Metal-Adhesive Polymers from Cu(I)-Catalyzed Azide-Alkyne
Cycloaddition
Yi Liu, David D. Díaz, K. Barry Sharpless, Valery V. Fokin,* and M.G. Finn*
Supporting Information
References to the application of the CuAAC reaction.
A decidedly incomplete list of citations for the use of the CuAAC reaction are provided here, to give the
reader an idea of the range of its application.
Bioconjugation
Materials
synthesis
Surface
functionalization
Drug discovery
1. Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.; Finn, M. G. J. Am. Chem.
Soc. 2003, 125, 3192-3193.
2. Link, A. J.; Tirrell, D. A. J. Am. Chem. Soc. 2003, 125, 11164-11165.
3. Speers, A. E.; Cravatt, B. F. Chem. Biol. 2004, 11, 535-546.
4. Lee, L. V.; Mitchell, M. L.; Huang, S.-J.; Fokin, V. V.; Sharpless, K. B.; Wong, C.-H. J. Am.
Chem. Soc. 2003, 125, 9588-9589.
5. Sen Gupta, S.; Kuzelka, J.; Singh, P.; Lewis, W. G.; Manchester, M.; Finn, M. G. Bioconj.
Chem. 2005, 16, 1572-1579.
6. Brennan, J. L.; Hatzakis, N. S.; Tshikhudo, T. R.; Dirvianskyte, N.; Razumas, V.; Patkar, S.;
Vind, J.; Svendsen, A.; Nolte, R. J. M.; Rowan, A. E.; Brust, M. Bioconj. Chem. 2006, 17,
1373-1375.
7. Hsu, T.-L.; Hanson, S. R.; Kishikawa, K.; Wang, S.-K.; Sawa, M.; Wong, C.-H. Proc. Nat.
Acad. Sci. USA 2007, 104, 2614-2619.
8. Zeng, Q.; Li, T.; Cash, B.; Li, S.; Xie, F.; Wang, Q. Chem. Commun. 2007, 1453-1455.
1. Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.; Voit, B.; Pyun, J.; Fréchet, J.
M. J.; Sharpless, K. B.; Fokin, V. V. Angew. Chem. Int. Ed. 2004, 43, 3928-3932.
2. Englert, B. C.; Bakbak, S.; Bunz, U. H. F. Macromolecules 2005, 38, 5868-5877.
3. Tsarevsky, N. V.; Sumerlin, B. S.; Matyjaszewski, K. Macromolecules 2005, 38, 3558-3561.
4. Li, H.; Cheng, F.; Duft, A. M.; Adronov, A. J. Am. Chem. Soc. 2005, 127, 14518-14524.
5. Joosten, J. A. F.; Tholen, N. T. H.; El Maate, F. A.; Brouwer, A. J.; van Esse, G. W.; Rijkers,
D. T. S.; Liskamp, R. M. J.; Pieters, R. J. ejoc 2005, 3182-3185.
6. Quémener, D.; Davis, T. P.; Barner-Kowollik, C.; Stenzel, M. H. Chem. Commun. 2006, 50515053.
7. Johnson, J. A.; Lewis, D. R.; Díaz, D. D.; Finn, M. G.; Koberstein, J. T.; Turro, N. J. J. Am.
Chem. Soc. 2006, 128, 6564-6565.
8. Lutz, J.-F. Angew. Chem. Int. Ed. 2007, 46, 1018-1025.
1. Fazio, F.; Bryan, M. C.; Blixt, O.; Paulson, J. C.; Wong, C.-H. J. Am. Chem. Soc. 2002, 124,
14397-14402.
2. Meng, J.-C.; Averbuj, C.; Lewis, W. G.; Siuzdak, G.; Finn, M. G. Angew. Chem. Int. Ed. 2004,
43, 1255-1260.
3. Collman, J. P.; Devaraj, N. K.; Chidsey, C. E. D. Langmuir 2004, 20, 1051-1053.
4. Lee, J. K.; Chi, Y. S.; Choi, I. S. Langmuir 2004, 20, 3844-3847.
5. Devaraj, N. K.; Miller, G. P.; Ebina, W.; Kakaradov, B.; Collman, J. P.; Kool, E. T.; Chidsey, C.
E. D. J. Am. Chem. Soc. 2005, 127, 8600-8601.
6. Lummerstorfer, T.; Hoffmann, H. J. Phys. Chem. B 2004, 108, 39663-3966.
7. Prakash, S.; Long, T. M.; Selby, J. C.; Moore, J. S.; Shannon, M. A. Anal. Chem. 2006, 79,
1661-1667.
8. Fleming, D. A.; Thode, C. J.; Williams, M. E. Chem. Mater. 2006, 18, 2327-2334.
1. Kolb, H. C.; Sharpless, K. B. Drug Disc. Today 2003, 8, 1128-1137.
2. Lewis, W. G.; Green, L. G.; Grynszpan, F.; Radic, Z.; Carlier, P. R.; Taylor, P.; Finn, M. G.;
Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 1053-1057.
