2-Azido-2-deoxycellulose: Synthesis and 1,3-dipolar cycloaddition

Article abstract of DOI:10.1002/hlca.200890064

Chitosan (1) was prepared by basic hydrolysis of chitin of an average molecular weight of 70000 Da, ¹H-NMR spectra indicating almost complete deacetylation. N-Phthaloylation of 1 yielded the known N-phthaloylchitosan (2), which was tritylated to provide 3a and methoxytritylated to 3b. Dephthaloylation of 3a with NH₂NH ₂·H₂O gave the 6-O-tritylated chitosan 4a. Similarly, 3b gave the 6-O-methoxytritylated 4b. CuSO₄-Catalyzed diazo transfer to 4a yielded 95% of the azide 5a, and uncatalyzed diazo transfer to 4b gave 82% of azide 5b. Further treatment of 5a with CuSO₄ produced 2-azido-2-deoxycellulose (7). Demethoxytritylation of 5b in HCOOH gave 2-azido-2-deoxy-3,6-di-O-formylcellulose (6), which was deformylated to 7. The 1,3-dipolar cycloaddition of 7 to a range of phenyl-, (phenyl)alkyl-, and alkylmonosubstituted alkynes in DMSO in the presence of CuI gave the 1,2,3-triazoles 8-15 in high yields.

Full text of DOI:10.1002/hlca.200890064

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Helvetica Chimica Acta – Vol. 91 (2008)
2-Azido-2-deoxycellulose: Synthesis and 1,3-Dipolar Cycloaddition
by Fuyi Zhang, Bruno Bernet, Ve´ronique Bonnet, Olivier Dangles, Francisco Sarabia, and
Andrea Vasella*
Laboratory of Organic Chemistry, Department of Chemistry and Applied Biosciences, ETH Zürich,
Wolfgang-Pauli-Strasse 10, CH-8093 Zürich (e-mail: vasella@org.chem.ethz.ch)
Chitosan (1) was prepared by basic hydrolysis of chitin of an average molecular weight of 70000 Da,
1H-NMR spectra indicating almost complete deacetylation. N-Phthaloylation of 1 yielded the known N-
phthaloylchitosan (2), which was tritylated to provide 3a and methoxytritylated to 3b. Dephthaloylation
of 3a with NH2NH2 · H2O gave the 6-O-tritylated chitosan 4a. Similarly, 3b gave the 6-O-methoxytrity-
lated 4b. CuSO4-Catalyzed diazo transfer to 4a yielded 95% of the azide 5a, and uncatalyzed diazo
transfer to 4b gave 82% of azide 5b. Further treatment of 5a with CuSO4 produced 2-azido-2-deoxycellu-
lose (7). Demethoxytritylation of 5b in HCOOH gave 2-azido-2-deoxy-3,6-di-O-formylcellulose (6), which
was deformylated to 7. The 1,3-dipolar cycloaddition of 7 to a range of phenyl-, (phenyl)alkyl-, and alkyl-
monosubstituted alkynes in DMSO in the presence of CuI gave the 1,2,3-triazoles 8 – 15 in high yields.
Introduction. – Chitin, an abundant polysaccharide of 1,4-linked 2-acetamido-2-
deoxy-b-d-glucopyranose (b-d-GlcNAc), is found in animals, fungi, and some bacteria
[1], and readily isolated by deproteinization and demineralization of crustacean shells
[2]. Chitosans, fully or partially deacetylated chitin derivatives, and their modifications
[3] possess antiviral and antimicrobial properties [4], and know a number of
applications, being useful in enzyme inhibition and immobilization [5], in grafts
copolymerization [6], as carriers for drugs [7] and genes [8], and for biomedical
purposes such as wound healing and immunostimulation [9]. Further applications
include their use as food supplements or preservatives [10], as adsorbents of metals
[11], for treatment of waste waters [12], as support for heterogeneous catalysis [13],
and as packaging material [14]. The NH2 group at C(2) of chitosan was modified in
many ways, mostly by N-alkylation [15], N-acylation [16], N-phosphorylation [17], N-
sulfation [18], and by condensation with thiolated reagents [19].
