Strain-promoted azide-alkyne cycloaddition with ruthenium(II)-azido complexes

Article abstract of DOI:10.1002/chem.201302502

The reactivity of an exemplary ruthenium(II)-azido complex towards non-activated, electron-deficient, and towards strain-activated alkynes at room temperature and low millimolar azide and alkyne concentrations has been investigated. Non-activated terminal and internal alkynes failed to react under such conditions, even under copper(I) catalysis conditions. In contrast, as expected, rapid cycloaddition was observed with electron-deficient dimethyl acetylenedicarboxylate (DMAD) as the dipolarophile. Since DMAD and related propargylic esters are excellent Michael acceptors and thus unsuitable for biological applications, we investigated the reactivity of the azido complex towards cycloaddition with derivatives of cyclooctyne (OCT), bicyclo[6.1.0]non-4-yne (BCN), and azadibenzocyclooctyne (ADIBO). While no reaction could be observed in the case of the less strained cyclooctyne OCT, the highly strained cyclooctynes BCN and ADIBO readily reacted with the azido complex, providing the corresponding stable triazolato complexes, which were amenable to purification by conventional silica gel column chromatography. An X-ray crystal structure of an ADIBO cycloadduct was obtained and verified that the formed 1,2,3-triazolato ligand coordinates the metal center through the central N2 atom. Importantly, the determined second-order rate constant for the ADIBO cycloaddition with the azido complex (k₂=6.9 × 10 ^-2 M^-1 s^-1) is comparable to the rate determined for the ADIBO cycloaddition with organic benzyl azide (k ₂=4.0 × 10^-1 M^-1 s^-1). Our results demonstrate that it is possible to transfer the concept of strain-promoted azide-alkyne cycloaddition (SPAAC) from purely organic azides to metal-coordinated azido ligands. The favorable reaction kinetics for the ADIBO-azido-ligand cycloaddition and the well-proven bioorthogonality of strain-activated alkynes should pave the way for applications in living biological systems.

Full text of DOI:10.1002/chem.201302502

DOI: 10.1002/chem.201302502
Strain-Promoted Azide–Alkyne Cycloaddition with
Ruthenium(II)–Azido Complexes
Thomas Cruchter,[a] Klaus Harms,[a] and Eric Meggers*[a, b]
Abstract: The reactivity of an exempla-
ry ruthenium(II)–azido complex to-
wards non-activated, electron-deficient,
and towards strain-activated alkynes at
room temperature and low millimolar
azide and alkyne concentrations has
been investigated. Non-activated termi-
nal and internal alkynes failed to react
under such conditions, even under cop-
per(I) catalysis conditions. In contrast,
as expected, rapid cycloaddition
was observed with electron-deficient di-
methyl acetylenedicarboxylate (DMAD)
as the dipolarophile. Since DMAD and
related propargylic esters are excellent
Michael acceptors and thus unsuitable
for biological applications, we investi-
gated the reactivity of the azido com-
plex towards cycloaddition with deriva-
tives of cyclooctyne (OCT), bicyclo-
G
tantly, the determined second-order
rate constant for the ADIBO cycload-
dition with the azido complex (k2 =6.9
ꢀ 10ꢀ2 mꢀ1 sꢀ1) is comparable to the rate
determined for the ADIBO cycloaddi-
tion with organic benzyl azide (k2 =4.0
ꢀ 10ꢀ1 mꢀ1 sꢀ1). Our results demonstrate
that it is possible to transfer the con-
cept of strain-promoted azide–alkyne
cycloaddition (SPAAC) from purely or-
ganic azides to metal-coordinated
azido ligands. The favorable reaction
kinetics for the ADIBO-azido-ligand
cycloaddition and the well-proven bio-
orthogonality of strain-activated al-
kynes should pave the way for applica-
tions in living biological systems.
Introduction
the concept of strain-promoted azide–alkyne cycloaddition
(SPAAC), which relies on the increased reactivity of strain-
ed cycloalkynes,[26–28] mostly cyclooctynes (Figure 1, left
arrow).[29] Over the last several years, SPAAC has been ex-
tensively used to covalently label azido-modified synthetic
molecules and biomolecules in a bioorthogonal fashion on
and in living cells[6–13,19–22] as well as on and in multicellular
organisms, including worms,[14,15] zebrafish,[16,17] and
mice.[8,14,18]
In recent years, the copper(I)-catalyzed azide–alkyne cyclo-
addition[1] (CuAAC) to form 1,2,3-triazoles has emerged as
a prime example of ’’click chemistry’’[2] reactions.[3] Whereas
the thermal azide–alkyne cycloaddition requires scope-limit-
ing high temperatures when unactivated substrates are used,
the presence of a copper(I) catalyst accelerates the reaction
between organic azides and terminal alkynes to an extent,
allowing the reaction to proceed rapidly at room tempera-
ture and low reactant concentrations.[1,3] However, the high
cytotoxicity of copper salts renders CuAAC unsuitable for
applications in living biological environments[4,5] and this has
motivated the Bertozzi group[5–18] and others[19–25] to utilize
[a] T. Cruchter, Dr. K. Harms, Prof. Dr. E. Meggers
Fachbereich Chemie
Philipps-Universitꢁt Marburg
Figure 1. Comparison of SPAAC with organic azides (established) and
ruthenium(II)–azido complexes (present work).
Hans-Meerwein-Strasse, 35043 Marburg (Germany)
Fax : (+49)6421-282-2189
E-mail: meggers@chemie.uni-marburg.de
[b] Prof. Dr. E. Meggers
College of Chemistry and Chemical Engineering,
Xiamen University, Xiamen 361005 (P.R. China)
Recently, there has been a steadily growing interest for
metal complexes in the life sciences.[30–43] The attractiveness
of metal complexes for the modulation, sensing, and imaging
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302502.
16682
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Chem. Eur. J. 2013, 19, 16682 – 16689

FULL PAPER
of biological processes calls for the development of bioor-
thogonal 1,3-dipolar cycloadditions involving metal-coordi-
nated azido ligands. Although, numerous publications have
appeared on the conversion of metal-coordinated azido li-
gands into metal-coordinated triazolato ligands,[44–68] the ma-
jority of these studies relied on alkynes as dipolarophiles
that are activated by conjugation with electron-withdrawing
groups, such as carboxylic esters and nitriles.[44–63] However,
due to their high electrophilicity and susceptibility to conju-
gate addition, such activated dipolarophiles are incompati-
ble with biological systems.[69–73] In contrast, reports on 1,3-
dipolar cycloadditions between metal-coordinated azido li-
gands and non-activated alkynes are rare.[65–68] In a notable
exception, Gray and co-workers reported rapid reactions be-
tween the electron-rich gold(I) azido complex [AuI-
Scheme 1. Cycloaddition of ruthenium(II)–azido complex 1 with DMAD
(2) providing triazolato complex 3 in 87% yield after chromatographic
purification.
