Synthesis of 1,2,3-triazoles from azide-derivatised aminocyclitols by catalytic diazo transfer and CuAAC click chemistry

FULL PAPER

DOI: 10.1002/ejoc.201301874

Synthesis of 1,2,3-Triazoles from Azide-Derivatised Aminocyclitols by

Catalytic Diazo Transfer and CuAAC Click Chemistry

Li Ji,^[a,b]Guo-Quan Zhou,^[c]Chao Qian,*^[a,b]and Xin-Zhi Chen^[a,b]

Keywords: Diazo compounds / Click chemistry / Azides / Molecular diversity / Aminocyclitols

Cu^II-catalysed diazo transfer and Cu^I-catalysed azide–alkyne

1,3-dipolar cycloaddition (CuAAC) “click chemistry” were

used to synthesis C₇N aminocyclitol-derivatised 1,2,3-tri-

azoles. In the course of this work, the -N=N- moiety was

transferred onto C₇N aminocyclitols such as validamine, vali-

enamine and valiolamine by employing imidazole-1-sulfonyl

azide as the diazo transfer reagent with catalysis by Cu^II, Zn^II

and Ni^II, in moderate to good yields. The obtained azidocyclit-

ols were coupled with various terminal alkynes under modi-

fied Meldal’s conditions with good to excellent yields. The

stereo- and regiochemistry of the products were confirmed

by 2D-NMR (NOESY and HMBC). One-pot syntheses of the

corresponding 1,2,3-triazoles, as safer and more efficient pro-

cedures, were also investigated and gave moderate to good

yields.

1. Introduction

Carbasugars (also known as pseudosugars) are attractive

in the context of new drug discovery.^[1]It has been pos-

tulated that their structural resemblance to the parent

sugars should facilitate their recognition by enzymes or

other biological systems in place of the related true sugars.^[2]

Meanwhile, the replacement of the oxygen atom with a

methylene group in the framework should make these com-

pounds more stable toward endogenous degradative en-

zymes, as well as leading to interesting biological properties,

mainly as antibiotics and glycosidase inhibitors.^[3]

C₇N aminocyclitols such as valienamine (1), validamine

(2) and valiolamine (3),^[4]important compounds related to

carbasugars, were first isolated as fragments of the valida-

mycins and fully characterised as possessing greater or

lesser degrees of enzyme inhibitory activity toward certain

glycosidases (Figure 1). In the light of this discovery, hun-

dreds of analogues have been synthesised and their bio-

logical activities have been evaluated, resulting in the dis-

covery of several pharmaceutical leads.^[4a]The most repre-

sentative example was voglibose (4),^[5]a clinically useful

drug in the treatment of diabetes.^[6]

Figure 1. Structures of aminocyclitols and voglibose.

During the last few years there has been increasing inter-

est in the use of “copper-catalysed azide–alkyne cycload-

dition” (CuAAC),^[7]the most extensively utilised reaction

in “click chemistry”.^[8]In carbohydrate chemistry, CuAAC

reactions have come to be increasingly applied for diversifi-

cation or modification of carbohydrates and syntheses of

neoglycoconjugates directed towards the understanding of

biological pathways, mechanisms and drug discovery,^[9]in-

cluding the generation of potential substrates or inhibitors

for a range of different enzymes.^[10,3b]For instance, β-linked

1-glycosyl-4-phenyltriazoles 5 and 6 (Figure 2), prepared

from β-glycosyl azides and phenylacetylene by CuAAC,

were assessed for inhibitory activity against three different

β-glycosidases.^[11]Moreover, organic compounds bearing

triazole derivatives of other different pharmacodynamic nu-

clei were found to display various forms of biological ac-

tivity, including anti-HIV activity,^[12]selective β₃adrenergic

[a] Department of Chemical and Biological Engineering, Zhejiang

University,

NO.38, Zheda Road, Hangzhou 310027, P. R. China

E-mail: chemtec@163.com

http://mypage.zju.edu.cn/supmoney

[b] Key Laboratory of Biomass Chemical Engineering of Ministry

of Education, Zhejiang University,

Zhejiang, P. R. China

[c] College of Chemical Engineering, Ningbo University of

Technology,

P. R. China

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201301874.

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Synthesis of 1,2,3-Triazoles from Azide-Derivatised Aminocyclitols

receptor inhibition^[13]and antibacterial activity,^[14]perhaps Table 1. Survey of the catalytic diazo transfer reation.

due in part to their ability to mimic certain aspects of a

peptide bond.

Entry^[a]Base

Metal salt

Solvent

Yield

[%]^[b]

Figure 2. Potential glycosidase inhibitors synthesised by “click

chemistry”.

1

2

3

4

5

6

7

8

KHCO₃

CuSO₄·5H₂O

Zn(OAc)₂

Ni(NO₃)₂·6H₂O

CuSO₄·5H₂O

Zn(OAc)₂

MeOH

THF

toluene

CH₂Cl₂

DMF

MeOH

DMF

54

38

88

78

63

23

trace

41

72

82

76

70

85

82

Na₂CO₃

K₂CO₃

TEA

To the best of our knowledge, there is no reported re-

search on the diversification of aminocyclitols through

CuAAC modification. In continuation of our ongoing

study of C₇N aminocyclitols,^[15]here we report a new and

facile procedure for the modification of aminocyclitols by

diazo transfer and CuAAC.

9

10

11

12

13

14

15

TEA

DIPEA

ZnCl₂

CuSO₄·5H₂O

Ni(NO₃)₂·6H₂O

2. Results and Discussion

DMF

67

[a] Conditions:

2 (1.0 mmol), ImSO₂N₃·HCl (1.2 equiv.), base

Our initial investigations focused on the introduction of

the azide group, a component regularly used in CuAAC,

into the substrates. Most commonly, an azide group is in-

troduced into a molecule by nucleophilic displacement of a

(2.0 equiv.), cat. (0.05 equiv.), room temp., 12 h. [b] Isolated yields

after peracetylation under conventional conditions.

nucleofuge by an azide ion.^[16]In contrast with that ap- the substrate and the azide group in the ImSO₂N₃under the

proach is diazo transfer, in which an –N=N– moiety is influence of the metal catalyst. Inorganic bases, including

transferred onto an existing amine group, with retention of KHCO₃(Table 1, Entry 1), Na₂CO₃(Table 1, Entry 2) and

configuration, rather than the entire azido group being in- K₂CO₃(Table 1, Entries 3–9), and organic bases, such as

corporated into a molecule.^[17]The first diazo transfer onto triethylamine (TEA) (Table 1, Entries 10–11) and N,N-di-

an amino sugar, by use of trifluoromethanesulfonyl azide isopropylethylamine (DIPEA, Table 1, Entries 12–15), were

(TfN₃), was reported in 1991 by Vasella et al.^[18]and was screened. The results demonstrated that K₂CO₃gave the

further improved by Wong et al.^[19]Although powerful, this highest yield (Table 1, Entries 3–5) and was a little better

procedure presents several disadvantages, such as difficulty than DIPEA (Table 1, Entries 12–15).

in the isolation of TfN₃and the requirement for an excess

As catalysts, various metal salts, including Cu^II, Ni^IIor

of toxic and costly triflic anhydride, which prohibit the ap- Zn^II, were examined. Copper sulfate (Table 1, Entries 3 and

plication of this protocol on a large scale. In 2007, God- 13) was found to be better than zinc acetate (Table 1, En-

dard-Borger reported the synthesis of imidazole-1-sulfonyl try 4), zinc chloride (Table 1, Entry 12) and nickel nitrate

azide hydrochloride as an efficient and shelf-stable diazo (Table 1, Entries 5 and 15), and this result was similar to

transfer reagent by a simple one-pot procedure.^[20]This rea- that reported by Wong.^[19a]

gent, as an efficient alternative to TfN₃, converted a diverse

range of amines into the corresponding azides with excel- most suitable solvent when either K₂CO₃(Table 1, Entry 3)

lent yields. or DIPEA (Table 1, Entry 13) was employed as base, due

Finally, solvent screening revealed that MeOH was the

In order to make full use of the existing amino groups to its good dissolving capacity for validamine, relative to

on aminocyclitols and for the sake of operational safety, we other solvents such as THF (Table 1, Entry 6), toluene

thus decided to use imidazole-1-sulfonyl azide as the diazo (Table 1, Entry 7) or CH₂Cl₂(Table 1, Entry 8). In addition,

transfer reagent in our reseach. Initially, according to the DMF, as a highly polar solvent, also gave a good yield of

available reports from Wong (TfN₃with Cu^II, Ni^IIor Zn^IIproduct, when accompanied by copper sulfate and DIPEA

as catalyst)^[19a]and Goddard-Borger (ImSO₂N₃·HCl with (Table 1, Entry 14).

Cu^IIas catalyst)^[20]for the diazo transfer, the reaction con-

With the optimal conditions (Table 1, Entry 3) in hand,

ditions were optimised systematically and various bases and the substrate scope of this reaction was examined with

transition metal salts were scanned (Table 1) with use of other C₇N aminocyclitols, including valienamine (1), valiol-

validamine (2) as the model substrate.

amine (2) and valienamine epoxide (10). The results are

Bases added in this procedure not only neutralised the listed in Table 2.

hydrogen chloride from ImSO₂N₃·HCl, but also played an

Even though the protocol for diazo transfer with imid-

essential role in the reaction between the amino group in azole-1-sulfonyl azide has been utilised extensively in the

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L. Ji, G.-Q. Zhou, C. Qian, X.-Z. Chen

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Table 2. Synthesis of different aminocyclitol-derived azides by cata-

lytic diazo transfer.

Figure 3. ORTEP drawing of valienamine azide tetraacetate (8).

Initially, we adopted a method based on the procedure

first described by Sharpless that involves 0.05 mol equiv. of

CuSO₄plus 0.2 mol equiv. of sodium ascorbate (NaAsc) as

a catalyst, in a 1:1 tBuOH/H₂O solvent mixture at room

temperature. Testing these conditions for coupling between

peracetylated validamine azide and phenylacetylene re-

vealed a low level of conversion into the desired product

[a] Isolated yields.

modification of amino acids^[21]and proteins,^[22]to the best (Table 3, Entry 1), even at a higher temperature (Table 3,

of our knowledge this transformation has not been applied Entries 2 and 3). Therefore, two variations of these condi-

to aminocyclitols. However, the reaction is expected to pro- tions (referred to as Methods I and II) were employed, al-

ceed by a mechanism very similar to that reported by Wong lowing significant improvement of the cycloaddition yields

et al.^[19b]

of the target products. In Method I, which was a modifica-

During the characterisation of azide 8, it was found that tion of Sharpless’s procedure, the reactions were conducted

Ogawa et al. had obtained 8 as early as 1985, in the total in non-redistilled DMF at 100 °C in the presence of

synthesis of (+)-valienamine.^[23]Unexpectedly, although the DIPEA. The yield of product was improved to 88% in 8 h

spectroscopic data (¹H NMR, see Experimental Section) for (Table 3, Entry 5). In Method II, Meldal’s conditions (CuX/

8 were identical to those for the corresponding racemate base) were adopted; different CuXs such as CuI (Table 3,

reported in the literature,^[23a]the physical properties [white Entries 6–8), CuBr (Table 3, Entry 9) and CuCl (Table 3,

solid and [α]²_D⁵= +103.7 (c = 0.98, CHCl₃)] of our product Entry 10) were scanned in the presence of Et₃N or DIPEA.

were very different from those of Ogawa’s optically active 8 The results demonstrated that DMF was still the most suit-

[syrup and [α]_D²⁰= +40 (c = 1.0, CHCl₃)]!^[23b]In order to able solvent, and CuI/DIPEA (Table 3, Entry 7) was shown

confirm the structure of 8, X-ray crystallographic analysis to be the best combination in this reaction. It should be

of a single crystal was carried out, as shown in Figure 3. noted that all the reactions afford single regioisomers (as

1

The result demonstrated that the product we obtained had judged by H NMR spectroscopy). The stereo- and regio-

the same structure as we expected. Therefore, it could be chemistry of the product, established by 2D-NMR spec-

concluded that the specific optical rotation reported by troscopy, is discussed in detail below. With optimised condi-

Ogawa et al. has a relatively large error, which might be tions in hand, we next sought to define the scope of the

caused either by partial racemisation of the product or by azidocyclitols and terminal alkynes (Table 4, below).

residual solvent.

During the purification of products, it was found that the

Since the discovery of the CuAAC reaction, a large solubilities of the triazoles in MeOH were very low, and

number of different sets of reaction conditions and various that after washing with small amounts of MeOH, the solids

forms of Cu^Icatalyst have been reported.^[7a]In carbo- obtained were found to be analytically pure by TLC and

hydrate chemistry, combinations such as i) Cu^IIand sodium NMR analyses (¹H and ¹³C). The yields of products in this

ascorbate,^{[24a–24c,11b,24d–24f]}ii) Cu^IIand Cu⁰,^[25]iii) Cu^IIand simplified procedure were only slightly smaller than those

ascorbic acid^[26]and iv) Cu^Iand base^[11a,27]have been devel- obtained after purification by column chromatography

oped. Moreover, besides conventional heating methods, mi- (from 94% to 87%).

crowave irradiation has also been introduced to accelerate

Subsequently, the substrate scope of this reaction was

also examined. As highlighted in Table 4, a variety of ter-

the reaction with sluggish substrates.^[27a,11b]

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Synthesis of 1,2,3-Triazoles from Azide-Derivatised Aminocyclitols

Table 3. Survey of the cycloaddition conditions.

Entry

Catalyst

Reductant or base

Solvent/time

T [°C]

Yield [%]^[a]

1

2

3

4

5

CuSO₄·5H₂O (0.05 equiv.)

NaAsc (0.2 equiv.)

NaAsc (0.2 equiv.),

DIPEA (1.0 equiv.)

TEA (1.0 equiv.)

H₂O/tBuOH (1:1)/48 h

H₂O/tBuOH (1:1)/24 h

toluene/24 h

DMF/12 h

DMF/8 h

room temp.

30

48

56

73

88

80

100

6

7

8

9

CuI (0.1 equiv.)

CuBr (0.1 equiv.)

CuCl (0.1 equiv.)

toluene/12 h

DMF/6 h

DMF/12 h

DMF/24 h

80

82

94 (87)

81

70

59

100

DIPEA (1.0 equiv.)