3. Mocharla, V. P.; Colasson, B.; Lee, L. V.; Röper, S.; Sharpless, K. B.; Wong, C.-H.; Kolb, H.
C. Angew. Chem. Int. Ed. 2005, 44, 116-120.
4. Whiting, M.; Muldoon, J.; Lin, Y.-C.; Silverman, S. M.; Lindstrom, W.; Olson, A.; Kolb, H. C.;
Finn, M. G.; Sharpless, K. B.; Elder, J. H.; Fokin, V. V. Angew. Chem. Int. Ed. 2005, 45,
1435-1439.
5. Van der Peet, P.; Gannon, C. T.; Walker, I.; Dinev, Z.; Angelin, M.; Tam, S.; Ralton, J. E.;
McConville, M. J.; Williams, S. J. ChemBioChem 2006, 7, 1384-1391.
6. Xie, J.; Seto, C. T. Bioorg. Med. Chem. 2007, 15, 458-473.
– S1 –
Organic
synthesis
Combinatorial
chemistry
1. Fazio, F.; Bryan, M. C.; Blixt, O.; Paulson, J. C.; Wong, C.-H. J. Am. Chem. Soc. 2002, 124,
14397-14402.
2. Seo, T. S.; Li, Z.; Ruparel, H.; Ju, J. J. Org. Chem. 2003, 68, 609-612.
3. Bodine, K. D.; Gin, D. Y.; Gin, M. S. J. Am. Chem. Soc. 2004, 126, 1638-1639.
4. Zhou, Z.; Fahrni, C. J. J. Am. Chem. Soc. 2004, 126, 8862-8863.
5. Jin, T.; Kamijo, S.; Yamamoto, Y. Eur. J. Org. Chem. 2004, 3789-3791.
6. Punna, S.; Kuzelka, J.; Wang, Q.; Finn, M. G. Angew. Chem. Int. Ed. 2005, 44, 2215-2220.
7. Gommermann, N.; Gehrig, A.; Knochel, P. Synlett 2005, 2796-2798.
8. Zhang, G.; Fang, L.; Zhu, L.; Sun, D.; Wang, P. G. Bioorg. Med. Chem. 2006, 14, 426-434.
1. Löber, S.; Rodriguez-Loaiza, P.; Gmeiner, P. Org. Lett. 2003, 5, 1753-1755.
2. Thomas, J. R.; Liu, X.; Hergenrother, P. J. J. Am. Chem. Soc. 2005, 127, 12434-12435.
3. Luo, S.; Xu, H.; Mi, X.; Li, J.; Zheng, X.-Q.; Cheng, J.-P. J. Org. Chem. 2006, 71, 9244-9247.
4. Goess, B. C.; Hannoush, R. N.; Chan, L. K.; Kirchhausen, T.; Shair, M. D. J. Am. Chem. Soc.
2006, 128, 5391-5403
Adhesive Testing Instrument
The failure load tests were performed by a custom instrument designed and built at our
institution, at a total cost of slightly less than $3,000, including parts and labor. The instrument is
configured as a mechanical bench incorporating a high-resolution stepper motor (Sanyo Denki
model 103H7123-0440, 1.8º step) which rotates a leadscrew. Rotation of the leadscrew drives an
attached load cell assembly (Omega Engineering Inc., model LC201-25) fore and aft. This
movement is used to apply horizontal force against a shaft (usually a nail) affixed vertically to a
plate surface. The force induced thereby resembles (but is not identical to) that of a 90 degree
peel test. An embedded microcontroller was programmed to control the motion of the stepper
motor, measure the applied force, and transmit the data to a host PC.
One revolution of the stepper motor, which drives the 24 threads-per-inch leadscrew,
moves the load cell assembly forward by 1/24 of an inch, or 1.058 mm. We used a microstepping
driver for the stepper motor (Gecko Drive model G201) capable of 10 microsteps per 1.8º of
motor rotation, giving a resolution of 2000 steps per revolution, resulting in a nominal maximum
linear resolution of 1.058/2000 = 0.005348 or 5.348 micrometers. In our experiments we can
operate the stepper motor in multiples of 10, 20, or 50 microsteps per increment of forward linear
movement, selectable from a front panel control, which correspond to linear step increments of
approximately 53.5, 107.0, and 267.4 µm, and 0.0442, 0.0884, and 0.221 mm/sec movement
speed, respectively. All of the data shown here was taken with the slowest setting, requiring
approximately 1 minute to traverse 3 mm.
The force against the nail is incrementally increased by repeated actuations of the stepper
motor until the adhesive joint fails. Once a force measurement “run” begins, data are
continuously streamed to a host PC over a serial RS-232 communications link. The data consist
of pairs of data points; an index number for each step (directly proportional to distance), and the
force associated with that step as measured by the signal from the load cell, digitized by an
analog-to-digital converter. A program running on the PC converts the data to engineering units,
plots the force-distance relationship in real time, and saves the data for subsequent analysis. A
conversion factor of 9.81 Newtons per kg-force was applied.
Indications of adhesive flexibility.
Although we have not yet paid sufficient attention to this issue, it is worth noting here
that adhesives made with bisphenol A-derived monomers 5, 6, 10, and 16 often, but not always,
exhibit a “rounded” load-displacement curve at the failure point, as shown in Figure S2. We
believe that bisphenol-A blocks impart more flexibility to the polymeric matrix, and a rounded
load-displacement curve at failure is consistent with this. This concept will be investigated
further.
