid (140 mg, 93%). Mp 199−200
(
General Procedure for Cu−NHC-Catalyzed AAC: 2-Azido-N-((S)-
2-methyl-1-(1-(2-(((S)-4-methyl-1-(trimethylsilyl)pent-1-yn-3-yl)-
amino)-2-oxoethyl)-1H-1,2,3-triazol-4-yl)propyl)acetamide (5a).
The NHC precursor 9 (15 mg, 0.05 mmol) was dissolved in
acetonitrile (3 mL) under nitrogen. To this was added CuCl (5 mg,
0.05 mmol) and sodium tert-butoxide (4.8 mg, 0.05 mmol). The
mixture was stirred for 3 h at rt. Then 3a (150 mg, 0.5 mmol) and
water (3 mL) were added successively to the reaction mixture, and the
resulting solution was stirred at rt for 24 h. After removal of the
solvent under vacuum, the crude product was purified by silica gel
chromatography (eluent: 5:1 hexane/acetone) to give 5a as a white
C. [α]2 = +124.1 (c 0.19, MeOH). H NMR (400 MHz, DMSO-d )
5
1
°
D
6
δ 9.07 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.08 (d, J = 8.0
Hz, 2H), 5.83 (s, 1H), 5.34−5.11 (m, 2H), 2.29 (s, 3H), 0.01 (s, 9H).
1
3
C NMR (100 MHz, DMSO-d ) δ 163.5, 140.4, 138.4, 138.4, 137.4,
6
+
1
29.8, 128.2, 52.5, 48.3, 21.2, −1.0. MS (ESI) m/z 301.1 [M + H] .
+
HRMS (ESI-TOF) calcd for C H N OSi [M + H] 301.1479, found
1
5
21
4
3
01.1480.
S)-4-(4-Methoxyphenyl)-3-(trimethylsilyl)-4,5-dihydro-[1,2,3]-
triazolo[1,5-a]pyrazin-6(7H)-one (4h). A white solid (149 mg, 94%).
(
2
5
2
5
1
solid (149 mg, 69%). Mp 108−109 °C. [α] = +170.8 (c 0.20,
Mp 171−172 °C. [α] = +136.9 (c 0.19, MeOH). H NMR (400
MHz, DMSO-d ) δ 9.05 (s, 1H), 7.12 (d, J = 8.8 Hz, 2H), 6.92 (d, J =
8
9
1
D
D
1
MeOH). H NMR (400 MHz, CD OD) δ 7.91 (s, 1H), 5.18 (s, 2H),
3
6
4
.97 (d, J = 7.6 Hz, 1H), 4.55 (d, J = 6.0 Hz, 1H), 3.93 (m, 2H), 2.30−
.4 Hz, 2H), 5.83 (s, 1H), 5.33−5.10 (m, 2H), 3.74 (s, 3H), −0.01 (s,
H). 13C NMR (100 MHz, DMSO-d ) δ 163.4, 159.8, 140.4, 137.6,
2.23 (m, 1H), 1.95−1.86 (m, 1H), 1.04−0.99 (m, 9H), 0.92 (d, J = 6.8
6
Hz, 3H), 0.18 (s, 9H). 13C NMR (100 MHz, CD OD) δ 168.3, 165.4,
33.4, 129.6, 114.6, 55.7, 52.2, 48.3, 31.1, −1.0. MS (ESI) m/z 317.1
3
+
+
124.1, 102.9, 87.9, 51.6, 51.5, 51.4, 32.8, 32.1, 18.3, 17.8, 17.6, 16.8,
[
M + H] . HRMS (ESI-TOF) calcd for C H N O Si [M + H]
15 21 4 2
+
−
19 33
1.5. MS (ESI) m/z 433.2 [M + H] . HRMS (ESI-TOF) calcd for
3
17.1428, found 317.1419.
S)-4-(Pyridin-3-yl)-4,5-dihydro-[1,2,3]triazolo[1,5-a]pyrazin-
(7H)-one (4i). This was further purified by silica gel chromatography
+
C H N O Si [M + H] 433.2490, found 433.2492.