10

[a] Isolated yields after column chromatography; simplified procedure in parentheses.

minal alkynes 12 could react efficiently with azide 7 to give handle. Thus, some procedures to generate azides in situ

the corresponding products in good yields after isolation with subsequent azide–alkyne cycloaddition have been re-

(Table 4, Entries 1–10). Azides 8, 9 and 11 could also react ported.^[28]In order to circumvent laborious purification by

smoothly with terminal alkynes to give moderate to good chromatography, we attempted to develop a convenient

yields (Table 4, Entries 11–30). Moreover, it was found that one-pot procedure for generating triazoles directly from

the substituents on phenylacetylene had no evident effect amines and avoiding the isolation of the azide intermedi-

on the yields of corresponding products. This conclusion ates. Wittmann et al.^[28c]reported a one-pot, two-step pro-

was consistent with the characteristics of CuAAC.

cedure, in which the first step was the generation of a series

With regard to the stereo- and regiochemistry of the of azides from various primary amines by use of TfN₃in

products (discussed here for the example of 15a: α-configu- combination with CuSO₄and solid sodium hydrogen carb-

ration of triazole, phenyl group in the triazole 4Ј-position), onate and the second step involved the addition of a ter-

especially those obtained at the relatively high temperatures minal acetylene along with sodium ascorbate and the Cu^I-

corresponding to those used in uncatalysed Huisgen-type stabilising ligand TBTA. Even though Wittmann’s pro-

cycloaddition, which provides mixtures of 1,4- and 1,5-tri- cedure is highly optimised, there are several practical limita-

azole regioisomers, these were unambiguously established tions to its employment in parallel or combinatorial synthe-

by NOESY and HMBC (Figure 4) experiments. Indeed, the sis, such as the use of TfN₃and microwave irradiation for

¹H 2D-NOESY spectrum shows correlations between 5Ј-H the CuAAC. An improved one-pot procedure utilising imid-

and 6-H and between 2-H and 2ЈЈ-H (Figure 5), and the azole-1-sulfonyl azide hydrochloride as a substitute for

¹H-¹³C HMBC experiment shows cross coupling between TfN₃has been reported by Smith et al.^[28d]Although this

5Ј-H and C-6, C-4Ј and C-1ЈЈ (Figure 6), in accordance with procedure is experimentally simple and suitable for parallel

the proposed structure for 15a.

chemistry, in particular avoiding the safety concerns associ-

ated with earlier procedures, the substrate scope of the

method is very narrow. Moreover, in Smith’s procedure, so-

dium ascorbate is added along with CuSO₄in the first step,

and could reduce Cu^IIinto Cu^Iimmediately, decreasing the

efficiency of Cu^II-catalysed diazo transfer and resulting in

the low yields for electron-deficient amines.

According to the optimal conditions for diazo transfer

(Table 1) and CuAAC (Table 3), the combination of copper

sulfate (0.05 equiv.) and DIPEA (2.0 equiv.) was chosen for

the first-step reaction in DMF. After consumption of the

aminocyclitol (TLC monitoring), sodium ascorbate

(0.2 equiv.) was added to the reaction mixture to reduce the

Figure 4. Significant NOESY and HMBC correlations in com-

pound 15a.

Although organic azides are stable under most reaction Cu^IIinto Cu^I, followed by the addition of the terminal alk-

conditions, those of low molecular weight or containing yne. Finally, the triazole was acetylated under conventional

several azide units tend to be explosive and are difficult to conditions, and the desired product could be purified by

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L. Ji, G.-Q. Zhou, C. Qian, X.-Z. Chen

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Table 4. Synthesis of different aminocyclitol-derived 1,2,3-triazoles.

[a] Isolated yields.

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Synthesis of 1,2,3-Triazoles from Azide-Derivatised Aminocyclitols

Figure 5. Expansion of the NOESY spectrum in the aromatic region.

Figure 6. Expansion of the HMBC spectrum in the aromatic region.

the simplified procedure described above. The results with

different substrates are listed in Table 5. The one-pot syn-

thesis of triazolylaminocyclitols circumvented the need for

3. Conclusion

In conclusion, we have synthesised C₇N aminocyclitol

purification of hazardous azides by chromatography and derivatives of 1,2,3-triazoles by Cu^II-catalysed diazo trans-

met the requirement of “click chemistry”.

fer and CuAAC. A diazo moiety is transferred onto a C₇N

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L. Ji, G.-Q. Zhou, C. Qian, X.-Z. Chen

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4.2. General Procedure for Preparation of Azide-Derivatised Amino-

cyclitols: Imidazole-1-sulfonyl azide hydrochloride (2.52 g,

12.0 mmol) was added to the aminocyclitol (10.0 mmol), K₂CO₃

(2.35 g, 17.0 mmol) and CuSO₄·5H₂O (25 mg, 0.1 mmol) in MeOH

(25 mL), and the mixture was stirred at room temp. for 12 h. It

was then concentrated and co-evaporated with toluene (20 mLϫ2).

Acetic anhydride was added to the residue in pyridine, and the

mixture was stirred overnight. It was then concentrated under re-

duced pressure, diluted with H₂O (100 mL) and extracted with

CH₂Cl₂(50 mLϫ3). The combined organic layers were washed

with hydrochloric acid (5%, 50 mLϫ2), NaHCO₃(5%, 50 mLϫ2)

and brine (50 mLϫ2), dried with anhydrous Na₂SO₄, filtered and

concentrated under reduced pressure. Flash chromatography gave

the azide.

Table 5. One-pot synthesis of triazolylaminocyclitols.

Entry Aminocyclitol

R–ϵ

Product

Yield [%]^[a]

1

2

3

4

5

6

7

8

2

1

3

12a

12b

12c

12d

12e

12f

12g

12h

12i

13a

13b

13c

13d

13e

13f

13g

13h

13i

76

80

75

72

73

83

82

81

76

86

85

76

80

78

89

72

76

75

78

72

73

74

83

80

78

4.2.1 (1S,2S,3R,4R,6S)-4-(Acetoxymethyl)-6-azidocyclohexane-

1,2,3-triyl Triacetate (7): White crystalline solid (88%), m.p. 63.3–

64.8 °C. [α]²_D⁵= +33.7 (c = 1.04, CHCl₃). ¹H NMR (400 MHz,

CDCl₃): δ = 5.43 (t, J = 9.9 Hz, 1 H, 2-H), 5.00 (dd, J = 10.2,

3.5 Hz, 1 H, 1-H), 4.96 (dd, J = 10.2, 8.6 Hz, 1 H, 3-H), 4.17 (dd,

J = 6.4, 3.3 Hz, 1 H, 6-H), 4.10 (dd, J = 11.5, 4.7 Hz, 1 H,

CHHOAc), 3.90 (dd, J = 11.5, 3.1 Hz, 1 H, CHHOAc), 2.36–2.22

(m, 1 H, 4-H), 2.10 (s, 3 H, CH₃COO), 2.05 (s, 3 H, CH₃COO),

2.03 (s, 3 H, CH₃COO), 2.01 (s, 3 H, CH₃COO), 1.96 (dt, J =

14.7, 3.7 Hz, 1 H, 5-H), 1.75–1.61 (m, 1 H, 5-H) ppm. ¹³C NMR

(101 MHz, CDCl₃): δ = 170.69 (CH₃COO), 169.97 (2 C,

CH₃COO), 169.89 (CH₃COO), 73.63 (C-3), 71.30 (C-2), 71.12 (C-

1), 62.80 (C-6), 58.86 (CH₂OAc), 34.68 (C-4), 28.98 (C-5), 20.69

(CH₃COO), 20.58 (CH₃COO), 20.57 (CH₃COO), 20.45

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

12j

13j

12a

12b

12c

12d

12e

12f

12g

12h

12k

12a

12b

12c

12d

12e

12f

12g

12i

14a

14b

14c

14d

14e

14f

14g

14h

14i

15a

15b

15c

15d

15e

15f

15g

15h

(CH COO) ppm. FT-IR (neat): ν

= 2927, 2100, 1741, 1369,

˜

3

max

1237, 1210, 1035, 967, 918, 726 cm^–1. MS (EI): m/z (%) = 43 (100),

121 (55), 122 (42), 138 (43), 181 (33), 198 (35), 240 (16), 312 (81),

330 (8), 372 (17) [M]⁺. HRMS (ESI-TOF): m/z calcd. for

C₁₅H₂₁N₃NaO₈[M + Na]⁺394.1226; found 394.1227.

[a] Isolated yields.

4.2.2 (1S,2S,3R,6S)-4-(Acetoxymethyl)-6-azidocyclohex-4-ene-1,2,3-

triyl Triacetate (8): White crystalline solid (92 %), m.p. 58.6–

59.2 °C. [α]²_D⁵= +103.7 (c = 0.98, CHCl₃) [ref.^[23b]syrup and [α]²_D⁰

= +40 (c = 1.0, CHCl₃)]. ¹H NMR (400 MHz, CDCl₃): δ = 5.95

(dd, J = 5.6, 1.0 Hz, 1 H, 5-H), 5.66 (d, J = 7.1 Hz, 1 H, 3-H), 5.50

(dd, J = 10.6, 7.2 Hz, 1 H, 2-H), 5.18 (dd, J = 10.6, 4.3 Hz, 1 H,

1-H), 4.70 (d, J = 13.4 Hz, 1 H, CHHOAc), 4.42 (d, J = 13.4 Hz,

1 H, CHHOAc), 4.42 (dd, J = 4.5, 5.7 Hz, 1 H, 6-H), 2.13 (s, 3 H,

C H ₃C O O ) , 2 . 0 6 ( s , 6 H , C H ₃C O O ) , 2 . 0 4 ( s , 3 H ,

CH₃COO) ppm.^{[23a] 13}C NMR (100 MHz, CDCl₃): δ = 169.21

(CH₃COO), 169.04 (CH₃COO), 168.89 (CH₃COO), 168.82

(CH₃COO), 135.48 (C-4), 122.41 (C-5), 68.98 (C-1), 68.80 (C-3),

68.58 (C-2), 61.59 (CH₂OAc), 55.70 (C-6), 19.64 (2 C, CH₃COO),

aminocyclitol derivative, such as validamine, valienamine or

valiolamine, by employing imidazole-1-sulfonyl azide as the

diazo transfer reagent with catalysis by Cu^IIin moderate to

good yields. The azidocyclitols can be linked with various

terminal alkynes under Meldal’s conditions with good to

excellent yields. To circumvent laborious purification of

products by chromatography, one-pot variants of the syn-

theses, as safer and more efficient procedures, were also in-

vestigated and gave moderate to good yields.

19.58 (CH COO), 19.45 (CH COO) ppm. FT-IR (neat): ν =

˜

max

3

2961, 2104, 1743, 1365, 1213, 1045, 977, 919, 867, 752 cm^–1. MS

(EI): m/z (%) = 43 (100), 123 (64), 137 (45), 138 (36), 165 (82), 180

(38), 207 (36), 310 (44), 327 (46), 370 (1) [M + 1]⁺. HRMS (ESI-

TOF): m/z calcd. for C₁₅H₁₉N₃NaO₈[M + Na]⁺392.1070; found

392.1074.

4. Experimental Section

4.1. General Methods: Melting points were determined with an X4-

Data microscope melting point apparatus and are uncorrected. Op-

tical rotation values were measured with a PerkinElmer P241 pola-

rimeter operating at 589 nm. Infrared (IR) spectra were recorded

with a Bruker Vector22 FT-IR spectrophotometer. Nuclear mag-

netic resonance (NMR) spectra were measured at 400 MHz (¹H)

or at 100 MHz (¹³C) with a Bruker Avance DRX 400 spectrometer;

HRMS were recorded with a Bruker MicroTOF-QII mass instru-

ment (ESI). All reactions were monitored by analytical thin-layer

chromatography (TLC, Merck) with detection by spraying with do-

decamolybdophosphoric acid in ethanol (5%, w/v) or ninhydrin in

ethanol (5%, w/v) and subsequent heating. Silica gel (300–

400 mesh) was used for flash chromatography. All reagents and sol-

vents were general reagent grade unless otherwise stated.

CCDC-969693 (for 8) contains 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.a-

c.uk/data_request/cif.

4.2.3 (1S,2R,3S,4S,6S)-4-(Acetoxymethyl)-6-azido-4-hydroxycyclo-

hexane-1,2,3-triyl Triacetate (9): White crystalline solid (82%), m.p.

117.3–118.7 °C (ref.^[29]122.8–124.2 °C). [α]²_D⁵= –13.4 (c = 1.00,

CHCl₃) [ref.^[29][α]²_D⁰= –13.2 (c = 2.00, CHCl₃)]. ¹H NMR

(400 MHz, CDCl₃): δ = 5.64 (t, J = 10.2 Hz, 1 H, 2-H), 5.04 (dd,

J = 10.4, 3.9 Hz, 1 H, 1-H), 5.01 (d, J = 10.2 Hz, 1 H, 3-H), 4.21

3628

www.eurjoc.org

Eur. J. Org. Chem. 2014, 3622–3636

Synthesis of 1,2,3-Triazoles from Azide-Derivatised Aminocyclitols

(q, J = 3.5 Hz, 1 H, 6-H), 3.95 (d, J = 11.4 Hz, 1 H, CHHOAc),

4.3.1 (1S,2S,3R,4R,6S)-4-(Acetoxymethyl)-6-(4-phenyl-1H-1,2,3-tri-

3.66 (d, J = 11.4 Hz, 1 H, CHHOAc), 3.39 (s, 1 H, OH), 2.08 (d, azol-1-yl)cyclohexane-1,2,3-triyl Triacetate (13a): This compound

J = 3.0 Hz, 1 H, 5-H), 2.05 (s, 3 H, CH₃COO), 2.01 (s, 3 H, was prepared from 7 (93 mg, 0.25 mmol) and phenylacetylene

CH₃COO), 2.00 (s, 3 H, CH₃COO), 1.95 (s, 3 H, CH₃COO), 1.91 (31 mg, 0.30 mmol) by Method A (103 mg, 87 %) or from 2 by

(d, J = 3.6 Hz, 1 H, 5-H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ =

169.23 (CH₃COO), 168.96 (CH₃COO), 168.84 (CH₃COO), 168.70

Method B (90 mg, 76%), as colourless needles, m.p. 227.3–228.1 °C.

1

[α]²_D⁵= +87.6 (c = 1.5, CHCl₃). H NMR (400 MHz, CDCl₃): δ =

(CH₃COO), 72.32 (C-4), 72.11 (C-3), 70.90 (C-2), 67.54 (C-1), 7.77 (dd, J = 5.1, 3.3 Hz, 2 H, Ar-H), 7.72 (s, 1 H, triazole H), 7.36

64.64 (CH₂OAc), 57.31 (C-6), 32.27 (C-5), 19.73 (CH₃COO), 19.54 (t, J = 7.5 Hz, 2 H, Ar-H), 7.32–7.24 (m, 1 H, Ar-H), 5.72 (t, J =

(CH₃COO), 19.50 (CH₃COO), 19.40 (CH₃COO) ppm. FT-IR 9.7 Hz, 1 H, 2-H), 5.13 (dd, J = 10.0, 5.2 Hz, 1 H, 1-H), 5.10 (dd,

(neat): ν

= 2927, 2105, 1739, 1375, 1229, 1162, 1038, 914, 810,

J = 4.8, 3.2 Hz, 1 H, 3-H), 5.09 (dd, J = 6.2, 3.1 Hz, 1 H, 6-H),

4.10 (dd, J = 11.6, 4.7 Hz, 1 H, CHHOAc), 3.86 (dd, J = 11.6,

˜

max

744 cm^–1. MS (EI): m/z (%) = 43 (100), 73 (32), 96 (22), 115

(89), 124 (25), 138 (43), 157 (85), 180 (49), 370 (88), 388 (8) 3.0 Hz, 1 H, CHHOAc), 2.99 (ddd, J = 13.8, 9.6, 3.8 Hz, 1 H, 4-

[M + 1]⁺. HRMS (ESI-TOF): m/z calcd. for C₁₅H₂₁N₃NaO₉[M +

H), 2.43–2.26 (m, 1 H, 5-H), 2.12–2.02 (m, 1 H, 5-H), 1.98 (s, 3 H,

CH₃COO), 1.98 (s, 3 H, CH₃COO), 1.92 (s, 3 H, CH₃COO), 1.88

(s, 3 H, CH₃COO) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 169.75

(CH₃COO), 169.18 (CH₃COO), 169.07 (CH₃COO), 168.50

(CH₃COO), 146.09 (triazole-C_quat), 129.09 (Ar-C_quat), 127.92 (Ar-

C), 127.42 (Ar-C), 124.73 (Ar-C), 120.40 (triazole-C), 70.82 (C-3),

70.19 (C-2), 70.16 (C-1), 61.76 (C-6), 55.92 (CH₂OAc), 34.80 (C-

4), 28.30 (C-5), 19.73 (CH₃COO), 19.62 (CH₃COO), 19.58

Na]⁺410.1175; found 410.1176.

