Strain-promoted azide-alkyne cycloadditions of benzocyclononynes

Article abstract of DOI:10.1021/jo300188y

Preliminary studies related to the design and development of new cycloalkyne reagents for metal-free click coupling are reported. Cyclononynes are more stable than cyclooctynes, and the robust benzocyclononyne platform offers spontaneous reactivity toward

Full text of DOI:10.1021/jo300188y

Brief Communication
pubs.acs.org/joc
Strain-Promoted Azide−Alkyne Cycloadditions of
Benzocyclononynes
Jumreang Tummatorn,† Paratchata Batsomboon, Ronald J. Clark, Igor V. Alabugin,
and Gregory B. Dudley*
Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306-4390, United States
S
* Supporting Information
ABSTRACT: Preliminary studies related to the design and develop-
ment of new cycloalkyne reagents for metal-free click coupling are
reported. Cyclononynes are more stable than cyclooctynes, and the
robust benzocyclononyne platform offers spontaneous reactivity
toward azides at rates competitive with other azidophiles that have
been employed for metal-free click coupling. Benzocyclononynes (e.g.,
1) provide valuable insight into the design of new cycloalkynes for
strain-promoted azide−alkyne cycloaddition (SPAAC) couplings for
applications in which side reactions and decomposition of the reagent
must be kept to a minimum.
he azide−alkyne cycloaddition (AAC) is the prototypical
T
example of what has come to be known as “click”
chemistry, or organic coupling reactions that meet specific
criteria for performance efficiency.1 Azides are superb click
partners: small, easy to introduce, stable to many common
reaction conditions, and reactive as 1,3-dipoles in the AAC
reaction among others.
The AAC reaction is exothermic but slow under ambient
conditions. Two recent strategies, copper catalysis and ring
strain, have emerged to overcome kinetic barriers and propel
the AAC reaction to the forefront of molecular sciences.2 The
copper-catalyzed azide−alkyne cycloaddition (CuAAC) of
terminal alkynes delivers 1,4-disubstituted 1,2,3-triazoles in a
regiocontrolled manner. The impact of this process can hardly
be overstated. However, the need for a copper catalyst makes
the CuAAC process nonideal for bioorthogonal coupling3 and
for many applications in inorganic/nanomaterials science.4
The strain-promoted azide−alkyne cycloaddition (SPAAC)
takes advantage of ground-state destabilization (strain) to
accelerate triazole formation under ambient or physiological
conditions.5 The metal-free SPAAC process is rapidly evolving
in myriad directions, increasing demand for cycloalkyne tools.
Current SPAAC tools are based on the cyclooctyne (OCT)
platform (Figure 1; strained cycloalkenes also merit attention).6
Cyclooctyne offers “explosive”7a reactivity toward azides but
also “is air-sensitive and rearranges and polymerizes easily.”7b
From there, reactivity can be enhanced beyond the level at
which the reagent can be isolated in pure form.8
Figure 1. Selected SPAAC reagents based on cyclooctyne (OCT) and
alternative alkene platforms for metal-free click coupling.
medium-ring cycloalkynes by ring expansion of vinylogous acyl
triflates (e.g., 2 → 3, Scheme 1)10c and now turn our attention
to the design and synthesis of cycloalkynes for SPAAC
coupling.
