Mechanistic studies on the Cu-catalyzed three-component reactions of sulfonyl azides, 1-alkynes and amines, alcohols, or water: Dichotomy via a common pathway

Article abstract of DOI:10.1021/jo800733p

(Chemical Equation Presented) Combined analyses of experimental and computational studies on the Cu-catalyzed three-component reactions of sulfonyl azides, terminal alkynes and amines, alcohols, or water are described. A range of experimental data including product distribution ratio and trapping of key intermediates support the validity of a common pathway in the reaction of 1-alkynes and two distinct types of azides substituted with sulfonyl and aryl(alkyl) groups. The proposal that bimolecular cycloaddition reactions take place initially between triple bonds and sulfonyl azides to give N-sulfonyl triazolyl copper intermediates was verified by a trapping experiment. The main reason for the different outcome from reactions between sulfonyl and aryl(alkyl) azides is attributed to the lability of the N-sulfonyl triazolyl copper intermediates. These species are readily rearranged to another key intermediate, ketenimine, into which various nucleophiles such as amines, alcohols, or water add to afford the three-component coupled products: amidines, imidates, or amides, respectively. In addition, the proposed mechanistic framework is in good agreement with the obtained kinetics and competition studies. A computational study (B3LYP/LACV3P*+) was also performed confirming the proposed mechanistic pathway that the triazolyl copper intermediate plays as a branching point to dictate the product distribution.

Full text of DOI:10.1021/jo800733p

Mechanistic Studies on the Cu-Catalyzed Three-Component
Reactions of Sulfonyl Azides, 1-Alkynes and Amines, Alcohols, or
Water: Dichotomy via a Common Pathway
Eun Jeong Yoo,† Ma˚rten Ahlquist,*,‡ Imhyuck Bae,† K. Barry Sharpless,‡
Valery V. Fokin,*,‡ and Sukbok Chang*,†
Department of Chemistry and School of Molecular Science (BK21), Korea AdVanced Institute of Science
and Technology (KAIST), Daejeon 305-701, Republic of Korea, and Department of Chemistry and The
Skaggs Institute of Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road,
La Jolla, California 92037
ahlquist@caltech.edu; fokin@scripps.edu; sbchang@kaist.ac.kr
ReceiVed April 3, 2008
Combined analyses of experimental and computational studies on the Cu-catalyzed three-component
reactions of sulfonyl azides, terminal alkynes and amines, alcohols, or water are described. A range of
experimental data including product distribution ratio and trapping of key intermediates support the validity
of a common pathway in the reaction of 1-alkynes and two distinct types of azides substituted with
sulfonyl and aryl(alkyl) groups. The proposal that bimolecular cycloaddition reactions take place initially
between triple bonds and sulfonyl azides to give N-sulfonyl triazolyl copper intermediates was verified
by a trapping experiment. The main reason for the different outcome from reactions between sulfonyl
and aryl(alkyl) azides is attributed to the lability of the N-sulfonyl triazolyl copper intermediates. These
species are readily rearranged to another key intermediate, ketenimine, into which various nucleophiles
such as amines, alcohols, or water add to afford the three-component coupled products: amidines, imidates,
or amides, respectively. In addition, the proposed mechanistic framework is in good agreement with the
obtained kinetics and competition studies. A computational study (B3LYP/LACV3P*+) was also
performed confirming the proposed mechanistic pathway that the triazolyl copper intermediate plays as
a branching point to dictate the product distribution.
Introduction
relying on a series of elaborate separate operations. However,
the fact that only a few practically useful catalytic tandem
reactions are available to date2 may be attributed to a poor
compatibility of catalysts with reacting functional groups in the
subsequent steps.
Tandem reactions,1 performed with a cascade, domino, or
zipper type, can link a series of reaction steps together in a single
operation. In general, an initial step generates a reactive
intermediate that undergoes further transformations with either
strategically positioned reactive centers in the same molecule
or other compounds in the reaction mixture. Over the past
decades, tandem reactions have gained a wide interest since they
can offer extremely high efficiency and selectivity without
Copper-catalyzed azide-alkyne cycloaddition (CuAAC),3
which is the best known click reaction,4 is an efficient way to
produce 1,4-disubstituted 1,2,3-triazoles. The scope of the
reaction is very broad with respect to both components.3
(2) (a) de Meijere, A.; von Zezschwitz, P.; Nu¨ske, H.; Stulgies, B. J.
Organomet. Chem. 2002, 653, 129–140. (b) Bruggink, A.; Schoevaart, R.;
Kieboom, T. Org. Process Res. DeV. 2003, 7, 622–640. (c) Lee, J. M.; Na, Y.;
Han, H.; Chang, S. Chem. Soc. ReV. 2004, 33, 302–312. (d) Yoshida, M.
J. Pharm. Soc. Jpn. 2004, 124, 425–435.
† Korea Advanced Institute of Science and Technology.
‡ The Scripps Research Institute.
(1) Bunce, R. A. Tetrahedron 1995, 51, 13103–13159.