4.2.4 (1R,2S,3R,4S,5R,6R)-1-(Acetoxymethyl)-5-azido-7-oxabi-

cyclo[4.1.0]heptane-2,3,4-triyl Triacetate (11): White crystalline so-

lid (73%), m.p. 84.8–85.8 °C. [α]²_D⁵= +50.1 (c = 0.58, CHCl₃). H

1

NMR (400 MHz, CDCl₃): δ = 5.47 (d, J = 8.3 Hz, 1 H, 3-H), 5.28

(dd, J = 10.7, 8.3 Hz, 1 H, 2-H), 4.91 (dd, J = 10.7, 6.0 Hz, 1 H,

1-H), 4.29 (dd, J = 5.7, 4.9 Hz, 1 H, 6-H), 4.28 (d, J = 12.3 Hz, 1

H, CHHOAc), 3.81 (d, J = 12.3 Hz, 1 H, CHHOAc), 3.49 (d, J =

4.8 Hz, 1 H, 5-H), 2.05 (s, 3 H, CH₃COO), 2.05 (s, 3 H, CH₃COO),

2.02 (s, 3 H, CH₃COO), 1.95 (s, 3 H, CH₃COO) ppm. ¹³C NMR

(101 MHz, CDCl₃): δ = 169.06 (CH₃COO), 168.99 (CH₃COO),

168.95 (CH₃COO), 168.33 (CH₃COO), 68.76 (C-2), 68.60 (C-3),

66.63 (CH₂OAc), 60.82 (C-1), 59.35 (C-4), 56.18 (C-5), 54.47 (C-

(CH COO), 19.56 (CH COO) ppm. FT-IR (neat): ν = 3046,

˜

max

3

1734, 1436, 1382, 1228, 1032, 971, 894, 763, 694 cm^–1. MS (EI):

m/z (%) = 43 (100), 107 (87), 116 (54), 125 (96), 149 (42), 167 (51),

185 (41), 223 (53), 403 (21), 473 (14) [M]⁺, 474 (7) [M + 1]⁺. HRMS

(ESI-TOF): m/z calcd. for C₂₃H₂₈N₃O₈[M + H]⁺474.1876; found

474.1866.

6), 19.55 (CH₃COO), 19.49 (CH₃COO), 19.48 (CH₃COO), 19.25 4.3.2 (1S,2S,3R,4R,6S)-4-(Acetoxymethyl)-6-[4-(4-methylphenyl)-

(CH COO) ppm. FT-IR (neat): ν = 2101, 1747, 1431, 1366,

1H-1,2,3-triazol-1-yl]cyclohexane-1,2,3-triyl Triacetate (13b): This

compound was prepared from 7 (93 mg, 0.25 mmol) and (4-meth-

ylphenyl)acetylene (35 mg, 0.30 mmol) by Method A (112 mg, 92%)

or from 2 by Method B (98 mg, 80%), as a white solid, m.p. 230.2–

230.9 °C. [α]²_D⁵= +99.9 (c = 1.08, CHCl₃). ¹H NMR (400 MHz,

CDCl₃): δ = 7.67 (s, 1 H, triazole H), 7.65 (d, J = 8.1 Hz, 2 H, Ar-

H), 7.17 (d, J = 7.9 Hz, 2 H, Ar-H), 5.72 (t, J = 9.8 Hz, 1 H, 2-

H), 5.13 (dd, J = 6.2, 3.9 Hz, 1 H, 1-H), 5.10 (dd, J = 4.5, 2.8 Hz,

1 H, 3-H), 5.07 (dd, J = 6.4, 2.9 Hz, 1 H, 6-H), 4.10 (dd, J = 11.6,

4.7 Hz, 1 H, CHHOAc), 3.86 (dd, J = 11.6, 3.1 Hz, 1 H,

CHHOAc), 3.10–2.88 (m, 1 H, 4-H), 2.40–2.32 (m, 1 H, 5-H), 2.31

(s, 3 H, ArCH₃), 2.10–2.02 (m, 1 H, 5-H), 1.98 (s, 3 H, CH₃COO),

1.98 (s, 3 H, CH₃COO), 1.92 (s, 3 H, CH₃COO), 1.87 (s, 3 H,

CH₃COO) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 169.75

(CH₃COO), 169.17 (CH₃COO), 169.08 (CH₃COO), 168.48

(CH₃COO), 146.16 (triazole-C_quat), 137.30 (Ar-C_quat), 128.59 (Ar-

C), 126.29 (Ar-C_quat), 124.64 (Ar-C), 120.04 (triazole-C), 70.86 (C-

3), 70.20 (C-2), 70.18 (C-1), 61.77 (C-6), 55.83 (CH₂OAc), 34.79

(C-4), 28.31 (C-5), 20.28 (ArCH₃), 19.73 (CH₃COO), 19.63

(CH₃COO), 19.59 (CH₃COO), 19.57 (CH₃COO) ppm. FT-IR

˜

3

max

1228, 1204, 1116, 1035, 742, 657 cm^–1. MS (EI): m/z (%) = 43 (100),

98 (55), 125 (46), 126 (48), 135 (59), 153 (73), 154 (94), 196 (78),

316 (32), 386 (2) [M + 1]⁺. HRMS (ESI-TOF): m/z calcd. for

C₁₅H₁₉N₃NaO₉[M + Na]⁺408.1019; found 408.1022.

4.3 General Procedure for Synthesis of Aminocyclitol Triazoles by

CuAAC. Method A: A solution of the appropriate azide

(0.25 mmol) and CuI (5.0 mg, 0.025 mmol, 0.1 equiv.) in degassed

DMF (5 mL) was stirred under nitrogen. The appropriate alkyne

(0.30 mmol, 1.2 equiv.) was then added, followed by the addition

of DIPEA (32.0 mg, 0.25 mmol, 1.0 equiv.). The solution was

stirred at 100 °C under nitrogen, and the reaction was complete

within 6 h as monitored by TLC (DCM/EtOAc 4:1). The mixture

was allowed to cool to room temp. and then diluted with EtOAc

(80 mL). The organic layer was washed with hydrochloric acid (5%,

50 mL ϫ 3), NaHCO₃(5 %, 50 mL ϫ 3) and brine (50 mL ϫ 2),

dried with anhydrous Na₂SO₄and concentrated to dryness to af-

ford a solid residue, which was washed with iced MeOH (2 mL) for

alkynes 12a–f or iced hexane (2 mL) for alkynes 12g–k. After sol-

vent removal under vacuum, the obtained solids were found to be

analytically pure by TLC and NMR analyses (¹H and ¹³C).

Method B: Imidazole-1-sulfonyl azide hydrochloride (63.0 mg,

12.0 mmol) was added to the aminocyclitol (0.25 mmol), DIPEA

(65.0 mg, 0.5 mmol) and CuSO₄·5H₂O (4.0 mg, 0. 025 mmol) in

degassed DMF (5 mL) and the mixture was stirred at room temp.

for 12 h. Sodium ascorbate (20.0 mg, 0.1 mmol) and the selected

alkyne (0.30 mmol, 1.2 equiv.) were added to the reaction mixture,

which was stirred at 100 °C under nitrogen for 8 h. Acetic anhy-

dride (160 mg, 1.5 mmol) and DMAP (5 mg) were added to the

residue, which was stirred overnight. The mixture was diluted with

H₂O (10 mL) and extracted with CH₂Cl₂(10 mLϫ3). The com-

bined organic layers were washed with hydrochloric acid (5 %,

10 mL ϫ 2), NaHCO₃(5 %, 10 mL ϫ 2) and brine (10 mL ϫ 2),

dried with anhydrous Na₂SO₄, filtered and concentrated to dryness

to afford a solid residue, which was washed with iced MeOH

(2 mL).

(neat): ν

= 3044, 1733, 1436, 1368, 1264, 1220, 1032, 979, 888,

˜

max

790 cm^–1. MS (EI): m/z (%) = 43 (100), 107 (73), 125 (80), 130 (72),

131 (90), 149 (44), 237 (100), 416 (43), 417 (41), 487 (19) [M]⁺, 488

(8) [M + 1]⁺. HRMS (ESI-TOF): m/z calcd. for C₂₄H₃₀N₃O₈[M +

H]⁺488.2033; found 488.2021.

4.3.3 (1S,2S,3R,4R,6S)-4-(Acetoxymethyl)-6-[4-(4-methoxyphen-

yl)-1H-1,2,3-triazol-1-yl]cyclohexane-1,2,3-triyl Triacetate (13c):

This compound was prepared from 7 (93 mg, 0.25 mmol) and (4-

methoxyphenyl)acetylene (40 mg, 0.30 mmol) by Method A

(103 mg, 82%) or from 2 by Method B (95 mg, 75%), as a white

solid, m.p. 195.0–195.3 °C. [α]²_D⁵= +103.2 (c = 1.24, CHCl₃). ¹H

NMR (400 MHz, CDCl₃): δ = 7.68 (d, J = 8.8 Hz, 2 H, Ar-H),

7.64 (s, 1 H, triazole H), 6.89 (d, J = 8.9 Hz, 2 H, Ar-H), 5.72 (t,

J = 9.8 Hz, 1 H, 2-H), 5.13 (dd, J = 6.7, 3.5 Hz, 1 H, 1-H), 5.09

(dd, J = 4.6, 3.0 Hz, 1 H, 3-H), 5.07 (t, J = 3.1 Hz, 1 H, 6-H), 4.10

(dd, J = 11.6, 4.7 Hz, 1 H, CHHOAc), 3.85 (dd, J = 11.6, 3.1 Hz,

Eur. J. Org. Chem. 2014, 3622–3636

www.eurjoc.org

3629

L. Ji, G.-Q. Zhou, C. Qian, X.-Z. Chen

FULL PAPER

1 H, CHHOAc), 3.77 (s, 3 H, ArOCH₃), 2.98 (dtt, J = 10.5, 7.0,

3.5 Hz, 1 H, 4-H), 2.41–2.24 (m, 1 H, 5-H), 2.11–2.01 (m, 1 H, 5-

H), 1.98 (s, 3 H, CH₃COO), 1.98 (s, 3 H, CH₃COO), 1.92 (s, 3

H, CH₃COO), 1.87 (s, 3 H, CH₃COO) ppm. ¹³C NMR (101 MHz,

CDCl₃): δ = 169.75 (CH₃COO), 169.17 (CH₃COO), 169.07

(CH₃COO), 168.49 (CH₃COO), 158.77 (Ar-C_quat), 145.94 (triazole-

C_quat), 126.04 (Ar-C), 121.81 (Ar-C_quat), 119.61 (triazole-C), 113.32

(Ar-C), 70.84 (C-3), 70.22 (C-2), 70.19 (C-1), 61.79 (C-6), 55.82

(CH₂OAc), 54.32 (ArOCH₃), 34.80 (C-4), 28.31 (C-5), 19.73

(CH₃COO), 19.63 (CH₃COO), 19.60 (CH₃COO), 19.57

840, 797 cm^–1. MS (EI): m/z (%) = 43 (100), 107 (100), 125 (100),

134 (83), 201 (76), 229 (100), 241 (100), 420 (50), 421 (79), 491

(28) [M]⁺, 492 (14) [M + 1]⁺. HRMS (ESI-TOF): m/z calcd. for

C₂₃H₂₇FN₃O₈[M + H]⁺492.1782; found 492.1778.

4.3.6 (1S,2S,3R,4R,6S)-4-(Acetoxymethyl)-6-[4-(4-nitrophenyl)-

1H-1,2,3-triazol-1-yl]cyclohexane-1,2,3-triyl Triacetate (13f): This

compound was prepared from 7 (93 mg, 0.25 mmol) and (4-ni-

trophenyl)acetylene (44 mg, 0.30 mmol) by Method A (120 mg,

93%) or from 2 by Method B (108 mg, 83%), as a white solid, m.p.

208.5–210.2 °C. [α]²_D⁵= +101.4 (c = 0.22, CHCl₃). ¹H NMR

(400 MHz, [D₆]DMSO): δ = 8.90 (s, 1 H, triazole H), 8.34 (d, J =

8.9 Hz, 2 H, Ar-H), 8.15 (d, J = 8.9 Hz, 2 H, Ar-H), 5.61 (t, J =

9.9 Hz, 1 H, 2-H), 5.45 (dd, J = 10.5, 5.2 Hz, 1 H, 1-H), 5.27 (dd,

J = 4.5, 2.8 Hz, 1 H, 3-H), 5.22 (dd, J = 10.9, 9.6 Hz, 1 H, 6-H),

4.04 (dd, J = 11.3, 5.6 Hz, 1 H, CHHOAc), 3.93 (dd, J = 11.2,

4.0 Hz, 1 H, CHHOAc), 2.93 (qd, J = 10.5, 5.1 Hz, 1 H, 4-H),

2.36–2.24 (m, 1 H, 5-H), 2.21 (ddd, J = 14.9, 4.9, 2.6 Hz, 1 H, 5-

H), 2.03 (s, 3 H, CH₃COO), 2.00 (s, 3 H, CH₃COO), 1.93 (s, 3 H,

CH₃COO), 1.88 (s, 3 H, CH₃COO) ppm. ¹³C NMR (101 MHz,

[D₆]DMSO): δ = 170.70 (CH₃COO), 170.16 (CH₃COO), 169.87

(CH₃COO), 169.80 (CH₃COO), 147.19 (triazole-C_quat), 144.00 (Ar-

(CH COO) ppm. FT-IR (neat): ν

= 2960, 1733, 1499, 1369,

˜

3

max

1246, 1222, 1032, 980, 810, 788 cm^–1. MS (EI): m/z (%) = 43 (100),

132 (44), 146 (57), 147 (69), 176 (38), 253 (100), 254 (52), 432 (66),

433 (39), 503 (23) [M]⁺, 504 (9) [M + 1]⁺. HRMS (ESI-TOF): m/z

calcd. for C₂₄H₃₀N₃O₉[M + H]⁺504.1982; found 504.1988.

4.3.4 (1S,2S,3R,4R,6S)-4-(Acetoxymethyl)-6-[4-(4-chlorophenyl)-

1H-1,2,3-triazol-1-yl]cyclohexane-1,2,3-triyl Triacetate (13d): This

compound was prepared from 7 (93 mg, 0.25 mmol) and (4-chlo-

rophenyl)acetylene (41 mg, 0.30 mmol) by Method A (113 mg,

89%) or from 2 by Method B (92 mg, 72%), as a white solid, m.p.