Considering that cyclooctyne stability can be a limiting
factor,7 we reasoned that SPAAC reactions of cyclononynes
should be investigated, perhaps by taking advantage of lessons
learned in the development of cyclooctyne reagents. Our
hypothesis is that benzocyclononynes will provide a balance of
stability and reactivity not available using the cyclooctyne
platform. We focus on benzocyclononynes (cf. 3, Scheme 1)
because (i) fused benzene rings enhance SPAAC reactivity,6a
(ii) a methylene spacer between the benzene ring and the
alkyne minimizes steric repulsion in the SPAAC transition
state,12 and (iii) our modular assembly of cycloalkynes10c
conveniently provides benzocyclononynes. Robust, reactive,
Design and synthesis of cycloalkynes that are stable to
diverse chemical environments and yet spontaneously reactive
toward azides is thus an important current challenge. This
challenge represents a methodological convergence of two of
our long-standing interests: organic reagents9 and high-value
alkynes.10,11 We recently disclosed a strategy for preparing
Received: January 27, 2012
Published: February 8, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Brief Communication
Reduction of ketone 3 with LiAlH4 provided alcohol 7; note
that ring expansion and reduction may be combined into a one-
pot process (2 → 7, Scheme 3). Compared to ketone 3, alcohol
Scheme 1. Cyclooctyne, Cyclononyne Platforms, and the
Preparation of Benzocyclononyne Ketone 3
Scheme 3. Stability and Reactivity of Alcohol 7
and user-friendly cycloalkyne tools may enable SPAAC
chemistry to grow in much the same way as the advent of
ruthenium alkylidene catalysts helped accelerate the develop-
ment of olefin metathesis chemistry.13 Preliminary studies into
the SPAAC coupling of benzocyclononynes are described
herein.
7 is more stable to acid and base and ca. 150-fold more reactive
toward benzyl azide (7 → 8), providing an 83% yield of
regioisomeric16 triazoles 8 after 6 h at room temperature. This
increase in reactivity is atypical SPAAC behavior, because
changing an sp2-center to an sp3-center should decrease
reactivity.6 We invoke the transannular π → π* interaction in
ketone 3 (or rather its absence in alcohol 7) to explain the
increased acid/base-stability and azide-reactivity of 7. The
reactivity of 7 is similar to activated oxanorbornadienes (cf.
Figure 1),17 which have been employed for bioorthogonal
ligation and radiolabeling, and about 10-fold less than OCT,5
the starting point in the development of cyclooctyne-based
reagents for metal-free click chemistry.
Studies on cycloalkynone 310c provide important insights
into cycloalkyne structure−activity relationships (Scheme 2).
Scheme 2. X-ray Structure, NBO Analysis Showing
Transannular π → π* Interaction, and Reactions of Ketone
3
From these initial studies, we proceed with the synthesis of
new cyclononynes for SPAAC coupling (Scheme 4). Concerns
Scheme 4. Synthesis and X-ray Structure of Cycloalkynol 12
The crystal structure of 3 shows (i) the proximity (2.69 Å) and
perpendicular orientation of the ketone (C1) to the alkyne
(C5−C6), and (ii) the lack of conjugation between the ketone
and the aromatic ring: the in-plane alkyne π-orbital is in near-
perfect Burgi−Dunitz alignment for transannular interaction
̈
with the ketone π*-orbital. NBO analysis of 3 (B3LYP/6-
31G(d,p) level) also points to transannular alkyne−ketone
interaction (Scheme 2).14
have been raised regarding the lipophilicity of certain SPAAC
reagents,6a so we increase hydrophilicity by adding methoxy
groups around the aromatic ring (except in the position closest
to the alkyne, to avoid the risk of negative steric interactions
with the approaching azide12). This structural modification also
reduces costs, as aldehyde 1018 is more accessible than 2-iodo-
benzaldehyde.
Chemical reactivity of keto-alkyne 3 is best understood in the
context of this interaction. Transannular keto-alkyne cycliza-
tion15 is induced by either acid (3 → 4, Scheme 2) or base (3
→ 5), but the ketone resisted reduction with NaBH4. These
observations suggest that keto-alkyne 3 is prone to cyclization
but unusually stable to external reagents. Nonetheless, the
alkyne showed modest reactivity with benzyl azide (3 → 6) at
room temperature.16
The synthesis of cycloalkynol 12 begins with vinylogous acyl
triflate 11, prepared in our usual manner (Scheme 4).10c
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The Journal of Organic Chemistry
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brine, dried over Na2SO4, and concentrated under reduced pressure.