2-Azido-2-deoxycellulose should be available from chitosan by diazo transfer. 1,3-
Cycloadditions of 2-azido-2-deoxycellulose to alkynes should introduce 1,2,3-triazolyl
side chains into chitosan and formally into cellulose, similarly as it is known for 6-azido-
6-deoxypolysaccharides [20][21]1). In the following, we describe the synthesis of 2-
azido-2-deoxycellulose and its reactivity in the 1,3-dipolar cycloaddition to alkynes,
leading to new chitin/cellulose derivatives.
Results and Discussion. – A priori, the desired 2-azido-2-deoxycellulose should be
available from chitosan (1) by diazo transfer from trifluoromethanesulfonyl azide,
1
)
For the preparation of 6-azido-6-deoxycellulose, -chitin, and -chitosan, see [22 – 25].
ꢀ 2008 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 91 (2008)
609
which is readily prepared in situ from NaN3 and trifluoromethanesulfonic anhydride
(Tf2O) [26][27]. We prepared chitosan according to an improved protocol of Kurita
et al. [28] by boiling low-molecular-mass chitin (average molecular weight: 70000 Da)
under reflux in 10m NaOH for 5 days (Scheme 1). The determination of high degrees of
deacetylation (DD) on the basis of the relative intensity of the NAc, HꢀC(1), and
1
HꢀC(2 – 6) signals [29] in the H-NMR spectrum of 1 proved convenient and more
precise than using CD and IR spectroscopy, or other methods [30]. A high DD
(> 99.5%; as compared to 91 – 92% for commercial chitosans) of the product was
evidenced by the almost complete disappearance of the NAc signal of 1. However,
2
although the CuSO4-catalyzed diazo transfer from TfN3 ) is known to tolerate H2O, it
did not provide more that 10 – 15% of the desired azide 7 from 1, on account of the low
solubility of 1 in MeOH (Scheme 1). The poor solubility of chitosan (1) in organic
solvents is indeed a frequently encountered problem in regioselective chemical
modifications of chitosan, resulting in unsatisfactory yields, low selectivities, and an
irregular structure of the product. For this reason, we transformed chitosan (1) into the
known phthalimide 2 [32]. Stirring a suspension of chitosan and 3 equiv. of phthalic
anhydride in DMF at 1308 for 15 h led to a clear, viscous solution that was treated with
H2O and then purified by Soxhlet extraction with EtOH to give 2 in 85% yield [32].
Tritylation and monomethoxytritylation of 2 provided the ethers 3a [32] and 3b,
respectively, in high yields3). The IR spectra of 2, 3a, and 3b show the expected weak
and strong absorptions of the phthalimido group at 1776 – 1777 and 1709 – 1716 cmꢀ1,
respectively. Dephthaloylation of 3a and 3b by treatment with NH2NH2 · H2O yielded
6-O-trityl chitosan 4a (65%) [32] and the 6-O-methoxytrityl chitosan 4b (62%),
respectively.
Scheme 1
Phth ¼ Phthaloyl; Tf ¼ trifluoromethylsulfonyl; Tr¼ trityl (¼triphenylmethyl); MTr¼ monomethoxy-
trityl (¼(4-methoxyphenyl)diphenylmethyl). a) Phthaloyl anhydride, DMF, 1308, 15 h; 85%. b) TrCl or
MTrCl, pyridine, 90 – 1008, 30 h; > 98% of 3a; 90% of 3b. c) NH2NH2 · H2O, H2O, 100 – 1108, 15 – 17 h;
65% of 4a; 62% of 4b. d) TfN3 in CH2Cl2, CuSO4, Et3N, H2O/MeOH, r.t., 15 d; 95%. e) CuSO4, toluene,
1108, 6 h; 95%. f) MeONa, TfN3 in CH2Cl2, 4-(dimethylamino)pyridine (DMAP), MeOH, r.t., 20 d;
82%. g) HCOOH, Et2O, r.t., 30 h; 88%. h) MeONa, MeOH, r.t., 12 h; 95%.