232.8–234.1 °C. [α]²_D⁵= +93.0 (c = 1.34, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ = 7.73 (s, 1 H, triazole H), 7.70 (d, J =

8.6 Hz, 2 H, Ar-H), 7.33 (d, J = 8.6 Hz, 2 H, Ar-H), 5.70 (t, J =

10.0 Hz, 1 H, 2-H), 5.14 (dd, J = 10.7, 4.6 Hz, 1 H, 1-H), 5.10 (dd,

J = 4.4, 2.4 Hz, 1 H, 3-H), 5.09 (dd, J = 4.7, 2.7 Hz, 1 H, 6-H),

4.10 (dd, J = 11.6, 4.7 Hz, 1 H, CHHOAc), 3.86 (dd, J = 11.6,

3.1 Hz, 1 H, CHHOAc), 3.05–2.84 (m, 1 H, 4-H), 2.40–2.30 (m, 1

H, 5-H), 2.14–2.03 (m, 1 H, 5-H), 1.99 (s, 3 H, CH₃COO), 1.98 (s,

3 H, CH₃COO), 1. 92 (s, 3 H, CH₃COO), 1.88 (s, 3 H,

CH₃COO) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 169.73

(CH₃COO), 169.14 (CH₃COO), 169.01 (CH₃COO), 168.52

(CH₃COO), 145.08 (triazole-C_quat), 133.15 (Ar-C_quat), 128.13 (Ar-

C), 127.66 (Ar-C_quat), 125.99 (Ar-C), 120.46 (triazole-C), 70.77 (C-

3), 70.15 (C-2), 70.09 (C-1), 61.74 (C-6), 56.05 (CH₂OAc), 34.81

(C-4), 28.29 (C-5), 19.73 (CH₃COO), 19.63 (CH₃COO), 19.59

C_quat), 137.30 (Ar-C_quat), 126.51 (Ar-C), 126.47 (triazole-C), 124.90

(Ar-C), 71.96 (C-3), 71.41 (C-2), 70.58 (C-1), 63.93 (C-6), 57.66

(CH₂OAc), 36.40 (C-4), 28.73 (C-5), 21.00 (CH₃COO), 20.88

(CH₃COO), 20.83 (CH₃COO), 20.71 (CH₃COO) ppm. FT-IR

(neat): ν

= 3102, 1755, 1732, 1509, 1354, 1255, 1032, 971, 840,

˜

max

805 cm^–1. MS (EI): m/z (%) = 43 (100), 107 (100), 125 (100), 167

(89), 185 (77), 227 (68), 268 (57), 431 (24), 448 (49), 518 (9) [M]⁺,

519 (6) [M + 1]⁺. HRMS (ESI-TOF): m/z calcd. for C₂₃H₂₇N₄O₁₀

[M + H]⁺519.1727; found 519.1712.

4.3.7 (1S,2S,3R,4R,6S)-4-(Acetoxymethyl)-6-(4-butyl-1H-1,2,3-

triazol-1-yl)cyclohexane-1,2,3-triyl Triacetate (13g): This com-

pound was prepared from 7 (186 mg, 0.50 mmol) and hex-1-yne

(49 mg, 0.60 mmol) by Method A (202 mg, 89 %) or from 2 by

Method B (188 mg, 83%), as a white solid, m.p. 161.0–161.7 °C.

(CH COO), 19.56 (CH COO) ppm. FT-IR (neat): ν = 3045,

˜

max

3

1

[α]²_D⁵= +103.5 (c = 0.51, CHCl₃). H NMR (400 MHz, CDCl₃): δ

1739, 1443, 1380, 1224, 1092, 1063, 1032, 971, 802 cm^–1. MS (EI):

m/z (%) = 43 (100), 91 (39), 107 (84), 125 (90), 150 (50), 167 (44),

185 (35), 257 (54), 437 (19), 507 (8) [M]⁺, 508 (4) [M + 1]⁺. HRMS

(ESI-TOF): m/z calcd. for C₂₃H₂₇ClN₃O₈[M + H]⁺508.1487;

found 508.1481.

= 7.20 (s, 1 H, triazole H), 5.62 (t, J = 9.9 Hz, 1 H, 2-H), 5.08 (dd,

J = 10.4, 5.4 Hz, 1 H, 1-H), 5.07 (dd, J = 10.2, 5.0 Hz, 1 H, 3-H),

4.98 (dd, J = 7.4, 4.5 Hz, 1 H, 6-H), 4.10 (dd, J = 11.6, 4.5 Hz, 1

H, CHHOAc), 3.85 (dd, J = 11.6, 2.9 Hz, 1 H, CHHOAc), 3.11–

2.86 (m, 1 H, 4-H), 2.66 (t, J = 7.7 Hz, 2 H, CH₂), 2.37–2.23 (m,

1 H, 5-H), 2.08–2.01 (m, 1 H, 5-H), 1.99 (s, 3 H, CH₃COO), 1.98

(s, 3 H, CH₃COO), 1.92 (s, 3 H, CH₃COO), 1.88 (s, 3 H,

CH₃COO), 1.67–1.52 (m, 2 H, CH₂), 1.40–1.23 (m, 2 H, CH₂), 0.87

(t, J = 7.4 Hz, 3 H, CH₃) ppm. ¹³C NMR (101 MHz, CDCl₃): δ =

169.72 (CH₃COO), 169.13 (CH₃COO), 168.95 (CH₃COO), 168.46

(CH₃COO), 146.72 (triazole-C_quat), 121.47 (triazole-C), 70.94 (C-

3), 70.24 (C-2), 70.17 (C-1), 61.80 (C-6), 55.40 (CH₂OAc), 34.83

(C-4), 30.42 (CH₂), 28.18 (C-5), 24.16 (CH₂), 21.25 (CH₂), 19.73

(CH₃COO), 19.63 (CH₃COO), 19.57 (CH₃COO), 19.54

4.3.5 (1S,2S,3R,4R,6S)-4-(Acetoxymethyl)-6-[4-(4-fluorophenyl)-

1H-1,2,3-triazol-1-yl]cyclohexane-1,2,3-triyl Triacetate (13e): This

compound was prepared from 7 (93 mg, 0.25 mmol) and (4-

fluorophenyl)acetylene (36 mg, 0.30 mmol) by Method A (110 mg,

90%) or from 2 by Method B (90 mg, 73%), as a white solid, m.p.

214.1–215.6 °C. [α]²_D⁵= +101.8 (c = 1.50, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ = 7.78–7.71 (m, 2 H, Ar-H), 7.71 (s, 1 H,

triazole H), 7.12–6.96 (m, 2 H, Ar-H), 5.71 (t, J = 9.8 Hz, 1 H, 2-

H), 5.14 (dd, J = 11.2, 4.1 Hz, 1 H, 1-H), 5.11 (dd, J = 9.5, 3.4 Hz,

1 H, 3-H), 5.09 (dd, J = 6.3, 3.1 Hz, 1 H, 6-H), 4.10 (dd, J = 11.6,

4.7 Hz, 1 H, CHHOAc), 3.86 (dd, J = 11.6, 3.1 Hz, 1 H,

CHHOAc), 3.02–2.91 (m, 1 H, 4-H), 2.42–2.27 (m, 1 H, 5-H), 2.08

(ddd, J = 15.1, 13.2, 4.4 Hz, 1 H, 5-H), 1.98 (s, 6 H, CH₃COO),

1.92 (s, 3 H, CH₃COO), 1.88 (s, 3 H, CH₃COO) ppm. ¹³C NMR

(101 MHz, CDCl₃): δ = 169.73 (CH₃COO), 169.14 (CH₃COO),

(CH COO), 12.78 (CH ) ppm. FT-IR (neat): ν = 2961, 2856,

˜

max

3

1733, 1437, 1382, 1033, 971, 894, 837, 795 cm^–1. HRMS (ESI-

TOF): m/z calcd. for C₂₁H₃₂N₃O₈[M + H]⁺454.2189; found

454.2195.

4.3.8 (1S,2S,3R,4R,6S)-4-(Acetoxymethyl)-6-(4-pentyl-1H-1,2,3-

triazol-1-yl)cyclohexane-1,2,3-triyl Triacetate (13h): This com-

169.01 (CH₃COO), 168.53 (CH₃COO), 161.77 (d, ¹J_C,F= 247.6 Hz,

3

Ar-C_quat), 145.26 (triazole-C_quat), 126.51 (d, J_C,F= 8.2 Hz, Ar-C), pound was prepared from 7 (193 mg, 0.50 mmol) and hept-1-yne

125.40 (d, ⁴J_C,F= 3.2 Hz, Ar-C_quat), 120.20 (triazole-C), 114.92 (d, (60 mg, 0.60 mmol) by Method A (220 mg, 91 %) or from 2 by

²J_C,F= 21.8 Hz, Ar-C), 70.79 (C-3), 70.21 (C-2), 70.14 (C-1), 61.79

(C-6), 56.01 (CH₂OAc), 34.84 (C-4), 28.30 (C-5), 19.72 (CH₃COO),

Method B (199 mg, 82%), as a white solid, m.p. 149.1–150.0 °C.

[α]²_D⁵= +97.7 (c = 0.26, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ =

19.61 (CH₃COO), 19.58 (CH₃COO), 19.55 (CH₃COO) ppm. FT- 7.20 (s, 1 H, triazole H), 5.62 (t, J = 9.9 Hz, 1 H, 2-H), 5.09 (dd,

IR (neat): ν

= 3044, 1736, 1444, 1382, 1261, 1225, 1032, 970,

J = 10.0, 5.0 Hz, 1 H, 1-H), 5.07 (dd, J = 10.4, 5.1 Hz, 1 H, 3-H),

˜

max

3630

www.eurjoc.org

Eur. J. Org. Chem. 2014, 3622–3636

Synthesis of 1,2,3-Triazoles from Azide-Derivatised Aminocyclitols

4.98 (dd, J = 7.2, 4.5 Hz, 1 H, 6-H), 4.10 (dd, J = 11.6, 4.5 Hz, 1

H, CHHOAc), 3.85 (dd, J = 11.6, 2.9 Hz, 1 H, CHHOAc), 3.13–

pound was prepared from 8 (92 mg, 0.25 mmol) and phenylacetyl-

ene (31 mg, 0.30 mmol) by Method A (108 mg, 92%) or from 2 by

2.84 (m, 1 H, 4-H), 2.65 (t, J = 7.7 Hz, 2 H, CH₂), 2.37–2.20 (m, Method B (101 mg, 86%), as a white solid, m.p. 177.8–178.1 °C.

1 H, 5-H), 2.11–2.01 (m, 1 H, 5-H), 1.99 (s, 3 H, CH₃COO), 1.98 [α]²_D⁵= +198.2 (c = 1.2, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ =

(s, 3 H, CH₃COO), 1.92 (s, 3 H, CH₃COO), 1.88 (s, 3 H, 7.87 (s, 1 H, triazole H), 7.77 (d, J = 7.1 Hz, 2 H, Ar-H), 7.36 (t,

CH₃COO), 1.69–1.54 (m, 2 H, CH₂), 1.35–1.23 [m, 4 H, (CH₂)₂], J = 7.5 Hz, 2 H, Ar-H), 7.27 (t, J = 7.4 Hz, 1 H, Ar-H), 6.01 (dd,

0.83 (t, J = 6.8 Hz, 3 H, CH₃) ppm. ¹³C NMR (101 MHz, CDCl₃):

J = 4.8, 0.7 Hz, 1 H, 5-H), 5.74 (t, J = 5.1 Hz, 1 H, 2-H), 5.56–

δ = 169.72 (CH₃COO), 169.13 (CH₃COO), 168.95 (CH₃COO), 5.39 (m, 2 H, 3-H and 1-H), 5.25 (dd, J = 10.2, 5.5 Hz, 1 H, 6-H),

168.45 (CH₃COO), 146.78 (triazole-C_quat), 121.44 (triazole-C), 4.72 (d, J = 13.8 Hz, 1 H, CHHOAc), 4.49 (d, J = 13.8 Hz, 1 H,

70.96 (C-3), 70.24 (C-2), 70.17 (C-1), 61.78 (C-6), 55.40 (CH₂OAc),

34.82 (C-4), 30.39 (CH₂), 28.20 (C-5), 28.00 (CH₂), 24.46 (CH₂),

21.38 (CH₂), 19.73 (CH₃COO), 19.63 (CH₃COO), 19.57

CHHOAc), 2.04 (s, 3 H, CH₃COO), 2.02 (s, 3 H, CH₃COO), 1.97

(s, 3 H, CH₃COO), 1.89 (s, 3 H, CH₃COO) ppm. ¹³C NMR

(101 MHz, CDCl₃): δ = 169.21 (CH₃COO), 169.16 (CH₃COO),

(CH₃COO), 19.54 (CH₃COO), 12.98 (CH₃) ppm. FT-IR (neat): 168.91 (CH₃COO), 168.60 (CH₃COO), 146.93 (triazole-C_quat),

= 2957, 2928, 1734, 1437, 1382, 1231, 1033, 970, 888, 136.89 (C-4), 129.25 (Ar-C_quat), 127.86 (Ar-C), 127.35 (Ar-C),

ν

˜

max

796 cm^–1. HRMS (ESI-TOF): m/z calcd. for C₂₂H₃₄N₃O₈[M + 124.81 (Ar-C), 120.29 (Ar-C), 118.59 (triazole-C), 69.37 (C-1),

H]⁺468.2346; found 468.2349.

67.32 (C-3), 67.11 (C-2), 61.65 (CH₂OAc), 54.68 (C-6), 19.71

(CH₃COO), 19.68 (CH₃COO), 19.62 (CH₃COO), 19.53

4.3.9 (1S,2S,3R,4R,6S)-4-(Acetoxymethyl)-6-[4-(phenoxymethyl)-

1H-1,2,3-triazol-1-yl]cyclohexane-1,2,3-triyl Triacetate (13i): This

compound was prepared from 7 (186 mg, 0.50 mmol) and prop-

argyl phenyl ether (79 mg, 0.60 mmol) by Method A (225 mg, 89%)

or from 2 by Method B (204 mg, 81%), as a white solid, m.p. 143.5–

143.8 °C. [α]²_D⁵= +86.0 (c = 0.40, CHCl₃). ¹H NMR (400 MHz,

CDCl₃): δ = 7.53 (s, 1 H, triazole H), 7.22 (dd, J = 8.7, 7.2 Hz, 2

H, Ar-H), 6.90 (t, J = 8.5 Hz, 3 H, Ar-H), 5.62 (t, J = 9.8 Hz, 1

H, 2-H), 5.17 (s, 2 H, CH₂OPh), 5.10 (dd, J = 7.3, 2.1 Hz, 1 H, 1-

H), 5.07 (dd, J = 7.3, 2.0 Hz, 1 H, 3-H), 5.02 (dd, J = 7.4, 4.6 Hz,

1 H, 6-H), 4.10 (dd, J = 11.6, 4.7 Hz, 1 H, CHHOAc), 3.85 (dd, J

= 11.6, 3.0 Hz, 1 H, CHHOAc), 3.13–2.86 (m, 1 H, 4-H), 2.39–

2.21 (m, 1 H, 5-H), 2.10–1.99 (m, 1 H, 5-H), 1.98 (s, 3 H,

CH₃COO), 1.98 (s, 3 H, CH₃COO), 1.91 (s, 3 H, CH₃COO), 1.78

(s, 3 H, CH₃COO) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 169.69

(CH₃COO), 169.10 (CH₃COO), 168.95 (CH₃COO), 168.43

(CH₃COO), 157.08 (Ar-C_quat), 142.83 (triazole-C_quat), 128.58 (Ar-

C), 123.59 (Ar-C), 120.33 (triazole-C), 113.76 (Ar-C), 70.75 (C-

3), 70.16 (C-2), 70.07 (C-1), 61.75 (C-6), 60.87 (CH₂OPh), 55.88

(CH₂OAc), 34.83 (C-4), 28.11 (C-5), 19.72 (CH₃COO), 19.62

(CH₃COO), 19.55 (CH₃COO), 19.40 (CH₃COO) ppm. FT-IR

(CH COO) ppm. FT-IR (neat): ν

= 1736, 1432, 1376, 1228,

˜

3

max

1164, 1110, 973, 810, 763, 695 cm^–1. MS (EI): m/z (%) = 43 (100),

116 (82), 123 (40), 124 (34), 166 (84), 208 (6), 221 (6), 239 (3), 281

(2), 471 (2) [M]⁺. HRMS (ESI-TOF): m/z calcd. for C₂₃H₂₆N₃O₈

[M + H]⁺472.1720; found 472.1725.