the expected 1,2,3-triazolato complex 3, which was isolated
in 87% yield (Scheme 1). An X-ray crystal structure of this
complex is shown in Figure 2 (Table 3, see below) and re-
veals that the Cs-symmetric triazolato ligand is bound to the
metal center by N2, which implies that an N1!N2 linkage
isomerization occurs in the course of the cycloaddition reac-
tion. This type of linkage isomerization has been reported
numerous times for 1,3-dipolar cycloadditions with metal-co-
ordinated azides.[44–62]
ACHTUNGTRENNUNG
(PPh3)(N3)] and terminal alkynes at room temperature.[65]
Interestingly, the resulting triazolato ligands are attached to
the gold(I) center by a carbon–gold bond and not, as expect-
ed, by a nitrogen–gold bond.[65] Veige and co-workers car-
ried out analogous reactions with [AuI
ACHTNUGTRNEUNG(PPh3)(N3)], but in-
stead of terminal alkynes they used gold(I) acetylides as di-
polarophiles. Consequently, they obtained binuclear gold(I)–
triazolato complexes.[66]
Over the last several years, our group has introduced co-
ordinatively inert metal complexes as sophisticated scaffolds
for the design of highly potent and selective kinase inhibi-
tors,[74–81] including complexes containing metal-coordinated
azido ligands.[76,80] We envisioned that a biocompatible 1,3-
dipolar cycloaddition with such metal-coordinated azido li-
gands would not only constitute an attractive imaging tool,
but would also enable us to modulate the inhibition proper-
ties of such complexes in real time within a living biological
system. We now demonstrate that it is possible to transfer
the concept of strain-promoted azide–alkyne cycloaddition
from purely organic azides to metal-coordinated azido li-
gands (Figure 1, right arrow) to obtain the corresponding
robust triazolato complexes under ambient conditions with
favorable reaction kinetics. To our knowledge, this is the
first example of strain-promoted azide–alkyne cycloaddition
applied to metal-coordinated azido ligands.
Figure 2. Molecular structure of ruthenium(II)–triazolato complex 3.
ORTEP drawing with 50% probability thermal ellipsoids. Hydrogen
atoms and positional disorder of the benzyl group have been omitted for
ꢀ
ꢀ
clarity. Selected bond lengths (ꢃ): Ru1 N1=2.106(6), Ru1 N2=
ꢀ
ꢀ
ꢀ
2.112(5), Ru1 N3=2.068(5), Ru1 S1=2.2824(19), Ru1 S2=2.2867(18),
Results and Discussion
ꢀ
Ru1 S3=2.2941(17).
Cycloaddition of ruthenium(II)–azido complex 1 with an
electron-deficient alkyne: In most of this study, we selected
ruthenium(II)–azido complex 1 as a representative model
complex. The ruthenium(II)–azido complex 1 is a readily
available azido-ligand-bearing derivative of coordinatively
inert pyridocarbazole-based ruthenium(II) complexes, previ-
ously introduced by our group. These complexes have been
designed to act as reversible kinase inhibitors and have
proven their stability in biological environments.[76,80] We
first confirmed the capability of the azido ligand of 1 to par-
ticipate in a rapid 1,3-dipolar cycloaddition by subjecting
1 to dimethyl acetylenedicarboxylate (DMAD, 2) at room
temperature. Within just 30 min, this experiment afforded
Attempted cycloadditions of ruthenium(II)–azido complex 1
with non-activated alkynes: Although the cycloaddition with
DMAD proceeded rapidly, DMAD and related propargylic
esters are excellent Michael acceptors and hence they react
with cellular thiols, causing glutathione depletion and pro-
tein cross-linking. Accordingly, such compounds are cytotox-
ic and thus unsuitable for biological applications.[69–73] There-
fore, we next turned our attention to non-activated alkynes,
which are well-known for their biocompatibility. However,
examination of a small library of terminal (4–6 Figure 3)
and internal alkynes (7–9 Figure 3) in terms of their reactivi-
Chem. Eur. J. 2013, 19, 16682 – 16689
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16683

E. Meggers et al.
Indeed, while we did not observe any reaction between
1 and the less strained OCT, we were pleased to observe
smooth cycloaddition reactions with BCN and ADIBO.
Table 1 shows the reactions of the BCN derivatives 11a and
11b with azido complex 1 to provide the triazolato com-
Table 1. Strain-promoted cycloadditions of 1 with BCN derivatives 11a
and 11b.
Figure 3. Terminal and internal alkynes tested for their ability to undergo
cycloaddition with ruthenium(II)–azido complex 1. None of these alkynes
displayed any reactivity towards 1 at ambient temperature (2–10 mm 1,
20–30 mm alkyne, CH2Cl2/DMF 5:1, RT, 5 d, sealed vial) or under cop-
per(I) catalysis conditions (7 mm 1, 20 mm terminal alkyne, DMF/H2O
3:1 and DMSO/H2O 3:1, 10 mol% CuSO4, 20 mol% sodium ascorbate,
RT, 1 d, sealed vial).
ty towards 1, resulted in a complete recovery of the starting
materials. It is worth noting that no products were formed
when the same reactions were carried out under copper(I)
catalysis conditions either.
BCN
Solvent
Conditions
Product
Yield
11a
11b
DMF
DMF
458C, overnight
RT, 4 d
13a
13b
74%
87%
Cycloadditions of ruthenium(II)–azido complexes with
strained alkynes: The recent impressive reports on strain-
promoted azide–alkyne cycloaddition[5–25] encouraged us to
next examine the reactivity of azido complex 1 towards
strain-activated alkynes. To our surprise, despite a careful
literature search, we were not able to find any report deal-
ing with a cycloaddition reaction between a metal-coordinat-
ed azido ligand and a strain-activated alkyne.
plexes 13a and 13b in 74% and 87% yield, respectively.
NMR analysis revealed that in analogy to the DMAD-de-
rived triazolato complex 3, the Cs-symmetric BCN-derived
triazolato ligands of 13a and 13b are attached to the ruthe-
nium center through N2. Products 13a,b displayed remark-
able stability and were purified by standard silica flash chro-
matography without any indication of partial decomposi-
tion.[84] It is worth noting that 13a and 13b were found to be
quite basic and the addition of Et3N during flash chromatog-
raphy was necessary to achieve elution.