The residue was purified by chromatography on silica (20% EtOAc/
hexanes) to give 4, 7.8 mg (87%), as a white solid, mp 92−93 °C. IR
Tandem cyclization/ring expansion was initiated by iodine−
lithium exchange, followed by ketone reduction with DIBAL-H.
This sequence will benefit from further optimization, but for
now reliably provides 12 in ca. 35% overall yield. Once
prepared, crystalline 12 is routinely stored in glass vials in a lab
refrigerator, where thus far it has proven to be indefinitely
stable.
The alcohol group of 12 provides a handle for attachment of
molecular cargo (e.g., fluorescent probes, radiolabels, etc.) for
delivery using SPAAC coupling. Using benzylamine as model
cargo, we prepared carbamate 1 (via the p-nitrophenyl
carbonate) for kinetic analysis (Scheme 5). Other amine-
tagged functionality can be attached in an analogous manner, as
will be described in future reports.
1
(neat): νmax 2935, 1650,1394, 1138, 729 cm−1. H NMR (400 MHz,
CDCl3) δ 7.56−7.51 (m, 2H), 7.42−7.36 (m, 2H), 3.62 (t, 2H, J = 3.0
Hz), 2.82 (tt, 2H, J = 6.0, 3.0 Hz), 2.58 (t, 2H, J = 6.1 Hz), 2.23
(pentet, 2H, J = 6.3 Hz). 13C NMR (100 MHz, CDCl3) δ 196.8, 160.2,
145.0, 142.3, 138.7, 128.8, 126.9, 124.8, 121.7, 38.2, 35.0, 23.6, 23.0.
HRMS (EI+) calcd for C13H12O (M)+ 184.0888; found 184.0888.
2,3-Dihydro-1H-cyclopenta[b]naphthalen-4-ol (5, Cycliza-
tion of 3 under Basic Conditions). Cycloalkynone 3 (21.6 mg,
0.12 mmol) in 2 M KOH in EtOH (2 mL) was stirred at rt for 30 min.
Purification as described above for 4 gave compound 5, 10.5 mg
(49%), as a white solid, mp 72−75 °C. IR (neat): νmax 3329, 2944,
1
1579, 1281, 1087, 1029 cm−1. H NMR (400 MHz, CDCl3) δ 8.11−
8.07 (m, 1H), 7.71−7.70 (m, 1H), 7.41−7.37 (m, 2H), 7.30 (s, 1H),
4.94 (s, 1H), 3.07 (td, 2H, J = 7.7, 1.0 Hz), 2.95 (t, 2H, J = 7.2 Hz),
2.19 (p, 2H, 7.4 Hz). 13C NMR (100 MHz, CDCl3) δ 146.3, 144.3,
134.5, 127.3, 125.4. 124.1, 123.7, 123.2, 120.9, 114.9, 33.1, 28.3, 25.9.
Cycloalkynol 7. To a solution of cyclononyne 3 (91 mg, 0.49
mmol) in THF (10 mL) at 0 °C was added LiAlH4 (19.0 mg, 0.49
mmol). The mixture was stirred for 30 min, and then 2 M NaOH was
added (50 μL), followed by MgSO4. After additional stirring for 15
min, the reaction mixture was filtered and concentrated. The crude
product was purified by chromatography on silica (30% EtOAc/
hexanes) to give compound 7, 67.7 mg (74%), as a yellow oil. IR
Scheme 5. Model Functionalization of 12 and “Click”
Reactivity of Carbamate 1
1
(neat): νmax 3377, 2933, 1452, 1437, 761 cm−1. H NMR (400 MHz,
CDCl3) δ 7.63 (d, 1H, J = 7.7 Hz), 7.30 (t, 1H, J = 7.5 Hz), 7.16 (t,
1H, J = 7.6 Hz), 7.05 (d, 1H, J = 7.5 Hz), 5.70 (t, 1H, J = 4.7 Hz), 3.90
(dt, 1H, J = 18.2, 3.2 Hz), 3.13 (d, 1H, J = 18.2 Hz), 2.27−2.17 (m,
2H), 2.14−2.07 (m, 1H), 2.01−1.91 (m, 1H), 1.89−1.81 (m, 2H). 13C
NMR (100 MHz, CDCl3) δ 146.2, 136.0, 128.9. 127.5, 126.9, 126.3,
90.6, 89.1, 72.3, 40.5, 27.2, 25.6, 19.7. HRMS (EI+) calcd for C13H13O
(M − H)+ 185.0966; found 185.0966.