4.3.12 (1S,2S,3R,6S)-4-(Acetoxymethyl)-6-[4-(4-methylphenyl)-1H-

1,2,3-triazol-1-yl]cyclohex-4-ene-1,2,3-triyl Triacetate (14b): This

compound was prepared from 8 (92 mg, 0.25 mmol) and 4-methyl

phenylacetylene (35 mg, 0.30 mmol) by Method A (113 mg, 93%)

or from 1 by Method B (103 mg, 85%), as a white solid, m.p. 139.3–

140.5 °C. [α]²_D⁵= +211.6 (c = 0.5, CHCl₃). ¹H NMR (400 MHz,

CDCl₃): δ = 7.81 (s, 1 H, triazole H), 7.66 (d, J = 8.1 Hz, 2 H, Ar-

H), 7.16 (d, J = 8.0 Hz, 2 H, Ar-H), 6.00 (dd, J = 4.9, 1.1 Hz, 1

H, 5-H), 5.73 (t, J = 5.1 Hz, 1 H, 2-H), 5.55–5.41 (m, 2 H, 3-H

and 1-H), 5.25 (dd, J = 9.7, 5.4 Hz, 1 H, 6-H), 4.72 (d, J = 13.8 Hz,

1 H, CHHOAc), 4.48 (d, J = 13.8 Hz, 1 H, CHHOAc), 2.30 (s, 3

H, ArCH₃), 2.04 (s, 3 H, CH₃COO), 2.01 (s, 3 H, CH₃COO), 1.96

(s, 3 H, CH₃COO), 1.89 (s, 3 H, CH₃COO) ppm. ¹³C NMR

(101 MHz, CDCl₃): δ = 169.20 (CH₃COO), 169.13 (CH₃COO),

168.90 (CH₃COO), 168.57 (CH₃COO), 147.00 (triazole-C_quat),

137.21 (C-4), 136.75 (Ar-C_quat), 128.52 (Ar-C), 126.45 (Ar-C_quat),

124.73 (Ar-C), 120.43 (C-5), 118.23 (triazole-C), 69.26 (C-1), 67.41

(C-3), 67.12 (C-2), 61.67 (CH₂OAc), 54.65 (C-6), 20.27 (ArCH₃),

19.69 (CH₃COO), 19.67 (CH₃COO), 19.61 (CH₃COO), 19.52

(neat): ν_max= 2962, 2929, 1737, 1598, 1496, 1381, 1232, 1032, 818,

˜

751 cm^–1. HRMS (ESI-TOF): m/z calcd. for C₂₄H₂₉N₃O₉[M +

H]⁺503.1904; found 503.1909.

4.3.10 (1S,2S,3R,4R,6S)-4-(Acetoxymethyl)-6-[4-(methoxycarbon-

yl)-1H-1,2,3-triazol-1-yl]cyclohexane-1,2,3-triyl Triacetate (13j):

This compound was prepared from 7 (186 mg, 0.50 mmol) and

methyl propargylate (50 mg, 0.60 mmol) by Method A (196 mg,

86%) or from 2 by Method B (172 mg, 76%), as a pink solid, m.p.

175.4–176.4 °C. [α]²_D⁵= +91.5 (c = 0.47, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ = 8.07 (s, 1 H, triazole H), 5.55 (t, J = 9.7 Hz,

1 H, 2-H), 5.15 (dd, J = 10.2, 5.1 Hz, 1 H, 1-H), 5.12 (dd, J = 7.1,

3.8 Hz, 1 H, 3-H), 5.08 (d, J = 10.4 Hz, 1 H, 6-H), 4.10 (dd, J =

11.5, 4.6 Hz, 1 H, CHHOAc), 3.90 (s, 3 H, OCH₃), 3.86 (dd, J =

11.5, 2.5 Hz, 1 H, CHHOAc), 2.98–2.78 (m, 1 H, 4-H), 2.42–2.31

(m, 1 H, 5-H), 2.17–2.04 (m, 1 H, 5-H), 1.99 (s, 6 H, CH₃COO),

1.92 (s, 3 H, CH₃COO), 1.90 (s, 3 H, CH₃COO) ppm. ¹³C NMR

(101 MHz, CDCl₃): δ = 169.65 (CH₃COO), 169.05 (CH₃COO),

168.75 (CH₃COO), 168.39 (CH₃COO), 159.99 (CO₂Me), 138.43

(triazole-C_quat), 128.48 (triazole-C), 70.21 (C-3), 70.01 (C-2), 69.92

(C-1), 61.77 (C-6), 56.61 (CH₂OAc), 51.25 (OCH₃), 34.87 (C-4),

27.98 (C-5), 19.71 (CH₃COO), 19.61 (CH₃COO), 19.50 (2 C,

(CH COO) ppm. FT-IR (neat): ν

= 2964, 1732, 1438, 1365,

˜

3

max

1264, 1219, 1031, 974, 819, 786 cm^–1. MS (EI): m/z (%) = 43 (100),

123 (100), 130 (100), 165 (69), 166 (100), 208 (34), 235 (40), 253

(25), 295 (15), 485 (14) [M]⁺, 486 (6) [M + 1]⁺. HRMS (ESI-TOF):

m/z calcd. for C₂₄H₂₈N₃O₈[M + H]⁺486.1876; found 486.1881.

4.3.13 (1S,2S,3R,6S)-4-(Acetoxymethyl)-6-[4-(4-methoxyphenyl)-

1H-1,2,3-triazol-1-yl]cyclohex-4-ene-1,2,3-triyl Triacetate (14c):

This compound was prepared from 8 (92 mg, 0.25 mmol) and 4-

methoxy phenylacetylene (40 mg, 0.30 mmol) by Method A

(109 mg, 87%) or from 1 by Method B (95 mg, 76%), as colourless

1

needles, m.p. 112.1–113.0 °C. [α]²_D⁵= +221.2 (c = 0.54, CHCl₃). H

NMR (400 MHz, CDCl₃): δ = 7.78 (s, 1 H, triazole H), 7.69 (d, J

= 8.7 Hz, 2 H, Ar-H), 6.88 (d, J = 8.8 Hz, 2 H, Ar-H), 6.00 (dd, J

= 4.9, 1.2 Hz, 1 H, 5-H), 5.72 (t, J = 5.1 Hz, 1 H, 2-H), 5.56–5.42

(m, 2 H, 3-H and 1-H), 5.24 (dd, J = 10.1, 5.5 Hz, 1 H, 6-H), 4.72

(d, J = 13.9 Hz, 1 H, CHHOAc), 4.48 (d, J = 13.8 Hz, 1 H,

CHHOAc), 3.76 (s, 3 H, ArOCH₃), 2.04 (s, 3 H, CH₃COO), 2.01

(s, 3 H, CH₃COO), 1.96 (s, 3 H, CH₃COO), 1.89 (s, 3 H,

CH₃COO) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 169.21

(CH₃COO), 169.14 (CH₃COO), 168.91 (CH₃COO), 168.60

CH COO) ppm. FT-IR (neat): ν_max= 3133, 2924, 1736, 1548, 1368,

˜

3

1222, 1034, 981, 839, 777 cm^–1. HRMS (ESI-TOF): m/z calcd. for

C₁₉H₂₅N₃O₁₀[M + H]⁺455.1540; found 455.1536.

4.3.11 (1S,2S,3R,6S)-4-(Acetoxymethyl)-6-(4-phenyl-1H-1,2,3-tri- (CH₃COO), 158.74 (Ar-C_quat), 146.77 (triazole-C_quat), 136.74 (C-

azol-1-yl)cyclohex-4-ene-1,2,3-triyl Triacetate (14a): This com- 4), 126.13 (Ar-C), 121.99 (Ar-C_quat), 120.45 (C-5), 117.79 (triazole-

Eur. J. Org. Chem. 2014, 3622–3636

www.eurjoc.org

3631

L. Ji, G.-Q. Zhou, C. Qian, X.-Z. Chen

FULL PAPER

C), 113.27 (Ar-C), 69.33 (C-1), 67.40 (C-3), 67.13 (C-2), 61.67 144.8–145.7 °C. [α]²_D⁵= +243.2 (c = 0.20, CHCl₃). ¹H NMR

(CH₂OAc), 54.64 (C-6), 54.31 (ArOCH₃), 19.70 (CH₃COO), 19.67 (400 MHz, [D₆]DMSO): δ = 8.95 (s, 1 H, triazole H), 8.35 (d, J =

(CH₃COO), 19.62 (CH₃COO), 19.53 (CH₃COO) ppm. FT-IR 8.7 Hz, 2 H, Ar-H), 8.20 (d, J = 8.9 Hz, 2 H, Ar-H), 6.23 (dd, J =

(neat): ν_max= 3044, 1732, 1499, 1451, 1365, 1244, 1220, 1028, 812,

4.5, 1.0 Hz, 1 H, 5-H), 5.91–5.69 (m, 2 H, 2-H and 3-H), 5.55 (dd,

J = 10.2, 5.2 Hz, 1 H, 1-H), 5.50 (dd, J = 10.2, 6.5 Hz, 1 H, 6-H),

˜

785 cm^–1. MS (EI): m/z (%) = 43 (100), 123 (87), 146 (100), 147

(71), 166 (65), 258 (92), 269 (46), 311 (29), 354 (35), 501 (12) 4.79 (d, J = 14.1 Hz, 1 H, CHHOAc), 4.61 (d, J = 13.8 Hz, 1 H,

[M]⁺, 502 (4) [M + 1]⁺. HRMS (ESI-TOF): m/z calcd. for

CHHOAc), 2.09 (s, 3 H, CH₃COO), 2.06 (s, 3 H, CH₃COO), 2.00

(s, 3 H, CH₃COO), 1.92 (s, 3 H, CH₃COO) ppm. ¹³C NMR

(101 MHz, [D₆]DMSO): δ = 170.30 (CH₃COO), 170.26

(CH₃COO), 169.91 (CH₃COO), 169.73 (CH₃COO), 147.20 (tri-

azole-C_quat), 144.74 (Ar-C_quat), 137.33 (Ar-C_quat), 137.03 (C-4),

126.53 (Ar-C), 125.05 (C-5), 124.85 (Ar-C), 122.33 (triazole-C),

69.76 (C-1), 68.98 (C-3), 67.66 (C-2), 62.72 (CH₂OAc), 56.41 (C-

6), 20.93 (CH₃COO), 20.85 (CH₃COO), 20.82 (CH₃COO), 20.76

C₂₄H₂₈N₃O₉[M + H]⁺502.1826; found 502.1827.

4.3.14 (1S,2S,3R,6S)-4-(Acetoxymethyl)-6-[4-(4-chlorophenyl)-1H-

1,2,3-triazol-1-yl]cyclohex-4-ene-1,2,3-triyl Triacetate (14d): This

compound was prepared from 8 (92 mg, 0.25 mmol) and (4-

chlorophenyl)acetylene (41 mg, 0.30 mmol) by Method A (115 mg,

91%) or from 1 by Method B (101 mg, 80%), as a white solid, m.p.

180.0–180.7 °C. [α]²_D⁵= +220.5 (c = 0.52, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ = 7.89 (s, 1 H, triazole H), 7.71 (d, J =

8.5 Hz, 2 H, Ar-H), 7.32 (d, J = 8.6 Hz, 2 H, Ar-H), 6.00 (dd, J =

5.0, 0.9 Hz, 1 H, 5-H), 5.74 (t, J = 5.1 Hz, 1 H, 2-H), 5.53–5.42

(m, 2 H, 3-H and 1-H), 5.26 (ddd, J = 8.4, 6.1, 2.9 Hz, 1 H, 6-H),

4.72 (d, J = 13.9 Hz, 1 H, CHHOAc), 4.49 (d, J = 13.9 Hz, 1 H,

CHHOAc), 2.04 (s, 3 H, CH₃COO), 2.02 (s, 3 H, CH₃COO), 1.97

(s, 3 H, CH₃COO), 1.89 (s, 3 H, CH₃COO) ppm. ¹³C NMR

(101 MHz, CDCl₃): δ = 169.19 (2 C, CH₃COO), 168.87

(CH₃COO), 168.64 (CH₃COO), 145.89 (triazole-C_quat), 137.14 (C-

4), 133.07 (Ar-C_quat), 128.05 (Ar-C), 127.84 (Ar-C_quat), 126.09 (Ar-

C), 120.06 (C-5), 118.73 (triazole-C), 69.63 (C-1), 67.23 (C-3), 67.11

(C-2), 61.63 (CH₂OAc), 54.78 (C-6), 19.71 (CH₃COO), 19.67

(CH₃COO), 19.60 (CH₃COO), 19.51 (CH₃COO) ppm. FT-IR

(CH COO) ppm. FT-IR (neat): ν

= 3122, 1743, 1604, 1508,

˜

3

max

1452, 1367, 1334, 1220, 1032, 847 cm^–1. MS (EI): m/z (%) = 43

(100), 95 (61), 106 (53), 123 (100), 124 (100), 165 (100), 166 (100),

266 (39), 284 (33), 326 (29), 516 (6) [M]⁺, 517 (4) [M + 1]⁺. HRMS

(ESI-TOF): m/z calcd. for C₂₃H₂₅N₄O₁₀[M + H]⁺517.1571; found

517.1569.

4.3.17 (1S,2S,3R,6S)-4-(Acetoxymethyl)-6-(4-butyl-1H-1,2,3-tri-

azol-1-yl)cyclohex-4-ene-1,2,3-triyl Triacetate (14g): This com-

pound was prepared from 8 (185 mg, 0.50 mmol) and hex-1-yne

(49 mg, 0.60 mmol) by Method A (189 mg, 84 %) or from 1 by

Method B (163 mg, 72%), as a white solid, m.p. 124.4–124.9 °C.