(
8
2
2
-Azido-N-((S)-cyclohexyl(1-(2-(((S)-1-cyclohexyl-3-
trimethylsilyl)prop-2-yn-1-yl)amino)-2-oxoethyl)-1H-1,2,3-triazol-
4-yl)methyl)acetamide (5b). A white solid (166 mg, 65%). Mp 158−
6
(
(
eluent: 2:1 hexane/acetone) to give a light-yellow oil (108 mg, 75%).
2
5
1
[α] = +67.6 (c 0.19, MeOH). H NMR (400 MHz, DMSO-d ) δ
D
6
59 °C. [α]D = +82.1 (c 0.17, MeOH). 1H NMR (400 MHz,
CD OD) δ 7.90 (s, 1H), 5.16 (s, 2H), 4.98 (d, J = 8.0 Hz, 1H), 4.54
d, J = 6.8 Hz, 1H), 3.91 (m, 2H), 1.92−1.56 (m, 12H), 1.31−0.99
25
1
9
.11 (s, 1H), 8.65 (s, 1H), 8.58 (s, 1H), 7.78 (d, J = 8.0 Hz, 1H), 7.54
13
3
(
s, 1H), 7.45−7.42 (m, 1H), 6.09 (s, 1H), 5.31−5.11 (m, 2H).
C
(
NMR (100 MHz, DMSO-d ) δ 164.4, 150.1, 148.9, 135.3, 132.1,
6
13
+
(m, 10H), 0.18 (s, 9H). C NMR (100 MHz, CD
OD) δ 168.2,
3
1
30.2, 49.7, 48.5. MS (ESI) m/z 216.1 [M + H] . HRMS (ESI-TOF)
+
165.4, 147.0, 124.2, 103.3, 87.9, 51.5, 51.5, 50.7, 42.4, 41.6, 29.6, 28.9,
calcd for C H N O [M + H] 216.0880, found 216.0877.
10
10
5
+
2
8.8, 28.4, 25.9, 25.6, 25.6, 25.5, −1.5. MS (ESI) m/z 513.3 [M + H] .
(
R)-4-(Furan-2-yl)-3-(trimethylsilyl)-4,5-dihydro-[1,2,3]triazolo-
1,5-a]pyrazin-6(7H)-one (4j). This was further purified by silica gel
chromatography (eluent: 5:1 hexane/acetone) to give a light-yellow
+
HRMS (ESI-TOF) calcd for C H N O Si [M + H] 513.3116,
25
41
8
2
[
found 513.3127.
2
5
2-Azido-N-((S)-1-(1-(2-oxo-2-(((S)-1-phenyl-4-(trimethylsilyl)but-
solid (121 mg, 88%). Mp 160−161 °C. [α] = +85.5 ( c 0.24,
MeOH). H NMR (400 MHz, DMSO-d ) δ 9.17 (d, J = 3.2 Hz, 1H),
D
1
3-yn-2-yl)amino)ethyl)-1H-1,2,3-triazol-4-yl)-2-phenylethyl)-
6
25
acetamide (5e). A white syrup (179 mg, 68%). [α] = +119.7 (c 0.15,
D
7
5
1
.64 (d, J = 0.8 Hz, 1H), 6.47−6.42 (m, 2H), 6.03 (d, J = 3.2 Hz, 1H),
1
MeOH). H NMR (400 MHz, CD OD) δ 7.77 (s, 1H), 7.31−7.18
13
3
.23−5.14 (m, 2H), 0.15 (s, 9H). C NMR (100 MHz, DMSO-d ) δ
6
(
1
=
m, 10H), 5.43−5.39 (m, 1H), 5.13−5.03 (m, 2H), 4.88−4.86 (m,
64.3, 152.0, 144.0, 140.6, 135.2, 111.3, 108.7, 48.5, 46.1, 31.1, −0.9.
H), 3.81 (s, 2H), 3.33−3.29 (m, 1H), 3.20−3.14 (m, 1H), 2.97 (d, J
+
MS (ESI) m/z 277.1 [M + H] . HRMS (ESI-TOF) calcd for
C H N O Si [M + H] 277.1115, found 227.1103.