We selected the cyclooctynes OCT (10),[6,18] BCN
(11a,b),[21] and ADIBO (12a–c)[24,25,82] for our study as they
are synthetically easily accessible and are reported to dis-
play a range of reactivities towards organic azides (Figure 4;
We then subjected 1 to the ADIBO derivatives 12a–c at
ambient temperature and again we observed smooth reac-
tions which, however, proceeded noticeably faster than the
corresponding reactions with BCN. The resulting triazolato
complexes 14a–c were isolated in 82–86% yield after chro-
matographic purification (Table 2). In spite of numerous ef-
forts, we did not obtain X-ray crystal structures of com-
plexes ACHTNUTRGNE1NUG 4a–c. However, an X-ray crystal structure of com-
plex 14d, which was analogously obtained in 83% yield by
the reaction of ruthenium(II)–azido complex 1’ with
ADIBO derivative 12c (Table 2), was obtained as shown in
Figure 5 (Table 3). The X-ray crystal structure of 14d re-
veals that the triazolato ligand again coordinates the ruthe-
nium center through N2. As the NMR signals (1H,13C) of
14d follow the same pattern as the signals of 14a–c, the tri-
Figure 4. Investigated cyclooctynes for RuII–azido-ligand SPAAC. Abbre-
viations: OCT (10): Cyclooctyne (ref. [18]), BCN (11a,b): bicyclo-
ACHTUNGTRENNUNG[6.1.0]non-4-yne (ref. [21]), ADIBO (12a–c): azadibenzocyclooctyne
(ref. [24]). Common synonyms for ADIBO: DIBAC (dibenzoazacyclooc-
tyne; ref. [25]), DBCO (azadibenzocyclooctyne; ref. [82]).
AHCTUNGTREGaNNNU zolato ligands of the latter are also attached through N2.
As with the BCN-derived triazolato complexes, all of the
ADIBO-derived triazolato complexes displayed remarkable
stability and showed no sign of partial decomposition during
chromatographic purification.[84] Again, the addition of Et3N
to the eluent during flash chromatography was necessary to
achieve elution of 14a–d. It is worth noting that we ob-
served two separate sets of close NMR signals at a ratio of
almost 1:1 for all isolated ADIBO-derived triazolato com-
plexes (14a–d) (1H,13C NMR; 278C; [D6]DMSO). Analysis
of the NMR spectra of 14a–d suggests that this is due to
see legend for definition of the abbreviations OCT, BCN,
and ADIBO). In fact, BCN and ADIBO have been report-
ed to be significantly more reactive towards organic azides
(k2,BCN =1.4 ꢀ 10ꢀ1 mꢀ1 sꢀ1 [21] 2,ADIBO =3.1 ꢀ 10ꢀ1 mꢀ1 sꢀ1[25]
k )
;
than OCT (k2 =2.4 ꢀ 10ꢀ3 mꢀ1 sꢀ1[6]). The increased reactivity
of BCN and ADIBO is attributed to additional ring strain
caused by the fused cyclopropane ring in the case of
BCN[21,83] and by the fused benzene rings in combination
with the exocyclic amide moiety in the case of ADIBO.[27,28]
16684
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ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 16682 – 16689

Strain-Promoted Azide–Alkyne Cycloaddition
FULL PAPER
Table 2. Strain-promoted cycloadditions of 1 with ADIBO derivatives
12a–c and of 1’ with 12c.
Table 3. Crystallographic data for ruthenium(II)–triazolato complexes 3
and 14d.
3
14d
formula
[C36H32N6O6RuS3]
[C45H43N7O4RuS3]
·2
G
·2ACHTGUNTERN(NUG C3H7NO)
1089.3
1calcd [gcmꢀ3
crystal system
space group
a [ꢀ]
b [ꢀ]
c [ꢀ]
]
1011.78
trigonal
R3
33.716(3)
33.716(3)
20.5052(15)
90
90
120
20187.(3)
18
0.778
triclinic
¯
P1
12.2748(16)
14.0557(16)
16.9461(19)
90.298(4)
106.275(4)
115.510(4)
2506.1(5)
2
a [8]
b [8]
Azide ADIBO Solvent
Conditions
Product Yield
g [8]
V [ꢃ3]
Z
1
1
1
1’
12a
12b
12c
12c
CH2Cl2/DMF 1:3 RT, overnight 14a
CH2Cl2/DMF 1:3 RT, overnight 14b
CH2Cl2/DMF 3:1 RT, overnight 14c
CH2Cl2/DMF 3:1 RT, overnight 14d
86%
86%
82%
83%
m [mmꢀ1
]
0.497
crystal size [mm]
Tmin / Tmax
measured reflns
independent reflns
obs. reflns [I>2s(I)]
Rint
0.030ꢀ0.070ꢀ0.150 0.180ꢀ0.090ꢀ0.040
0.6508 / 0.7453
45627
0.92 / 0.98
33799
8610
9315
3515
6862
0.2168
0.0729
R
G
0.0737, 0.1734
0.872
0.0433, 0.1113
1.027
S[b]
reflns, restraints, parameters 8610, 426, 442
9315, 36, 584
0.508, ꢀ0.366
1max, D1min (eꢃꢀ3
)
0.975, ꢀ0.460
[a] R1 =Sj jFo jꢀjFc j j/SjFo j ; wR2 =[w(F2oꢀF2c)2/Sw(Fo2)2]1/2
.
[b] S={S[w(F2oꢀF2c)2]/(nꢀp)}1/2
.
Table 4. Experimentally determined rate constants for the SPAACs of
benzyl azide and RuII–azido complex 1 with BCN cyclooctyne 11b and
ADIBO cyclooctyne 12c.[a]
Azide
Alkyne
Solvent
k2 [Lmolꢀ1 sꢀ1
]
complex 1
complex 1
BnN3
BCN (11b)
ADIBO (12c)
BCN (11b)
DMF
2.7ꢀ10ꢀ4
6.9ꢀ10ꢀ2
5.7ꢀ10ꢀ2
4.0ꢀ10ꢀ1
CH2Cl2/DMF 2:1
CH2Cl2/DMF 2:1
CH2Cl2/DMF 2:1
BnN3
ADIBO (12c)
Figure 5. Molecular structure of ruthenium(II)–triazolato complex 14d.
ORTEP drawing with 50% probability thermal ellipsoids. Hydrogen
atoms and positional disorder of the isopropoxy group have been omitted
[a] Each experiment was carried out in duplicate at 258C in a sealed
flask in a temperature-controlled water bath. Rate constants were deter-
mined by means of HPLC. See Supporting Information for further de-
tails.