– S2 –
Note: In preliminary experiments, the addition of 7+23+Cu to the J-B Weld adhesive did not
improve the latter’s performance.
Figure S1. (a) Two arrays
of copper nails bound to
copper plates; (b) the
home-built adhesive
testing instrument.
Figure S2. Sample load-displacement curves from the home-built instrument for mixtures of the
indicated components under identical conditions.
50
50
5 + 22
6 + 22
40
40
30
30
20
20
10
10
0
0
load
(N)
displacement (mm)
displacement (mm)
– S3 –
Table S1. Adhesive strength given by maximum load before failure for combinations of azides
and alkynes (20 µmol each) in the presence of 0.4 µmol (2 mol%) CuPF6•4MeCN (curing time 3
days at room temperature). Results in excess of 3.0 kgs are highlighted as an arbitrary cutoff to
identify highly effective compositions. Except for results incorporating added ligand (marked by
asterisks), the data here are plotted in Figure 2 of the paper. The adhesive area was the same
in each case (2.0 x 10-5 m2); maximum load before failure is calculated using the conversion of
1 Pa = 1 newton per m2.
Entry
Azide
Alkyne
Load (N)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
1
1
1
2
3
3
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
6
7
7
7
7
7
7
7
7
7
20
21
23
20
22
23
16
18
22
23
13
14
15
16
20
21
22
22
23
23
22
23
13
14
15
16
17
20
21
22
22
4.9 ± 2
9.8 ± 2
17 ± 3
4.9 ± 4
14 ± 4
7.8 ± 1
18 ± 1
13 ± 4
36 ± 2
31 ± 4
0
18 ± 2
7.8 ± 2
18 ± 5
13 ± 3
28 ± 2
31 ± 6
30 ± 3 *
32 ± 4
28 ± 2
28 ± 3
21 ± 2
4.9 ± 1
12 ± 1
24 ± 3
33 ± 3
11 ± 1
19 ± 1
12 ± 2
38 ± 11
30 ± 6 *
Load per
area (MPa)
0.25 ± 0.10
0.50 ± 0.10
0.85 ± 0.15
0.25 ± 0.20
0.70 ± 0.20
0.40 ± 0.05
0.90 ± 0.05
0.65 ± 0.20
1.9 ± 0.10
1.6 ± 0.20
0
0.90 ± 0.10
0.40 ± 0.10
0.90 ± 0.25
0.65 ± 0.15
1.5 ± 0.10
1.6 ± 0.30
1.6 ± 0.15 *
1.7 ± 0.20
1.5 ± 0.10
1.4 ± 0.15
1.1 ± 0.10
0.25 ± 0.05
0.60 ± 0.05
1.2 ± 0.15
1.7 ± 0.15
0.55 ± 0.05
0.95 ± 0.05
0.60 ± 0.10
2.0 ± 0.55
1.6 ± 0.30 *
Entry
Azide
Alkyne
Load (N)
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
7
7
7
8
8
8
8
8
8
8
8
8
8
8
9
9
10
10
10
10
10
10
10
11
12
23
23
25
16
18
18
19
21
22
22
23
23
24
25
22
23
15
16
17
21
22
23
23
22
22
92 ± 2
53 ± 4 *
18 ± 5
26 ± 1
20 ± 5
16 ± 4 *
5.6 ± 2
10 ± 2
44 ± 4
52 ± 4 *
31 ± 3
44 ± 4 *
47 ± 5
29 ± 1
27 ± 2
19 ± 3
6±1
14 ± 5
0
19 ± 3
28 ± 2
10 ± 3
15 ± 2 *
23 ± 5
4.9 ± 2
55 ± 3
15 ± 3
5.9 ± 1
28 ± 3
45 ± 3
J-B Weld (12 mg)
Crazy Glue (20 µL)
Amazing Goop (10 mg)
Metal Epoxy (10 mg)
Copper Bond (7.5 mg)
* Reactions performed in the presence of 1 equiv. TBTA per Cu.
– S4 –
Load per
area (MPa)
4.7 ± 0.10
2.7 ± 0.20
0.9 ± 0.25
1.3 ± 0.05
1.0 ± 0.25
0.80 ± 0.20
0.30 ± 0.10
0.50 ± 0.10
2.3 ± 0.20
2.7 ± 0.20
1.6 ± 0.15
2.3 ± 0.20
2.4 ± 0.25
1.5 ± 0.05
1.4 ± 0.10
0.95 ± 0.15
0.30 ± 0.05
0.70 ± 0.25
0
0.95 ± 0.15
1.45 ± 0.10
0.50 ± 0.15
0.75 ± 0.10
1.15 ± 0.25
0.25 ± 0.10
2.8 ± 0.15
0.75 ± 0.15
0.30 ± 0.05
1.5 ± 0.15
2.3 ± 0.15
Confirmation with Instron instrument.
An Instron Materials Testing System 5544 in the laboratory of Prof. Jonathan Wilker of
Purdue University was fitted with U-joints secured in chuck grips, and was used for lap shear
testing of a small selection of samples. Each sample was secured onto the top U-joint using a
metal rod (Figure S3a) and the instrument was calibrated setting the load to 0 Newtons. A
second metal rod was inserted through the lower U-joint (Figure S3b). The sample was then
pulled apart at a constant rate while measuring the load in Newtons. The area of adhesive
coverage was measured on the separated plates after the lap shear test.
a
b
Figure S3. Lap shear testing
with Instron 5544 instrument.