5520 J. Org. Chem. 2008, 73, 5520–5528
10.1021/jo800733p CCC: $40.75 2008 American Chemical Society
Published on Web 06/17/2008

Cu-Catalyzed Three-Component Reactions
TABLE 1. Reactivity of Different Azides in the Presence of
Aminesa
SCHEME 1
entry
R1
solvent
conv (%)b A/Bb yield (%)c
1
2
3
4
PhCH2
PhCH2
PhCH2
Ph
PhCO
(4-NO2)C6H4CO THF
(PhO)2PO
PhSO2
(4-Me)C6H4SO2 THF
THF
CH3CN
>99
>99
>99
95
27
>99
81
>99
>99
>99
>99:1
>99:1
>99:1
>99:1
1:>99
1:>99
1:>99
2:98
88 (A)
92 (A)
90 (A)
82 (A)
9 (B)
41 (B)
58 (B)
93 (B)
89 (B)
82 (B)
t-BuOH/H2Od
THF
THF
THF
5
However, when acyl, sulfonyl, or phosphoryl azides are
employed, the corresponding triazoles are obtained in poor yield
under the standard CuAAC conditions (vide infra). In fact, in
the presence of primary or secondary amines, sulfonyl azides
produce amidines in excellent yield at room temperature.5a,c The
scope of this mild three-component reaction is extremely broad
with regard to all three components, and phosphoryl azides also
served as a high-yielding type of azide to give the corresponding
N-phosphoryl amidines.5b Likewise, the copper-catalyzed reac-
tion of sulfonyl azides, 1-alkynes, and alcohols readily takes
place to afford imidates under similar conditions.6 Additionally,
a novel nonconventional approach for the formation of acyl
sulfonamides has been developed by using the same procedure,
employing water as the third reactant in this case (Scheme 1).7,22
The synthetic utility of generated molecules from the Cu-
catalyzed three-component couplings has been extensively
investigated in various areas. For example, amidine derivatives
are utilized as potent pharmacophores8 as well as efficient
organocatalysts.9 Imidates are used as key intermediates for the
conversion to useful synthetic building blocks,10 and acyl
sulfonamides are well-known to have interesting bioactivities.11
Moreover, this catalytic approach has been readily applied to
the preparation of other types of synthetically interesting
compounds such as azetidinimines,12 iminocoumarins,13 and
indoline derivatives.14 Recently, CuAAC with sulfonyl azides
was also employed for the synthesis of macrocycles.15 While
appreciation of the Cu-catalyzed three-component reaction as
a tool for the synthesis of high utility continues to expand, a
6e
7e
8
THF
THF
9
1:>99
1:>99
10 MeSO2
a Conditions: phenylacetylene (0.5 mmol), azide (1.2 equiv),
diisopropylamine (1.2 equiv), CuI (10 mol %) in the indicated solvent.
b Determined by 1H NMR relative to an internal standard,
1,3-benzodioxane.
c Isolated
yield.
d t-BuOH/H2O
)
3:1.
e Decomposition of azides occurred simultaneously and no detectable
side products resulting from reaction with phenylacetylene were
observed.
more detailed mechanistic description is required to further
synthetic developments. Herein, we report our results of detailed
mechanistic investigations of the Cu-catalyzed three-component
reaction based on the product distribution, intermediate trapping
experiments, kinetic parameters, and computational studies.
Results and Discussion
Product Distribution in the Cu-Catalyzed Three-Compo-
nent Reactions. While CuAAC between aryl- or alkyl azides
and 1-alkynes readily provides 1,4-disubstituted 1,2,3-triazoles,
it was observed that sulfonyl azides predominantly yield
amidines when the reaction is carried out in the presence of
primary or secondary amines.5a We were, therefore, interested
in the reactivity of similarly electron-deficient azides and the
effects of their substitution on the outcome of the reaction (i.e.,
triazole to amidine product ratio). As Table 1 illustrates, both
yields and chemoselectivity of these reactions are indeed
strongly dependent on the nature of the participating azides.
As expected, both benzyl and phenyl azides readily partici-
pated in the cycloaddition reaction, and no incorporation of the
diisopropylamine in the product was observed (Table 1, entries
1-4). In sharp contrast, when benzoyl azide was employed, an
amidine species (B, R1 ) PhCO) was exclusively observed with
much lower efficiency (entry 5). Introduction of an electron-
withdrawing group on the benzoyl azide reactants significantly
accelerated the reaction, leading to the corresponding amidine
in better yield (41%), still with excellent selectivity (entry 6).
Phosphoryl azide was similarly reactive, producing the corre-
sponding amidine species exclusively (entry 7). Unsurprisingly,
sulfonyl azides were the most reactive in this reaction, providing
amidines in highest yields, regardless of their electronic proper-
ties (entries 8-10).
(3) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew.
Chem., Int. Ed. 2002, 41, 2596–2599. (b) Tornoe, C. W.; Christensen, C.; Meldal,
M. J. Org. Chem. 2002, 67, 3057–3064.
(4) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001,
40, 2004–2021.
(5) (a) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038–
2039. (b) Kim, S. H.; Jung, D. Y.; Chang, S. J. Org. Chem. 2007, 72, 9769–
9771. (c) Kim, J. Y.; Kim, S. H.; Chang, S. Tetrahedron Lett. 2008, 49, 1745–
1749.
(6) Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S. Org. Lett. 2006, 8,
1347–1350.
(7) (a) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005,
127, 16046–16047. (b) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2007, 46,
1897–1900. (c) Cho, S. H.; Hwang, S. J.; Chang, S. Org. Synth. 2008, 85, 131–
137. (d) Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2008, 47, 2836–2839.
(8) Greenhill, J. V.; Lue, P. Prog. Med. Chem. 1993, 30, 203–326.
(9) (a) Boyd, G. V. In The Chemistry of Amidines and Imidates; Patai, S.,
Rappoport, Z., Eds.; Wiley: New York, 1991; Vol. 2,Chapter 8. (b) Barker, J.;
Kilner, M. Coord. Chem. ReV. 1994, 133, 219–300. (c) Birman, V. B.; Li, X.;
Han, Z. Org. Lett. 2007, 9, 37–40.
(10) (a) Neilson, D. G. In The Chemistry of Amdines and Imidates; Patai,
S., Ed.; John Wiley & Sons: London, UK, 1975; Chapter 8. (b) Kantlehner, W.
Synthesis of Iminium Salts, Orthoesters and Related Compounds. In Compre-
hensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford,
UK, 1991; Vol. 2, pp 485-599. (c) Kochi, T.; Ellman, J. A. J. Am. Chem. Soc.