ꢀ
ꢀ
for clarity. Selected bond lengths (ꢃ): Ru1 N1=2.108(3), Ru1 N2=
ꢀ
ꢀ
ꢀ
2.140(3), Ru1 N3=2.092(3), Ru1 S1=2.2997(9), Ru1 S2=2.2877(9),
ꢀ
Ru1 S3=2.3060(8).
approximately 250 times faster than with BCN cyclooctyne
11b under almost identical reaction conditions. This differ-
ence in reactivity towards 1 is remarkable since benzyl azide
only reacts roughly seven times faster with ADIBO cyclooc-
tyne 12c than with BCN cyclooctyne 11b. Furthermore,
a comparison of the reactivity of each cyclooctyne derivative
towards both benzyl azide and coordinated azide 1 reveals
that ADIBO cyclooctyne 12c reacts approximately six times
faster with benzyl azide than with azido complex 1 and that
BCN cyclooctyne 11b reacts about 200 times faster with or-
ganic benzyl azide than with coordinated azide 1.
a slow (with respect to the NMR timescale) interconversion
of two conformers of the eight-membered rings of 14a–d,
a phenomenon that is well-known for rigid dibenzofused
eight-membered rings (see Supporting Information for fur-
ther details and discussion).[85–87]
Kinetics experiments: To gain more insight into the kinetics
of the strain-promoted cycloadditions with azido complex 1,
we experimentally determined the second-order rate con-
stants of the reactions of 1 with BCN derivative 11b and
ADIBO derivative 12c. For comparison, we also determined
the rate constants for the corresponding reactions with
benzyl azide.[88] The obtained rate constants are summarized
in Table 4 and confirm our observation that ruthenium(II)–
azido complex 1 is significantly more reactive towards
ADIBO cyclooctynes than towards BCN cyclooctynes. In
fact, azido complex 1 reacted with ADIBO cyclooctyne 12c
Conclusion
In summary, we report that cycloadditions between an ex-
emplary ruthenium(II)–azido complex and strained cyclooc-
tynes readily occur under ambient conditions. These results
Chem. Eur. J. 2013, 19, 16682 – 16689
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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16685

E. Meggers et al.
CH2,[9]aneS3); 13C NMR (100 MHz, [D6]DMSO): d=169.3 (C=OImide), 169.2
(C=OImide), 162.3 (2C, (CO)OMe), 154.4 (Cq,Pycarb), 152.1 (Cq,Pycarb), 151.1
(CHPycarb), 143.5 (Cq,Pycarb), 138.7 (2C, C=N), 137.4 (Cq,Benzyl), 132.1
(CHPycarb), 129.2 (Cq,Pycarb), 128.6 (2C, CHBenzyl), 127.2 (2C, CHBenzyl), 127.2
(CHBenzyl), 126.0 (CHPycarb), 124.0 (CHPycarb), 123.7 (CHPycarb), 123.7
(Cq,Pycarb), 121.1 (Cq,Pycarb), 118.9 (CHPycarb), 115.1 (CHPycarb), 114.9
(Cq,Pycarb), 110.4 (Cq,Pycarb), 51.4 (2C, (CO)OCH3), 40.6 (CH2,Benzyl), 35.0
(CH2,[9]aneS3), 34.1 (CH2,[9]aneS3), 33.9 (CH2,[9]aneS3), 31.6 (CH2,[9]aneS3), 31.5
(CH2,[9]aneS3), 29.3 ppm (CH2,[9]aneS3); IR (film): n˜ =2944, 1718, 1688, 1383,
demonstrate that the concept of strain-promoted azide–
alkyne cycloaddition (SPAAC) is not limited to organic
azides, but also readily applicable to transition-metal-coordi-
nated azides. The presented reactions were carried out in
DMF and DMF/CH2Cl2 due to solubility restrictions, where-
as living biological systems exhibit an aqueous environment.
However, strain-promoted azide–alkyne cycloadditions and
concerted 1,3-dipolar cycloadditions in general, are known
to be less solvent-dependant and even drastic solvent altera-
tions have been shown to cause the rate constants of
SPAACs to vary within one or not much more than one
orders of magnitude.[89,90] Moreover, highly polar protic sol-
vents, such as methanol and water, have been found to pro-
mote the reaction rates of SPAACs.[89] Thus, we are confi-
dent that more soluble ruthenium(II)–azido complexes or
other coordinatively inert azido complexes will be able to
react with strain-activated alkynes in aqueous media under
ambient conditions. The favorable reaction kinetics, in par-
ticular in the case of ADIBO, should allow applications in
living biological systems, for which high rate constants are
necessary to counterbalance cytotoxicity-limiting concentra-
tion restrictions. The scope and the limitations of SPAAC
with coordinatively inert azido complexes within biological
systems will be subject to future work. Moreover, apart
from applications in living biological systems, this chemistry
might be attractive for other areas of research. For instance,
in consideration of the remarkable stability of 13a,b and
14a–d, this chemistry might be used to attach azido com-
plexes to cyclooctyne-functionalized surfaces and macromo-
lecules under ambient conditions.
1225, 1080, 745, 700, 627, 502 cmꢀ1
; HRMS (ESI): m/z calcd for
C36H32N6O6RuS3Na: 865.0489 [M+Na]+; found: 865.0502; X-ray quality
crystals of 3 were grown at RT by slow diffusion of hexanes into a concen-
trated CH2Cl2 solution of 3 (liquid-liquid diffusion technique).
Ruthenium(II)–triazolato complex 13a: A vial with
a stir bar was
charged with azido complex 1 (27.0 mg, 38.6 mmol, 1.00 equiv). A solu-
tion of BCN cyclooctyne 11a (33.2 mg, 173 mmol, 4.47 equiv) in DMF
(400 mL) was added and the vial sealed with a screw cap. The mixture
was allowed to stir overnight at 458C. The next morning, TLC analysis
indicated full conversion. All volatiles were removed in vacuo (458C)
and the crude product was purified by flash chromatography (CH2Cl2/
MeOH/Et3N 600:30:15!600:60:15). The combined product fractions
were diluted with toluene (to avoid excessive Et3N enrichment) and all
volatiles were removed in vacuo. The residue was dissolved in CH2Cl2
and washed successively with sat. NH4Cl, sat. NaHCO3, and sat. NaCl.