Solid copper rectangles (1” x 1 cm) were cut from oxygen-free alloy 101 Cu bars (1” x
48” x 0.125”, purchased from McMaster-Carr, Inc.) A 3/8-inch hole was drilled in the “top” half
of each to allow threading onto the rod anchored to the Instron grip joints. One surface of each
rectangular piece was polished with 120-grit sandpaper until uniformly shiny. The surface was
then rinsed sequentially with water, acetone, and water, and then allowed to dry in ambient air
and stored in a sealed container. The candidate adhesive was applied to two surfaces, and these
were then placed together so that the holes were at opposite ends. Heating was applied if
indicated, and the plates were allowed to cure for the indicated period. In the case of azidealkyne mixtures, 1M stock solutions of the each component were made in THF, the the
concentration referring to total azide or total alkyne. When additional Cu compounds were used,
the azide and alkyne solutions were first premixed, a solution of Cu compound was added, and
the mixture was quickly mixed and deposited on the metal plate surfaces. After waiting several
minutes for the solvent to evaporate, the plates were placed together in the standard (head-to-tail)
orientation, and were allowed to cure for the indicated time.
Figures S4 and S5 show the results from Instron testing; Table S2 summarizes the values
obtained. The sawtooth pattern for one of the 7+23 samples (Figure S4b, dark blue trace), and
the relatively flat line around 1000 N for another (Figure S4b, light blue trace) indicate that not
all of the adhesive in these materials failed at the same time. The relative strengths of the
commercial adhesives were found to be the same using both instruments. However, the 7+23
sample cured at room temperature outperformed the same material cured at 70°C, contradicting
the results obtained from the peel test using our homemade instrument. The differing nature of
the tests (peel vs. shear) and the differing surface areas and amounts of adhesive involved make
such discrepancies reasonable. Overall, our instrument’s peel test performs at least as
reproducibly as the Instron shear test for the purposes of adhesive screening, at far lower cost
and greater throughput.
– S5 –
Figure S4. Sample load-displacement curves for mixtures of the indicated components under
identical conditions.
(a) 7 + 20, RT
(b) 7 + 23, RT
(c) 7 + 23, 70 °C
800
1400
800
700
1200
700
600
1000
load 500
(N) 400
800
600
500
400
600
300
200
400
100
200
0
0
0
0.2
0.4
0.6
0.8
extension (mm)
1.0
1.2
300
200
100
0
0
0.5
1.0
1.5
2.0
2.5
extension (mm)
3.0
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
extension (mm)
Figure S5. Plates after Instron lap shear tests; the values below each are the maximum load
(N) before failure. Adhesive failure was assigned to those samples which showed peeling of the
adhesive away from the metal surface, one plate showing large patches of bare metal with the
companion plate showing adhesive at those places. Samples showing adhesive at the same
places on both plates were judged to have experienced cohesive failure.
Amazing Goop
JB Weld
Copper Bond
7 + 20, RT
7 + 23, RT
7 + 23, 70 °C
– S6 –
Table S2. Adhesive strength in lap shear testing on Instron instrument. Load = maximum load before
failure; average of 4-5 samples. Errors are standard deviations of these values.
Sample
cure temp.
Load (N)
Amazing Goop
JB Weld
Copper Bond
7 + 20
7 + 23
7 + 23
n/a
n/a
n/a
RT
RT
70 °C
535 ± 172
1044 ± 49
670 ± 121
592 ± 104
771 ± 341
441 ± 189
Load per area
apparent failure mode
(Mpa)
3.5 ± 1.1
adhesive failure
6.5 ± 0.83
adhesive failure
4.3 ± 0.71
adhesive failure
5.4 ± 1.6
cohesive failure
6.3 ± 2.5
adhesive failure
2.9 ± 1.3
mixed
Details of Synthesis
Solvents were purified according to literature procedures.[1] Thin-layer chromatography
(TLC) was carried out using aluminum sheets, precoated with silica gel 60F (Merck 5554). The
plates were inspected by UV-light prior to development with KMnO4 solution. Melting points
were determined on an Electrothermal 9300 apparatus and are uncorrected. Proton and carbon
nuclear magnetic resonance spectra (1H-NMR and 13C-NMR) spectra were recorded on a Varian
300 or 400, or Bruker Avance500, using the deuterated solvent as lock and the residual
protonated solvent as internal standard. All chemical shifts are quoted using the  scale, and all
coupling constants (J) are expressed in Hertz (Hz). High-resolution mass spectra (HRMS) were
recorded at the mass spectrometry facility at The Scripps Research Institute, La Jolla. HPLC
was performed on an Agilent 1100 LC/MSD with an Agilent 1100 SL mass spectrometer, eluting
with 0.1% trifluoroacetic acid (TFA) in H2O and 0.05% TFA in MeCN.
Compounds 1,[2] 2,[3] 3,[4] 4,[3] 7,[3], 12,[5], 13,[6] 16,[7] 18,[3] and 19[3] were prepared
according to literature procedures. Compounds 14, 15, 19, and 22 were kindly donated from the
Sharpless and Fokin group compound libraries. Compound 20 is commercially available.