2
)
)
WARNING: neat TfN3 has been reported to be explosive [31]!
For a regioselective silylation of 2, see [33].
3

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As expected, the C(6)-O-tritylated chitosans 4a and 4b are far more soluble in
MeOH than 1. The CuSO4-catalyzed diazo transfer from TfN3 to 4a required 15 days at
room temperature, until a negative Kaiser test [34] evidenced less than 0.5% of free
NH2 groups. The azide 5a (95%) was obtained in a high yield, but the Cu salts could not
be completely removed by washing with H2O, or by treatment with NaCS2NEt2 · 3 H2O
[35]. The uncatalyzed diazo transfer [26] of Tf2O to the monomethoxytrityl ether 4b in
the presence of MeONa and 4-(dimethylamino)pyridine in MeOH at room temper-
ature also proceeded slowly, and was continued until the Kaiser test was negative (17
days), to provide 82% of 5b4). The introduction of the N3 group was evidenced by a
strong IR absorption of 5a and 5b at 2116 and 2109 cmꢀ1, respectively. Detritylation by
treating 5a with CuSO4 in boiling toluene afforded 95% of the desired azide 7, which
was, however, contaminated with Cu salts. Treatment of the monomethoxytrityl ether
5b with HCOOH gave 2-azido-2-deoxy-3,6-di-O-formylcellulose (6) in 88% yield. The
CHO groups of 6 are evidenced by the C¼O band at 1720 cmꢀ1. The formate 6 was
deacylated by treating a suspension of 6 in DMSO with MeONa, to generate 7 in 95%
yield. The IR spectrum of 7 shows a sharp and strong N3 band at 2112 cmꢀ1. A negative
Kaiser test and a negative fluorescence test5) evidenced the absence of amino groups in
7.
The CuI-catalysed 1,3-dipolar cycloaddition of azides to monosubstituted alkynes
was used in a few cases to modify 6-azido-6-deoxypolysaccharides [37]. It leads
selectively to 4-substituted 1,2,3-triazoles, while ca. 1:1 mixtures of 4-and 5-substituted
1,2,3-triazoles are obtained in the absence of CuI catalysis [38][39], as we had
experienced in an early application of the ꢁclick reactionꢂ to the synthesis of modified
cyclodextrins [40]. The reactivity of 2-azido-2-deoxycellulose (7) in this cycloaddition
was evaluated by treating 7 with monosubstituted alkynes in DMSO in the presence of
CuI [41] (Scheme 2). Phenyl-, (phenyl)alkyl-, and alkylacetylenes were transformed in
high yields at 60 – 1008 within 48 – 72 h into the 4-substituted 1,2,3-triazoles 8 – 15
(Table 1). A complete cycloaddition was evidenced by the absence of an azido band in
the IR spectra of the products. The 1,2,3-triazolyl group of 8 – 15 is evidenced by a
weak, broad IR band at 1640 – 1668 cmꢀ1. Two bands appearing at 694 – 702 and 720 –
763 cmꢀ1 are assigned to the monosubstituted Ph group of 8 – 116).
The solubility of 6, 7, and 12 was determined for solutions in DMSO, pyridine, and
MeOH (Table 2). The three compounds are sparingly soluble, DMSO proving the best
solvent. As expected, the diformate 6 is more highly soluble than the unprotected azide
7.
Attempts to obtain well-resolved 1H-and 13C-NMR spectra of 6 – 15 in (D6)DMSO
failed. Strong line broadening prevented an assignment of the signals, especially for the
glycosyl H-and Ca-toms. However, the structures of
5b, 6 – 9, and 13 were
4
)
When the reaction was performed at 50 – 608, TfN3 was consumed within 6 h (reaction of TfN3 with
MeONa?), but the Kaiser test was still positive.
5
6
)
)
The reaction with fluorescamine allows detection of 0.1% of unreacted amino groups [36].
The attempted 1,3-dipolar cycloaddition of 7 to nitriles in DMSO at ꢁ 1008 failed even for nitriles
activated by electron-withdrawing substituents, such as 3-hydroxypropanenitrile, 4-nitrobenzoni-
trile, and toluenesulfonyl and benzoyl cyanide, while heating 7 to 130 – 1508 for more than 2 days in
the presence of 4 – 6 equiv. of the nitriles resulted in only a partial transformation.