2004, 126, 15652–15653.
A similar trend on the azide reactivity was also observed when
alcohols were used as nucleophiles (Table 2). It should be noted
that a tertiary amine additive, representatively triethylamine, was
required to obtain satisfactory yields. As expected, reaction of
phenylacetylene with benzyl azide afforded the corresponding
triazole (A, R1 ) PhCH2) as a major product even in the
presence of benzyl alcohol (entry 1). Reaction of sulfonyl azides,
in sharp contrast, resulted in almost exclusive formation of
(11) Humphrey, J. M.; Chamberlin, A. R. Chem. ReV. 1997, 97, 2243–2266.
(12) (a) Whiting, M.; Fokin, V. V. Angew. Chem., Int. Ed. 2006, 45, 3157–
3161. (b) Xu, X.; Cheng, D.; Li, J.; Guo, H.; Yan, J. Org. Lett. 2007, 9, 1585–
1587.
(13) Cui, S.-L.; Lin, X.-F.; Wang, Y.-G. Org. Lett. 2006, 8, 4517–4520.
(14) Yoo, E. J.; Chang, S. Org. Lett. 2008, 10, 1163–1166.
(15) Jin, Y.; Fu, H.; Yin, Y.; Jiang, Y.; Zhao, Y. Synlett 2007, 901–904.
J. Org. Chem. Vol. 73, No. 14, 2008 5521

Yoo et al.
TABLE 2. Ratio of Product Distribution in the Formation of
Imidatesa
product (entry 3). When the reaction was carried out at 50 °C,
the tendency for the formation of imidate was further increased
(entry 4).
Triazole Intermediacy in the Three-Component
Reactions. The observed dependence of product ratio on the
reaction conditions strongly implicates a triazole intermediate
in the copper-catalyzed three-component reactions involving
sulfonyl and phosphoryl azides. However, since the isolated
triazoles bearing N-sulfonyl or N-phosphoryl groups are stable
under the reaction conditions we employed, they cannot be
intermediates in the reaction pathway. In addition, the ratio of
the product mixtures remained constant throughout the course
of the reaction,17 confirming again that neutral triazole is not
the precursor for the formation of reactiVe intermediates under
the reaction conditions.18 On the other hand, when an isolated
N-sulfonyl triazole (1) was treated with a strong base such as
n-BuLi,19 the corresponding amidine (3) was isolated in high
yield in the presence of diisopropylamine (eq 1).
pKa
yield
(%)d
entry
R1
PhCH2
(4-Me)C6H4SO2 Et3N
(4-Me)C6H4SO2 Et3N
(4-Me)C6H4SO2 2,6-lutidine
(4-Me)C6H4SO2 pyridine
(4-Me)C6H4SO2 (2-MeO)C5H4N
additive
Et3N
(THF)b
A/Cc
1
12.5
12.5
12.5
7.2
5.5
2.6
>99:1
1:>99
1:>99
1:3.2
1:2.7
4.7:1
94
63
86
93
54
64
2
3e
4
5
6
a Conditions: phenylacetylene (0.5 mmol), azide (1.2 equiv), benzyl
alcohol (1.2 equiv), additive (1.2 equiv), CuI (0.05 mmol). Conversion
of all reactions was over 99%. b pKa of conjugate acid of amine
additives employed (ref 16). c Determined by 1H NMR based on an
internal standard, 1,3-benzodioxane. d Isolated yield of the combined
products. e Chloroform was used as a solvent.
TABLE 3. Dependence of Product Distribution on Reaction
Temperaturesa
entry
temp (°C)
time (h)
conv (%)b
1/2b
This result reveals that while the parent triazoles are stable,
the deprotonated triazole species is readily converted to a
reactive intermediate that can subsequently react with nucleo-
philes (e.g., amines, alcohols, or water). Therefore, in analogy
to the reaction intermediate in the CuAAC of aryl or alkyl
azides, the N-sulfonyl triazolyl copper species seems also to be
a key intermediate in the route to amidines (imidates or
amides).20 In support of this hypothesis, we attempted to trap
the proposed triazolyl copper intermediates. When phenylacety-
lene and p-toluenesulfonyl azide were allowed to react with
iodine monochloride (ICl) in the presence of triethylamine and
CuI (1.0 equiv), 5-iodo-1-sulfonyltriazole (5) could be isolated
with up to 50% yield (eq 2).21 This chemical trapping experi-
ment supports the intermediacy of a σ-copper triazolyl species
such as 4.
1
2
3
4
-25
0
25
50
12
9
2
32
>99
>99
>99
>99:1
9.3:1
1:3.2
1:5.9
0.5
a Conditions: phenylacetylene (0.5 mmol), p-toluenesulfonyl azide
(1.2 equiv), benzyl alcohol (1.2 equiv), 2,6-lutidine (1.2 equiv) and CuI
(0.05 mmol). b Determined by 1H NMR relative to an internal standard
(1,4-dimethoxybenzene).
imidate species (C, R1 ) (4-Me)C6H4SO2) (entry 2). Confirming
our earlier observation,6 the imidate yield was noticeably
increased when chloroform was used as a solvent (entry 3). It
is noteworthy that chemoselectivity was dependent on the nature
of amine additives even under otherwise identical conditions.
For example, while an imidate (C, R1 ) (4-Me)C6H4SO2) was
obtained exclusively when Et3N additive was used (entry 2),
the selectivity was significantly decreased in the presence of
2,6-lutidine (entry 4). It seems that the acidity of the employed
base’s conjugated acid has a great influence on the observed
selectivity: more acidic conjugated acids favor formation of the
triazole. The use of 2-methoxypyridine (pKa ) 2.6 in THF) led
to the preferential formation of triazole species (entry 6).