13
6.8 Hz, 2H), 0.14 (s, 9H). C NMR (100 MHz, CD OD) δ 168.0,
3
+
12
17
4
2
1
1
+
65.2, 137.4, 136.6, 129.4, 129.0, 128.0, 127.9, 126.5, 126.3, 123.8,
(S)-4-(1H-Indol-3-yl)-3-(trimethylsilyl)-4,5-dihydro-[1,2,3]triazolo-
03.7, 88.2, 51.5, 51.5, 43.5, 41.1, 40.0, −1.6. MS (ESI) m/z 529.2 [M
[1,5-a]pyrazin-6(7H)-one (4k). This was further purified by silica gel
+
+
H] . HRMS (ESI-TOF) calcd for C H N O Si [M + H]
2
7
33
8
2
chromatography (eluent: 5:1 hexane/acetone) to give an orange-
yellow solid (138 mg, 85%). Mp 256−257 °C. [α] = +116.2 ( c 0.10,
MeOH). H NMR (400 MHz, DMSO-d ) δ 11.19 (s, 1H), 8.95 (d, J =
5
29.2492, found 529.2483.
2
5
D
2
-Azido-N-((S,E)-1-(1-(2-oxo-2-(((S,E)-1-phenyl-5-(trimethylsilyl)-
1
6
pent-1-en-4-yn-3-yl)amino)ethyl)-1H-1,2,3-triazol-4-yl)-3-
2
.0 Hz, 1H), 7.39−7.31 (m, 2H), 7.10−6.89 (m, 3H), 6.16 (d, J = 1.6
phenylallyl)acetamide (5f). A white solid (198 mg, 72%). Mp 115−
13
Hz, 1H), 5.35−5.14 (m, 2H), −0.16 (s, 9H). C NMR (100 MHz,
DMSO-d ) δ 163.6, 140.3, 138.1, 136.9, 125.5, 125.1, 122.0, 119.6,
1
25
1
1
16 °C. [α]D = −20.3 (c 0.20, MeOH). H NMR (400 MHz,
6
CD OD) δ 7.36 (s, 1H), 7.35−7.31 (m, 4H), 7.29−7.24 (m, 6H), 6.81
3
+
18.7, 114.1, 112.3, 48.2, 46.0, −1.1. MS (ESI) m/z 326.1 [M + H] .
(
d, J = 15.6 Hz, 1H), 6.69 (d, J = 16.0 Hz, 1H), 6.55−6.49 (m, 1H),
+
HRMS (ESI-TOF) calcd for C H N OSi [M + H] 326.1432, found
16
20
5
6.25−6.20 (m, 1H), 5.94 (d, J = 6.4 Hz, 1H), 5.49−5.47 (m, 1H), 5.23
3
26.1426.
S)-4-(4-Methoxyphenyl)-3-phenyl-4,5-dihydro-[1,2,3]triazolo-
1,5-a]pyrazin-6(7H)-one (4l). Reaction time: 3 h. This was further
purified by silica gel chromatography (eluent: 5:1 hexane/acetone) to
13
(
s, 2H), 3.98 (s, 2H), 0.22 (s, 9H). C NMR (100 MHz, CD OD) δ
3
(
1
1
4
68.0, 165.2, 147.2, 136.4, 136.1, 132.2, 132.1, 128.3, 128.2, 127.8,
27.6, 126.3, 126.3, 126.2, 124.9, 124.2, 101.9, 89.0, 56.9, 51.6, 51.5,
[
+
3.3, −1.6. MS (ESI) m/z 553.2 [M + H] . HRMS (ESI-TOF) calcd
2
5
give a light-yellow oil (128 mg, 80%). [α] = +137.9 ( c 0.38, MeOH).
+
D
for C H N NaO Si [M + Na] 575.2310, found 575.2296.