Helvetica Chimica Acta – Vol. 91 (2008)
611
Scheme 2
a) 4.0 equiv. of Ph(CH2)xC ꢂ CH (x ¼ 0, 1, 2, or 3), CuI, DMSO, 80 – 1008, 48 – 60 h; 86 – 90%. b) 4.0 –
10.0 equiv. of Me(CH2)xC ꢂ CH (x ¼ 2, 3, 4, or 5), CuI, DMSO, 60 – 1008, 50 – 72 h; 85 – 93%.
Table 1. 1,3-Dipolar Cycloadditions of 7 to Monosubstituted Alkynes: Conditions, Products, and Yields
Alkyne
Conditions
Product (Yield [%])
PhC ꢂ CH
60 h, 808
50 h, 808
48 h, 1008
40 h, 1008
72 h, 608
60 h, 808
50 h, 1008
72 h, 1008
8 (87)
9 (90)
PhCH2C ꢂ CH
Ph(CH2)2C ꢂ CH
Ph(CH2)3C ꢂ CH
Pent-1-yne
10 (88)
11 (86)
12 (93)
13 (90)
14 (88)
15 (85)
Hex-1-yne
Hept-1-yne
Oct-1-yne
Table 2. Solubility [g/l] of 6, 7, and 12 in DMSO, Pyridine, and MeOH
6
7
12
DMSO
Pyridine
MeOH
4.6
1.2
1.0
2.8
0.8
1.4
1.2
0.8
0.2
corroborated by solid state CP/MAS 13C-NMR spectroscopy. Their chemical shifts are
listed together with those of b-chitin [42], chitosan [43], and cellulose II [44] in Table 3,
and the spectra of 6, 7, and 9 are depicted in the Figure.
The CP/MAS 13C-NMR spectra of 5b, 6 – 9, and 13 show the presence of a single
compound. The spectra, and especially the chemical shifts of C(1), C(4), and C(2)/
C(3), resemble those of b-chitin and chitosan. C(2) and C(6) of 5b and 6 resonate as a
broad signal at ca. 65.5 ppm, whereas the spectra of 7 – 9 and 13 show two signals at
65.3 – 66.1 and 61.0 – 62.1 ppm. A comparison with b-chitin and chitosan suggests that
the former signal corresponds to C(2) and the latter one to C(6). As expected, the CP/
MAS 13C-NMR spectra of 5b, 6 – 9, and 13 differ significantly from the spectrum of
cellulose II, which is strongly influenced by the intra-and intermolecular Hb- onding
network of HOꢀC(2) and HOꢀC(6) (see [45] and refs. cit. therein).
The chemical shifts for C(4) and C(5) of the 1,2,3-triazolyl unit of 8, 9, and 10
(146.1 – 147.9 and 125.1 – 126 ppm) confirm the formation of 4-substituted 1,2,3-

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Figure. CP/MAS 13C-NMR Spectra of 6, 7, and 9
Table 3. CP/MAS 13C-NMR Chemical Shifts [ppm] of 5b, 6 – 9, 13, b-Chitin [42], Chitosan [43], and
Cellulose II [44]
C(1)
C(4)
C(3), C(2), C(6) C(4’) C(5’) other C
C(5)
5b
101.1 (br.)
82 (br.)
75.3
65.4 (br.)
–
–
MTrO: 159.0, 148.2 (br.)
141.9 (br.), 128.4,
112.8 (br.), 87.0, 54.9
2 CH¼O: 162.6
–
6
7
8
9
102.5
102.6
102.4 (br.)
103.5
103.3 (br.)
104.1
82.3 (br.) 75.4
82 (br.)
84.7
85.4
85.1 (br.) 75.3
65.5 (br.)
66.1, 62.1
65.3, 61.2
65.2, 61.0
65.9, 61.4
55.2, 60.8
58.9 (br.)