However, the possibility that the influence of the steric effects
and the nature of the basic nitrogen atom (sp2 vs sp3) may also
play a role in determining selectivity cannot be ruled out.
Likewise, intermediate 4 can be captured with electrophiles
other than ICl. For instance, with 10 equiv of allyl iodide in
anhydrous acetonitrile, 5-allyl-1-sulfonyltriazole (6) is isolated
in 51% yield (eq 3).22 Under neutral to slightly acidic pH, the
trap of intermediate 4 by proton generates N-sulfonyl triazoles
albeit in low yield. For example, performing the reaction
between 4-acetamidobenzenesulfonyl azide and phenylacetylene
in t-BuOH/H2O (1:1, 0.1 M) in the presence of 2 mol % of
Performing the reaction at different temperatures provided a
further mechanistic insight. In fact, the product distribution
proved to be highly sensitive to the temperature variation, as
shown in Table 3.
(16) Rodima, T.; Kaljurand, I.; Pihl, A.; Maemets, V.; Leito, I.; Koppel, I. A.
J. Org. Chem. 2002, 67, 1873–1881.
When phenylacetylene, p-toluenesulfonyl azide, and benzyl
alcohol were allowed to react at -25 °C in the presence of CuI
and 2,6-lutidine, triazole 1 was produced almost exclusively,
albeit very slowly (Table 3, entry 1). However, as the temper-
ature was increased, the imidate pathway took over and the yield
of imidate 2 was gradually increased. For example, the amount
of triazole was substantially decreased at 0 °C, although it was
still the major product (entry 2). The ratio was reversed at room
temperature, providing the corresponding imidate as a major
(17) For details, see the Supporting Information.
(18) Sua´rez, A.; Fu, G. C. Angew. Chem., Int. Ed. 2004, 43, 3580–3582.
(19) Raap, R. Can. J. Chem. 1971, 49, 1792–1798.
(20) (a) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210–216. (b)
Rodionov, V. O.; Fokin, V. V.; Finn, M. G. Angew. Chem., Int. Ed. 2005, 44,
2210–2215.
(21) Wu, Y.-M.; Deng, J.; Li, Y.; Chen, Q.-Y. Synthesis 2005, 8, 1314–
1318.
(22) Cassidy, M. P.; Raushel, J.; Fokin, V. V. Angew. Chem., Int. Ed. 2006,
45, 3154–3157.
5522 J. Org. Chem. Vol. 73, No. 14, 2008

Cu-Catalyzed Three-Component Reactions
SCHEME 2. Ring–Chain Isomerization of N-Sulfonyl Triazolyl Copper Intermediate
CuSO4 and Na-ascorbate/ascorbic acid (10 mol % each) results
in the formation of 1-sulfonyltriazole product (42%).
to ketenimines (F) could be envisioned as the well-known
Dimroth rearrangement28 via the R-diazoimino species (E). The
Dimroth rearrangement, also called an amidine rearrangement,
is a ring-chain isomerization process whereby the heterocyclic
ring is broken. Release of molecular nitrogen from E followed
by the hetero-Wolff rearrangement29 provides the key keten-
imine intermediate (F), which is in equilibrium with ynamides
species (G). It is highly plausible to assume that the in situ
generated ketenimine species (F)19 reacts readily with amines,
alcohol, or water to give the three-component coupled products.
In this route, concurrent release of N2 might be a main driving
force for the transformation of the triazolyl copper species (D)
to the key ketenimine intermediate (F).
Validity of Ketenimine as a Key Intermediate. On the basis
of previously reported synthetic procedures,23 amidine com-
pounds could be prepared starting from N-sulfonamides via
ketenimine species (eq 4).24 It is also well-known that alcohols
or water readily participate in the reaction with ketenimine
leading to imidates25 or amides.26 In fact, when (N-tosyl)phe-
nylacetamide (7) was treated with PPh3Br2 in the presence of
Et3N, an in situ generated ketenimine species (8) was reacted
with diisopropylamine to provide the corresponding amidine
(3) in good yield. It was also revealed that the efficiency of the
hydroamination step was not significantly influenced by the
presence of a copper catalyst.
On the basis of the above depicted mechanistic pathways,
the observed dependence of product distribution on the base
additives (Table 2) and reaction temperatures (Table 3) can be
subsequently explained.30 Since the protonation process of the
triazolyl copper species (D, Scheme 2) is expected to take place
more readily in the presence of more acidic proton donors, the
corresponding N-sulfonyl triazole compounds can be more
efficiently trapped when 2,6-lutidine additives are present
compared to Et3N base. Taking advantage of the concomitant
entropic contribution, release of a dinitrogen molecule from the
N-sulfonyl triazolyl copper species (D) would be accelerated at
higher temperatures.
Intermediacy of the ketenimine was further supported by
additional trapping experiments. As already reported, when an
isolated 1-benzenesulfonyl-4-phenyltriazole was treated with
n-BuLi followed by N-benzylideneaniline, an azetidinimine
product could be obtained albeit in low yield.12a Since the
product azetidinimine is generated by the nucleophilic attack
of the N-benzylideneaniline at the in situ generated ketenimine,
this result again strongly indicates the ketenimine intermediacy
in the ring-opening process of triazole species. More importantly,
the same type of azetidinimines were also obtained in high yields
from the Cu-catalyzed reaction of p-toluenesulfonyl azides and
1-alkynes in the presence of imines.12a
Kinetics. The kinetic profile of the Cu-catalyzed three-
component reactions was examined by competition studies under
the amidine-generating conditions. Measurement of the relative
rates of reactions of para-substituted phenylacetylene derivatives
revealed that electron-withdrawing substituents slightly acceler-
ated the reaction (Figure 1a). Hammett plotting of log(krel) versus
σp- shows the F value of ca. 0.5 (r ) 0.99), implying that there
is buildup of negative charge in the rate-limiting transition stage.