2-(2-Iodo-3,4,5-trimethoxybenzyl)-3-oxocyclohex-1-enyl
Trifluoromethanesulfonate (11). Reductive condensation of 1,3-
cyclohexanedione (9) with aldehyde 1018 according to our general
procedure10c gave VAT 11, 780 mg (76%), as colorless crystals, mp
60−61 °C. IR (neat): νmax 2940, 1670, 1480, 1417, 1388, 1330, 1213,
The second-order rate constant for the reaction of 1 with
benzyl azide is 4.6 × 10−4 M−1 s−1. This level of reactivity
surpasses many oxanorbornadiene reagents and lands within an
order of magnitude of OCT (2.4 × 10−3 M−1 s−1), indicating
that this cyclononyne platform may be sufficiently reactive for
applications in metal-free click chemistry. Further development
of these reagents appears promising.
In conclusion, the benzocyclononyne platform can provide
useful levels of SPAAC reactivity. This preliminary communi-
cation addresses the rapidly growing demand for cycloalkyne
tools for metal-free click coupling. We anticipate that
cycloalkynol 12 will be valuable for applications in which
problematic background reactivity, i.e., decomposition and/or
side reactions with other functional groups, outweighs the
advantages of hyperfast coupling with azides. We expect more
reactive variants of benzocyclononyne to be identified going
forward by rechanneling insights from the development of
cyclooctyne reagents. Our efforts are progressing on several
fronts, including (i) optimization of the synthesis of cyclo-
alkynol 12, (ii) elucidating19 and applying new design
principles for the development of more reactive benzocyclo-
nonyne derivatives, and (iii) collaborative application of
benzocyclononynes to current challenges in chemical biology
and inorganic/nanomaterials science.
1
1137, 984 cm−1. H NMR (400 MHz) δ 6.43 (s, 1H), 3.87 (s, 3H),
3.84 (s, 3H), 3.79 (s, 3H), 3.77 (s, 2H), 2.86 (t, 2H, J = 6.2 Hz), 2.54
(t, 2H, J = 6.4 Hz), 2.16 (pt, 2H, J = 6.4 Hz). 13C NMR (100 MHz) δ
196.8, 163.1, 153.4, 153.2, 140.7, 135.7, 130.1, 118.4 (q, JCF = 304 Hz),
108.5, 88.3, 60.9, 60.7, 56.0, 36.8, 35.0, 28.9, 20.6. HRMS (EI+) calcd
for C17H18F3IO7S (M)+ 549.9770; found 549.9778.