The separated organic layer was dried over Na2SO4. After solvent remov-
al and drying in vacuo, the desired triazolato complex 13a (25.4 mg,
28.5 mmol, 74%) was obtained as a dark purple solid. TLC: Rf =0.23
(CH2Cl2/MeOH 5:1 + Et3N); 1H NMR (500 MHz, [D6]DMSO): d=9.07
(dd, J=8.3 Hz, J=1.3 Hz, 1H; HPycarb), 9.02 (dd, J=5.1 Hz, J=1.3 Hz,
1H; HPycarb), 8.72 (d, J=7.9 Hz, 1H; HPycarb), 7.76 (d, J=8.3 Hz, 1H;
HPycarb), 7.72 (dd, J=8.3 Hz, J=5.0 Hz, 1H; HPycarb), 7.47 (ddd, J=8.3 Hz,
J=7.0 Hz, J=1.4 Hz, 1H; HPycarb), 7.44–7.39 (m, 2H; Harom,Benzyl), 7.38–
7.32 (m, 2H; Harom,Benzyl), 7.30–7.23 (m, 2H; 1ꢀHPycarb, 1ꢀHarom,Benzyl), 4.90
(s, 2H; CH2,Benzyl), 3.75 (d, J=7.2 Hz, 2H; CH2OAc), 3.25–3.15 (m, 1H;
CH2,[9]aneS3), 3.10–3.00 (m, 2H; CH2,[9]aneS3), 2.95–2.55 (m, 5H; CH2,[9]aneS3),
2.52–2.35 (m, 5H; 3ꢀCH2,[9]aneS3, 2ꢀCH2CH2-(C=N)), 2.20–1.85 (m, 5H;
2ꢀCH2CH2-(C=N), 2ꢀCH2CH2-(C=N), 1ꢀCH2,[9]aneS3), 1.93 (s, 3H;
(CO)CH3), 0.90–0.74 (m, 2H; CH2CH2-(C=N)), 0.74–0.65 (m, 2H;
CHbridgehead), 0.45 ppm (ms, 1H; CHCH2OAc); 13C NMR (125 MHz,
[D6]DMSO): d=170.4 ((C=O)Me), 169.4 (C=OImide), 169.3 (C=OImide),
154.7 (Cq,Pycarb), 152.3 (Cq,Pycarb), 150.6 (CHPycarb), 143.8 (Cq,Pycarb), 142.1
(2C, C=N), 137.5 (Cq,Benzyl), 131.5 (CHPycarb), 129.0 (Cq,Pycarb), 128.6 (2C,
CHBenzyl), 127.3 (2C, CHBenzyl), 127.2 (CHBenzyl), 125.7 (CHPycarb), 123.9
(CHPycarb), 123.8 (Cq,Pycarb), 123.3 (CHPycarb), 121.1 (Cq,Pycarb), 118.7
(CHPycarb), 115.3 (CHPycarb), 114.7 (Cq,Pycarb), 109.9 (Cq,Pycarb), 67.6
(CH2OAc), 40.6 (CH2,Benzyl), 35.0 (CH2,[9]aneS3), 34.3 (CH2,[9]aneS3), 33.8
(CH2,[9]aneS3), 31.4 (CH2,[9]aneS3), 31.4 (CH2,[9]aneS3), 29.1 (CH2,[9]aneS3), 28.0
(2C, 2ꢀCH2CH2-(C=N)), 25.5 (2C, 2ꢀCH2CH2-(C=N)), 23.6 (2C, 2ꢀ
CHbridgehead), 22.8 (CHCH2OAc), 20.7 ppm ((CO)CH3); IR (film): n˜ =
Experimental Section
Remarks: Cyclooctyne 10 was synthesized according to published proce-
dures.[91] General experimental remarks, NMR signal assignment remarks,
the syntheses of the RuII–azido complexes 1 and 1’, the syntheses of
11a,b (BCN) and 12a–c (ADIBO), detailed crystallographic data of 3
and 14d, detailed information concerning the kinetics experiments and
the related kinetic plots (Table 4), and additional information relating to
the two sets of NMR signals observed for 14a–d are provided in the Sup-
porting Information. CCDC-943048 (3) and CCDC-943049 (14d) contain
the supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
2929, 1737, 1690, 1385, 1348, 1335, 1227, 820, 746, 704, 628, 444, 424 cmꢀ1
;
HRMS (ESI): m/z calcd for C42H43N6O4RuS3: 893.1555 [M+H]+; found:
893.1550.
Ruthenium(II)–triazolato complex 13b: A vial with
a stir bar was
charged with azido complex 1 (31.7 mg, 45.2 mmol, 1.00 equiv). A solu-
tion of BCN cyclooctyne 11b (16.7 mg, 65.7 mmol, 1.45 equiv) in DMF
(900 mL) was added and the vial sealed with a screw cap. After 4 d stir-
ring at RT, full conversion was indicated by TLC analysis (first TLC anal-
ysis). The product was isolated as described for 13a and purified by flash
chromatography (CH2Cl2/MeOH/Et3N 40:2:1!20:2:1). The desired tria-
zolato complex 13b (37.7 mg, 39.5 mmol, 87%) was obtained as a dark
purple solid. TLC: Rf =0.32 (CH2Cl2/MeOH 5:1 + Et3N); 1H NMR
(500 MHz, [D6]DMSO): d=9.06 (d, J=8.4 Hz, 1H; HPycarb), 9.02 (d, J=
5.0 Hz, 1H; HPycarb), 8.71 (d, J=7.8 Hz, 1H; HPycarb), 7.90 (d, J=7.5 Hz,
2H; Harom,Benzyl), 7.76 (d, J=8.4 Hz, 1H; HPycarb), 7.72 (dd, J=8.2 Hz, J=
5.2 Hz, 1H; HPycarb), 7.65–7.57 (m, 1H; Harom,Benzyl), 7.53–7.44 (m, 3H; 2ꢀ
Harom,Benzyl, 1ꢀHPycarb), 7.44–7.38 (m, 2H; Harom,Benzyl), 7.35 (dd, J=7.6 Hz,
J=7.6 Hz, 2H; Harom,Benzyl), 7.30–7.21 (m, 2H; 1ꢀHarom,Benzyl, 1ꢀHPycarb),
4.90 (s, 2H; CH2,Benzyl), 4.04 (d, J=7.2 Hz, 2H; CH2OBz), 3.25–3.15 (m,
1H; CH2,[9]aneS3), 3.13–2.97 (m, 2H; CH2,[9]aneS3), 2.96–2.57 (m, 5H;
Ruthenium(II)–triazolato complex 3: Azido complex
1 (10.0 mg,
14.3 mmol, 1.00 equiv) was dissolved in a mixture of CH2Cl2 (6.0 mL) and
DMF (1.2 mL). Dimethyl acetylenedicarboxylate (2, 26.5 mL, 216 mmol,
15.1 equiv) was added under stirring. After 30 min stirring at RT, full
conversion was indicated by TLC analysis. All volatiles were removed in
vacuo (458C) and the crude product was purified by flash chromatogra-
phy (CH2Cl2/MeOH 10:1). After solvent removal and drying in vacuo,
the desired triazolato complex 3 (10.5 mg, 12.5 mmol, 87%) was obtained