29
32
8
2
1
H NMR (400 MHz, DMSO-d ) δ 9.21 (d, J = 2.4 Hz, 1H), 7.62−7.60
6
2-Azido-N-((S)-(1-(2-oxo-2-(((S)-1-(p-tolyl)-3-(trimethylsilyl)prop-
(
6
(
m, 2H), 7.37−7.28 (m, 3H), 7.17−7.15 (m, 2H), 6.85−6.82 (m, 2H),
2-yn-1-yl)amino)ethyl)-1H-1,2,3-triazol-4-yl)(p-tolyl)methyl)-
13
25
.22 (d, J = 3.2 Hz, 1H), 5.41−5.18 (m, 2H), 3.69 (s, 3H). C NMR
100 MHz, DMSO-d ) δ 163.5, 159.6, 141.3, 132.3, 130.7, 129.1,
acetamide (5g). A white solid (214 mg, 81%). Mp 85−86 °C. [α]
=
D
1
−8.6 (c 0.36, MeOH). H NMR (400 MHz, CD OD) δ 7.73 (s, 1H),
7.36 (d, J = 8.0 Hz, 2H), 7.27 (d, J = 8.0 Hz, 2H), 7.20−7.18 (m, 4H),
6
3
1
29.0, 128.4, 128.2, 126.9, 114.6, 55.6, 51.8, 48.9. MS (ESI) m/z 321.1
F
dx.doi.org/10.1021/jo5011262 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
6
2
1
1
+
.32 (s, 1H), 5.86 (s, 1H), 5.19−5.10 (m, 2H), 4.00−3.91 (m, 2H),
Special Scientific Foundation for Outstanding Young Teachers
in Shanghai (ZZGJD13020), City Level Subjects of Shanghai
University of Engineering and Technology (14XKCZ04), the
Program for Special Appointment (Eastern Scholar) at
Shanghai Institutions of Higher Education, and startup funding
from Shanghai University of Engineering Science (E1-0501-14-
0124 and NHRC-2014-05).
.35 (m, 6H), 0.20 (s, 9H). 13C NMR (100 MHz, CD OD) δ 167.9,
3
65.1, 137.8, 137.4, 136.8, 135.5, 129.0, 129.0, 126.9, 126.6, 124.6,
03.0, 88.7, 51.5, 51.4, 49.5, 45.0, 19.7, −1.6. MS (ESI) m/z 529.2 [M
+
+
H] . HRMS (ESI-TOF) calcd for C H N O Si [M + H]
2
7
33
8
2
5
29.2490, found 529.2498.
2
-Azido-N-((S)-(4-methoxyphenyl)(1-(2-(((S)-1-(4-methoxyphen-
yl)-3-(trimethylsilyl)prop-2-yn-1-yl)amino)-2-oxoethyl)-1H-1,2,3-tri-
azol-4-yl)methyl)acetamide (5h). A white solid (221 mg, 79%). Mp
2
5
1
6
1−62 °C. [α] = −9.4 (c 0.17, MeOH). H NMR (400 MHz,
D
REFERENCES
CD OD) δ 7.73 (s, 1H), 7.40 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.8 Hz,
■
3
2
2
H), 6.93−6.90 (m, 4H), 6.30 (s, 1H), 5.85 (s, 1H), 5.18−5.05 (m,
(1) For a review, see: Agalave, S. G.; Maujan, S. R.; Pore, V. S.
Chem.Asian J. 2011, 6, 2696−2718.
13
H), 3.99−3.89 (m, 2H), 3.80−3.79 (m, 6H), 0.20 (s, 9H). C NMR
(
100 MHz, CD OD) δ 167.9, 165.0, 159.7, 159.5, 148.2, 131.8, 130.4,
(2) (a) Michael, A. J. Prakt. Chem. 1893, 46, 94. (b) Kirmse, W.;
Horner, L. Justus Liebigs Ann. Chem. 1958, 614, 1−3. (c) Huisgen, R.
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Ed. Engl. 1963, 2, 565−598. (e) Huisgen, R. Angew. Chem., Int. Ed.
Engl. 1963, 2, 633−645.
3
1
4
28.3, 128.0, 124.5, 113.8, 113.7, 103.1, 88.7, 54.4, 54.4, 51.5, 51.4,
9.3, 44.7, −1.5. MS (ESI) m/z 561.2 [M + H] . HRMS (ESI-TOF)
+
+
calcd for C H N NaO Si [M + Na] 583.2208, found 583.2203.
27
32
8
4
2
-Azido-N-((R)-furan-2-yl(1-(2-(((R)-1-(furan-2-yl)-3-
(
trimethylsilyl)prop-2-yn-1-yl)amino)-2-oxoethyl)-1H-1,2,3-triazol-
(
3) (a) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
25
4
-yl)methyl)acetamide (5j). A light-yellow oil (180 mg, 75%). [α] =
D
1
2
002, 67, 3057−3064. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V.