–
–
–
–
75.8
74.8
75.1
147.9 125.8 Ph: 141.2, 128.9
146.1
147.5 125.1 Bu: 31.9, 25.9, 23.0, 14.1
–
–
–
a
)
PhCH2: 138.6, 128.7, 31.1
13
b-Chitin
Chitosan
83.4
81 (sh)
73.9
75.9
–
–
–
NHAc: 173.6, 22.8
–
–
104.8
b
b
Cellulose II 108.3, 106.2 89.9, 88.7
)
)
a) Shoulder of Ph signal (ca. 126 ppm). b) C(2), C(3), and C(5): 77.8, 75.9, and 73.8 ppm; C(6): 64.2 and
63.6 ppm.
triazoles (compare with 143 – 148 and 117 – 126 ppm for monomeric 4-substituted 1,2,3-
triazoles [46] in solution, differing clearly from the chemical shifts (131 and 139 ppm) of
5-substituted 1,2,3-triazoles [47]).

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We thank the ETH Zürich and the Swiss National Science Foundation for generous support, Dr. Anu
Koivula, Espoo, for a generous gift of cellulases, Mr. Nicolas Bogliotti for the solubility measurements,
and Prof. Dr. Beat Meier and Mr. Thomas Westfeld for the CP/MAS 13C-NMR spectra.
Experimental Part
Chitosan (1) [28]. A suspension of chitin (6.0 g, average molecular weight: 70 kDa) in 10n NaOH
soln. (360 ml) was kept under reflux for 5 d. After filtration, the solid was washed with water until pH 7.0
and dried (P2O5) to give 1 (4.70 g, 98%). For 1H-NMR spectroscopy, a suspension of 1 (10 mg) in D2O/
10.8n DCl 98 :2 (2 ml) was stirred at 608 until a clear soln. was formed. IR (ATR): 3358m (br.), 2866w
(br.), 1590w, 1419w, 1374m, 1194w, 1147m, 1057s, 1015s, 988s, 889s, 804m, 734m, 661s. 1H-NMR
(300 MHz, D2O, 708; cf. [29]): 5.05 (br. s, HꢀC(1)); 4.06, 3.90 (2 br. s, HꢀC(3), HꢀC(4), HꢀC(5), 2
HꢀC(6)); 3.36 (br. s, HꢀC(2)); 2.20 (s, < 0.5%, NAc). Anal. calc. for C6H11NO4 (161.16): C 44.72, H
6.88, N 8.69; found: C 44.31, H 6.95, N 8.16.
N-Phthaloylchitosan (2). According to [32], a mixture of 1 (4.73 g, 29.02 mmol amino-group equiv.)
and phthalic anhydride (13.0 g, 87.74 mmol) in anh. DMF (95.0 ml) was stirred at 1308 for 7 h and diluted
with DMF (100 ml), affording a clear soln. The mixture was stirred at 1308 for 15 h, cooled to r.t., and
poured into ice-water. The precipitate was collected by filtration, washed completely by Soxhlet
extraction with EtOH for ca. 9 h and dried (P2O5) to give 2 (7.3 g, 85%). IR (ATR) : 3474w (br.), 2942w
(br.), 1776w, 1709s, 1611w, 1468w, 1384s, 1286m, 1255m, 1196w, 1111m, 1062s, 1035s, 1011s, 968m, 873m,
792m, 741m, 718s, 666m.
N-Phthaloyl-6-O-(triphenylmethyl)chitosan (3a). According to [32], a soln. of 2 (170 mg, 590 mmol
amino-group equiv.) in pyridine (8 ml) was treated with TrCl (2.10 g, 7.52 mmol), stirred for 24 h at 908
under Ar, cooled to r.t., and poured into EtOH. The precipitate was filtered off, and washed with EtOH
and Et2O. Drying gave 3a (310 mg, quant.). IR (KBr): 3438m, 2922w, 1777m, 1716s, 1489w, 1469w, 1388s,
1110m, 1020m, 719m.