As shown Figure 1b, the reaction was also sensitive to the
electronic variation of benzenesulfonyl azides (F ) 0.3, r )
0.99), indicating that electron-withdrawing group on the azide
accelerates the reaction more readily.
Therefore, it is reasonable to assume that ketenimine species
are involved in our three-component coupling reactions upon
release of a nitrogen molecule from the labile N-sulfonyl
triazolyl copper intermediates (Scheme 2). We recently reported
that N-sulfonyl triazolyl copper species (D) have much higher
propensity for the ring-opening process comparing to N-aryl or
alkyl triazolyl intermediates.27 This proposal is also supported
by the computational studies which revealed that the activation
energy of the ring-opening process of N-methanesulfonyl
triazolyl complex is 84 kJ mol-1 lower than that of the
corresponding N-methyl species. One of the most plausible ring-
opening routes from the N-sulfonyl triazolyl copper species (D)
(23) Differding, E.; Ghosez, L. Tetrahedron Lett. 1985, 26, 1647–1650.
(24) (a) Motoyoshiya, J.; Teranishi, A.; Mikoshiba, R.; Yamamoto, I.; Gotoh,
H.; Enda, J.; Ohshiro, Y.; Agawa, T. J. Org. Chem. 1980, 45, 5385–5387. (b)
Sung, K.; Wu, S.-H.; Wu, R.-R.; Sun, S.-Y. J. Org. Chem. 2002, 67, 4298–
4303.
(25) Sauers, R. R.; Van Arnum, S. D. Phosphorus, Sulfur, and Silicon 2003,
178, 2169–2181.
(26) Bendikov, M.; Duong, H. M.; Bolanos, E.; Wudl, F. Org. Lett. 2005, 7,
783–786.
(27) Yoo, E.; Ahlquist, M.; Kim, S. H.; Bae, I.; Fokin, V. V.; Sharpless,
K. B.; Chang, S. Angew. Chem., Int. Ed. 2007, 46, 1730–1733.
(28) (a) Brown, D. J.; Harper, J. S. J. Chem. Soc. 1963, 1276–1284. (b) Perrin,
D. D. J. Chem. Soc. 1963, 1284–1290. (c) Gilchrist, T. L.; Gymer, G. E. AdV.
Heterocycl. Chem. 1974, 16, 33–85. (d) Gilchrist, T. L. AdV. Heterocycl. Chem.
1987, 41, 41–74. (e) Fujii, T.; Itaya, T. Heterocycles 1998, 48, 359–390. (f)
Katritzky, A. R.; Ji, F. B.; Fan, W.-Q.; Gallos, J. K.; Greenhill, J. V.; King,
R. W.; Steel, P. J. J. Org. Chem. 1992, 57, 190–195. (g) Boivin, J.; Huppe´, S.;
Zard, S. Z. Tetrahedron Lett. 1995, 36, 5737–5740.
Further insightful data were acquired by determining pseudo-
first-order rates from the reaction of phenylacetylene, p-
(29) Kirmse, W. Eur. J. Org. Chem. 2002, 2193–2256.
(30) (a) Hermes, M. E.; Marsh, F. D. J. Am. Chem. Soc. 1967, 89, 4760–
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1970, 35, 3444–3448.
J. Org. Chem. Vol. 73, No. 14, 2008 5523

Yoo et al.
nitrogen to amidine products.32 Alternatively, aziridination of
enamine with copper nitrenoids,33 which may be derived from
the copper-mediated decomposition of sulfonyl azides, also can
be proposed. However, the hydroamination route (path a) is not
compatible with the reaction sequence especially when water
is involved as a reagent. Moreover, since the three-component
reactions are applicable only to terminal alkynes, validity of
this path a cannot be sustained. Another possibility involving
the ynamide intermediate is also readily ruled out on the basis
of similar reasoning (Scheme 3, path b).34
The possibility of direct nucleophilic attack of the terminal
nitrogen of sulfonyl azide by copper acetylide can be envisioned.
However, even though copper acetylide may be sufficiently
nucleophilic,35 no previous examples of such reaction between
copper acetylides and azides are known, and the likely product
of this pathway, 1,5-disubstituted triazole, has not been ob-
served.36
In Scheme 4, we offer a plausible mechanistic pathway and
intermediates involved in the Cu-catalyzed three-component
reactions based on the experimental data and considerations
described above. We propose that the initial steps of the reaction
between terminal alkynes and sulfonyl azides are similar to the
previously proposed pathway for the reactions involving aryl
and alkyl azides.20 Although it is likely that more than one
copper atom is involved in the catalysis (vide supra),20b,39 only
species containing single copper are shown. The cupracycle
formation proceeds via the reaction of copper acetylide with
sulfonyl azide. In fact, an amidine compound was produced
from the reaction of preformed copper acetylide with sulfonyl
azide and amine. Coordination of the sulfonyl azide to the
copper of the acetylide is followed by stepwise triazole ring
formation. Once the N-sulfonyl triazolyl copper species (D) is
formed, it can undergo ring-chain isomerization leading to a
ketenimine intermediate (F) upon release of dinitrogen molecule.
Subsequent addition of certain nucleophilic reagents, such as
amines, alcohols, or water, to the ketenimine intermediates takes
place as the last step affording the final products, amidines,
imidates, or amides.