as a dark purple solid. TLC: Rf =0.50 (CH2Cl2/MeOH 5:1); 1H NMR
(400 MHz, [D6]DMSO): d=9.15–9.06 (m, 2H; HPycarb), 8.72 (d, J=7.9 Hz,
1H; HPycarb), 7.79 (dd, J=8.4 Hz, J=5.1 Hz, 1H; HPycarb), 7.79 (d, J=
8.4 Hz, 1H; HPycarb), 7.49 (ddd, J=8.3 Hz, J=7.0 Hz, J=1.5 Hz, 1H;
HPycarb), 7.45–7.38 (m, 2H; Harom,Benzyl), 7.38–7.32 (m, 2H; Harom,Benzyl),
7.32–7.24 (m, 2H; 1ꢀHPycarb, 1ꢀHarom,Benzyl), 4.90 (s, 2H; CH2,Benzyl), 3.54
(s, 6H; (CO)OCH3), 3.20–2.90 (m, 5H; CH2,[9]aneS3), 2.88–2.65 (m, 3H;
CH2,[9]aneS3), 2.63–2.44 (m, 3H; CH2,[9]aneS3), 2.27–2.14 ppm (m, 1H;
16686
www.chemeurj.org
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 16682 – 16689

Strain-Promoted Azide–Alkyne Cycloaddition
FULL PAPER
CH2,[9]aneS3), 2.55–2.33 (m, 5H; 3ꢀCH2,[9]aneS3, 2ꢀCH2CH2-(C=N)), 2.21–
2.06 (m, 3H; 1ꢀCH2,[9]aneS3, 2ꢀCH2CH2-(C=N)), 2.06–1.90 (m, 2H;
7.90–7.79 (m, 1H; HPycarb), 7.79–7.71 (m, 1H; HPycarb), 7.49 (dd, J=7.7 Hz,
J=7.7 Hz, 1H; HPycarb), 7.45–7.39 (m, 2H; Harom,Benzyl), 7.38–7.32 (m, 2H;
Harom,Benzyl), 7.31–6.73 (m, 10H; 1ꢀHarom,Benzyl, 1ꢀHPycarb, 8ꢀHADIBO), 5.33
(d, J=16.0 Hz) + 5.28 (d, J=16.1 Hz, 1H; CH2,8-Ring), 4.91 (s, 2H;
CH2,Benzyl), 3.97 (d, J=16.1 Hz) + 3.92 (d, J=16.3 Hz, 1H; CH2,8-Ring),
3.30–2.20 (m, 12H; CH2,[9]aneS3), 1.16 (s) + 1.10 ppm (s, 3H; N(CO)CH3);
13C NMR (125 MHz, [D6]DMSO): d=169.4 (C=OImide), 169.3 (C=OImide),
168.3 (C=OAmide), 155.0 (Cq,Pycarb), 152.3 (Cq,Pycarb), 150.9 + 150.8 (1C;
CHPycarb), 144.1 + 144.1 (1C; Cq,Pycarb), 141.1 + 140.8 (1C; Cq,ADIBO), 140.6
(Cq,ADIBO), 139.0 (Cq,ADIBO), 137.5 (Cq,Benzyl), 133.4 (Cq,ADIBO), 133.1–132.7
(1C; Cq,ADIBO), 131.8 (CHPycarb), 131.2 (Cq,ADIBO), 130.8 + 130.5 (1C;
CH2CH2-(C=N)), 0.95–0.72 (m, 4H; 2ꢀCH2CH2-(C=N), 2ꢀCHbridgehead),
0.65–0.55 ppm (m, 1H; CHCH2OBz); 13C NMR (125 MHz, [D6]DMSO):
d=169.4 (C=OImide), 169.2 (C=OImide), 165.7 ((C=O)Ph), 154.7 (Cq,Pycarb),
152.3 (Cq,Pycarb), 150.6 (CHPycarb), 143.8 (Cq,Pycarb), 142.0 (2C, C=N), 137.5
(Cq,Benzyl), 133.1 (CHBenzyl), 131.4 (CHPycarb), 129.9 (Cq,Benzyl), 129.0 (3C, 2ꢀ
CHBenzyl, 1ꢀCq,Pycarb), 128.7 (2C, CHBenzyl), 128.6 (2C, CHBenzyl), 127.3 (2C,
CHBenzyl), 127.2 (CHBenzyl), 125.7 (CHPycarb), 123.9 (CHPycarb), 123.8
(Cq,Pycarb), 123.4 (CHPycarb), 121.1 (Cq,Pycarb), 118.7 (CHPycarb), 115.3
(CHPycarb), 114.7 (Cq,Pycarb), 109.9 (Cq,Pycarb), 68.4 (CH2OBz), 40.6
(CH2,Benzyl), 35.0 (CH2,[9]aneS3), 34.3 (CH2,[9]aneS3), 33.8 (CH2,[9]aneS3), 31.4
(CH2,[9]aneS3), 31.4 (CH2,[9]aneS3), 29.1 (CH2,[9]aneS3), 28.0 (2C, 2ꢀCH2CH2-
(C=N)), 25.5 (2C, 2ꢀCH2CH2-(C=N)), 23.7 (2C, 2ꢀCHbridgehead),
22.8 ppm (CHCH2OBz); IR (film): n˜ =2930, 1692, 1383, 1335, 1268, 1227,
CHADIBO), 129.7–128.7 (3C; 1ꢀCq,Pycarb
,
2ꢀCHADIBO), 128.6 (2C;
CHBenzyl), 127.7–127.0 (3C; CHADIBO), 127.3 (2C; CHBenzyl), 127.2
(CHBenzyl), 125.9–125.6 (2C; 1ꢀCHPycarb, 1ꢀCHADIBO), 125.5–125.2 (1C;
CHADIBO), 124.0–123.8 (1C; CHPycarb), 123.8 (Cq,Pycarb), 123.3 (CHPycarb),
121.2 (Cq,Pycarb), 118.8 (CHPycarb), 115.2 (CHPycarb), 114.9 (Cq,Pycarb), 110.0
1108, 1098, 745, 709, 626, 503 cmꢀ1
; HRMS (ESI): m/z calcd for
C47H45N6O4RuS3: 955.1713 [M+H]+; found: 955.1700.
(Cq,Pycarb), 53.3 + 53.1 (1C; CH2,8-Ring), 40.6 (CH2,Benzyl) 35.2–33.4 (3C;
,
CH2,[9]aneS3), 32.3–31.1 (2C; CH2,[9]aneS3), 29.6 + 29.1 (1C; CH2,[9]aneS3),
Ruthenium(II)–triazolato complex 14a: ADIBO cyclooctyne 12a
(24.0 mg, 63.8 mmol, 1.10 equiv) was dissolved in a mixture of CH2Cl2
(4.0 mL) and DMF (4.0 mL). A solution of azido complex 1 (40.4 mg,
57.7 mmol, 1.00 equiv) in DMF (8.0 mL) was added under stirring and the
mixture was stirred for 17 h at RT. Full conversion was indicated by TLC
analysis. All volatiles were removed in vacuo (458C) and the crude prod-
uct was purified by flash chromatography (CH2Cl2/MeOH/Et3N
400:10:5). The combined product fractions were diluted with toluene (to
avoid excessive Et3N enrichment) and all volatiles were removed in
vacuo. The residue was dissolved in CH2Cl2 and washed successively with
sat. NH4Cl, sat. NaHCO3, and sat. NaCl. The separated organic layer was
dried over Na2SO4. After solvent removal and drying in vacuo, the de-
sired triazolato complex 14a (53.2 mg, 49.4 mmol, 86%) was obtained as
21.8–21.5 ppm (1C; NACTHNUTRGNEUNG(C=O)CH3); IR (film): n˜ =2923, 1693, 1661, 1386,
1339, 1309, 1228, 745, 700, 628, 502 cmꢀ1; HRMS (ESI): m/z calcd for
C47H40N7O3RuS3: 948.1403 [M+H]+; found: 948.1382.