AcCl / Pyridine / CH2Cl2
NaN3 / LiClO4 / MeCN
O
O
90 ºC
O
S1
O
N3
O
OH
O
5
N3
OH
N3
O
OAc
O
6
N3
OAc
5: A mixture of S1 (15.0 g, 44.0 mmol), NaN3 (4.30 g, 0.132 mol) and LiClO4 (14.1 g, 0.132
mol) in MeCN (90 mL) was heated to 90 ºC for overnight. After the reaction mixture was cooled
down to room temperature, H2O (200 mL) was added, and the mixture was extracted by ethyl
acetate (2 x 200 mL). The organic layers were combined, dried (MgSO4), filtered and
concentrated to give the crude product (18.5 g, 98%) as light orange viscous oil, which was
further purified by flash column chromatography (SiO2: EA/Hexanes 1:2 to 1:1) to yield 5 (9.5
g) as colorless viscous oil. 1H NMR (CDCl3, 300 MHz, 298 K):  = 7.14 (d, J = 8.7 Hz, 4 H),
6.81 (d, J = 8.7 Hz, 4 H), 4.13 (m, 2 H), 3.98 (d, J = 5.1 Hz, 4 H), 3.51 (m, 4 H), 2.34 (br s, 2 H),
1.63 (s, 6 H); 13C NMR (CDCl3, 125 MHz, 298 K):  = 156.5, 144.3, 128.3, 114.4, 69.8, 69.5,
53.9, 42.2, 31.5; MS m/z (relative intensity) 399.1 [M–N2+H]+ (100%), 449.1 [M+Na]+ (85%);
HRMS for C21H26N6O4: [M]+, calcd 449.1913, found 449.1902.
– S7 –
6: To a solution of 5 (0.170 g, 0.400 mmol), pyridine (0.158 g, 2.00 mmol) in CH2Cl2 (5 mL)
was added acetyl chloride (0.094 g, 1.20 mmol) dropwise at 0 ºC and the mixture was stirred for
2 hours. The mixture was partitioned between H2O/CH2Cl2, and the organic layer was washed
with NaHSO4 (10%, 10 mL), NaHCO3 (10%, 10 mL) and brine (10 mL). The organic phase was
dried (Na2SO4), filtered, and concentrated to give 6 as colorless oil (0.220 g, 99%). 1H NMR
(CDCl3, 400 MHz, 298 K):  = 7.21 (d, J = 8.6 Hz, 4 H), 6.88 (d, J = 8.7 Hz, 4 H), 5.34 (p, J =
5.1 Hz, 2 H), 4.17 (d, J = 5.1 Hz, 4 H), 3.69 (d, J = 5.1 Hz, 4 H), 2.20 (s, 6 H), 1.71 (s, 6 H); 13C
NMR (CDCl3, 125 MHz, 298 K):  = 170.1, 155.9, 143.8, 127.7, 113.9, 70.7, 65.9, 50.7, 41.7,
30.9, 20.8; MS m/z (relative intensity) 483.1 [M–N2+H]+ (70%), 511.1 [M+H]+ (45%), 533.2
[M+Na]+ (100%); HRMS C25H30N6O6: [M+Na]+, calcd 533.2125, found 533.2115.
OAc
OH
O
N3
N3
N
O
N
O
N
O
NaN3 / NH4Cl / H2O
N
N
O
O
N
O
O
HO
S2
N
N
N3
90 ºC
O
O
AcCl / Pyridine / CH2Cl2
OH
AcO
8
O
N3
O
9
N3
N3
OAc
N
8: A mixture of S2 (50.0 g, 0.170 mol), NaN3 (65.6 g, 1.01 mol), NH4Cl (36.0 g, 0.670 mol) in
H2O (250 mL) was stirred and heated at 90 ºC for 24 hours. The mixture was cooled down to
room temperature and then extracted with ethyl acetate (3 x 200 mL). The organic layers were
combined, washed with brine, dried (MgSO4), filtered and concentrated to give colorless viscous
oil (63.6 g, 89%). 1H NMR (CDCl3, 300 MHz, 298 K):  = 4.20–4.11 (m, 6 H), 3.92–3.88 (m, 3
H), 3.46–3.38 (m, 6 H), 3.18 (br s, 3 H); 13C NMR (CDCl3, 125 MHz, 298 K):  = 207.8, 150.3,
150.2, 69.0, 54.8, 46.7, 46.6, 46.6, 31.3. MS m/z (relative intensity) 399.1 [M–N2+H]+ (35%),
427.1 [M+H]+ (25%), 449.1 [M+Na]+ (100%); HRMS for C12H18N12O6: [M+Na]+, calcd
449.1370, found 449.1360.