FIGURE 1. Hammett plotting in the Cu-catalyzed three-component
reactions with (a) para-substituted phenylacetylenes and (b) para-
substituted benzenesulfonyl azide derivatives.
toluenesulfonyl azide, and diisopropylamine in the presence of
CuI. Initial rates were measured at different concentrations of
each reactant as well as of the catalyst. NMR analysis of aliquots
taken from the reaction mixture at regular intervals revealed
the rate dependence of each reacting species on the concentra-
tions of reactants ranging from 2.8 to 233 mM (Figure 2).17
Overall, in the amidine-forming reactions, the following rate
law was obtained under CuI-catalytic conditions:
rate ) k[CuI]1.4[TsN3]0.7[PhC≡CH]0.3[HN(i-Pr)2]0.0 (5)
That is, the reaction is close to second order in the [CuI], first
order in sulfonyl azide, and half-order in alkyne if we use
normalization. In the previous kinetic studies of the reactions
of benzyl azides with phenylacetylenes, the reaction was also
second in copper pointing to the involvement of dinuclear copper
intermediated in the rate-determining step.20b Importantly, the
reaction rate was completely independent of the amine con-
centration. Although a precise description of the kinetic behavior
of each reacting component is not tried at the present, this result
clearly suggests that the addition of amine to the ketenimine
intermediate is not involved in the rate-determining stages.
Mechanistic Proposal for the Cu-Catalyzed Three-
Component Reactions. Although several mechanistic possibili-
ties were surmised after finding the Cu-catalyzed three-
component coupling reactions, some experimental data obtained
thereafter clarified most of those pathways. First, a route through
hydroamination between alkynes and amines as the first step
was envisioned (Scheme 3, path a).31 In fact, several examples
of the thermal cycloaddition between resultant enamines with
sulfonyl azides have been known affording triazoline moieties,
which subsequently undergo cycloreversion upon the loss of
(32) (a) Croce, P. D.; Stradi, R. Tetrahedron 1977, 33, 865–867. (b)
Fioravanti, S.; Pellacani, L.; Ricci, D.; Tardella, P. A. Tetrahedron: Asymmetry
1997, 8, 2261–2266. (c) Xu, Y.; Wang, Y.; Zhu, S. Synthesis 2000, 513–516.
(d) Xu, Y.; Zhu, S. Tetrahedron 2001, 57, 4337–4341.
(33) (a) Evans, D. A.; Bilodeau, M. T.; Faul, M. M. J. Am. Chem. Soc. 1994,
116, 2742–2753. (b) Diaz-Requejo, M. M.; Perez, P. J.; Brookhart, M.;
Templeton, J. L. Organometallics 1997, 16, 4399–4402.
(34) Peterson, L. I.; Britton, E. C. Tetrahedron Lett. 1968, 9, 5357–5360.
(35) Qian, H.; Shao, L.-X.; Huang, X. Synlett 2001, 1571–1572.
(36) Helwig, R.; Hanack, M. Chem. Ber. 1985, 118, 1008–1021.
(37) Since copper(I) species often form tricoordinate complexes, the bis-
pyridine acetylide complex was modeled (X2), which was found to be close to
isoenergetic with X1. When the anionic ligand is a worse σ donor, e.g., chloride,
the tricoordinate species is more favored. In a recent computational study by
Ahlquist and Fokin,39 it was illustrated how a second copper atom could stabilize
the cycloaddition transition state as well as the following intermediate, explaining
the observed second order dependence of copper on the rate. In the current study
we will mainly discuss mononuclear copper acetylides, since the interest is to
compare the reactivity of N-sulfonyl azides to the N-alkyl analogues
.
(31) (a) Pohlki, F.; Doye, S. Chem. Soc. ReV. 2003, 32, 104–114. (b) Beller,
M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368–
3398. (c) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 37, 673–686. (d) Alonso,
F.; Beletskaya, I. P.; Yus, M. Chem. ReV. 2004, 104, 3079–3160. (e) Odom,
A. L. Dalton Trans. 2005, 225–233.
(38) It is possible that a second nitrogen ligand (pyridine) can bind to the
copper in the triazolyl intermediate X10 to form a complex X10(Py), although
this step was calculated to be slightly endothermic (10 kJ mol-1). This further
shows that stronger σ-donors favor dicoordinate copper(I) centers.
(39) Ahlquist, M.; Fokin, V. V. Organometallics 2007, 26, 4389–4391.
5524 J. Org. Chem. Vol. 73, No. 14, 2008

Cu-Catalyzed Three-Component Reactions
FIGURE 2. Initial rate measurement with the four reacting species in the CuI-catalyzed amidine synthesis: (a) CuI, (b) TsN3, (c) phenylacetylene,
and (d) diisopropylamine.
SCHEME 3
SCHEME 4. Proposed Mechanistic Pathways for the Cu-Catalyzed Three-Component Reactions
It should be noted that the cuprated triazole species plays
the key role in determining the outcome of the reaction. That
is, ketenimine compounds can be generated via the ring-opening
rearrangement from the cuprated triazole. Otherwise, the copper
triazole may be trapped upon protonation as triazole compound.
Although the three-component coupled products are provided
with excellent selectivity under the developed reaction condi-
tions, the trapping conditions were also previously developed
by us to deliver N-sulfonyl triazole compounds (H).27 In fact,
as can be seen above, the choice of suitable base additives and
reaction temperatures are the most important key factors in
controlling the product distribution.
Computational Studies. The experimental evidence for the
formation of a triazolyl intermediate prompted us to determine
the mechanistic parameters for its formation and breakdown
using computational methods, performed at the density func-
tional theory (DFT) B3LYP/LACV3P*+ level. The correspond-
ing formation of an N-alkyl or aryl triazolyl copper species has
been previously investigated.20 Therefore, the present study
focuses on the reactivity of sulfonyl azides. A mononuclear
copper acetylide with one pyridine spectator ligand on copper
was chosen as a stating point (X1, Figure 3).37 The first
intermediate is the cupracycle X7 formed after the proximal
nitrogen of the azide coordinates to the copper atom. The
J. Org. Chem. Vol. 73, No. 14, 2008 5525

Yoo et al.