+
13.9 (c 0.33, MeOH). H NMR (400 MHz, CD OD) δ 7.96 (s, 1H),
3
V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596−2599. For
selected reviews, see: (c) Hein, J.; Fokin, V. V. Chem. Soc. Rev. 2010,
7
.51−7.49 (m, 2H), 6.47−6.32 (m, 5H), 5.97 (m, 1H), 5.24−5.15 (m,
13
2
H), 3.99−3.91 (m, 2H), 0.20 (s, 9H). C NMR (100 MHz,
3
2
9, 1302−1315. (d) Kappe, C. O.; Van der Eycken, E. Chem. Soc. Rev.
010, 39, 1280−1290. (e) Liang, L.; Astruc, D. Coord. Chem. Rev.
CD OD) δ 168.0, 165.2, 151.7, 150.5, 145.6, 142.9, 142.9, 142.6,
3
1
24.7, 110.1, 107.6, 107.4, 100.3, 88.1, 51.4, 51.3, 43.9, 39.4, −1.7. MS
+
2011, 255, 2933−2945. (f) Jewett, J. C.; Bertozzi, C. R. Chem. Soc. Rev.
2010, 39, 1272−1279.
(
(
ESI) m/z 481.1 [M + H] . HRMS (ESI-TOF) calcd for
+
C H N O Si [M + H] 481.1763, found 481.1766.
21
25
8
4
4) (a) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int.
General Procedure for Microwave-Assisted Acid Hydrolysis: (S)-2-
Ed. 2001, 40, 2004−2021. (b) Evans, R. A. Aust. J. Chem. 2007, 60,
384−395.
(5) (a) Kolb, H. C.; Sharpless, K. B. Res. Focus 2003, 8, 1128−1137.
(b) Gil, M. V.; Arevalo, M. J.; Lopez, O. Synthesis 2007, 1589−1620.
(c) Aureggi, V.; Sedelmeier, G. Angew. Chem., Int. Ed. 2007, 46, 8440−
8444. (d) Demko, Z. P.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002,
(
(
5-(Amino(cyclohexyl)methyl)-1H-1,2,3-triazol-1-yl)acetic Acid
13b). Compound 4b (55 mg, 0.22 mmol) was added to 6 M
aqueous HCl (2.7 mL), and the mixture was heated under microwave
conditions at 85 °C for three cycles of 1 h each. The solution was
washed with CHCl (4 × 3 mL), and the aqueous layer was evaporated
3
under vacuum to give compound 13b as a light-yellow solid (44.6 mg,
2
5
1
8
5% yield). Mp 96−97 °C. [α] = +11.1 (c 0.75, MeOH). H NMR
41, 2110−2113. (e) Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic,
Z.; Carlier, P. R.; Taylor, P.; Finn, M. G.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 1053−1057. (f) Pachon, L. D.; Van
́
D
(
400 MHz, CD OD) δ 7.98 (s, 1H), 5.54−5.39 (AB, J = 18.0 Hz,
H), 4.45 (d, J = 9.2 Hz, 1H), 2.04−1.28 (m, 11H). C NMR (100
3
AB
13
2
́
MHz, CD OD) δ 168.4, 135.4, 132.1, 49.2 (2C), 41.0, 28.7, 28.6, 25.3,
Maarseveen, J. H.; Rothenberg, G. Adv. Synth. Catal. 2005, 347, 811−
815. (g) Lipshutz, B. H.; Taft, B. R. Angew. Chem., Int. Ed. 2006, 45,
8235−8238.
3
+
2
2
5.1 (2C). HRMS (ESI-TOF) calcd for C H N NaO [M + Na]
61.1322, found 261.1319.
S,E)-2-(5-(1-Amino-3-phenylallyl)-1H-1,2,3-triazol-1-yl)acetic
11 18 4 2
(
(6) (a) Zhang, L.; Chen, X.; Xue, P.; Sun, H. H. Y.; Williams, I. D.;
Sharpless, K. B.; Fokin, V. V.; Jia, G. J. Am. Chem. Soc. 2005, 127,
15998−15999. (b) Boren, B. C.; Narayan, S.; Rasmussen, L. K.;
Zhang, L.; Zhao, H.; Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc.
Acid (13f). A yellow solid (45.4 mg, 80% yield). Mp 127−128 °C.
2
5
1
[α] = +103.4 (c 0.30, MeOH). H NMR (400 MHz, D O) δ 7.91 (s,
D
2
1
H), 7.46−7.44 (m, 2H), 7.37−7.32 (m, 3H), 6.82 (d, J = 16.0 Hz,
H), 6.32 (dd, J = 15.6, 8.0 Hz, 1H), 5.33 (d, J = 8.0 Hz, 1H), 5.04
1
2
008, 130, 8923−8930. (c) Rasmussen, L. K.; Boren, B. C.; Fokin, V.