[α]²_D⁵= +144.0 (c = 0.50, CHCl₃). H NMR (400 MHz, CDCl₃): δ

1

= 7.32 (s, 1 H, triazole H), 5.98 (dd, J = 4.8, 1.0 Hz, 1 H, 5-H),

5.67 (t, J = 5.1 Hz, 1 H, 2-H), 5.53 (d, J = 6.6 Hz, 1 H, 3-H), 5.40

(dd, J = 10.1, 6.7 Hz, 1 H, 1-H), 5.20 (dd, J = 10.1, 5.4 Hz, 1 H,

6-H), 4.71 (d, J = 13.7 Hz, 1 H, CHHOAc), 4.47 (d, J = 13.7 Hz,

1 H, CHHOAc), 2.66 (t, J = 7.6 Hz, 2 H, CH₂), 2.03 (s, 3 H,

CH₃COO), 2.01 (s, 3 H, CH₃COO), 1.97 (s, 3 H, CH₃COO), 1.87

(s, 3 H, CH₃COO), 1.60 (dt, J = 15.3, 7.6 Hz, 2 H, CH₂), 1.38–

1.26 (m, 2 H, CH₂), 0.87 (t, J = 7.4 Hz, 3 H, CH₃) ppm. ¹³C NMR

(101 MHz, CDCl₃): δ = 169.18 (CH₃COO), 169.04 (CH₃COO),

168.79 (CH₃COO), 168.59 (CH₃COO), 147.57 (triazole-C_quat),

136.35 (C-4), 120.83 (C-5), 119.48 (triazole-C), 68.97 (C-1), 67.51

(C-3), 67.15 (C-2), 61.70 (CH₂OAc), 54.37 (C-6), 30.43 (CH₂),

24.36 (CH₂), 21.26 (CH₂), 19.67 (2 C, CH₃COO), 19.63

(CH₃COO), 19.47 (CH₃COO), 12.78 (CH₃) ppm. FT-IR (neat):

(neat): ν

= 3049, 1743, 1437, 1373, 1222, 1028, 968, 906, 763,

˜

max

634 cm^–1. MS (EI): m/z (%) = 43 (100), 123 (55), 124 (43), 150 (67),

166 (100), 180 (7), 208 (7), 220 (5), 272 (4), 505 (3) [M]⁺. HRMS

(ESI-TOF): m/z calcd. for C₂₃H₂₅ClN₃O₈[M + H]⁺506.1330;

found 506.1330.

4.3.15 (1S,2S,3R,6S)-4-(Acetoxymethyl)-6-[4-(4-fluorophenyl)-1H-

1,2,3-triazol-1-yl]cyclohex-4-ene-1,2,3-triyl Triacetate (14e): This

compound was prepared from 8 (92 mg, 0.25 mmol) and (4-

fluorophenyl)acetylene (36 mg, 0.30 mmol) by Method A (109 mg,

89%) or from 1 by Method B (95 mg, 78%), as a white solid, m.p.

155.2–156.8 °C. [α]²_D⁵= +213.5 (c = 0.54, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ = 7.85 (s, 1 H, triazole H), 7.75 (dd, J = 8.6,

5.4 Hz, 2 H, Ar-H), 7.04 (t, J = 8.7 Hz, 2 H, Ar-H), 6.01 (d, J =

4.9 Hz, 1 H, 5-H), 5.74 (t, J = 5.1 Hz, 1 H, 2-H), 5.55–5.40 (m, 2

H, 3-H and 1-H), 5.32–5.18 (m, 1 H, 6-H), 4.72 (d, J = 13.8 Hz, 1

H, CHHOAc), 4.49 (d, J = 13.8 Hz, 1 H, CHHOAc), 2.04 (s, 3 H,

CH₃COO), 2.02 (s, 3 H, CH₃COO), 1.97 (s, 3 H, CH₃COO), 1.89

(s, 3 H, CH₃COO) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 169.19

(2 C, CH₃COO), 168.88 (CH₃COO), 168.65 (CH₃COO), 161.77 (d,

¹J_C,F= 247.5 Hz, Ar-C_quat), 146.09 (triazole-C_quat), 137.09 (C-4),

ν

= 2961, 2855, 1735, 1436, 1228, 1112, 1028, 972, 912,

˜

max

796 cm^–1. MS (EI): m/z (%) = 43 (100), 95 (52), 123 (100), 124 (63),

165 (100), 166 (78), 207 (13), 452 (2) [M + 1]⁺. HRMS (ESI-TOF):

m/z calcd. for C₂₁H₃₀N₃O₈[M + H]⁺452.2033; found 452.2036.

4.3.18 (1S,2S,3R,6S)-4-(Acetoxymethyl)-6-(4-pentyl-1H-1,2,3-tri-

azol-1-yl)cyclohex-4-ene-1,2,3-triyl Triacetate (14h): This com-

pound was prepared from 8 (185 mg, 0.50 mmol) and hept-1-yne

(58 mg, 0.60 mmol) by Method A (201 mg, 86 %) or from 1 by

Method B (178 mg, 76%), as a white solid, m.p. 106.0–106.7 °C.

3

4

126.60 (d, J_C,F= 8.2 Hz, Ar-C), 125.55 (d, J_C,F= 3.2 Hz, Ar-

C_quat), 120.14 (C-5), 118.39 (triazole-C), 114.84 (d, ²J_C,F= 21.8 Hz,

Ar-C), 69.63 (C-1), 67.28 (C-3), 67.14 (C-2), 61.64 (CH₂OAc),

54.75 (C-6), 19.71 (CH₃COO), 19.67 (CH₃COO), 19.60

1

[α]²_D⁵= +128.0 (c = 0.40, CHCl₃). H NMR (400 MHz, CDCl₃): δ

= 7.32 (s, 1 H, triazole H), 5.98 (dd, J = 4.9, 1.3 Hz, 1 H, 5-H),

5.67 (t, J = 5.1 Hz, 1 H, 2-H), 5.53 (d, J = 6.6 Hz, 1 H, 3-H), 5.40

(dd, J = 10.1, 6.7 Hz, 1 H, 1-H), 5.20 (dd, J = 10.1, 5.4 Hz, 1 H,

6-H), 4.71 (d, J = 13.6 Hz, 1 H), 4.47 (d, J = 13.7 Hz, 1 H), 2.65

(t, J = 7.6 Hz, 2 H), 2.03 (s, 3 H), 2.01 (s, 3 H), 1.97 (s, 3 H), 1.87

(s, 3 H), 1.61 (dd, J = 9.9, 5.1 Hz, 2 H), 1.35–1.20 (m, 4 H), 0.83

(t, J = 7.0 Hz, 3 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 169.18

(CH₃COO), 169.04 (CH₃COO), 168.79 (CH₃COO), 168.57

(CH₃COO), 147.61 (triazole-C_quat), 136.37 (C-4), 120.81 (C-5),

119.47 (triazole-C), 69.00 (C-1), 67.51 (C-3), 67.15 (C-2), 61.70

(CH₂OAc), 54.37 (C-6), 30.38 (CH₂), 28.02 (CH₂), 24.65 (CH₂),

21.37 (CH₂), 19.66 (2 C, CH₃COO), 19.63 (CH₃COO), 19.47

(CH COO), 19.51 (CH COO) ppm. FT-IR (neat): ν = 3141,

˜

max

3

1741, 1494, 1439, 1376, 1225, 1029, 908, 840, 798 cm^–1. MS (EI):

m/z (%) = 43 (100), 107 (81), 123 (100), 124 (100), 134 (100), 166

(100), 208 (22), 239 (20), 257 (14), 299 (6), 489 (5) [M]⁺. HRMS

(ESI-TOF): m/z calcd. for C₂₃H₂₅FN₃O₈[M + H]⁺490.1626; found

490.1626.

4.3.16 (1S,2S,3R,6S)-4-(Acetoxymethyl)-6-[4-(4-nitrophenyl)-1H-

1,2,3-triazol-1-yl]cyclohex-4-ene-1,2,3-triyl Triacetate (14f): This

compound was prepared from 8 (92 mg, 0.25 mmol) and (4-

nitrophenyl)acetylene (36 mg, 0.30 mmol) by Method A (123 mg,

95%) or from 1 by Method B (115 mg, 89%), as a white solid, m.p.

(CH COO), 12.98 (CH ) ppm. FT-IR (neat): ν = 2961, 2857,

˜

max

3

3632

www.eurjoc.org

Eur. J. Org. Chem. 2014, 3622–3636

Synthesis of 1,2,3-Triazoles from Azide-Derivatised Aminocyclitols

1735, 1446, 1376, 1227, 1027, 972, 911, 799 cm^–1. MS (EI): m/z (%)

NMR (400 MHz, CDCl₃): δ = 7.95 (s, 1 H, triazole H), 7.57 (d, J

= 43 (100), 95 (51), 123 (100), 124 (56), 165 (100), 166 (79), 207 = 8.0 Hz, 1 H, Ar-H), 7.12 (d, J = 7.9 Hz, 1 H, Ar-H), 5.73 (t, J

(18), 216 (8), 327 (3), 466 (3) [M + 1]⁺. HRMS (ESI-TOF): m/z

= 10.2 Hz, 1 H, 2-H), 5.62 (s, 1 H, OH), 5.30 (td, J = 5.9, 2.5 Hz,

1 H, 6-H), 5.18 (d, J = 9.9 Hz, 1 H, 3-H), 5.18 (dd, J = 10.9, 5.3 Hz,

1 H, 1-H), 4.12 (d, J = 11.4 Hz, 1 H, CHHOAc), 3.76 (d, J =

11.4 Hz, 1 H, CHHOAc), 2.52 (dd, J = 16.1, 2.5 Hz, 1 H, 5-H),

2.45 (dd, J = 16.2, 6.0 Hz, 1 H, 5-H), 2.29 (s, 3 H, ArCH₃), 2.02

(s, 3 H, CH₃COO), 2.01 (s, 3 H, CH₃COO), 1.93 (s, 2 H,

CH₃COO), 1.83 (s, 3 H, CH₃COO) ppm. ¹³C NMR (101 MHz,

CDCl₃): δ = 169.31 (CH₃COO), 168.99 (CH₃COO), 168.91

(CH₃COO), 168.36 (CH₃COO), 146.70 (triazole-C_quat), 137.40 (Ar-

calcd. for C₂₂H₃₂N₃O₈[M + H]⁺466.2189; found 466.2188.

4.3.19 (1S,2S,3R,6S)-4-(Acetoxymethyl)-6-(4-{[4-(tert-butyl)-

phenoxy]methyl}-1H-1,2,3-triazol-1-yl)cyclohex-4-ene-1,2,3-triyl

Triacetate (14i): This compound was prepared from 8 (185 mg,

0.50 mmol) and propargyl [4-(tert-butyl)]phenyl ether (113 mg,

0.60 mmol) by Method A (206 mg, 85%) or from 1 by Method B

(182 mg, 75%), as a pink solid, m.p. 82.2–82.7 °C. [α]²_D⁵= +109.3

1

(c = 0.30, CHCl₃). H NMR (400 MHz, CDCl₃): δ = 7.65 (s, 1 H,

C_quat), 128.57 (Ar-C), 125.95 (Ar-C_quat), 124.64 (Ar-C), 120.51 (tri-

triazole H), 7.23 (d, J = 8.8 Hz, 2 H, Ar-H), 6.85 (d, J = 8.8 Hz, 2

H, Ar-H), 5.97 (dd, J = 4.8, 1.2 Hz, 1 H, 5-H), 5.69 (t, J = 4.9 Hz,

1 H, 2-H), 5.54 (d, J = 6.4 Hz, 1 H, 3-H), 5.41 (dd, J = 9.9, 6.5 Hz,

1 H, 1-H), 5.21 (dd, J = 9.9, 5.4 Hz, 1 H, 6-H), 5.13 (s, 2 H, Ar-

OCH₂), 4.70 (d, J = 13.8 Hz, 1 H, CHHOAc), 4.46 (d, J = 13.8 Hz,

1 H, CHHOAc), 2.02 (s, 3 H, CH₃COO), 2.00 (s, 3 H, CH₃COO),

1.97 (s, 3 H, CH₃COO), 1.80 (s, 3 H, CH₃COO), 1.22 [s, 9 H,

C(CH₃)₃] ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 169.16

(CH₃COO), 169.01 (CH₃COO), 168.76 (CH₃COO), 168.47

(CH₃COO), 154.93 (Ar-C_quat), 143.66 (Ar-C_quat), 142.99 (triazole-

azole-C), 70.67 (C-4), 70.64 (C-3), 70.03 (C-2), 67.15 (C-1), 64.88

(CH₂OAc), 55.56 (C-6), 32.95 (C-5), 20.27 (ArCH₃), 19.78

(CH₃COO), 19.54 (CH₃COO), 19.49 (CH₃COO), 19.47

(CH COO) ppm. FT-IR (neat): ν

= 1742, 1430, 1374, 1226,

˜

3

max

1068, 1031, 971, 901, 814, 640 cm^–1. MS (EI): m/z (%) = 43 (100),

123 (97), 132 (62), 160 (57), 183 (52), 240 (30), 253 (28), 433 (30),

503 (39) [M]⁺, 504 (17) [M + 1]⁺. HRMS (ESI-TOF): m/z calcd.

for C₂₄H₃₀N₃O₉[M + H]⁺504.1982; found 504.1978.

4.3.22 (1S,2R,3S,4S,6S)-4-(Acetoxymethyl)-4-hydroxy-6-[4-(4-meth-

oxyphenyl)-1H-1,2,3-triazol-1-yl]cyclohexane-1,2,3-triyl Triacetate

(15c): This compound was prepared from 9 (97 mg, 0.25 mmol)

and 4-methoxy phenylacetylene (40 mg, 0.30 mmol) by Method A

(107 mg, 82%) or from 3 by Method B (93 mg, 72%), as a white

solid, m.p. 160.3–161.2 °C. [α]²_D⁵= +48.9 (c = 1.36, CHCl₃). ¹H

NMR (400 MHz, CDCl₃): δ = 7.92 (s, 1 H, triazole H), 7.59 (d, J

= 8.7 Hz, 2 H, Ar-H), 6.84 (d, J = 8.7 Hz, 2 H, Ar-H), 5.74 (t, J

= 10.2 Hz, 1 H, 2-H), 5.68 (s, 1 H, OH), 5.30 (td, J = 5.9, 2.3 Hz,

1 H, 6-H), 5.18 (d, J = 9.9 Hz, 1 H, 3-H), 5.18 (dd, J = 10.5, 5.8 Hz,

1 H, 1-H), 4.12 (d, J = 11.4 Hz, 1 H, CHHOAc), 3.77 (d, J =

11.1 Hz, 1 H, CHHOAc), 3.75 (s, 3 H, ArOCH₃), 2.53 (dd, J =

16.1, 2.2 Hz, 1 H, 5-H), 2.45 (dd, J = 16.2, 6.1 Hz, 1 H, 5-H), 2.02

(s, 3 H, CH₃COO), 2.01 (s, 3 H, CH₃COO), 1.93 (s, 3 H,

CH₃COO), 1.84 (s, 3 H, CH₃COO) ppm. ¹³C NMR (101 MHz,

CDCl₃): δ = 169.32 (CH₃COO), 169.00 (CH₃COO), 168.91

(CH₃COO), 168.39 (CH₃COO), 158.82 (Ar-C_quat), 146.45 (triazole-

C_quat), 126.05 (Ar-C), 121.42 (Ar-C_quat), 120.07 (triazole-C), 113.31

(Ar-C), 70.69 (C-4), 70.65 (C-3), 70.02 (C-2), 67.18 (C-1), 64.87

(CH₂OAc), 55.58 (C-6), 54.31 (ArOCH₃), 32.99 (C-5), 19.78

(CH₃COO), 19.54 (CH₃COO), 19.50 (CH₃COO), 19.48

C_quat), 136.66 (C-4), 125.32 (Ar-C), 121.79 (C-5), 120.44 (triazole-

C), 113.25 (Ar-C), 68.65 (C-1), 67.45 (C-3), 67.03 (C-2), 61.67

(CH₂OAc), 61.05 (ArOCH₂), 54.69 (C-6), 33.07 [C(CH₃)₃], 30.48

[C(CH₃)₃], 19.66 (CH₃COO), 19.64 (CH₃COO), 19.62 (CH₃COO),

19.37 (CH COO) ppm. FT-IR (neat): ν

= 2961, 2870, 1742,

˜

3

max

1512, 1368, 1216, 1030, 907, 866, 729 cm^–1. MS (EI): m/z (%) = 43

(100), 95 (52), 123 (93), 135 (87), 165 (69), 176 (29), 218 (12), 320

(10), 557 (1) [M]⁺, 558 (1) [M + 1]⁺. HRMS (ESI-TOF): m/z calcd.

for C₂₈H₃₆N₃O₉[M + H]⁺558.2452; found 558.2448.