FIGURE 3. Reaction coordinates for the stepwise cycloaddition of two types of azides to a copper acetylide, which yield a triazolyl copper intermediate.
Numbers in italics are the relative energies (in kJ mol-1).
transition state for this step was located (X3ts), in which the
C2-N3 distance was calculated at 1.97 Å. Attempts to locate a
prereactive complex with the azide coordinated to the copper
failed. Instead the result was a structure where the azide and
the copper acetylide were only interacting by weak intermo-
lecular interactions. The explanation for the failure to locate a
complex with the azide coordinated is likely that the calculations
were performed including the implicit Poisson-Boltzmann
solvent model throughout the optimizations. The barrier was
therefore calculated from the separated reactants.
X4 to the triazolyl species (X10) was calculated to be highly
exothermic (-184 kJ mol-1).
The triazolyl intermediate then becomes a branching point
of the two subsequent reactions: (i) direct protonation yields
the N-sulfonyl triazole or (ii) N2 extrusion leads to the
ketenimine intermediate. For the latter, a stepwise mechanism
was characterized that involves a ring-opening process giving
an R-diazoimine intermediate with subsequent N2 release. The
ring-opening step was shown to be significantly accelerated by
the presence of the sulfonyl group, explaining the experimental
observation that aryl and alkyl azides do not give amidines
(imidates or amides) via the ring-opening rearrangement process.
Breaking of the C-N bond in the diazoimine species was found
to be relatively facile, and a comparison between the CuI
substituted versus the protonated diazoimine showed that the
presence of the copper center has a favorable influence on the
N2 elimination.27
For methanesulfonyl azide (X4) used in this study, the overall
metallacycle formation barrier (X3ts) was calculated at 57 kJ
mol-1. To compare this to the more frequently utilized alkyl
azides, the overall cycloaddition barrier for methyl azide (X5)
to the copper acetylide (X1) was calculated. This barrier was
found to be substantially higher (X6ts), 78 kJ mol-1, thus
indicating that sulfonyl azides react even more readily with
copper acetylides than alkyl azides. In the methyl azide reaction,
the C2-N3 distance was found to be 1.91 Å (X6ts), which is
slightly shorter than in the methanesulfonyl azide transition state
(X3ts, 1.97 Å), thus implying a later transition state in the
methyl azide case.
Herein the reaction step has been remodeled with the pyridine
ligand (Figure 4).38 Ring-opening of X10 takes place via
transition state X12ts with a calculated activation barrier of 52
kJ mol-1. In the transition state (X12ts), the scissile N1-N2
bond is elongated to 2.27 Å, while the bond between the other
two nitrogen atoms (N2-N3) is significantly shortened to 1.15
Å. The species resulting from the ring-opening process is a
diazoiminyl copper complex X13, where the N-N-C angle in
the diazo moiety is practically linear (175°). The transformation
from X10 to X13 was calculated to be endothermic by 28 kJ
The reaction between X1 and X4 results in the formation of
the cupracycle intermediate X7. This reaction step was calcu-
lated to be endothermic by 30 kJ mol-1, which is again
substantially more favorable for the methansulfonyl azide than
the methyl azide for which an endothermicity of 48 kJ mol-1
was calculated (X8). As expected, the subsequent formation of
the second C-N bond takes place via transition state X9ts with
a very low barrier of merely 2 kJ mol-1, leading to the triazolyl
copper intermediate (X10), in line with the experimental
observations. The reaction of the separated reactants X1 and
mol-1
.
The dissociation of the dinitrogen molecule can now take
place, and this conversion proceeds via a transition state X14ts
where the breaking C-N bond was elongated to 1.71 Å and
the N2 fragment was bent, with an N-N-C angle of 133°. The
5526 J. Org. Chem. Vol. 73, No. 14, 2008

Cu-Catalyzed Three-Component Reactions
withdrawing group substituted aryl sulfonyl azide may fit this
computational result.
Conclusions
The experimental results obtained from the product distribu-
tion, intermediate trapping studies, and kinetic profiling offer
key insights into the mechanistic pathways of the copper-
catalyzed three-component reactions of sulfonyl azides, 1-alkynes
and amines, alcohols, or water. 1-Sulfonyl triazolyl copper
species, formed via a stepwise cycloaddition of copper acetylide
and sulfonyl azide, are a crucial branching point that controls
the subsequent steps: protonation leading to (N-sulfonyl)triazoles
or ring-opening producing ketenimine species. Computational
studies reveal that the triazolyl copper species having an N1-
sulfonyl group has much lower activation energy for the
hypothetical ring-opening step compared to that of the N1-alkyl
substituents. This consideration may explain why the Dimroth-
type rearrangement occurs so readily with 5-cuprated 1-sulfonyl
triazoles. Better mechanistic understanding of these three-
component catalytic reactions is offered by the present study,
providing additional opportunities for developing new and useful
synthetic methodologies.
Experimental Section
FIGURE 4. Reaction pathway for the proposed stepwise N2 dissociation
from the triazolyl copper intermediate X10. Numbers in italics are
relative energies (in kJ mol-1).
Procedure for the Product Distribution Experiment on the
Type of Azides (Table 1). To a stirred mixture of phenylacetylene
(51.2 mg, 0.5 mmol), indicated azide (0.6 mmol), and CuI (9.5
mg, 0.05 mmol) in solvent (1.0 mL) was slowly added diisopro-
pylamine (0.085 mL, 0.6 mmol) at 25 °C. After the reaction mixture
was stirred for 12 h at room temperature, it was diluted with CH2Cl2
(2 mL) and then quenched with saturated NH4Cl aqueous solution
(3 mL). The mixture was stirred for an additional 30 min at room
temperature and two layers were separated. The aqueous layer was
extracted with CH2Cl2 (3 × 3 mL) and the combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo.