9: To a solution of 8 (1.80 g, 4.23 mmol), pyridine (5.00 g, 63.4 mmol) in CH2Cl2 (20 mL) was
added acetyl chloride (1.66 g, 21.1 mmol) dropwise at 0 ºC and the mixture was stirred for 2
hours. The mixture was partitioned between H2O/CH2Cl2 (20 mL/20 mL), and the organic layer
was washed with NaHSO4 (10%, 20 mL), NaHCO3 (10%, 20 mL) and brine (20 mL). The
organic phase was dried (Na2SO4), filtered, concentrated, and purified by flash column
chromatography (SiO2: CH2Cl2/MeOH 12:1) to give 9 as pale yellow oil (1.60 g, 69%). 1H
NMR (CDCl3, 300 MHz, 298 K):  = 5.32–5.29 (m, 3 H), 4.29–4.27 (m, 3 H), 4.13–4.04 (m, 3
H), 3.59–3.51 (m, 6 H), 2.14 (br s, 9 H). 13C NMR (CDCl3, 125 MHz, 298 K):  = 171.1, 171.1,
171.0, 149.3, 70.6, 52.1, 52.0, 44.4, 44.4, 44.3, 21.2. MS m/z (relative intensity) 525.0 [M–
N2+H]+ (10%), 575.0 [M+Na]+ (25%); HRMS for C18H24N12O9: [M+Na]+, calcd 575.1687, found
575.1685.
+
N3
O
OH
O
7
N3
OH
O
N3
O
N3
O
DMAP/ Pyridine / CH2Cl2 N3
O
O
O
O
O
N3
O
10
S3
N3
– S8 –
N3
Tetraazide 10: To a solution of 5 (0.500 g, 1.17 mmol), pyridine (0.900 g, 11.7 mmol), 4-N,Ndimethylamino-pyridine (DMAP, 43 mg, 0.350 mmol) in CH2Cl2 (2 mL) was added diazide S3
(0.730 g, 3.05 mmol) dropwise at 0 ºC and the mixture was stirred at room temperature for 2
hours. The mixture was partitioned between H2O/CH2Cl2 (10 mL/10 mL), and the organic layer
was washed with NaHSO4 (10%, 10 mL), NaHCO3 (10%, 10 mL) and brine (10 mL). The
organic phase was dried (Na2SO4), filtered and concentrated to give 10 as yellow oil (0.750 g,
99%). 1H NMR (CDCl3, 500 MHz, 298 K):  = 7.22 (d, J = 8.8 Hz, 4 H), 6.88 (d, J = 8.8 Hz, 4
H), 5.37 (p, J = 5.2 Hz, 2 H), 4.18 (d, J = 5.2 Hz, 4 H), 3.70 (d, J = 5.2 Hz, 4 H), 3.45 (t, J = 6.6
Hz, 4 H), 2.57 (t, J = 7.2 Hz, 4 H), 2.01 (p, J = 7.0 Hz, 4 H), 1.71 (s, 6 H); 13C NMR (CDCl3,
125 MHz, 298 K):  = 172.4, 156.4, 144.3, 128.3, 114.4, 71.4, 66.5, 51.3, 50.9, 42.2, 31.6, 31.4,
24.6; MS m/z (relative intensity) 621.3 [M–N2+H]+ (100%), 671.3 [M+Na]+ (15%); HRMS for
C29H36N12O6: [M+Na]+, calcd 671.2778, found 671.2772.
N3
OH
+
N3
O
HC(OMe)3 / CH2Cl2 / PTSA•H2O
O
OH
N3
O
O
N3
N3
O
O
N3
S4
2
11
11: To a mixture of 2 (0.590 g, 5.66 mmol), 1,4-dioxo-cyclohexane S4 (0.300 g, 2.69 mmol), ptoluenesulfonic acid monohydrate (PTSA•H2O, 26 mg, 0.130 mmol) in CH2Cl2 (10 mL) was
added methyl orthoformate (1.00 g, 5.48 mmol) and the mixture was stirred overnight at 40 ºC.
The mixture was evaporated, and the crude mixture was recrystalized from EA/Hexanes to get
11 as white solid (0.98 g, 80%). M.p. 94–96 ºC. 1H NMR (CDCl3, 400 MHz, 298 K):  = 3.72 (s,
8 H), 3.53 (s, 8 H), 1.90 (s, 8 H); 13C NMR (CDCl3, 125 MHz, 298 K):  = 98.5, 63.3, 52.6, 38.7,
28.5. MS m/z (relative intensity) 421.1 [M–N2+H]+ (100%), 471.1 [M+Na]+ (10%); HRMS for
C16H24N12O4: [M+Na]+, calcd 471.1941, found 471.1927.
+
NH2
CH2Cl2 / –40 ºC
SO2Cl2
O H
N S N
H O
S5
17
17: To a solution of SO2Cl2 (0.854 g, 6.33 mmol) in CH2Cl2 (10 mL) was added a solution of
diethylpropargyl amine S5 (2.81 g, 25.3 mmol) in CH2Cl2 (5 mL) at –40ºC. After the addiction
was complete, the mixture was stirred overnight at room temperature. The white precipitate was
filtered and the filtrate was washed with H2O. The organic layer was dried (Na2SO4), filtered,
and concentrated to give 17 as a white solid (1.58 g, 56%). M.p.: 113.5–115.0 ºC .1H NMR
(CDCl3, 400 MHz, 298 K):  = 4.83 (s, 2 H), 2.55 (s, 2 H), 1.93 (qd, J = 7.4 Hz, 14.8 Hz, 2 H),
1.80 (qd, J = 7.4 Hz, 14.8 Hz, 2 H), 0.99 (t, J = 7.4 Hz, 6 H). 13C NMR (CDCl3, 125 MHz, 298
K):  = 85.7, 74.5, 57.6, 31.9, 8.4. MS m/z (relative intensity) 285.0 [M+H]+ (100%), 307.0
[M+Na]+ (7%); HRMS for C14H24N2O2S: [M+Na]+, calcd 307.1456, found 307.1453.