(
AB, JAB = 17.6 Hz, 2H). 13C NMR (100 MHz, D O) δ 172.2, 136.9,
2
V. Org. Lett. 2007, 9, 5337−5339. (d) Majireck, M. M.; Weinreb, S. M.
1
35.0, 134.7, 132.8, 129.3, 129.0, 127.1, 120.7, 52.1, 47.3. HRMS (ESI-
J. Org. Chem. 2006, 71, 8680−8683.
+
TOF) calcd for C H N NaO [M + Na] 281.1009, found 281.1001.
13
14
4
2
(
́
7) (a) Díez-Gonzalez, S.; Stevens, E. D.; Nolan, S. P. Chem.
Commun. 2008, 4747−4749. (b) Glorius, F. Top. Organomet. Chem.
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ASSOCIATED CONTENT
Supporting Information
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̈
*
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2010, 49, 6940−6952. (d) Mahatthananchai, J.; Bode, J. W. Acc. Chem.
Res. 2014, 47, 696−707. (e) N-Heterocyclic Carbenes in Transition
Metal Catalysis and Organocatalysis; Cazin, C. S. J., Ed.; Springer:
Dordrecht, The Netherlands, 2010.
NMR spectra of all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
(
́
8) (a) Díez-Gonzalez, S.; Correa, A.; Cavallo, L.; Nolan, S. P.
AUTHOR INFORMATION
Corresponding Authors
E-mail: sungaris@gmail.com.
E-mail: wangbing@fudan.edu.cn.
■
Chem.Eur. J. 2006, 12, 7558−7564. Two examples using a simple
symmetric alkyne were reported in this paper. (b) Nakamura, T.;
Terashima, T.; Ogata, K.; Fukuzawa, S. Org. Lett. 2011, 13, 620−623.
*
*
(
́
c) Díez-Gonzalez, S.; Collinson, J. M.; Wilton-Ely, J. D. E. T. Chem.
Notes
Commun. 2013, 49, 11358−11360.
The authors declare no competing financial interest.
(9) For cycloaddition of azides to internal alkynes, see: (a) Balducci,
E.; Bellucci, L.; Petricci, E.; Taddei, M.; Tafi, A. J. Org. Chem. 2009, 74,
1
314−1321. (b) Mont, N.; Mehta, V. P.; Appukkuttan, P.; Beryozkina,
ACKNOWLEDGMENTS
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T.; Toppet, S.; Van Hecke, K.; Van Meervelt, L.; Voet, A.; DeMaeyer,
M.; Van der Eycken, E. J. Org. Chem. 2008, 73, 7509−7516. (c) Brawn,
R. A.; Welzel, M.; Lowe, T.; Panek, J. S. Org. Lett. 2010, 12, 336−339.
The authors thank Professor Erkang Fan (University of
Washington) for helpful discussions and are grateful for
financial support from the Shanghai Municipal Education
Commission (14ZZ159), the Shanghai Municipal Science and
Technology Commission (12430501300), the National Natural
Science Foundation of China (21072032 and 21272039), the
(d) De Moliner, F.; Crosignani, S.; Galatini, A.; Riva, R.; Basso, A. ACS
Comb. Sci. 2011, 13, 453−457. (e) Fiandanese, V.; Maurantonio, S.;
Punzi, A.; Rafaschieri, G. Org. Biomol. Chem. 2012, 10, 1186−1195.
For an interesting stepwise formal cycloaddition, see: (f) Zhang, H.;
G
dx.doi.org/10.1021/jo5011262 | J. Org. Chem. XXXX, XXX, XXX−XXX

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(
17) Slow addition of a dilute solution of the same substrate to the
Cu−NHC catalyst produced the “dimer” and “trimer” in a 65:35 ratio
(
as determined by LC−MS). We thank one of the reviewers for the
constructive suggestion of the possibility of reaction kinetics involving
a quasi-stationary low concentration of the desilyled alkyne
intermediate.
H
dx.doi.org/10.1021/jo5011262 | J. Org. Chem. XXXX, XXX, XXX−XXX