1
FIGURE 5. Change of Mulliken charges in triazolyl intermediate X10
and transition state X12ts.
Conversion and ratio were determined by H NMR relative to an
internal standard, 1,3-benzodioxane. The crude residue was purified
by flash column chromatography to give the major product, triazoles
or amidines, as a white solid.
activation energy relative to the diazoiminyl complex X13 was
calculated to be 50 kJ mol-1. Since X13 is higher in energy
than the triazolyl intermediate X10, the reaction has an effective
barrier of 78 kJ mol-1. This activation barrier is low enough
for it to take place easily at ambient temperatures, yet it is not
too low to be uncontrollable. We showed that under the right
conditions the triazolyl intermediate could be trapped and
formed selectively by simply using the right acidity and reacting
at lower temperature (0 °C).27 Resulting from the dissociation
of the dinitrogen fragment is the keteneiminyl complex X15,
which was located by simply optimizing a slightly distorted
geometry of the transition state X14ts.
In addition, the above calculation results suggest that N2
dissociation might be the rate-determining step (RDS). Shown
in Figure 5 is the Mulliken charge in the triazolyl intermediate
X10 and transition state X12ts, which was related to the RDS.
It revealed that the Mulliken charge on the C2-carbon of the
acetylenes went from +0.84 in X10 to -0.01 in X12ts. The
partial charge on the N1-nitrogen was more negative in the
transition state X12ts than in the triazolyl intermediate X10.
These results might distinctly corroborate the experimentally
obtained positive F-values of the Hammett plot with substituted
acetylene and sulfonyl azides (Figure 1). In fact, the experi-
mental observation that the reaction is favored by electron-
deficient aryl acetylene and accelerated by the electron-
Procedure for the Trapping Experiment of Triazolyl
Intermediate (Eq 2). To a stirred solution of phenylacetylene (1,
204.3 mg, 2.0 mmol), p-toluenesulfonyl azide (473.3 mg, 2.4
mmol), ICl (2.4 mL of 1.0 M solution, 2.4 mmol), and CuI (380.9
mg, 2.0 mmol) in THF (8 mL) was added Et3N (0.335 mL, 2.4
mmol) under an N2 atmosphere at 0 °C. After the reaction mixture
was stirred at 0 °C for 12 h, it was diluted with CH2Cl2 (5 mL)
and then quenched with saturated NH4Cl aqueous solution (10 mL).
After the separation of the two layers, the aqueous layer was
extracted with CH2Cl2 (3 × 5 mL). The combined organic layers
were dried over MgSO4, filtered, and concentrated in vacuo. The
crude residue was purified by flash column chromatograph (EtOAc/
n-hexane, 1:3) to afford the desired product as a yellowish liquid,
1-(4-methylbenzenesulfonyl)-4-phenyl-5-iodo-1,2,3-triazole (5, 420.6
mg, 49.5%).
1-(4-Methylbenzenesulfonyl)-4-phenyl-5-iodo-1,2,3-triazole
(5). Yellowish liquid; 1H NMR (400 MHz, CDCl3) δ 8.06 (d, J )
8.5 Hz, 2H), 7.82 (d, J ) 8.4 Hz, 2H), 7.43-7.38 (m, 5H), 2.44 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 147.5, 133.1, 130.4, 129.3,
129.2, 128.9, 128.5, 128.3, 21.9; IR (KBr) ν 3064, 1609, 1494,
1456, 1124, 1034, 978 cm-1; HRMS (FAB) m/z calcd for
C15H12IN3O2S [M + H]+ 425.9773, found 425.9757.
Procedure for the Transformation of Amide to Amidine
via Ketenimine (Eq 4). A solution of 4-methyl-N-phenylacetyl-
benzenesulfonamide (7, 72.0 mg, 0.25 mmol), PPh3Br2 (220.0 mg,
0.5 mmol), CuI (10 mol %, 4.8 mg), and Et3N (0.070 mL, 0.5
J. Org. Chem. Vol. 73, No. 14, 2008 5527

Yoo et al.
mmol) in THF (2 mL) was stirred under an N2 atmosphere at 25
°C. After the reaction mixture was stirred for 1 h, diisopropylamine
(0.175 mL, 1.25 mmol) was added, and then the mixture was stirred
for 2 h at room temperature. It was then diluted with CH2Cl2 (2
mL) and quenched with saturated NH4Cl aqueous solution (3 mL).
The mixture was stirred for an additional 30 min and two layers
were separated. The aqueous layer was extracted with CH2Cl2 (3
× 3 mL), and the combined organic layers were dried over MgSO4,
filtered, and concentrated in vacuo. The crude residue was purified
by flash column chromatograph (EtOAc/n-hexane, 1:1) to afford
the desired product as a white solid, N1,N1-diisopropyl-N2-(4-
methylbenzensulfonyl)-2-phenylacetamidine (3, 75.4 mg, 81.0%).
KOSEF grant (No. R01-2007-000-10618-0). We also acknowl-
edge the Korea Basic Science Institute (KBSI) for the mass
analysis.
Supporting Information Available: Experimental details of
the product distribution, trapping studies, kinetic studies,
characterization, copies of 1H and 13C NMR spectra of the newly
obtained products (5) in the present studies, X,Y,Z coordinates
for the calculated compounds/transition states, and energies of
the respective geometries. This material is available free of
charge via the Internet at http://pubs.acs.org.
Acknowledgment. This research was supported by a Korea
Research Foundation Grant (KRF-2005-015-C00248) and a
JO800733P
5528 J. Org. Chem. Vol. 73, No. 14, 2008