Ruthenium(II)–triazolato complex 14c: A flask was charged with azido
complex 1 (45.4 mg, 64.9 mmol, 1.00 equiv), DMF (3.0 mL), and CH2Cl2
(3.0 mL). A solution of ADIBO cyclooctyne 12c (25.0 mg, 90.8 mmol,
1.40 equiv) in CH2Cl2 (6.0 mL) was added under stirring and the mixture
was stirred overnight at RT. The next morning, full conversion was indi-
cated by TLC analysis. The product was isolated as described for 14a and
purified by flash chromatography (CH2Cl2/MeOH/Et3N 400:10:5). The
desired triazolato complex 14c (52.1 mg, 53.4 mmol, 82%) was obtained
as a dark purple solid. TLC: Rf =0.21 (CH2Cl2/MeOH 20:1 + Et3N);
1H NMR (500 MHz, [D6]DMSO): d=9.15–9.06 (m, 2H; HPycarb), 8.72 (d,
J=7.9 Hz, 1H; HPycarb), 7.85–7.70 (m, 2H; HPycarb), 7.51–7.43 (m, 1H;
HPycarb), 7.43–7.38 (m, 2H; Harom,Benzyl), 7.37–7.30 (m, 2H; Harom,Benzyl),
7.30–7.08 (m, 6H; 1ꢀHarom,Benzyl, 1ꢀHPycarb, 4ꢀHADIBO), 7.00–6.73 (m, 4H;
HADIBO), 5.49 (d, J=17.0 Hz) + 5.46 (d, J=17.0 Hz, 1H; CH2,8-Ring), 4.89
(s, 2H; CH2,Benzyl), 4.12 (d, J=17.1 Hz) + 4.09 (d, J=17.2 Hz, 1H; CH2,8-
Ring), 3.39–2.20 (m, 12H; CH2,[9]aneS3), 1.72 (sept, J=6.7 Hz) + 1.66 (sept,
a
dark purple solid. TLC: Rf =0.30 (CH2Cl2/MeOH 20:1 + Et3N);
1H NMR (600 MHz, [D6]DMSO): d=9.19–9.06 (m, 2H; HPycarb), 8.75 (d,
J=8.5 Hz) + 8.73 (d, J=8.5 Hz, 1H; HPycarb), 7.88 (d, J=8.4 Hz) + 7.85
(d, J=8.3 Hz, 1H; HPycarb), 7.81–7.72 (m, 1H; HPycarb), 7.51 (dd, J=
7.7 Hz, J=7.7 Hz, 1H; HPycarb), 7.45–7.39 (m, 2H; Harom,Benzyl), 7.34 (dd,
J=7.6 Hz, J=7.6 Hz, 2H; Harom,Benzyl), 7.31–6.72 (m, 10H; 1ꢀHarom,Benzyl
,
1ꢀHPycarb, 8ꢀHADIBO), 6.32 (ms, 1H; NH), 5.39 (d, J=16.3 Hz) + 5.34 (d,
J=16.0 Hz, 1H; CH2,8-Ring), 4.91 (s, 2H; CH2,Benzyl), 4.02 (d, J=16.5 Hz) +
J=6.8 Hz, 1H; CH
CH
(CH3)2), ꢀ0.20 (d, J=6.6 Hz) + ꢀ0.32 ppm (d, J=6.6 Hz, 3H; CH-
AHCTUNGTRENNUNG
(CH3)2); 13C NMR (125 MHz, [D6]DMSO): d=175.0 (C=OAmide), 169.4 +
ACHTUGNTRNEN(UNG CH3)2), 0.59 (d, J=6.8 Hz) + 0.56 (d, J=6.8 Hz, 3H;
3.98 (d, J=16.3 Hz, 1H; CH2,8-Ring), 3.25–2.22 (m, 14H; 12ꢀCH2,[9]aneS3
2ꢀCH2CH2N), 1.94–1.81 (m, 1H; N(CO)CH2), 1.35 (s) + 1.33 (s, 9H; C-
(CH3)3), 1.35–1.27 ppm (m, 1H; N(CO)CH2); 13C NMR (125 MHz,
,
ACHTUNGTRENNUNG
T
169.4 (1C; C=OImide), 169.3 + 169.2 (1C; C=OImide), 154.9 + 154.8 (1C;
Cq,Pycarb), 152.4 + 152.3 (1C; Cq,Pycarb), 150.7 + 150.7 (1C; CHPycarb), 144.0
(Cq,Pycarb), 141.1 + 141.0 (1C; Cq,ADIBO), 140.5 + 140.4 (1C; Cq,ADIBO),
139.2 (Cq,ADIBO), 137.5 (Cq,Benzyl), 133.8 + 133.7 (1C; Cq,ADIBO), 133.2
(Cq,ADIBO), 131.8–131.4 (2C; 1ꢀCHPycarb, 1ꢀCHADIBO), 130.4 + 130.4 (1C;
Cq,ADIBO), 129.2 + 129.0 (1C; Cq,Pycarb), 128.6 + 128.6 (1C; CHADIBO),
128.5 (2C; CHarom,Benzyl), 128.2–127.7 (3C; CHADIBO), 127.3 (CHADIBO),
[D6]DMSO): d=169.5 + 169.3 (1C; C=OAmide), 169.4 (C=OImide), 169.2
(C=OImide), 155.2 + 155.1 (1C; C=OCarbamate), 154.9 + 154.8 (1C; Cq,Pycarb),
152.3 + 152.3 (1C; Cq,Pycarb), 150.9 + 150.8 (1C; CHPycarb), 144.1 + 144.0
(1C; Cq,Pycarb), 141.1 + 140.9 (1C; Cq,ADIBO), 139.9 (Cq,ADIBO), 139.0 +
139.0 (1C; Cq,ADIBO), 137.5 (Cq,Benzyl), 133.4–133.0 (2C; Cq,ADIBO), 131.8
(CHPycarb), 131.0 + 131.0 (1C; Cq,ADIBO), 130.9 + 130.6 (1C; CHADIBO),
129.1 + 129.1 (1C; Cq,Pycarb), 129.7–129.0 (2C; CHADIBO), 128.6 (2C;
CHBenzyl), 127.8–127.1 (3C; CHADIBO), 127.3 (2C; CHBenzyl), 127.2
(CHBenzyl), 125.9–125.6 (2C; CHPycarb + CHADIBO), 125.5 + 125.3 (1C;
CHADIBO), 123.9 (CHPycarb), 123.8 (Cq,Pycarb), 123.3 + 123.2 (1C; CHPycarb),
127.2 (2C; CHarom,Benzyl), 127.2 (CHarom,Benzyl), 125.7–125.3 (3C; 1ꢀCHPycarb
,
2ꢀCHADIBO), 124.0–123.6 (2C; 1ꢀCHPycarb, 1ꢀCq,Pycarb), 123.2 + 123.2
(1C; CHPycarb), 121.1 (Cq,Pycarb), 118.7 (CHPycarb), 115.2 (CHPycarb), 114.9 +
114.9 (1C; Cq,Pycarb), 109.9 + 109.9 (1C; Cq,Pycarb), 53.2 + 52.9 (1C; CH2,8-
Ring), 40.5 (CH2,Benzyl), 35.2–33.4 (3C; CH2,[9]aneS3), 32.0–31.3 (2C;
121.1 (Cq,Pycarb), 118.8
CHPycarb), 114.9 (Cq,Pycarb), 110.1 (Cq,Pycarb), 77.4 (3C; C