4.3.20 (1S,2R,3S,4S,6S)-4-(Acetoxymethyl)-4-hydroxy-6-(4-phenyl-

1H-1,2,3-triazol-1-yl)cyclohexane-1,2,3-triyl Triacetate (15a): This

compound was prepared from 9 (97 mg, 0.25 mmol) and phenyl-

acetylene (31 mg, 0.30 mmol) by Method A (108 mg, 88%) or from

3 by Method B (92 mg, 75%), as a white solid, m.p. 216.7–218.2 °C.

[α]²_D⁵= +62.6 (c = 0.20, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ =

8.04 (s, 1 H, triazole H), 7.73–7.63 (m, 2 H, Ar-H), 7.38–7.29 (m,

2 H, Ar-H), 7.29–7.22 (m, 1 H, Ar-H), 5.74 (t, J = 10.2 Hz, 1 H,

2-H), 5.51 (s, 1 H, OH), 5.32 (td, J = 6.0, 2.4 Hz, 1 H, 6-H), 5.20

(dd, J = 10.2, 5.3 Hz, 1 H, 1-H), 5.19 (d, J = 9.9 Hz, 1 H, 3-H),

4.12 (d, J = 11.4 Hz, 1 H, CHHOAc), 3.77 (d, J = 11.4 Hz, 1 H,

CHHOAc), 2.53 (dd, J = 16.1, 2.4 Hz, 1 H, 5-H), 2.45 (dd, J =

16.1, 6.1 Hz, 1 H, 5-H), 2.02 (s, 3 H, CH₃COO), 2.01 (s, 3 H,

CH₃COO), 1.93 (s, 3 H, CH₃COO), 1.84 (s, 3 H, CH₃COO) ppm.

¹³C NMR (101 MHz, CDCl₃): δ = 169.33 (CH₃COO), 168.96

(CH₃COO), 168.89 (CH₃COO), 168.40 (CH₃COO), 146.62 (tri-

azole-C_quat), 128.80 (Ar-C_quat), 127.92 (Ar-C), 127.49 (Ar-C_quat),

124.74 (Ar-C), 120.83 (triazole-C), 70.76 (C-4), 70.64 (C-3), 69.96

(C-2), 67.13 (C-1), 64.89 (CH₂OAc), 55.63 (C-6), 32.95 (C-5), 19.78

(CH₃COO), 19.53 (CH₃COO), 19.49 (CH₃COO), 19.47

(CH COO) ppm. FT-IR (neat): ν

= 3173, 2920, 1750, 1369,

˜

3

max

1248, 1221, 1204, 1033, 817, 681 cm^–1. MS (EI): m/z (%) = 43 (100),

147 (82), 176 (58), 256 (57), 269 (43), 448 (37), 449 (25), 491 (18),

519 (43) [M]⁺, 520 (17) [M + 1]⁺. HRMS (ESI-TOF): m/z calcd.

for C₂₄H₃₀N₃O₁₀[M + H]⁺520.1931; found 520.1925.

4.3.23 (1S,2R,3S,4S,6S)-4-(Acetoxymethyl)-6-[4-(4-chlorophenyl)-

1H-1,2,3-triazol-1-yl]-4-hydroxycyclohexane-1,2,3-triyl Triacetate

(15d): This compound was prepared from 9 (97 mg, 0.25 mmol)

and (4-chlorophenyl)acetylene (41 mg, 0.30 mmol) by Method A

(106 mg, 81%) or from 3 by Method B (96 mg, 73%), as a white

solid, m.p. 242.7–244.5 °C. [α]²_D⁵= +62.5 (c = 0.92, CHCl₃). ¹H

NMR (400 MHz, CDCl₃): δ = 8.05 (s, 1 H, triazole H), 7.59 (d, J

= 8.4 Hz, 2 H, Ar-H), 7.28 (d, J = 8.3 Hz, 2 H, Ar-H), 5.76 (t, J

= 10.2 Hz, 1 H, 2-H), 5.35 (td, J = 6.1, 1.6 Hz, 1 H, 6-H), 5.27 (s,

1 H, OH), 5.21 (dd, J = 11.1, 7.8 Hz, 1 H, 1-H), 5.19 (d, J = 9.5 Hz,

1 H, 3-H), 4.12 (d, J = 11.4 Hz, 1 H, CHHOAc), 3.78 (d, J =

11.4 Hz, 1 H, CHHOAc), 2.57 (dd, J = 16.0, 1.5 Hz, 1 H, 5-H),

2.44 (dd, J = 16.1, 6.2 Hz, 1 H, 5-H), 2.04 (s, 3 H, CH₃COO),

2.02 (s, 3 H, CH₃COO), 1.95 (s, 3 H, CH₃COO), 1.84 (s, 3 H,

CH₃COO) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 169.32

(CH₃COO), 168.88 (CH₃COO), 168.81 (CH₃COO), 168.50

(CH₃COO), 145.49 (triazole-C_quat), 133.24 (Ar-C_quat), 128.09 (Ar-

(CH COO) ppm. FT-IR (neat): ν

= 1735, 1425, 1383, 1230,

˜

3

max

1035, 974, 819, 765, 696, 626 cm^–1. MS (EI): m/z (%) = 43 (100),

123 (100), 146 (62), 179 (92), 183 (58), 226 (23), 239 (30), 328 (23),

370 (29), 419 (23), 489 (23) [M]⁺, 490 (11) [M + 1]⁺. HRMS (ESI-

TOF): m/z calcd. for C₂₃H₂₈N₃O₉[M + H]⁺490.1826; found

490.1823.

4.3.21 (1S,2R,3S,4S,6S)-4-(Acetoxymethyl)-4-hydroxy-6-[4-(4-meth-

ylphenyl)-1H-1,2,3-triazol-1-yl]cyclohexane-1,2,3-triyl Triacetate

(15b): This compound was prepared from 9 (97 mg, 0.25 mmol)

and 4-methyl phenylacetylene (35 mg, 0.30 mmol) by Method A

(106 mg, 84%) or from 3 by Method B (98 mg, 78%), as a white

solid, m.p. 220.5–221.7 °C. [α]²_D⁵= +54.2 (c = 1.12, CHCl₃). ¹H

Eur. J. Org. Chem. 2014, 3622–3636

www.eurjoc.org

3633

L. Ji, G.-Q. Zhou, C. Qian, X.-Z. Chen

FULL PAPER

C), 127.28 (Ar-C_quat), 125.88 (Ar-C), 120.73 (triazole-C), 70.92 (C-

compound was prepared from 9 (194 mg, 0.50 mmol) and hex-1-

4), 70.62 (C-3), 69.81 (C-2), 67.15 (C-1), 64.90 (CH₂OAc), 55.76 yne (49 mg, 0.60 mmol) by Method A (212 mg, 91%) or from 3 by

(C-6), 33.03 (C-5), 19.76 (CH₃COO), 19.53 (CH₃COO), 19.50 Method B (188 mg, 80%), as a white solid, m.p. 143.3–143.5 °C.

= 3044, [α]²_D⁵= +41.5 (c = 0.4, CHCl₃). H NMR (400 MHz, CDCl₃): δ =

1

(CH COO), 19.46 (CH COO) ppm. FT-IR (neat): ν

˜

3

max

1742, 1431, 1376, 1222, 1069, 1029, 974, 816, 631 cm^–1. MS (EI):

7.32 (s, 1 H, triazole H), 6.13 (s, 1 H, OH), 5.64 (t, J = 10.2 Hz, 1

m/z (%) = 43 (100), 123 (100), 141 (54), 150 (45), 152 (49), 180 (45), H, 2-H), 5.16 (dd, J = 9.1, 5.0 Hz, 1 H, 6-H), 5.16 (d, J = 10.1 Hz,

183 (52), 273 (29), 404 (17), 453 (17), 523 (22) [M]⁺, 525 (9) [M + 2]. 1 H, 1-H), 5.10 (dd, J = 10.3, 5.8 Hz, 1 H, 3-H), 4.13 (d, J =

HRMS (ESI-TOF): m/z calcd. for C₂₃H₂₇N₃O₉[M + H]⁺524.1436;

found 524.1440.

11.4 Hz, 1 H, CHHOAc), 3.72 (d, J = 11.4 Hz, 1 H, CHHOAc),

2.65 (t, J = 7.6 Hz, 2 H, CH₂), 2.47 (dd, J = 16.1, 6.0 Hz, 1 H, 5-

H), 2.40 (dd, J = 16.1, 2.2 Hz, 1 H, 5-H), 2.04 (s, 3 H, CH₃COO),

2.03 (s, 3 H, CH₃COO), 1.92 (s, 3 H, CH₃COO), 1.86 (s, 3 H,

CH₃COO), 1.64–1.49 (m, 2 H, CH₂), 1.30 (dt, J = 14.6, 7.4 Hz, 2

H, CH₂), 0.87 (t, J = 7.3 Hz, 3 H, CH₃) ppm. ¹³C NMR (101 MHz,

CDCl₃): δ = 169.26 (CH₃COO), 169.05 (CH₃COO), 168.84

(CH₃COO), 168.22 (CH₃COO), 147.32 (triazole-C_quat), 122.16 (tri-

azole-C), 70.64 (C-4), 70.34 (2 C, C-3 and C-2), 67.08 (C-1), 64.81

(CH₂OAc), 55.26 (6-H), 32.92 (5-H), 30.40 (CH₂), 24.11 (CH₂),

21.18 (CH₂), 19.80 (CH₃COO), 19.57 (CH₃COO), 19.49

(CH₃COO), 19.42 (CH₃COO), 12.74 (CH₃) ppm. FT-IR (neat):

4.3.24 (1S,2R,3S,4S,6S)-4-(Acetoxymethyl)-6-[4-(4-fluorophenyl)-

1H-1,2,3-triazol-1-yl]-4-hydroxycyclohexane-1,2,3-triyl Triacetate

(15e): This compound was prepared from 9 (97 mg, 0.25 mmol) and

(4-fluorophenyl)acetylene (36 mg, 0.30 mmol) by Method A

(108 mg, 85%) or from 3 by Method B (94 mg, 74%), as a white

solid, m.p. 228.5–229.2 °C. [α]²_D⁵= +59.2 (c = 1.04, CHCl₃). ¹H

NMR (400 MHz, CDCl₃): δ = 8.03 (s, 1 H, triazole H), 7.69–7.57

(m, 2 H, Ar-H), 7.07–6.93 (m, 2 H, Ar-H), 5.76 (t, J = 10.2 Hz, 1

H, 2-H), 5.38 (s, 1 H, OH), 5.34 (td, J = 6.0, 2.2 Hz, 1 H, 6-H),

5.21 (dd, J = 10.4, 6.0 Hz, 1 H, 1-H), 5.20 (dd, J = 8.0, 1.9 Hz, 1

H, 3-H), 4.12 (d, J = 11.4 Hz, 1 H, CHHOAc), 3.78 (d, J = 11.4 Hz,

1 H, CHHOAc), 2.57 (dd, J = 16.1, 2.2 Hz, 1 H, 5-H), 2.45 (dd, J

= 16.1, 6.2 Hz, 1 H, 5-H), 2.03 (s, 3 H, CH₃COO), 2.01 (s, 3 H,

CH₃COO), 1.94 (s, 3 H, CH₃COO), 1.84 (s, 3 H, CH₃COO) ppm.

¹³C NMR (101 MHz, CDCl₃): δ = 169.34 (CH₃COO), 168.91

(CH₃COO), 168.83 (CH₃COO), 168.49 (CH₃COO), 161.79 (d,

¹J_C,F= 247.9 Hz, Ar-C_quat), 145.68 (triazole-C_quat), 126.48 (d, ³J_C,F

ν

_max= 2926, 2854, 1736, 1428, 1382, 1231, 973, 946, 904, 802 cm^–1.

˜

MS (EI): m/z (%) = 43 (100), 123 (41), 126 (25), 152 (17), 183 (14),

206 (12), 308 (10), 322 (8), 350 (11), 470 (2) [M + 1]⁺. HRMS

(ESI-TOF): m/z calcd. for C₂₁H₃₂N₃O₉[M + H]⁺470.2139; found

470.2141.