H
N
O
O
O
N
H
O
+
CsCO3 / DMF / 25 ºC
O
O
N
Br
N
O
23
S6
– S9 –
O
23: To a solution of S6 (1.00 g, 5.10 mmol) and propargyl bromide (1.82 g, 15.3 mmol) in DMF
(5 mL) was added Cs2CO3 (4.99 g, 15.3 mmol) and the mixture was stirred overnight. The
mixture was partitioned between H2O/CH2Cl2 (50 mL/50 mL), and the organic layer was washed
with brine, dried (Na2SO4), filtered, concentrated and purified by flash column chromatography
(SiO2: EA/Hexanes 1:4) to give product as yellow oil (1.29 g, 93%), which slowly solidifies
under vacuum. It exists as a mixture of several rotamers in solution. 1H NMR (CDCl3, 400 MHz,
298 K):  = 4.70 (m, 4 H), 4.52 (m, 2 H), 4.25 (m, 2 H), 2.45 (m, 2 H), 2.30 (m, 2 H). 13C NMR
(CDCl3, 100 MHz, 298 K):  = 154.7, 154.3, 154.1, 153.7, 77.4, 77.1, 75.9, 75.6, 74.0, 73.8,
54.7, 54.4, 41.4, 41.1, 40.3, 40.0. MS m/z (relative intensity) 273.0 [M+H]+ (100%), 295.0
[M+Na]+ (14%); HRMS for C14H12N2O4: [M+Na]+, calcd 295.0695, found 295.0697.
O
O
O
O
NaH / DMF / 25 ºC
+
O
O
O
Br
OH
OH
TFA / CH2Cl2 / 25 ºC
HO
O
OH
OH
O
OH
O
O
24
S7
O
25
24: NaH (1.26 g, 52.6 mmol) was added to a solution of S7[8] (1.00 g, 5.26 mmol) in DMF (10
mL) and the mixture was stirred at room temperature for 5 mins. To this mixture was added
propargyl bromide (2.50 g, 21.0 mmol, 80wt% solution in toluene) dropwise and was stirred
overnight. The reaction was quenched by H2O (100 mL) and the mixture was extracted with
CH2Cl2 (3x50 mL). The organic layers were combined, washed with brine, dried (Na2SO4),
filtered, concentrated, and purified by flash column chromatography (SiO2: EA/Hexanes 1:5 to
3:7) to give 24 as white solid (1.10 g, 69%). M.p. 82.5-84.0 ºC. 1H NMR (CDCl3, 300 MHz, 298
K):  = 5.53 (d, J = 1.2 Hz, 1 H), 4.52 (m, 2 H), 4.48 (m, 1 H), 4.45 (m, 2 H), 4.37 (d, J = 2.4 Hz,
2 H), 4.27 (dd, J = 2.4 Hz, 1.2 Hz, 4 H), 4.07 (dd, J = 1.2 Hz, 1.2 Hz, 1 H), 2.50 (t, J = 2.4 Hz, 2
H), 2.47 (t, J = 2.4 Hz, 1 H). 13C NMR (CDCl3, 300 MHz, 298 K):  = 103.4, 79.6, 79.2, 75.9,
75.4, 73.5, 70.3, 68.0, 67.5, 57.4, 57.0. MS m/z (relative intensity) 305.0 [M+H]+ (100%); HRMS
for C16H16O6: [M + Na]+, calcd 327.0845, found 327.0837.
25: A mixture of 24 (0.30 g, 0.60 mmol), TFA (5 mL) in CH2Cl2 (5 mL) was stirred overnight at
room temperature. The mixture was concentrated, and the residue was subjected to column
chromatography to give 25 as a white solid (0.29 g, 99%). M.p. 115.0-117.0 ºC. 1H NMR
(CD3OD, 300 MHz, 298 K):  = 4.48 (d, J = 2.4 Hz, 2 H), 4.43 (d, J = 2.4 Hz, 2 H), 3.86 (t, J =
2.4 Hz, 1 H), 3.43 (m, 4 H), 3.26 (t, J = 2.4 Hz, 1 H), 2.79 (t, J = 2.4 Hz, 1 H), 2.77 (t, J = 2.4
Hz, 2 H). 13C NMR (CD3OD, 75 MHz, 298 K):  = 81.5, 80.4, 80.2, 80.1, 74.8, 74.6, 74.2, 71.9,
59.8, 59.7. MS m/z (relative intensity) 295.0 [M+H]+ (38%), 317.0 [M+Na]+ (100%); HRMS for
C15H18O6: [M+Na]+, calcd 317.1001, found 317.1003.
O
H
N
O
O
O
N
H
S6
O
CsCO3 / DMF / 25 ºC
+
O
N
N
O
Br
26
S8
– S10 –
O
26: To a solution of S6 (0.600 g, 3.06 mmol) and 5-iodopentyne S8 (3.29 g, 10.1 mmol) in DMF
(5 mL) was added Cs2CO3 (1.96 g, 10.1 mmol) and the mixture was stirred overnight at 40 ºC.