6-O-[(4-Methoxyphenyl)diphenylmethyl]-N-phthaloylchitosan (3b). A soln. of 2 (6.00 g, 20.6 mmol
amino-group equiv.) in pyridine (120 ml) was treated with MTrCl (60.0 g, 177.1 mmol). The soln. was
stirred at 1008 for 30 h under Ar, cooled to r.t., and poured into EtOH. The precipitate was filtered off
and washed with EtOH to give 5 (10.40 g, 90%). A small sample was dissolved in CH2Cl2, treated with
MeOH, and resulting precipitate of 3b was filtered off. This procedure was repeated eight times to obtain
pure 3b for analysis. IR (ATR): 3477w (br.), 2933w (br.), 1777w, 1714s, 1608w, 1509m, 1491w, 1467w,
1447w, 1385s, 1300w, 1250m, 1176m, 1031s, 874w, 830m, 795w, 767m, 740m, 719s, 700s, 670m, 631m.
6-O-(Triphenylmethyl)chitosan (4a). According to [32], a suspension of 3a (220 mg, 420 mmol
amino-group equiv.) and NH2NH2 · H2O (5 ml) in H2O (10 ml) was stirred at 1008 for 15 h, cooled to r.t.,
and evaporated. The residue was three times suspended in H2O (15 ml) and evaporated. The colourless
precipitate in H2O was filtered off, and washed with EtOH and Et2O. Drying gave 4a (109 mg, 65%). IR
(KBr): 3455s, 2865m, 1602w, 1383w, 1091s, 607w.
6-O-[(4-Methoxyphenyl)diphenylmethyl]chitosan (4b). A suspension of 3b (7.30 g, 12.9 mmol
amino-group equiv.) and NH2NH2 · H2O (155 ml) in H2O (300 ml) was stirred at 1108 for 17 h and cooled
to r.t. After concentration to 100 ml, the precipitate was filtered off and washed with EtOH. The solid
was suspended in fresh NH2NH2 · H2O (100 ml), and the treatment was repeated until disappearance of
the C¼O band in the IR spectrum. The mixture was cooled to r.t. and evaporated. The residue was
suspended in H2O (150 ml), and the precipitate was filtered off and washed with EtOH to give 4b (3.5 g,
62%). A small sample was dissolved in CH2Cl2 and treated with MeOH. The resulting precipitate of 4b
was filtered off. This procedure was repeated seven times to obtain pure 4b for analysis. IR (ATR): 3451w
(br.), 2876w (br.), 1655w, 1607w, 1583w, 1509m, 1495w, 1446w, 1300w, 1249m, 1178m, 1154m, 1031s,
901m, 830m, 796m, 756m, 727m, 700s, 631m.
2-Azido-2-deoxy-6-O-(triphenylmethyl)cellulose (5a). A vigorously stirred suspension of 4a
(100 mg, ca. 270 mmol amino-group equiv.) in H2O (3.8 ml) was treated with CuSO4 (2.6 mg, 14.5 mmol),
a soln. of TfN3 (8.068 mmol) in CH2Cl2 (3.2 ml), and Et3N (604 ml, 4.36 mmol), diluted dropwise with
MeOH (16.6 ml), and stirred at r.t. for 15 days. After concentration to ca. 5 ml, the precipitate was

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Helvetica Chimica Acta – Vol. 91 (2008)
filtered off and washed with EtOH and Et2O. Drying gave 5a (100 mg, 95%) contaminated with Cu salts.
IR (KBr): 3453s, 2920w, 2116s, 1630w, 1374w, 1314w, 1154m, 1074s, 608w.