4.3.27 (1S,2R,3S,4S,6S)-4-(Acetoxymethyl)-4-hydroxy-6-[4-(phen-

oxymethyl)-1H-1,2,3-triazol-1-yl]cyclohexane-1,2,3-triyl Triacetate

(15h): This compound was prepared from 9 (194 mg, 0.50 mmol)

and (prop-2-ynyloxy)benzene (79 mg, 0.60 mmol) by Method A

(220 mg, 85%) or from 3 by Method B (203 mg, 78%), as a white

solid, m.p. 176.4–177.3 °C. [α]²_D⁵= +47.5 (c = 0.4, CHCl₃). ¹H

NMR (400 MHz, CDCl₃): δ = 7.84 (s, 1 H, triazole H), 7.20 (t, J

= 7.9 Hz, 2 H, Ar-H), 6.87 (dd, J = 10.8, 3.7 Hz, 3 H, Ar-H), 5.64

(t, J = 10.1 Hz, 1 H, 2-H), 5.61 (s, 1 H, OH), 5.25 (dd, J = 9.9,

4.3 Hz, 1 H, 6-H), 5.17 (d, J = 10.1 Hz, 1 H, 1-H), 5.15 (dd, J =

10.6, 5.6 Hz, 1 H, 3-H), 5.10 (s, 2 H, ArOCH₂), 4.10 (d, J =

11.4 Hz, 1 H, CHHOAc), 3.74 (d, J = 11.4 Hz, 1 H, CHHOAc),

2.45 (d, J = 4.0 Hz, 2 H, 5-H), 2.02 (s, 3 H, CH₃COO), 2.00 (s, 3

H , C H ₃C O O ) , 1 . 9 1 ( s, 3 H , C H ₃C O O ) , 1 . 7 4 ( s, 3 H ,

CH₃COO) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 169.29

(CH₃COO), 168.94 (CH₃COO), 168.80 (CH₃COO), 168.27

(CH₃COO), 156.98 (Ar-C_quat), 143.33 (triazole-C_quat), 128.59 (Ar-

C), 124.09 (Ar-C), 120.37 (triazole-C), 113.75 (Ar-C), 70.61 (C-

4), 70.58 (C-3), 69.88 (C-2), 67.02 (C-1), 64.87 (CH₂OAc), 60.64

(ArOCH₂), 55.63 (6-H), 32.78 (5-H), 19.77 (CH₃COO), 19.53

(CH₃COO), 19.47 (CH₃COO), 19.27 (CH₃COO) ppm. FT-IR

4

= 8.2 Hz, Ar-C), 125.06 (d, J_C,F= 3.3 Hz, Ar-C_quat), 120.51 (tri-

2

azole-C), 114.90 (d, J_C,F= 21.8 Hz, Ar-C), 70.90 (C-4), 70.66 (C-

3), 69.87 (C-2), 67.18 (C-1), 64.92 (CH₂OAc), 55.74 (C-6), 33.03 (C-

5), 19.75 (CH₃COO), 19.52 (CH₃COO), 19.49 (CH₃COO), 19.45

(CH COO) ppm. FT-IR (neat): ν

= 3045, 1738, 1494, 1428,

˜

3

max

1382, 1230, 1068, 974, 809, 647 cm^–1. MS (EI): m/z (%) = 43 (100),

123 (100), 134 (87), 164 (78), 183 (62), 257 (51), 346 (22), 388 (27),

437 (35), 507 (34) [M]⁺, 508 (16) [M + 1]⁺. HRMS (ESI-TOF): m/z

calcd. for C₂₃H₂₇FN₃O₉[M + H]⁺508.1731; found 508.1730.

4.3.25 (1S,2R,3S,4S,6S)-4-(Acetoxymethyl)-4-hydroxy-6-[4-(4-

nitrophenyl)-1H-1,2,3-triazol-1-yl]cyclohexane-1,2,3-triyl Triacetate

(15f): This compound was prepared from 9 (97 mg, 0.25 mmol) and

(4-nitrophenyl)acetylene (44 mg, 0.30 mmol) by Method A (122 mg,

91%) or from 3 by Method B (111 mg, 83%), as a white solid, m.p.

238.5–239.4 °C. [α]²_D⁵= +90.2 (c = 0.58, CHCl₃). ¹H NMR

(400 MHz, [D₆]DMSO): δ = 9.11 (s, 1 H, triazole H), 8.38 (d, J =

8.7 Hz, 2 H, Ar-H), 8.18 (d, J = 9.0 Hz, 2 H, Ar-H), 5.84 (s, 1 H,

OH), 5.71 (t, J = 9.1 Hz, 1 H, 2-H), 5.53 (t, J = 4.6 Hz, 1 H, 6-H),

5.48 (dd, J = 10.4, 6.0 Hz, 1 H, 1-H), 5.28 (d, J = 9.0 Hz, 1 H, 3-

H), 4.08 (d, J = 11.2 Hz, 1 H, CHHOAc), 3.84 (d, J = 11.2 Hz, 1

H, CHHOAc), 2.61 (dd, J = 15.4, 5.4 Hz, 1 H, 5-H), 2.43 (dd, J =

15.4, 2.7 Hz, 1 H, 5-H), 2.09 (s, 3 H, CH₃COO), 2.08 (s, 3 H,

CH₃COO), 2.04 (s, 3 H, CH₃COO), 1.91 (s, 3 H, CH₃COO) ppm.

¹³C NMR (101 MHz, [D₆]DMSO): δ = 170.46 (CH₃COO), 169.98

(CH₃COO), 169.76 (CH₃COO), 169.67 (CH₃COO), 147.14 (tri-

azole-C_quat), 144.62 (Ar-C_quat), 137.43 (Ar-C_quat), 126.42 (Ar-C),

124.94 (Ar-C), 124.65 (triazole-C), 71.98 (C-4), 71.70 (C-3), 69.98

(C-2), 68.82 (C-1), 66.43 (CH₂OAc), 57.13 (C-6), 33.74 (C-5), 21.05

(CH₃COO), 20.86 (CH₃COO), 20.77 (CH₃COO), 20.70

(neat): ν

= 2962, 2926, 1738, 1596, 1496, 1377, 1034, 976, 821,

˜

max

754 cm^–1. MS (EI): m/z (%) = 43 (100), 94 (33), 123 (38), 176 (73),

194 (21), 236 (29), 356 (25), 398 (12), 426 (7), 520 (4) [M + 1]⁺.

HRMS (ESI-TOF): m/z calcd. for C₂₄H₃₀N₃O₁₀[M + H]⁺

520.1931; found 520.1926.

4.3.28 (1R,2S,3R,4S,5R,6R)-1-(Acetoxymethyl)-5-(4-phenyl-1H-

1,2,3-triazol-1-yl)-7-oxabicyclo[4.1.0]heptane-2,3,4-triyl Triacetate

(16a): This compound was prepared from 11 (193 mg, 0.50 mmol)

and phenylacetylene (61 mg, 0.60 mmol) by Method A (225 mg,

92%), as a white solid, m.p. 227.2–227.8 °C. [α]²_D⁵= +151.0 (c =

0.4, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 8.21 (s, 1 H, triazole

H), 7.87–7.75 (m, 2 H, Ar-H), 7.37 (t, J = 7.5 Hz, 2 H, Ar-H),

7.32–7.24 (m, 1 H, Ar-H), 5.82 (dd, J = 7.5, 4.2 Hz, 1 H, 6-H),

5.59 (d, J = 7.8 Hz, 1 H, 3-H), 5.42 (dd, J = 10.5, 7.8 Hz, 1 H, 2-

H), 5.17 (dd, J = 10.4, 7.5 Hz, 1 H, 1-H), 4.39 (d, J = 12.4 Hz, 1

H, CHHOAc), 3.97 (d, J = 12.4 Hz, 1 H, CHHOAc), 3.72 (d, J =

(CH COO) ppm. FT-IR (neat): ν

= 1740, 1602, 1517, 1429,

˜

3

max

1379, 1346, 1216, 1070, 1029, 822 cm^–1. MS (EI): m/z (%) = 43

(100), 123 (100), 141 (54), 183 (48), 191 (63), 284 (50), 415 (33),

447 (16), 464 (17), 534 (20) [M]⁺, 535 (9) [M + 1]⁺. HRMS (ESI-

TOF): m/z calcd. for C₂₃H₂₇N₄O₁₁[M + H]⁺535.1676; found

535.1676.

4.3.26 (1S,2R,3S,4S,6S)-4-(Acetoxymethyl)-6-(4-butyl-1H-1,2,3- 4.2 Hz, 1 H, 5-H), 2.10 (s, 3 H, CH₃COO), 2.03 (s, 3 H, CH₃COO),

triazol-1-yl)-4-hydroxycyclohexane-1,2,3-triyl Triacetate (15g): This

1.95 (s, 3 H, CH₃COO), 1.74 (s, 3 H, CH₃COO) ppm. ¹³C NMR

3634

www.eurjoc.org

Eur. J. Org. Chem. 2014, 3622–3636

Synthesis of 1,2,3-Triazoles from Azide-Derivatised Aminocyclitols

(101 MHz, CDCl₃): δ = 168.97 (CH₃COO), 168.71 (CH₃COO),

168.35 (CH₃COO), 168.28 (CH₃COO), 147.43 (triazole-C_quat),

129.23 (Ar-C_quat), 127.86 (Ar-C), 127.38 (Ar-C), 124.84 (Ar-C),

119.14 (triazole-C), 67.95 (C-2), 66.80 (C-3), 66.49 (CH₂OAc),

60.49 (C-1), 60.18 (C-4), 55.85 (C-6), 53.93 (C-5), 19.54

(CH₃COO), 19.47 (2 C, CH₃COO), 19.05 (CH₃COO) ppm. FT-IR

Acknowledgments

The authors are grateful for the support from the National Natural

Science Foundation of China (NSFC) (grant number 21376213),

the Research Fund for the Doctoral Program of Higher Education

of China (grant number 20120101110062), the Zhejiang Low Car-

bon Fatty Amine Engineering Technology Research Centre (grant

number 2012E10033) and the Natural science foundation of

Ningbo (grant number 2013A610020). The authors also thank Dr.

Jin-qiang Liu for his help in X-ray crystallographic analysis.

(neat): ν

= 1740, 1381, 1234, 1096, 1079, 1033, 1029, 974, 938,

˜

max

801, 716 cm^–1. MS (EI): m/z (%) = 43 (100), 116 (88), 123 (66), 165

(91), 207 (11), 237 (7), 255 (6), 417 (3), 487 (6) [M]⁺, 488 (7) [M +

1]⁺. HRMS (ESI-TOF): m/z calcd. for C₂₃H₂₆N₃O₉[M + H]⁺

488.1669; found 488.1673.

4.3.29 (1R,2S,3R,4S,5R,6R)-1-(Acetoxymethyl)-5-[4-(4-chloro-

phenyl)-1H-1,2,3-triazol-1-yl]-7-oxabicyclo[4.1.0]heptane-2,3,4-

triyl Triacetate (16b): This compound was prepared from 11

(193 mg, 0.50 mmol) and (4-chlorophenyl)acetylene (82 mg,

0.60 mmol) by Method A (246 mg, 94 %), as a white solid, m.p.

246.2–247.0 °C. [α]²_D⁵= +146.5 (c = 0.4, CHCl₃). ¹H NMR

(400 MHz, CDCl₃): δ = 8.20 (s, 1 H, triazole H), 7.75 (d, J =

8.5 Hz, 2 H, Ar-H), 7.35 (d, J = 8.5 Hz, 2 H, Ar-H), 5.82 (dd, J =

7.5, 4.2 Hz, 1 H, 6-H), 5.58 (d, J = 7.9 Hz, 1 H, 3-H), 5.41 (dd, J

= 10.6, 7.9 Hz, 1 H, 2-H), 5.15 (dd, J = 10.6, 7.5 Hz, 1 H, 1-H),

4.39 (d, J = 12.4 Hz, 1 H, CHHOAc), 3.95 (d, J = 12.4 Hz, 1 H,

CHHOAc), 3.70 (d, J = 4.3 Hz, 1 H, 5-H), 2.10 (s, 3 H, CH₃COO),

2.04 (s, 3 H, CH₃COO), 1.96 (s, 3 H, CH₃COO), 1.75 (s, 3 H,

CH₃COO) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 168.96

(CH₃COO), 168.68 (CH₃COO), 168.33 (CH₃COO), 168.30

(CH₃COO), 146.43 (triazole-C_quat), 133.17 (Ar-C_quat), 128.07 (Ar-

C), 127.74 (Ar-C_quat), 126.10 (Ar-C), 119.18 (triazole-C), 67.90 (C-

2), 66.71 (C-3), 66.44 (CH₂OAc), 60.42 (C-1), 60.28 (C-4), 55.82

(C-6), 53.98 (C-5), 19.53 (CH₃COO), 19.47 (CH₃COO), 19.46

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˜

max

3

1375, 1225, 1092, 1032, 970, 937, 908, 815, 740, 710 cm^–1. MS (EI):

m/z (%) = 43 (100), 111 (21), 123 (64), 139 (26), 150 (31), 165 (48),

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4.3.30 (1R,2S,3R,4S,5R,6R)-1-(Acetoxymethyl)-5-(4-butyl-1H-

1,2,3-triazol-1-yl)-7-oxabicyclo[4.1.0]heptane-2,3,4-triyl Triacetate

(16c): This compound was prepared from 11 (193 mg, 0.50 mmol)

and hex-1-yne (49 mg, 0.60 mmol) by Method A (216 mg, 92%), as

a white solid, m.p. 170.9–171.3 °C. [α]²_D⁵= +94.5 (c = 0.4, CHCl₃).

¹H NMR (400 MHz, CDCl₃): δ = 7.70 (s, 1 H, triazole H), 5.74

(dd, J = 7.5, 4.2 Hz, 1 H, 6-H), 5.56 (d, J = 7.8 Hz, 1 H, 3-H), 5.36

(dd, J = 10.4, 7.8 Hz, 1 H, 2-H), 5.11 (dd, J = 10.4, 7.5 Hz, 1 H,

1-H), 4.37 (d, J = 12.3 Hz, 1 H), 3.93 (d, J = 12.3 Hz, 1 H), 3.66

(d, J = 4.2 Hz, 1 H, 5-H), 2.67 (t, J = 7.5 Hz, 2 H, CH₂), 2.09 (s,

3 H, CH₃COO), 2.03 (s, 3 H, CH₃COO), 1.95 (s, 3 H, CH₃COO),

1.71 (s, 3 H, CH₃COO), 1.61 (dt, J = 13.1, 7.5 Hz, 2 H, CH₂),

1.39–1.24 (m, 2 H, CH₂), 0.87 (t, J = 7.4 Hz, 3 H, CH₃) ppm. ¹³C

NMR (101 MHz, CDCl₃): δ = 168.97 (CH₃COO), 168.71

(CH₃COO), 168.32 (CH₃COO), 168.28 (CH₃COO), 148.10 (tri-

azole-C_quat), 120.20 (triazole-C), 67.99 (C-2), 66.89 (C-3), 66.59

(CH₂OAc), 60.59 (C-1), 60.01 (C-4), 55.97 (C-6), 53.64 (C-5), 30.44

(CH₂), 24.38 (CH₂), 21.24 (CH₂), 19.54 (CH₃COO), 19.50

(CH₃COO), 19.46 (CH₃COO), 18.96 (CH₃COO), 12.78

(CH ) ppm. FT-IR (neat): ν

= 2962, 2928, 1739, 1431, 1378,

˜

3

max

1233, 1083, 1032, 973, 937, 804 cm^–1. MS (EI): m/z (%) = 43 (100),

96 (13), 111 (22), 123 (17), 139 (10), 153 (8), 166 (5), 192 (6), 217

(4), 354 (3), 468 (1) [M]⁺. HRMS (ESI-TOF): m/z calcd. for

C₂₁H₃₀N₃O₉[M + H]⁺468.1982; found 468.1980.

Supporting Information (see footnote on the first page of this arti-

cle): ¹H and ¹³C NMR spectra of compounds 7, 8, 9, 11, 13a–j,

1

14a–i, 15a–h, 16a–c and H-¹H NOESY, HMBC and HSQC spec-

tra of compound 15a.

Eur. J. Org. Chem. 2014, 3622–3636

www.eurjoc.org

3635

L. Ji, G.-Q. Zhou, C. Qian, X.-Z. Chen

FULL PAPER

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Received: December 17, 2013

Published Online: April 17, 2014

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Eur. J. Org. Chem. 2014, 3622–3636

Article Doi

Synthesis of 1,2,3-triazoles from azide-derivatised aminocyclitols by catalytic diazo transfer and CuAAC click chemistry

DOI: 10.1002/ejoc.201301874

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