The mixture was partitioned between H2O/CH2Cl2 (30 mL/30 mL) and the aqueous layer was
extracted with CH2Cl2 (2x20 mL). The organic layers were combined, washed with brine, dried
(Na2SO4), filtered, concentrated and purified by flash column chromatography (SiO2:
EA/Hexanes 1:8 to 1:5) to give product as colorless oil (0.81 g, 81%). It exists as a mixture of
several rotamers in solution. 1H NMR (CDCl3, 400 MHz, 298 K):  = 4.89–4.60 (m, 4 H), 3.65–
3.62 (m, 4 H), 2.57–2.53 (m, 2 H), 2.31 (m, 4 H), 2.03 (s, 2 H), 1.92–1.91 (m, 4 H); 13C NMR
(CDCl3, 125 MHz, 298 K):  = 155.7, 155.5, 155.4, 155.2, 83.7, 83.6, 83.5, 77.9, 77.8, 77.5,
77.3, 75.7, 75.6, 75.6, 69.6, 69.5, 69.5, 54.4, 54.2, 50.4, 49.9, 27.2, 27.0, 26.8, 26.7, 16.4. MS
m/z (relative intensity) 329.0 [M+H]+ (100%), 351.0 [M+Na]+ (8%); HRMS for C18H20N2O4:
[M+Na]+, calcd 351.1321, found 351.1315.
Spectroscopic data for compounds provided by the Sharpless laboratory
14: 1H NMR (CDCl3, 500 MHz, 298 K):  = 5.95 (s, 1 H), 3.75 (d, J = 2.6 Hz, 4
H), 2.37 (t, J = 2.6 Hz, 2 H), 1.52 (s, 9 H); 13C NMR (CDCl3, 125 MHz, 298 K):
 = 154.7, 81.0, 77.5, 74.7, 45.9, 28.7. MS m/z (relative intensity) 231.0 [M+Na]+
(10%).
BocHN
14
15: 1H NMR (CDCl3, 600 MHz, 298 K):  = 4.56-4.03 (m, 4 H), 2.22 (t, J = 2.6
Hz, 2 H), 1.49 (s, 18 H); 13C NMR (CDCl3, 150 MHz, 298 K): 154.2, 82.1, 79.0,
78.5, 72.9, 72.3, 41.9, 39.7, 28.4. MS m/z (relative intensity) 331.0 [M+Na]+
(45%).
19: 1H NMR (CDCl3, 500 MHz, 298 K):  = 3.93 (pent, J = 5.3 Hz, 2 H), 3.69
(td, J = 9.3, 6.9 Hz, 2 H), 3.62 (td, J = 9.3, 6.9 Hz, 2 H), 2.82 (br s, 2 H), 2.49 (td,
J = 7.0, 2.7 Hz, 4 H), 2.47 (br s, 2 H), 2.13-2.02 (m, 6 H), 1.89-1.84 (m, 2 H); 13C
NMR (CDCl3, 125 MHz, 298 K):  = 81.7, 79.8, 69.7, 66.8, 34.2, 28.9, 27.0,
20.7. MS m/z (relative intensity) 209.1 [M-OCH2CH2CCH]+ (100%).
22: 1H NMR (CDCl3, 500 MHz, 298 K):  = 5.49 (s, 1 H), 4.63 (d, J = 4.8 Hz, 1
H), 4.37 (d, J = 2.1 Hz, 2 H), 4.32 (m, 4 H), 4.00 (d, J = 7.5 Hz, 1 H), 3.80 (m, 1
H), 3.74 (t, J = 6.4 Hz, 2.1 Hz, 1 H), 3.65 (m, 1 H), 3.56 (m, 1 H), 2.47 (m, 3 H).
MS m/z (relative intensity) 277 [M+H]+ (18%).
N
Boc
N
N
Boc
15
O
S
O
19
O
O
O
22
– S11 –
O
O
References
1. Perrin, D. D.; Armarego, W. F. L. Purification of Laboratory Chemicals; Pergamon, Oxford,
1989.
2. Iyer, S. S.; Anderson, A. S.; Reed, S.; Swanson, B.; Schmidt, J. G. Tetrahedron Lett. 2004,
45, 4285-4288.
3. Diaz, D. D.; Punna, S.; Holzer, P.; McPherson, A. K.; Sharpless, K. B.; Fokin, V. V.; Finn, M.
G. J. Poly. Sci. A–Poly. Chem. 2004, 42, 4392-4403.
4: Ironmonger, A.; Stockley, P.; Nelson, A. Org. Biomol. Chem. 2005, 3, 2350-2353.
5: Loren, J. C.; Sharpless, K. B. Synthesis 2005, 9, 1914-1918.
6. Vilenchik, Y. M.; Pitirimova, S. G.; Krylova, I. V. U.S.S.R. 1973, 372210, 19730301.
7. McArdle, C. P.; Jennings, M. C.; Vittal, J. J.; Puddephatt, R. J. Chem. Eur. J. 2001, 7, 35723583.
8. Lee, N.-Y.; Jang, W.-J.; Yu, S.-H.; Im, J.; Chung, S.-K. Tetrahedron Lett. 2005, 46, 60636066.
– S12 –