2-Azido-2-deoxy-6-O-[(4-methoxyphenyl)diphenylmethyl]cellulose (5b). A mixture of 4b (4.40 g,
ca. 10.15 mmol amino-group equiv.) and MeONa (2.57 g, 47.59 mmol) in MeOH (198 ml) was treated
with a soln. of TfN3 (110 mmol) in CH2Cl2 (160 ml) and 4-(dimethylamino)pyridine (5.20 g, 42.46 mmol)
and stirred at r.t. under Ar for 7 d. After the addition of additional TfN3 (110 mmol) in CH2Cl2 (160 ml),
stirring at r.t. was continued for 10 d; after that time, a negative Kaiser test was obtained. The mixture was
concentrated, and the precipitate was filtered off, washed with CH2Cl2 and MeOH, and dried to give 5b
(3.82 g, 82%). IR (ATR): 3460w (br.), 2878w (br.), 2109m, 1655w, 1607w, 1581w, 1509m, 1446w, 1299w,
1249m, 1217m, 1177m, 1152m, 1030s, 830m, 796w, 756m, 726w, 699s, 631m. 1H-NMR (300 MHz, CDCl3):
7.41, 7.25 (2 br. s, 12 arom. H); 6.85 (br. s, 2 arom. H); 4.20 – 3.80 (br. s, 2 H); 3.73 (br. s, MeO); 3.49, 3.34
(2 br. s, 5 H).
Kaiser Test [34]. A few milligrams of 5a or 5b was treated with 3 drops of soln. A (20 g of phenol in
5 ml of abs. EtOH), 3 drops of soln. B (2 ml of 10ꢀ2 m aq. KCN in 100 ml of pyridine), and 3 drops of soln.
C (0.5 g of ninhydrin in 10 ml of abs. EtOH). The yellow soln. was heated to 1008 for 3 min. A persisting
yellow colour indicates the absence of amino groups.
2-Azido-2-deoxy-3,6-di-O-formylcellulose (6). A suspension of 5b (5.00 g, ca. 10.88 mmol amino-
group equiv.) in Et2O (75 ml) was treated with HCOOH (75 ml), stirred at r.t. for 30 h and poured into
acetone. The precipitate was filtered off, washed with CH2Cl2 and MeOH, and dried to give 6 (2.32 g,
88%). IR (ATR): 3418w (br.), 2918w, 2112m, 1720m, 1484w, 1435w, 1404w, 1373w, 1313w, 1152m, 1014s,
950s, 821m, 767m, 698m.
2-Azido-2-deoxycellulose (7). a) From 5a. A suspension of 5a (100 mg, ca. 270 mmol amino-group
equiv.) in toluene (4 ml) was treated with CuSO4 (100 mg, 557 mmol) and stirred at reflux for 6 h. The
solid was filtered off and washed with acetone. Drying gave 7 (44 mg, 95%) contaminated with Cu salts.
b) From 6. A suspension of 6 (100 mg, 0.411 mmol) in MeOH (15 ml) was treated with MeONa
(55 mg, 1.02 mmol), stirred at r.t. for 12 h, and filtered. The solid was washed with CH2Cl2 and MeOH,
and dried to give 7 (73.1 mg, 95%). IR (ATR): 3362m (br.), 2931w, 2887w, 2112s, 1371w, 1311w, 1276w,
1254w, 1197m, 1149m, 1059s, 1027s, 949m, 896m.
Quant. Fluorescence Test for Measuring Residual Amino Group of 7 [36]. Solns. of 7 (1 mg) and
glucosamine (6.5 mg and 6 dilutions) in deionized H2O (5 ml, pH adjusted to 8 with Et3N) were treated
with a fluorescamine soln. (333 ml of 3 mg of fluorescamine soln. in 1 ml of MeCN). The excitation
wavelength was 405 nm, and the emission of fluorescence was measured at 535 nm and 248. A comparison
of the curve of 7 with that of glucosamine indicated a negligible presence of amino groups in 7.
General Procedure for the 1,3-Dipolar Cycloadditions of 7 to Alkynes. A suspension of 7 (50 mg, ca.
0.267 mmol saccharide units) and CuI (2.0 mg) in DMSO (1 ml) was treated with the alkyne (4 equiv.)
and heated to 60 – 1008 until complete disappearance of the IR band at 2112 cmꢀ1. The mixture was
cooled to r.t., and dialysed against H2O. The solid was filtered off, washed with CH2Cl2 and MeOH, and
dried to give the triazoles 8 – 15.
2-Deoxy-2-(4-phenyl-1H-1,2,3-triazol-1-yl)cellulose (8). The mixture was heated to 808 for 60 h.