Cycloalkynol 12. Tandem cyclization/ring expansion of VAT 11
according to our general procedure10c gave the corresponding
cycloalkynone in 52% yield as colorless crystals, mp 91−92 °C. IR
1
(neat): νmax 1938, 1689, 1596, 1400, 1323, 1122, 997 cm−1. H NMR
(400 MHz) δ 6.44 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H), 3.84 (s, 3H),
3.83−3.81 (m, 1H), 3.09 (dd, 1H, J = 19.1, 1.4 Hz), 2.87−2.80 (m,
1H), 2.75−2.64 (m, 2H), 2.27−2.13 (m, 2H), 2.06−2.00 (m, 1H). 13C
NMR (100 MHz) δ 208.7, 153.0, 150.1, 140.3, 133.8, 131.3, 108.4,
90.0, 88.5, 61.3, 60.8, 56.1, 43.1, 27.6, 24.2, 18.8. HRMS (EI+) calcd
for C16H18O4 (M)+ 274.1205; found 274.1204. This cycloalkynone
intermediate (193 mg, 0.70 mmol) was dissolved in CH2Cl2 (8.4 mL)
at −78 °C and treated dropwise with DIBAL (2.10 mL, 1 M in
toluene, 2.1 mmol). After 30 min at −78 °C, the reaction mixture was
quenched by addition of 2 M NaOH (1.8 mL) at −78 °C and followed
by MgSO4. After additional stirring for 15 min, the reaction mixture
was filtered and concentrated under reduced pressure. The residue was
purified by chromatography on silica (20−30% EtOAc/hexanes) to
provide cycloalkynol 12, 170 mg (87%), as colorless crystals, mp 85−
1
86 °C. IR (neat): νmax 2996, 2397, 1598, 1494, 1321, 1117 cm−1. H
EXPERIMENTAL SECTION
NMR (400 MHz) δ 6.40 (s, 1H) 5.48−5.43 (m, 1H), 4.00 (s, 3H),
3.90 (dt, 1H, J = 7.6, 2.9 Hz), 3.84 (s, 3H), 3.83 (s, 3H), 2.98 (dd, 1H,
J = 18.2, 1.2 Hz), 2.27−2.13 (m, 3H), 2.10−1.90 (m, 3H). 13C NMR
(100 MHz) δ 152.9, 151.7, 141.2, 132.4, 131.2, 108.6, 09.5, 88.7, 73.5,
61.3, 60.7, 56.0, 42.0, 27.4, 26.1, 19.9. HRMS (EI+) calcd for C16H20O4
(M)+ 276.1362; found 276.1362.
■
2,3,4,9-Tetrahydro-1H-fluoren-1-one (4, Cyclization of 310c
under Acidic Conditions). Cycloalkynone 3 (9.0 mg, 0.05 mmol)
and p-TsOH (0.93 mg, 0.0049 mmol) were stirred in MeOH (1 mL)
at rt for 18 h. The mixture was diluted with H2O (5 mL) and extracted
with EtOAc (2 × 20 mL). The combined extracts were washed with
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The Journal of Organic Chemistry
Brief Communication
Carbamate 1. A solution of 4-nitrophenyl chloroformate (25 mg,
0.12 mmol) in CH2Cl2 (1 mL) was added dropwise via syringe to a
solution of benzocyclononye 12 (30.8 mg, 0.115 mmol) and pyridine
(22.5 μL) in CH2Cl2 (0.65 mL) at 0 °C. The resulting mixture was
stirred for 10 h at rt and cooled to 0 °C, and then Et3N (48 μL, 0.34
mmol) and benzylamine (24 μL, 0.22 mmol) were added slowly via
syringe. The resulting mixture was stirred for 6 h at rt and then diluted
with EtOAc (5 mL). The solution was washed with 1 M KHSO4 (2 ×
5 mL), saturated NaHCO3, and brine. The organic phase was dried
over Na2SO4, filtered, and concentrated under reduced pressure, and
the residue was purified by chromatography on silica (20−25%
EtOAc/hexanes) to furnish 39.1 mg (83%) of 1 as a white solid, mp
95−96 °C. IR (neat): νmax 3266, 2936, 1707, 1685, 1597, 1493, 1454,
1434, 1323, 1239, 1196, 1171 cm−1. 1H NMR (400 MHz) δ 7.29−7.21
(m, 5H), 6.69 (t, 1H, J = 5.47 Hz), 6.43 (s, 1H,), 5.07 (br s, 1H),
4.38−4.18 (m, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.84 (s, 3H), 2.91 (d,
1H, J = 17.7 Hz), 2.34−2.19 (m, 4H), 1.94−180 (m, 1H), 1.77−1.76
(m, 1H). 13C NMR (100 MHz) δ 156.7, 154.0, 152.0, 141.4, 138.4,
135.8, 128.5, 127.31, 127.26, 126.8, 107.9, 91.8, 90.9, 74.5, 60.9, 60.5,
55.7, 44.9, 35.5, 26.9, 26.2, 19.9. HRMS (EI+) calcd for C24H27NO5Na
(M + Na)+ 432.1787; found 432.1770.