(1C; CH2,8-Ring), 40.6 (CH2,Benzyl), 36.1 + 36.0 (1C; CH2CH2N), 35.1–34.1
(2C; CH2,[9]aneS3), 33.8 + 33.7 (1C; CH2,[9]aneS3), 33.4 + 33.3 (1C; N(C=
O)CH2), 31.9–31.3 (2C; CH2,[9]aneS3), 29.4 29.2 (1C; CH2,[9]aneS3),
28.2 ppm (C(CH3)3); IR (film): n˜ =2923, 1690, 1493, 1383, 1335, 1227,
+
118.8 (1C; CHPycarb), 115.2
+ 115.2 (1C;
E
CH2,[9]aneS3), 29.7 (CH
ACHTUNGTRENNUNG
(1C; CH(CH3)2), 18.0 + 17.7 ppm (1C; CHACTHUNGTRENNNUG
R
T
2850, 1689, 1644, 1580, 1493, 1382, 1335, 1265, 1226, 1136, 1078, 744, 697,
626, 497 cmꢀ1; HRMS (ESI): m/z calcd for C49H44N7O3RuS3: 976.1717
[M+H]+; found: 976.1704.
+
ACHTUNGTRENNUNG
1163, 1137, 745, 697, 627, 499 cmꢀ1
; HRMS (ESI): m/z calcd for
Ruthenium(II)–triazolato complex 14d: A flask was charged with azido
complex 1’ (22.7 mg, 34.0 mmol, 1.00 equiv), CH2Cl2 (3.0 mL), and DMF
(1.7 mL). A solution of ADIBO cyclooctyne 12c (12.0 mg, 43.6 mmol,
1.28 equiv) in CH2Cl2 (2.0 mL) was added under stirring and the mixture
stirred at RT. After 2 h 15 min, full conversion was indicated by TLC
analysis. The mixture was left stirring overnight and the reaction was
worked up the following morning. The product was isolated as described
for 14a and purified by flash chromatography (CH2Cl2/MeOH/Et3N
400:20:5). The desired triazolato complex 14d (26.6 mg, 28.2 mmol, 83%)
was obtained as a dark green solid. TLC: Rf =0.16 (CH2Cl2/MeOH 15:1
+ Et3N); 1H NMR (500 MHz, [D6]DMSO): d=10.90 (s) + 10.89 (s, 1H;
NH), 9.13–9.01 (m, 2H; HPycarb), 8.25 (ms, 1H; HPycarb), 7.72 (dd, J=
C53H51N8O5RuS3: 1077.2195 [M+H]+; found: 1077.2199.
Ruthenium(II)–triazolato complex 14b: A flask was charged with azido
complex 1 (63.0 mg, 90.0 mmol, 1.00 equiv) and DMF (19 mL). A solution
of ADIBO cyclooctyne 12b (33.0 mg, 134 mmol, 1.48 equiv) in CH2Cl2
(6.5 mL) was added under stirring and the mixture was stirred overnight
at RT. The next morning, full conversion was indicated by TLC analysis.
The product was isolated as described for 14a and purified by flash chro-
matography (CH2Cl2/MeOH/Et3N 200:10:5). The desired triazolato com-
plex 14b (73.2 mg, 77.3 mmol, 86%) was obtained as a dark purple solid.
TLC: Rf =0.07 (CH2Cl2/MeOH 20:1
[D6]DMSO): d=9.20–9.05 (m, 2H; HPycarb), 8.78–8.67 (m, 1H; HPycarb),
+
Et3N); 1H NMR (500 MHz,
Chem. Eur. J. 2013, 19, 16682 – 16689
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16687

E. Meggers et al.
8.2 Hz, J=5.0 Hz) + 7.69 (dd, J=8.4 Hz, J=5.1 Hz, 1H; HPycarb), 7.72–
7.63 (m, 1H; HPycarb), 7.29–7.06 (m, 5H; 1ꢀCHPycarb, 4ꢀCHADIBO), 7.02–
6.80 (m, 4H; CHADIBO), 5.51 (d, J=17.2 Hz) + 5.48 (d, J=16.9 Hz, 1H;
CH2,8-Ring), 4.62 (sept, J=6.1 Hz) + 4.62 (sept, J=6.1 Hz, 1H; CaromOCH-
[16] K. W. Dehnert, J. M. Baskin, S. T. Laughlin, B. J. Beahm, N. N.
Naidu, S. L. Amacher, C. R. Bertozzi, ChemBioChem 2012, 13, 353–
357.
[17] S. T. Laughlin, J. M. Baskin, S. L. Amacher, C. R. Bertozzi, Science
2008, 320, 664–667.
ACHTUNGTRENNUNG
[18] P. V. Chang, J. A. Prescher, E. M. Sletten, J. M. Baskin, I. A. Miller,
N. J. Agard, A. Lo, C. R. Bertozzi, Proc. Natl. Acad. Sci. USA 2010,
107, 1821–1826.
G
ACHTUNGTRENNUNG
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125.6–125.3 (2C; CHADIBO), 124.1 + 124.1 (1C; Cq,Pycarb), 122.8 + 122.7
(1C; CHPycarb), 121.0 (Cq,Pycarb), 117.1
(CHPycarb), 114.5 (Cq,Pycarb), 110.7–110.3 (1C; Cq,Pycarb), 109.9 + 109.7 (1C;
CHPycarb), 70.5 + 70.5 (1C; CaromOCH(CH3)2), 53.1 + 52.9 (1C; CH2,8-
Ring), 35.2–33.3 (3C; CH2,[9]aneS3), 32.1–31.3 (2C; CH2,[9]aneS3), 29.7 ((C=
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O)CH(CH3)2); IR (film): n˜ =2968, 1712, 1697, 1639, 1601, 1492, 1458,
+ 117.0 (1C; CHPycarb), 115.6
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Received: June 28, 2013
Published online: October 31, 2013
Chem. Eur. J. 2013, 19, 16682 – 16689
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
16689