Yield: 87%. IR (ATR): 3416w (br.), 2884w, 1640w (br.), 1484w, 1458w, 1362w (br.), 1205m, 1150m,
1066s, 1029s, 818m, 763m, 694m.
2-(4-Benzyl-1H-1,2,3-triazol-1-yl)-2-deoxycellulose (9). The mixture was heated to 808 for 50 h.
Yield: 90%. IR (ATR): 3439w (br.), 2905w, 1658w (br.), 1547w, 1496w, 1454w, 1347w, 1207m, 1151m,
1066s, 1050s, 1026s, 1000s, 897w, 829m, 771w, 720m, 702m.
2-Deoxy-2-[4-(2-phenylethyl)-1H-1,2,3-triazol-1-yl]cellulose (10). The mixture was heated to 1008
for 48 h. Yield: 88%. IR (ATR): 3417w (br.), 2929w, 1640w (br.), 1603w, 1548w, 1496w, 1453w, 1372w,
1215m, 1151m, 1065s, 1031s, 897w, 821m, 749m, 699m.
2-Deoxy-2-[4-(3-phenylpropyl)-1H-1,2,3-triazol-1-yl]cellulose (11). The mixture was heated to 1008
for 40 h. Yield: 90%. IR (ATR): 3438w (br.), 2931w, 2861w, 1654w (br.), 1601w, 1549w, 1496w, 1453w,
1350w, 1298w, 1207m, 1151s, 1058s, 1029s, 901w, 821m, 745m, 699m.
2-Deoxy-2-(4-propyl-1H-1,2,3-triazol-1-yl)cellulose (12). The mixture (10 equiv. of pent-1-yne) was
heated to 608 for 72 h. Yield: 93%. IR (ATR): 3393w (br.), 2958w, 2934w, 2870w, 1646w (br.), 1548w,
1456w, 1374w, 1316w, 1207m, 1149m, 1058s, 1033s, 932w, 898w, 824m.

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2-(4-Butyl-1H-1,2,3-triazol-1-yl)-2-deoxycellulose (13). The mixture was heated to 808 for 60 h.
Yield: 90%. IR (ATR): 3416w (br.), 2953w, 2932w, 2870w, 1666w (br.), 1548w, 1456w, 1376w, 1303w,
1204m, 1149m, 1064s, 998m, 897w, 823m.
2-Deoxy-2-(4-pentyl-1H-1,2,3-triazol-1-yl)cellulose (14). The mixture was heated to 1008 for 50 h.
Yield: 88%. IR (ATR): 3438w (br.), 2930w, 2861w, 1658w (br.), 1550w, 1376w, 1303w, 1205m, 1149s,
1066s, 998m, 898w, 823m.
2-Deoxy-2-(4-hexyl-1H-1,2,3-triazol-1-yl)cellulose (15). The mixture was heated to 1008 for 72 h.
Yield: 85%. IR (ATR): 3417w (br.), 2931w, 2870w, 1668w (br.), 1531w, 1458w, 1366w, 1206s, 1150s, 1063s,
1033s, 811m.
Solubility of 6, 7, and 12 in DMSO, Pyridine, and MeOH. A suspension of a dried sample (14 h at
high vacuum over P2O5) of the substrate (10 mg) in the given solvent (0.85 ml) was sonicated at 508 for
5 h. After centrifugation (14,000 rpm) for 10 min, 0.5 ml of the supernatant were evaporated and dried
for 4 h at high vacuum. The data are listed in Table 2.
CP/MAS 13C-NMR Spectra of 5b, 6 – 9, and 13. The CP/MAS 13C-NMR spectra were recorded at 258
on a 600-MHz (for 6 and 7) or a 300-MHz apparatus (for 5b, 8, 9, and 13) with adamantane as external
reference. Conditions: 2048 scans, MAS frequence: 15 kHz, 100 kHz SPINAL64 decoupling during
acquisition, CP variance for 3 ms: 65 kHz for H and 50 kHz for C. The chemical shifts are listed in
Table 3, and the spectra of 6, 7, and 9 are depicted in the Figure.
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Received January 30, 2008