1:1 molar ratio of cycloalkynes and azide. The second order rate
constants were obtained by plotting the inverse concentration versus
time in seconds. The cycloalkyne derivatives 1, 3, 7, and 12 (1.0
equiv), benzyl azide (1.0 equiv), and the internal standard (1.0 equiv)
were dissolved in CD3CN (0.05 M) at rt (∼25 °C) in an NMR tube;
1H NMR spectra were acquired immediately and every 2 h. Note that
the reaction with cycloalkynone 3 was conducted at higher
concentration (1.0 M). The internal standards for each experiment
were as follows: 1, 1-bromo-3,5-dimethylbenzene; 3 and 7, 1-bromo-
3,5-dimethoxybenzene; and 12, 2-bromoanisole.
ASSOCIATED CONTENT
■
S
* Supporting Information
X-ray files in CIF format, ORTEP plots, plots of kinetic data,
and copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org. The supple-
mentary crystallographic data for compounds 3 and 12 have
also been deposisted with the Cambridge Crystallographic Data
Centre (CCDC 847775 and 847776, respectively). These data
can be obtained free of charge via the Internet at http://www.
ccdc.cam.ac.uk/cgi-bin/catreq.cgi.
General Procedure for the Synthesis of Triazole Derivatives
8, 13, and 14. Cycloalkynol 7, 11, or 1 (1.0 equiv) and benzyl azide
(1.0 equiv) were stirred in CH3CN (0.05 M) at rt for 36 h and then
concentrated under reduced pressure. The residue was purified by
chromatography on silica (20% MeOH/CHCl3) to give triazole
regioisomers.16
AUTHOR INFORMATION
■
Corresponding Author
Triazoles 8. Reaction stirred in MeOH (0.5 M) for 6 h. Yield 43 mg
(83%), colorless oil. IR (neat): νmax 3368, 2937, 1455, 1240, 1044, 731
cm−1. 1H NMR (400 MHz, CDCl3) δ 7.40 (br s) 7.36−7.03 (m), 6.84
*E-mail: gdudley@chem.fsu.edu.
Present Address
†Chulabhorn Research Institute, Bangkok, Thailand.
(br s), 5.62 (d, part of AB, JAB = 16.2 Hz), 5.45 (d, B part AB, JAB
15.6 Hz), 5.39 (d, A part AB, JAB = 15.6 Hz), 5.31 (B part AB, JAB
=
=
Notes
15.6 Hz), 5.18 (br s), 4.99 (br s), 4.16 (br s), 4.04 (s), 4.01 (s), 3.85
(br s), 3.00 (br s), 2.58 (br d, J = 12.0 Hz), 2.34 (br s), 1.90 (br s),
1.75−1.62 (m), 1.50 (br s), 1.30 (br s), 0.97−0.91 (m). 13C NMR
(100 MHz, CDCl3) δ 144.8, 144.6 (br), 143.4 (br), 132.5, 131.0 (br),
130.6 (br), 129.0, 128.8, 128.2, 128.1, 127.8 (br), 127.1, 126.8, 126.7,
51.9, 51.7, 30.1, 27.6, 24.5, 23.3, 22.2, 19.2. HRMS (EI+) calcd for
C20H21ON3 (M)+ 319.1685; found 319.1689.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported in part by the Florida State
University and in part by grants from the National Science
Foundation (Dudley Lab: NSF-CHE 0749918; Alabugin Lab:
NSF-CHE 0848686). We thank Ron Ramsubhag (Dudley Lab)
for assistance with the preparation and distribution of
benzocyclononyne derivatives and Brian Gold (Alabugin Lab)
for the illustration of the calculated transannular interaction in
ketone 3. We thank Prof Hedi Mattoussi (FSU), Prof Deryn
Fogg (University of Ottawa), and Prof Jeff Keillor (University
of Ottawa) for helpful discussions regarding potential
applications for benzocyclononyne compounds.
Triazoles 13. Yield 7.3 mg (85%), colorless oil. IR (neat): νmax
3380, 2938, 1734, 1597, 1495, 1455, 1323, 1267, 1239, 1120, 1001
cm−1. 1H NMR (600 MHz, CDCl3) δ 7.35 (s), 7.33−7.27 (m), 7.12−
7.09 (m), 6.74, 5.91 (br s), 5.73 (d, A part AB, JAB = 16.2 Hz), 5.48 (d,
B part AB, JAB = 16.2 Hz), 5.45 (d, A part AB, JAB = 15.8 Hz), 5.37 (d,
B part AB, JAB = 15.8 Hz), 5.26 (s), 4.07 (s), 4.04 (s), 3.89 (s), 3.88
(s), 3.85 (s), 3.81 (s), 3.82 (s), 3.62 (s), 2.69 (br s), 2.53 (br s), 2.02
(br s), 1.86−1.82 (m), 1.77 (br s), 1.67 (br s), 1.46 (br s), 1.26 (br s).
13C NMR (125 MHz, CDCl3) δ 152.7, 151.8, 151.5, 145.3, 144.5 (br
s), 141.5, 140.9, 135.4, 135.3, 132.7, 131.7, 129.0, 128.9, 128.24,
128.20, 127.3 (br s), 126.9, 126.8 (br s), 110 (br s), 67.7 (br s), 61.5,
61.4, 60.7, 60.6, 30.6, 27.9 (br s), 25.0, 23.7, 22.0, 19.0. HRMS (EI+)
calcd for C23H27N3O4Na (M + Na)+ 432.1899; found 432.1912.
Triazoles 14. Yield 34 mg (90%), colorless oil. IR (neat): νmax 3328,
2936, 1710, 1596, 1496, 1455, 1412, 1328, 1126, 1027 cm−1. 1H NMR
(600 MHz, CD3CN) δ 7.61 (s), 7.39 (br s), 7.33−7.27 (m), 7.24 (d,
7.9 Hz), 7.10 (d, 7.0 Hz), 6.66 (s), 6.39 (d, A part AB, JAB = 6.8 Hz),
6.38 (d, B part AB, JAB = 6.8 Hz), 6.17 (s), 6.07 (br s), 5.88 (br s), 5.67
(d, A part AB, JAB = 15.8 Hz), 5.61 (d, A part AB, JAB = 15.8 Hz), 5.46
(d, A part AB, JAB = 15.9 Hz), 5.36 (d, A part AB, JAB = 15.8 Hz),
4.28−4.19 (m), 3.84 (s), 3.83 (s), 3.77 (s), 3.76 (s), 3.63 (s), 2.52 (d),
2.04 (br s), 1.90 (br s), 1.76 (br s), 1.60 (br s), 1.44 (br s), 1.29 (s)
0.98 (br). 13C NMR (125 MHz, CD3CN) δ 157.1 (br), 154.6, 153.2
(br), 145.8 (br), 145.4 (br), 142.2 (br), 140.64, 140.58, 137.3, 137.2,
133.9 (br), 131.5, 129.9, 129.7, 129.3, 129.0, 128.9, 127.99, 127.96,
127.89, 127.85, 69.7, 62.04, 62.01, 61.1, 61.0, 56.5, 56.4, 52.4, 51.9,
45.1, 32.0. 30.3 (br), 30.0 (br), 29.3 (br), 25.3 (br), 23.9, 22.8, 19.5.
HRMS (EI+) calcd for C31H34N4O5Na (M + Na)+ 565.2427; found
565.2424.
REFERENCES
■
(1) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
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